National PBM Drug Monograph

Pregabalin (Lyrica^®^) C-V

November 2007

VHA Pharmacy Benefits Management Strategic Healthcare Group and the
Medical Advisory Panel

# Executive Summary: 

Pregabalin is a gabapentin-like agent that has been approved in the U.S.
for painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN),
partial seizures (PS), and fibromyalgia (FBM). The purposes of this
monograph are to (1) evaluate the available evidence of safety,
tolerability, efficacy, cost, and other pharmaceutical issues that would
be relevant to evaluating pregabalin for possible addition to the VA
National Formulary; (2) evaluate whether pregabalin and gabapentin
exhibit a class effect; (3) define the role of pregabalin in therapy;
and (4) identify parameters for its rational use in the VA.

## Mechanism of action

-   Pregabalin binds to the alpha~2~-delta (A2D) receptors of an
    auxiliary subunit associated with voltage-gated calcium channels in
    central nervous system tissues, and thereby inhibits influx of
    calcium and release of glutamate, norepinephrine, substance P, and
    other neurotransmitters.

## Pharmacokinetics

-   Absorption of pregabalin is rapid and bioavailability seems to be
    better (≥ 90%) than that of gabapentin (27% to 60%).

-   Unlike gabapentin, pregabalin exhibits linear pharmacokinetics and
    has low intersubject pharmacokinetic variability.

-   Like gabapentin, pregabalin is eliminated primarily via renal
    excretion and is nearly proportional to creatinine clearance.

## Dosage and Administration

-   Painful diabetic neuropathy: Administer pregabalin in 3 divided
    doses. Initiate at 150 mg daily; may increase to maximum of 300 mg
    daily. Starting therapy with lower and less frequent doses would be
    reasonable measures to improve tolerability and patient convenience.

-   Postherpetic neuralgia and partial-onset seizures: Administer
    pregabalin in 2 or 3 divided doses. Initiate at 150 mg daily; may
    increase to maximum of 600 mg daily.

-   Fibromyalgia: Administer pregabalin in 2 divided doses, starting at
    150 mg daily. The recommended maximum daily dose is 450 mg. Doses
    above 450 mg daily did not confer additional benefit and increased
    the risk of adverse events.

## Summary of Efficacy and Safety Findings 

### Neuropathic pain

-   Based on a meta-analysis of randomized trials evaluating the effects
    of pregabalin and gabapentin, each relative to placebo, pregabalin
    may be associated with a relatively high rate of withdrawals due to
    adverse events, and the evidence does not support that there are
    differences between the two agents in terms of responder rates in
    PDN and PHN.

-   One trial showed that the onset of effect of pregabalin was as early
    as 2 days after initiation of fixed-dose pregabalin in the treatment
    of PHN.

-   Daily doses of pregabalin 300 and 600 mg are efficacious in reducing
    pain, whereas the efficacy of 150 mg is inconsistent.

-   The findings of long-term open-label extension studies do not
    suggest that loss of efficacy due to tolerance is a problem with
    long-term treatment.

### Partial-onset seizures

-   The evidence from 3 placebo-controlled randomized clinical trials
    (RCTs) showed that add-on pregabalin, dosed two or three times
    daily, is efficacious in reducing the frequency of PS and secondary
    generalized seizures in adults (weighing 50 to 135 kg) who are not
    adequately controlled on available antiepileptic drugs (AEDs) and
    are refractory to at least one AED.

-   The number-needed-to-treat for benefit (NNTB) for at least 50%
    reduction in seizure frequency at the highest dose evaluated (600 mg
    daily) was 3 (95% CI: 2 to 4) as compared with an NNTB of 6 (3
    to 20) for gabapentin at the highest dose evaluated (1800 mg
    daily).^1^ The overlapping confidence intervals of this indirect
    comparison do not allow one to conclude that there is a difference
    between the two agents.

-   Response to pregabalin is dose-dependent and the minimally effective
    dose is 150 mg daily. Thrice daily, but not twice daily, dosing of
    pregabalin (600 mg in divided doses) has been shown to significantly
    increase the number of patients who become *seizure-free.*

    Fibromyalgia

-   Pregabalin is the first drug to be FDA-approved for the management
    of fibromyalgia.

-   There are no head-to-head trials comparing pregabalin with other
    agents for this indication*.*

-   Four large clinical trials support the efficacy and safety of
    pregabalin in improving most of the major symptoms of fibromyalgia,
    particularly pain and sleep disturbances. One of these trials
    supports the durability of efficacy for up to 24 weeks, and is one
    of few trials available showing longer-term benefit of a drug for
    fibromyalgia.

-   Indirect comparisons of pregabalin and gabapentin, based on NRS-30
    responder rates relative to placebo, suggest that the two agents are
    comparable in the percentage of patients who achieve a clinically
    meaningful reduction in pain. However, the body of evidence to
    support the use of pregabalin in fibromyalgia is stronger than that
    for gabapentin.

## Adverse events

-   Indirect comparisons of the rates of withdrawals due to adverse
    events suggest that pregabalin and gabapentin are not consistently
    dissimilar in terms of tolerability across different trials.

-   Weight gain ≥ 7% above baseline had a placebo-corrected incidence of
    6% on pregabalin across all trials and was not reported---but
    possibly not evaluated---for gabapentin.

-   The most common adverse events leading to withdrawal, as well as
    overall, were dizziness and somnolence for either pregabalin or
    gabapentin.

-   Dizziness, somnolence, weight gain ≥ 7% over baseline,
    edema / peripheral edema, ophthalmologic events, increased creatine
    kinase, and decreased platelet count are listed as precautions in
    the product information for pregabalin. None of these are listed as
    precautions for gabapentin.

-   Postmarketing reports of angioedema led to the inclusion of this
    potentially life-threatening adverse event as a warning/precaution
    in the product labeling for pregabalin.

## Drug Abuse and Dependence

-   Pregabalin is classified in the U.S. as a controlled substance
    schedule V. The overall rate of euphoria reported as an adverse
    event was 4% (range, 1% to 12%) in pregabalin-treated patients and
    1% in placebo-treated patients in controlled clinical trials.

## Evaluation of Pregabalin for Class Effect in Neuropathic Pain

-   In indirect comparisons of pregabalin and gabapentin, the relative
    benefit increase for efficacy (numerical rating scale \[NRS\]-50)
    for both agents are similar and the relative risk increase for
    withdrawals due to adverse events for the two agents do not support
    a difference between the two agents. Overall, pregabalin and
    gabapentin have similar adverse event profiles. The main difference
    in their safety characteristics is the controlled substance
    (schedule V) classification of pregabalin because of its causal
    relationship with euphoria. Some experts feel that the controlled
    substance classification is of little clinical relevance and that
    there is a class effect between pregabalin and gabapentin.

## Conclusions

## Pregabalin is the first agent to be FDA-approved for management of fibromyalgia, for which it has the largest body of evidence of efficacy and safety for this indication. Pregabalin is the second agent to be approved for neuropathic pain (PDN and PHN) as well as partial epilepsy in the A2D-receptor binding class of antiepileptic drugs. The advantages of pregabalin relative to gabapentin include greater potency (mg/kg), better oral bioavailability, linear pharmacokinetics, smaller intra- and intersubject pharmacokinetic variability, and shorter titration (although many patients may not tolerate pregabalin with the 1- to 2-week titration periods used in clinical trials). To a certain extent, these pharmacologic and pharmacokinetic advantages may have translated into clinical advantages in that pregabalin showed somewhat more consistent efficacy across large, multicenter PDN trials and gained FDA approval for PDN, whereas gabapentin was less consistently efficacious and failed to receive FDA approval for this indication. Recommendations 

# Pregabalin should be made available to patients who meet criteria for use. Introduction

Pregabalin is a gabapentin-like agent that has been approved in the U.S.
for painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN),
partial seizures (PS), and fibromyalgia (FBM). Investigation into its
potential application for a number of other indications is being
pursued, and based on our literature searches, it has been evaluated in
10 neurologic, psychiatric, and pain conditions. According to the
manufacturer (J. Yanchik, verbal communication, October 2005), the New
Drug Application for pregabalin was the largest ever submitted to the
Food and Drug Administration.

The purposes of this monograph are to (1) evaluate the available
evidence of safety, tolerability, efficacy, cost, and other
pharmaceutical issues that would be relevant to evaluating pregabalin
for possible addition to the VA National Formulary; (2) evaluate whether
pregabalin and gabapentin exhibit a class effect; (3) define the role of
pregabalin in therapy; and (4) identify parameters for its rational use
in the VA.

# Pharmacology/Pharmacokinetics

## Mechanism of action

The exact mechanism of action of pregabalin is unclear. Pregabalin binds
with high affinity to the alpha~2~-delta (α2δ or A2D) receptors of an
auxiliary subunit associated with voltage-gated calcium channels in
central nervous system tissues, and is believed to thereby inhibit
calcium influx at nerve terminals and decrease release of glutamate,
norepinephrine, substance P, and other neurotransmitters. This recently
discovered mechanism of action is likely responsible for pregabalin's
(and gabapentin's) analgesic, antiseizure, and anxiolytic activities.
Pregabalin is a substrate for the system L neutral amino acid
transporter. Prolonged application of pregabalin to cultured neurons has
also been shown to increase the density of gamma-aminobutyric acid
(GABA) transporter protein and increase the rate of functional GABA
transport. Electrophysiologic analysis using dorsal root ganglia
neurones of neonatal rats showed that pregabalin can reversibly
*enhance* (as opposed to inhibit) K^+^-evoked Ca^2+^ transients, whereas
this pharmacologic effect has not been observed with gabapentin.^2^ In
addition, pregabalin and gabapentin together were not additive in their
modulatory effects on calcium channels. Therefore, the mechanism of
pregabalin is similar to that of gabapentin; however, subtle differences
have been demonstrated.

## Pharmacokinetics

The pharmacokinetic characteristics of pregabalin are compared with
those of gabapentin in Table 1.

Table 1 Comparative Pharmacokinetic Characteristics

  ------------------------------ ---------------- -----------------------
  Pharmacokinetic Property       Pregabalin       Gabapentin

  Absorption--Time to Cmax (h)   1.5              1.5--4

  Bioavailability                ≥ 90%            27%--60%^†^

  Effect of food on absorption   ↓ rate, ↔ extent 14% ↑ in AUC and Cmax

  Protein Binding                None             3%

  Metabolism                     Negligible       None

  Elimination                    Renal            Renal

  Half-life (h)                  6.3              5--7

  Dose-Concentration             Proportional     Disproportionate
  Relationship                                    
  ------------------------------ ---------------- -----------------------

^†^ Corresponding to 4800 to 900 mg / day; inversely proportional to
dose

Absorption of pregabalin is rapid and bioavailability seems to be better
(≥ 90%) than that of gabapentin (27% to 60%). Food does not affect
absorption of either drug to a clinically relevant degree. Like
gabapentin, pregabalin is eliminated primarily via renal excretion and
is nearly proportional to creatinine clearance. Pregabalin clearance is
decreased in patients with renal impairment. Pregabalin exhibits linear
pharmacokinetics; therefore, doubling the dose results in doubling of
the pregabalin peak plasma concentration and exposure over the daily
dosage range. Intersubject pharmacokinetic variability is low. These
characteristics contrast with those of gabapentin, which tends to have a
nonlinear dose-concentration properties and high intersubject
variability. These differences are attributable to a higher affinity of
pregabalin, relative to gabapentin, to an active L-type amino acid
transport system in the upper small intestine.

## Pharmacokinetic characteristics in special populations

As seen with gabapentin, the oral clearance of pregabalin decreases with
age, consistent with age-related impairment in renal function. Hepatic
impairment is not expected to alter pregabalin pharmacokinetics.
Pharmacokinetic analyses have shown that gender, race, and menopausal
status do not alter pregabalin pharmacokinetics.

# FDA-approved Indication(s) and Off-label Uses

## FDA-approved indications

-   Management of neuropathic pain associated with diabetic peripheral
    neuropathy (referred to in this monograph as painful diabetic
    neuropathy, PDN)

-   Management of postherpetic neuralgia (PHN)

-   Adjunctive therapy for adult patients with partial-onset seizures
    (PS)

-   Management of fibromyalgia (FBM)

## Off-label uses under evaluation

-   Treatment of generalized anxiety disorder in adults (reported in 5
    published RCTs.)^3-7^ The FDA issued a "non-approvable" letter for
    the initial review of pregabalin in generalized anxiety disorder in
    August 2004. According to the manufacturer (J. Yanchick, e-mail,
    22 February 2006), there are an additional 3 unpublished trials, and
    7 of the 8 trials showed pregabalin to be superior to placebo in the
    primary efficacy variable. Negotiations with the FDA continue for
    this indication. In January 2006, the European Medicines
    \[Evaluation\] Agency (EMEA) approved pregabalin for adult
    generalized anxiety disorder based on the U.S. new drug application
    data.

-   Treatment of social anxiety disorder / social phobia (reported in 1
    RCT^8^)

-   Reduction of neuropathic pain associated with spinal cord injury
    (reported as meeting abstract only^9^)

-   Treatment of postoperative dental pain (reported in 1 RCT)^10^

## Off-label uses not supported by current evidence

-   Treatment of chronic low back pain: 2 large, adequately-powered
    placebo-controlled trials showed that pregabalin is ineffective for
    chronic low back pain (reported as meeting abstract only.^11^)

-   Treatment of chronic pain associated with osteoarthritis of the hip
    (reported as meeting abstract only^12^). A 12-week multicenter
    double-blind randomized controlled trial in 296 patients with
    osteoarthritis of the knee (81% of patients) or hip (19% of
    patients) failed to show a statistically significant difference
    between pregabalin (either 300 or 600 mg daily) and placebo in the
    primary efficacy measure (weekly mean pain score) at study end
    point. Post hoc analyses showed some benefits at certain time points
    with pregabalin 600 mg daily; however, these results are only
    exploratory and need further evaluation.

-   Treatment of panic disorder: one double-blind, randomized, placebo-
    and paroxetine-controlled trial (N = 354, Protocol 1008-091) failed
    to show significant efficacy of 10-week therapy with either
    pregabalin (600 mg daily) or paroxetine (40 mg daily) in the
    treatment of panic disorder; and 2 combined multicenter Phase III
    trials (Protocols 1008-093 and 1008-192), in which 271 patients
    entered an 8-week open-label run-in and 165 patients were randomized
    to a 26-week randomized, placebo-controlled double-blind maintenance
    phase, showed no significant efficacy of pregabalin (400 mg daily)
    in the treatment and relapse prevention of panic disorder with or
    without agoraphobia (available as nonconfidential unpublished trial
    summaries).^13,14^

# Current VA National Formulary Alternatives

There are a number of formulary alternatives to pregabalin for its
FDA-approved indications, including gabapentin and other antiepileptic
drugs (Table 2). Pregabalin would be the most logical alternative for
gabapentin because of their similar mechanisms of action and overlapping
clinical indications.

For fibromyalgia, there is a larger body of evidence to support the use
of pregabalin than there is for gabapentin. There are four randomized
trials showing the efficacy and safety of pregabalin, including three
placebo-controlled trials (N = 529, 745, and 748) and a 24-week
double-blind, randomized, discontinuation / durability trial (N = 1051
for safety; N = 566 for efficacy / durability).^15^ In contrast, there
is only one trial that supports the use of gabapentin in
fibromyalgia.^16^ This 12-week, randomized, double-blind trial (N = 150,
90% women) was sponsored by the National Institutes of Health's National
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). It
showed that treatment with gabapentin (1200 to 2400 mg daily) for 12
weeks significantly improved pain, fatigue, sleep, and patient global
impression of change, and was well tolerated by most patients.

Of the formulary alternatives, the tricyclic antidepressants, notably
amitriptyline and the tricyclic skeletal muscle relaxant,
cyclobenzaprine, have the strongest evidence of efficacy in
fibromyalgia.^17-19^ These agents have a moderate degree of efficacy
overall and have been shown to be efficacious for improving pain,
quality of sleep, fatigue, stiffness, and sense of well-being. However,
most of the randomized trials were short (6 to 12 weeks), and the
long-term benefit of these agents is uncertain. The longest
placebo-controlled trial confirmed the short-term (1-month) benefit of
amitriptyline and cyclobenzaprine, but failed to show significant
benefit over placebo for either agent at 6 months.^20^ Indirect
comparisons are difficult, since studies evaluated the tricyclic
antidepressants using outcome measures unlike those used in recent
trials involving newly approved agents.

Table 2 Formulary alternatives for FDA-approved indications of
pregabalin

+----------------+------------------------------------+---------------+
| **Pregabalin   | **Formulary Alternatives**         | **Gui         |
| FDA-approved   |                                    | dance** /** R |
| indication**   |                                    | estrictions** |
+----------------+------------------------------------+---------------+
| Painful        | Tricyclic antidepressant agents    | No            |
| diabetic       | (TCAs)^21-23^                      |               |
| neuropathy     |                                    | No            |
|                | Venlafaxine^24^                    |               |
|                |                                    | No            |
|                | Carbamazepine^21,22,25^            |               |
|                |                                    | Yes           |
|                | Gabapentin^21-23,25-29^            | (National)    |
|                |                                    |               |
|                | Phenytoin^22,25^                   | No            |
|                |                                    |               |
|                | Valproate^30,31^                   | No            |
|                |                                    |               |
|                | Capsaicin 0.075% cream^22,32-34^   | No            |
|                |                                    |               |
|                | Tramadol^22,35^                    | No            |
+----------------+------------------------------------+---------------+
| Postherpetic   | Tricyclic antidepressant agents    | No            |
| neuralgia      | (TCAs)^21,22,36^                   |               |
|                |                                    | Yes           |
|                | Gabapentin ^21,22,25,36-38^        | (National)    |
|                |                                    |               |
|                | Capsaicin 0.075% cream^39,40^      | No            |
|                |                                    |               |
|                | Opioids^41^                        | Yes           |
|                |                                    | (National)^†^ |
+----------------+------------------------------------+---------------+
| Partial-onset  | Carbamazepine^42-44^               | No            |
| seizures,      |                                    |               |
| adjunctive     | Gabapentin ^45-52^                 | No            |
| therapy        |                                    |               |
| (adults)       | Lamotrigine^53-60^                 | Yes (VISN)    |
|                |                                    |               |
|                | Phenytoin^43,61^                   | No            |
|                |                                    |               |
|                | Valproate^42,62-65^                | No            |
|                |                                    |               |
|                | Topiramate^66-80^                  | Yes (VISN)    |
+----------------+------------------------------------+---------------+
| Fibromyalgia   | TCA Antidepressants:               | TCAs: No      |
|                | Amitriptyline,^20,81-89^           |               |
|                |                                    | CBP: No       |
|                | TCA Non-antidepressant:            |               |
|                | Cyclobenzaprine^20,90-95^          | TRAM: Yes     |
|                |                                    | (VISN)        |
|                | Tramadol^96,97^ (+                 |               |
|                | Acetaminophen^98^)                 | SSRIs: Yes    |
|                |                                    | (National)    |
|                | SSRIs: Fluoxetine^84,87,99,100^;   |               |
|                | Paroxetine^101,102^                | GBP: Yes      |
|                |                                    | (National)    |
|                | Gabapentin^16^                     |               |
|                |                                    | VEN/DUL:      |
|                | SNRIs: Venlafaxine^103^            | No/Yes        |
+----------------+------------------------------------+---------------+

^†^ Criteria for use of oxycodone controlled-release

# Dosage and Administration

Pregabalin is available in 8 strengths, as 25-, 50-, 75-, 100-, 150-,
200-, 225-, and 300-mg capsules.

Pregabalin may be administered with or without food. The recommended
initial dose is 150 mg daily in 3 divided doses (50 mg 3 times daily)
for painful diabetic neuropathy, 2 or 3 divided doses (75 mg 2 times
daily or 50 mg 3 times daily) for postherpetic neuralgia or partial
onset seizures, or 2 divided doses for fibromyalgia (Table 3). Lower
initial doses may be necessary in elderly patients. For painful diabetic
neuropathy, the manufacturer is evaluating initial doses given 2 times
daily and cannot recommend that dosing schedule at this time. However,
it would be reasonable to start with twice daily dosing and increase to
thrice daily dosing if pain breaks through on the less frequent dosing
schedule.

The maximum recommended daily dose of pregabalin in painful diabetic
neuropathy is 300 mg. A higher dose of 600 mg did not provide
significantly greater benefit and was less tolerated. In postherpetic
neuralgia and partial onset seizures, patients who have continued
symptoms and tolerate 300 mg daily may have their daily doses increased
to a maximum of 600 mg. In fibromyalgia, 450 mg is the recommended
maximum daily dose; 600 mg daily did not provide additional benefit and
increased the incidence of adverse events.

Table 3 Pregabalin dosage, normal renal function (CrCl ≥ 60 ml / min)

  -------------------- -------------- ----------------- ------------------ ------------------
  **Dosing parameter** **Painful      **Postherpetic\   **Partial-onset\   **Fibromyalgia**
                       diabetic       neuralgia**       seizures**         
                       neuropathy**                                        

  Initial daily dose   50 mg 3 times  75 mg 2 times     75 mg 2 times      75 mg 2 times
                       daily\         daily or\         daily or\          daily\
                       (150 mg / d)   50 mg 3 times     50 mg 3 times      (150 mg / d)
                                      daily\            daily\             
                                      (150 mg / d)      (150 mg / d)       

  Interval before      1 wk           1 wk              Base on individual ≤ 1 wk
  increasing initial                                    response           
  dose to 300 mg / d                                                       

  Interval before      Not applicable 2 to 4 wk         Base on individual Base on individual
  making subsequent                                     response           response
  dosage increases                                                         

  Maximum daily dose   300 mg / d     600 mg / d        600 mg / d         450 mg / d
  -------------------- -------------- ----------------- ------------------ ------------------

When pregabalin is discontinued, taper the dose gradually over a minimum
of 1 week.

## Patients with renal impairment

Since pregabalin is eliminated primarily by renal excretion, doses must
be adjusted in patients who have renal impairment (CrCl \< 60 ml / min)
or undergo hemodialysis as shown in Table 4.

Table 4 Pregabalin dosage adjustment based on renal function

  ---------------- -- --------------------- -- ---------------- -------- ---------- -- ------------------
  **CrCl\             **Percentage of          **Total daily                           **No. of
  (ml  /  min)**      normal recommended       dose\                                   doses / day^†^**
                      daily dose**             (mg / d)**                              

  ≥ 60                100%                     150              300      600           2 or 3

  30--60              50%                      75               150      300           2 or 3

  15--30              25%                      25--50           75       150           1 or 2

  \< 15               12.5%                    25               25--50   75            1

                                               **Supplemental                          
                                               dose (mg)^‡^**                          

  Hemodialysis        In addition to           25--50           50--75   100--150      Single dose
                      adjusted daily dose                                              
                      (for CrCl \< 15)                                                 
  ---------------- -- --------------------- -- ---------------- -------- ---------- -- ------------------

**^†^** Divide total daily dose by no. of doses / day to obtain
mg / dose

^‡^ In addition to adjusted daily dose (for CrCl \< 15), give a
supplemental dose as indicated after every 4-hour hemodialysis session

Pregabalin and gabapentin are compared in regards to their dosage and
administration features in Table 5.

Table 5 Dosage and administration: comparison of pregabalin and
gabapentin

+-----------------------+-----------------------+-----------------------+
|                       | **Pregabalin**        | **Gabapentin**        |
+-----------------------+-----------------------+-----------------------+
| Administration in     | With or without food  | With or without food  |
| regards to food       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Dosage formulation    | Capsules              | Tablets, scored       |
|                       |                       | (brand, generic)      |
|                       |                       |                       |
|                       |                       | Capsules (generic)    |
+-----------------------+-----------------------+-----------------------+
| Dosage range (mg/d)   | 150 to 300 / 600      | 300 to 3600           |
+-----------------------+-----------------------+-----------------------+
| Dosage frequency      | 2 to 3, initiation    | 1 to 2 during         |
| (doses/d)             | and maintenance       | initiation            |
|                       |                       |                       |
|                       |                       | 3 for maintenance     |
+-----------------------+-----------------------+-----------------------+
| Dosing based on renal | Yes                   | Yes                   |
| function              |                       |                       |
+-----------------------+-----------------------+-----------------------+

Pregabalin is available only as capsules, whereas gabapentin is
available in both scored tablets and capsules. Pregabalin may be
administered in 2 or 3 divided daily doses and has a more narrow dosage
titration range, consisting of 2 to 3 dosage levels (150 to
300 / 450 / 600 mg daily). In contrast, gabapentin is generally given in
3 divided daily doses (except it may be started as a single daily dose
then twice daily during initiation of therapy) and has multiple dosage
titration levels in the range of 900 to 3600 mg daily.

# Summary of Efficacy and Safety Findings 

Efficacy and safety information were obtained from the manufacturer's
AMCP dossier, the medical review by the FDA,^104^ published literature,
and the scientific review of pregabalin by the European Medicines
\[Evaluation\] Agency (EMEA). No information on pregabalin was found on
the Web site of the National Institutes of Health and Clinical
Excellence (NICE).

The published evidence consists of the results of 1 meta-analysis, 3
placebo-controlled trials in PDN, 3 in PHN, 1 in mixed neuropathic pain
(PDN and PHN), 4 placebo-controlled trials and 4 long-term open-label
studies (discussed in a review article) in partial-onset seizures, and 1
fixed-dose proof-of-concept placebo-controlled trial (FBM). There were
no published head-to-head trials or prospective studies evaluating
effectiveness in natural settings.

One additional, unpublished placebo-controlled trial in PDN was obtained
from the EMEA scientific review. A poster presentation of a pooled
analysis of results from PDN and PHN trials was available from the AMCP
dossier. Unpublished, confidential trial results were made available for
1 active-control trial in PDN, 2 placebo-controlled trials in PHN, 2
open-label extension studies in PHN, 2 open-label extension studies in
mixed neuropathic pain (PDN and PHN), and 3 fixed-dose
placebo-controlled trials in FBM. (These numbers differ from the
available data submitted to the FDA; according to one FDA Medical
Review,^104^ the New Drug Application safety results were based on 11
U.S. controlled clinical trials, 16 non-U.S. controlled clinical trials,
1 uncontrolled non--U.S. clinical study, and pharmacokinetic data from
20 clinical trials \[*sic*\]).There are 4 fixed-dose placebo-controlled
FBM trials (including one durability and safety trial) of which 3 were
followed by open-label extension studies. Only 2 of these randomized
trials (Protocol A0081077 / 1077 / F1 / RELIEF and Protocol A0081059 /
1059 / F2 / FREEDOM) were used to show efficacy of pregabalin in FBM for
FDA approval; all 4 trials were used to evaluate safety.

All of the trials available in the AMCP dossier involved titration of
pregabalin to fixed doses, except for two trials (one in mixed
neuropathic pain and one in partial seizures \[PS\]) that included
flexible dosing treatment arms.

For further details on the results of the clinical trials, refer to
Appendix: Clinical Trials (page [33](#appendix-clinical-trials)).

### Neuropathic Pain

The total number of patients (N = 2244) evaluated in all of the
randomized controlled trials (RCTs) evaluating pregabalin in neuropathic
pain is the largest for any antineuralgic agent studied thus far. The
population sizes in the individual RCTs are also among the largest of
the RCTs conducted for any agent used to treat neuropathic pain.

#### Efficacy Outcome Measures

At least 30% reduction in pain on an 11-point numerical rating scale
(NRS-30), which is considered to be a clinically relevant degree of pain
reduction, corresponds to ratings of much improved or very much improved
on the Patient Global Impression of Change (PGIC) scale.^105^

At least 50% reduction in pain on an 11-point numerical rating scale
(NRS-50) corresponds to the highest degree of improvement, i.e., a PGIC
rating of very much improved. Previous reports have used the NRS-50 as
an indicator of clinically relevant pain reduction.

#### Pregabalin versus Gabapentin, indirect comparisons from meta-analysis

-   Indirect comparisons of pregabalin and gabapentin, based on
    meta-analysis of randomized trials evaluating their effects relative
    to placebo, suggest that pregabalin may be associated with a
    relatively high rate of withdrawals due to adverse events, and the
    findings provide no evidence to support treatment differences in
    terms of responder rates in PDN and PHN^106^ (also see Data
    Compilation Tables, page [19](#data-compilation-tables)). The NNTB
    (95% CI) for pregabalin (overall dosage range, 150 to 600 mg) in
    these two neuropathic pain types was 4.2 (3.4 to 5.4), and the NNTH
    (95% CI) was 11.7 (8.3 to 19.9). Across various types of neuropathic
    pain disorders (i.e., painful diabetic neuropathy, postherpetic
    neuralgia, phantom limb pain, spinal cord injury, HIV-related
    neuropathy, and mixed neuropathic pain types), different study
    designs, and different dosage regimens (overall daily dosage range,
    900 to 3600 mg), the overall NNTB of gabapentin for at least 50%
    pain relief in the intent-to-treat analysis population (95% CI) was
    5.1 (4.1 to 6.8) and the NNTH based on rates of withdrawal due to
    adverse events was 26.1 (14.1 to 170) (7 of 10 trials with data,
    N = 1241).

> Table 6 Indirect comparison of pregabalin and gabapentin, NPP

+---------------+---------------------+--------------+----------------+
|               |                     | **           | **Gabapentin** |
|               |                     | Pregabalin** |                |
|               |                     |              | **900--3600    |
|               |                     | **150--600   | mg/d**         |
|               |                     | mg/d**       |                |
+---------------+---------------------+--------------+----------------+
| **Result**    | **Outcome measure** | **PDN, PHN** | **Various      |
|               |                     |              | NPP**          |
+---------------+---------------------+--------------+----------------+
| NNTB (95% CI) | NRS-50 responder    | 4.2          | 5.1 (4.1 to    |
|               | rate                | (3.4--5.4)   | 6.8)           |
+---------------+---------------------+--------------+----------------+
|               |                     |              |                |
+---------------+---------------------+--------------+----------------+
| NNTH (95% CI) | WDAEs               | 11.7         | 26.1 (14.1 to  |
|               |                     | (8.3--19.9)  | 170)           |
+---------------+---------------------+--------------+----------------+
|               |                     |              |                |
+---------------+---------------------+--------------+----------------+
| Source:       |                     |              |                |
| Finnerup      |                     |              |                |
| (2005) ^106^  |                     |              |                |
|               |                     |              |                |
| NNTB,         |                     |              |                |
| Number-ne     |                     |              |                |
| eded-to-treat |                     |              |                |
| for benefit;  |                     |              |                |
| NNTH,         |                     |              |                |
| Number-ne     |                     |              |                |
| eded-to-treat |                     |              |                |
| for harm;\    |                     |              |                |
| NPP,          |                     |              |                |
| Neuropathic   |                     |              |                |
| pain; PDN,    |                     |              |                |
| Painful       |                     |              |                |
| diabetic      |                     |              |                |
| neuropathy;   |                     |              |                |
| PHN,          |                     |              |                |
| postherpetic  |                     |              |                |
| neuralgia,\   |                     |              |                |
| WDAEs,        |                     |              |                |
| Withdrawals   |                     |              |                |
| due to        |                     |              |                |
| adverse       |                     |              |                |
| events        |                     |              |                |
+---------------+---------------------+--------------+----------------+

-   Pregabalin has been more consistent than gabapentin in producing
    favorable results in PDN trials and achieved FDA approval for PDN,
    whereas gabapentin did not obtain approval for PDN (only one^26^ of
    two large major efficacy trials of gabapentin in PDN showed a
    significant benefit whereas two major efficacy trials of pregabalin
    both showed superiority over placebo).

-   One trial showed that the onset of effect (i.e., first statistically
    significant analgesic effect) of pregabalin was as early as 2 days
    after initiation of fixed-dose pregabalin (300 or 600 mg daily
    depending on creatinine clearance) in the treatment of PHN.^107^
    Studies involving gabapentin have not reported results by daily pain
    scores within the first week of therapy and therefore, it is unclear
    whether pregabalin has a faster onset than gabapentin. Among trials
    that presented weekly or monthly pain scores, the onset of effect
    seemed to be similar for pregabalin (1 week)^108-110^ and gabapentin
    (1 to 2 weeks).^26,37,38^ In a trial comparing fixed and flexible
    dosing regimens in patients with PDN or PHN, the onset of effect was
    1 week for the fixed dose and 2 weeks for the titrated dose.^111^

-   The indirect comparisons should be interpreted cautiously because
    they have not been confirmed by head-to-head trials (comparisons of
    pregabalin with other antiepileptic drugs \[AEDs\]).

#### Painful Diabetic Neuropathy 

####### Pregabalin versus Placebo

-   Results of 3 published RCTs and 1 unpublished RCT reviewed by the
    EMEA showed that pregabalin in doses of 300 and 600 mg daily are
    superior to placebo in reducing pain scores by a clinically relevant
    degree and in significantly improving sleep interference scores,
    patient and clinical global impressions of change, and certain
    domains of quality of life, whereas pregabalin 75 mg daily was shown
    to have no therapeutic benefit over placebo in patients with painful
    diabetic neuropathy. Additional unpublished data have shown the
    150-mg dose to have some therapeutic effect^112^; however, results
    with this dose are inconsistent.

-   Pregabalin 600 mg daily showed no additional benefit over 300 mg in
    PDN (1 trial).^109^

-   Two^113,114^ of four PDN trials and one^115^ of five
    placebo-controlled trials did *not* exclude nonresponders to
    gabapentin ≥ 1200 mg daily and the remainder excluded such patients
    because of its similar mechanism of action to that of pregabalin. If
    response to gabapentin predicts response to pregabalin, this
    exclusion may have favored finding beneficial results with
    pregabalin.

#### Postherpetic neuralgia

####### Placebo-controlled trials

-   Pregabalin in fixed doses of 150 to 600 mg daily decrease
    postherpetic neuralgia pain (3 trials,^107,108,115^ beginning as
    early as 2 days after start of treatment.^107^ (See Appendix Table
    3.)

-   Placebo-corrected NRS-50 responder rates show a dose-response
    relationship, ranging from 16% to 18% for pregabalin 150 mg, 18% to
    19% for 300 mg, and 30% for serum creatinine--adjusted doses of
    300/600 mg daily.

#### Mixed neuropathic pain (PDN or PHN)

####### Placebo-controlled trials

-   One placebo-controlled RCT in patients with neuropathic pain showed
    that a statistically significant difference in analgesic effect,
    relative to placebo, was obtained at week 1 with a fixed dose of
    pregabalin (600 mg daily) and at week 2 with a flexible dosing
    regimen (no statistical analysis for the difference between the two
    pregabalin groups) (Appendix Table 5).^111^

-   Both regimens of pregabalin were generally well-tolerated. The
    fixed-dose regimen, however, appeared to be less tolerated than the
    flexible dosing regimen.

-   According to EMEA pooled analyses of all neuropathic pain trials
    (PDN and PHN), pregabalin was shown to be efficacious in PDN
    (polyneuropathy) and PHN (mononeuropathy) at fixed doses up to 300
    and 600 mg daily. The mean difference in pain score between
    pregabalin and placebo ranged from --0.18 to --1.57 for 300 mg daily
    and --0.64 to --2.02 for 600 mg daily.^113^ Lower doses are either
    inconsistently efficacious (150 mg daily) or not efficacious (75 mg
    daily).

-   An NRS-50 response is achieved by 16% to 46% of patients at doses of
    300 mg daily, and 32% to 50% of patients at doses equivalent to
    600 mg daily.^113^ Improvements in sleep interference, patient and
    clinical global impression of change, and other secondary outcome
    measures generally supported the primary efficacy measures. Quality
    of life and effects on mood were inconsistent, with the exception of
    improvement in bodily pain.

####### Meta-analysis

-   According to the EMEA scientific discussion on pregabalin, a
    meta-analysis of all 9 completed fixed-dose neuropathic pain (PDN
    and PHN) trials (excluding the amitriptyline-controlled trial and
    ineffective 75‑mg dose arms), showed that pregabalin produces a
    substantial treatment effect (difference, 0.28 to 0.47 depending on
    dose group) that is larger in PHN than PDN trials.

-   The difference between twice daily and thrice daily dosing regimens
    in placebo-corrected treatment effect size is substantial---but of
    uncertain clinical relevance---for only the 300-mg dose.

####### Long-term noncomparative studies

-   Preliminary, unpublished results of a combined analysis of 4
    unpublished long-term (2-year) open-label extension studies (PDN and
    PHN) showed that the efficacy of flexibly dosed pregabalin was
    durable, producing consistent pain control for up to 2 years
    (abstract).^116^

-   The adverse event profile of pregabalin was similar to that in
    short-term trials.

-   According to the EMEA scientific review, the findings of long-term
    open-label extension studies did not definitively show durability of
    efficacy because of their design and number of dropouts. In a
    retrospective cohort analysis of 4 extension studies involving
    patients who had benefited from pregabalin treatment, pain scores
    remained stable.^113^

-   Altogether, the data do not suggest that loss of efficacy due to
    tolerance is a problem with long-term treatment.

### Partial-onset seizures

####### Placebo-controlled trials

-   The evidence from 3 placebo-controlled RCTs showed that add-on
    pregabalin, dosed two or three times daily, is efficacious in
    reducing the frequency of PS and secondary generalized seizures in
    adults (weighing 50 to 135 kg) who are not adequately controlled on
    available AEDs and are refractory to at least one AED (Table 18,
    Table 19, Appendix Table 8).

-   The NNTB for at least 50% reduction in seizure frequency at the
    highest dose evaluated (600 mg daily) was 3 (95% CI: 2 to 4). This
    is slightly better than the NNTB of 6 (3 to 20) for gabapentin at
    the highest dose evaluated (1800 mg daily)^1^; however, the
    overlapping confidence intervals of this indirect comparison do not
    allow one to conclude that there is a difference between the two
    agents.

-   Thrice daily, but not twice daily, dosing of pregabalin (600 mg in
    divided doses) has been shown to significantly increase the number
    of patients who become *seizure-free*, particularly for the last
    28-day period (2 of 4 trials).^117,118^

-   Response to pregabalin is dose-dependent and the minimally effective
    dose is 150 mg daily. A mixed-effects model analyzing data from the
    three partial epilepsy trials estimated that a dose-response
    relationship occurs in 75% of patients with refractory PS, and that
    a dose of 186 mg daily is associated with a 50% reduction in seizure
    frequency from baseline.^119^

-   The early evidence from short-term (12-week) trials using mostly
    fixed-dosed regimens suggests that the drug is well-tolerated
    overall, and lower doses (150 and 300 mg daily) are better tolerated
    than the highest dose (600 mg daily).

-   The percentages of patients discontinuing due to adverse events
    seemed to be larger on the highest dose of pregabalin, 600 mg daily
    as compared with lower doses when doses were started with
    titration^118^ and without titration.^120^ Dizziness and somnolence
    were the most frequently reported treatment-emergent adverse
    events.^118,120^

### Fibromyalgia

Pregabalin is currently the only drug FDA-approved for the management of
FBM. There have been no trials comparing pregabalin with other active
agents in the treatment of FBM.

####### Placebo-controlled trials

-   A large, fair-quality, 8-week multicenter, double-blind,
    placebo-controlled, proof-of-concept RCT (N = 530 randomized; 529
    included in intent-to-treat analysis) showed pregabalin 450 mg daily
    (in 3 divided daily doses), but not 300 or 150 mg daily, was
    efficacious in improving pain, fatigue, global impressions, sleep,
    and quality of life in patients with FBM.^121^ It failed to show
    efficacy in terms of fibromyalgia intensity scores and anxiety and
    depression scores. This is currently the only *published* trial
    showing efficacy of pregabalin in FBM.

-   Two unpublished multicenter, double-blind, placebo-controlled trials
    (1077 / F1 / RELIEF (first of two pivotal trials) and 1056 / LIFT)
    showed that pregabalin monotherapy, particularly at higher doses
    (300--600 mg daily) consistently improved two of the major symptoms
    of fibromyalgia (i.e., pain and sleep) and patient's global
    impression of change. Pregabalin therapy variably improved
    Fibromyalgia Impact Questionnaire scores (a tool that measures
    fibromyalgia-related functional ability) and measures of anxiety,
    depression, and quality of life. Both studies failed to show
    improvement in fatigue with pregabalin therapy.

-   The RELIEF trial showed no incremental benefit with pregabalin
    600 mg over 450 mg daily, but there was an increased risk of adverse
    events with the higher dose. The maximum recommended dose approved
    by the FDA for fibromyalgia is 450 mg daily.

-   A third unpublished study (Study 1059 / F2 / FREEDOM, second of two
    pivotal trials) that evaluated the time to loss of therapeutic
    response showed that the efficacy of pregabalin was durable for up
    to 24 weeks. This study is notable because fibromyalgia treatment
    studies of this length are lacking and because another study had
    previously failed to show that either amitriptyline or
    cyclobenzaprine maintains efficacy for the same length of time.^20^

####### Pregabalin versus Gabapentin, indirect comparisons from placebo-controlled trials

-   Indirect comparisons of pregabalin and gabapentin, based on NRS-30
    responder rates relative to placebo, suggest that the two agents are
    comparable in the percentage of patients who achieve a clinically
    meaningful reduction in pain.

Table 7 Indirect comparisons of pregabalin and gabapentin, FBM

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 18%" />
<col style="width: 0%" />
<col style="width: 24%" />
<col style="width: 22%" />
<col style="width: 0%" />
<col style="width: 2%" />
<col style="width: 0%" />
<col style="width: 19%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td colspan="3"><p><strong>Pregabalin</strong></p>
<p><strong>300–600 mg/d</strong></p></td>
<td colspan="2"></td>
<td colspan="2"><p><strong>Gabapentin</strong></p>
<p><strong>1200–2400 mg/d</strong></p></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"></td>
<td><strong>Study 1077: N = 750</strong></td>
<td colspan="2"><strong>Study 1056: N = 748</strong></td>
<td colspan="2"></td>
<td><strong>N = 150</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Result</strong></td>
<td colspan="2"><blockquote>
<p><strong>Outcome measure</strong></p>
</blockquote></td>
<td><strong>Fixed Dosing After Titration</strong></td>
<td colspan="2"><strong>Fixed Dosing After Titration</strong></td>
<td colspan="2"></td>
<td><strong>Flexible Dosing</strong></td>
</tr>
<tr class="even">
<td colspan="2">NNTB (95% CI)</td>
<td colspan="2">NRS-50 responder rate</td>
<td><p>300 mg: 11 (6–143)</p>
<p>450 mg: 9 (5–29)</p>
<p>600 mg: 7 (4–16)</p></td>
<td colspan="2">NSD</td>
<td colspan="2"></td>
<td>—</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="2">NRS-30 responder rate</td>
<td><p>300 mg: 8 (5–42)</p>
<p>450 mg: 5 (3–10)</p>
<p>600 mg: 6 (4–12)</p></td>
<td colspan="2">NSD</td>
<td colspan="2"></td>
<td>5 (3–22)</td>
</tr>
<tr class="even">
<td colspan="2">NNTH (95% CI)</td>
<td colspan="2">WDAEs</td>
<td><p>300 mg: NSD</p>
<p>450 mg: 10 (6–38)</p>
<p>600 mg: 7 (5–16)</p></td>
<td colspan="2"><p>300 mg: 13 (7–143)</p>
<p>450 mg: 9 (5–30)</p>
<p>600 mg: 5 (3–7)</p></td>
<td colspan="2"></td>
<td>NSD</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="10"><p>Sources: AMCP Dossier, June 2007 (Studies 1077 /
RELIEF and 1056 / LIFT)<sup>15</sup>, Arnold (2007)<sup>16</sup></p>
<p>Note: 600 mg daily is not FDA-approved</p>
<p>NNTB, Number-needed-to-treat for benefit; NNTH,
Number-needed-to-treat for harm;<br />
NPP, Neuropathic pain; PDN, Painful diabetic neuropathy; PHN,
postherpetic neuralgia,<br />
WDAEs, Withdrawals due to adverse events</p></td>
</tr>
</tbody>
</table>

# Adverse events

## Pooled analysis, pregabalin versus placebo

A pooled analysis in the EMEA scientific discussion of pregabalin showed
a number of adverse events that occurred at significantly higher rates
on pregabalin than placebo (Table 8).

Table 8 Pooled analysis of adverse events (all trials)

+-----------------------------+----------------------------------------+
|                             | **Placebo-corrected incidence          |
|                             | (PGB--PBO)**                           |
+-----------------------------+----------------------------------------+
| **Adverse event**           | **N = 5232 PGB**                       |
|                             |                                        |
|                             | **N = 2290 PBO**                       |
+-----------------------------+----------------------------------------+
| *Any AE*                    | 13.6%                                  |
+-----------------------------+----------------------------------------+
| *Significantly different    |                                        |
| from PBO\**                 |                                        |
+-----------------------------+----------------------------------------+
| Dizziness                   | 20.4%                                  |
+-----------------------------+----------------------------------------+
| Somnolence                  | 14.8%                                  |
+-----------------------------+----------------------------------------+
| Dry mouth                   | 5.7%                                   |
+-----------------------------+----------------------------------------+
| Weight gain                 | 4.8%                                   |
+-----------------------------+----------------------------------------+
| Amblyopia                   | 4.4%                                   |
+-----------------------------+----------------------------------------+
| Peripheral edema            | 4.2%                                   |
+-----------------------------+----------------------------------------+
| Thinking abnormal           | 4.0%                                   |
+-----------------------------+----------------------------------------+
| Ataxia                      | 3.6%                                   |
+-----------------------------+----------------------------------------+
| Incoordination              | 3.4%                                   |
+-----------------------------+----------------------------------------+
| Euphoria                    | 3.4%                                   |
+-----------------------------+----------------------------------------+
| Constipation                | 2.5%                                   |
+-----------------------------+----------------------------------------+
| Confusion                   | 2.2%                                   |
+-----------------------------+----------------------------------------+
| Asthenia                    | 2.1%                                   |
+-----------------------------+----------------------------------------+
| Amnesia                     | 1.9%                                   |
+-----------------------------+----------------------------------------+
| Diplopia                    | 1.6%                                   |
+-----------------------------+----------------------------------------+
| Increased appetite          | 1.5%                                   |
+-----------------------------+----------------------------------------+
| Accidental injury           | 1.3%                                   |
+-----------------------------+----------------------------------------+
| Tremor                      | 1.1%                                   |
+-----------------------------+----------------------------------------+
| Flatulence                  | 1.1%                                   |
+-----------------------------+----------------------------------------+

Source: EMEA Scientific Discussion of Pregabalin^113^

\* p \< 0.05 for odds ratio or Fisher's Exact test

Euphoria, one of the adverse events that occurred at a significantly
higher rate on pregabalin than placebo, was inconsistently reported as a
common adverse event with pregabalin and has not been reported as a
common adverse event with gabapentin. The FDA's evaluation of
pregabalin's potential for drug dependence and abuse led to
classification of pregabalin as a schedule V drug (similar to
benzodiazepines). The EMEA did not categorize pregabalin as a controlled
substance.

## Indirect comparisons of pregabalin and gabapentin

Considering differences in study populations, rates of dosage titration,
and use of co-medications across trials, indirect comparisons of the
rates of withdrawals due to adverse events suggest that pregabalin and
gabapentin are not consistently dissimilar in terms of tolerability
across different trials when categorized by diagnostic indication. The
types of common adverse events are also not consistently dissimilar,
with the exception of weight gain, which had placebo-corrected
incidences that were at least twice as high in pregabalin PDN, PHN, and
PS trials than in corresponding gabapentin trials (Table 9).

Table 9 Placebo-corrected incidences of adverse events by diagnosis

<table style="width:100%;">
<colgroup>
<col style="width: 30%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 3%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="9"><strong>Placebo-corrected Incidence
(Drug–Placebo)</strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="4"><strong>Pregabalin</strong></td>
<td></td>
<td colspan="4"><strong>Gabapentin</strong></td>
</tr>
<tr class="odd">
<td><strong>Adverse event</strong></td>
<td><strong>PDN</strong></td>
<td><strong>PHN</strong></td>
<td><strong>PS</strong><sup>†</sup></td>
<td><strong>FBM</strong></td>
<td></td>
<td><strong>PDN</strong></td>
<td><strong>PHN</strong></td>
<td><strong>PS</strong><sup>†</sup></td>
<td><strong>FBM</strong></td>
</tr>
<tr class="even">
<td>SAEs</td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td></td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
</tr>
<tr class="odd">
<td>WDAEs</td>
<td><strong>5%</strong></td>
<td>7%</td>
<td><strong>9%</strong></td>
<td>9%</td>
<td></td>
<td>2.1%</td>
<td>7%</td>
<td>0%</td>
<td>8%</td>
</tr>
<tr class="even">
<td>Common TEAEs<sup>‡</sup></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Dizziness</p>
</blockquote></td>
<td>16.0%</td>
<td>17%</td>
<td><strong>21%</strong></td>
<td><strong>29%</strong></td>
<td></td>
<td>18.9%*</td>
<td>20.5%</td>
<td>10.2%</td>
<td>16%</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Somnolence</p>
</blockquote></td>
<td>9%</td>
<td>11%</td>
<td>11%</td>
<td>16%</td>
<td></td>
<td>16.4%*</td>
<td>16.1%</td>
<td>10.6%</td>
<td>11%</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Peripheral edema</p>
</blockquote></td>
<td><strong>7%</strong></td>
<td>8%</td>
<td><strong>3%</strong></td>
<td><strong>4%</strong></td>
<td></td>
<td>NR</td>
<td>6.1%</td>
<td>1.2%</td>
<td>NR</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Ataxia</p>
</blockquote></td>
<td><strong>2%</strong></td>
<td>4%</td>
<td>11%</td>
<td>NR</td>
<td></td>
<td>NR</td>
<td>3.3%</td>
<td>6.9%</td>
<td>NR</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Fatigue</p>
</blockquote></td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>3%</td>
<td></td>
<td>NR</td>
<td>NR</td>
<td><strong>6.0%</strong></td>
<td><strong>NR</strong></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Headache</p>
</blockquote></td>
<td>NR</td>
<td><strong>2%</strong></td>
<td>NR</td>
<td>0%</td>
<td></td>
<td><strong>7.0%</strong></td>
<td>0.2%</td>
<td>NR</td>
<td>5%</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Diarrhea</p>
</blockquote></td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td></td>
<td><strong>2.1%</strong></td>
<td><strong>2.6%</strong></td>
<td>NR</td>
<td>4%</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Weight gain/increase</p>
</blockquote></td>
<td><strong>4%</strong></td>
<td><strong>4%</strong></td>
<td><strong>11%</strong></td>
<td>9%</td>
<td></td>
<td>NR</td>
<td>1.8%</td>
<td>1.3%</td>
<td>8%<sup>§</sup></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Vision blurred / Amblyopia</p>
</blockquote></td>
<td>2%</td>
<td>2%</td>
<td>6%</td>
<td>7%</td>
<td></td>
<td>NR</td>
<td>1.8%</td>
<td>3.1%</td>
<td>5%</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Constipation</p>
</blockquote></td>
<td>2%</td>
<td>3%</td>
<td>2%</td>
<td>5%</td>
<td></td>
<td>NR</td>
<td>2.1%</td>
<td>0.7%</td>
<td>NR</td>
</tr>
</tbody>
</table>

Sources: Product information for pregabalin^122^ and gabapentin,^123^
Backonja (1998),^26^ and Arnold (2007)^16^

Total number of patients by diagnosis was not reported.

\* p ≤ 0.004, gabapentin vs. placebo

^†^ Add-on therapy in patients with partial-onset seizures; for
pregabalin, patients were adults and for gabapentin, patients were \> 12
years old.

^‡^ Incidence ≥ 10% in any treatment group and numerically higher in all
drug than in placebo group for either pregabalin or gabapentin, for any
indication

^§^ p ≤ 0.05, gabapentin vs. placebo

NR, Not reported (not a common or most frequently reported adverse
event, as defined in the study); PDN, Painful diabetic neuropathy; PHN,
Postherpetic neuralgia; PS, Partial seizures; TEAE, Treatment-emergent
adverse event

**Bolded** figures indicate placebo-corrected incidences that were at
least twice as high on the drug with the bolded value than on the other
drug, or reported as a common adverse event on the drug with the bolded
value but not the other, for respective diagnostic indications

Weight gain ≥ 7% above baseline had a placebo-corrected incidence of 6%
on pregabalin across all trials and was not reported for gabapentin;
however, it is possible that weight gain ≥ 7% was not a measured outcome
in gabapentin trials.

The most common adverse events leading to withdrawal were dizziness and
somnolence for either pregabalin or gabapentin, and this was a
consistent finding across different diagnostic indications (Table 10).

Table 10 Types of adverse events

<table>
<colgroup>
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 2%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 14%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="9"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="4"><strong>Pregabalin</strong></td>
<td></td>
<td colspan="4"><strong>Gabapentin</strong></td>
</tr>
<tr class="odd">
<td><strong>Adverse event</strong></td>
<td><strong>PDN</strong></td>
<td><strong>PHN</strong></td>
<td><strong>PS</strong><sup>†</sup></td>
<td><strong>FBM</strong></td>
<td></td>
<td><strong>PDN</strong></td>
<td><strong>PHN</strong></td>
<td><strong>PS</strong><sup>†</sup></td>
<td><strong>FBM</strong></td>
</tr>
<tr class="even">
<td>Most common WDAEs<sup>†</sup></td>
<td><p>Dizziness</p>
<p>Somnolence</p></td>
<td><p>Dizziness</p>
<p>Somnolence</p></td>
<td><p>Dizziness</p>
<p>Somnolence</p>
<p>Ataxia</p></td>
<td><p>Dizziness</p>
<p>Somnolence</p></td>
<td></td>
<td>Dizziness</td>
<td><p>Dizziness</p>
<p>Somnolence</p>
<p>Nausea</p></td>
<td><p>Dizziness</p>
<p>Somnolence</p>
<p>Nausea/Vomiting</p>
<p>Fatigue</p>
<p>Ataxia</p></td>
<td>NR</td>
</tr>
</tbody>
</table>

Sources: Product information for pregabalin^122^ and gabapentin,^123^
and Backonja (1998)^26^

NR, Not reported; SAE, Serious adverse event; WDAE, Adverse event
leading to withdrawal; WDSAE, Serious adverse event leading to
withdrawal

^†^ Add-on therapy in patients with partial-onset seizures; for
pregabalin trials, patients were adults and for gabapentin trials,
patients were \> 12 years old.

^†^ Definitions of most common adverse events leading to withdrawal for
PHN and PS differed between pregabalin and gabapentin. For pregabalin
PDN, PHN, and PS, and gabapentin PDN, the definition used here was ≥ 2%
on drug and \< 1% on placebo. For gabapentin PHN and PS, the adverse
events listed as the "most common" adverse events leading to withdrawal
were used.

# Contraindications

Hypersensitivity to pregabalin or any of its components

# Warnings

*Withdrawal of antiepileptic drugs*. If pregabalin is to be
discontinued, gradually taper the dose over a minimum of 1 week to
prevent increased seizure frequency in patients with seizure disorders.

*Tumorigenic potential*. An unexpectedly high incidence of
hemangiosarcoma was observed in two strains of mice in preclinical *in
vivo* lifetime carcinogenicity studies. The clinical significance of the
increased risk of vascular tumors in mice is unknown. In clinical
studies, new tumors or worsening of pre-existing tumors was reported in
57 patients during 6,396 patient-years of exposure to pregabalin in
patients \> 12 years old. The effect of pregabalin on the incidence of
tumors cannot be determined in the absence of a comparator cohort.

The warnings listed in the product information for pregabalin and
gabapentin are summarized in Table 11. Pregabalin lacks the warning of
sudden and unexplained death in patients with epilepsy, which is listed
for gabapentin.

Table 11 Warnings: comparison of pregabalin and gabapentin

  ----------------------- ----------------------- -----------------------
  **Warning**             **Pregabalin**          **Gabapentin**

  **Withdrawal of         Gradually taper dose    Do not abruptly
  antiepileptic drugs**   over a minimum of 1     discontinue treatment
                          week                    

  **Tumorigenic           Hemangiosarcoma (mice)  Pancreatic acinar
  potential**                                     adenocarcinoma (male
                                                  rats)

  **Sudden and            Not listed as a Warning It is unknown whether
  unexplained death in                            the incidence is or is
  patients with                                   not affected by
  epilepsy**                                      treatment
  ----------------------- ----------------------- -----------------------

Sources: Pregabalin product information^124^; gabapentin product
information.^1^

# Precautions 

Dizziness, somnolence, weight gain ≥ 7% over baseline,
edema / peripheral edema, ophthalmologic events, increased creatine
kinase, and decreased platelet count are listed as precautions in the
product information for pregabalin. None of these are listed as
precautions for gabapentin, although some of them were reported as
adverse events in clinical trials with gabapentin (Table 12).

Table 12 Precautions for pregabalin: indirect comparison with gabapentin

  ---------------------------------- --------------------- -- ---------------- -----------
                                     **Placebo-corrected                       
                                     Incidence                                 
                                     (Drug--Placebo)**                         

                                     **Pregabalin**           **Gabapentin**   

  **Precautions for Pregabalin**     **All CCTs**             **PHN**          **PS**^†^

  *Caused by pregabalin*                                                       

  Dizziness                          20%                      20.5%            10.2%

  Somnolence                         14%                      16.1%            10.6%

  Weight gain ≥ 7% over baseline     6%                       NR               NR

  Peripheral edema                   4%                       6.1%             0.8%

  *Associated with pregabalin*                                                 

  Blurred vision / Amblyopia         4%                       1.8%             3.1%

  Reduced visual acuity              2%                       NR               NR

  Visual field changes               1%                       NR               NR

  Funduscopic changes                0%                       NR               NR

  Increased creatine kinase (≥ 3     1%                       NR               NR
  times ULN)                                                                   

  Decreased platelet count^‡^        1%                       NR               NR

  PR interval prolongation           PNR                      NR               NR
  ---------------------------------- --------------------- -- ---------------- -----------

Sources: Product information for pregabalin^124^ and gabapentin,^1^

CCT, Controlled clinical trials; NR, Not reported; PHN, Postherpetic
neuralgia; PNR, Percentages (incidences on pregabalin vs. placebo) not
reported; PS, Partial seizures

^†^ Add-on therapy in patients \> 12 years old with partial-onset
seizures

^‡^ Potentially clinically significant decreases (20% below baseline and
 \< 150 x 10^3^/μl

The following ophthalmologic events, not listed in Table 12, have also
occurred with gabapentin (placebo-corrected incidence): conjunctivitis
(1.2%) and diplopia (1.2%) in PHN trials, and diplopia (4.0%) in add-on
PS trials.

## Caused by pregabalin

*Dizziness and Somnolence*. In clinical trials, dizziness and somnolence
occurred in 29% and 22%, respectively, of pregabalin-treated patients
versus 9% and 8%, respectively, of placebo-treated patients and were the
adverse events that most frequently led to withdrawal (4% each).
Dizziness and somnolence began shortly after the start of therapy, and
in short-term trials, persisted until the last dose in 31% and 46% of
patients, respectively. Higher doses of pregabalin were more likely to
be associated with these adverse events.

*Weight Gain*. In clinical trials up to 13 weeks long, 8% of
pregabalin-treated patients as compared with 2% of placebo-treated
patients experienced weight gain of 7% or more over baseline weight, and
0.2% withdrew from the trials because of this adverse event. Weight gain
was related to dose and duration of pregabalin therapy. The clinical
implications of pregabalin-associated weight gain, such as the long-term
risks of cardiovascular effects and development or worsening of diabetes
mellitus, are unknown. No adverse effects on blood pressure and glycemic
control (i.e., HgA1c) were observed during short-term clinical trials.

*Edema and Peripheral Edema*. Edema, primarily reported as peripheral
edema, occurred in 6% of pregabalin-treated patients and 2% of
placebo-treated patients. A small percentage (0.6%) of pregabalin
patients and no placebo patients withdrew because of this adverse event.
Peripheral edema occurred in patients without clinically significant
cardiac or peripheral vascular disease, and had no apparent association
with cardiovascular complications or laboratory changes suggestive of
renal or hepatic dysfunction. Patients taking both pregabalin and a
thiazolidinedione antidiabetic agent had higher frequencies of weight
gain and peripheral edema compared with patients taking either drug
alone. Thiazolidinediones have been associated with weight gain and / or
fluid retention that potentially led to or exacerbated heart failure.
Providers should use caution when administering pregabalin to patients
who are taking thiazolidinediones or who have congestive heart failure
(New York Heart Association Class III or IV cardiac status).

## Associated with Pregabalin

*Ophthalmologic Effects*. Vision-related events, primarily blurred
vision, occurred in a higher percentage of patients treated with
pregabalin (6%) than with placebo (2%). In the majority of cases,
symptoms resolved with continued dosing. Reduced visual acuity occurred
in 7% of pregabalin-treated patients and 5% of placebo-treated patients.
Visual field changes and funduscopic changes occurred in 13% and 2%,
respectively, on pregabalin versus 12% and 2% on placebo.

*Increased Creatine Kinase*. Increases in creatine kinase at least three
times the upper limit of normal were seen in 2% of pregabalin patients
and 1% of placebo patients. The mean excursions in creatine kinase (from
baseline to maximum value) were 60 U/l for pregabalin and 28 U/l for
placebo. In all controlled trials, across different patient populations,
3 patients on pregabalin developed rhabdomyolysis. A causal relationship
is unclear because the patients had confounding risk factors. Patients
should be advised to report unexplained muscle pain, tenderness, or
weakness, particularly if present with malaise or fever. If myopathy is
diagnosed or suspected, or if marked increases in creatine kinase levels
occur, pregabalin treatment should be discontinued.

*Decreased Platelet Count*. In all controlled trials, 3% of pregabalin
patients and 2% of placebo patients developed potentially clinically
significant decreases in platelets (i.e., 20% below baseline value
and \< 150 x 10^3^/μl). Increases in bleeding-related adverse events
were not observed during pregabalin treatment in randomized controlled
trials.

*PR Interval Prolongation*. Small increases in PR interval (mean, 3 to 6
msec at pregabalin ≥ 300 mg daily) were observed without higher risks of
PR increases ≥ 25% from baseline, PR interval  \> 200 msec, or second-
or third-degree AV block. No predictors of PR interval prolongation were
identified in limited subgroup analyses.

## Special populations

*Fertility*. The mean difference between placebo- and pregabalin-treated
men in mean percentage of sperm with normal motility was \< 4% in a
3-month double-blind, placebo-controlled trial (N = 46 healthy males).
The mean change from baseline in either group did not exceed 2%.

*Pregnancy and Lactation*. Reproductive toxicity has been observed in
animals exposed to pregabalin. No well-designed studies have evaluated
pregabalin in pregnant women. Pregabalin should not be used during
pregnancy unless the potential benefits outweigh the risks. Women of
childbearing potential should always use effective contraception during
pregabalin treatment. It is not known whether pregabalin is excreted in
breast milk of humans.

*Geriatric Use*. No overall differences in safety and efficacy were seen
between older (≥ 65 years) and younger patients in controlled clinical
studies of pregabalin in neuropathic pain and epilepsy. However, older
individuals may be more sensitive to certain drugs and have renal
impairment. The dose of pregabalin should be adjusted in elderly
patients according to their renal function.

Pregabalin and gabapentin differ in their secretion into breast milk of
lactating women and effects in elderly patients (Table 13).

Table 13 Special population precautions: comparison of pregabalin and
gabapentin

  --------------- --------------------------- -- --------------------------
  **Special       **Pregabalin**                 **Gabapentin**
  Population**                                   

  Pregnancy       Category C                     Category C

  Lactation       Secretion in human milk is     Secreted in human milk
                  unknown                        

  Elderly         No overall differences in      ↑ effect in patients ≥ 75
                  effects between patients       y old vs. younger patients
                  ≥ 65 y and younger patients    
  --------------- --------------------------- -- --------------------------

Sources: Product information for pregabalin^124^ and gabapentin,^1^

# Drug Abuse and Dependence

*Controlled Substance Schedule V*. Pregabalin (450 mg, single dose)
produced subjective effects rated as "good drug effect," "high," and
"liking" in a study of 15 recreational users of sedative / hypnotic
drugs, including alcohol. These effects were similar to those produced
by diazepam (30 mg, single dose).

The overall rate of euphoria reported as an adverse event was 4% (range,
1% to 12%) in pregabalin-treated patients and 1% in placebo-treated
patients in controlled clinical trials (N = 5500). Some patients
developed symptoms suggestive of withdrawal effects due to physiologic
dependence (including insomnia, nausea, headache, or diarrhea) after
abrupt or rapid discontinuation of pregabalin. Providers should evaluate
patients for a history of drug abuse and monitor them for signs and
symptoms of pregabalin misuse or abuse.

In comparison, gabapentin was not evaluated for drug abuse and
dependence potential in human studies, and is not recognized as a drug
associated with substance use disorder.

# Postmarketing Adverse Events

*Angioedema.* Reports of angioedema in routine postmarketing safety
surveillance led to addition of this adverse event under *Warnings and
Precautions* in the product information. Angioedema, including swelling
of the face, tongue, lips, gums, throat, and larynx, has been reported
during initial and chronic treatment with pregabalin. Some cases
involved life-threatening angioedema and respiratory compromise
requiring emergency treatment. Immediate discontinuation of pregabalin
is indicated in these situations. Caution should be used when
considering pregabalin therapy in patients with a history of angioedema.
Patients may be at increased risk of developing angioedema if they take
other drugs associated with angioedema (e.g., angiotensin converting
enzymes inhibitors / ACEIs). There were rare reports of angioedema
during clinical trials. Gabapentin has also been associated with
angioedema in postmarketing surveillance reports; however, angioedema is
not listed under *Warnings and Precautions* in the product information
for gabapentin.^123^

The following adverse events have been reported in case reports:

*Asterixis (negative myoclonus) leading to recurrent falls*.^125^ In
clinical trials, myoclonus was reported in at least 2% of patients with
partial epilepsy treated with pregabalin 600 mg/day and at a rate ≥ 2%
higher than that in both the placebo and pregabalin 150 mg/day group.
Asterixis with falls have also been reported with gabapentin.^126^

*Pregabalin withdrawal--related delirium / encephalopathy with focal
vasogenic cerebral edema*.^127^

*Decompensation of chronic heart failure*.^128^

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

A search of the Web sites for the Institute of Safe Medication Practices
(<http://www.ismp.org/>) and the United States Pharmacopeia
(<http://www.usp.org/>) found no reports of look-alike/sound-alike
medication name confusion involving pregabalin or Lyrica to date.

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

> LA/SA for generic name *pregabalin*: Pregnyl, Prevalite, progesterone,
> Prograf, proguanil
>
> LA/SA for trade name *Lyrica*: Lysine, Lymerix, , Lutera, Luride

# Drug Interactions

## Drug-Drug Interactions

Pregabalin is associated with a limited number of pharmacodynamic drug
interactions. Like gabapentin, pregabalin is primarily eliminated by the
kidney and is not highly protein bound. Pregabalin is not expected to
cause pharmacokinetic drug interactions due to altered drug metabolism
or protein binding.

Table 14 Drug interactions involving pregabalin

  ------------------------------------------------- ---------------------
  **Object Drug**                                   **Potential effects**

  *Pharmacodynamic interaction*                     

  Oxycodone                                         Additive effects on
                                                    cognitive and gross
                                                    motor function

  Lorazepam                                         

  Ethanol                                           

                                                    

  *Pharmacokinetic interaction*                     

  Carbamazepine                                     No clinically
                                                    significant effects
                                                    on object drug
                                                    expected

  Lamotrigine                                       

  Phenobarbital                                     

  Phenytoin                                         

  Topiramate                                        

  Valproate                                         
  ------------------------------------------------- ---------------------

Source: Product information for pregabalin.^124^ This list of drug
interactions is not all-inclusive. Consult appropriate references for
further information.

## Drug-Lab Interactions

None reported.

# Data Compilation Tables

## Effect size by diagnosis

Measures of effect size for pregabalin are shown for FDA-approved
indications in Table 15 to Table 19.

*PDN and PHN.* The number-needed-to-treat for benefit (NNTB) based on
NRS-50 ranged from 3 to 6 across neuropathic pain trials. In 4 trials,
there were no significant differences between any dose of pregabalin (75
to 600 mg daily) and placebo in the rate of withdrawals due to adverse
events. However, maximal doses (equivalent of 600 mg daily) were
associated with a significant treatment difference in 7 trials, and the
number-needed-to-treat for harm (NNTH) was relatively small, ranging
from 4 to 11 across trials. This finding suggests that there may be a
relatively narrow benefit-to-risk (of intolerance) ratio at the highest
dose.

*Partial seizures*. The NNTB for at least 50% reduction in seizure
frequency (SF-50) varied from 3 to 6 across fixed-dose trials, depending
on pregabalin dose. Using flexible dosing, the NNTB for SF-50 was 5 (95%
CI: 3 to 10). The number-needed-to-treat for harm (NNTH) based on the
rate of withdrawals due to adverse events were not significant for lower
fixed doses (50 and 150 mg) and was low, relative to the NNTB, at the
highest evaluated dose (600 mg), ranging from 4 to 8 across trials. The
relatively low NNTHs probably reflect the use of fixed dose regimens,
since one trial showed that flexible dosing was better tolerated.^129^

*Fibromyalgia.* Pregabalin is moderately efficacious in the management
of fibromyalgia-related pain, with NNTB for NRS-50 ranging from 6 to 11
across two trials, for doses ranging from 300 to 600 mg daily (Table
20). The NNTH for withdrawals due to adverse events was 13 in one trial
with pregabalin 300 mg daily; 9 to 10 across 2 trials at 450 mg (the
maximum FDA-approved daily dose); and 5 to 7 across 2 trials at 600 mg
daily (a dose not approved by the FDA). In the single published trial
evaluating pregabalin^121^ the rates of withdrawals due to adverse
events were similar between each of the pregabalin treatment groups and
the placebo group. In the discontinuation trial (Study 1059 / F2 /
FREEDOM; Table 21), the similarity between pregabalin and placebo in
terms of rates of withdrawals could be attributed to the enrichment
design of the trial---patients who did not tolerate open-label
pregabalin in the 6-week dose optimization phase could have dropped out
of the study before the double-blind randomized phase. Although the
relatively low tolerability could be attributed to the use of fixed
doses, the dosage regimens were not truly fixed because 1- or 2-week
dose titration phases were used for either all pregabalin doses (Studies
1077 / F1 / RELIEF and 1056 / LIFT) or only the higher doses (450 and
600 mg daily).^121^ In summary, consistent with the trials for PDN, PHN,
and POS, the relatively low NNTH values suggest that pregabalin may be
poorly tolerated in patients with fibromyalgia, particularly at higher
doses.

Table 15 Painful Diabetic Neuropathy

<table style="width:100%;">
<colgroup>
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"></td>
<td colspan="8">Lesser (2004)<sup>109</sup></td>
<td colspan="2"></td>
<td colspan="4">Rosenstock (2004)<sup>110</sup></td>
<td colspan="2"></td>
<td colspan="6">Richter (2005)<sup>114</sup></td>
<td colspan="2"></td>
<td colspan="7">Study 149 (EMEA 2004)<sup>113</sup></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="8">T.I.D. Fixed dosing, 5 wk</td>
<td colspan="2"></td>
<td colspan="4">T.I.D. Fixed dosing, 8 wk</td>
<td colspan="2"></td>
<td colspan="6">T.I.D. Fixed dosing, 6 wk</td>
<td colspan="2"></td>
<td colspan="7">B.I.D. Fixed dosing, 12 wk</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="6">Pregabalin (mg / d)</td>
<td colspan="2">PBO</td>
<td colspan="2"></td>
<td colspan="2">Pregabalin (mg / d)</td>
<td colspan="2">PBO</td>
<td colspan="2"></td>
<td colspan="4">Pregabalin (mg / d)</td>
<td colspan="2">PBO</td>
<td colspan="2"></td>
<td colspan="6">Pregabalin (mg / d)</td>
<td>PBO</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2">600</td>
<td colspan="2">300</td>
<td colspan="2">75</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">300</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">600</td>
<td colspan="2">150</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">300/600</td>
<td colspan="2">300</td>
<td colspan="2">150</td>
<td>—</td>
</tr>
<tr class="odd">
<td colspan="4"><em>Efficacy measure: NRS-50</em></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Responder Rate</td>
<td colspan="2">48%</td>
<td colspan="2">41%</td>
<td colspan="2">25%</td>
<td colspan="2">18%</td>
<td colspan="2"></td>
<td colspan="2">40%</td>
<td colspan="2">14.5%</td>
<td colspan="2"></td>
<td colspan="2">39%</td>
<td colspan="2">19%</td>
<td colspan="2">15%</td>
<td colspan="2"></td>
<td colspan="2">46%</td>
<td colspan="2">33%</td>
<td colspan="2">34%</td>
<td>30%</td>
</tr>
<tr class="odd">
<td colspan="2">NNTB (95% CL)</td>
<td colspan="2">3 (2, 6)</td>
<td colspan="2">4 (2, 7)</td>
<td colspan="2">NSD</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">4 (3, 9)</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">4 (3, 8)</td>
<td colspan="2">NSD</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">6 (3, 50)</td>
<td colspan="2">NSD</td>
<td colspan="2">NSD</td>
<td>—</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="4"><em>Efficacy measure: NRS-30</em></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Responder Rate</td>
<td colspan="2">65%</td>
<td colspan="2">62%</td>
<td colspan="2">37%</td>
<td colspan="2">33%</td>
<td colspan="2"></td>
<td colspan="2">50%</td>
<td colspan="2">35%</td>
<td colspan="2"></td>
<td colspan="2">NR</td>
<td colspan="2">NR</td>
<td colspan="2">NR</td>
<td colspan="2"></td>
<td colspan="2">NR</td>
<td colspan="2">NR</td>
<td colspan="2">NR</td>
<td>—</td>
</tr>
<tr class="odd">
<td colspan="2"><p>NNTB</p>
<p>(95% CL)</p></td>
<td colspan="2">3 (2, 5)</td>
<td colspan="2">3 (2, 7)</td>
<td colspan="2">NSD</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">NSD (p = 0.08)</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">—</td>
<td colspan="2">—</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">—</td>
<td colspan="2">—</td>
<td colspan="2">—</td>
<td>—</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="4"><em>Safety measure: WDAEs</em></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td>Event rate</td>
<td colspan="2">12.2%</td>
<td colspan="2">3.7%</td>
<td colspan="2">2.7%</td>
<td colspan="2">3.1%</td>
<td colspan="2"></td>
<td colspan="2">10.5%</td>
<td colspan="2">2.9%</td>
<td colspan="2"></td>
<td colspan="2">8.5%</td>
<td colspan="2">2.5%</td>
<td colspan="2">4.7%</td>
<td colspan="2"></td>
<td colspan="2">12.9%</td>
<td colspan="2">11.1%</td>
<td colspan="2">5.0%</td>
<td colspan="2">3.1%</td>
</tr>
<tr class="odd">
<td><p>NNTH</p>
<p>(95% CL)</p></td>
<td colspan="2">NSD (p = 0.068)</td>
<td colspan="2">NSD</td>
<td colspan="2">NSD</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">NSD</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">NSD</td>
<td colspan="2">NSD</td>
<td colspan="2">—</td>
<td colspan="2"></td>
<td colspan="2">10 (6, 42)</td>
<td colspan="2">NSD (p = 0.057)</td>
<td colspan="2">NSD</td>
<td colspan="2">—</td>
</tr>
</tbody>
</table>

Table 16 Postherpetic Neuralgia

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 10%" />
<col style="width: 13%" />
<col style="width: 9%" />
<col style="width: 1%" />
<col style="width: 12%" />
<col style="width: 4%" />
<col style="width: 1%" />
<col style="width: 6%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 5%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="3">Sabatowski (2004)<sup>108</sup></th>
<th></th>
<th colspan="2">Dworkin (2003)<sup>107</sup></th>
<th></th>
<th colspan="4">Van Seventer (2006)<sup>115</sup></th>
</tr>
<tr class="odd">
<th></th>
<th colspan="3">T.I.D. Fixed dosing, 8 wk</th>
<th></th>
<th colspan="2">T.I.D. Fixed dosing, 8 wk</th>
<th></th>
<th colspan="4">B.I.D. Fixed dosing, 13 wk</th>
</tr>
<tr class="header">
<th></th>
<th colspan="2">Pregabalin (mg / d)</th>
<th>PBO</th>
<th></th>
<th>Pregabalin (mg / d)</th>
<th>PBO</th>
<th></th>
<th colspan="3">Pregabalin (mg / d)</th>
<th>PBO</th>
</tr>
<tr class="odd">
<th></th>
<th>300</th>
<th>150</th>
<th>—</th>
<th></th>
<th>300 / 600</th>
<th>—</th>
<th></th>
<th>300 / 600</th>
<th>300</th>
<th>150</th>
<th>—</th>
</tr>
<tr class="header">
<th></th>
<th>N = 76</th>
<th>N = 81</th>
<th>N = 81</th>
<th></th>
<th></th>
<th></th>
<th></th>
<th>N = 90</th>
<th>N = 98</th>
<th>N = 87</th>
<th>N = 93</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="2"><em>Efficacy measure: NRS-50</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Responder Rate</p>
</blockquote></td>
<td>28%</td>
<td>26%</td>
<td>10%</td>
<td></td>
<td>50%</td>
<td>20%</td>
<td></td>
<td>37.5%</td>
<td>26.5%</td>
<td>26.4%</td>
<td>7.5%</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>NNTB (95% CI)</p>
</blockquote></td>
<td>6 (3, 17)</td>
<td>6 (4, 22)</td>
<td>—</td>
<td></td>
<td>3 (2, 6)</td>
<td>—</td>
<td></td>
<td>3<br />
(2, 5)</td>
<td>5<br />
(3, 11)</td>
<td>5<br />
(3, 12)</td>
<td>—</td>
</tr>
<tr class="even">
<td colspan="2"><em>Efficacy measure: NRS-30</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Responder Rate</p>
</blockquote></td>
<td>50%</td>
<td>37%</td>
<td>19%</td>
<td></td>
<td>63%</td>
<td>25%</td>
<td></td>
<td>52%</td>
<td>41%</td>
<td>39%</td>
<td>18%</td>
</tr>
<tr class="even">
<td><blockquote>
<p>NNTB (95% CL)</p>
</blockquote></td>
<td>3 (2, 6)</td>
<td>5 (3, 20)</td>
<td>—</td>
<td></td>
<td>3 (2, 4)</td>
<td>—</td>
<td></td>
<td>3 (2, 5)</td>
<td>4 (3, 10)</td>
<td>5 (3, 13)</td>
<td>—</td>
</tr>
<tr class="odd">
<td colspan="2"><em>Safety measure: WDAEs</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Event rate</td>
<td>15.8%</td>
<td>11.1%</td>
<td>9.9%</td>
<td></td>
<td>31.5%</td>
<td>4.8%</td>
<td></td>
<td>21.1%</td>
<td>15.3%</td>
<td>8.0%</td>
<td>5.4%</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>NNTH (95% CL)</p>
</blockquote></td>
<td>NSD</td>
<td>NSD</td>
<td>—</td>
<td></td>
<td>4 (3, 6)</td>
<td>—</td>
<td></td>
<td>6 (4, 16)</td>
<td>10 (5, 67)</td>
<td>NSD</td>
<td>—</td>
</tr>
</tbody>
</table>

dd, Divided doses

Table 17 Mixed neuropathic pain (PDN and PHN)

+-------------------------+-----------------+----------------+---------+
|                         | **Freynhagen    |                |         |
|                         | (2005)^111^**   |                |         |
+-------------------------+-----------------+----------------+---------+
|                         | **B.I.D.        |                |         |
|                         | Flexible vs.    |                |         |
|                         | Fixed dosing,   |                |         |
|                         | 12 wk**         |                |         |
+-------------------------+-----------------+----------------+---------+
|                         | PGB~Flex~       | PGB600         | PBO     |
+-------------------------+-----------------+----------------+---------+
|                         | N = 141         | N = 132        | N = 65  |
+-------------------------+-----------------+----------------+---------+
| Efficacy Measure:       |                 |                |         |
| NRS-50                  |                 |                |         |
+-------------------------+-----------------+----------------+---------+
| > Responder Rate (%)    | 48.2            | 52.3           | 24.2    |
+-------------------------+-----------------+----------------+---------+
| > NNTB (95% CI)         | 4.2 (2.7, 9.5)  | 3.6 (2.4, 6.9) | ---     |
+-------------------------+-----------------+----------------+---------+
|                         |                 |                |         |
+-------------------------+-----------------+----------------+---------+
| Efficacy Measure:       |                 |                |         |
| NRS-30                  |                 |                |         |
+-------------------------+-----------------+----------------+---------+
| Responder Rate (%)      | 59.0            | 66.4           | 37.1    |
+-------------------------+-----------------+----------------+---------+
| NNTB (95% CL)           | 4.6 (2.7, 13.6) | 3.4 (2.3, 6.8) | ---     |
+-------------------------+-----------------+----------------+---------+
|                         |                 |                |         |
+-------------------------+-----------------+----------------+---------+
| Safety Measure: WDAEs   |                 |                |         |
+-------------------------+-----------------+----------------+---------+
| Event rate (%)          | 17.0            | 25.0           | 7.7     |
+-------------------------+-----------------+----------------+---------+
| NNTH (95% CL)           | NSD             | 6 (4, 13)      | ---     |
+-------------------------+-----------------+----------------+---------+

Table 18 Partial-onset Seizures (Fixed Doses)

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 5%" />
<col style="width: 1%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 1%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="3"><p><strong>Beydoun (2005)<sup>117</sup></strong></p>
<p><strong>Study 1008-009</strong></p></td>
<td></td>
<td colspan="3"><p><strong>Arroyo (2004)<sup>118</sup> and Miller
(2003){Miller, 2003 #119</strong></p>
<p><strong>Study 1008-011</strong></p></td>
<td></td>
<td colspan="5"><strong>French (2003) <sup>120</sup></strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="3"><p><strong>B.I.D. vs. T.I.D. Fixed dosing,</strong></p>
<p><strong>12 wk</strong></p></td>
<td></td>
<td colspan="3"><p><strong>T.I.D. Fixed dosing,</strong></p>
<p><strong>12 wk</strong></p></td>
<td></td>
<td colspan="5"><p><strong>B.I.D. Fixed dosing without
titration,</strong></p>
<p><strong>12 wk</strong></p></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>Pregabalin (mg/d)</strong></td>
<td><strong>PBO</strong></td>
<td></td>
<td colspan="2"><strong>Pregabalin (mg/d)</strong></td>
<td><strong>PBO</strong></td>
<td></td>
<td colspan="4"><strong>Pregabalin (mg/d)</strong></td>
<td><strong>PBO</strong></td>
</tr>
<tr class="even">
<td></td>
<td><p><strong>600</strong></p>
<p><strong>(t.i.d.)</strong></p></td>
<td><p><strong>600</strong></p>
<p><strong>(b.i.d.)</strong></p></td>
<td><strong>—</strong></td>
<td></td>
<td><strong>600</strong></td>
<td><strong>150</strong></td>
<td><strong>—</strong></td>
<td></td>
<td><strong>600</strong></td>
<td><strong>300</strong></td>
<td><strong>150</strong></td>
<td><strong>50</strong></td>
<td><strong>—</strong></td>
</tr>
<tr class="odd">
<td></td>
<td><strong>N = 111</strong></td>
<td><strong>N = 103</strong></td>
<td><strong>N = 98</strong></td>
<td></td>
<td><strong>N = 92</strong></td>
<td><strong>N = 99</strong></td>
<td><strong>N = 96</strong></td>
<td></td>
<td><strong>N = 89</strong></td>
<td><strong>N = 90</strong></td>
<td><strong>N = 86</strong></td>
<td><strong>N = 88</strong></td>
<td><strong>N = 100</strong></td>
</tr>
<tr class="even">
<td colspan="4"><em>Efficacy Measure: RRatio</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Difference (mean)</p>
</blockquote></td>
<td>–36.7</td>
<td>–29.0</td>
<td>—</td>
<td></td>
<td>–32.3</td>
<td>–12.4</td>
<td>—</td>
<td></td>
<td>–33</td>
<td>–24</td>
<td>–17</td>
<td>–2</td>
<td>—</td>
</tr>
<tr class="even">
<td><blockquote>
<p>95% CI</p>
</blockquote></td>
<td>–46.4, –27.0</td>
<td>–38.9, –19.0</td>
<td>—</td>
<td></td>
<td>–40.6, –24.0</td>
<td>–20.5, –4.3</td>
<td>—</td>
<td></td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>—</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>p-value vs. PBO</p>
</blockquote></td>
<td> &lt; 0.001</td>
<td> &lt; 0.001</td>
<td>—</td>
<td></td>
<td>≤ 0.0001</td>
<td>0.0007</td>
<td>—</td>
<td></td>
<td>≤0.0001</td>
<td>≤0.0001</td>
<td>≤0.0001</td>
<td>≤0.0001</td>
<td></td>
</tr>
<tr class="even">
<td><blockquote>
<p>p-value vs PGB</p>
</blockquote></td>
<td>—</td>
<td>—</td>
<td></td>
<td></td>
<td>≤ 0.0001</td>
<td>—</td>
<td>—</td>
<td></td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
</tr>
<tr class="odd">
<td colspan="4"><em>Efficacy Measure: SR–50</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Responder Rate</p>
</blockquote></td>
<td>49%</td>
<td>43%</td>
<td>9%</td>
<td></td>
<td>43.5%</td>
<td>14.1%</td>
<td>6.2%</td>
<td></td>
<td>51%</td>
<td>40%</td>
<td>31%</td>
<td>15%</td>
<td>14%</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>NNTB (95% CI)</p>
</blockquote></td>
<td><p>3</p>
<p>(2–4)</p></td>
<td><p>3</p>
<p>(2–4)</p></td>
<td>—</td>
<td></td>
<td><p>3</p>
<p>(2–4)</p></td>
<td>NSD</td>
<td>—</td>
<td></td>
<td><p>3</p>
<p>(2–4)</p></td>
<td><p>4</p>
<p>(3–7)</p></td>
<td><p>6</p>
<p>(3–18)</p></td>
<td>NSD</td>
<td>—</td>
</tr>
<tr class="even">
<td><blockquote>
<p>p-value vs PGB</p>
</blockquote></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>≤0.001</td>
<td>—</td>
<td>—</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="4"><em>Efficacy Measure: Seizure-free during last
28 d</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Responder Rate</td>
<td>15%</td>
<td>NR</td>
<td>3%</td>
<td></td>
<td>12%</td>
<td>7%</td>
<td>1%</td>
<td></td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>—</td>
</tr>
<tr class="odd">
<td>NNTB (95% CL)</td>
<td>NSD</td>
<td>—</td>
<td>—</td>
<td></td>
<td>0.002</td>
<td>0.065</td>
<td>—</td>
<td></td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="4"><em>Safety Measure: WDAEs</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Event rate</td>
<td>19%</td>
<td>26%</td>
<td>7%</td>
<td></td>
<td>18.5%</td>
<td>10.1%</td>
<td>6.2%</td>
<td></td>
<td>23.6%</td>
<td>14.4%</td>
<td>1.2%</td>
<td>6.8%</td>
<td>5%</td>
</tr>
<tr class="odd">
<td>NNTH (95% CL)</td>
<td>8 (5, 34)</td>
<td>5 (3, 11)</td>
<td>—</td>
<td></td>
<td>8 (5, 34)</td>
<td>NSD</td>
<td>—</td>
<td></td>
<td>5 (4, 11)</td>
<td>11 (6, 100)</td>
<td>NSD</td>
<td>NSD</td>
<td>—</td>
</tr>
</tbody>
</table>

Table 19 Partial-onset Seizures (Flexible Dosing)

+----------------------------------+-------------+------------+-------+
|                                  | **Elger     |            |       |
|                                  | (2          |            |       |
|                                  | 005)^129^** |            |       |
+----------------------------------+-------------+------------+-------+
|                                  | **B.I.D.    |            |       |
|                                  | Fixed vs.   |            |       |
|                                  | Flexible    |            |       |
|                                  | dosing,**   |            |       |
|                                  |             |            |       |
|                                  | **12 wk**   |            |       |
+----------------------------------+-------------+------------+-------+
|                                  | *           |            | **    |
|                                  | *Pregabalin |            | PBO** |
|                                  | (mg/d)**    |            |       |
+----------------------------------+-------------+------------+-------+
|                                  | **600**     | **         | **    |
|                                  |             | 150--600** | ---** |
+----------------------------------+-------------+------------+-------+
|                                  | **N = 137** | *          | **N = |
|                                  |             | *N = 131** |  73** |
+----------------------------------+-------------+------------+-------+
| *Efficacy Measure: RRatio*       |             |            |       |
+----------------------------------+-------------+------------+-------+
| > Difference vs. PBO (mean)      | --27.0      | --15.8     | ---   |
+----------------------------------+-------------+------------+-------+
| > 95% CI                         | --38.5,     | --27.4,    | ---   |
|                                  | --15.6      | --4.3      |       |
+----------------------------------+-------------+------------+-------+
| > p-value vs. PBO                | 0.0001      | --0.0091   | ---   |
+----------------------------------+-------------+------------+-------+
| > Difference vs. PGB150--600     | --11.2      | ---        | ---   |
| > (mean)                         |             |            |       |
+----------------------------------+-------------+------------+-------+
| > p-value vs. PGB150--600        | 0.0337      | ---        | ---   |
+----------------------------------+-------------+------------+-------+
| *Efficacy Measure: SR--50*       |             |            |       |
+----------------------------------+-------------+------------+-------+
| > Responder Rate                 | 45%         | 31%        | 11%   |
+----------------------------------+-------------+------------+-------+
| > NNTB (95% CI)                  | 3 (2, 4)    | 5 (3, 10)  | ---   |
+----------------------------------+-------------+------------+-------+
| > p-value vs PBO                 | 0.001       | 0.001      | ---   |
+----------------------------------+-------------+------------+-------+
| > p-value vs. PGB150--600        | 0.016       | ---        | ---   |
+----------------------------------+-------------+------------+-------+
| *Efficacy Measure: Seizure-free  |             |            |       |
| during last 28 d*                |             |            |       |
+----------------------------------+-------------+------------+-------+
| Responder Rate                   | 12.4%       | 12.2%      | 8.2%  |
+----------------------------------+-------------+------------+-------+
| NNTB (95% CL)                    | NSD         | NSD        | ---   |
+----------------------------------+-------------+------------+-------+
|                                  |             |            |       |
+----------------------------------+-------------+------------+-------+
| *Safety Measure: WDAEs*          |             |            |       |
+----------------------------------+-------------+------------+-------+
| Event rate                       | 33.0%       | 12.0%      | 7.0%  |
+----------------------------------+-------------+------------+-------+
| NNTH (95% CL)                    | 4 (3, 6)    | NSD        | ---   |
+----------------------------------+-------------+------------+-------+

SF-50, 50% reduction in seizure frequency

Table 20 Fibromyalgia (Fixed Dosing)

<table>
<colgroup>
<col style="width: 15%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 4%" />
<col style="width: 2%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 2%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4"><p><strong>Unpublished</strong></p>
<p><strong>Study 1077 / F1 / RELIEF<sup>†</sup></strong></p></td>
<td></td>
<td colspan="4"><p><strong>Unpublished</strong></p>
<p><strong>Study 1056 / LIFT</strong></p></td>
<td></td>
<td colspan="5"><strong>Crofford, et al.<sup>121</sup></strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="4"><p><strong>B.I.D. Fixed dosing</strong></p>
<p><strong>after 2-wk titration</strong></p>
<p><strong>14 wk</strong></p>
<p><strong>Monotherapy Pivotal Trial</strong></p></td>
<td></td>
<td colspan="4"><p><strong>B.I.D. Fixed dosing</strong></p>
<p><strong>after 1 wk titration</strong></p>
<p><strong>13 wk</strong></p></td>
<td></td>
<td colspan="5"><p><strong>B.I.D. Fixed dosing</strong></p>
<p><strong>(1 wk titration for 450 mg)</strong></p>
<p><strong>8 wk</strong></p>
<p><strong>Phase II/III proof-of-concept (LOCF)</strong></p></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="3"><strong>Pregabalin (mg/d)</strong></td>
<td><strong>PBO</strong></td>
<td></td>
<td colspan="3"><strong>Pregabalin (mg/d)</strong></td>
<td><strong>PBO</strong></td>
<td></td>
<td colspan="4"><strong>Pregabalin (mg/d)</strong></td>
<td><strong>PBO</strong></td>
</tr>
<tr class="even">
<td></td>
<td><strong>600</strong></td>
<td><strong>450</strong></td>
<td><strong>300</strong></td>
<td><strong>—</strong></td>
<td></td>
<td><strong>600</strong></td>
<td><strong>450</strong></td>
<td><strong>300</strong></td>
<td><strong>—</strong></td>
<td></td>
<td><strong>450</strong></td>
<td><strong>300</strong></td>
<td><strong>150</strong></td>
<td></td>
<td><strong>—</strong></td>
</tr>
<tr class="odd">
<td><strong>N</strong></td>
<td><strong>188</strong></td>
<td><strong>190</strong></td>
<td><strong>183</strong></td>
<td><strong>184</strong></td>
<td></td>
<td><strong>190</strong></td>
<td><strong>183</strong></td>
<td><strong>185</strong></td>
<td><strong>190</strong></td>
<td></td>
<td><strong>132</strong></td>
<td><strong>134</strong></td>
<td><strong>132</strong></td>
<td></td>
<td><strong>131</strong></td>
</tr>
<tr class="even">
<td colspan="15"><em>Efficacy Measure: End point mean pain score on
11-point NRS</em></td>
<td></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Change (mean)</p>
</blockquote></td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td></td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td></td>
<td>–2.1</td>
<td>–1.7</td>
<td>–1.3</td>
<td></td>
<td>–1.1</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Difference</p>
</blockquote></td>
<td>–1.00</td>
<td>–0.98</td>
<td>–0.71</td>
<td>Ref</td>
<td></td>
<td>–0.66</td>
<td>–0.47</td>
<td>–0.43</td>
<td>Ref</td>
<td></td>
<td>–0.93</td>
<td>NR</td>
<td>NR</td>
<td></td>
<td>Ref</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>p-value</p>
</blockquote></td>
<td>&lt;0.0001</td>
<td>&lt;0.0001</td>
<td>0.0009</td>
<td>Ref</td>
<td></td>
<td>0.0070</td>
<td>0.0449</td>
<td>0.0449</td>
<td>Ref</td>
<td></td>
<td>0.0009</td>
<td>NSD</td>
<td>NSD</td>
<td></td>
<td>Ref</td>
</tr>
<tr class="even">
<td colspan="15"><em>Efficacy Measure: NRS-50</em></td>
<td></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Responder Rate</p>
</blockquote></td>
<td>30%</td>
<td>27%</td>
<td>24%</td>
<td>15%</td>
<td></td>
<td>27%</td>
<td>25%</td>
<td>25%</td>
<td>20%</td>
<td></td>
<td>29%</td>
<td>19%</td>
<td>13%</td>
<td></td>
<td>13%</td>
</tr>
<tr class="even">
<td><blockquote>
<p>p-value</p>
</blockquote></td>
<td>0.0010</td>
<td>0.0038</td>
<td>0.0372</td>
<td>Ref</td>
<td></td>
<td>NSD</td>
<td>NSD</td>
<td>NSD</td>
<td>NSD</td>
<td></td>
<td>0.003</td>
<td>NSD</td>
<td>NSD</td>
<td></td>
<td>Ref</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>NNTB, calc (95% CI)</p>
</blockquote></td>
<td>7 (4–16)</td>
<td>9 (5–29)</td>
<td>11 (6–143)</td>
<td>—</td>
<td></td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td></td>
<td>6 (4–16)</td>
<td>—</td>
<td>—</td>
<td></td>
<td>—</td>
</tr>
<tr class="even">
<td colspan="15"><em>Efficacy Measure: NRS-30</em></td>
<td></td>
</tr>
<tr class="odd">
<td>Responder Rate</td>
<td>48%</td>
<td>50%</td>
<td>42%</td>
<td>30%</td>
<td></td>
<td>44%</td>
<td>43%</td>
<td>43%</td>
<td>35%</td>
<td></td>
<td>48%</td>
<td>38%</td>
<td>31%</td>
<td></td>
<td>27%</td>
</tr>
<tr class="even">
<td>p-value</td>
<td>0.0006</td>
<td>0.0002</td>
<td>0.0172</td>
<td>Ref</td>
<td></td>
<td>NSD</td>
<td>NSD</td>
<td>NSD</td>
<td>Ref</td>
<td></td>
<td>0.003</td>
<td>NSD</td>
<td>NSD</td>
<td></td>
<td>Ref</td>
</tr>
<tr class="odd">
<td>NNTB, calc (95% CI)</td>
<td>6 (4–12)</td>
<td>5 (3–10)</td>
<td>8 (5–42)</td>
<td>—</td>
<td></td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td></td>
<td>5 (3–10)</td>
<td>—</td>
<td>—</td>
<td></td>
<td>—</td>
</tr>
<tr class="even">
<td colspan="15"><em>Efficacy Measure: End point Score on Fibromyalgia
Impact Questionnaire (FIQ) Total Score (0–100)</em></td>
<td></td>
</tr>
<tr class="odd">
<td>Change</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>–14.9</td>
<td>–15.7</td>
<td>–16.2</td>
<td>–13.7</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Difference</td>
<td>–5.34</td>
<td>–5.24</td>
<td>NR</td>
<td>Ref</td>
<td></td>
<td>NR</td>
<td>NR</td>
<td>NR</td>
<td>Ref</td>
<td></td>
<td>ND</td>
<td>ND</td>
<td>ND</td>
<td></td>
<td>ND</td>
</tr>
<tr class="odd">
<td>p-value</td>
<td>0.0034</td>
<td>0.0041</td>
<td>NSD</td>
<td>Ref</td>
<td></td>
<td>NSD</td>
<td>NSD</td>
<td>NSD</td>
<td>Ref</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="15"><em>Efficacy Measure: “Very much improved” or “much
improved” at end point on Patient Global Impression of Change
(PGIC)</em></td>
<td></td>
</tr>
<tr class="odd">
<td>% of Pts</td>
<td>44%</td>
<td>47%</td>
<td>32%</td>
<td>24%</td>
<td></td>
<td>46%</td>
<td>41%</td>
<td>43%</td>
<td>35%</td>
<td></td>
<td>52%</td>
<td>45%</td>
<td>32%</td>
<td></td>
<td>26%</td>
</tr>
<tr class="even">
<td>p-value</td>
<td>0.0005</td>
<td>&lt;0.0001</td>
<td>0.0034</td>
<td>Ref</td>
<td></td>
<td>0.0127</td>
<td>0.0467</td>
<td>0.0183</td>
<td>Ref</td>
<td></td>
<td>0.003</td>
<td>0.004</td>
<td>NSD</td>
<td></td>
<td>Ref</td>
</tr>
<tr class="odd">
<td colspan="15"><em>Safety Measure: WDAEs</em></td>
<td></td>
</tr>
<tr class="even">
<td>Event rate</td>
<td>26%</td>
<td>22%</td>
<td>16%</td>
<td>12%</td>
<td></td>
<td>33%</td>
<td>22%</td>
<td>19%</td>
<td>11%</td>
<td></td>
<td>13%</td>
<td>7%</td>
<td>8%</td>
<td></td>
<td>8%</td>
</tr>
<tr class="odd">
<td>NNTH (95% CL)</td>
<td>7 (5–16)</td>
<td>10 (6–38)</td>
<td>—</td>
<td>—</td>
<td></td>
<td>5 (3–7)</td>
<td>9 (5–30)</td>
<td>13 (7–143)</td>
<td>—</td>
<td></td>
<td>—</td>
<td>—</td>
<td>—</td>
<td></td>
<td>—</td>
</tr>
</tbody>
</table>

**^†^** Studies 1077 / F1 / RELIEF and 1056 / LIFT: Types of analyses
that were performed to account for missing data were unclear (i.e.,
modified Baseline Observation Carried Forward \[BOCF\] or Last
Observation Carried Forward (LOCF)). In Study 1077, NRS-30 and NRS-50
values reported in the manufacturer's AMCP Dossier and shown above are
not the same as those shown in the Product Information, Figure 8.

Table 21 Fibromyalgia Treatment Discontinuation Trial (Fixed Dosing)

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 0%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4"><p><strong>Unpublished</strong></p>
<p><strong>Study 1059 / F2 / FREEDOM</strong></p></td>
<td></td>
<td colspan="4"></td>
<td colspan="3"></td>
<td colspan="8"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="4"><p><strong>B.I.D. Fixed dosing,</strong></p>
<p><strong>Pivotal enriched durability trial</strong></p>
<p><strong>6-wk dose optimization then</strong></p>
<p><strong>26-wk double-blind tx</strong></p></td>
<td></td>
<td colspan="4"></td>
<td colspan="3"></td>
<td colspan="8"></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="3"><strong>Pregabalin (mg/d)</strong></td>
<td><strong>PBO</strong></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="5"></td>
<td colspan="3"></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td><strong>600</strong></td>
<td><strong>450</strong></td>
<td><strong>300</strong></td>
<td><strong>—</strong></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="odd">
<td><strong>N</strong></td>
<td><strong>143</strong></td>
<td><strong>73</strong></td>
<td><strong>63</strong></td>
<td><strong>287</strong></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="even">
<td colspan="21"><em>Durability Measure: Time to loss of therapeutic
response in 25% of patients<sup>†</sup></em></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Time (d)</p>
</blockquote></td>
<td colspan="3">34 (all PGB)</td>
<td>7</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="even">
<td><blockquote>
<p>95% CI</p>
</blockquote></td>
<td colspan="3">21–48</td>
<td>5–9</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>p-value</p>
</blockquote></td>
<td colspan="3">≤ 0.0001</td>
<td>Ref</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="even">
<td colspan="21"><em>Durability Measure: Loss of therapeutic response by
end of double-blind phase</em></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>% of Pts</p>
</blockquote></td>
<td colspan="3">32%</td>
<td>61%</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="even">
<td><blockquote>
<p>p-value</p>
</blockquote></td>
<td colspan="3">NR</td>
<td>Ref</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="odd">
<td colspan="21"><em>Durability Measure: Time to PGIC lack of
improvement in 25% of patients</em></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Time (d)</td>
<td colspan="3">25</td>
<td>14</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="odd">
<td>p-value</td>
<td colspan="3">&lt;0.0001</td>
<td>Ref</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="even">
<td colspan="21"><em>Durability Measure: Time to FIQ worsening (total
score and 10 subscores)</em></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Time (d)</td>
<td colspan="3">NR</td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="even">
<td>p-value</td>
<td colspan="3">&lt;0.0001, all tests</td>
<td>Ref</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="odd">
<td colspan="21"><em>Safety Measure: Withdrawals due to adverse
events</em></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Event rate</td>
<td>10%</td>
<td>11%</td>
<td>8%</td>
<td>5%</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
<tr class="odd">
<td>NNTH (95% CI)</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>Ref</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
</tr>
</tbody>
</table>

^†^ Time of loss of therapeutic response was determined from the pain
VAS score (0--100 mm) or from worsening of fibromyalgia symptoms
necessitating an alternative treatment as deemed by the clinical
judgment of the principal investigator. The change in VAS score that
constituted a loss of therapeutic response was defined as \< 30%
reduction from the open-label baseline visit during two consecutive
vistis of the double-blind phase starting from Visit 9 onwards. The
first of the two visits defined the time to loss of therapeutic
response, and the second visit confirmed the loss of therapeutic
response.

## Evaluation of Pregabalin for Class Effect in Neuropathic Pain

Efficacy and tolerability results of fair-quality, parallel-group trials
were pooled to explore whether pregabalin and gabapentin exhibit a class
effect in neuropathic pain,^130^ which is expected to be the most common
indication for both drugs. Trials that used a flexible dosing approach
were preferred in order to approximate actual dosing practices. A single
trial that involved a flexible dosing treatment arm was available for
pregabalin. This trial compared flexible dosing with fixed dosing in
patients with either PDN or PHN.^111^ The results of two trials
evaluating gabapentin were pooled to create a case mix somewhat similar
to that of the pregabalin trial; one used flexible dosing in PDN,^26^
and the other involved forced dosage titration to fixed doses in
PHN.^37^

The relative benefit increase for achieving NRS-50 was similar in
direction and magnitude for the two agents (Table 22). For withdrawals
due to adverse events, the relative risk increase was 1.21 for
pregabalin and 0.47 for gabapentin; however, the 95% confidence
intervals overlapped. These preliminary findings do not support
exclusion of a class effect. The primary difference between pregabalin
and gabapentin, at least in terms of safety, is the controlled substance
classification of pregabalin.. Some experts feel that the controlled
substance classification is of little clinical relevance and that there
is a class effect between pregabalin and gabapentin.

Table 22 Fair-quality flexible and fixed dosing trials (PDN, PHN)

  -------------------------- ---------------------- ---------------------
                             **Pregabalin**         **Gabapentin**

                             **150--600 mg/d**      **Up to 3600 mg/d**

  **No. of RCTs**            **1**                  **2**

  *Responder Rate (NRS-50)*                         

  Drug, n/N (%)              68/141 (48.2)          94/197 (47.7)

  Placebo, n/N (%)           16/65 (24.2)           39/197 (19.8)

  RBI (95% CL)               0.99 (0.25, 2.16)      1.41 (0.76, 2.31)

  NNTB (95% CL)              4 (3, 9)               3.6 (3, 6)

  *WDAEs*                                           

  Drug (n/N)                 24/141 (17.0)          28/197 (14.2)

  Placebo (n/N)              5/65 ((7.7)            19/197 (9.6)

  **RRI (95% CL)**           **1.21 (--0.12,        **0.47 (--0.15,
                             4.52)**                1.55)**

  NNTH (95% CL)              NSD                    NSD
  -------------------------- ---------------------- ---------------------

References: Pregabalin---Freynhagen (2004)^111^; Gabapentin---Backonja
(1998)^26^, Rowbotham (1998)^37^

NNTB, Number-needed-to-treat for benefit; NNTH, Number-needed-to-treat
for harm; NRS-50, At least 50% reduction in pain on an 11-point
Numerical Rating Scale; RBI, Relative benefit increase; RRI, Relative
Risk Increase; WDAE, Withdrawals due to adverse events

# Pharmacoeconomic Analysis

At initial and maximum doses, pregabalin seems to be more costly than
gabapentin when the measured outcome is percentage of patients achieving
a minimal clinically important difference in pain (NRS-30, at least 30%
reduction in pain score on an 11-point numerical rating scale) for PDN
and PHN (see Table 23), and percentage of patients achieving SF-50 for
PS. Responder rates at doses greater than 1800 mg daily were not
available for gabapentin in PS. At the maximal *evaluated* doses,
pregabalin (600 mg daily) is 3 times more costly as gabapentin (1800 mg
daily); however, these may not be comparable doses in PS since
gabapentin doses as high as 3600 mg daily have been used.

Table 23 Cost-effectiveness profile

  ------------ ------------ -- ---------------- ------------- -- ----------- --------- -------- --------- -- ------------- ------------ --------------- -------------
               **Dose**        **Cost /                          **NNTB                                      **Yearly Cost                              
                               Patient**                         (time                                       / Responder**                              
                                                                 period)**                                                                              

  **Drug**     **(mg/d)**      **Per Day**      **Per Year**     **PDN**     **PHN**   **PS**   **FBM**      **PDN**       **PHN**      **PS**          **FBM**

  Pregabalin   150--600        \$2.46           \$901            3\          3--6\     3--6\                                                            
  cap                                                            (5 wk)      (8 wk)    (12 wk)                                                          

                                                                 1\          1\        1--2\                 \$901         \$901        \$901--\$1802   
                                                                 (1 y)       (1 y)     (1 y)                                                            

               300--450        \$2.46           \$901            ---         ---       ---      5--8\        ---           ---          ---             
                                                                                                (14 wk)                                                 

                                                                                                2\                                                      \$1802
                                                                                                (1 y)                                                   

                                                                                                                                                        

                                                                                                                                                        

  Gabapentin   600--1800       \$0.08--\$0.24   \$29--\$88       NR^†^       4^‡^\     7--9\                                                            
  tab                                                                        (7 wk)    (12                                                              
                                                                                       wk)^§^                                                           

                                                                 ---         1\        2\                    NC            \$29--\$88   \$58--\$176     
                                                                             (1 y)     (1 y)                                                            

                                                                                                                                                        

               1200--2400      \$0.17--\$0.33   \$61--\$121      ---         ---       ---      5\           ---           ---          ---             
                                                                                                (12 wk)                                                 

                                                                                                1\                                                      \$61--\$121
                                                                                                (1 y)                                                   
  ------------ ------------ -- ---------------- ------------- -- ----------- --------- -------- --------- -- ------------- ------------ --------------- -------------

Lowest FSS acquisition costs as of 12 February 2008

NNTB, Number-needed-to-treat for benefit. For PDN, PHN, and FBM, NNTB
was calculated using at least 30% reduction in pain on an 11-point
numerical rating scale. For PS, at least 50% reduction in seizure
frequency was used. NNTBs extrapolated to 1 year assumes that the
relative treatment benefit remains constant over time.

PDN, Painful diabetic neuropathy; PHN, Postherpetic neuropathy; PS,
Partial seizures

^†^ Using an NNTB of 4, calculated on the basis of NNTB from at least
moderate improvement on CGIC of 4 (94% CI: 2--8) over 8 weeks (NNTB of 1
over 1 y), the yearly cost per responder would be \$197--\$690 for
gabapentin in PDN, assuming that the relative benefit remains constant
over time. (Note: NNTB was 2 (95% CI: 2--4) on PGIC.)^26^

^‡^ From Comments to Rice (2001)^131^; gabapentin 1800 and 2400 mg/d.

^§^ From Neurontin Product Information (2005).^1^

## VA-oriented incremental cost-effectiveness ratio model for neuropathic pain

Pfizer developed a customizable cost-effectiveness model using
techniques of dynamic simulation to estimate, over time, the effects of
flexibly dosed pregabalin and other treatments (particularly,
gabapentin) on daily pain experience and medical costs in patients with
moderate or severe pain due to PDN or PHN.^132^ In the dynamic
simulation process, hypothetical patients are randomly assigned an
average pretreatment pain score based on the distribution of
patient-level mean pain scores observed in Freynhagn, et al. (2005;
protocol 1008-155).^111^ Efficacy data for gabapentin were based on
results of protocols 945-210 and 945-211.^26,37^ Each of the 1000
patients in the hypothetical cohort are stepped through the model, one
at a time, yielding expected values for all outcomes for each patient
and summaries of these outcomes for the entire cohort. The primary
outcome measure in the model is "a day with no or mild pain." Efficacy
rates reflected 12 weeks of treatment with pregabalin (mean daily dose
375 mg; range, 150 to 600 mg) and 8 weeks of treatment with gabapentin
(mean daily dose, 2400 mg; range, 900 to 3600 mg).

VHA PBM requested that gabapentin be used as the comparator drug, that
different time frames (12 and 52 weeks) be used in scenarios, and that
VHA costs be used for medication and neuropathic pain--related services.
Default model parameters were used for probability of primary care
and/or specialist visits and health-state utilities. In the context of
the assumptions used for the impact model, the manufacturer states that
there are no clinically relevant differences in the safety profiles of
pregabalin and gabapentin, and the same assumption was made for other
comparator drugs. Therefore, adverse events were not considered in the
model. It was also assumed that treatment discontinuations due to
adverse events or inefficacy occurred at the same frequencies across
therapies.

The incremental cost per additional day with no or mild pain on
pregabalin (150 to 600 mg daily, flexible dosing) relative to gabapentin
(mean flexible dose, 2400 mg daily) in mixed neuropathic pain (PDN and
PHN) ranged from --\$182 to \$670 over 52 weeks for drug costs only (and
--\$229 to \$622 for all health care costs). The incremental cost per
quality-adjusted life year (QALY) gained was \$2711 (95% CI: \$682 to
\$4328).

The manufacturer concluded that pregabalin provided more days of no or
mild pain than gabapentin and that the incremental cost-effectiveness
ratios (ICERs) and QALYs obtained in the analysis were within the range
of other valued medical interventions, such as treatment of chronic
noncancer pain, use of proton pump inhibitors for gastroesophageal
reflux disease, and treatment of major depression.

Limitations of this pharmacoeconomic analysis include omission of safety
costs, efficacy rates that seem to be inconsistent with published rates,
extrapolation of short-term efficacy rates to 52 weeks, and incomplete
disclosure of calculations.

## VA-oriented incremental cost-effectiveness ratio model for partial-onset seizures

A cost-effectiveness model using dynamic simulation was used to estimate
the impact of add-on pregabalin, other selected add-on antiepileptic
drug therapy, and no add-on therapy (i.e. standard therapy alone) on the
frequency of seizure-free days in adults with partial epilepsy
refractory to at least one antiepileptic agent. In the model, a
hypothetical cohort of 1000 patients are randomly assigned a
pretreatment monthly average number of seizure-days, based on the pooled
distribution of mean seizure-days at baseline among patients who
participated in two randomized controlled trials (protocols 1008-011 and
1008-034).^118,120^ A predicted number of seizure-days is then randomly
assigned to each month using a Poisson distribution with a mean equal to
the pretreatment mean frequency of seizure-days and a variance equal to
that mean. Seizure-day rates are permitted to vary randomly from patient
to patient. The model allows adverse events and discontinuations due to
adverse events or inefficacy. Each patient is randomly stepped through
the model to yield expected values for all outcomes for each patient in
the cohort. The model then calculates summary measures of the expected
patient outcomes, including mean duration of study therapy, percentage
of patients discontinuing therapy, mean number of seizure-free days (the
primary outcome of interest), percentage of patients experiencing
selected adverse events, and quality-adjusted life expectancy. Duration
of therapy may be customized to one year (i.e., no treatment
discontinuations) or less than one year (assuming withdrawal due to
adverse events or inefficacy). The median reduction in seizure frequency
was 36.7% for pregabalin 300 mg daily, 43.0% for pregabalin 600 mg
daily, and 26.0% for gabapentin 1800 mg daily. Daily medication costs
and costs of neurology clinic visits reflected current VA prices.
Incremental cost-effectiveness of other antiepileptic drugs
(lamotrigine, levetiracetam, oxcarbazepine, and topiramate) were also
calculated but not discussed here.

The estimated incremental cost per additional day without seizures was
\$18 (95% CI: \$16 to \$21) for pregabalin and \$11 (\$8 to \$17) for
gabapentin. The cost per additional QALY gained was \$29,533 (95% CI:
\$25,775 to \$34,941) for pregabalin and \$17,520 (\$10,819 to \$29,647)
for gabapentin. When expected costs of care for adverse events per
patient (including drug and specialist visits) are added to the model,
the costs are \$19 (\$17 to \$22) per additional day without seizures
and \$34,574 (\$28,738 to \$46,643) per QALY gained for pregabalin and
\$10 (\$7 to \$15) and \$19,288 (\$10,866 to \$40,134), respectively,
for gabapentin.

The manufacturer concluded that pregabalin provides a greater number of
seizure-free days than other second-generation antiepileptic drugs; the
ICERs and QALYs for pregabalin are within the range of other medical
interventions; and that at a price of \$2.70 per 1800-mg dose of
gabapentin, the ICER for pregabalin is dominant.

Limitations of this model include questionable derivation of efficacy
rates and incomplete disclosure of calculations.

# Conclusions

Pregabalin is the first agent to be FDA-approved for management of
fibromyalgia, for which it has the largest body of evidence of efficacy
and safety for this indication. Pregabalin is the second agent to be
approved for neuropathic pain (PDN and PHN) as well as partial epilepsy
in the A2D-receptor binding class of antiepileptic drugs. The advantages
of pregabalin relative to gabapentin include greater potency (mg/kg),
better oral bioavailability, linear pharmacokinetics, smaller intra- and
intersubject pharmacokinetic variability, and shorter titration
(although many patients may not tolerate pregabalin with the 1- to
2-week titration periods used in clinical trials). To a certain extent,
these pharmacologic and pharmacokinetic advantages may have translated
into clinical advantages in that pregabalin showed somewhat more
consistent efficacy across large, multicenter PDN trials and gained FDA
approval for PDN, whereas gabapentin was less consistently efficacious
and failed to receive FDA approval for this indication.

In terms of NRS-50 or NRS-30 responder rates based on limited data,
pregabalin and gabapentin are similar in efficacy in neuropathic pain
and fibromyalgia. Using SF-50 responder rates in PS, pregabalin may be
slightly more effective than gabapentin, but confidence intervals
overlap.

Overall, the adverse event profiles of pregabalin and gabapentin are
similar. The main exceptions to the similarity in safety characteristics
are the controlled substance (schedule V) classification and the
warning/precaution of potentially life-threatening angioedema with
pregabalin. The comparative tolerability of the two agents is still
unclear.

Based on indirect comparisons (which should be considered inconclusive),
there may be other possible dissimilarities which could be clinically
important in some individuals. Weight gain ≥ 7% over baseline, adverse
ophthalmologic events, euphoria, increased creatine kinase, decreased
platelet count, and PR interval prolongation may be more likely to occur
during pregabalin therapy, whereas gabapentin may be more likely to be
associated with fatigue and diarrhea.

Pharmacoeconomic analyses suggest that generic gabapentin is more
cost-effective than pregabalin, although pregabalin incremental
cost-effectiveness ratios and QALYs are within the range of other
medical interventions.

# Recommendations

-   Pregabalin should be made available to patients who meet criteria
    for use.

-   Since pregabalin is considered to have a class effect, it should be
    considered a treatment alternative in patients with PDN, PHN, or PS
    who have had a documented inadequate response, intolerance,
    hypersensitivity, or contraindication to gabapentin.

-   There is stronger evidence to support the first-line use of
    pregabalin for fibromyalgia than there is for gabapentin.

-   There is no evidence to support combined therapy with pregabalin and
    gabapentin.

-   Although there is considerable published evidence supporting its use
    for the treatment of generalized anxiety disorder; the PBM SHG
    recommends that clinicians await further FDA evaluation of
    pregabalin for this indication.

-   Pregabalin should not be used for chronic low back pain, chronic
    pain due to hip osteoarthritis, and panic disorder, given
    preliminary evidence suggesting lack of efficacy in these
    conditions.

# References:

**Prepared November 2007. Contact person: F. Goodman, PharmD, BCPS**

# Appendix: Clinical Trials

A literature search was performed on PubMed/Medline (1966 to October
2005) and the Cochrane Registry of Controlled Trials using the search
terms *pregabalin* and *Lyrica*. The search was limited to studies
performed in humans and published in English language. Reference lists
of review articles and the manufacturer's AMCP dossier were searched for
relevant clinical trials. All systematic reviews and randomized
controlled trials evaluating efficacy and safety, and observational
studies evaluating durability of response and safety were included.

# Abbreviations Used in Appendix Tables

> AE, Adverse event
>
> AED, Antiepileptic drug
>
> BL, Baseline
>
> CGIC (-much), Clinical Global Impression of Change (scale rating of at
> least "much improved")
>
> CL, Confidence limits
>
> DFH, Drug-free holiday
>
> Diff, Difference (PGB -- PBO)
>
> EP, End point
>
> EQ-5D, EuroQoL Health Utilities Index
>
> FBM IS, Fibromyalgia Intensity Score on Manual Tender Point Survey
> (MTPS), 0--10
>
> HADS, Hospital Anxiety and Depression Scale, 0--21
>
> LSM (PS), Least squares mean (pain score on 11-point numerical rating
> scale, 0--10)
>
> MAF GFI, Multidimensional Assessment of Fatigue Global Fatigue Index,
> 1--50
>
> MOS OSP, Medical Outcomes Study---Sleep Subscale, Overall Sleep
> Problems Index, 0--100
>
> N, Number of patients enrolled; N~R~ and N~A~ not specified
>
> N~A~, Number of patients analyzed
>
> ND, Not done
>
> NNTB-50 or NNTB-30, Number-needed-to-treat for benefit based on number
> of patients achieving NRS-50 or NRS-30, respectively
>
> N~R~, Number of patients randomized
>
> NRS-50 or NRS-30 denotes at least 50% or 30% improvement from
> baseline, respectively, on 11-point Numerical Rating Scale for pain
>
> OCA, Observed case analysis
>
> PEM, Primary efficacy measure
>
> PGIC-imp, VMI, -much, or -min denotes Patient Global Impression of
> Change scale rating of "improvement" (not otherwise defined), "very
> much improved", at least "much improved" or at least "minimally
> improved," respectively
>
> QoSS, Quality of Sleep Score, 0--10
>
> Responder Rate-50, percentage of patients who have at least a 50%
> reduction in 28-d seizure frequency compared with baseline
>
> RR-50 or -30, Responder Rate for ≥ 50% or ≥ 30% reduction in pain
> score from baseline
>
> RRatio, Response ratio; reduction in partial seizure frequency;
> calculated as the difference in 28-d seizure frequencies at the end of
> the study period and the baseline period, divided by the sum of the
> **end point** and baseline seizure frequencies, and multiplied by 100
>
> SAE, Serious adverse event
>
> SF-36, Short-form 36 Health Survey
>
> SFI, Seizure-free interval
>
> SF-MPQ, Short-form McGill Pain Questionnaire
>
> TCAD, Tricyclic antidepressant
>
> TR, Treatment-related
>
> TRSAE, Treatment-related serious adverse event
>
> ULN, Upper limit of normal
>
> WDAE, Withdrawal due to adverse event
>
> WDTRAE, Withdrawal due to treatment-related adverse event
>
> WDLE, Withdrawal due to lack of efficacy
>
> WDSAE, Withdrawal due to serious adverse event
>
> Δ, Mean change from baseline to end point, unless otherwise specified
>
> †, Denotes calculated value
>
> ‡, p-values for both NRS-50 and -30

Appendix Table 1 Painful Diabetic Neuropathy: active-control trials

+---------+--------------+----------------------+---------------------+
| **Cit   | **Major      | **Efficacy Results** | **Safety Results**  |
| ation** | Eligibility  |                      |                     |
|         | Criteria,**  |                      |                     |
| **      |              |                      |                     |
| Design, | **Population |                      |                     |
| Qu      | Profile**    |                      |                     |
| ality** |              |                      |                     |
+=========+==============+======================+=====================+
| No      |              |                      |                     |
| trials  |              |                      |                     |
+---------+--------------+----------------------+---------------------+

Appendix Table 2 Painful diabetic neuropathy: placebo-controlled trials

+--------+-----------+--------------------+---+-------------------------+
| **Cita | **Major   | **Efficacy         | * |                         |
| tion** | El        | Results**          | * |                         |
|        | igibility |                    | S |                         |
| **D    | Cr        |                    | a |                         |
| esign, | iteria,** |                    | f |                         |
| Qua    |           |                    | e |                         |
| lity** | **P       |                    | t |                         |
|        | opulation |                    | y |                         |
|        | Profile** |                    | R |                         |
|        |           |                    | e |                         |
|        |           |                    | s |                         |
|        |           |                    | u |                         |
|        |           |                    | l |                         |
|        |           |                    | t |                         |
|        |           |                    | s |                         |
|        |           |                    | * |                         |
|        |           |                    | * |                         |
+========+===========+====================+===+=========================+
| Lesser | Inclusion | Average Daily Pain | D |                         |
| (20    | criteria: | score (0--10       | e |                         |
| 04)^10 | Age \> /  | Numerical Rating   | a |                         |
| 9,133^ | = 18      | Scale)             | t |                         |
|        | years;    |                    | h |                         |
| Study  | type 1 or |   --------- --     | s |                         |
| 029    | 2         | ------- ---------  | a |                         |
|        | diabetes  | --------- -------- | n |                         |
| MC DB  | mellitus; |   Average          | d |                         |
| PC PG  | distal    |    PGB600    PGB30 | O |                         |
| RCT    | symmetric | 0    PGB75     PBO | t |                         |
|        | sen       |   dail             | h |                         |
| ITT,   | sorimotor | y                  | e |                         |
| LOCF   | polyn     |                    | r |                         |
|        | europathy |   pain             | S |                         |
| Total  | for 1 to  |                    | e |                         |
| N~R~   | 5 y;      |                    | r |                         |
|  = 338 | stable    |                    | i |                         |
|        | ant       |                    | o |                         |
| *In    | idiabetic | N = 81    N = 81   | u |                         |
| terven | me        |   N = 77    N = 97 | s |                         |
| tions* | dication; |                    | A |                         |
|        | completed |   EP LSM           | d |                         |
| Preg   | at least  |   3.60      3.80   | v |                         |
| abalin | 4 daily   |     4.91      5.06 | e |                         |
| 75,    | pain      |                    | r |                         |
| 300,   | diaries   |   Diff             | s |                         |
| or 600 | during    |      --1.45    --1 | e |                         |
| mg/d   | baseline  | .26    --0.15    0 | E |                         |
| (in 3  | phase;    |                    | v |                         |
| d      | average   |   95% CL           | e |                         |
| ivided | baseline  |    --2.06,   --1.8 | n |                         |
| doses) | daily     | 6,   --0.76,   --- | t |                         |
| vs.    | pain      |                    | s |                         |
| P      | score     |       ‑0.85     ‑0 | : |                         |
| lacebo | \>/= 4    | .65     0.45       | N |                         |
| for 5  | (on 0 to  |                    | o |                         |
| wk     | 10        |   p-value          | d |                         |
|        | scale);   |    .0001     .0001 | e |                         |
| (75-   | score of  |      NSD       --- | a |                         |
| and    | \>/= 40   |                    | t |                         |
| 300-mg | mm on     |   Δ^†^             | h |                         |
| doses  | visual    | --2.60    --2.40   | s |                         |
| s      | analog    |   --1.79    --1.54 | ; |                         |
| tarted | scale     |   --------- --     | 8 |                         |
| w      | (VAS)     | ------- ---------  | S |                         |
| ithout |           | --------- -------- | A |                         |
| titr   | Exclusion |                    | E |                         |
| ation; | criteria: | Onset of first     | s |                         |
| 600-mg |           | statistically      | ( |                         |
| dose   | failed to | significant        | 4 |                         |
| was    | respond   | difference from    | o |                         |
| ti     | to        | placebo: 1 wk      | n |                         |
| trated | previous  | (pregabalin 300    | P |                         |
| over 1 | g         | and 600 mg / d).   | G |                         |
| wk,    | abapentin |                    | B |                         |
| then   | \>/= 1200 | Responder rates (% | 6 |                         |
| fixed  | mg/d for  | of patients) at 5  | 0 |                         |
| for 4  | PDN       | wk                 | 0 |                         |
| wk)    |           |                    | , |                         |
|        | *P        |   ----------- ---  | 1 |                         |
| *A     | opulation | --------- -------- | o |                         |
| llowed | Profile*  | ---- ------- ----- | n |                         |
| co-    |           |   Outcome     P    | P |                         |
| medica | Age, mean | GB600       PGB300 | G |                         |
| tions* | (range),  |        PGB75   PBO | B |                         |
|        | y: 59.9   |                    | 7 |                         |
| A      | (26 to    |   NRS-50           | 5 |                         |
| cetami | 85)       | 48           41    | , |                         |
| nophen |           |         \~25    18 | 3 |                         |
| (up to | M  /  F:  |                    | o |                         |
| 3      | 202  /    |   NRS-30           | n |                         |
| g/d);  | 135       | 65           62    | P |                         |
| sel    |           |         \~37    33 | B |                         |
| ective | Race,     |                    | O |                         |
| ser    | white  /  |   p-value†‡        | ) |                         |
| otonin | black  /  | \<  .0001    \<  . |   |                         |
| re     | other, n  | 0001   NSD     --- | W |                         |
| uptake | (%): 318  |                    | i |                         |
| inhi   | (94.4)    |   NNT-50†     3    | t |                         |
| bitors |  /  12    |             4      | h |                         |
| (      | (3.6)  /  |        NC      --- | d |                         |
| stable | 7 (2.1)   |                    | r |                         |
| doses) |           |   95% CL†     2    | a |                         |
|        | Estimated | , 6         2, 7   | w |                         |
| *Fair  | CrCl,     |                --- | a |                         |
| qu     | mean,     |                    | l |                         |
| ality* | ml / min: |   NNT-30†     3    | s |                         |
|        | 98.1      |             3      | ( |                         |
| *R     |           |        NC      --- | % |                         |
| esults | Diabetes  |                    | o |                         |
| may be | type, 1   |   95% CL†     2    | f |                         |
| appl   |  /  2, n  | , 5         2, 7   | p |                         |
| icable | (%): 31   |                --- | a |                         |
| to     | (9.2)  /  |   ----------- ---  | t |                         |
| shor   | 306       | --------- -------- | i |                         |
| t-term | (90.8)    | ---- ------- ----- | e |                         |
| tre    |           |                    | n |                         |
| atment | Baseline  | Sleep interference | t |                         |
| of     | pain      | score, short-form  | s |                         |
| com    | score,    | McGill Pain        | ) |                         |
| pliant | mean      | Questionnaire, VAS |   |                         |
| pa     | (range):  | score, Present     |   |                         |
| tients | 6.4 (2.9  | Pain Intensity     |   |                         |
| with   | to 10.0)  | score, PGIC and    | - |                         |
| stable |           | CGIC               | - |                         |
| di     | Ant       | "improvement," and | - |                         |
| abetes | idiabetic | SF-36 social       | - |                         |
| but    | me        | function and       | - |                         |
| not    | dication, | bodily pain        | - |                         |
| neces  | Insulin   | domains: for each  | - |                         |
| sarily |  /  Oral, | outcome, the       | - |                         |
| those  | n (%):    | results showed     | - |                         |
| who    | 142       | statistically      | - |                         |
| have   | (42.1)    | significant        | - |                         |
| not    |  /  247   | (p \< 0.05)        | - |                         |
| res    | (73.3)    | treatment benefit  | - |                         |
| ponded |           | on pregabalin 300  |   |                         |
| to     |           | and 600 but not    | - |                         |
| gaba   |           | 75 mg / d vs.      | - |                         |
| pentin |           | placebo.           | - |                         |
| ≥ 1    |           |                    | - |                         |
| 200 mg |           | POMS,              | - |                         |
|  / d.* |           | tension-anxiety    | - |                         |
|        |           | mood scale results | - |                         |
|        |           | showed a           | - |                         |
|        |           | statistically      |   |                         |
|        |           | significant        | - |                         |
|        |           | (p \< 0.05)        | - |                         |
|        |           | treatment benefit  | - |                         |
|        |           | on pregabalin 300  | - |                         |
|        |           | but not 600 or     | - |                         |
|        |           | 75 mg / d vs.      | - |                         |
|        |           | placebo.           | - |                         |
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+--------+-----------+--------------------+---+-------------------------+
| Rose   | Inclusion | Average Daily Pain | S |                         |
| nstock | criteria: | score (0--10       | A |                         |
| (20    | Age at    | Numerical Rating   | E |                         |
| 04)^11 | least 18  | Scale)             | s |                         |
| 0,133^ | y; type 1 |                    | : |                         |
|        | or 2      |   ---------        | N |                         |
| Study  | diabetes  | --------- -------- | o |                         |
| 131    | mellitus; |   Resul            | n |                         |
|        | sy        | ts   PGB 300   PBO | e |                         |
| MC DB  | mmetrical |   fo               | o |                         |
| PC PG  | painful   | r                  | n |                         |
| RCT    | symptoms  |                    | p |                         |
|        | in distal |   Average          | r |                         |
| ITT,   | ex        |   N = 76    N = 70 | e |                         |
| LOCF   | tremities |   da               | g |                         |
|        | for 1 to  | ily                | a |                         |
| Total  | 5 y prior |   pa               | b |                         |
| N~R~   | to study; | in                 | a |                         |
|  = 146 | symptoms  |                    | l |                         |
|        | att       |   EP LSM           | i |                         |
| *In    | ributable |     3.99      5.46 | n |                         |
| terven | to        |                    | ( |                         |
| tions* | sen       |   Diff             | n |                         |
|        | sorimotor |      --1.47    --- | o |                         |
| Preg   | diabetic  |                    | t |                         |
| abalin | p         |   95               | r |                         |
| 300    | eripheral | % CL    --2.19,    | e |                         |
| mg/d   | ne        |                    | p |                         |
| (in 3  | uropathy; |         --0.75     | o |                         |
| d      | score of  |                    | r |                         |
| ivided | at least  |   p-               | t |                         |
| doses) | 40 mm on  | value   .0001      | e |                         |
| vs.    | 100-mm    |                    | d |                         |
| P      | visual    |   Δ^†^             | f |                         |
| lacebo | analog    |    --2.5     --0.8 | o |                         |
| for 8  | scale     |                    | r |                         |
| wk     | (VAS);    |   p-               | P |                         |
| (fixe  | c         | value   NA         | B |                         |
| d-dose | ompletion |                    | O |                         |
| r      | of at     |   Δ (BL t          | ) |                         |
| egimen | least 4   | o  --2.2     --0.4 |   |                         |
| w      | daily     |   En               | W |                         |
| ithout | diaries   | d of Wk            | i |                         |
| titr   | during    |   1)               | t |                         |
| ation) | the week  |                    | h |                         |
|        | preceding |                    | d |                         |
| *A     | rando     |   p-               | r |                         |
| llowed | mization; | value   0.0001     | a |                         |
| co-    | minimum   |   ---------        | w |                         |
| medica | average   | --------- -------- | a |                         |
| tions* | daily     |                    | l |                         |
|        | pain      | CL, Confidence     | s |                         |
| Stable | score of  | limits; LSM, Least | ( |                         |
| antidi | 4 on      | squares mean;      | % |                         |
| abetic | 11-point  | Δ, Change; †,      | o |                         |
| medica | numerical | Denotes calculated | f |                         |
| tions; | rating    | value              | p |                         |
| a      | scale     |                    | a |                         |
| cetami | (NRS)     | Responder rates (% | t |                         |
| nophen | during    | of patients) at 8  | i |                         |
| up to  | baseline  | wk                 | e |                         |
| 4 g/d; | period;   |                    | n |                         |
| ASA up | normal    |   -------------- - | t |                         |
| to 325 | chest     | ----------- ------ | s |                         |
| mg/d   | X-ray     |   Outcome          | ) |                         |
| for MI | within    |   PGB 300      PBO |   |                         |
| or TIA | prior 2   |                    |   |                         |
| prophy | y;        |   NRS-50           |   |                         |
| laxis; | baseline  |  40.0         14.5 | - |                         |
| SSRIs  | h         |                    | - |                         |
| at     | emoglobin |   p-value          | - |                         |
| stable | A1c \</=  |      0.001         | - |                         |
| doses; | 11%       |                    | - |                         |
| drugs  |           |   NRS-30           | - |                         |
| and    | Exclusion |  50.0         35.0 | - |                         |
| suppl  | criteria: |                    | - |                         |
| ements | failed to |   NNT-50†          | - |                         |
| used   | respond   |   4            --- | - |                         |
| for    | to        |                    | - |                         |
| di     | previous  |   95% CL†          | - |                         |
| abetic | treatment |   3, 9         --- | - |                         |
| peri   | with      |                    |   |                         |
| pheral | g         |   NNT-30           | - |                         |
| neuro  | abapentin |      NSD           | - |                         |
| pathy; | ≥ 1200    |                    | - |                         |
| AEDs   | mg/d for  |      (p = 0.08)    | - |                         |
| for    | treatment |                    | - |                         |
| pain;  | of pain   |   95% CL†          | - |                         |
| TCADs, | a         |   ---          --- |   |                         |
| cen    | ssociated |                    | - |                         |
| trally | with      |   PGIC-imp         | - |                         |
| acting | diabetic  |    67           39 | - |                         |
| anal   | ne        |                    | - |                         |
| gesics | uropathy. |   p-value          | - |                         |
|        |           |      0.001         | - |                         |
| *Fair  | *P        |                    |   |                         |
| qu     | opulation |   NNT-PGIC-imp     |   |                         |
| ality* | Profile*  |   4            --- | W |                         |
|        |           |                    | i |                         |
| *May   | P         |   95% CL           | t |                         |
| apply  | regabalin |   2, 8         --- | h |                         |
| to     | (N = 76)  |   -------------- - | d |                         |
| shor   | vs.       | ----------- ------ | r |                         |
| t-term | Placebo   |                    | a |                         |
| tre    | (N = 70)  | Sleep interference | w |                         |
| atment |           | score, SF-MPQ      | a |                         |
| w      | Age,      | total score, VAS   | l |                         |
| ithout | mean, y:  | score, and PPI     | s |                         |
| dosage | 59.2 vs.  | score, SF-36       |   |                         |
| titr   | 60.3      | bodily pain, POMS  |   |                         |
| ation; |           | tension / anxiety  |   |                         |
| may    | M / F:    | and total mood     | P |                         |
| not    | 55.3% /   | disturbance: for   | G |                         |
| apply  | 44.7% vs. | each outcome       | B |                         |
| to     | 57.1% /   | measure (end point |   |                         |
| n      | 42.9%     | LSM), the results  |   |                         |
| onresp |           | showed             |   |                         |
| onders | E         | statistically      |   |                         |
| to     | thnicity, | significant        | P |                         |
| gaba   | White /   | (p ≤ 0.0364)       | B |                         |
| pentin | Black /   | improvement on     | O |                         |
| ≥ 1200 | Other:    | pregabalin 300 vs. |   |                         |
| mg/d.* | 84.2% /   | placebo            |   |                         |
| Exc    | 7.9% /    |                    |   |                         |
| lusion | 7.9% vs.  | PGIC (see          |   |                         |
| of     | 91.4% /   | Responder Rates    |   |                         |
| g      | 4.3% /    | above) and CGIC    |   |                         |
| abapen | 4.3%      | improvement        |   |                         |
| tin(≥  |           | results also       |   |                         |
| 1200 m | Duration  | showed a           |   |                         |
| g / d) | of        | statistically      |   |                         |
| n      | diabetes, | significant (p ≤   |   |                         |
| onresp | mean, y:  | 0.004) treatment   |   |                         |
| onders | 9.3 vs.   | benefit on         |   |                         |
| may    | 9.4       | pregabalin vs.     |   |                         |
| bias   |           | placebo.           |   |                         |
| r      |           |                    |   |                         |
| esults |           |                    | 3 |                         |
| in     |           |                    | 0 |                         |
| favor  |           |                    | 0 |                         |
| of     |           |                    |   |                         |
| PGB.   |           |                    |   |                         |
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+--------+-----------+--------------------+---+-------------------------+
| R      | Inclusion | Average Daily Pain | D |                         |
| ichter | criteria: | score (0--10       | e |                         |
| (20    | age ≥18   | Numerical Rating   | a |                         |
| 05)^11 | y;        | Scale)             | t |                         |
| 4,133^ | diabetic, |                    | h |                         |
|        | distal,   |                    | s |                         |
| Study  | s         | --------- -------- | : |                         |
| 10     | ymmetric, |  -------- -------- | N |                         |
| 08-014 | sen       |   Results   PGB    | o |                         |
|        | sorimotor | 600   PGB150   PBO | n |                         |
| MC     | polyn     |   for              | e |                         |
| (29)   | europathy |                    |   |                         |
| DB PC  | for 1‑5 y |                    | N |                         |
| PG RCT | with      |   average   N = 82 | o |                         |
| with   | HgA1c     |    N = 79   N = 85 | n |                         |
| open   | ≤ 11%;    |   daily            | f |                         |
| -label | SF-MPQ    |                    | a |                         |
| fol    | 100-mm    |   pain             | t |                         |
| low-on | VAS score |                    | a |                         |
| study  | ≥ 40 mm;  |                    | l |                         |
|        | completed |   EP LSM    4.29   | S |                         |
| ITT,   | at least  |      5.11     5.55 | e |                         |
| LOCF   | 4 daily   |                    | r |                         |
|        | pain      |   Diff      --0    | i |                         |
| Total  | diaries;  | .44   --1.26   --- | o |                         |
| N~R~   | average   |                    | u |                         |
|  = 246 | score of  |   95% CL    NR     | s |                         |
|        | ≥ 4 on    |        NR       NR | A |                         |
| *In    | daily     |                    | d |                         |
| terven | Pain      |   p-value   .00    | v |                         |
| tions* | Rating    | 02    .1763    --- | e |                         |
|        | Scale     |                    | r |                         |
| Preg   | (0--10)   |   Δ^†^      --2.4  | s |                         |
| abalin | over the  |     --1.5    --1.2 | e |                         |
| 150 or | 7 d prior |                    | E |                         |
| 600    | to        |   p-value   .0     | v |                         |
| mg / d | rand      | 002    NR       NR | e |                         |
| (in 3  | omization |                    | n |                         |
| d      |           | --------- -------- | t |                         |
| ivided | Exclusion |  -------- -------- | s |                         |
| doses) | criteria: |                    | ( |                         |
| vs.    | p         | Responder rates (% | n |                         |
| P      | reviously | of patients) at    | , |                         |
| lacebo | treated   | week 6             | % |                         |
| for 6  | with      |                    | ) |                         |
| wk     | pr        |   -                |   |                         |
| (inc   | egabalin; | ---------- ------- |   |                         |
| luding | CrCl ≤ 6  | - -------- ------- |   |                         |
| 2 wk   | 0 ml/min; |   Outcome     PGB  | - |                         |
| titr   | serious   | 600   PGB300   PBO | - |                         |
| ation) | hepatic,  |   measure          | - |                         |
|        | res       |                    | - |                         |
| *A     | piratory, |                    | - |                         |
| llowed | or        |   NRS-50      39%  | - |                         |
| co-    | he        |       19%      15% | - |                         |
| medica | matologic |                    | - |                         |
| tions* | illness;  |   p-value     .00  | - |                         |
|        | unstable  | 2     .423     --- |   |                         |
| ASA    | CVD;      |                    | - |                         |
| for MI | sy        |   NNTB-50†    4    | - |                         |
| proph  | mptomatic |       ---      --- | - |                         |
| ylaxis | PVD;      |                    | - |                         |
| and    | abnormal  |   95% CL†     3,   | - |                         |
| TIAs;  | ECG or    | 8     ---      --- | - |                         |
| APAP   | 2-min     |                    | - |                         |
| ≤      | rhythm    |                    | - |                         |
| 3 g/d; | strip;    |                    |   |                         |
| stable | n         |                    | - |                         |
| doses  | eurologic |                    | - |                         |
| of     | disorders |  PGIC-much   51.8% | - |                         |
| SSRIs  | unrelated |     NR       28.2% | - |                         |
|        | to        |                    | - |                         |
| *Fair  | diabetic  |   p-value     .00  | - |                         |
| qu     | ne        | 2     .235     --- | - |                         |
| ality* | uropathy; |                    | - |                         |
|        | c         |                    |   |                         |
| *R     | linically |  CGIC-much   45.2% | - |                         |
| esults | si        |     NR       22.8% | - |                         |
| may be | gnificant |                    | - |                         |
| appl   | abno      |   p-value     .00  | - |                         |
| icable | rmalities | 2     .708     --- | - |                         |
| to     | on visual |   -                | - |                         |
| shor   | field and | ---------- ------- | - |                         |
| t-term | acuity    | - -------- ------- | - |                         |
| trea   | tests     |                    |   |                         |
| tment* | (specific | NNTB-50,           |   |                         |
|        | tests and | Numb               |   |                         |
|        | req       | er-needed-to-treat |   |                         |
|        | uirements | for benefit based  |   |                         |
|        | not       | on number of       |   |                         |
|        | d         | patients achieving |   |                         |
|        | elineated | NRS-50.            |   |                         |
|        | here);    |                    |   |                         |
|        | chronic   | NRS-50, At least   |   |                         |
|        | hepatitis | 50% improvement on |   |                         |
|        | B or      | 11-point Numerical |   |                         |
|        | hepatitis | Rating Scale       | P |                         |
|        | B within  | (definition of     | G |                         |
|        | previous  | responders)        | B |                         |
|        | 3 mo; HIV |                    | 6 |                         |
|        | i         | PGIC-much, At      | 0 |                         |
|        | nfection; | least much         | 0 |                         |
|        | use of    | improved on        |   |                         |
|        | a         | Patient Global     |   |                         |
|        | nalgesics | Impression of      |   |                         |
|        | other     | Change scale       | P |                         |
|        | than ASA  |                    | G |                         |
|        | (≤        | CGIC-much, At      | B |                         |
|        |  325 mg/d | least much         | 1 |                         |
|        | for       | improved on        | 5 |                         |
|        | pr        | Clinical Global    | 0 |                         |
|        | ophylaxis | Impression of      |   |                         |
|        | of MI and | Change scale       |   |                         |
|        | TIAs),    |                    |   |                         |
|        | aceta     | PGB600 but not     | P |                         |
|        | minophen, | PGB300 was         | B |                         |
|        | antide    | superior to        | O |                         |
|        | pressants | placebo in         |   |                         |
|        | other     | decreasing SF-MPQ  |   |                         |
|        | than      | end point scores   |   |                         |
|        | SSRIs,    | (sensory,          | S |                         |
|        | AEDs,     | affective, VAS,    | A |                         |
|        | neur      | PPI) (p = .0002)   | E |                         |
|        | oleptics, | and sleep          |   |                         |
|        | or any    | interference       |   |                         |
|        | co        | scores             |   |                         |
|        | ncomitant | (p = 0.0004).      |   |                         |
|        | m         |                    |   |                         |
|        | edication | PGB600 and PGB300  |   |                         |
|        | that      | were better than   |   |                         |
|        | could     | placebo in SF-36   | N |                         |
|        | alter     | QoL bodily pain    |   |                         |
|        | effect of | domain (53.7 and   | = |                         |
|        | study     | 52.9 vs. 45.5,     |   |                         |
|        | treatment | respectively;      | 8 |                         |
|        | within    | p = 0.01).         | 2 |                         |
|        | the 14 or |                    |   |                         |
|        | 30 d      | POMS scores: NSD   |   |                         |
|        | prior to  |                    |   |                         |
|        | start of  |                    | N |                         |
|        | study;    |                    |   |                         |
|        | other     |                    | = |                         |
|        | severe    |                    |   |                         |
|        | pain that |                    | 7 |                         |
|        | could     |                    | 9 |                         |
|        | confound  |                    |   |                         |
|        | ass       |                    |   |                         |
|        | essments; |                    |   |                         |
|        | abuse of  |                    | N |                         |
|        | illicit   |                    |   |                         |
|        | drugs or  |                    | = |                         |
|        | alcohol   |                    |   |                         |
|        | within    |                    | 8 |                         |
|        | the last  |                    | 5 |                         |
|        | year      |                    |   |                         |
|        |           |                    |   |                         |
|        | *P        |                    |   |                         |
|        | opulation |                    | T |                         |
|        | Profile*  |                    | o |                         |
|        |           |                    | t |                         |
|        | Age,      |                    | a |                         |
|        | mean, y:  |                    | l |                         |
|        | 57.0 y    |                    |   |                         |
|        |           |                    |   |                         |
|        | Mal       |                    |   |                         |
|        | e/Female: |                    |   |                         |
|        | 60.6% /   |                    |   |                         |
|        | 39.4%     |                    | 5 |                         |
|        |           |                    |   |                         |
|        | White:    |                    | ( |                         |
|        | 83.7%     |                    | 6 |                         |
|        |           |                    | . |                         |
|        | Type I /  |                    | 1 |                         |
|        | II DM: 9% |                    | ) |                         |
|        | / 91%,    |                    |   |                         |
|        | ave. 9 y  |                    |   |                         |
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+--------+-----------+--------------------+---+-------------------------+
| Unpub  | *P        | Average Daily Pain |   | Deaths and Other        |
| lished | opulation | score (0--10       |   | Serious Adverse Events: |
| (EMEA  | profile*  | Numerical Rating   |   | NR                      |
| 2004   |           | Scale)             |   |                         |
| )^113^ | Age (y,   |                    |   | Withdrawals (% of       |
|        | range of  |   --------- -----  |   | patients)               |
| Study  | means),   | ------- ---------  |   |                         |
| D      | 4         | --------- -------- |   |   -------               |
| PN-149 | 7.6--59.5 |   Results          |   | ------ ------------ --- |
|        |           | PGB300/600   PGB30 |   | ----- -------- -------- |
| MC DB  | Duration  | 0    PGB150    PBO |   |                         |
| PC PG  | of DM (y, |                    |   |             PGB300/600  |
| RCT    | range of  |             N =    |   |   PGB300   PGB150   PBO |
|        | medians), |  98       N = 96   |   |                         |
| mITT   | 11--12.5  |   N = 96    N = 93 |   |   Withd                 |
| (re    |           |                    |   | rawals   N = 101      N |
| ceived | Type I DM |   EP LSM    3      |   |  = 99   N = 99   N = 97 |
| ≥ 1    | (%,       | .69         4.48   |   |                         |
| dose   | range),   |     4.33      4.66 |   |   T                     |
| and    | 14%--16%  |                    |   | otal         23         |
| not    |           |   Diff             |   |    20       17       18 |
| wit    | Type II   | --0.97       --0.1 |   |                         |
| hdrawn | DM (%,    | 8    --0.33    --- |   |   WD                    |
| b      | range),   |                    |   | AEs         12.9        |
| ecause | 84%--86%  |   95% CL           |   |   11.1     5.0      3.1 |
| of     |           | --1.58,      --0.7 |   |   -------               |
| regu   |           | 9,   --0.94,   --- |   | ------ ------------ --- |
| latory |           |                    |   | ----- -------- -------- |
| or     |           |    --0.36       0. |   |                         |
| ethics |           | 43      0.28       |   | Adverse events (% of    |
| com    |           |                    |   | patients)               |
| mittee |           |   p-value          |   |                         |
| deci   |           | 0.0054       0.558 |   |   ------                |
| sions) |           |      0.558     --- |   | ------ ------------ --- |
|        |           |                    |   | ----- -------- -------- |
| Total  |           |   Δ^†^      2      |   |   A                     |
| N~R~   |           | .91         1.92   |   | dverse      PGB300/600  |
|  = 396 |           |     1.87      1.74 |   |   PGB300   PGB150   PBO |
|        |           |                    |   |   event                 |
| *I     |           |   p-value          |   |                         |
| nterve |           |  NR           NR   |   |                         |
| ntions |           |       NR        NR |   |                         |
| (mg/d, |           |   --------- -----  |   |          N = 101      N |
| dosed  |           | ------- ---------  |   |  = 99   N = 99   N = 97 |
| b.i    |           | --------- -------- |   |                         |
| .d.):* |           |                    |   |   ≥ 1 AE                |
|        |           | Responder rates (% |   |                         |
| Preg   |           | of patients) at    |   |                         |
| abalin |           | week 12            |   |   *Reported in          |
| 3      |           |                    |   |                         |
| 00/600 |           |   ----------       |   |   ≥10% of               |
|        |           | ------------ ----- |   |                         |
| Preg   |           | --- -------- ----- |   |   patients in           |
| abalin |           |   Outcome          |   |                         |
| 300    |           |   PGB300/600   PGB |   |   any group*            |
|        |           | 300   PGB150   PBO |   |                         |
| Preg   |           |   measur           |   |                         |
| abalin |           | e                  |   |   Dizziness             |
| 150    |           |                    |   |                         |
|        |           |                    |   |                         |
| P      |           |   NRS-50           |   |   Somnolence            |
| lacebo |           |    46           33 |   |                         |
|        |           |        34       30 |   |                         |
| For 12 |           |                    |   |   Peripheral            |
| wk     |           |   p-value          |   |                         |
| (1 +   |           |   0.04         0.7 |   |   edema                 |
| 11 wk) |           | 4     0.74     --- |   |                         |
|        |           |                    |   |                         |
| *A     |           |   NNTB-50†         |   |   Headache              |
| llowed |           |   7            NSD |   |                         |
| co-m   |           |       NSD      --- |   |                         |
| edicat |           |                    |   |   *Reported on          |
| ions:* |           |   95% CL†          |   |                         |
| APAP   |           |   4, 50        --- |   |   PGB but not           |
| up to  |           |       ---      --- |   |                         |
| 3--4   |           |   ----------       |   |   PBO*                  |
| g/d    |           | ------------ ----- |   |                         |
| p      |           | --- -------- ----- |   |                         |
| .r.n.; |           |                    |   |   Accidental            |
| others |           |                    |   |                         |
| u      |           |                    |   |   injury                |
| nknown |           |                    |   |                         |
|        |           |                    |   |                         |
| *Q     |           |                    |   |   Euphoria              |
| uality |           |                    |   |                         |
| not    |           |                    |   |   ------                |
| eva    |           |                    |   | ------ ------------ --- |
| luable |           |                    |   | ----- -------- -------- |
| (      |           |                    |   |                         |
| insuff |           |                    |   | Other specific AEs      |
| icient |           |                    |   | reported in \>/= 5% of  |
| i      |           |                    |   | patients in any         |
| nforma |           |                    |   | pregabalin group:       |
| tion)* |           |                    |   |                         |
|        |           |                    |   |                         |
| *Ex    |           |                    |   |                         |
| ternal |           |                    |   |                         |
| va     |           |                    |   |                         |
| lidity |           |                    |   |                         |
| not    |           |                    |   |                         |
| eval   |           |                    |   |                         |
| uable* |           |                    |   |                         |
+--------+-----------+--------------------+---+-------------------------+

Appendix Table 3 Postherpetic neuralgia: placebo-controlled trials

+--------+------------+-------------------------+---------------------+
| **Cita | **Major    | **Efficacy Results**    | **Safety Results**  |
| tion** | E          |                         |                     |
|        | ligibility |                         |                     |
| **D    | C          |                         |                     |
| esign, | riteria,** |                         |                     |
| Qua    |            |                         |                     |
| lity** | **         |                         |                     |
|        | Population |                         |                     |
|        | Profile**  |                         |                     |
+========+============+=========================+=====================+
| D      | Inclusion  | Average Daily Pain      | Deaths: NR          |
| workin | criteria:  | score (0--10 Numerical  |                     |
| (2003  | ≥ 18 y     | Rating Scale)           | Nonfatal Serious    |
| )^107^ | old; PHN,  |                         | Adverse Events (n,  |
|        | defined as |   --------              | %)                  |
| Study  | pain       | - ------------ -------- |                     |
| 100    | present    |   Ave                   |   ------- --        |
| 8-127, | for  \> 3  | rage   PGB300/600   PBO | ---------- -------- |
| U.S.   | mo after   |                         |   SAE               |
|        | healing of |   daily                 |    PGB300/600   PBO |
| MC     | HZ skin    |     N = 88       N = 84 |                     |
| (29)   | rash; pain |                         |                     |
| DB PC  | at least   | pain                    | N = 89       N = 84 |
| PG RCT | 40 mm on   |                         |                     |
| with   | 100-mm VAS |   EP L                  |   Tota              |
| op     | of SF-MPQ; | SM    3.60         5.29 | l   NR           NR |
| tional | completed  |                         |                     |
| open   | at least 4 |   Dif                   |   WDSA              |
| -label | daily pain | f      --1.69       --- | E   NR           NR |
| ext    | diaries;   |                         |                     |
| ension | mean daily |   95%                   |   TRSA              |
|        | pain       |  CL    --2.33,      --- | E   0 (0.0)      NR |
| ITT,   | rating of  |                         |   ------- --        |
| LOCF   | 4 on       |           --1.05        | ---------- -------- |
|        | 11-point   |                         |                     |
| Total  | NRS;       |   p-v                   | Withdrawals (n, %)  |
| N~R~   | normal     | alue   0.0001       --- |                     |
| = 173, | chest      |                         | <table>             |
| N~A~   | X-ray      |   Δ^†^                  | <colgroup>          |
|  = 172 | within     |      --2.7        --1.1 | <col                |
|        | previous   |   --------              | st                  |
| *In    | 2 y        | - ------------ -------- | yle="width: 43%" /> |
| terven |            |                         | <col                |
| tions* | Exclusion  | Onset of first          | st                  |
|        | criteria:  | statistically           | yle="width: 32%" /> |
| Preg   | other      | significant difference  | <col                |
| abalin | severe     | in scores: 2 wk for     | st                  |
| 300 or | pain that  | pain, 1 wk for sleep    | yle="width: 24%" /> |
| 60     | might      | interference.           | </colgroup>         |
| 0 mg/d | confound   |                         | <tbody>             |
| (in 3  | as         | Responder rates (% of   | <tr class="odd">    |
| d      | sessments; | patients) at 8 wk       | <                   |
| ivided | previous   |                         | td>Withdrawals</td> |
| doses) | neurolytic |   ---------             | <td>PGB300/600</td> |
| dep    | or         | -- ------------ ------- | <td>PBO</td>        |
| ending | neu        |   Outco                 | </tr>               |
| on     | rosurgical | me     PGB300/600   PBO | <tr class="even">   |
| CrCl   | therapy    |                         | <td>Total</td>      |
| vs.    | for PHN;   |   NRS-50                | <td>31              |
| P      | failed     |      50.0%        20.2% | (34.8)</td>         |
| lacebo | gabapentin |                         | <td>10              |
| for 8  | ≥          |   p-                    | (11.9)</td>         |
| wk     | 1200 mg/d; | value     0.001         | </tr>               |
| inc    | baseline   |                         | <tr class="odd">    |
| luding | CrCl ≤ 30  |   NN                    | <td>WDLE</td>       |
| 1 wk   | ml/min;    | T-50†     3             | <td>0 (0.0)</td>    |
| tit    | WBC        |                         | <td>6 (7.1)</td>    |
| ration |  \< 2      |   95                    | </tr>               |
|        | 500/mm^3^; | % CL†     (2, 6)        | <tr class="even">   |
| *A     | PMN        |                         | <td>WDAEs</td>      |
| llowed |  \< 1      |   NRS-                  | <td>28              |
| co-    | 500/mm^3^; | 30      \~67%        NR | (31.5)</td>         |
| medica | platelets  |                         | <td>4 (4.8)</td>    |
| tions* |  \< 100 x  |   p-                    | </tr>               |
|        | 1          | value     NC            | <tr class="odd">    |
| If     | 0^3^/mm^3^ |                         | <td><blockquote>    |
| doses  |            |   NN                    | <p>p-va             |
| stable | *          | T-30†     NC            | lue<sup>†</sup></p> |
| for    | Population |                         | </blockquote></td>  |
| 30 d   | profile:*  |   95                    | <td                 |
| prior  |            | % CL†     NC            | colspan="2          |
| to     | Age, mean, |                         | "> &lt; 0.0001</td> |
| ba     | y: 71.5    |   PGIC-                 | </tr>               |
| seline |            | Min.   84%          26% | <tr class="even">   |
| and    | Male 46.8% |                         | <td>NNTH (95%       |
| during |            |   p-                    | CL)</td>            |
| study: | White      | value     0.001         | <td colspan="2">4   |
| na     | 94.8%      |                         | (3, 6)</td>         |
| rcotic |            |   CG                    | </tr>               |
| and    | Duration   | IC-Min.   NR            | <tr class="odd">    |
| nonna  | of PHN,    |                         | <td                 |
| rcotic | mean, mo:  |   p-                    | colspan="3">(11%    |
| analg  | 33.8       | value      \< 0.05      | of PGB patients     |
| esics; |            |   ---------             | withdrew because    |
| a      | Low CrCl   | -- ------------ ------- | of                  |
| cetami | stratum    |                         | somnolence.)</td>   |
| nophen | ( \> 30,   | At study end point, PGB | </tr>               |
| ≤      | ≤ 60       | was better than PBO on  | </tbody>            |
| 4 g/d; | ml/min),   | SF-MPQ sensory,         | </table>            |
| N      | 31.8%      | affective, and total    |                     |
| SAIDS, |            | pain scores (p \<       | Adverse events (n,  |
| ASA,   | Normal     | 0.005); SF-MPQ VAS pain | %)                  |
| ant    | CrCl       | and PPI pain scores;    |                     |
| idepre | stratum    | sleep interference      |   ------------ --   |
| ssants | ( \> 6     | scores beginning at     | ---------- -------- |
| (incl  | 0 ml/min), | wk 1 (p = 0.0001);      |   Adverse           |
| uding. | 68.2%      | Medical Outcomes Study  |    PGB300/600   PBO |
| S      |            | (MOS) Sleep Scale sleep |   event             |
| SRIs). |            | problem index; and      |                     |
|        |            | SF-36 bodily pain and   |                     |
| *Fair  |            | general health          |                     |
| qu     |            | perception scales.      | N = 89       N = 84 |
| ality* |            | Greater improvement was |                     |
|        |            | seen with PGB than PBO  |   ≥ 1 AE       7    |
| *May   |            | on the POMS             | 7 (87)      53 (63) |
| apply  |            | depression-dejection    |                     |
| to     |            | scale but the           |   *Report           |
| shor   |            | difference did not      | ed in               |
| t-term |            | reach the level of      |   ≥ 10% i           |
| trea   |            | statistical             | n                   |
| tment; |            | significance (mean      |   either            |
| may    |            | score, 6.70 vs. 8.47;   |                     |
| not    |            | p = 0.051).             |   group*            |
| apply  |            |                         |                     |
| to     |            |                         |                     |
| n      |            |                         |   Dizziness         |
| onresp |            |                         |     25 (28.1)    10 |
| onders |            |                         |                     |
| to     |            |                         |              (11.9) |
| gaba   |            |                         |                     |
| pentin |            |                         |   Somnolence   2    |
| ≥ 1200 |            |                         | 2 (24.7)    6 (7.1) |
| mg/d*  |            |                         |                     |
|        |            |                         |   Peripheral   1    |
|        |            |                         | 7 (19.1)    2 (2.4) |
|        |            |                         |   edema             |
|        |            |                         |                     |
|        |            |                         |                     |
|        |            |                         |   Amblyopia    1    |
|        |            |                         | 0 (11.2)    1 (1.2) |
|        |            |                         |                     |
|        |            |                         |   Dry mouth    1    |
|        |            |                         | 0 (11.2)    2 (2.4) |
|        |            |                         |                     |
|        |            |                         |   *Report           |
|        |            |                         | ed on               |
|        |            |                         |   PGB but           |
|        |            |                         |  not                |
|        |            |                         |   PBO*              |
|        |            |                         |                     |
|        |            |                         |                     |
|        |            |                         |   Ataxia       6    |
|        |            |                         |  (6.7)      0 (0.0) |
|        |            |                         |                     |
|        |            |                         |   Confusion    6    |
|        |            |                         |  (6.7)      0 (0.0) |
|        |            |                         |                     |
|        |            |                         |   Speech       5    |
|        |            |                         |  (5.6)      0 (0.0) |
|        |            |                         |   disorde           |
|        |            |                         | r                   |
|        |            |                         |   ------------ --   |
|        |            |                         | ---------- -------- |
|        |            |                         |                     |
|        |            |                         | Patients reporting  |
|        |            |                         | maximum AE          |
|        |            |                         | intensity of mild   |
|        |            |                         | to moderate: 81% on |
|        |            |                         | PGB vs. 92% on PBO  |
+--------+------------+-------------------------+---------------------+
| Saba   | *Inclusion | Average Daily Pain      | Deaths: 1 (MI on    |
| towski | criteria:* | score (0--10 Numerical  | PBO)                |
| (2004  | pain       | Rating Scale)           |                     |
| )^108^ | present    |                         | Other Serious       |
|        | for more   |   --------- -----       | Adverse Events: 1   |
| Study  | than 6 mo  | ---- --------- -------- | on PGB300; 4 on     |
| 100    | after      |   Results               | PGB150, and 3 on    |
| 8-045, | healing of | PGB300    PGB150    PBO | PBO, including      |
| E      | HZ rash;   |                         | **ventricular       |
| urope, | age ≥ 18   |             N =         | extrasystoles**     |
| Aus    | y;         |  76    N = 81    N = 81 | considered possibly |
| tralia | completed  |                         | or probably related |
|        | at least 4 |   EP LSM    4           | to study medication |
| MC DB  | daily pain | .76      5.14      6.33 | (2 on PGB150, 1 on  |
| PC PG  | diaries    |                         | PBO) and            |
| RCT    | during 7-d |   Diff                  | **confusion** (1 on |
| with   | baseline   | --1.57    --1.20    --- | PGB150).            |
| OL     | phase;     |                         |                     |
| ext    | average    |   95% CL                | Withdrawals (n, %   |
| ension | daily pain | --2.20,   --1.81,   --- | of patients)        |
|        | ≥ 4; score |                         |                     |
| ITT,   | ≥ 40 mm on |    --0.95    --0.58     |   --                |
| LOCF   | 100-mm VAS |                         | ----------- ------- |
|        | of SF-MPQ  |   p-value               | - -------- -------- |
| N~R~   |            | 0.001     0.002     --- |                 PG  |
|  = 238 | *Exclusion |                         | B300   PGB150   PBO |
|        | criteria:* |   Δ^†^      --          |                     |
| I      | active     | 2.2     --1.8     --0.3 |                     |
| nterve | m          |   --------- -----       | Withdrawals   N = 7 |
| ntions | alignancy; | ---- --------- -------- | 6   N = 81   N = 81 |
|        | clinically |                         |                     |
| Preg   | s          | Onset of first          |   Total         1   |
| abalin | ignificant | statistically           | 6       10       20 |
| 150    | re         | significant treatment   |                     |
| mg/d   | spiratory, | difference: 1 wk for    |               (21.1 |
| vs.    | he         | both pain and sleep     | )   (12.3)   (24.7) |
| Preg   | matologic, | interference (PGB300,   |                     |
| abalin | hepatic,   | PGB150)                 |   W                 |
| 300    | or         |                         | DAEs         12     |
| mg/d   | card       | Responder rates (% of   |    9 (11.1) 8 (9.9) |
| vs.    | iovascular | patients) at week 8     |                     |
| P      | disease;   |                         |  (15.8)             |
| lacebo | failed PHN |   ----------- -         |                     |
| (in 3  | treatment  | ------- -------- ------ |   W                 |
| d      | with       |   Outcome               | DLE          1 (1.3 |
| ivided | gabapentin |   PGB300   PGB150   PBO | )  0 (0.0)  7 (8.6) |
| daily  | ≥          |   measure               |   --                |
| doses) | 1200 mg/d; |                         | ----------- ------- |
| for    | neurolytic |                         | - -------- -------- |
| 8 wk,  | or         |   NRS-50                |                     |
| inc    | neu        |   27.6     25.9     9.9 | Adverse events (%   |
| luding | rosurgical |                         | of patients)        |
| 1-wk   | therapy    |   p-value               |                     |
| tit    | for PHN;   |   0.006    0.006    --- |   ------------ ---- |
| ration | skin       |                         | ---- -------- ----- |
|        | condition  |   NNTB-50†              |                PG   |
| A      | or severe  |   6        6        --- | B300   PGB150   PBO |
| llowed | non-PHN    |                         |                     |
| co     | pain that  |   95% CL†               |   ≥ 1 AE       8    |
| -medic | might      |   3, 17    4, 22    --- | 3       NR       NR |
| ations | compromise |                         |                     |
|        | as         |                         |   *Reported in      |
| Stable | sessments; |                         |                     |
| re     | CrCl       |                         |   ≥ 10% of          |
| gimens | ≤          |   NRS-30                |                     |
| of     |  30 ml/min |    50       37       19 |   patients in       |
| APAP   |            |                         |                     |
| up to  | Population |   p-value               |   either PGB        |
| 3 g/d; | profile    |   NR       NR       --- |                     |
| N      | (ranges    |                         |   group*            |
| SAIDs; | across     |   NNTB-30               |                     |
| opioid | treatment  |   3        5        --- |                     |
| or     | groups):   |                         |   Dizziness    2    |
| non    |            |   95% CL                | 8       12       15 |
| opioid | Age, mean, |   2, 6     3, 20    --- |                     |
| analg  | y:         |                         |   Somnolence        |
| esics; | 71.3--73.2 |                         | 24       15       7 |
| ant    |            |                         |                     |
| idepre | Male       |                         |   Peripheral        |
| ssants | 41%--48%   |   PGIC-much             | 13       3        0 |
|        |            |  38.2     30.9     13.5 |   edema             |
| Proh   | White,     |                         |                     |
| ibited | 98%--100%  |   p-value               |                     |
| medic  |            |   0.002    0.064    --- |   Headache          |
| ations | CrCl,      |                         | 11       11       4 |
|        | mean,      |   CGIC-much             |                     |
| New    | ml/min:    |    NR       NR       NR |   Dry mouth         |
| analg  | 48.9--62.9 |                         | 7        11       4 |
| esics; |            |   p-value               |                     |
| ben    | Duration   |    NR       NR       NR |   *Reported on      |
| zodiaz | of PHN,    |   ----------- -         |                     |
| epines | mean, mo:  | ------- -------- ------ |   PGB but not       |
| and    | 40.7--44.8 |                         |                     |
| AEDs   |            | Both PGB doses were     |   PBO*              |
| re     | Co-m       | significantly better    |                     |
| quired | edications | than PBO (p ≤ 0.006) in |                     |
| 14-d   | (% of      | MPQ VAS scores; sleep   |   Peripheral        |
| w      | patients): | interference scores (as | 13       3        0 |
| ashout |            | early as wk 1); SF-36   |   edema             |
|        | --A        | mental health domain.   |                     |
| Fair   | nalgesics: |                         |                     |
| q      | 31%--46%   | On the SF-36, PGB was   |   Infection         |
| uality |            | better than PBO in      | 7        3        0 |
|        | -          | mental health (PGB300,  |   ------------ ---- |
| May    | -Antiinfla | PGB150); bodily pain    | ---- -------- ----- |
| apply  | mmatories: | (PGB300), and vitality  |                     |
| to     | 12%--21%   | (PGB300).               | PGB300:             |
| shor   |            |                         |                     |
| t-term | --Antide   | PGB150 was numerically  | Rated AEs mild (%   |
| trea   | pressants: | better (p = 0.056) and  | of patients): 37%   |
| tment; | 17%--22%   | PGB300 was              |                     |
| may    |            | statistically           | Rated AEs moderate  |
| not    |            | significantly better    | (% of patients):    |
| apply  |            | (p = 0.024) than PBO in | 34%                 |
| to     |            | the Zung Self-Rating    |                     |
| n      |            | Depression Scale index. | More patients in    |
| onresp |            |                         | the PGB300 group    |
| onders |            |                         | experienced weight  |
| to     |            |                         | gain  \>  7% from   |
| gaba   |            |                         | baseline to         |
| pentin |            |                         | termination (14%    |
| ≥ 1200 |            |                         | for PGB300 vs. 4%   |
| mg/d   |            |                         | for PGB150 and 4%   |
| and    |            |                         | for PBO).           |
| pa     |            |                         |                     |
| tients |            |                         |                     |
| with   |            |                         |                     |
| renal  |            |                         |                     |
| impa   |            |                         |                     |
| irment |            |                         |                     |
| (CrCl  |            |                         |                     |
| ≤ 30 m |            |                         |                     |
| l/min) |            |                         |                     |
| or     |            |                         |                     |
| other  |            |                         |                     |
| signi  |            |                         |                     |
| ficant |            |                         |                     |
| morbi  |            |                         |                     |
| dities |            |                         |                     |
+--------+------------+-------------------------+---------------------+
|        |            |                         |                     |
+--------+------------+-------------------------+---------------------+
| Van    | Inclusion  | Average Daily Pain      | Deaths: None        |
| Se     | criteria:  | score (0--10 Numerical  |                     |
| venter | *≥ 18      | Rating Scale)           | Serious adverse     |
| (20    | years old; |                         | events: 10 on PGB   |
| 06)^11 | pain for   |   ---                   | vs. 2 on PBO        |
| 5,133^ | more than  | ------ ------------ --- |                     |
|        | 3 mo after | ----- -------- -------- | Serious adverse     |
| Study  | healing of |   Results   PGB300/600  | events considered   |
| 10     | HZ skin    |   PGB300   PGB150   PBO | related to          |
| 08-196 | rash;      |                         | treatments: Total 2 |
|        | SF-MPQ VAS |                         | on PGB---1 on       |
| MC DB  | score      |          N = 90       N | PGB300 / 600        |
| PC PG  | ≥ 40 mm;   |  = 98   N = 87   N = 93 | (dizziness, face    |
| Phase  | average    |                         | edema, myasthenia,  |
| III    | daily pain |   EP LSM                | peripheral edema,   |
| RCT    | score ≥ 4  |                         | somnolence) and 1   |
| with   | over the   |                         | on PGB300           |
| OL     | 7 d prior  |   Diff      --1.47      | (anaphylactoid      |
| fol    | to         |   --1.07   --0.88   --- | reaction).          |
| low-on | rand       |                         |                     |
| (study | omization; |   95% CL                | A total of          |
| 100    | stable or  |                         | 126 / 368 (34%)     |
| 8-198) | normal     |                         | were withdrawn      |
|        | chest      |   p-value   0.0003      | during the          |
| ITT,   | X-ray      |   0.0016   0.0077   --- | double-blind phase, |
| LOCF   | within     |                         | primarily because   |
|        | past 1 yr* |   Δ^†^                  | of lack of efficacy |
| N~R~   |            |                         | (57 patients, 16%)  |
| = 370; | Exclusion  |   ---                   | and adverse events  |
| N~ITT~ | criteria:  | ------ ------------ --- | (46 patients, 13%). |
|  = 368 | malignancy | ----- -------- -------- |                     |
| (stra  | within     |                         | Most frequent AEs   |
| tified | past 2 y   | Onset of first          | leading to          |
| by     | except     | statistically           | withdrawal:         |
| center | basal cell | significant treatment   | dizziness,          |
| and    | carcinoma; | difference: wk 1        | somnolence, ataxia. |
| CrCl)  | neurolytic |                         |                     |
|        | or         | Responder rates (% of   | Withdrawals (n)     |
| I      | neu        | patients) at week 13    |                     |
| nterve | rosurgical |                         |   ------------- -   |
| ntions | therapy    |   ---                   | ----------- ------- |
|        | for PHN;   | --------- ------------  | - -------- -------- |
| Preg   | CrCl ≤ 30  | -------- -------- ----- |                     |
| abalin | ml / min;  |   O                     |     PGB300/600   PG |
| 150,   | WBC        | utcome      PGB300/600  | B300   PGB150   PBO |
| 300,   |  \< 250    |   PGB300   PGB150   PBO |                     |
| or 600 | 0 / mm^3^; |   measure               |   Withdrawals       |
| mg/d   | PMN \< 150 |                         |  N = NR       N = N |
| (based | 0 / mm^3^; |                         | R   N = NR   N = NR |
| on     | platel     |   N                     |                     |
| CrCl;  | ets \< 100 | RS-50       37.5        |   Total             |
| d      | x          |   26.5     26.4     7.5 |      NR           N |
| ivided | 10^3       |                         | R       NR       NR |
| twice  | ^ / mm^3^; |   p                     |                     |
| daily  | clinically | -value      0.001       |   WDSAEs            |
| doses) | s          |   0.001    0.001    --- |       2             |
| vs.    | ignificant |                         | 1        0        0 |
| P      | or         |   N                     |                     |
| lacebo | unstable   | NTB-50^†^   3           |   WDTRAEs           |
| for 13 | hepatic,   |   5        5        --- |       18            |
| wk,    | re         |                         | 15       7        4 |
| inc    | spiratory, |   9                     |                     |
| luding | or         | 5% CL^†^    2, 5        |   WDLE              |
| 1-wk   | h          |   3, 11    3, 12    --- |      NR           N |
| tit    | ematologic |                         | R       NR       NR |
| ration | illnesses; |                         |   ------------- -   |
|        | unstable   | PGIC-much    36         | ----------- ------- |
| CrCl   | card       |    27       23       16 | - -------- -------- |
| 30--60 | iovascular |                         |                     |
| m      | disease;   |   p                     | Despite dosage      |
| l/min: | abnormal   | -value      0.003       | differences based   |
| max.   | ECG;       |   NSD      0.020    --- | on renal function,  |
| rand   | immunoco   |                         | more patients with  |
| omized | mpromised; |                         | CrCl 30--60 ml/min  |
| dose   | history of | CGIC-much    38         | withdrew due to AEs |
| 300    | chronic    |    25       25       17 | than patients with  |
| mg/d   | hepatitis  |                         | CrCl \> 60 ml/min   |
|        | B or C;    |   p                     | (data not           |
| CrCl   | hepatitis  | -value      0.003       | reported).          |
|  \> 60 | within     |   NSD      NSD      --- |                     |
| m      | past 3 mo; |   ---                   | Of the 368 patients |
| l/min: | HIV        | --------- ------------  | who received study  |
| max.   | infection; | -------- -------- ----- | medication, 70%     |
| rand   | other      |                         | experience ≥ 1 AE.  |
| omized | severe     | All PGB dosage levels   |                     |
| dose   | pain that  | were significantly      | Most frequent AEs:  |
| 600    | may        | better than PBO in      | dizziness,          |
| mg/d   | interfere  | sleep interference, in  | somnolence, and     |
|        | with       | MOS sleep disturbance   | peripheral edema.   |
| *A     | as         | and overall sleep       |                     |
| llowed | sessments; | problems index; and in  | Most AEs were mild  |
| co-m   | skin       | SF-MPQ except for       | or moderate in      |
| edicat | condition  | PGB150 for VAS and      | intensity.          |
| ions:* | within     | PGB150 and PGB300 for   |                     |
| NR     | affected   | PPI.                    |                     |
|        | dermatome  |                         |                     |
|        | that could | Only PGB300/600 was     |                     |
|        | alter      | significantly better    |                     |
|        | sensation; | than PBO on CGIC and    |                     |
|        | prohibited | only PGB300 was         |                     |
|        | m          | significantly better    |                     |
|        | edications | than PBO on PGIC.       |                     |
|        | (l         |                         |                     |
|        | ong-acting | Only PGB300/600 was     |                     |
|        | benzod     | significantly better    |                     |
|        | iazepines, | than PBO on any SF-36   |                     |
|        | AEDs)      | domain (bodily pain);   |                     |
|        | without    | however, all PGB groups |                     |
|        | a          | were significantly      |                     |
|        | ppropriate | better than PBO on the  |                     |
|        | washout;   | EQ-5D Utility and VAS   |                     |
|        | history of | AUC.                    |                     |
|        | alcohol or |                         |                     |
|        | illicit    | Allodynia and           |                     |
|        | drug abuse | hyperalgesia (% of      |                     |
|        | within     | patients): NSD          |                     |
|        | past 2 y;  |                         |                     |
|        | clinically |                         |                     |
|        | s          |                         |                     |
|        | ignificant |                         |                     |
|        | or         |                         |                     |
|        | unstable   |                         |                     |
|        | medical or |                         |                     |
|        | p          |                         |                     |
|        | sychologic |                         |                     |
|        | condition  |                         |                     |
|        |            |                         |                     |
|        | Population |                         |                     |
|        | profile:   |                         |                     |
|        | ≥ 65 y     |                         |                     |
|        | old, 76%;  |                         |                     |
|        | White 99%; |                         |                     |
|        | Males 46%; |                         |                     |
|        | Normal     |                         |                     |
|        | CrCl       |                         |                     |
|        | ( \> 60    |                         |                     |
|        | ml / min)  |                         |                     |
|        | 69%; low   |                         |                     |
|        | CrCl       |                         |                     |
|        | (30--60    |                         |                     |
|        | ml / min)  |                         |                     |
|        | 32%        |                         |                     |
+--------+------------+-------------------------+---------------------+
|        |            |                         |                     |
+--------+------------+-------------------------+---------------------+

Appendix Table 4 Postherpetic neuralgia: open-label studies

+-----------------+-----------------+-----------------+-----------------+
| **Citation**    | **Major         | **Efficacy      | **Safety        |
|                 | Eligibility     | Results**       | Results**       |
| **Design,       | Criteria,**     |                 |                 |
| Quality**       |                 |                 |                 |
|                 | **Population    |                 |                 |
|                 | Profile**       |                 |                 |
+=================+=================+=================+=================+
| No studies      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

Appendix Table 5 Mixed neuropathic pain (PDN and PHN):
placebo-controlled trials

+------------+---------------+--------------------+--------------------+
| **         | **Major       | **Efficacy         | **Safety Results** |
| Citation** | Eligibility   | Results**          |                    |
|            | Criteria,**   |                    |                    |
| **Design   |               |                    |                    |
| ,Quality** | **Population  |                    |                    |
|            | Profile**     |                    |                    |
+============+===============+====================+====================+
| Freynhagen | *Inclusion    | Average Daily Pain | Deaths and Serious |
| (          | criteria:*    | score (0--10       | Adverse Events (%  |
| 2005)^111^ | age ≥ 18 y;   | Numerical Rating   | of patients)       |
|            | SF-MPQ VAS    | Scale)             |                    |
| Study      | score         |                    |   --               |
| 1008-155,  | ≥ 40 mm;      |   ------           | ----- -----------  |
| Europe     | average daily | --- ----------- -- | --------- -------- |
|            | pain score    | --------- -------- |           PGB~Fle  |
| MC (60) DB | ≥ 4 over the  |   A                | x~   PGB600    PBO |
| PC PG      | 7 d prior to  | verage   PGB~Flex~ |                    |
| Phase III  | r             |    PGB600      PBO |                    |
| RCT        | andomization; |   daily            |         N = 141    |
|            | for PAN       |                    |   N = 132   N = 65 |
| mITT       | patients, a   |   pain             |                    |
|            | diagnosis of  |                    |   Death   0        |
| Sp         | type I or II  |                    |        2         0 |
| ecifically | DM, HgA1C     |                    |                    |
| measured   | ≤ 11%;        |       N = 141      |   TR      0        |
| weight     | diagnosis of  | N = 132     N = 65 |        0         0 |
| changes    | painful,      |                    |   Death            |
| and        | distal,       |   E                |                    |
| peripheral | symmetrical,  | P LSM    3.8       |                    |
| and        | sensorimotor  |    3.6         5.0 |   SAEs    0        |
| non        | p             |                    |        2         0 |
| peripheral | olyneuropathy |   D                |   --               |
| edema      | due to DM for | iff      1.2       | ----- -----------  |
|            | at least      |    1.4         --- | --------- -------- |
| N~R~ = 338 | 6 mo; for PHN |   (calc.)          |                    |
|            | patients,     |                    | Withdrawals (% of  |
| Pregabalin | pain present  |                    | patients)          |
| flexible   | for more than |   9                |                    |
| dose vs.   | 3 mo after    | 5% CL    NR        |   -----            |
| fixed dose | healing of HZ |    NR          --- | -------- --------- |
| vs.        | rash.         |                    | -- -------- ------ |
| Placebo    |               |   p                |                    |
| for 12 wk  | *Exclusion    | -value   ≤ 0.01    |                    |
| (dd        | criteria:*    |    ≤ 0.01      --- |                    |
| b.i.d.)    | clinically    |                    |                    |
|            | significant   |   Δ^†^             |   Wi               |
| > Flexible | or unstable   |       --2.89       | thdrawals   PGB~Fl |
| > dose     | medical       | --3.09      --1.62 | ex~   PGB600   PBO |
| > (PGB     | condition;    |                    |                    |
| ~Flex~) =  | malignancy    |   p                |   Tot              |
| escalating | within past   | -value   0.002     | al         34.8    |
| > doses of | 2 y except    |     \< 0.001   --- |      37.9     46.2 |
| > 150,     | for basal     |   ------           |                    |
| > 300,     | cell          | --- ----------- -- |   WD               |
| > 450, and | carcinoma;    | --------- -------- | AEs         17.0   |
| >          | anticipated   |                    |       25.0     7.7 |
| 600 mg / d | need for      | Onset of first     |                    |
| > titrated | surgery       | statistically      |   W                |
| > at       | during study; | significant        | DSAEs        6.4   |
| > weekly   | previous      | difference from    |        3.0      NR |
| >          | pregabalin;   | placebo: wk 2      |                    |
|  intervals | abnormal ECG; | (PGB~Flex~) vs.    |   W                |
| >          | CrCl \<       | wk 1 (PGB600)      | DLC          NR    |
| > Fixed    |  60 ml / min; |                    |        NR       NR |
| > dose     | WBC \<        | Responder rates (% |   -----            |
| > (P       | 2500 / mm^3^; | of patients) at 5  | -------- --------- |
| GB600) = 6 | PMN \<        | wk                 | -- -------- ------ |
| 00 mg / d, | 1500 / mm^3^; |                    |                    |
| > starting | pla           |   ------           | Most frequent AEs  |
| > with     | telets \< 100 | ----- -----------  | leading to         |
| >          | x             | ----------- ------ | withdrawal:        |
| 300 mg / d | 1             |   Out              | dizziness, nausea, |
| > for 1 wk | 0^3^ / mm^3^; | come     PGB~Flex~ | vertigo,           |
| > then     | abused        |    PGB600      PBO | somnolence.        |
| >          | illicit drugs |                    |                    |
| 600 mg / d | or alcohol    |   NRS-             | Adverse events (%  |
| > for      | within past   | 50      48.2       | of patients)       |
| > 11 wk    | 2 y; use of   |   52.3        24.2 |                    |
| >          | prohibited    |                    |   ---------------  |
| > *Fair    | medication    |   p-v              | ----- -----------  |
| > quality* | without       | alue      \< 0.001 | --------- -------- |
| >          | adequate      |     \< 0.001   --- |                    |
| >          | washout;      |                    |            PGB~Fle |
|  *External | history of    |   NRS-             | x~   PGB600    PBO |
| >          | chronic       | 30      59.0       |                    |
|  validity: | hepatitis B   |   66.4        37.1 |                    |
| > Possibly | or C;         |                    |         N = 141    |
| >          | hepatitis B   |   p-v              |   N = 132   N = 65 |
| applicable | or C within   | alue     0.003     |                    |
| > to       | past 3 mo;    |     \< 0.001   --- |   ≥ 1 AE           |
| > veteran  | HIV           |                    |           68.8     |
| >          | infection;    |   NNT              |     74.2      44.6 |
| population | neurologic    | -50†     4.2       |                    |
| > except   | disorders     |    3.6         --- |   *Associ          |
| >          | other than    |                    | ated AEs^†^ (      |
| experience | PDN or other  |   95%              |                    |
| > in       | severe pain   |  CL†     2.7, 9.5  |   ≥ 10% o          |
| >          | that may      |    2.4, 6.9    --- | f patients in      |
|  non-white | interfere     |                    |                    |
| > p        | with          |   NNT              |   any gro          |
| opulations | assessments;  | -30†     4.6       | up)*               |
| > is very  | history of    |    3.4         --- |                    |
| > limited. | pernicious    |                    |                    |
| > Flexible | anemia;       |   95%              |   Dizziness        |
| > dosing   | untreated     |  CL†     2.7, 13.6 |            19.1    |
| > schedule | hy            |    2.3, 6.8    --- |      28.8      4.6 |
| > more     | pothyroidism; |                    |                    |
| > closely  | skin          |   PGIC             |   Peripheral       |
| > reflects | conditions in | -much   52.0       |  edema     15.6    |
| > clinical | the area of   |   53.6        30.5 |      7.6       3.1 |
| > practice | neuropathy    |                    |                    |
| > than     | that may      |   p-v              |   Weight gai       |
| > fixed    | alter         | alue      \< 0.01  | n          12.1    |
| > dosing   | sensation;    |     \< 0.01    --- |      13.6      3.1 |
| >          | amputations   |                    |                    |
|  regimen.* | other than    |   CG               |   Somnolence       |
|            | toes; past    | IC-min    ND       |            10.6    |
|            | neurolytic or |     ND          ND |      12.9      0.0 |
|            | neurosurgical |   ------           |                    |
|            | therapy for   | ----- -----------  |   Nausea           |
|            | PHN           | ----------- ------ |            5.0     |
|            |               |                    |      10.6      1.0 |
|            | *Population   | **All PGB**        |                    |
|            | profile:*     |                    |   *Report          |
|            | Age, mean, y: | **NNT-50: 3.8 (95% | ed on PGB but      |
|            | 62.2;         | CI: 2.6--7.3;      |                    |
|            | age \< 65 y:  | p \< 0.001)**      |   not PBO          |
|            | 52.4%; Male   |                    | *                  |
|            | 54.1; White   | **NNT-30: 3.9 (95% |                    |
|            | 97.6%; PDN    | CI: 2.6--8.3;      |                    |
|            | 73.7%; PHN    | p \< 0.001)**      |   Somnolence       |
|            | 26.3%; CrCl,  |                    |            10.6    |
|            | mean:         |                    |      12.9      0.0 |
|            | 88.1 ml / min |                    |                    |
|            |               |                    |   Asthenia         |
|            |               |                    |            6.4     |
|            |               |                    |      9.1       0.0 |
|            |               |                    |                    |
|            |               |                    |   Facial/Per       |
|            |               |                    | iorbital   2.2     |
|            |               |                    |      2.3       0.0 |
|            |               |                    |   edema            |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |   Generalize       |
|            |               |                    | d or abd.  0.7     |
|            |               |                    |      0.8       0.0 |
|            |               |                    |   edema            |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |   ---------------  |
|            |               |                    | ----- -----------  |
|            |               |                    | --------- -------- |
|            |               |                    |                    |
|            |               |                    | *^†^ Associated    |
|            |               |                    | AEs---not defined* |
|            |               |                    |                    |
|            |               |                    | Specific Weight    |
|            |               |                    | Change Measures    |
|            |               |                    | (Per protocol)     |
|            |               |                    |                    |
|            |               |                    |   --               |
|            |               |                    | --------- -------- |
|            |               |                    | --- -------- ----- |
|            |               |                    |                    |
|            |               |                    | Weight      PGB~Fl |
|            |               |                    | ex~   PGB600   PBO |
|            |               |                    |   Change           |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |  ≥7%         13.9  |
|            |               |                    |        7.0      NR |
|            |               |                    |   Increase (%      |
|            |               |                    |                    |
|            |               |                    |   of               |
|            |               |                    |                    |
|            |               |                    |   patients)        |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |  ≥7%         0.7   |
|            |               |                    |        0.8      NR |
|            |               |                    |   Decrease (%      |
|            |               |                    |                    |
|            |               |                    |   of               |
|            |               |                    |                    |
|            |               |                    |   patients)        |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |                    | Mean Change 1.9    |
|            |               |                    |       1.6      0.2 |
|            |               |                    |   (kg)             |
|            |               |                    |                    |
|            |               |                    |   --               |
|            |               |                    | --------- -------- |
|            |               |                    | --- -------- ----- |
+------------+---------------+--------------------+--------------------+
| Freynhagen |               | Secondary measures | **Numb             |
| (          |               | (p-values vs. PBO) | er-needed-to-treat |
| 2005)^111^ |               |                    | for harm for All   |
|            |               |   -                | PGB, most common   |
| Study      |               | ------------- ---- | AEs (≥** 10% of    |
| 1008-155   |               | ------- ---------- | patients)          |
|            |               |   Outcome          |                    |
| (cont'd)   |               | PGB~Flex~   PGB600 |   -                |
|            |               |   measure          | ----------- ------ |
|            |               |                    |                    |
|            |               |                    |               NNTH |
|            |               |   Sleep            |                    |
|            |               | ≤ 0.01      ≤ 0.01 |   Dizziness    5.2 |
|            |               |   Interfere        |                    |
|            |               | nce                |                    |
|            |               |                    |  Peripheral   11.6 |
|            |               |   SF-MPQ           |   edema            |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |   Sensory          |  Weight gain  10.3 |
|            |               |    NSD         NSD |                    |
|            |               |                    |   Somnolence   8.5 |
|            |               |   Affective        |                    |
|            |               |    NSD         NSD |                    |
|            |               |                    |  Nausea       16.2 |
|            |               |   Total            |   -                |
|            |               |    NSD         NSD | ----------- ------ |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |  VAS            \< |                    |
|            |               |  0.001    \< 0.001 |                    |
|            |               |                    |                    |
|            |               |   PPI              |                    |
|            |               |  0.014       0.012 |                    |
|            |               |                    |                    |
|            |               |   SF-36            |                    |
|            |               |                    |                    |
|            |               |                    |                    |
|            |               |   Mental healt     |                    |
|            |               | h  0.001       NSD |                    |
|            |               |                    |                    |
|            |               |   EQ-5D            |                    |
|            |               |    NSD         NSD |                    |
|            |               |                    |                    |
|            |               |   Utility Inde     |                    |
|            |               | x  NSD         NSD |                    |
|            |               |                    |                    |
|            |               |   VAS              |                    |
|            |               |     0.005       NR |                    |
|            |               |   -                |                    |
|            |               | ------------- ---- |                    |
|            |               | ------- ---------- |                    |
+------------+---------------+--------------------+--------------------+

Appendix Table 6 Neuropathic pain (PDN and PHN): open-label studies

+---------------+------------------+-----------------+-----------------+
| **Citation**  | **Major          | **Efficacy      | **Safety        |
|               | Eligibility      | Results**       | Results**       |
| **Design,     | Criteria,**      |                 |                 |
| In            |                  |                 |                 |
| terventions** | **Population     |                 |                 |
|               | Profile**        |                 |                 |
| ***Quality    |                  |                 |                 |
| rating***     |                  |                 |                 |
|               |                  |                 |                 |
| ***External   |                  |                 |                 |
| validity***   |                  |                 |                 |
+===============+==================+=================+=================+
| No studies    |                  |                 |                 |
+---------------+------------------+-----------------+-----------------+
|               |                  |                 |                 |
+---------------+------------------+-----------------+-----------------+

Appendix Table 7 Neuropathic pain (PDN and PHN): pooled analyses

+----------------+------------+----------------------+----------------+
| **Citation**   | **Major    | **Efficacy Results** | **Safety       |
|                | E          |                      | Results**      |
| **Design,      | ligibility |                      |                |
| I              | C          |                      |                |
| nterventions** | riteria,** |                      |                |
|                |            |                      |                |
| ***Quality     | **         |                      |                |
| rating***      | Population |                      |                |
|                | Profile**  |                      |                |
| ***External    |            |                      |                |
| validity***    |            |                      |                |
+================+============+======================+================+
| Freeman (2005, | *E         | Average Daily Pain   | Withdrawals    |
| po             | ligibility | score (0--10         | due to adverse |
| ster)^112,133^ | criteria*  | Numerical Rating     | events and     |
|                | Not        | Scale)               | trea           |
| Pooled         | reported   |                      | tment-emergent |
| analysis of    |            |   ---------          | adverse events |
| data from 6 DB | *          |  --------- --------- |                |
| PC RCTs of 5   | Population |  --------- --------- |   -----------  |
| to 12 weeks'   | Profile:*  |                      | - ------ ----- |
| duration.      | Age, mean, |        PGB 600   PGB |   Adverse      |
| Patients had   | y: 59;     |  300   PGB 150   PBO |     All    PBO |
| diagnoses of   | White,     |                      |   event        |
| postherpetic   | 92%; Male, |   Average            |        PGB     |
| neuralgia      | 57%;       |    N = 431   N = 266 |                |
| (PHN) (1       | Weight,    |    N = 176   N = 473 |   Led to       |
| trial),^107^   | 92 kg      |                      |     10.7   4.2 |
| painful        |            | daily                |   withdr       |
| diabetic       | Baseline   |                      | awal           |
| neuropathy     | mean pain  |                      |                |
| (PDN) (2       | score      | pain                 |   *Most        |
| publ           | (11-point  |                      | common         |
| ished^109,110^ | NRS), 6.5  |                      |   TEAEs*       |
| and 2          |            |   **End              |                |
| unpublished    |            |     --2.35    --2.04 |                |
| trials,        |            |     --1.48    --2.74 |   Dizziness    |
| studies        |            |                      |     22.0   4.0 |
| 1008-040 and   |            | point**              |                |
| 1008-149), or  |            |                      |   Somnolenc    |
| either PHN or  |            |                      | e   12.1   2.3 |
| PDN (1         |            | LSM Δ (BL            |                |
| trial).^111^   |            |                      |   *Other       |
|                |            |                      |                |
| N = 1346 (873  |            | to EP)†              |   notabl       |
| Pregabalin vs. |            |                      | e              |
| 473 Placebo)   |            |                      |   TEAEs*       |
|                |            |                      |                |
| Interventions  |            | p-value   ≤ 0.007    |                |
|                |            |                      |   Periphera    |
| Pregabalin     |            |                      | l   10.0   2.3 |
| 150, 300, 600  |            |           vs. PBO    |   edema        |
| mg / d (in 2   |            |                      |                |
| or 3 divided   |            |                      |   -----------  |
| doses) vs.     |            |                      | - ------ ----- |
| Placebo for 5, |            | Δ (BL to             |                |
| 8, 9, or 12 wk |            |                      | Peripheral     |
| (varied among  |            |                      | edema was not  |
| trials)        |            | EP-Wk 1)             | associated     |
|                |            |                      | with           |
| (Data on       |            |                      | cardiovascular |
| 75 mg / d,     |            |                      | complications  |
| evaluated in   |            | p-value              | or changes in  |
| one trial, was |            |                      | renal or       |
| not presented  |            |   ---------          | hepatic        |
| in the AMCP    |            |  --------- --------- | laboratory     |
| dossier        |            |  --------- --------- | test values,   |
| because it is  |            |                      | and rarely led |
| considered to  |            | Responder rates (%   | to treatment   |
| be             |            | of patients)         | di             |
| no             |            |                      | scontinuation. |
| ntherapeutic.) |            |   ---------          |                |
|                |            | ----- ---------- --- |                |
| Quality not    |            | ------- ----- ------ |                |
| assessable.    |            |   Outcom             |                |
|                |            | e        PGB 600     |                |
|                |            | PGB 300    PGB   PBO |                |
|                |            |                      |                |
|                |            |                      |                |
|                |            |               150    |                |
|                |            |                      |                |
|                |            |   NRS-5              |                |
|                |            | 0         46         |                |
|                |            |  39         27    22 |                |
|                |            |                      |                |
|                |            |   p-valu             |                |
|                |            | e        \< 0.001    |                |
|                |            | \< 0.001   NR    --- |                |
|                |            |                      |                |
|                |            |   NRS-3              |                |
|                |            | 0         62         |                |
|                |            |  55         43    37 |                |
|                |            |                      |                |
|                |            |   p-value            |                |
|                |            |       ≤ 0.04     ≤ 0 |                |
|                |            | .04     ≤0    ≤ 0.04 |                |
|                |            |                      |                |
|                |            |                      |                |
|                |            |               .04    |                |
|                |            |                      |                |
|                |            |   NNT                |                |
|                |            | -50†                 |                |
|                |            |                      |                |
|                |            |                      |                |
|                |            |   95%                |                |
|                |            |  CL†                 |                |
|                |            |                      |                |
|                |            |                      |                |
|                |            |   PGI                |                |
|                |            | C-imp                |                |
|                |            |                      |                |
|                |            |                      |                |
|                |            |   p-v                |                |
|                |            | alue                 |                |
|                |            |                      |                |
|                |            |                      |                |
|                |            |   NNT                |                |
|                |            | -PGIC-imp            |                |
|                |            |                      |                |
|                |            |                      |                |
|                |            |   95%                |                |
|                |            |  CL                  |                |
|                |            |                      |                |
|                |            |   ---------          |                |
|                |            | ----- ---------- --- |                |
|                |            | ------- ----- ------ |                |
|                |            |                      |                |
|                |            | Sleep interference   |                |
|                |            | scores (p \< .0025,  |                |
|                |            | all pregabalin       |                |
|                |            | groups vs. placebo)  |                |
|                |            | and health status on |                |
|                |            | PGIC (p \< .001, all |                |
|                |            | pregabalin doses)    |                |
|                |            | were significantly   |                |
|                |            | improved.            |                |
+----------------+------------+----------------------+----------------+

Appendix Table 8 Partial-onset seizures: placebo-controlled trials
(adjunctive therapy)

+-------+------------+---------------------+--------------------------+
| **    | **Major    | **Efficacy          | **Safety Results**       |
| Citat | E          | Results**           |                          |
| ion** | ligibility |                     |                          |
|       | C          |                     |                          |
| **De  | riteria,** |                     |                          |
| sign, |            |                     |                          |
| Qual  | **         |                     |                          |
| ity** | Population |                     |                          |
|       | Profile**  |                     |                          |
+=======+============+=====================+==========================+
| Be    | *Inclusion | Baseline            | Adverse events (% of     |
| ydoun | Criteria:* | difference:         | patients)                |
| (     | ≥          | slightly higher     |                          |
| 2005) | *18 *years | incidence of        | <table>                  |
| ^117^ | old; 50 to | generalized         | <colgroup>               |
|       | 135 kg;    | seizures in PGB     | <col                     |
| Study | epilepsy   | b.i.d. group than   | style="width: 37%" />    |
| 1008  | with       | PGB t.i.d. group    | <col                     |
| -009, | partial    | (data NR).          | style="width: 21%" />    |
| P     | seizures;  |                     | <col                     |
| fizer | EEG within | **Disposition of    | style="width: 21%" />    |
| ^133^ | past 2 y   | Patients**          | <col                     |
|       | consistent |                     | style="width: 18%" />    |
| MC    | with       | <table>             | </colgroup>              |
| (43)  | diagnosis  | <colgroup>          | <tbody>                  |
| DB PC | of         | <col                | <tr class="odd">         |
| PG    | f          | st                  | <td></td>                |
| RCT,  | ocal-onset | yle="width: 41%" /> | <td><p>PGB200</p>        |
| Phase | epilepsy;  | <col                | <p>t.i.d.</p></td>       |
| III   | at least 3 | st                  | <td><p>PGB300</p>        |
| (     | partial    | yle="width: 20%" /> | <p>b.i.d.</p></td>       |
| adjun | seizures   | <col                | <td>PBO</td>             |
| ctive | during the | st                  | </tr>                    |
| the   | month      | yle="width: 20%" /> | <tr class="even">        |
| rapy) | prior to   | <col                | <td></td>                |
|       | screening; | st                  | <td>N = 111</td>         |
| U.S., | at least 6 | yle="width: 17%" /> | <td>N = 103</td>         |
| C     | partial    | </colgroup>         | <td>N = 98</td>          |
| anada | seizures   | <tbody>             | </tr>                    |
|       | during the | <tr class="odd">    | <tr class="odd">         |
| mITT  | 8-wk       | <td></td>           | <td>Deaths</td>          |
|       | baseline   | <td><p>PGB200</p>   | <td>0.0</td>             |
| N     | period     | <p>t.i.d.</p></td>  | <td>0.0</td>             |
| ~R~ = | with no    | <td><p>PGB300</p>   | <td>0.0</td>             |
|  313; | 4-wk       | <p>b.i.d.</p></td>  | </tr>                    |
| N~A~  | se         | <td>PBO</td>        | <tr class="even">        |
| = 312 | izure-free | </tr>               | <td>Nonfatal SAEs</td>   |
|       | periods; 1 | <tr class="even">   | <td>3.6</td>             |
| Int   | to 3 AEDs  | <td></td>           | <td>5.8</td>             |
| erven | dosed      | <td>N = 111</td>    | <td>4.1</td>             |
| tions | within     | <td>N = 103</td>    | </tr>                    |
|       | t          | <td>N = 98</td>     | <tr class="odd">         |
| Prega | herapeutic | </tr>               | <td>TR Nonfatal          |
| balin | range;     | <tr class="odd">    | SAE</td>                 |
| 2     | refractory | <td>Completed       | <td>0.0</td>             |
| 00 mg | to  \> 1   | study (%)</td>      | <td>1.0</td>             |
| t     | AED at     | <td>76.6</td>       | <td>0.0</td>             |
| .i.d. | maximum    | <td>68.3</td>       | </tr>                    |
| vs.   | tolerated  | <td>82.7</td>       | <tr class="even">        |
| Prega | dose; no   | </tr>               | <td>WDSAE</td>           |
| balin | p          | <tr class="even">   | <td>0.0</td>             |
| 3     | rogressive | <td>p-value</td>    | <td>2.9</td>             |
| 00 mg | structural | <td>NR</td>         | <td>2.0</td>             |
| b     | a          | <td>NR</td>         | </tr>                    |
| .i.d. | bnormality | <td>—</td>          | <tr class="odd">         |
| vs.   | on CT scan | </tr>               | <td>WDAE</td>            |
| Pl    | or MRI     | </tbody>            | <td>NR</td>              |
| acebo | within     | </table>            | <td>NR</td>              |
| for   | past 2 y   |                     | <td>NR</td>              |
| 1     |            | **Selected Efficacy | </tr>                    |
| 2 wk, | *Exclusion | Outcomes**          | <tr class="even">        |
| incl  | Criteria:* |                     | <td>≥ 1 AE</td>          |
| uding | Treatable  | <table>             | <td>94.6</td>            |
| 1 wk  | cause of   | <colgroup>          | <td>99.0</td>            |
| titra | seizures;  | <col                | <td>72.4</td>            |
| tion; | absence    | st                  | </tr>                    |
| DB    | seizures;  | yle="width: 41%" /> | </tbody>                 |
| trea  | Lenn       | <col                | </table>                 |
| tment | ox-Gastaut | st                  |                          |
| st    | Syndrome;  | yle="width: 20%" /> | **Rated AEs mild or      |
| arted | p          | <col                | moderate (n):            |
| after | rogressive | st                  | "majority"**             |
| an    | neurologic | yle="width: 20%" /> |                          |
| 8-wk  | or         | <col                | **Associated AEs^†^      |
| bas   | systemic   | st                  | (≥ 10% in any group)**   |
| eline | disorders; | yle="width: 17%" /> | (% of patients)          |
| p     | WBC \< 250 | </colgroup>         |                          |
| eriod | 0 / mm^3^; | <tbody>             | <table>                  |
|       | PMN \< 150 | <tr class="odd">    | <colgroup>               |
| *Al   | 0 / mm^3^, | <td></td>           | <col                     |
| lowed | platel     | <td><p>PGB200</p>   | style="width: 33%" />    |
| c     | ets \< 100 | <p>t.i.d.</p></td>  | <col                     |
| o-med | x          | <td><p>PGB300</p>   | style="width: 22%" />    |
| icati | 10^3       | <p>b.i.d.</p></td>  | <col                     |
| ons:* | ^ / mm^3^; | <td>PBO</td>        | style="width: 22%" />    |
| S     | cardi      | </tr>               | <col                     |
| table | ovascular, | <tr class="even">   | style="width: 22%" />    |
| dose  | he         | <td>Outcome         | </colgroup>              |
| of    | matologic, | Measure</td>        | <tbody>                  |
| s     | hepatic,   | <td>N = 111</td>    | <tr class="odd">         |
| ingle | or renal   | <td>N = 103</td>    | <td></td>                |
| anti  | disease;   | <td>N = 98</td>     | <td><p>PGB200</p>        |
| depre | status     | </tr>               | <p>t.i.d.</p></td>       |
| ssant | e          | <tr class="odd">    | <td><p>PGB300</p>        |
| for   | pilepticus | <td>RRatio (        | <p>b.i.d.</p></td>       |
| mild  | within     | mean)</td>          | <td>PBO</td>             |
| depre | past 1 y;  | <td>–36.1</td>      | </tr>                    |
| ssion | s          | <td>–28.4</td>      | <tr class="even">        |
|       | ignificant | <td>0.6</td>        | <td>≥ 1 AE</td>          |
| Fair  | p          | </tr>               | <td>2.7</td>             |
| qua   | sychiatric | <tr class="even">   | <td>4.8</td>             |
| lity: | disorder   | <td>p-value</td>    | <td>3.1</td>             |
|       | or         | <td>≤ 0.0001</td>   | </tr>                    |
| Ext   | recurrent  | <td>≤ 0.0001</td>   | <tr class="odd">         |
| ernal | severe     | <td>—</td>          | <td>Dizziness</td>       |
| vali  | depression | </tr>               | <td>37.8</td>            |
| dity: | within     | <tr class="odd">    | <td>41.7</td>            |
| May   | past 1 y;  | <td>Responder       | <td>12.2</td>            |
| be    | any        | rate-50 (%)</td>    | </tr>                    |
| li    | c          | <td>49</td>         | <tr class="even">        |
| mited | oncomitant | <td>43</td>         | <td>Somnolence</td>      |
| to    | medication | <td>9</td>          | <td>23.4</td>            |
| pat   | that could | </tr>               | <td>30.1</td>            |
| ients | alter      | <tr class="even">   | <td>12.2</td>            |
| with  | medication | <td>p-value</td>    | </tr>                    |
| dif   | response   | <td>≤ 0.001</td>    | <tr class="odd">         |
| ficul | or seizure | <td>≤ 0.001</td>    | <td>Ataxia</td>          |
| t-to- | frequency; | <td>—</td>          | <td>27.0</td>            |
| treat | illicit    | </tr>               | <td>16.5</td>            |
| sei   | drugs or   | <tr class="odd">    | <td>6.1</td>             |
| zures | alcohol    | <td>Seizure-free    | </tr>                    |
|       | abuse      | during last</td>    | <tr class="even">        |
|       | within     | <td></td>           | <td>Weight gain</td>     |
|       | past 1 y;  | <td></td>           | <td>15.3</td>            |
|       | received   | <td></td>           | <td>20.4</td>            |
|       | gabapentin | </tr>               | <td>2.0</td>             |
|       | unless     | <tr class="even">   | </tr>                    |
|       | di         | <td>28-d (n)</td>   | <tr class="odd">         |
|       | scontinued | <td>15</td>         | <td>Amblyopia</td>       |
|       | at least   | <td>NR</td>         | <td>17.1</td>            |
|       | 1 wk prior | <td>3</td>          | <td>9.7</td>             |
|       | to         | </tr>               | <td>4.1</td>             |
|       | baseline   | <tr class="odd">    | </tr>                    |
|       |            | <td>p-value</td>    | <tr class="even">        |
|       | *          | <td>0.012</td>      | <td>Asthenia</td>        |
|       | Population | <td>NSD</td>        | <td>11.7</td>            |
|       | Profile    | <td>—</td>          | <td>13.6</td>            |
|       | (          | </tr>               | <td>5.1</td>             |
|       | N = 312):* | <tr class="even">   | </tr>                    |
|       | Age (y,    | <td>42-d (n)</td>   | <tr class="odd">         |
|       | range of   | <td>7</td>          | <td>Diplopia</td>        |
|       | means)     | <td>NR</td>         | <td>13.5</td>            |
|       | 3          | <td>0</td>          | <td>9.7</td>             |
|       | 8.4--39.6; | </tr>               | <td>4.1</td>             |
|       | Male 50%;  | <tr class="odd">    | </tr>                    |
|       | White      | <td>p-value</td>    | <tr class="even">        |
|       | 85.3%;     | <td>0.015</td>      | <td>Thinking             |
|       | average    | <td>NSD</td>        | abnormal</td>            |
|       | duration   | <td></td>           | <td>10.8</td>            |
|       | of         | </tr>               | <td>8.7</td>             |
|       | epilepsy   | <tr class="even">   | <td>1.0</td>             |
|       | 25.7 y;    | <td>56-d (n)</td>   | </tr>                    |
|       | median     | <td>6</td>          | </tbody>                 |
|       | seizure    | <td>NR</td>         | </table>                 |
|       | frequency  | <td>0</td>          |                          |
|       | 9.5        | </tr>               | *^†^ Associated AEs,     |
|       | (PGB200    | <tr class="odd">    | defined as those         |
|       | t.i.d.),   | <td>p-value</td>    | considered definitely,   |
|       | 10 (PGB300 | <td>0.031</td>      | probably, or possibly    |
|       | b.i.d.),   | <td>NSD</td>        | related to study         |
|       | and 11     | <td>—</td>          | medication and events    |
|       | (PBO).     | </tr>               | with inassessable        |
|       |            | <tr class="even">   | association due to       |
|       |            | <td>∆ SFI, median   | insufficient             |
|       |            | (d)</td>            | information*             |
|       |            | <td>218.3</td>      |                          |
|       |            | <td>142.3</td>      |                          |
|       |            | <td>26.2</td>       |                          |
|       |            | </tr>               |                          |
|       |            | </tbody>            |                          |
|       |            | </table>            |                          |
+-------+------------+---------------------+--------------------------+
| A     | *Inclusion | Baseline            | Adverse events (% of     |
| rroyo | criteria*: | difference: The     | patients)                |
| (     | Same as    | percentage of       |                          |
| 2004) | for        | patients with a     |   ---------- --------    |
| ^118^ | Beydoun    | history of          | -- ---------- ---------- |
| and   | (2005)     | generalized         |              P           |
| M     |            | seizures was higher | GB600     PGB150     PBO |
| iller | *Exclusion | in PGB600 (6.5%)    |                          |
| (     | criteria*: | and PGB150 (9.1%)   |              N  =        |
| 2003) | Same as    | groups vs. PBO      | 92   N  =  99   N  =  96 |
| ^119^ | for        | group (3.1%).       |                          |
|       | Beydoun    |                     |   Deaths     0           |
| Study | (2005)     | **Disposition of    | .0        0.0        0.0 |
| 1008  |            | Patients**          |                          |
| -011, | *          |                     |   Nonfatal   3           |
| P     | Population |   ------            | .3        4.0        5.2 |
| fizer | profile    | ----- ---------- -- |   SAEs                   |
| ^133^ | (          | -------- ---------- |                          |
|       | N = 287)*: |                     |                          |
| MC    | Age, group |              PGB600 |   TR         1           |
| (45)  | mean       |      PGB150     PBO | .1        1.0        1.4 |
| DB PC | 36.4--38.1 |                     |   Nonfatal               |
| PG    | y; Male    |                     |                          |
| RCT,  | 50.5%;     |         N  =  92    |   SAE                    |
| Phase | White      | N  =  99   N  =  96 |                          |
| III   | 92.7%;     |                     |                          |
| (     | Average    |                     |   WDSAE      2           |
| adjun | duration   | Completed   75.0    | .2        1.0        1.0 |
| ctive | of         |     88.9       86.6 |                          |
| the   | epilepsy   |   study (%)         |   WDAE       1           |
| rapy) | 24.2 y     |                     | 8.5       10.1       6.2 |
|       |            |                     |                          |
| Eu    |            |                     |   WDIE       1           |
| rope, |            |  p-value     NR     | .1        0.0        5.2 |
| U.K., |            |      NR         --- |                          |
| Austr |            |   ------            |   ≥ 1 AE     87          |
| alia, |            | ----- ---------- -- | .0       75.8       63.5 |
| South |            | -------- ---------- |   ---------- --------    |
| A     |            |                     | -- ---------- ---------- |
| frica |            | **Selected**        |                          |
|       |            | Efficacy Outcomes   | AEs rated mild or        |
| N     |            |                     | moderate: "most"         |
| ~R~ = |            |   ---------         |                          |
|  288; |            | ----- ---------- -- | Severe, associated AEs:  |
| N~A~  |            | -------- ---------- | 12 patients (4%) overall |
| = 287 |            |   Ou                |                          |
|       |            | tcome        PGB600 | SAEs: hemiplegia         |
| Int   |            | .    PGB150     PBO | (n = 1), maculopapular   |
| erven |            |                     | rash, amblyopia and      |
| tions |            |  Measure            | dizziness                |
| (n    |            |                     |                          |
| umber |            |                     | Common WDAEs: dizziness, |
| of    |            |   (All pa           | asthenia, ataxia         |
| daily |            | rtial   N  =  92    |                          |
| doses |            | N  =  99   N  =  96 | Common AEs: somnolence,  |
| not   |            |                     | dizziness                |
| repor |            |  seizures)          |                          |
| ted): |            |                     | Other notable AEs:       |
|       |            |                     | accidental injury,       |
| Prega |            |   RR                | dose-related weight      |
| balin |            | atio ( mean) --31.4 | gain, myoclonus,         |
| 600 m |            |      --11.5     0.9 | peripheral edema         |
| g / d |            |                     |                          |
| vs.   |            |   p-                |                          |
| Prega |            | value        ≤0.000 |                          |
| balin |            | 1    0.0007     --- |                          |
| 150 m |            |                     |                          |
| g / d |            |   Di                |                          |
| vs.   |            | ff in means  --32.3 |                          |
| Pl    |            |      --12.4     --- |                          |
| acebo |            |                     |                          |
| for   |            |   95                |                          |
| 1     |            | % CL         --40.6 |                          |
| 2 wk, |            | ,    --20.5,    --- |                          |
| incl  |            |                     |                          |
| uding |            |                 --2 |                          |
| a     |            | 4.0     --4.3       |                          |
| 1-wk  |            |                     |                          |
| titr  |            |   Re                |                          |
| ation |            | sponder      43.5   |                          |
| pe    |            |      14.1       6.2 |                          |
| riod; |            |                     |                          |
| DB    |            |  rate-50 (%)        |                          |
| trea  |            |                     |                          |
| tment |            |                     |                          |
| fol   |            |   p-                |                          |
| lowed |            | value vs.    ≤0.001 |                          |
| an    |            |      .087       --- |                          |
| 8-wk  |            |                     |                          |
| bas   |            |  PBO                |                          |
| eline |            |                     |                          |
| pe    |            |                     |                          |
| riod. |            |   p-                |                          |
|       |            | value vs.    ≤0.001 |                          |
| Qua   |            |      ---        --- |                          |
| lity: |            |                     |                          |
| Fair  |            |  PGB150             |                          |
|       |            |                     |                          |
| Ext   |            |                     |                          |
| ernal |            |                     |                          |
| vali  |            |  Seizure-free       |                          |
| dity: |            |                     |                          |
| Li    |            |                     |                          |
| mited |            |  during last        |                          |
| to    |            |                     |                          |
| pat   |            |                     |                          |
| ients |            |                     |                          |
| with  |            | 28-d (%)       12   |                          |
| refra |            |        7          1 |                          |
| ctory |            |                     |                          |
| pa    |            |   p-                |                          |
| rtial |            | value        0.002  |                          |
| seiz  |            |      0.065      --- |                          |
| ures; |            |                     |                          |
| may   |            |   4                 |                          |
| not   |            | 2-d (%)       NR    |                          |
| apply |            |       NR         NR |                          |
| to    |            |                     |                          |
| ve    |            |                     |                          |
| teran |            |  p-value            |                          |
| popul |            |                     |                          |
| ation |            |                     |                          |
|       |            |   5                 |                          |
|       |            | 6-d (%)       NR    |                          |
|       |            |       NR         NR |                          |
|       |            |                     |                          |
|       |            |                     |                          |
|       |            |  p-value            |                          |
|       |            |                     |                          |
|       |            |                     |                          |
|       |            |   ∆ S               |                          |
|       |            | FI, median  132.5   |                          |
|       |            |     25.5       17.9 |                          |
|       |            |                     |                          |
|       |            |  (d)                |                          |
|       |            |                     |                          |
|       |            |   ---------         |                          |
|       |            | ----- ---------- -- |                          |
|       |            | -------- ---------- |                          |
|       |            |                     |                          |
|       |            | Analysis of         |                          |
|       |            | treatment effects   |                          |
|       |            | showed a linear PGB |                          |
|       |            | dose-response       |                          |
|       |            | (p≤0.0001).         |                          |
+-------+------------+---------------------+--------------------------+
| F     | *Inclusion | **Disposition of    | Adverse events (% of     |
| rench | criteria:* | patients**          | patients)                |
| (     | Same as    |                     |                          |
| 2003) | for        |   -                 |   ---------- ----        |
| ^120^ | Beydoun    | ---------- -------- | ------ -------- -------- |
|       | (2005),    | - -------- -------- | -- ---------- ---------- |
| Study | except     |  -------- --------- |                          |
| 1008  | that age   |               PG    |    PGB600     PGB300   P |
| -034, | and weight | B600.   PGB300   PG | GB150     PGB50      PBO |
| P     | criteria   | B150   PGB50    PBO |                          |
| fizer | were ≥ 12  |                     |              N           |
| ^133^ | y and      |                     |  =  89   N90      N  =   |
|       | ≥ 40 kg.   |  Outcome     N = 89 | 86   N  =  88   N  =  96 |
| MC    |            |     N = 90   N = 86 |                          |
| (76)  | *Exclusion |    N = 88   N = 100 |   Death                  |
| DB PC | criteria:* |   Measure           |    0.0        0.0      0 |
| PG    | Same as    |                     | .0        0.0        0.0 |
| RCT,  | for        |                     |                          |
| Phase | Beydoun    |                     |   Nonfatal               |
| III   | (2005)     |   Completed   68.   |    4.5        3.3      2 |
| (     |            | 5      78.9     92. | .3        3.4        4.0 |
| adjun | Population | 0     88.6     87.0 |   SAE                    |
| ctive | profile    |   study (%)         |                          |
| the   | (N = 453): |                     |                          |
| rapy) | Male       |                     |                          |
|       | 48.1%,     |                     |   TR                     |
| mITT  | White      |   p-value     NR    |    1.1        0.0      0 |
|       | 85.0%,     |         NR       NR | .0        0.0        1.0 |
| N     | average    |        NR       --- |   Nonfa                  |
| ~R~ = | duration   |   -                 | tal                      |
|  455; | of         | ---------- -------- |                          |
| N~A~  | epilepsy   | - -------- -------- |   SAE                    |
| = 453 | 25 y;      |  -------- --------- |                          |
|       | Three      |                     |                          |
| Int   | concurrent | Selected Efficacy   |                          |
| erven | AEDs 15.6% | Outcomes            |   WDSAE                  |
| tions | to 24.0%   |                     |    2.2        1.1      0 |
| (     | per        |   -------           | .0        0.0        0.0 |
| twice | treatment  | ------- --------- - |                          |
| daily | group      | -------- ---------  |   ≥ 1 AE                 |
| dos   |            | --------- --------- |   88.8       84.4     70 |
| ing): |            |   O                 | .9       67.0       74.0 |
|       |            | utcome        PGB60 |                          |
| Prega |            | 0.   PGB300    PGB1 |   Severe A               |
| balin |            | 50    PGB50     PBO | E  14.6       7.8      4 |
| 600 m |            |   Measure           | .7        6.8        6.0 |
| g / d |            |                     |   ---------- ----        |
| vs.   |            |                     | ------ -------- -------- |
| 300 m |            |                     | -- ---------- ---------- |
| g / d |            |   (All              |                          |
| vs.   |            | partial   N = 89    |   ---------------- ----  |
| 150 m |            |  N = 90    N = 86   | ------ -------- -------- |
| g / d |            |   N = 88    N = 100 | -- ---------- ---------- |
| vs.   |            |   seizures)         |   **TEAEs (≥             |
| 50 m  |            |                     | 10%                      |
| g / d |            |                     |                          |
| vs.   |            |                     |   in Any Grou            |
| Pl    |            |   RRa               | p)**                     |
| acebo |            | tio (mean,  --37.4  |                          |
| for   |            |    --27.8    --20.5 |                          |
| 12    |            |     --6.2     --3.8 |                          |
| wk,   |            |   PEM)              |    PGB600     PGB300   P |
| no    |            |                     | GB150     PGB50      PBO |
| titr  |            |                     |                          |
| ation |            |                     |                    N     |
| pe    |            |   p                 |  =  89   N90      N  =   |
| riod. |            | -value        ≤0.00 | 86   N  =  88   N  =  96 |
| DB    |            | 01   ≤0.0001   ≤0.0 |                          |
| trea  |            | 001   0.4232    --- |   Dizziness              |
| tment |            |                     |    42.7       31.1     1 |
| was   |            |                     | 6.3       9.1        9.0 |
| st    |            | Responder      51   |                          |
| arted |            |       40        31  |   Somnolence             |
| foll  |            |        15        14 |   28.1       17.8     17 |
| owing |            |   rate-50 (%)       | .4       10.2       11.0 |
| an    |            |                     |                          |
| 8-wk  |            |                     |   Accidental             |
| bas   |            |                     |    12.4       11.1     5 |
| eline |            |   p                 | .8        14.8       5.0 |
| pe    |            | -value        ≤0.00 |   injury                 |
| riod. |            | 1    ≤0.001    ≤0.0 |                          |
|       |            | 06    0.840\`   --- |                          |
| *Fair |            |                     |                          |
| qual  |            |                     |   Ataxia                 |
| ity.* |            | Seizure-free   NR   |    14.6       10.0     1 |
|       |            |       NR        NR  | 0.5       3.4        3.0 |
| *Ext  |            |        NR        NR |                          |
| ernal |            |   during last       |   Asthenia               |
| val   |            |                     |    10.1       12.2     8 |
| idity |            |                     | .1        5.7        8.0 |
| li    |            |   28, 42, or        |                          |
| mited |            |                     |   Headache               |
| (     |            |                     |   5.6        5.6      9. |
| relat |            |   56 d              | 3        6.8        13.0 |
| ively |            |                     |                          |
| young |            |                     |   Infection              |
| mean  |            |                     |   3.4        5.6      9. |
| age,  |            |   p                 | 3        9.1        10.0 |
| m     |            | -value        ---   |                          |
| ostly |            |      ---       ---  |   Blurred vision         |
| fem   |            |       ---       --- |    10.1       7.8      3 |
| ales, |            |   -------           | .5        3.4        5.0 |
| o     |            | ------- --------- - |                          |
| utpat |            | -------- ---------  |   Tremor                 |
| ients |            | --------- --------- |    11.2       6.7      3 |
| with  |            |                     | .5        3.4        3.0 |
| refra |            |                     |                          |
| ctory |            |                     |   Weight gain            |
| pa    |            |                     |    12.4       6.7      2 |
| rtial |            |                     | .3        1.1        0.0 |
| seizu |            |                     |                          |
| res)* |            |                     |   Incoordination         |
|       |            |                     |    10.1       3.3      2 |
|       |            |                     | .3        2.3        1.0 |
|       |            |                     |                          |
|       |            |                     |   Dry Mouth              |
|       |            |                     |    10.1       2.2      1 |
|       |            |                     | .2        2.3        1.0 |
|       |            |                     |   ---------------- ----  |
|       |            |                     | ------ -------- -------- |
|       |            |                     | -- ---------- ---------- |
|       |            |                     |                          |
|       |            |                     | **AEs rated mild or      |
|       |            |                     | moderate: "most"**       |
+-------+------------+---------------------+--------------------------+
| Elger | Inclusion  | Disposition of      | Adverse events (% of     |
| (     | criteria:  | patients            | patients)                |
| 2005) |            |                     |                          |
| ^129^ | Similar to |                     |   -----------            |
| Study | those for  |  ----------- ------ | --- ------------- ------ |
| 1008  | Beydoun    | ------- ----------- | ----------- ------------ |
| -157, | (2005),    | ------ ------------ |                          |
| P     | except at  |               *     |          **PGB600**    * |
| fizer | least 4    | *PGB600.**   **PGB1 | *PGB150--600**   **PBO** |
| ^133^ | (instead   | 50--600**   **PBO** |                          |
|       | of 3)      |                     |                          |
| MC    | partial    |   **Outcome   **N   |       **N = 137**   **N  |
| (53)  | seizures   | = 137**   **N = 131 | = 131**       **N = 73** |
| DB Pc | had to     | **       **N = 73** |                          |
| PG    | occur      |   Measur            |   De                     |
| RCT,  | within the | e**                 | aths         0.0         |
| Phase | 6-wk       |                     |    0.0               0.0 |
| III   | baseline   |                     |                          |
| (     | period     |   Complete          |   No                     |
| adjun | with no    | d   58            7 | nfatal SAEs  4.0         |
| ctive | 4-wk       | 6                77 |    5.0               1.0 |
| the   | se         |   study             |                          |
| rapy) | izure-free | (%)                 |   T                      |
|       | periods    |                     | R Nonfatal    NR         |
| N     |            |                     |     NR                NR |
| ~R~ = | Exclusion  |                     |                          |
|  341; | criteria:  |                     |  SAE                     |
| N~A~  |            |                     |                          |
| = 341 | Similar to |                     |                          |
|       | those of   |  ----------- ------ |   W                      |
| Int   | Beydoun    | ------- ----------- | DSAE          NR         |
| erven | (2005)     | ------ ------------ |     NR                NR |
| tions | with the   |                     |                          |
| (di   | addition   | Selected Efficacy   |   WD                     |
| vided | of the     | Outcomes            | AE^†^        33.0        |
| doses | following: |                     |    12.0              7.0 |
| b.i   | CrCl       | <table>             |                          |
| .d.): | ≤          | <colgroup>          |   **WDAE                 |
|       | 60 ml/min; | <col                | , first  **24.0\***    * |
| Prega | ALT, AST,  | st                  | *3.0**           **0.0** |
| balin | bilirubin, | yle="width: 40%" /> |                          |
| 600   | urea, or   | <col                |  wk**                    |
|  mg/d | creatinine | st                  |                          |
| (     | values     | yle="width: 23%" /> |                          |
| fixed | above      | <col                |   ≥ 1                    |
| from  | twice the  | st                  |  AE         87.6         |
| d     | ULN;       | yle="width: 22%" /> |   86.3              63.0 |
| ay 1) | received   | <col                |                          |
| vs.   | treatment  | st                  |   **"Sev                 |
| Prega | with       | yle="width: 13%" /> | ere"     **23.0**      * |
| balin | CNS-active | </colgroup>         | *10.0**          **4.0** |
| 150   | compounds  | <tbody>             |                          |
| --600 | except a   | <tr class="odd">    |  AE**                    |
|  mg/d | single     | <td><strong>Outcome |                          |
| (fle  | anti       | Me                  |                          |
| xible | depressant | asure</strong></td> |                          |
| do    | and        | <td><strong>PG      |                          |
| sing; | standard   | B600.</strong></td> |                          |
| st    | AEDs;      | <td><strong>PGB15   |                          |
| arted | received   | 0-600</strong></td> |   **We                   |
| at    | felbamate; | <td><stron          | ight gain  **19**        |
| 150   | received   | g>PBO</strong></td> |  **16**            **3** |
|  mg/d | v          | </tr>               |                          |
| and   | igabatrin, | <tr class="even">   |  ≥7%**                   |
| tit   | unless     | <td><strong>(All    |                          |
| rated | di         | partial             |                          |
| by    | scontinued | seiz                |   **Ne                   |
| 150   | at least 6 | ures)</strong></td> | w or       **28**        |
|  mg/d | wk prior   | <td><strong>N       |  **16**            **9** |
| incre | to         | = 137</strong></td> |                          |
| ments | screening  | <td><strong>N       |  intensified             |
| every | and had no | = 131</strong></td> |                          |
| 1--2  | clinically | <td><strong>N       |                          |
| wk)   | s          |  = 73</strong></td> |  neurological            |
| vs.   | ignificant | </tr>               |                          |
| Pla   | findings   | <tr class="odd">    |                          |
| cebo; | on formal  | <td>RRatio vs.      |  findings**              |
| total | visual     | PBO (diff in        |                          |
| trea  | field      | means, PEM)</td>    |   -----------            |
| tment | ex         | <td>–27.0</td>      | --- ------------- ------ |
| dur   | amination; | <td>–15.8</td>      | ----------- ------------ |
| ation | received   | <td>—</td>          |                          |
| 1     | Phe        | </tr>               | ^†^ Patients on fixed    |
| 2 wk, | nobarbital | <tr class="even">   | PGB600 also withdrew due |
| incl  | or         | <td>95% CL</td>     | to AEs earlier than      |
| uding | primidone  | <td>–38.5,          | those on titrated        |
| a     | unless     | –15.6</td>          | PGB150--600              |
| 6-wk  | di         | <td>–27.4,          |                          |
| bas   | scontinued | –4.3</td>           | \* p = 0.0001 for PGB600 |
| eline | at least   | <td>—</td>          | vs. PGB150--600 and PBO  |
| p     | 30 d prior | </tr>               |                          |
| eriod | to         | <tr class="odd">    | AEs rated mild or        |
|       | screening  | <td>p-value vs.     | moderate: "most"         |
| *Fair |            | PBO</td>            |                          |
| qua   | Population | <td>0.0001</td>     | 5 Most Common TEAEs,     |
| lity* | profile:   | <td>–0.0091</td>    | occurred more commonly   |
|       | Male       | <td>—</td>          | in PGB groups vs. PBO:   |
| *Li   | 49.9%;     | </tr>               | dizziness, ataxia,       |
| mited | White      | <tr class="even">   | weight gain, asthenia,   |
| g     | 97.4%;     | <td>RRatio vs.      | somnolence               |
| enera | Average    | PGB150–600          |                          |
| lizab | duration   | (mean)</td>         | TEAEs occurring more     |
| ility | of         | <td>–11.2</td>      | frequently in PGB600     |
| to    | epilepsy   | <td>—</td>          | than PGB150--600:        |
| vet   | 25.2 y;    | <td>—</td>          | dizziness, ataxia        |
| erans | Percentage | </tr>               |                          |
| with  | of         | <tr class="odd">    |                          |
| dif   | patients   | <td><blockquote>    |                          |
| ficul | taking 1,  | <p>p-value vs.      |                          |
| t-to- | 2, and ≥3  | PGB150–600</p>      |                          |
| treat | AEDs, 23%, | </blockquote></td>  |                          |
| seiz  | 50%, and   | <td>0.0337</td>     |                          |
| ures* | 26%,       | <td>—</td>          |                          |
|       | res        | <td>—</td>          |                          |
|       | pectively; | </tr>               |                          |
|       | Median     | <tr class="even">   |                          |
|       | baseline   | <td>Responder       |                          |
|       | seizure    | rate-50 (%)</td>    |                          |
|       | frequency, | <td>45</td>         |                          |
|       | 9 per      | <td>31</td>         |                          |
|       | 28 d.      | <td>11</td>         |                          |
|       |            | </tr>               |                          |
|       |            | <tr class="odd">    |                          |
|       |            | <td><blockquote>    |                          |
|       |            | <p>p-value vs.      |                          |
|       |            | PBO</p>             |                          |
|       |            | </blockquote></td>  |                          |
|       |            | <td>0.001</td>      |                          |
|       |            | <td>0.001</td>      |                          |
|       |            | <td>—</td>          |                          |
|       |            | </tr>               |                          |
|       |            | <tr class="even">   |                          |
|       |            | <td><blockquote>    |                          |
|       |            | <p>p-value vs.      |                          |
|       |            | PGB150–600</p>      |                          |
|       |            | </blockquote></td>  |                          |
|       |            | <td>0.016</td>      |                          |
|       |            | <td>—</td>          |                          |
|       |            | <td>—</td>          |                          |
|       |            | </tr>               |                          |
|       |            | <tr class="odd">    |                          |
|       |            | <td>Seizure-free    |                          |
|       |            | during last 28 d    |                          |
|       |            | (%)</td>            |                          |
|       |            | <td>12.4<br />      |                          |
|       |            | (NSD)</td>          |                          |
|       |            | <td>12.2<br />      |                          |
|       |            | (NSD)</td>          |                          |
|       |            | <td>8.2</td>        |                          |
|       |            | </tr>               |                          |
|       |            | <tr class="even">   |                          |
|       |            | <td>Seizure-free    |                          |
|       |            | during 84-d tx      |                          |
|       |            | period (%)</td>     |                          |
|       |            | <td>5<br />         |                          |
|       |            | (NSD)</td>          |                          |
|       |            | <td>4<br />         |                          |
|       |            | (NSD)</td>          |                          |
|       |            | <td>2</td>          |                          |
|       |            | </tr>               |                          |
|       |            | </tbody>            |                          |
|       |            | </table>            |                          |
+-------+------------+---------------------+--------------------------+
|       |            |                     |                          |
+-------+------------+---------------------+--------------------------+

Table 24 Partial seizures: long-term, open-label studies

+-----------------+-----------------+-----------------+-----------------+
| **Citation**    | **Major         | **Efficacy      | **Safety        |
|                 | Eligibility     | Results**       | Results**       |
| **Design,       | Criteria,**     |                 |                 |
| Quality**       |                 |                 |                 |
|                 | **Population    |                 |                 |
|                 | Profile**       |                 |                 |
+=================+=================+=================+=================+
| Ryvlin (2005,   |                 | In long-term    | Long-term       |
| review)^134^    |                 | open-label      | open-label      |
|                 |                 | trials, the     | pregabalin      |
| 4 long-term (2  |                 | efficacy of     | treatment was   |
| y), OL studies  |                 | pregabalin was  | well tolerated  |
|                 |                 | maintained with |                 |
|                 |                 | respect to 50%  |                 |
|                 |                 | responder rates |                 |
|                 |                 | suggesting no   |                 |
|                 |                 | obvious         |                 |
|                 |                 | tolerance       |                 |
|                 |                 | developing over |                 |
|                 |                 | 2 years.        |                 |
|                 |                 | Seizure-free    |                 |
|                 |                 | rates were 8.9% |                 |
|                 |                 | and 5.8% for    |                 |
|                 |                 | the last 6      |                 |
|                 |                 | months and 1    |                 |
|                 |                 | year of         |                 |
|                 |                 | pregabalin      |                 |
|                 |                 | treatment,      |                 |
|                 |                 | respectively.   |                 |
+-----------------+-----------------+-----------------+-----------------+

Table 25 Fibromyalgia: placebo-controlled trials

+-------+----------------+---------------------+---------------------+
| **    | **Major        | **Efficacy          | **Safety Results**  |
| Citat | Eligibility    | Results**           |                     |
| ion** | Criteria,**    |                     |                     |
|       |                |                     |                     |
| **De  | **Population   |                     |                     |
| sign, | Profile**      |                     |                     |
| Inter |                |                     |                     |
| venti |                |                     |                     |
| ons** |                |                     |                     |
|       |                |                     |                     |
| ***Qu |                |                     |                     |
| ality |                |                     |                     |
| rati  |                |                     |                     |
| ng*** |                |                     |                     |
|       |                |                     |                     |
| *     |                |                     |                     |
| **Ext |                |                     |                     |
| ernal |                |                     |                     |
| v     |                |                     |                     |
| alidi |                |                     |                     |
| ty*** |                |                     |                     |
+=======+================+=====================+=====================+
| Cro   | *Inclusion     | **Disposition of    | Adverse events (%   |
| fford | criteria*      | Patients**          | of patients)        |
| (     |                |                     |                     |
| 2005) | Met ACR        |   ----------- -     |   -------------- -  |
| ^121^ | diagnostic     | -------- ---------  | -------- ---------  |
|       | criteria for   | --------- --------- | --------- --------- |
| P     | FBM; Males or  |                     |                     |
| roof- | nonpregnant,   |      PGB450    PGB3 |      PGB450    PGB3 |
| of-co | nonlactating   | 00    PGB150    PBO | 00    PGB150    PBO |
| ncept | females; Age ≥ |                     |                     |
| trial | 18 y; Normal   |                     |                     |
|       | chest X-ray in |  N = 132   N = 134  |  N = 132   N = 134  |
| MC    | past 2 y;      |   N = 132   N = 131 |   N = 132   N = 131 |
| (40)  | SF-MPQ 100-mm  |                     |                     |
| DB PC | VAS score      |   Comple            |   Deaths            |
| Phase | ≥ 40 mm;       | ted   75        82. |                     |
| I     | Completed ≥ 4  | 8      78        74 |                     |
| I/III | daily pain     |   stud              |                     |
| RCT   | diaries and    | y (%)               |   Nonfata           |
| with  | average score  |                     | l SAEs              |
| 1-wk  | ≥ 4 on daily   |                     |                     |
| bas   | Pain Rating    |   p-value           |                     |
| eline | Scale (0--10)  |      NR        NR   |   TR Nonf           |
|       | over the 7-d   |       NR        --- | atal                |
| (     | pre            |   ----------- -     |                     |
| monot | -randomization | -------- ---------  |   SAE               |
| herap | period         | --------- --------- |                     |
| y)--- |                |                     |                     |
| mITT, | *Exclusion     | Selected Efficacy   |                     |
| LOCF  | criteria*      | Outcomes            |   WDSAE             |
|       |                |                     |                     |
| Opt   | Active         |   ----------------  |                     |
| ional | malignancy in  | - ------------- --- |                     |
| entry | past 2 y;      | ---------- -------- |   WDAE^†^           |
| into  | failed         | ----- ------------- |        13        8  |
| OL    | previous       |                     |         8         8 |
| foll  | gabapentin     |         **PGB450**  |                     |
| ow-on | ≥1200 mg/d for |    **PGB300**    ** |   WDAE, f           |
| trial | FBM pain; CrCl | PGB150**    **PBO** | irst wk             |
| (1008 | ≤ 60 ml/min;   |                     |                     |
| -033) | WBC \< 2500 /  |   **Outcome         |                     |
|       | mm^3^; PMN     |     **N = 132**   * |   ≥ 1 AE            |
| N     | \< 1500 /      | *N = 134**   **N =  |       92        88  |
| ~R~ = | mm^3^;         | 132**   **N = 131** |        78        77 |
|  530; | Platelets \<   |   Mea               |                     |
| N~A~  | 100 x 10^3^ /  | sure**              |   "Severe           |
| (     | mm^3^;         |                     | " AE                |
| mITT) | Westergren ESR |                     |                     |
| = 529 | \> 40 mm/h;    |                     |                     |
|       | ANA ≥ 3 U; RF  |   *Pa               |                     |
| *Inte | \> 80 IU/ml;   | in/FBM*             |                     |
| rvent | inflammatory   |                     |                     |
| ions* | muscle or      |                     |                     |
|       | rheumatologic  |                     |   Weight            |
| Di    | disease,       |   Ep LSMPS          | gain                |
| vided | active         |  (PEV)    \~4.9     |                     |
| doses | infections, or |      \~5.2          |   ≥7%               |
| t     | untreated      | \~5.8         \~5.8 |                     |
| .i.d. | endocrine      |                     |                     |
|       | disorders;     |   Differ            |                     |
| Prega | Serious        | ence        --0.93  |   New or            |
| balin | hepatic,       |        NR           |                     |
| 150,  | respiratory,   |   NR            Ref |                     |
| 300,  | hematologic,   |                     |   intensi           |
| or    | or immunologic |   p-valu            | fied                |
| 450   | illness;       | e           0.0009  |                     |
| mg/d  | Unstable       |        NSD          |   neurolo           |
| (450  | cardiovascular |   NSD           --- | gical               |
| was   | disease;       |                     |                     |
| st    | Immu           |   RR-50 (           |   finding           |
| arted | nocompromised; | %)         28.9     | s                   |
| at    | Other severe   |       18.9          |                     |
| 300   | pain that      |  13.0          13.2 |                     |
| mg/d  | could confound |                     |                     |
| and   | FBM pain       |   p-valu            |                     |
| incr  | assessments;   | e           0.003   |                     |
| eased | Illicit drug   |        NSD          |                     |
| to    | or alcohol     |   NSD           --- |   Dizzine           |
| 450   | abuse in past  |                     | ss      \*        \ |
| on    | 2 y; Abnormal  |   RR-30 (           | *                   |
| day   | ECG; Had       | %)         48.4     |                     |
| 4)    | pending or     |       37.9          |   Somnole           |
|       | currently      |  31.3          27.1 | nce     \*        \ |
| PBO   | receiving      |                     | *                   |
|       | monetary       |   p-valu            |   -------------- -  |
| 8 wk  | compensation   | e           0.003   | -------- ---------  |
| (1 wk | as a result of |        NSD          | --------- --------- |
| titra | Worker's       |   NSD           NSD |                     |
| tion, | Compensation,  |                     | \* Higher incidence |
| 7 wk  | Workman's      |   FBM IS            | vs. PGB150 and PBO  |
| fixed | Compensation,  |             --4.7   |                     |
| dose) | civil          |        --4.7        | AEs rated mild to   |
|       | litigations,   |                 5.2 | moderate: "Most"    |
| *Al   | disability     |                     |                     |
| lowed | claims, or     |   p-valu            | Most common:        |
| c     | current        | e           0.052   | Dizziness,          |
| o-med | involvement in |        0.052        | somnolence,         |
| icati | out-of-court   |   NSD           --- | headache, dry mouth |
| ons:* | settlements    |                     |                     |
| As    | for claims     |   *Sl               |                     |
| pirin | pertinent to   | eep*                |                     |
| ≤ 325 | patient's FBM; |                     |                     |
| mg/d, | Used           |                     |                     |
| APAP  | prohibited     |                     |                     |
| ≤ 4   | pain or sleep  |   QoSS              |                     |
| g/d,  | meds (i.e.,    |             4.0     |                     |
| s     | skeletal       |        4.7          |                     |
| ympto | muscle         |   4.9           5.3 |                     |
| matic | relaxants,     |                     |                     |
| ant   | be             |   p-valu            |                     |
| i-mig | nzodiazepines, | e           0.0003  |                     |
| raine | an             |        0.0348       |                     |
| a     | tidepressants, |   NSD           --- |                     |
| gents | a              |                     |                     |
|       | ntiepileptics, |   MOS O             |                     |
| *Fair | opioids,       | SP           40     |                     |
| qua   | ant            |         45          |                     |
| lity* | i-Parkinson's, |    46            54 |                     |
|       | c              |                     |                     |
| *Ext  | orticosteroids |   p-valu            |                     |
| ernal | within 7 d of  | e           0.003   |                     |
| valid | study; tender  |        0.005        |                     |
| ity:* | point          |   0.005         --- |                     |
| Unl   | injections or  |                     |                     |
| ikely | fluoxetine     |   *Fa               |                     |
| to    | within 30 d);  | tigue*              |                     |
| apply | Unstable       |                     |                     |
| to    | medical or     |                     |                     |
| m     | psychologic    |                     |                     |
| ostly | conditions     |   MAFGFI            |                     |
| male  |                |            29.4     |                     |
| ve    | *Population    |       29.4          |                     |
| teran | Profile        |  30.7          32.9 |                     |
| popul | (N = 529)*:    |                     |                     |
| ation | Male (8.5%);   |   p-valu            |                     |
| with  | Age, mean 48.6 | e           0.019   |                     |
| co-m  | y; White       |        0.019        |                     |
| orbid | 93.2%. Mean    |   NSD           --- |                     |
| ities | duration of    |                     |                     |
| *and  | FBM 9 y; mean  |   *Mo               |                     |
| able  | baseline pain  | od*                 |                     |
| to    | score (11-pt   |                     |                     |
| d     | NRS) range/tx  |                     |                     |
| iscon | gp: 6.9--7.3.  |                     |                     |
| tinue |                |   HADS-a            |                     |
| FBM   |                | nxiety      7.6     |                     |
| me    |                |        8.4          |                     |
| dicat |                |   8.4           8.4 |                     |
| ions* |                |                     |                     |
|       |                |   p-valu            |                     |
|       |                | e           NSD     |                     |
|       |                |        NSD          |                     |
|       |                |   NSD           NSD |                     |
|       |                |                     |                     |
|       |                |   HADS-d            |                     |
|       |                | epression   6.6     |                     |
|       |                |        7.2          |                     |
|       |                |   6.8           7.4 |                     |
|       |                |                     |                     |
|       |                |   p-valu            |                     |
|       |                | e           NSD     |                     |
|       |                |        NSD          |                     |
|       |                |   NSD           NSD |                     |
|       |                |                     |                     |
|       |                |   *Gl               |                     |
|       |                | obal*               |                     |
|       |                |                     |                     |
|       |                |                     |                     |
|       |                |                     |                     |
|       |                |   PGIC VM           |                     |
|       |                | I or MI    51.6     |                     |
|       |                |       44.8          |                     |
|       |                |  32.0          26.2 |                     |
|       |                |   (%)               |                     |
|       |                |                     |                     |
|       |                |                     |                     |
|       |                |                     |                     |
|       |                |                     |                     |
|       |                |   p-v               |                     |
|       |                | alue                |                     |
|       |                |                     |                     |
|       |                |                     |                     |
|       |                |   ----------------  |                     |
|       |                | - ------------- --- |                     |
|       |                | ---------- -------- |                     |
|       |                | ----- ------------- |                     |
|       |                |                     |                     |
|       |                | Onset and           |                     |
|       |                | persistence of      |                     |
|       |                | significant         |                     |
|       |                | improvement in      |                     |
|       |                | weekly mean pain    |                     |
|       |                | scores relative to  |                     |
|       |                | PBO (p \< 0.05):    |                     |
|       |                | Wk 1--7 for PGB450; |                     |
|       |                | Wk 1--5 for PGB300; |                     |
|       |                | Wk 1--2 for PGB150. |                     |
+-------+----------------+---------------------+---------------------+