![](media/image1.png){width="5.96875in" height="0.41944444444444445in"}

Top of Form

## Complete Summary

#### GUIDELINE TITLE

Pharmacologic management of neuropathic pain: evidence-based
recommendations.

#### BIBLIOGRAPHIC SOURCE(S)

Dworkin RH, O\'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS,
Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS,
Stacey BR, Treede RD, Turk DC, Wallace MS. Pharmacologic management of
neuropathic pain: evidence-based recommendations. Pain 2007 Dec
5;132(3):237-51. \[135 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17920770)

#### GUIDELINE STATUS

This is the current release of the guideline.

This updates a previous version: Dworkin RH, Backonja M, Rowbotham MC,
Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS,
Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader
KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM.
Advances in neuropathic pain: diagnosis, mechanisms, and treatment
recommendations. Arch Neurol 2003 Nov;60(11):1524-34. \[70 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14623723)

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory information
has been released.

-   [December 12, 2007,
    Carbamazepine](http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine):
    The U.S. Food and Drug Administration (FDA) has provided
    recommendations for screening that should be performed on specific
    patient populations before starting treatment with carbamazepine.

-   [May 2, 2007, Antidepressant
    drugs](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Antidepressant):
    Update to the existing black box warning on the prescribing
    information on all antidepressant medications to include warnings
    about the increased risks of suicidal thinking and behavior in young
    adults ages 18 to 24 years old during the first one to two months of
    treatment.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Neuropathic pain (NP)

**Note**: The treatment of trigeminal neuralgia (tic douloureux), for
which there are distinct treatment recommendations, was not considered.
On the basis of recent recommendations for the diagnosis of neuropathic
pain, conditions for which there is no evidence of lesions affecting
nervous system somatosensory pathways (e.g., fibromyalgia, irritable
bowel syndrome) were also not considered.

#### GUIDELINE CATEGORY

Management\
Treatment

#### CLINICAL SPECIALTY

Anesthesiology\
Family Practice\
Geriatrics\
Internal Medicine\
Neurological Surgery\
Neurology\
Obstetrics and Gynecology\
Oncology\
Orthopedic Surgery\
Pharmacology\
Physical Medicine and Rehabilitation\
Podiatry\
Psychiatry\
Psychology\
Rheumatology\
Sports Medicine\
Urology

#### INTENDED USERS

Advanced Practice Nurses\
Nurses\
Pharmacists\
Physician Assistants\
Physicians\
Podiatrists

#### GUIDELINE OBJECTIVE(S)

-   To briefly review the results of randomized clinical trials (RCTs)
    examining medications for the treatment of neuropathic pain (NP)

-   To present up-to-date evidence-based guidelines for the
    pharmacologic management of NP that take into account clinical
    efficacy, adverse effects, impact on health-related quality of life,
    convenience, and costs

-   To provide specific recommendations for the use of these medications

#### TARGET POPULATION

Adult patients with neuropathic pain

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis/Evaluation**

1.  Assessment including identifying the underlying disease, response to
    prior therapies, comorbid conditions, and presence of depression and
    anxiety

2.  Frequent reassessment of pain and its adverse effects

**Pharmacological Treatment/Management**

1.  Patient education and support

2.  First-line medications

    -   Tricyclic antidepressants (TCAs)

    -   Selective serotonin and norepinephrine reuptake inhibitors
        (SSNRIs)

    -   Calcium channel alpha 2-delta ligands

    -   Topical lidocaine

3.  Second-line medications

    -   Opioid analgesics

    -   Tramadol

4.  Third-line medications

    -   Antiepileptics

    -   Antidepressants

    -   Mexiletine, N-methyl- D-aspartate (NMDA) receptor antagonists,
        and topical capsaicin

#### MAJOR OUTCOMES CONSIDERED

-   Clinical effectiveness, measured by pain relief

-   Adverse effects/drug interactions

-   Ease of use

-   Health-related quality of life

-   Cost

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases\
Searches of Unpublished Data

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Relevant publications were identified through Medline searches
(1966--2007), examination of reference lists of relevant published
articles and book chapters, and personal knowledge of the authors. Only
studies of oral or topical pharmacotherapy in adults were considered,
and the recommendations do not apply to the treatment of pediatric
neuropathic pain. The treatment of trigeminal neuralgia (tic
douloureux), for which there are distinct treatment recommendations was
not considered. On the basis of recent recommendations for the diagnosis
of neuropathic pain (NP), conditions for which there is no evidence of
lesions affecting nervous system somatosensory pathways (e.g.,
fibromyalgia, irritable bowel syndrome) were also not considered.

In evaluating the literature and developing recommendations, the
Cochrane Database and other recent systematic reviews were emphasized.
Efficacy was considered to have been demonstrated if the results of a
randomized clinical trial (RCT) found statistically significantly
greater pain reduction versus placebo for the primary outcome measure
and was evaluated according to the Oxford Centre for Evidence-based
Medicine levels of evidence. All medications with efficacy supported by
at least one systematic review or positive placebo-controlled or
dose-response RCT (levels of evidence criterion 1b or better), in which
reduction of chronic NP was a primary or co-primary endpoint were
considered for inclusion. Published data, unpublished data (when
available), and the clinical experience of the authors were used to
evaluate each of these medications in terms of degree of efficacy,
safety, tolerability, drug interactions, ease of use, and impact on
health-related quality of life.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**1a**: Systematic review (SR) (with homogeneity) of randomized
controlled trials

**1b**: Individual RCT (with narrow Confidence Interval)

**1c**: All or none (met when [all]{.underline} patients died before the
treatment because available, but now some survive on it; or when some
patients died before the treatment became available, but
[none]{.underline} now die on it)

**2a**: SR (with homogeneity) of cohort studies

**2b**: Individual cohort study (including low quality RCT; e.g., \<80%
follow-up)

**2c**: \"Outcomes\" Research; Ecological studies

**3a**: SR (with homogeneity) of case-control studies

**3b**: Individual Case-Control Study

**4**: Case-series (and poor quality cohort and case-control studies)

**5**: Expert opinion without explicit critical appraisal, or based on
physiology, bench research, or \"first principles\"

**Source**: Oxford Centre for Evidence-based Medicine. Levels of
evidence and grades of recommendation. Available at:
[http://www.cebm.net/levels_of_evidence.asp](http://www.cebm.net/index.aspx?o=1025)

#### METHODS USED TO ANALYZE THE EVIDENCE

Review\
Review of Published Meta-Analyses

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Consensus Development Conference)

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The consensus meeting on which these treatment recommendations are based
and the preparation of this article were conducted under the auspices of
the International Association for the Study of Pain (IASP) Neuropathic
Pain Special Interest Group with additional support provided by the
Neuropathic Pain Institute, both of which have received unrestricted
support for their activities from multiple pharmaceutical companies. No
individuals employed by pharmaceutical companies were involved in the
consensus meeting on which these recommendations are based or in the
preparation of this article. Prior to the consensus meeting, all
participants were provided with copies of existing treatment guidelines,
systematic reviews and meta-analyses, and recently published randomized
clinical trials (RCTs). This literature and the authors\' clinical and
research experience were reviewed during the consensus meeting.
Systematic reviews and RCTs published after the meeting were reviewed
subsequently.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**A**: Consistent level 1 studies

**B**: Consistent level 2 or 3 studies ***or*** extrapolations from
level 1 studies

**C**: Level 4 studies ***or*** extrapolations from level 2 or 3 studies

**D**: Level 5 evidence ***or*** troublingly inconsistent or
inconclusive studies of any level

**Source**: Oxford Centre for Evidence-based Medicine. Levels of
evidence and grades of recommendation. Available at:
[http://www.cebm.net/levels_of_evidence.asp](http://www.cebm.net/index.aspx?o=1025)

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Grades of recommendation (A-D) and levels of evidence (1a-5) are defined
at the end of the \"Major Recommendations\" field.

**General Management Considerations and Recommendations**

Assessment of neuropathic pain (NP) should focus on identifying and
treating the underlying disease processes and peripheral or central
nervous system lesions, response to prior therapies, and comorbid
conditions that can be affected by therapy. Particular attention should
be paid to identifying coexisting depression, anxiety, sleep
disturbances, and other adverse impacts of NP on health-related quality
of life, and both pain and its adverse effects should be reassessed
frequently. Patient education and support are critical components of the
successful management of NP. Careful explanation of the cause of NP and
the treatment plan are essential. Patient and provider expectations
regarding treatment effectiveness and tolerability must be discussed,
and realistic treatment goals should be established with patients.
Non-pharmacologic methods of coping with pain should be discussed,
including the importance of stress reduction, good sleep hygiene,
physical therapy, and other potentially useful interventions.

There is insufficient evidence to rank first-line medications for NP by
their degree of efficacy or safety. Clinicians must consider several
other factors when selecting a specific medication for a patient with
NP, including: (1) the potential for adverse outcomes associated with
medication-related side effects; (2) potential drug interactions; (3)
comorbidities that may also be relieved by the non-analgesic effects of
the medication (e.g., sleep disturbance, depression, anxiety); (4) costs
associated with therapy; (5) the potential risks of medication abuse;
and (6) the risks of intentional and unintentional overdose. These
potentially competing factors must be prioritized according to the
specific needs of each patient with NP.

Individual variation in the response to the medications used to treat NP
is substantial and unpredictable. Although evidence-based
recommendations encourage the use of specific medications, the overall
approach should be recognized as a stepwise process intended to identify
the medication, or medication combination, that provides the greatest
pain relief and fewest side effects for a given patient (see the Table
below). If an adequate trial of one medication fails to adequately
relieve pain or causes intolerable side effects, treatment should be
discontinued and a different medication should be selected for a trial.
If a medication is well tolerated and provides partial pain relief, it
should be continued and a second medication with a distinct mechanism of
action added.

In addition to potential additive analgesic benefits, combination
therapy may provide analgesia more quickly by combining a medication
with a rapid onset of effect with one that requires several weeks of
treatment before maximum benefit is achieved. These potential advantages
of combination therapy must be weighed against the possibility of
additive adverse effects, drug interactions, increased cost, and reduced
adherence to a more complex treatment regimen.

**Table - Stepwise Pharmacologic Management of Neuropathic Pain (NP)**

+-----------------------------------------------------------------------+
| **Step 1**                                                            |
|                                                                       |
| -   Assess pain and establish the diagnosis of NP \[Dworkin et al.,   |
|     2003; Cruccu et al., 2004); if uncertain about the diagnosis,     |
|     refer to a pain specialist or neurologist.                        |
|                                                                       |
| -   Establish and treat the cause of NP; if uncertain about           |
|     availability of treatments addressing NP etiology, refer to       |
|     appropriate specialist.                                           |
|                                                                       |
| -   Identify relevant comorbidities (e.g., cardiac, renal, or hepatic |
|     disease, depression, gait instability) that might be relieved or  |
|     exacerbated by NP treatment, or that might require dosage         |
|     adjustment or additional monitoring of therapy.                   |
|                                                                       |
| -   Explain the diagnosis and treatment plan to the patient, and      |
|     establish realistic expectations.                                 |
|                                                                       |
| **Step 2**                                                            |
|                                                                       |
| -   Initiate therapy of the disease causing NP, if applicable.        |
|                                                                       |
| -   Initiate symptom treatment with one or more of the following:     |
|                                                                       |
|     -   A secondary amine tricyclic antidepressant (TCA)              |
|         (nortriptyline, desipramine) or a selective serotonin and     |
|         norepinephrine reuptake inhibitor (SSNRI) (duloxetine,        |
|         venlafaxine)                                                  |
|                                                                       |
|     -   A calcium channel alpha 2-sigma ligand, either gabapentin or  |
|         pregabalin                                                    |
|                                                                       |
|     -   For patients with localized peripheral NP: topical lidocaine  |
|         used alone or in combination with one of the other first-line |
|         therapies                                                     |
|                                                                       |
|     -   For patients with acute neuropathic pain, neuropathic cancer  |
|         pain, or episodic exacerbations of severe pain, and when      |
|         prompt pain relief during titration of a first-line           |
|         medication to an efficacious dosage is required, opioid       |
|         analgesics or tramadol may be used alone or in combination    |
|         with one of the first-line therapies                          |
|                                                                       |
| -   Evaluate patient for non-pharmacologic treatments, and initiate   |
|     if appropriate.                                                   |
|                                                                       |
| **Step 3**                                                            |
|                                                                       |
| -   Reassess pain and health-related quality of life frequently.      |
|                                                                       |
| -   If substantial pain relief (e.g., average pain reduced to         |
|     [\<]{.underline}3/10) and tolerable side effects, continue        |
|     treatment.                                                        |
|                                                                       |
| -   If partial pain relief (e.g., average pain remains                |
|     [\>]{.underline}4/10) after an adequate trial (see Table 3 in the |
|     original guideline document), add one of the other first-line     |
|     medications.                                                      |
|                                                                       |
| -   If no or inadequate pain relief (e.g., \<30% reduction) at target |
|     dosage after an adequate trial (see Table 3 in the original       |
|     guideline document), switch to an alternative first-line          |
|     medication.                                                       |
|                                                                       |
| **Step 4**\                                                           |
| \                                                                     |
| If trials of first-line medications alone and in combination fail,    |
| consider second- and third-line medications or referral to a pain     |
| specialist or multidisciplinary pain center.                          |
+-----------------------------------------------------------------------+

**First-line Medications**

Three medications or medication classes are recommended as first-line
treatment for patients with NP (**grade A recommendation**). Table 2 in
the original guideline document summarizes treatment selection
considerations. Prescribing information for each of these
medications---including starting dosage, titration requirements, target
dosage, and duration of an adequate trial---is provided in Table 3 of
the original guideline document.

*Tricyclic Antidepressants (TCAs) and Selective Serotonin and
Norepinephrine Reuptake Inhibitors (SSNRIs)*

TCAs are typically inexpensive and usually administered once daily. The
presence of depression is not required for the analgesic effects of
these medications, although they may be particularly useful in patients
with inadequately treated depression. The most common side effects of
TCAs include sedation, anticholinergic effects (e.g., dry mouth,
constipation, and urinary retention), and orthostatic hypotension.
Secondary amine TCAs (nortriptyline and desipramine) are preferred
because they are better tolerated than tertiary amine TCAs
(amitriptyline and imipramine) but have comparable analgesic efficacy.
Amitriptyline in particular should be avoided in elderly patients.

The decision to start a TCA should also consider the possibility of
cardiac toxicity. Data suggest that the lowest effective dosage of a TCA
should be used in all patients with NP, and that TCAs should be avoided
in patients who have ischemic heart disease or an increased risk of
sudden cardiac death. A screening electrocardiogram (ECG) is recommended
before beginning treatment with TCAs in patients over 40 years of age.
TCAs should be used cautiously in patients at risk for suicide or
accidental death from overdose. They can cause or exacerbate cognitive
impairment and gait disturbances in elderly patients, and may predispose
to falls. Toxic TCA levels may result if TCAs are administered together
with medications that inhibit cytochrome P450 2D6, such as selective
serotonin reuptake inhibitors (SSRIs).

Starting doses of TCAs should be low, and the dosage should be titrated
slowly until pain is adequately controlled or side effects limit
continued titration (see Table 3 in the original guideline document).
Although monitoring medication levels is not usually necessary, it may
reduce the risk of cardiac toxicity at dosages greater than 150 mg/day.

Duloxetine is an SSNRI that inhibits the reuptake of both serotonin and
norepinephrine. It has demonstrated significantly greater pain relief
compared with placebo in patients with painful diabetic peripheral
neuropathy (DPN) but it has not been studied in other types of NP.
Duloxetine has a generally favorable side effect profile and dosing is
simple. Nausea is the most common side effect, but it occurs less
frequently if treatment is initiated at 30 mg/day and titrated after one
week to 60 mg/day, an efficacious dosage at which pain relief can occur
within one week (see Table 3 in the original guideline document). As a
new medication, there is limited long-term safety information and
efficacy data are limited to studies of painful DPN.

Venlafaxine is an SSNRI that inhibits serotonin reuptake at lower
dosages and both serotonin and norepinephrine reuptake at higher
dosages. Randomized clinical trials (RCTs) in patients with painful DPN
and painful polyneuropathies of various types including DPN demonstrated
efficacy at dosages of 150 to 225 mg/day. RCTs in other populations,
including those with post-mastectomy pain, various peripheral and
central NP conditions, and post herpetic neuropathy (PHN), demonstrated
inconsistent or negative results. In one RCT, 5% of venlafaxine-treated
patients developed ECG changes, and monitoring is therefore recommended
in patients with cardiovascular risk factors. Venlafaxine is available
in both short- and long-acting formulations. Two-to-four weeks is often
required to titrate to an effective dosage, and patients should be
tapered gradually from venlafaxine because of the risk of
discontinuation syndrome (see Table 3 in the original guideline
document).

*Calcium Channel alpha 2-delta Ligands*

Gabapentin is generally safe, has no clinically important drug
interactions, and is available in generic formulations. The main
dose-limiting side effects are somnolence and dizziness, which are
reduced by gradual dosage titration, and peripheral edema. In some
patients, particularly the elderly, gabapentin can cause or exacerbate
cognitive or gait impairment. Several weeks can be required to reach an
effective dosage, which is usually between 1800 and 3600 mg/day
(administered in three divided doses, increasing the night-time dose
preferentially). Dosage reduction is necessary in patients with renal
insufficiency. The onset of activity can be seen as early as the second
week of therapy when titration is rapid, but peak effect usually occurs
approximately two weeks after a therapeutic dosage is achieved.
Therefore, an adequate trial may require two months or more (see Table 3
in the original guideline document).

Pregabalin produces dose-dependent side effects similar to those of
gabapentin. It has also demonstrated anxiolytic effects in RCTs of
generalized anxiety disorder, which may provide additional benefit in
patients with chronic pain. Like gabapentin, it has no clinically
important drug interactions but requires dosage reduction in patients
with renal impairment. Studies indicate that treatment can be initiated
at 150 mg/day (in either two or three divided doses), although a
starting dose of 75 mg at bedtime is used by some clinicians to reduce
the likelihood of early side effects in elderly patients and in others
especially prone to side effects (see Table 3 in the original guideline
document). The potential for twice daily dosing and the linear
pharmacokinetics of pregabalin may contribute to relatively greater ease
of use compared with gabapentin, but the overall efficacy and
tolerability of these two medications appear similar. However, onset of
pain relief with pregabalin can be more rapid than with gabapentin
because its starting dosage of 150 mg/day is efficacious. Upward dosage
titration can reach 300 mg/day within one to two weeks, and the maximum
benefits typically occur after two weeks of treatment at target dosages
of 300 to 600 mg/day. Because it is a new medication, long-term safety
of pregabalin is not as well established as it is for gabapentin.

*Topical Lidocaine*

As a topical preparation, lidocaine patch 5% is recommended for patients
with localized peripheral NP but not for patients with central NP. When
used as recommended, the only side effects that occur with the lidocaine
patch 5% are mild skin reactions (e.g., erythema and localized rash).
Blood levels are minimal with the approved maximum dosing of three
patches/day applied for 12 h and also when four patches/day are applied
for 18 h. Nonetheless, use of the lidocaine patch 5% should be avoided
in patients receiving oral Class I antiarrhythmic medications (e.g.,
mexiletine) and in patients with severe hepatic dysfunction, in whom
excessive blood concentrations are theoretically possible.

The efficacy of lidocaine gel was demonstrated in patients with PHN and
allodynia, but not in patients with human immunodeficiency virus (HIV)
neuropathy. Because of its safety and ease of use, lidocaine gel can be
considered when the lidocaine patch 5% is not available, application of
a patch is problematic, or the cost of the lidocaine patch 5% precludes
its use.

**Second-line Medications That Can Be Used for First-line Treatment in
Select Clinical Circumstances**

Opioid analgesics and tramadol have demonstrated efficacy in multiple
RCTs in patients with NP, and when patients do not have a satisfactory
response to the first-line medications alone or in combination, opioid
agonists can be used as second-line treatment alone or in combination
with the first-line medications (**grade A recommendation**).

In select clinical circumstances, opioid analgesics and tramadol can
also be considered for first-line use (see the Table below).

**Table -- Circumstances in Which Opioid Analgesics and Tramadol Can Be
Considered for First-line Treatment of Neuropathic Pain**

+-----------------------------------------------------------------------+
| -   During titration of a first-line medication to an efficacious     |
|     dosage for prompt pain relief                                     |
|                                                                       |
| -   Episodic exacerbations of severe pain                             |
|                                                                       |
| -   Acute neuropathic pain                                            |
|                                                                       |
| -   Neuropathic cancer pain                                           |
+-----------------------------------------------------------------------+

*Opioid Analgesics*

Treatment of chronic NP with opioid agonists should generally be
reserved for patients who have failed to respond to or cannot tolerate
the first-line medications. This recommendation is consistent with
published guidelines for the use of opioids in chronic non-cancer pain
that have been prepared by various groups. Opioids can be considered for
first-line use in select circumstances (see Table above). Typically,
such first-line use of opioids should be reserved for circumstances in
which suitable alternatives cannot be identified and should be on a
short-term basis to the extent possible.

Before initiating treatment with opioid analgesics, clinicians should
identify and address risk factors for abuse, which include active
substance abuse, prior history of opioid or other drug abuse, other
major psychiatric pathology, and family history of substance abuse.
Response to treatment, side effects, and signs of opioid misuse or abuse
should be monitored on a regular basis, as has been described in
guidelines for opioid use in chronic non-cancer pain. It is recommended
that clinicians without opioid expertise obtain consultation from
appropriate specialists in developing a treatment plan for challenging
patients.

The most common opioid-related side effects are nausea, constipation,
and sedation. Although nausea and sedation typically decrease after
several weeks of treatment, constipation may not; it usually requires
concurrent management, especially in the elderly or other groups with
risk factors for this problem. Opioids should be used cautiously in
patients at risk for suicide or accidental death from overdose. In
elderly patients, opioids can also cause or exacerbate cognitive
impairment and gait disturbances, increasing the risk of falls. In
contrast to abuse or addiction, physical dependence develops in all
patients chronically treated with opioid analgesics, and patients must
be advised that they should not discontinue these medications on their
own.

The effective opioid dosage varies widely among patients, and either of
two strategies for the initiation of treatment can be used depending on
the specific clinical circumstances. For opioid-naive patients,
treatment can be initiated with an oral immediate-release opioid at a
dose equivalent to 10--15 mg of morphine every 4 h or on an as needed
basis, with conversion to a long-acting opioid after a few days, when
the approximate daily dosage has been identified (see Table 3 in the
original guideline document). Treatment can also be initiated with a
long-acting opioid (e.g., extended-release oral morphine or oxycodone,
or transdermal fentanyl). Fixed-schedule dosing with a long-acting
opioid is generally preferred, although RCTs in patients with NP are
needed to compare the efficacy and safety of short versus long-acting
opioids. Titration should continue until satisfactory pain relief is
achieved or unacceptable side effects persist despite attempts to
improve tolerability (e.g., laxatives for constipation). Treatment with
a short-acting opioid on an as needed basis may be appropriate to
continue in selected patients with NP who have episodes of markedly
increased pain; until the role of such \"rescue\" treatment has been
more adequately characterized for patients with NP, treatment approaches
used for patients with other types of chronic pain, including cancer
pain, can be followed. As with all of the medications recommended for
NP, the lowest effective dosages of opioid analgesics should be used. If
an adequate trial of therapy has not produced clinically meaningful pain
relief, patients should be tapered off their opioid analgesic and an
alternative treatment administered.

*Tramadol*

As with opioids, tramadol is associated with abuse potential; although
rates of tramadol abuse have remained very low despite new branded and
generic formulations, some recent reports suggest that the rate of
recreational tramadol use may be rising.

The most common side effects of tramadol are somnolence, constipation,
dizziness, nausea, and orthostatic hypotension, which occur more
frequently with rapid dosage escalation. Tramadol can cause or
exacerbate cognitive impairment and gait disturbances in elderly
patients. It can also precipitate seizures in patients with a history of
seizures or in those receiving medications that reduce seizure
threshold. Concurrent use of other serotonergic medications (including
SSRIs and SSNRIs) may increase the risk of serotonin syndrome, and
combination therapy with these medications must be undertaken
cautiously.

As for opioid analgesics, tramadol is recommended primarily for patients
who have not responded to the first-line medications but it can also be
considered for first-line use in select clinical circumstances (see the
Table above). Tramadol is available in both short- and long-acting
formulations; for the short-acting formulation, the starting dosage is
50 mg once or twice daily, with gradual titration to a maximum of 400
mg/day. Dosage reduction is necessary in patients with renal or hepatic
disease and in the elderly (see Table 3 in the original guideline
document).

**Generally Third-line Medications**

There are a number of other medications that would generally be used as
third-line treatments but that could also be used as second-line
treatments in some circumstances (e.g., when treatment with an opioid
agonist is not indicated or when the patient\'s treatment history
suggests greater potential for their effectiveness). These medications
include certain other antiepileptic (carbamazepine, lamotrigine,
oxcarbazepine, topiramate, valproic acid) and antidepressant (bupropion,
citalopram, paroxetine) medications, mexiletine, N-methyl- D-aspartate
(NMDA) receptor antagonists, and topical capsaicin. Recommendations for
their use are based on efficacy in a single RCT or inconsistent results
from multiple RCTs and the clinical experience of the authors (**grade B
recommendation**). Refer to the original guideline document for
information regarding third-line medications.

**Additional Recommendations for Central NP**

Based on the results of a small number of RCTs, the following specific
medications should be considered for patients with central NP: TCAs for
central post-stroke pain; calcium channel alpha 2-delta ligands for
spinal cord injury pain; and cannabinoids for NP associated with
multiple sclerosis (**grade B recommendation**). Lack of long-term
follow-up data, limited availability, and concerns over precipitating
psychosis or schizophrenia, especially in individuals with environmental
or genetic risk factors, restrict the use of cannabinoids to second-line
therapy for patients with multiple sclerosis NP at present, and
additional trials are needed to further establish their efficacy and
safety.

Many patients with central NP either do not have one of these diagnoses
or require alternative therapy. In these situations, the first- and
second-line medications recommended for peripheral NP can be considered
for the treatment of central NP (except for topical lidocaine). However,
it must be acknowledged that the evidence base for such treatment is
limited.

**Conclusions**

TCAs, SSNRIs, calcium channel alpha 2-delta ligands, and topical
lidocaine have demonstrated efficacy in NP and are recommended as
first-line medications. In patients who have failed to respond to these
first-line medications alone and in combination, opioid analgesics or
tramadol can be used as a second-line treatment alone or in combination
with one of the first-line medications. Opioid analgesics and tramadol
can also be considered for first-line use in select clinical
circumstances.

Patients who have not responded adequately to these medications used
alone and in combination can be treated with one or more other
recommended medications. For patients who have not responded adequately
to pharmacologic management or those who have pain that is associated
with challenging comorbidities or with a high level of disability or
distress, prompt consultation with a pain specialist or
multidisciplinary pain management center is recommended, including
consideration of a broad array of non-pharmacologic therapies and
invasive treatments.

It is important to emphasize that pharmacologic management of the
patient with chronic NP should be considered an integral component of a
more comprehensive approach that also includes non-pharmacologic
treatments. Non-pharmacologic treatments for NP require increased
attention and evaluation in controlled trials in which they are
administered alone and also in combination with pharmacologic therapies.

**[Definitions]{.underline}**:

**Grades of Recommendations**

**A**: Consistent level 1 studies

**B**: Consistent level 2 or 3 studies ***or*** extrapolations from
level 1 studies

**C**: Level 4 studies ***or*** extrapolations from level 2 or 3 studies

**D**: Level 5 evidence ***or*** troublingly inconsistent or
inconclusive studies of any level

**Levels of Evidence**

**1a**: Systematic review (SR) (with homogeneity) of randomized
controlled trials

**1b**: Individual RCT (with narrow Confidence Interval)

**1c**: All or none (met when [all]{.underline} patients died before the
treatment because available, but now some survive on it; or when some
patients died before the treatment became available, but
[none]{.underline} now die on it)

**2a**: SR (with homogeneity) of cohort studies

**2b**: Individual cohort study (including low quality RCT; e.g., \<80%
follow-up)

**2c**: \"Outcomes\" Research; Ecological studies

**3a**: SR (with homogeneity) of case-control studies

**3b**: Individual Case-Control Study

**4**: Case-series (and poor quality cohort and case-control studies)

**5**: Expert opinion without explicit critical appraisal, or based on
physiology, bench research, or \"first principles\"

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### REFERENCES SUPPORTING THE RECOMMENDATIONS

[References open in a new
window](http://www.guideline.gov/summary/select_ref.aspx?doc_id=11724)

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

-   Recommendations for first-line treatments are consistent with the
    results of multiple randomized clinical trials (RCTs) (Oxford Centre
    for Evidence-based Medicine grade A recommendation) and the clinical
    experience of the authors.

-   Recommendations for opioid analgesics and tramadol as generally
    second-line treatments are consistent with the results of multiple
    RCTs (grade A recommendation), the clinical experience of the
    authors, and published guidelines and recommendations for their use.

-   Recommendations for other medications that would generally be used
    as third-line treatments but that could also be used as second-line
    treatments in some circumstances are based on a single positive RCT
    or inconsistent results from multiple trials (grade B
    recommendation) and the authors\' clinical experience.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Effective and appropriate use of medication for the treatment/management
of chronic neuropathic pain based on clinical effectiveness (significant
pain reduction), minimal adverse effects, improvement in quality of
life, and cost

#### POTENTIAL HARMS

**Drug-related Adverse Effects**

Refer to the \"Major Recommendations\" field, and the original guideline
document including Table 3 for detailed discussion of the adverse
effects associated with first-, second-, and third-line medications.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   Amitriptyline should be avoided in elderly patients.

-   Tricyclic antidepressants (TCAs) should be avoided in patients who
    have ischemic heart disease or an increased risk of sudden cardiac
    death.

-   Use of the lidocaine patch 5% should be avoided in patients
    receiving oral Class I antiarrhythmic drugs (e.g., mexiletine) and
    in patients with severe hepatic dysfunction, in whom excessive blood
    concentrations are theoretically possible.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

The methodology used in randomized clinical trials (RCTs) of neuropathic
pain (NP) varies, and there are few head-to-head comparisons of
different medications, making it difficult to compare the relative
efficacy and safety of many medications. Little is known regarding the
treatment response of patients with mild-to-moderate NP because RCTs
have typically evaluated chronic NP of moderate to severe intensity.
Moreover, treatment duration has generally not exceeded three months in
the RCTs of any treatments for NP, and knowledge of the long-term
benefits and risks of treatment is therefore inadequate. Unfortunately,
there is insufficient evidence to rank first-line medications for NP by
their degree of efficacy or safety.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Dworkin RH, O\'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS,
Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS,
Stacey BR, Treede RD, Turk DC, Wallace MS. Pharmacologic management of
neuropathic pain: evidence-based recommendations. Pain 2007 Dec
5;132(3):237-51. \[135 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17920770)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2003 Nov (revised 2007 Aug)

#### GUIDELINE DEVELOPER(S)

Fourth International Conference on the Mechanisms and Treatment of
Neuropathic Pain - Independent Expert Panel\
International Association for the Study of Pain - Medical Specialty
Society

#### SOURCE(S) OF FUNDING

Support for the consensus meeting on which this article is based was
provided by the International Association for the Study of Pain (IASP)
Neuropathic Pain Special Interest Group and by the Neuropathic Pain
Institute, both of which have received unrestricted support for their
activities from multiple pharmaceutical companies.

#### GUIDELINE COMMITTEE

Not stated

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Authors*: Robert H. Dworkin, Alec B. O\'Connor, Miroslav Backonja, John
T. Farrar, Nanna B. Finnerup, Troels S. Jensen, Eija A. Kalso, John D.
Loeser, Christine Miaskowski, Turo J. Nurmikko, Russell K. Portenoy,
Andrew S.C. Rice, Brett R. Stacey, Rolf-Detlef Treede, Dennis C. Turk,
Mark S. Wallace

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

All authors received an honorarium for participation in the consensus
meeting from the University of Rochester Office of Professional
Education.

RHD has received research support, consulting fees, or honoraria in the
past year from Allergan, Balboa, CombinatoRx, Dara, Eli Lilly, Endo,
EpiCept, Fralex, GlaxoSmithKline, GW Pharmaceuticals, Johnson & Johnson,
KAI Pharmaceuticals, Merck, NeurogesX (also stock options), Ono,
Organon, Pfizer, Supernus, US Food and Drug Administration, US National
Institute of Health, US Veterans Administration, Wyeth, and XTL
Biopharmaceuticals.

ABO has received research support from Endo and the Mayday Fund, and is
the recipient of an institutional career development award
(T32AG020493-02) from the National Institute on Aging.

MB has received research support, consulting fees, or honoraria in the
past year from Allergan, Astellas, Cephalon, Dov, Eli Lilly, Eisia,
Endo, Johnson & Johnson, Merck, NeurogesX, Novartis, Pfizer, Schwarz,
and Xenoport.

JTF has received research support, consulting fees, or honoraria in the
past year from Abbott, Adolor, Allergan, Celgene, Cephalon, Eli Lilly,
GW Pharmaceuticals, Ortho McNeil, Pfizer, Philadelphia Health Care
Trust, Purdue, and UCB Pharma.

NBF has received research support or honoraria in the past year from
Neurosearch A/S and UCB Nordic.

TSJ has received research support, consulting fees, or honoraria in the
past year from Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Lundbeck
Research Foundation, and Pfizer.

JDL has received a grant from Purdue and honoraria from Endo, Medtronic,
Pfizer, and US National Institute of Health.

TJN has received research support, consulting fees, or honoraria in the
past year from Eli Lilly, GW Pharmaceuticals, Medtronic, Pain Relief
Foundation, Pfizer, Schwarz, UCB Pharma, and UK Department of Health.

RKP has received research support, consulting fees, or honoraria in the
past year from Abbott, Ametek, Bayer, Biovail, Cephalon, Cytogel, Endo,
Forest, GlaxoSmithKline, GW Pharmaceuticals, Janssen, King, Ligand,
Medgenex, Merck, Mylan, Neuromed, Organon, Ortho McNeil, Painceptor,
Pfizer, Pharmos, Progenics, Sarentis, Solvay, UCB Pharma, Wex, and
Xenon.

ASCR has received research support, consulting fees, honoraria, or
travel expenses in the past two years from Amgen, Boehringer Ingelheim,
Eisai, Eli Lilly, GlaxoSmithKline, Novartis, Ono Pharma, Organon,
Pfizer, Sanofi Pasteur/MSD, Solvay, Spinifex, Trophus, and UCB Pharma.

BRS has received research support, consulting fees, or honoraria from
Celgene, DepoMed, Eli Lilly, and Pfizer.

RDT has received research support, consulting fees, or honoraria from
Allergan, Boehringer Ingelheim, Bundesministerium fur Bildung und
Forschung, Deutsche Forschungsgemeinschaft, GlaxoSmithKline, Grunenthal,
Merck Sharpe & Dohme, Pfizer, Schwarz, and US National Institute of
Health.

DCT has received consulting fees or honoraria in the past year from
Abbott, Alpharma, Astra-Zeneca, Celgene, Eli Lilly, GlaxoSmithKline,
PriCara/Ortho-McNeil, Schwarz, and Wyeth.

#### GUIDELINE STATUS

This is the current release of the guideline.

This updates a previous version: Dworkin RH, Backonja M, Rowbotham MC,
Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS,
Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader
KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM.
Advances in neuropathic pain: diagnosis, mechanisms, and treatment
recommendations. Arch Neurol 2003 Nov;60(11):1524-34. \[70 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14623723)

#### GUIDELINE AVAILABILITY

Electronic copies: Not available at this time.

Print copies: Available from Robert H. Dworkin, PhD, Department of
Anesthesiology, University of Rochester School of Medicine and
Dentistry, 601 Elmwood Avenue, Box 604, Rochester, NY 14642; Email:
<robert_dworkin@urmc.rochester.edu>.

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on May 4, 2004. The information
was verified by the guideline developer on May 20, 2004. This summary
was updated on May 3, 2005 following the withdrawal of Bextra
(valdecoxib) from the market and the release of heightened warnings for
Celebrex (celecoxib) and other nonselective nonsteroidal
anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI on
June 16, 2005, following the U.S. Food and Drug Administration advisory
on COX-2 selective and non-selective non-steroidal anti-inflammatory
drugs (NSAIDs). This summary was updated by ECRI on October 3, 2005,
following the U.S. Food and Drug Administration advisory on Paxil
(paroxetine). This summary was updated by ECRI on December 12, 2005,
following the U.S. Food and Drug Administration advisory on Paroxetine
HCL - Paxil and generic paroxetine. This summary was updated by ECRI on
May 31, 2006 following the U.S. Food and Drug Administration advisory on
Paxil (paroxetine hydrochloride). This summary was updated by ECRI on
November 15, 2006, following the FDA advisory on Lamictal (lamotrigine).
This summary was updated by ECRI on November 22, 2006, following the FDA
advisory on Effexor (venlafaxine HCl). This summary was updated by ECRI
Institute on November 6, 2007, following the U.S. Food and Drug
Administration advisory on Antidepressant drugs. This NGC summary was
updated by ECRI Institute on February 14, 2008. The updated information
was verified by the guideline developer on February 20, 2008.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
under the auspices of medical specialty societies, relevant professional
associations, public or private organizations, other government
agencies, health care organizations or plans, and similar entities.

Guidelines represented on the NGC Web site are submitted by guideline
developers, and are screened solely to determine that they meet the NGC
Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
concerning the content or clinical efficacy or effectiveness of the
clinical practice guidelines and related materials represented on this
site. Moreover, the views and opinions of developers or authors of
guidelines represented on this site do not necessarily state or reflect
those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or
hosting of guidelines in NGC may not be used for advertising or
commercial endorsement purposes.

Readers with questions regarding guideline content are directed to
contact the guideline developer.

Bottom of Form

© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008