Conditions: Sickle Cell Disease
Keywords: Pain control
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 90
Healthy volunteers: no

Brief summary:
This is a phase II double-blind placebo-controlled clinical trial evaluating the effect of gabapentin when added to standard pain management for patients with sickle cell disease experiencing acute pain crisis in the ambulatory care setting.

Sickle cell pain is different for every patient. Some patients get complete relief from routine pain medicines, and others need more time or more doses of pain medicines before the pain goes away completely. It is known that humans have many types of pain, including something called neuropathic pain. Neuropathic pain in other conditions (such as diabetes) has been treated successfully with a medicine called gabapentin. The investigators in this study suspect that some sickle cell pain is a combination of pain types. They would like to see if adding gabapentin to the usual pain medicines makes pain go away faster or more completely.

Primary Objective:

* To assess the analgesic efficacy of gabapentin vs. placebo for pain during vaso-occlusive crisis (VOC) in participants with sickle cell disease (SCD). A response to study drug will be defined by a decrease in pain score of ≥ 33% between presentation to the acute care setting and assessment at 3 hours post administration of study drug.

Secondary Objective:

* To compare the total morphine equivalent dose (mg/kg) used to control pain during VOC between presentation to the acute care setting and assessment at 3 hours post administration of study drug in the gabapentin vs. placebo groups.

Detailed description:
Upon participant enrollment, study staff will randomize the participant to one of 2 possible treatment arms: a single dose of gabapentin or a single dose of placebo. Morphine or other opioid and non-steroidal anti-inflammatory drugs will be available to both groups as needed for pain and will be administered according to the current standard of care for pain in VOC from the Department of Hematology at St. Jude Children's Research Hospital (SJCRH). Randomization will be performed in the SJCRH pharmacy by a pharmacist. The randomization will be stratified by three age categories (1-3 years of age, 4-6 years, and 7 years or older) for which distinct pain assessment tools are applied and for 2 pain score categories at assessment at presentation (4-6 and 7-10, respectively). A block randomization with block sizes varying randomly between 4 and 6 will be used in each stratum.

Pain scores will be obtained at presentation to the acute care setting and 3 hours (± 15 minutes) post administration of study drug. Participants who were discharged will be contacted by study staff between 24 and 72 hours following administration of study drug to see if there have been any side effects. Patients who were admitted after administration of the study drug will be monitored through hospital record to determine if any unexpected events occurred. After this follow up, participation in the study is complete.

Arms:
arm 1: Patients will be randomized to receive one dose of gabapentin. arm 2: Patients will be randomized to receive one dose of placebo.

Interventions: intervention 1: Gabapentin intervention 2: Placebo
Intervention descriptions: intervention 1: Gabapentin is supplied as an oral suspension. Patients randomized to the gabapentin arm will receive a single dose of gabapentin as soon after enrollment as feasible. The gabapentin dose will be given orally and will be approximately 15 mg/kg with a maximum dose of 900 mg. intervention 2: Placebo will be prepared by the SJCRH pharmacy and will be similar in appearance, quantity and taste to the gabapentin drug. Patients randomized to the placebo arm will receive a single dose of placebo as soon after enrollment as feasible. The placebo dose will be given orally and will be approximately 15 mg/kg with a maximum dose of 900mg.

Protocol document:
Prot_SAP_000.pdf: 
 
Revision 3.2, dated: 10-12-2017 
 
 
 
 
IRB Approval date: 07-02-2018 
Protocol document date: 06-20-2018 
   
 
 
  
 
 
 
 
St. Jude 
PMVOC ID# NCT01954927 
Initial version, dated:  02-28-2013, (IRB Approved: 06-25-13) Activation date 00-00-00 
Amendment 1.0, dated 08-16-13 (IRB Approved: 09-24-13) Activated: 10-07-13 
Amendment 2.0, dated 03-28-2014 (IRB Approved: 05-13-14) Activated: 05-21-14 
Revision 2.1, dated 6-19-14 (IRB Approved: 07-19-14) Activated: 07-24-14 
Amendment 3.0, dated 12-02-2014 (IRB Approved: 02-24-2015) Activated: 03-30-2015 
Revision 3.1, dated 1-25-16 
Un-numbered Revision, dated: 08-28-2017 (IRB Approved: 09-15-2017) 
Revision 3.2, dated: 10-12-2017, (IRB Approved: 11-16-2017) 
Un-numbered Revision, dated: 06-20-2018 (IRB Approved: 07-02-2018) 
 
 
 
PAIN MANAGEMENT OF VASO-OCCLUSIVE CRISIS IN CHILDREN AND 
YOUNG ADULTS WITH SICKLE CELL DISEASE 
IND/IDE # 119125 
 
 
 
 
 
Principal Investigator: 
Doralina Anghelescu, MD 
Division of Anesthesiology 
 
 
 
 
 
Co-Investigators: 
Jane Hankins, MD1 
Latika Puri, MD1 
Guolian Kang, PhD3 
Chen Li3 
 
 
1Department of Hematology 
2Division of Anesthesiology 
3Department of Biostatistics 
 
 
 
 
 
 
 
 
 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee  38105-3678 
Telephone:  (901) 595-3300 
 


 
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IRB Approval date: 07-02-2018 
Protocol document date: 06-20-2018 
   
 
 
  
 
 
 
 
                               Contents of this document may not be extracted without permission from the Principal Investigator. 
 
PMVOC - Pain Management of Vaso-occlusive Crisis in Children and Young Adults 
with Sickle Cell Disease 
Principal Investigators: Doralina Anghelescu, MD and Kerri Nottage, MD 
IND Holder: St. Jude Children’s Research Hospital, # 119125 
Brief Overview: This is a phase II double-blind placebo-controlled clinical trial 
evaluating the effect of gabapentin when added to standard pain management for patients 
with sickle cell disease experiencing acute pain crisis in the ambulatory care setting. 
Patients will be randomized to receive a single oral dose of gabapentin or placebo as soon 
as feasible after enrollment.  Pain scores and opioid requirement will be measured and 
compared across treatment arms, along with the outcomes of discharge from clinic versus 
admission to the inpatient unit.   
Intervention: Gabapentin 15mg/kg vs placebo (single dose by mouth) 
Brief Outline of Treatment Plan: Participants will receive a single dose of study drug 
by mouth as soon as feasible after enrollment, while standard pain management is 
provided concurrently.  The remainder of care for the painful event will continue per 
institutional standards according to clinical indication, including reassessment and 
documentation of pain and additional doses of pain medicines by IV or oral route.  
Treating clinicians will determine if the patient may be discharged home or if admission 
is warranted.   
Study Design: Phase II double-blind placebo-controlled therapeutic trial. 
Sample Size: 166 participants divided evenly between active and placebo arms.  
Data Management:  Data management and statistical analysis will be provided locally 
by the Anesthesia Division and Biostatistics Department at St. Jude Children’s Research 
Hospital 
Human Subjects:  The risks to subject will be related to the toxicity of gabapentin.  The 
expected side effect is somnolence.  Patients will be informed of this and other minor 
side effects during informed consent discussion.  Adverse events will be monitored and 
reported and treated appropriately. 


 
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Table of Contents  
 
List of Collaborating Investigators/Institutions 
Protocol Summary 
 
1.0     OBJECTIVES ..................................................................................................1 
1.1   Primary Objective....................................................................................1 
1.2   Secondary Objectives ..............................................................................1 
1.3   Exploratory Secondary Objectives ..........................................................1 
Figure 1: Pain assessment time points and study objectives…...………...….2 
2.0     BACKGROUND AND RATIONALE ............................................................3 
2.1   Background .............................................................................................3 
Table 1: Summary of results of gabapentin for surgical pain presented by Straube, 
et al in a Cochrane Review, 2010, page 8 [15]………………………………5 
Table 2: Characteristics of the studies included in the Peng (2007) 
 meta-analysis .………………………………………………………………9 
Table 3: Randomized Controlled Trials investigating gabapentin for surgical pain, 
2010 – 2013………………………………………………………………….11 
2.2   Rationale ..................................................................................................15 
3.0     RESEARCH PARTICIPANT ELIGIBILITY CRITERIA 
          AND STUDY ENROLLMENT ......................................................................16 
3.1   Inclusion Criteria .....................................................................................16 
3.2   Exclusion Criteria ....................................................................................16 
3.3   Research Participant Recruitment and Screening ...................................17 
3.4   Enrollment on Study ................................................................................17 
3.5   Procedures for Identifying and Randomizing Research Participants…..18 
4.0     TREATMENT PLAN ......................................................................................18 
4.1   Treatment.................................................................................................18 
4.2   Dose Modifications .................................................................................19 
4.3   Concomitant Therapy ..............................................................................18 
4.4   Supportive Care .......................................................................................19 
5.0     DRUG INFORMATION .................................................................................19 
5.1   Gabapentin (Neurontin®)…………………………………………..…..19 
5.2   Placebo………………………………………………………………….21 
6.0     REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ................21 
6.1   Pre-Study Evaluations .............................................................................21 
6.2   Evaluations during Therapy ....................................................................22 
6.3   Response Evaluations ..............................................................................22 
6.4   Off-Study Evaluations .............................................................................22 
6.5   Long-Term Follow-up Evaluations .........................................................23 
7.0     EVALUATION CRITERIA ............................................................................23 


 
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7.1   Response Criteria ....................................................................................23 
7.2   Toxicity Evaluation Criteria  ...................................................................23 
8.0     OFF THERAPY AND OFF STUDY CRITERIA ...........................................23 
8.1  Off Therapy Criteria  ..............................................................................24 
8.2  Off Study Criteria. ..................................................................................24 
9.0    SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS .........24 
9.1   Reporting Adverse Experiences and Deaths ...........................................24 
           9.2   Reporting to the Sponsor and/or Federal Agencies ................................25 
           9.3   Emergency Unblinding ...........................................................................26 
10.0    DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY 
 
10.1  Data Collection .......................................................................................26 
 
10.2  Study Monitoring....................................................................................26 
10.3  Confidentiality ........................................................................................28 
11.0    STATISTICAL CONSIDERATIONS............................................................28 
11.1  Sample Size ............................................................................................28 
11.2  Randomization ........................................................................................29 
11.3  Statistical Analysis………………………………………………………30 
12.0    OBTAINING INFORMED CONSENT .........................................................32 
12.1    Consent at Age of Majority……………………………………………….....32 
13.0    REFERENCES ...............................................................................................33 
Appendices 
Appendix I: Schedule of Evaluations 
Appendix II: Tests Performed for Good Clinical Care 
Appendix III:  Recruitment Materials 
Appendix IV: Gabapentin Drug Formulation 
Appendix V: Gabapentin Placebo Drug Formulation 


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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
To assess the analgesic efficacy of gabapentin (vs. placebo) for pain during 
vaso-occlusive crisis (VOC) in participants with sickle cell disease (SCD). A 
response to study drug will be defined by a decrease in pain score of ≥33% 
between presentation to the acute care setting and assessment at 3 hours post 
administration of study drug. 
 
1.2 
Secondary Objective 
 
To compare the total morphine equivalent dose (mg/kg) used to control pain 
during VOC between presentation to the acute care setting and assessment at 3 
hours post administration of study drug in the gabapentin vs. placebo groups.  
 
1.3      Exploratory Objectives 
 
1.3.1 To assess the analgesic efficacy of gabapentin (vs. placebo) for pain 
during VOC in participants with SCD, as defined by a decrease in pain 
scores of ≥33% between presentation to the acute care setting and the 
point of decision for either hospital admission or discharge to home, in 
the gabapentin and placebo groups. 
1.3.2 To compare the total morphine equivalent dose (mg/kg) used to control 
pain during VOC between presentation to the acute care setting and the 
point of decision for either admission or discharge to home, in the 
gabapentin and placebo groups. 
1.3.3 To compare the rate of admission related to pain management, in the 
gabapentin vs. placebo groups. 
1.3.4 To compare the change in pain score from time of administration of 
study drug to assessment at 3 hours post administration of study drug in 
the gabapentin vs. placebo groups. 
1.3.5 To compare the change in pain score from time of administration of 
study drug to the point of decision for either admission or discharge to 
home, in the gabapentin and placebo groups. 
 
 
 


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Figure 1. Pain Assessment Time Points and Study Objectives 
Objective 1.3.1: Decrease in pain score by ≥33% from presentation until decision to admit/discharge patient 
Objective 1.2: Morphine requirement from presentation until 3h post 
study drug 
Objective 1.3.4: Change in pain score 
from study drug until 3h post study 
Objective 1.1: Decrease in pain score by ≥33% from baseline until 3h 
post study drug 
Objective 1.3.5: Change in pain score from study drug until 
admit/discharge 
Objective 
1.3.3: Rate 
of 
admission 
Objective 1.3.2: Morphine requirement from presentation until decision to admit/discharge patient from ACU 
Pr
es
en
ta
ti
o
n 
to 
A
St
ud
y 
Dr
ug 
Ad
mi
nis
tra
tio
3h 
after 
study 
drug 
 (+/- 
30 
minut
A
d
mi
ssi
on 
/ 
dis
ch


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2.0  
BACKGROUND AND RATIONALE 
 
 
2.1 
Background:  
 
Gabapentin has been used successfully to treat neuropathic pain [1-3], and 
nociceptive pain [4].  The mechanism of action is binding of the α-2-δ subunits of 
the voltage-dependent calcium ion channels, which blocks the development of 
hyperalgesia and central sensitization [5, 6].  The reasons for the effectiveness of 
gabapentin for nociceptive pain are based on several considerations: 
 
1. 
Gabapentin has been shown to prevent central sensitization, manifested as 
hyperalgesia, a known phenomenon in postoperative pain [7].  The 
mechanism for reduction of central sensitization is the reduction of 
hyperexcitability of secondary nociceptive neurons in the dorsal horn, 
through suppressing the release of excitatory amino acids in the spinal cord 
in response to noxious stimuli [8]. 
2. 
Gabapentin and morphine may be synergistic due to separate actions on the 
peripheral and central nervous system [9]. 
3. 
Gabapentin may decrease the postoperative morphine requirement by 
preventing the development of opioid tolerance [10]. 
Sixteen randomized controlled trials were included in a systematic review of 
gabapentin use for postoperative pain [4]. 
Among three different gabapentin regimens including a single dose of 1200 mg 
preoperatively, a <1200 mg single dose preoperatively, multiple doses 
perioperatively (both preoperatively and postoperatively), the regimens of single 
doses of 1200 mg or less were found effective by two measures of analgesic 
efficacy: 1) reduced pain intensity scores, and 2) reduced opioid consumption for 
the first 24 hours postoperatively. The single dose regimen of 1200 mg also 
prolonged the time to first request for rescue analgesia with opioid. 
In a randomized controlled study of gabapentin 15 mg/kg single dose versus 
placebo in children aged 9 to 18 years undergoing spinal fusion surgery, the 
investigators found a significant decrease in the total morphine consumption in 
the gabapentin group, in the recovery room, and at postoperative day 1 and 2 [11]. 
The pain scores were also significantly decreased in the gabapentin group in the 


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recovery room and at postoperative day 1.  In this study, gabapentin versus 
placebo was administered postoperatively for 5 days, at doses of 5 mg/kg TID; the 
analgesic benefit of gabapentin was only found for the first 2 days postoperatively 
based on diminished opioid consumption and only for the first postoperative day 
based on both decreased opioid consumption and decreased pain scores. The 
authors concluded that perioperative use of gabapentin seems to be an effective 
adjunct to improve pain control and is recommended as an initial loading dose of 
gabapentin and continued treatment for 2 days after spinal fusion surgery. 
The current algorithms for management of pain associated with VOC in SCD are 
not satisfactory.  The most effective pain treatment should intervene early in the 
course of a VOC, in the prodromal phase; early intervention could prevent or 
minimize tissue damage [12].  If we can demonstrate that a therapeutic 
intervention with a single dose of gabapentin can provide analgesic efficacy, this 
drug could be utilized as an early intervention, which can be initiated at home, in 
the prodromal phase of a VOC. 
In addition to ample evidence of efficacy for management of neuropathic pain, 
gabapentin has proven opioid-sparing effects in an acute pain setting, that of acute 
postoperative pain, in adults [13, 14] and children [11].  The regimen applied in 
the pediatric postoperative setting, in children 9 to 18 years, was gabapentin 15 
mg/kg versus placebo, given preoperatively.  After surgery, the regimen 
continued as 5 mg/kg or placebo 3 times a day for 5 days.  This regimen of an 
initial preoperative loading dose and continued oral gabapentin postoperatively 
decreased the total morphine consumption and pain scores up to 2 days 
postoperatively, but no benefit was demonstrated beyond 2 days.   
 
Additional Literature review of gabapentin for acute postoperative pain 
Cochrane review 
A Cochrane review has evaluated the single oral dose, randomized, double-blind, 
placebo-controlled trials of gabapentin for relief of established moderate to severe 
postoperative pain in adults (>15 yrs) [15]; the dose evaluated in the review was a 
250 mg single dose administered preoperatively.  Studies were assessed for 
methodological quality and data extracted by two review authors independently.  
Numbers of participants with at least 50% of maximum possible total pain relief 
(TOTPAR) or summed pain intensity difference (SPID) with gabapentin or 
placebo were calculated and used to derive relative benefit (RB) or risk (RR), and 
number-needed-to-treat-to-benefit (NNT).  Numbers of participants using rescue 


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medication, and time to its use, were sought as additional measures of efficacy. 
Information on adverse events and withdrawals was collected.  Four unpublished 
studies met inclusion criteria; in three, participants had pain following dental 
surgery, and one followed major orthopedic surgery; 177 participants were treated 
with a single dose of gabapentin 250 mg, 21 with gabapentin 500 mg, and 172 
with placebo. At least 50% pain relief over 6 hours was achieved by 15% with 
gabapentin 250 mg and 5% with placebo; giving a RB of 2.5 (95% CI 1.2 to 5.0) 
and an NNT of 11 (6.4 to 35).  Significantly fewer participants needed rescue 
medication within 6 hours with gabapentin 250 mg than with placebo; NNT to 
prevent use 5.8.  About one third of participants reported adverse events with both 
gabapentin 250 mg and placebo.  No serious adverse events occurred with 
gabapentin.  The authors’ conclusions were that gabapentin 250 mg is statistically 
superior to placebo in the treatment of established acute postoperative pain, but 
the NNT of 11 for at least 50% pain relief over 6 hours with gabapentin 250 mg is 
of limited clinical value and inferior to commonly used analgesics.  Gabapentin 
250 mg is not clinically useful as a stand-alone analgesic in established acute 
postoperative pain, though this is probably the first demonstration of analgesic 
effect of an antiepileptic in established acute pain.   
 
Table 1.  Summary of results of gabapentin for surgical pain presented by Straube, et al in a Cochrane 
Review, 2010, page 8 [15] 
Summary of results: gabapentin 250 mg versus placebo 
Outcome 
Studies Gabapentin 
(%) 
Placebo 
(%) 
Summary statistic 
Number of participants with ≥50% pain 
relief over 6 hours 
3 
15 
5 
NNT: 11 (6.4 to 35) 
Number of participants using rescue 
medication over 6 hours 
3 
68 
86 
NNTp: 5.8 (3.8 to 12) 
Number of participants with ≥1 adverse 
event 
3 
28 
32 
NNH: not calculated 
 
Based on the evidence that low dose gabapentin (250 mg, approximately 3-
5mg/kg in adults) has limited efficacy, we propose a higher dose regimen in our 
study intervention, at 15 mg/kg, maximum 900 mg. 
Meta-analyses and systematic reviews 


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Three meta-analyses [16-18] and one systematic review [4] provide reviews of 
placebo controlled RCTs of the use of gabapentin for perioperative pain control in 
adults.  The systematic review [4] included 16 RCTs in the analysis.  A total of 
1151 patients were studied, of whom 614 patients received gabapentin. 
Gabapentin was given as a single preoperative dose in 11 [13, 19-27], as two 
separate preoperative doses in 1 [28], and as more than two doses in the 
perioperative period in four clinical trials [14, 29-31].  The dosages of gabapentin 
administered ranged between 300 and 1200 mg. To facilitate quantitative analysis, 
three subgroups were created: (i) group receiving single dose of gabapentin 1200 
mg preoperatively; (ii) group receiving single dose of gabapentin less than 1200 
mg preoperatively; and (iii) group receiving multiple doses of gabapentin in the 
perioperative period.  Pain intensity, total analgesic consumption and time to first 
request for rescue analgesia were analyzed separately in each subgroup.   
Eight trials used a single preoperative dose of 1200 mg gabapentin in the 
treatment group [13, 19, 22, 24-27, 32] Combined data on pain intensity in six 
studies [13, 21, 22, 25-27, 32] showed a significant decrease in pain intensity at 
rest with gabapentin compared with control in the early by weighted mean 
differences (WMD, -16.55 mm; 95% CI -25.66 to -7.44) and late (WMD, -10.87 
mm; 95% CI -20.90 to -0.84) postoperative period at 6 and 24 h, respectively.  
Combined data from three studies that reported on opioid consumption at 24 h 
[13, 22, 24] showed that the WMD of -27.9 mg (95% CI -31.52 to -24.29) was in 
favor of gabapentin.  Meta-analysis of the two studies with data on the time to 
first request for rescue analgesic [13, 32] showed that gabapentin produced a 
statistically significant delay in time to first request for analgesia (WMD 7.42 
min; 95% CI 0.49–14.34). 
Five studies with seven treatment arms used a single preoperative dose of 
gabapentin that was less than1200 mg [20-23, 27]. The dose range was between 
300 and 900 mg.  Combined data from all five RCTs showed a statistically 
significant decrease in pain intensity at rest with gabapentin compared with 
control in the early postoperative period at 6 h (WMD, -22.43 mm; 95% CI -27.66 
to -17.19).  Combined data from four RCTs [20-23] showed lower pain scores at 
rest in the gabapentin group in the late postoperative period at 24 h (WMD, -13.18 
mm; 95% CI -19.68 to -6.68).  Combined data from four RCTs [20-23] showed 
that gabapentin reduced postoperative morphine consumption compared with 
control (WMD, -15.98 mg; 95% CI -23.45 to -8.50).  None of the five studies 
measured time to first analgesia as an outcome. 


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Five studies reported gabapentin given as multiple doses perioperatively.  
Gabapentin was administered as follows in these five studies: 1) two separate 400 
mg doses preoperatively [28]; 2) 600 mg 1 h preoperatively and then three times a 
day for 24 h postoperatively [30]; 3)1200 mg of gabapentin before surgery 
followed by 600 mg 8 hourly for an additional three doses [29]; 4) 400 mg 
gabapentin the night before surgery and then 400 mg three times a day for 10 days 
[14]; and 5)1200 mg gabapentin preoperatively, followed by 1200 mg on the 
morning of the first and second postoperative day [31].  Only two out of the five 
trials had data suitable for meta-analysis for the pain intensity outcome measure 
[14, 30]; the combined data did not show any difference between gabapentin and 
control groups at both 6 and 24 h after surgery.  Only one study measured 24 h 
morphine consumption as an outcome [31]: it showed a 24% reduction in total 
patient-controlled analgesia morphine usage in the gabapentin group compared 
with the control group.  Only one study presented the time to first request for 
rescue analgesic data as an outcome and reported no difference between the 
gabapentin and control groups [14]. 
This systematic review demonstrated that preoperative gabapentin administration 
was useful for postoperative pain management.  A single preoperative dose of 
gabapentin, 1200 mg or less, effectively reduced pain intensity and opioid 
consumption for the first 24 h after surgery.  In the subgroup that received a single 
1200 mg of gabapentin preoperatively, the time to first request for rescue 
analgesia was also prolonged.  However, multiple dosing with gabapentin 
preoperatively and continued postoperatively did not appear to reduce VAS pain 
scores. 
This systematic review therefore demonstrates a potential role for preemptive 
gabapentin as an adjunct to standard postoperative pain management.  In the 
groups receiving a single dose of gabapentin preoperatively, the reduction in pain 
scores appeared to be more pronounced in the early postoperative period.  
However, this reduction was still significant at 24 h and was 
associated with a significant reduction in opioid consumption.  
The conclusion of the systematic review was that perioperative administration of 
gabapentin is effective in reducing pain scores, opioid requirements and opioid-
related adverse effects in the first 24 h after surgery.  Sedation was associated 
with its use but no serious adverse effects were observed. 
One meta-analysis [18] evaluated eighteen studies [13, 14, 19-34] encompassing 
1181 patients; mean ages ranged from 29 to 52 years of age.  The most common 


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dose of gabapentin assessed was1200 mg daily (12 studies), with some studies 
using doses as low as 300 mg daily (Table 2).   Eleven studies [13, 19-27, 32] 
administered gabapentin as a single dose within 1 h to 2 h before surgery; the 
remainder involved initiating therapy on the day before surgery or continuing it 
for up to 10 days after surgery (Table 2).  Gabapentin caused a significant 
reduction in postoperative pain at rest [13, 14, 19-31, 33, 34] in the first 24 h, by 
27% to 39% (7.2 mm to 14.3 mm on a scale of 0 mm to 100 mm), regardless of 
whether treatment effects were expressed as ratios of means or weighted mean 
differences.  Similarly, aside from 24 h after surgery, gabapentin significantly 
reduced pain with movement [13, 14, 19, 20, 25, 28-30, 33] by 18% to 28% (VAS 
8.2 mm to 10.2 mm) after surgery.  Fourteen studies [14, 19, 20, 22, 23, 25-27, 
33], encompassing 1027 participants, reported effects on cumulative 24 h 
analgesic consumption.  Gabapentin resulted in a 35% reduction in total analgesic 
consumption over the first 24 h following surgery (ratio of means 0.65, 95% CI 
0.59 to 0.72; P<0.001), albeit with significant heterogeneity (I2=84.4%).  The 
data on time to first analgesic was available in three studies [13, 24, 32], (171 
patients); it was delayed 7.9 min by gabapentin (95% CI 4.2 to 11.6; P<0.001), 
with minimal heterogeneity (I2=0%). 
This meta-analysis concluded that perioperative administration of gabapentin 
reduces pain scores, both at rest and with movement following various surgeries, 
lengthens the time for analgesic rescue, decreases the consumption of opioids and 
lowers rates of opioid-related side effects. The pain score at rest was reduced by 
27% to 39% (VAS 7.2 mm to 14.3 mm on a 
scale of 0 mm to 100 mm) during the first 24 h, and the pain score with movement 
was reduced by 18% to 28% (VAS 8.2 mm to 10.2 mm) in the first 12 h. 
The two meta-analyses on the topic of perioperative use of gabapentin published 
prior to Peng’s meta-analysis of 18 studies were less extensive and included only 
eight [16], and 12 [17] studies, respectively; therefore they are not included in this 
literature review. 
The evidence of effectiveness of gabapentin as an adjunct to reduce acute 
postoperative pain has further generated the question of whether gabapentin 
would also be effective in preventing chronic post-surgical pain.  A recent 
combined systematic review and meta-analysis reviewed the effectiveness of 
gabapentin and pregabalin in the perioperative period for the prevention of 
chronic post-surgical pain [35] and concluded that perioperative administration of 
gabapentin and pregabalin is effective in reducing the long-term incidence of 
chronic post-surgical pain. 


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Table 2.  Characteristics of the studies included in the Peng (2007) meta-analysis 
Study  
Procedure  
n  
Treatment arm  
Control 
arm              
Anesthesia  
Gynecological procedures 
Dierking et al (34)  
Abdominal hysterectomy  
80 
Gabapentin 1200 mg 1 h before surgery, and 600 mg 8 h, 16 h and 24 h after initial 
dose 
Placebo 
General  
Gilron et al (35)  
Abdominal hysterectomy  
52 
Gabapentin 1800 mg daily starting 1 h before surgery to postoperative day 2 
Placebo  
General  
Rorarius et al [32] 
Vaginal hysterectomy  
90 
Gabapentin 1200 mg 150 min before surgery 
Oxazepam 
15 mg  
General  
Turan et al [25]  
Abdominal hysterectomy 
50 
Gabapentin 1200 mg 1 h before surgery  
Placebo  
General  
Turan et al [34]*  
Abdominal hysterectomy 
50 
Gabapentin 1200 mg daily starting 1 h before surgery to postoperative day 2 
Placebo  
General  
Yoon et al [33] 
Abdominal hysterectomy  
32 
Gabapentin 800 mg before surgery (400 mg the night before surgery and 400 mg 30 
min before surgery)   
Placebo 
General  
Orthopedic procedures 
Menigaux et al [13]  
Knee surgery  
40 
Gabapentin 1200 mg 2 h before surgery  
Placebo  
General  
Pandey et al [21] 
Spine surgery  
56 
Gabapentin 300 mg 2 h before surgery  
Placebo  
General  
Pandey et al [22] 
Spine surgery  
100 
Any of four doses of gabapentin (300 mg, 600 mg, 900 mg or 1200 mg) 1 h before 
surgery 
Placebo  
General  
Radhakrishnan et al [28] 
Spine surgery  
60 
Gabapentin 800 mg before surgery (400 mg the night before surgery and 400 mg 2 h 
before surgery)  
Placebo  
General  
Tuncer et al [27] 
Major orthopedic surgery  
45 
Any of two doses of gabapentin (800 mg or 1200 mg) 1 h before surgery 
Placebo  
General  
Turan et al [24]  
Spine surgery  
50 
Gabapentin 1200 mg 1 h before surgery  
Placebo  
General  
Turan et al [31]  
Lower limb surgery  
40 
Gabapentin 1200 mg daily starting 1 h before surgery to postoperative day 2  
Placebo  
General & 
epidural 
Other procedures 
Dirks et al [19]  
Breast surgery  
70 
Gabapentin 1200 mg 1 h before surgery  
Placebo  
General  
Fassoulaki et al [14]† 
Breast surgery  
50 
Gabapentin 1200 mg daily starting evening before surgery to postoperative day 10 
Placebo  
General  
Pandey et al [20]  
Laparoscopic cholecystectomy 
206 
Gabapentin 300 mg 1 h to 2 h before surgery  
Placebo  
General  
Pandey et al [23]    
Open nephrectomy  
60 
Gabapentin 600 mg either 2 h before surgery or following surgical incision. 
  
  
Turan et al [26]  
Ear-nose-throat surgery  
50 
Gabapentin 1200 mg 1 h before surgery  
Placebo  
Sedation  
*Additional two arms that assessed celecoxib (alone and in conjunction with gabapentin) were excluded; †Additional arm that assessed mexilitene was excluded 


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Other RCTs of gabapentin in the perioperative period (2010-2013) 
Clinical studies with a RCT design, published recently (2010-2013) and not included 
in any previous meta-analyses or systematic reviews, are presented in Table 3.  Of 20 
RCTs, 16 found a positive outcome for at least one outcome measure, while 4 studies 
had negative or inconclusive results.  The only pediatric study [11] is also included in 
Table 3. 
Based on the comprehensive literature review, which is suggestive of the efficacy of 
gabapentin for nociceptive acute postoperative pain, we propose that the nociceptive 
pain encountered in the VOC crisis could also be responsive to the addition of 
gabapentin to the other two classes of medications representing the current standard 
of care, opioids and non-steroidal anti-inflammatory drugs.  
Based on evidence that a single dose regimen has better analgesic efficacy than multi-
dose regimens, we proposed a single dose of gabapentin of 15mg/kg, maximum 
900mg.


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Table 3.  Randomized Controlled Trials investigating gabapentin for surgical pain, 2010 – 2013. 
Author, Year 
[Reference] 
n 
(analyzed) Population 
Intervention 
Outcome measure 
Results 
Paul, 2013 
[36] 
101 
Total Knee 
Arthroplasty, adults 
PBO vs Gaba 600mg 
preop + 200mg q8h 
x2d 
Cumulative morphine consumption at 
72h;  pain scores and pt satisfaction 
- 
No effect on morphine consumption;  No effect on pain 
scores or pt satisfaction 
Clarke, 2013 
[37] 
50  
(44) 
Adult females with 
anxiety + surgery 
PBO vs Gaba 1200 
preop 
Reduction in preop anxiety 
+ 
gabapentin prior to surgery reduces preoperative anxiety 
scores and pain catastrophizing scores and increases 
sedation prior to entering the operating room. 
Lee, 2013 
[38] 
80  
(71) 
Elective thyroid 
surgery, adults 
PBO vs Gaba 600mg 
preop 
Reduction of incidence of postop sore 
throat at rest and during swallow; 
Reduction of intensity of postop sore 
throat at rest and during swallow 
+ 
gaba reduced sore throat incidence and intensity at rest, 
but not during swallow. 
Short, 2012 
[39]  
132 
(126) 
Elective cesarean 
delivery, adult 
women 
PBO vs Gaba 600mg 
preop vs Gaba 
300mg preop 
Pain on movement at 24h; pt 
satisfaction, supplimental opioid, other 
endpoints related to childbearing 
none Results did not reach statistical significance, insufficient 
power to detect difference 
Adam, 2012 
[40] 
64 
Surgery under GA, 
adults 
PBO vs Gaba 
1200mg 
Reduction of preop anxiety; preop 
sedation without amnesia 
+ 
Statistically significant decrease of one anxiety measure, 
decrease (not stat sig) of second anxiety measure.  No 
significant differences in sedation or memory or pt 
satisfaction 
Ajori, 2012 
[41] 
170 
(130) 
Abdominal 
hysterectomy, adult 
women 
PBO vs Gaba 600mg 
preop 
Reduction of postop pain; opioid, 
antiemetic consumption at 24h 
+ 
Significant decreases in all measures. 
Kinney, 2012 
[36] 
120 
elective thoracotomy, 
adults 
active PBO vs Gaba 
600mg preop 
Pain scores, opioid consumption, side 
effects x48h 
- 
No analgesic benefit 
Behdad, 2012 
[42] 
61 
Abdominal 
hysterectomy, adult 
women 
PBO vs Gaba 
(100mg 1 day prior, 
300mg 2h preop) 
Pain, nausea, vomiting, vitals, 
morphine use 
+ 
Except in the first hour after operation (p = 0.02), there 
was no significant differences between the two groups in 
morphine use. 


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Author, Year 
[Reference] 
n 
(analyzed) Population 
Intervention 
Outcome measure 
Results 
Deniz, 2012 
[43] 
51 
Radical retropubic 
protatectomy, adult 
males 
Gaba 900mg preop 
vs none 
Opioid consumption, pain scores, 
rescue analgesia 
+ 
Lower pain scores and reduced rescue analgesia; no 
difference in opioid consumption. 
Ozgencil, 
2011 
[44] 
90 
laminectomy and 
discectomy, adults 
PBO vs Gaba 600 vs 
Pregaba 150mg q12h 
x2 preop 
morphine consumption, pain scores, 
preop anxiety, pt satisfaction 
+ 
Both gaba and pregaba showed significant positive effects 
in all measurement categories. 
Panah- Khahi, 
2011[45] 
64 
Lower extremity 
orthopedic surgery, 
adults 
PBO vs 300mg Gaba 
preop 
Pain scores, time to rescue opioid, 
total opioid consumption 
+ 
Pain scores significantly lower at 2h, no differences later. 
Ucak, 2011 
[46] 
40 
CABG, adults 
PBO vs Gaba 1200 
preop and x2d 
pain (at rest and coughing), tramadol 
use 
+ 
Gabapentin significantly reduced the intensity of pain and 
tramadol consumption in the early postoperative period 
after CABG surgery. Pain scores at 1 and 3 months after 
surgery were low in both groups, with no significant 
difference between the groups. 
Spence, 2011 
[47] 
70 
Shoulder 
arthroscopy, adults 
PBO vs Gaba 300mg 
preop then BID x2d 
Average pain scores; opioid 
consumption, AE, sleep 
- 
No analgesic benefit 
Ghai, 2011 
[48] 
90 
Abdominal 
hysterectomy, adult 
women 
PBO vs Gaba 900 vs 
300 Pregaba preop 
Analgesic consumption x24h; pain 
scores, time to rescue analgesia 
+ 
Significantly lower analgesic consumption for both Gaba 
and Pregaba vs placebo; Pain scores lower for first hour 
then no differences; rescue analgesia time lowest for 
pregaba then gaba then PBO. 
Khan, 2011 
[49] 
175 
lumbar laminectomy, 
adults 
7 groups: 600, 900, 
1200mg gaba preop 
vs postop vs PBO 
Morphine consumption, time to rescue 
analgesia, pain scores 
+ 
Gabapentin 900 or 1200 mg, administered either pre- or 
post-incision, was found to be effective in pain 
management following lumbar laminectomy. Similar 
doses of gabapentin provide  he same post-operative 
analgesia whether administered pre- or post-incision. 
Moore, 2011 
[50] 
46  
(44) 
Cesarean delivery, 
adult women 
PBO vs Gaba 600mg 
Pain scores, satisfaction, opioid 
consumption, side effects; neonatal 
interventions 
+ 
Preoperative gabapentin 600 mg in the setting of 
multimodal analgesia reduces postcesarean delivery pain 
and increases maternal satisfaction in comparison with 
placebo.  Opioid consumption did not differ. 


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Author, Year 
[Reference] 
n 
(analyzed) Population 
Intervention 
Outcome measure 
Results 
Syal, 2010 
[51] 
120 
Open 
cholycystectomy, 
adults 
4 groups: PBO, 
APAP 1000mg, Gaba 
1200mg, APAP + 
Gaba; administered 
preop 
Rescue analgesic (time, number, and 
total amount); pain score (rest and 
mvmt) 
+ 
Group 3 had lower pain scores at rest and on movement at 
all time intervals in comparison to the Group 1. Similarly 
Group 4 had lower pain scores at rest and on movement at 
all time intervals in comparison to the Placebo Group. 
Patients who consumed Gabapentin alone had lower 
scores at all time intervals in comparison to Group 2 but 
the difference in resting score was statistically significant 
only at 0, 1, 2 and 24 hours post-operatively while 
movement score was statistically significant at all time 
intervals except at 6 hours 
Bang, 2010 
[52] 
46 
Arthroscopic rotator 
cuff repair, adults 
PBO vs Gaba 200mg 
preop 
Pain scores; opioid consumption and 
side effects 
+ 
Significant decrease in pain scores, no difference in opioid 
consumption 
Amr, 2010 
[53] 
150 
Partial or radical 
mastectomy, adult 
women 
PBO vs Gaba 
300mg/d vs 
venlafaxine 37.5 
mg/d 
Pain scores, analgesic requirements 
+ 
Pain after movement was reduced by gabapentin from the 
second to tenth postoperative day but no difference was 
found regarding pain during rest. Gabapentin reduced 
morphine consumed in the first 24 hours postoperatively. 
The analgesic requirements from the second to tenth days 
were reduced compared to the control group.  
Rapchuk, 2010 
[54] 
60 
Cardiac surgery, 
adults 
PBO vs Gaba 
1200mg preop and 
600mg BID x2d 
Postop opioid, pain, sleep, pt 
satisfaction 
none No differences 
Rusy, 2010 
[11] 
59 
Spinal fusion, 
Pediatric 
PBO vs Gaba 
15mg/kg preop and 
5mg/kg TID 
total morphine consumption, pain 
scores 
+ 
Significantly less morphine used, reduced pain scores 
initially. 
 
 
 


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There is emerging evidence that patients with SCD experience neuropathic 
pain as a component of their acute pain episodes. Allodynia and hyperalgesia 
are symptoms commonly experienced by patients with SCD and are defining 
characteristics of neuropathic pain [55]. In one survey of adult patients seen at 
a SCD specialty clinic, 90% of 145 patients verbalized pain descriptors 
consistent with neuropathic pain [56]. Another evaluation of 56 SCD patients 
age >14 years revealed that 40% experienced definite or probable neuropathic 
pain. Only 4% of patients were receiving treatment directed at neuropathic 
pain [57].  No formal studies have been completed using gabapentin in patients 
with SCD. 
 
Based on the evidence suggesting that patients with SCD experience 
neuropathic pain, the analgesic benefit of gabapentin demonstrated in the acute 
pain setting, and the limited length of time that patients stay in the acute care 
setting for pain management for VOC, we propose an intervention consisting 
of a single dose gabapentin of 15 mg/kg, as soon as possible after presentation 
to the hospital, in addition to the current standard of practice which includes 
the use of an opioid and a non-steroidal anti-inflammatory drug for pain in 
VOC. 
 
Age-appropriate pain assessment tools are used in our institution as per the 
pain standard of care: the Faces, Legs, Arms, Cry and Consolability (FLACC) 
pain scale for children younger than 4 years [58], Wong Baker FACES for 
children 4 to 6 years [59, 60], and NRS for those 7 years or older [61, 62]. 
The FLACC scale is a 5 item scale that raters use to score each of the 5 
categories: F (faces), L (legs), A (activity), C (cry), and C (consolability), 
which are scores from 0 to 2 (Merkel 1997). The reliability and validity data on 
the FLACC tool are extensive [58, 63-65].  
 
The Wong Baker FACES is a horizontal scale of 6 hand-drawn faces, now 
scored from 0 to 10, that range from a smiling “no hurt” face on the left to a 
crying “hurts worst” face on the right [60]; faces pain scales have been used in 
numerous to measure acute, procedural and recurrent pain, as reported in a 
systematic review of faces scales for the self-report of pain intensity in 
children[66].  The Wong Baker FACES has adequate psychometric properties, 
and it is easy and quick to use [60, 66, 67] and inexpensive to reproduce.  The 
greatest strength of this is its acceptability; studies have consistently found that 
the WBFPRS was preferred by children of all ages, parents, and practitioners, 
when compared with other faces pain scales[68-70].  In a systematic review of 
the psychometric properties, interpretability and feasibility of self-report pain 


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intensity measures for use in clinical trials in children and adolescents, the 
Wong Baker FACES, is reported to have reliability, validity, high feasibility, 
and responsivity in terms of detecting change in children’s pain intensity for 
ages 3 to18 years[67]. 
 
2.2 
Rationale 
 
An extensive literature review is presented in section 2.1, in support of the 
clinical relevance of gabapentin, particularly in the setting of acute nociceptive 
pain. 
Our hypothesis is that the addition of gabapentin to the current standard 
regimen of non-steroidal anti-inflammatory drugs and opioids, in the ACS of 
VOC-related pain, will improve the quality of pain control.  The rationale 
supporting this expected effect includes the following:  
a. The concept of “rational poly-pharmacy”, which supports the concurrent 
use of drugs with distinctly different mechanisms of action to produce 
analgesia [30, 71].  Gabapentin-related analgesia is based on a different 
mechanism of action (at the α-2-δ subunit of the voltage-dependent 
calcium channel) than opioid analgesia (mu opioid receptor agonist effect) 
and non-steroidal anti-inflammatory drugs (cyclooxygenase inhibition);  
b. Proven analgesic efficacy in the acute pain setting of postoperative pain in 
adults [13, 14] and children [11].  Additional evidence is provided in the 
literature review section of the background, based on 43 references. 
c. Evidence that one of the mechanisms of acute pain in the VOC may be a 
neuropathic mechanism, based on demonstration of hyperalgesia and 
allodynia in animal models of sickle cell disease [72, 73]; hyperalgesia and 
allodynia are clinical characteristics of neuropathic pain;  
d. Evidence that the combination of opioid and gabapentin is more effective 
than either one intervention alone, in the context of chronic pain [30];  
Repetitive VOC events and associated acute pain episodes, like any other 
repetitive pain events, may contribute to the development of neuroplasticity 
and central sensitization. The neuronal phenomena of neuroplasticity and 
central sensitization are responsive to therapy with gabapentin [74-78].  
Furthermore, there is evidence from animal studies that gabapentin is more 
effective in modulating nociceptive transmission in the presence of 
inflammation [74] and central sensitization [75], and the potency of the 


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antinociceptive effect is directly related to the intensity of sensitization [76].  
The presence of both phenomena of inflammation and neuropathic pain 
mechanisms has been supported by the finding of neurochemical changes in 
the spinal cord and peripheral nerves in the transgenic sickle mouse model 
[73], and pain has been found to be related to a mechanism of ischemia and 
reperfusion injury, which exacerbates hyperalgesia [72].  Based on the 
contribution of neuroplasticity and central sensitization in the development of 
pain in repetitive VOC episodes [12] and the evidence of efficacy of 
gabapentin 
in 
modulating 
nociceptive 
mechanisms 
associated 
with 
inflammation and central sensitization, we expect an intervention with 
gabapentin for VOC pain to provide analgesic efficacy. 
 
 
 
3.0  
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY  
ENROLLMENT  
 
According to institutional and NIH policy, the study will recruit research 
participants regardless of gender and ethnic background.  Institutional 
experience confirms broad representation in this regard. 
 
3.1 
Inclusion Criteria  
 
3.1.1 Participant must have sickle cell disease (any genotype), documented in 
the St. Jude medical record. 
3.1.2 Participant must be seeking care for acute vaso-occlusive pain at St. 
Jude Children’s Research Hospital. 
3.1.3 Participant age must be ≥1 year and <21 years. 
 
3.2 
Exclusion Criteria  
 
3.2.1 Prior randomization in this study. 
3.2.2 Mild pain (score <4), or pain for which treatment with opioid is not 
indicated. 
3.2.2 Pregnant or lactating females. 
3.2.3 Decreased GFR (<60ml/min/1.73m2) as estimated by the revised 
Schwartz equation. 
3.2.4 Current treatment with gabapentinoid drugs (gabapentin or pregabalin). 
3.2.5 Known seizure disorder. 
3.2.6 Current treatment with antiepileptic agents. 


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3.2.5 Pain in combination with other clinical symptoms that require 
additional interventions, including fever with focus, acute chest 
syndrome, acute injury, or splenic sequestration.  
3.2.6 Allergy to gabapentin. 
3.2.7 Current participation in another research study with an IND/IDE agent 
(including SCATE and TWiTCH trials). 
3.2.8 Inability or unwillingness of research participant or legal  
guardian/representative to give written informed consent. 
 
3.3 
Research Participant Recruitment and Screening 
 
St. Jude patients with sickle cell disease will be educated about the availability 
of this study by study staff or hematology staff as appropriate during routine 
visits to the clinic.  Informational flyers will be available for distribution 
(Appendix III).  Providing information to patients and family in advance of an 
acute pain crisis should assist in the informed consent process by giving 
patients the opportunity to ask questions and consider options prior to a 
qualifying pain event. 
 
Potentially eligible patients will be referred to the study team from the primary 
clinical team (Hematology Service) when the patient calls or arrives at the 
acute care setting with complaint of vaso-occlusive pain crisis.  With the 
agreement of the primary clinical team, a study team member will approach the 
patient to initiate/continue informed consent discussions while standard pain 
management workup is ongoing.  
 
When informed consent is obtained and the patient is enrolled, a member of 
the study team will inform the pharmacy and the randomization procedure will 
be initiated. The pharmacy order sets will be activated for the study drug.   
Delegated clinicians will order the study drug as per protocol section 4.0. 
 
3.4 
Enrollment on Study at St. Jude 
 
A member of the study team will confirm potential participant eligibility as 
defined in Section 3.1-3.2, and will complete and sign the ‘Participant 
Eligibility Checklist’.  The study team will enter the eligibility checklist 
information into the Patient Protocol Manager (PPM) system. Eligibility will 
be reviewed, and a research participant-specific consent form and assent 
document (where applicable) will be generated. The complete signed 


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consent/assent form(s) must be faxed or emailed to the CPDMO at 
 to 
complete the enrollment process. 
 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A staff 
member is on call Saturday, Sunday, and holidays from 8:00 am to 5:00 pm.  
Enrollments may be requested during weekends or holidays by calling the 
CPDMO “On Call” cell phone 
 or referencing the “On Call 
Schedule” on the intranet). 
 
3.5 
Procedures for Identifying and Randomizing Research Participants 
 
Eligibility of research participants will be confirmed between the study staff 
and treating clinician from the Hematology service. A member of the study 
team will then approach the patient and the legally authorized representative 
regarding the study. If the research participant and/or parent agree to 
participate, the randomization plan established by the study biostatistician will 
be accessed according to Section 11.2.  
 
 
4.0 
TREATMENT PLAN 
 
4.1 
Treatment 
 
Upon each participant’s enrollment, study staff will randomize the participant 
to one of 2 possible treatment arms (see section 11 for randomization 
procedure) and order the study treatment.  The pharmacy will dispense the 
dose of study treatment (gabapentin vs. placebo) to the clinic or medicine room 
as soon as possible.   
 
Study drug and other interventions will be administered and documented 
according to hospital policy by any appropriate clinical staff.  All caregivers 
and study personnel will be blinded to the treatment assignment. Based on 
previous research experience at St. Jude, administration of the study drug is 
estimated to occur no later than 2 hours after patient’s first opioid pain  
medication in the acute care setting.   
 
4.2 
Dose Modifications 
 
Medication dosing may be modified for research recipients based upon actual 
body weight or adjusted ideal body weight when clinically indicated. Criteria 


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for medication calculations based on body weight/body surface area can be 
found in any version of the St. Jude Formulary. Medication doses may be 
rounded to the nearest integer or to the nearest appropriate quantity when 
clinically or pharmaceutically indicated as per the MD and PharmD. 
The maximum dose is 900mg. 
 
4.3    Concomitant Therapy 
 
It is expected that participants in this study may be receiving concomitant 
therapies unrelated to the primary interests of this study.  Only the study 
treatment and IV administered pain control treatments will be analyzed to 
determine the study outcomes.  Patients on long-term treatments for sickle cell 
disease (e.g. hydroxyurea or chronic transfusion therapy) will be recorded for 
analysis.   
 
4.4 
Supportive Care 
 
Primary pain management for the participant is of consummate importance.  
Investigators expect for participants to receive standard pain management, 
which could include IV fluids, opioid pain medicine, NSAIDS, and/or other 
interventions.  Participants may show additional clinical signs warranting 
evaluation, such as fever or hypoxia, and will be evaluated appropriately.  
 
Orders for standard pain management or other clinical interventions may be 
performed concurrently with administration of study drug.  Caregivers are 
encouraged to refer to hospital policy for assessing, documenting, and 
reporting pain and other symptoms to the clinical team. Comprehensive sickle 
cell care will be managed by the Hematology team. 
 
 
5.0 
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION  
 
To allow for the study team and participants to remain blinded to the treatment 
assignment, the study drug will be labeled by the pharmacy as Gabapentin/Placebo 
(PMVOC 100 mg/mL) followed by applicable dose and administration instructions. 
 
5.1 
GABAPENTIN (Neurontin®)  
 
Source and Pharmacology: Gabapentin is a white to off-white crystalline 
solid that is freely soluble in water. Its mechanism of action in preventing 


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seizures is not known. Gabapentin is not appreciably metabolized in humans; 
pharmacological effects are from the activity of the parent compound. It is 
eliminated unchanged in the urine. Patients with renal impairment should have 
dosage adjustments. Administration with food has little effect on absorption of 
gabapentin. In a single-dose gabapentin pharmacokinetics study in healthy 
infants and children, the mean maximum concentration was achieved 2.31 
hours after a single oral dose in 48 children ages 1 month to 12 years of age. 
Dosing for 1 month to 2 years of age of the immediate-release gabapentin 
syrup was 10 mg/kg. Dosing for children greater than 2 years of age of the 
immediate-release capsules was based on weight and ranged from 8 mg/kg to 
12.5 mg/kg as follows: 200 mg for 16 to 25 kg; 300 mg for 26 to 36 kg; 400 
mg for 37 to 50 kg. The mean maximum concentrations were 3.74 mcg/mL for 
< 5 years of age (n=27) and 4.52 mcg/mL for ≥ 5 years of age (n=21). The 
single dose of gabapentin was well tolerated with seven participants reporting 
mild treatment-associated adverse events. The adverse events included 
asthenia, truncal ataxia, dizziness, drowsiness, somnolence, and vomiting [79].  
 
Formulation and Stability: Gabapentin is supplied as an oral suspension 
containing 100 mg/mL. The St. Jude Children’s Research Hospital Pharmacy 
will compound an oral suspension from commercially available capsules 
following pediatric drug formulation worksheets previously agreed upon by the 
FDA (Appendix IV). The oral suspension is stable for 3 months under 
refrigerated conditions between 2 and 8°C (36 and 46°F).  The oral suspension 
will be stored between 2 and 8°C (36 and 46°F) in amber plastic prescription 
bottles for up to 3 months with continuous temperature monitoring. 
 
Toxicity:  Patients 3 – 12 years old treated with gabapentin for epilepsy 
reported the following central nervous system related adverse events: 
emotional lability, hostility, thought disorder and hyperkinesia in addition to 
CNS depression (dizziness, somnolence, fatigue, ataxia, and nystagmus). In 
placebo controlled trials of gabapentin in children taking other antiepileptic 
drugs, the following were also seen at higher frequency in the treatment group 
than the placebo group: viral infection, bronchitis, pharyngitis, rhinitis,  
respiratory infection, coughing, otitis media, fever, nausea and/or vomiting, 
diarrhea, depression, headache, diplopia, blurred vision, nervousness, seizures, 
pruritus, dyspepsia, constipation, weight gain, anorexia, leukopenia, back pain, 
and peripheral edema.  
 
Do not administer within two hours of aluminum or magnesium containing 
antacids.  


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Supplier: Commercially available 
 
Dosage and Route of Administration: Participants randomized to the active 
treatment arm will receive approximately 15 mg/kg gabapentin PO one time, 
as soon as feasible after enrollment.  The maximum dose is 900mg (9mL).   
 
5.2 
PLACEBO 
 
Patients randomized to the placebo arm will receive oral suspension similar in 
appearance, quantity and taste to the active treatment arm.  Placebo suspension 
will be compounded with commercially available suspending and flavored 
syrup vehicles (Ora Plus/Ora Sweet) with flavoring added (Appendix V).  The 
solution will be stored in the refrigerator. Placebo suspension will be prepared 
by the St. Jude Children’s Research Hospital Pharmacy.  
 
 
6.0  
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
Subsections of 6.0 are in tabular form in Appendix I.   
 
6.1 
Pre-Study Evaluations 
 
At a minimum, one baseline pain assessment will be documented in the medical 
record upon presentation to the acute care setting.  Participants may have 
received opioids or other pain relieving interventions from home supply prior to 
arrival. 
 
Prior to enrollment, glomerular filtration rate estimate will be calculated using 
the Schwartz equation based on the patient’s most recent clinically obtained 
creatinine value documented in MILLI not more than 6 months prior to the pain 
event. 
 
Female patients of childbearing potential must have documentation in MILLI of 
negative pregnancy test not more than 2 weeks prior to enrollment.  Females 
currently receiving Depo-Provera at St. Jude may use documentation of 
negative pregnancy up to 6 weeks prior to enrollment.  Female participants 
without negative test on record as described should have negative test 
documented in MILLI prior to enrollment. Either serum or urine testing may be 
used. 


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6.2 
Evaluations During Therapy 
 
Data for research purposes will be collected from the hospital medical records 
for the event, including visit duration, pain scores, and IV administered pain 
interventions given, as performed according to hospital standards of care.  
Only St. Jude pharmacists are unblinded to treatment assignment.   
 
Pain assessments throughout the acute event will be performed by any clinical 
staff as per hospital standards (Appendix II).  Researchers will analyze pain 
scores at baseline (at presentation), 15 minutes prior to or 15 minutes after the 
time of study drug administration, at 3 hours after study drug administration, 
and at point of decision for either admission or discharge to home (for patients 
who continue to be treated for pain longer than 3 hours after study drug is 
administered).    
 
The pain scales used are the numerical rating system, the Faces Pain Scale, and 
the FLACC pain scale (for patients 7 years or older, ages 4-6 years, or less than 
4 years, respectively) (Appendix II).  Patients unwilling or unable to provide a 
score on the age-appropriate scale may use another scale if indicated.   
 
Clinicians will obtain other studies as needed for good patient care. 
 
 
6.3 
Response Evaluations 
 
No special tests and/or evaluations are required to evaluate response during 
study treatment.  Significant pain will be treated by the primary care team as 
clinically indicated. 
 
 
6.4 
Off-Study Evaluations 
 
Pain scores will be captured at 3 hours after the study drug is administered. 
The 3 hours post study drug pain score may be obtained up to 30 minutes 
before or after the 3 hour time point. The 3 hours post study drug pain score 
can be collected either in person or via phone. Patients who need additional 
pain management or other care will have a pain score at the time of decision 
for admission or discharge home.   
Participants will be taken off study after a toxicity evaluation is performed / 
attempted within 72 hours following study drug administration (see section 
7.2). 
 


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6.5 
Long-Term Follow-up Evaluations 
 
No long-term evaluations are planned.  
 
Participants will be notified of their treatment assignment (gabapentin or 
placebo) after the completion of data collection for the last participant enrolled.  
Notification will be performed by a member of the study team in person (when 
feasible) or by letter at the earliest convenience of the study team and 
documented in the study files. 
 
7.0  
EVALUATION CRITERIA 
 
7.1 
Response Criteria 
 
The response to therapy will be measured by pain intensity scores and total 
opioid use as described in the study objectives.   
 
7.2 
Toxicity Evaluation Criteria 
 
Toxicity will graded according to the NCI CTCAE (version 4.0).  Only new 
or worsening problems (i.e. significant changes in lab values from baseline) 
occurring after the administration of study drug will be captured for this 
study, as sickle cell patients may have steady-state or pre-existing values that 
fall in the range of toxicity per the CTCAE (e.g. anemia, fever, pain).  
Worsening pain scores after enrollment will not be captured or reported as 
AEs, but will be managed clinically.  Hospital admission for VOC is an 
expected outcome and will not be captured/reported as an AE. 
 
All participants must remain at St. Jude for at least 3 hours following 
administration of study drug to allow for monitoring of toxicity. 
 
Participants that were discharged will be contacted by study staff between 24 
and 72 hours following the administration of study drug to screen for 
unexpected events.  Patients that were admitted after administration of the 
study drug will be monitored through hospital records to determine if any 
unexpected events occurred.  These patients will also be contacted directly by 
study staff. Patients will remain on study until discharged so all clinical notes 
can be reviewed to determine toxicity. 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND  
OFF-STUDY CRITERIA 


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8.1  
Off-therapy criteria 
 
Because study therapy consists of a single oral dose of study drug, there are no 
off-therapy criteria.  Refer to section 8.2, Off-Study Criteria. 
 
8.2 
Off-Study Criteria 
 
8.1.1 Death 
8.1.2 Lost to follow-up 
8.1.3 Request of the Patient/Parent 
8.1.4 Refusal of therapy 
8.1.5 Discretion of the Study PI, such as the following  
• 
The researcher decides that continuing in the study would be 
harmful  
• 
A treatment is needed that is not allowed on this study 
• 
The participant’s condition gets worse 
• 
New information is learned that a better treatment is available, or 
that the study is not in the participant’s best interest 
8.1.6 Study evaluations are complete 
8.1.7 Unblinding of participant or study team to participant’s treatment 
assignment 
 
9.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
 
9.1 
Reporting Adverse Experiences and Deaths  
 
Principal investigators are responsible for promptly reporting to the IRB any 
adverse events that are unanticipated, serious, and that may represent potential 
harm or increased risk to research participants. When an unanticipated death 
occurs, the PI should report it to the Director of the Office of Human Subjects’ 
Protection immediately, by phone: 
 
 
 
A reportable event entry into TRACKS should follow within 48 hours. 
Serious, unanticipated, and related or possibly related events must be reported 
within 10 working days. At the same time, the investigator will notify the 
study sponsor (NIH or pharmaceutical company), cooperative group, and/or 
the FDA, as appropriate. To report adverse events in gene therapy trials, 


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investigators 
should 
use 
specific 
RAC 
forms 
found 
at 
http://www4.od.nih.gov/oba/RAC/Adverse_Event_Template.doc .  
 
The principal investigator is responsible for reviewing the aggregate toxicity 
reports and reporting to the IRB if the frequency or severity of serious 
toxicities exceed those expected as defined in the protocol or based on clinical 
experience or the published literature. Any proposed changes in the consent 
form or research procedures resulting from the report are to be prepared by the 
study team and submitted with the report to the IRB for approval.  
 
The following definitions apply:  
 
A serious event refers to any event in which the outcome is fatal or life-
threatening, results in permanent disability, causes inpatient hospitalization or 
prolongs existing inpatient hospitalization, or is a congenital anomaly, cancer,  
or overdose.  Hospitalization due to the presenting VOC will not be reported as 
a serious event. 
 
An unanticipated adverse event refers to those not identified in their nature, 
severity, or frequency in the current risk documents (e.g., investigator’s 
brochure), or consistent with the investigational plan.  
 
The following are considered reportable: Any injuries, serious event or other 
unanticipated adverse events involving risk to participants or others which 
occur at a frequency above that considered acceptable by the investigators and 
the IRB. (FDA) As described in HRPP Policy 01.720, the OHSP Director or 
designee performs the initial review of unanticipated problems or serious 
adverse event reports. Internal reports of events that are unanticipated, serious, 
and related or possibly related to study interventions or procedures are then 
forwarded to the IRB Chair or designee and if necessary, referred to the full 
IRB. Based on the frequency and seriousness of adverse events, the IRB Chair 
or Committee may deem it necessary to suspend or terminate a research study 
or studies.  
 
9.2 
Reporting to the Sponsor and/or Federal Agencies 
 
9.2.1 Notification of Federal Agencies by Investigator  
 
Copies of all correspondence to the St. Jude IRB, including serious 
adverse event reports, are provided to the St. Jude Office of Regulatory 


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Affairs via the electronic reporting system (TRACKS).  All FDA 
related correspondence and reporting will be conducted through the 
Regulatory Affairs Office. 
The FDA will be notified in writing (IND safety report) of any serious 
and unexpected adverse event associated with an investigational 
treatment or device. Annual reports, which will include the up-to-date 
clinical and safety data, will be submitted to the FDA at least annually. 
9.2.2 Recording Adverse Events and Serious Adverse Events 
 
Adverse events will be evaluated and documented by the clinical staff 
and investigators.  The CRAs are responsible for documenting adverse 
events 
and 
entering 
them 
into 
the 
CRIS 
protocol-specific 
database.  AEs that are classified as serious, unexpected, and at least 
possibly related will be reported expeditiously to the St. Jude IRB as 
described in protocol section 9.1.  All other events will be reported to 
the IRB as part of the continuing review process.   
 
As stated in section 7.2, only new or worsening problems occurring 
after the administration of study drug will be reported as adverse 
events, as sickle cell patients may have pre-existing conditions that fall 
in the range of toxicity per the CTCAE and are not related to study 
drug (e.g. anemia, fever, pain).  Any event occurring more than 72 
hours after administration of study drug will not be captured.  
 
9.3 Emergency Unblinding 
 
In the case of a medical emergency or in the event of a serious medical condition, 
when knowledge of the investigational product is essential for the clinical 
management or welfare of the subject, an investigator or other physician 
managing the subject may decide to unblind that subject’s treatment code. 
 
The physician managing the medical emergency or serious condition should 
attempt to contact the principal investigator to discuss options prior to 
unblinding, and the principal investigator should approve the unblinding, when 
applicable. However, ensuring patient safety is the primary objective when the 
decision to unblind the treatment assignment is made. 
 
The principal investigator or designated study personnel will complete an order in 
MILLI with the request to unblind the patient’s treatment arm. The principal 


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investigator or treating clinician will contact pharmacy to receive the unblinding 
information. 
 
All occurrences of emergency unblinding will be reported to the IRB according 
to the criteria established in protocol section 9.0, and the FDA, when applicable.  
In a majority of cases, emergency unblinding will occur while managing a serious 
adverse event (SAE), and will therefore be reported with the SAE.  If the 
unblinding event is not directly associated with an SAE, the same timeline and 
mechanism for reporting SAEs will be used to notify the IRB of the event 
(section 9.1). 
 
10.0 
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY 
 
10.1 
Data Collection  
 
Members of the clinical care team will complete documentation in the 
electronic medical record for each study encounter. Data will then be 
abstracted into a secure database by study staff, which serves as the electronic 
case report forms (eCRFs). Records from the study which identify the study 
participant will be kept confidential in a secured area. 
 
10.2 
Study Monitoring 
 
Source document verification of eligibility for all SJCRH cases will be 
performed within two weeks of completion of enrollment. This will include 
verification of appropriate documentation of consent. Monitoring of timeliness 
of serious adverse event reporting will be done as events are reported in 
TRACKS.  
 
Monitoring of this protocol is considered to be in the High Risk 3 category.  
The Monitoring Plan is outlined in a separate document from this protocol, but 
has been submitted for review and approval by the Clinical Trials Scientific 
Review Committee and the Institutional Review Board. 
 
Continuing reviews by the IRB and CT-SRC will occur at least annually.  In 
addition, SAE reports in TRACKS are reviewed in a timely manner by the 
IRB/ OHSP. 
 
 
10.3 
Confidentiality 
 


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Source documents from the study which identify the participant will be kept 
confidential in a secured area and a password-protected database.  Any list 
containing the study number and the medical record number will be maintained 
in a password-protected electronic file and will be destroyed after all data have 
been analyzed. 
 
The medical records of study participants may be reviewed by the St. Jude 
IRB, FDA, clinical research monitors, and other authorized regulatory 
personnel. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
This is a double-blind placebo-controlled clinical trial evaluating the effect of 
gabapentin when added to standard pain management for patients with sickle cell 
disease experiencing acute pain crisis in the ambulatory care setting. The primary 
study objective is to assess the analgesic efficacy of gabapentin for pain during VOC 
in participants with SCD, by comparing the proportion of participants with a decrease 
of ≥ 33% in pain scores between presentation to the acute care setting and assessment 
at 3 hours post administration of study drug, in the gabapentin and placebo groups. The 
intention-to-treat principle will be followed and all eligible, randomized subjects will 
be analyzed in the primary analysis as randomized. 
 
11.1 
Sample size 
 
Retrospective review of 26 months of records (August 1, 2010 to October 1, 
2012) indicated that 137 patients, ages 1-18, experienced VOC due to SCD and 
were administered opioids. We analyzed the pain scores from a subset of 40 
patients between the ages of 8 and 18 who had received opioid(s) and also had 
pain scores documented at baseline and end of the visit. We found a reduction 
in the pain scores from baseline to discharge or admission of ≥ 33% [81-83] in 
45% of patients (18/40). The hypothesis is that treatment with gabapentin has 
better analgesic efficacy than placebo in the treatment of pain during VOC, 
when added to the current standard of care for pain during VOC which 
comprises opioids and non-steroidal anti-inflammatory drugs. An increase in 
the proportion of patients with ≥ 33% reduction of the pain scores from 45% to 
at least 65% between presentation and assessment at 3 hours post 
administration of study drug is considered clinically meaningful [81-83]. 
 
Let Pt and Pc be the proportions of participants with a decrease of ≥ 33% in 
pain scores between presentation to the acute care setting (ACS) and 3 hours 
post study drug administration, in the gabapentin and placebo groups, 


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respectively. We wish to test whether there is a significant difference in the 
proportions of participants with a decrease of ≥ 33% in pain scores in two 
groups and formulate the following hypothesis: the null hypothesis H0: ∆ = Pt  - 
Pc = 0 against the 1-sided alternative hypothesis H1: ∆ > 0. With the design 
parameters of a type I error rate (α) of 0.05 and a type II error rate (β) of 0.2, 
assuming one interim analysis and ∆ = 0.2 under H1, we will need a total of 
166 patients (83 per group) for our two sample test. The interim analysis will 
be conducted to assess efficacy and futility, when there are 96 subjects 
randomized. We will recommend that the trial will be halted for efficacy (in 
favor of H1) if the nominal p-value for the interim analysis is less than or equal 
to 0.0143. We will recommend the trial should be halted for futility (in favor of 
H0) if the nominal p-value for the interim analysis is greater than or equal to 
0.2249. If H0 is true, this interim analysis has a 79% probability of stopping in 
favor of H0. If H1 is true, this interim analysis has a 53% probability of 
stopping in favor of H1. To account for the planned interim analysis, the final 
analysis will be at the nominal p-value of 0.0447; thus maintaining the overall 
type I error rate at 0.05. This plan is based on the binomial two-sample 
difference in proportions with a non-binding interim analysis based on power 
family spending functions with alpha and beta spending parameters set to 0.1 
(EAST software v5.3). 
 
Accrual: Based on the retrospective data, we can expect to prospectively 
evaluate 63 patients for enrollment per year. If we enroll and randomize 2/3 of 
the eligible patients, the enrollment would reach 42 patients per year. 
Therefore, it will take approximately four years to enroll all 166 patients 
necessary to address the primary objective.  
 
11.2 
Randomization 
 
Eligible patients with an established diagnosis of pain and VOC will be 
consented and randomized to receive a single dose of gabapentin or placebo.  
Morphine or other opioid and non-steroidal anti-inflammatory drugs will be 
available to both groups as needed for pain and will be administered according 
to the current standard of care for pain in VOC from the Department of 
Hematology. Randomization will be performed in SJCRH pharmacy by a 
pharmacist, using the randomization program developed by the Department of 
Biostatistics. The randomization will be stratified by three age categories (1-3yr, 
4-6yr, ≥7yr) for which distinct pain assessment tools are applied and for 2 pain 
scores categories at assessment at presentation: 4- 6 and 7-10, respectively.  A 


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block randomization with block sizes varying randomly between 4 and 6 will 
be used in each stratum.   
 
11.3 
Statistical analysis 
 
11.3.1 Primary Objective 
 
To assess the analgesic efficacy of gabapentin (vs. placebo) for pain during 
VOC in participants with SCD. A response to study drug will be defined by a 
decrease in pain score of ≥33% between presentation to the acute care setting 
and assessment at 3 hours post administration of study drug. 
 
For each patient, if the reduction of the pain scores between presentation to the 
acute care setting and 3 hours post administration of study drug is 33% or 
greater, then this patient will be defined as having a successful intervention. 
The proportions of successful interventions in the gabapentin and placebo 
groups will be estimated and compared using Z-test (PROC FREQ procedure 
in SAS).  
 
11.3.2  Secondary Objective 
 
To compare the total morphine dose or morphine equivalent (mg/kg) used to 
control pain during VOC between presentation to the acute care setting and 
assessment at 3 hours post administration of study drug in the gabapentin vs. 
placebo groups.  
 
Summary statistics of the total morphine dose or morphine equivalent (mg/kg) 
used to control pain during VOC between presentation to the acute care setting 
and 3 hours post administration of study drug, in the gabapentin and placebo 
groups will be provided. Test of normality such as Shapiro-Wilk test will be 
applied to the total morphine dose or morphine equivalent (mg/kg) to examine 
their deviation from the normal distribution. A two-sample t-test or Wilcoxon 
rank sum test will be used to compare the total morphine dose or morphine 
equivalent (mg/kg) for the gabapentin vs. placebo groups depending on 
whether the normality assumption of the data holds.   
 
11.3.3 Exploratory Objectives 
 
1. To assess the analgesic efficacy of gabapentin for pain during VOC in 
participants with SCD, as defined by a decrease in pain scores of ≥33% 


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between presentation to the acute care setting and the point of decision for 
either hospital admission or discharge to home, in the gabapentin and 
placebo groups.  
 
Statistical methods used to analyze this objective will be the same as those 
used for the primary objective. 
 
2. To compare the total morphine dose or morphine equivalent (mg/kg) used 
to control pain during VOC between presentation to the acute care setting 
and the point of decision for either admission or discharge to home, in the 
gabapentin and placebo groups. 
 
Statistical methods used to analyze this objective will be the same as those 
used for the secondary objective. 
 
3. To compare the rate of admission related to pain management, in the 
gabapentin vs. placebo groups. 
 
Statistical methods used to analyze this objective will be the same as the 
analysis used for the primary objective. 
 
4. To compare the change in pain score from time of administration of study 
drug to assessment at 3 hours post administration of study drug in the 
gabapentin vs. placebo groups. 
 
The numeric changes in pain scores will be compared using the statistical 
methods of the secondary objective.  Changes in pain score will also be 
evaluated as a proportion of those with a decrease of ≥33% and analyzed 
by the methods of the primary objective. 
 
5. To compare the change in pain score from time of administration of study 
drug to the point of decision for either admission or discharge to home, in 
the gabapentin and placebo groups. 
 
The numeric changes in pain scores will be compared using the statistical 
methods of the secondary objective.  Changes in pain score will also be 
evaluated as a proportion of those with a decrease of ≥33% and analyzed 
by the methods of the primary objective. 
 
 


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12.0  OBTAINING INFORMED CONSENT 
 
Eligible patients will be approached by a member of the study team regarding the study 
purpose, methods and design details. Both verbal and written assent and consent 
procedures will be completed in a private room and follow our institutional guidelines.  
 
Because acute VOC pain and timely treatments can interfere with adequate participation 
in the consent discussion, the study team has requested modifications to the informed 
consent process. Potentially eligible participants who are age 18 or older may ask to select 
a surrogate decision maker for the consent process.  In this case, investigators will follow 
the St. Jude HRPP policy 01.725, “Surrogate Consent for Human Subjects Research”.  
Likewise, potential participants who are less than 18 years old may decline to give written 
or verbal assent for participation; the written consent will be completed by the patient’s 
legally authorized representative acting on behalf of the interests of the minor participant.   
 
The consent/assent process will be documented in the medical record per institutional 
guidelines. Research participants and parents may decline participation without 
repercussions. Refusals will be documented in the research records and examined for any 
possible patterns. All research participants who meet eligibility criteria regardless of 
gender or minority status are fully eligible to participate in this study. All data will be kept 
confidential and stored in a locked file inside locked offices. 
 
12.1 
Consent at Age of Majority 
 
The age of majority in the state of Tennessee is 18 years old.  Because study 
drug is given only once, reconsenting at the age of majority is not expected.   
 
12.2 
Consent When English is Not the Primary Language 
 
When English is not the patient, parent, or legally authorized representative’s 
primary language, the Social Work department will determine the need for an 
interpreter.  This information documented in the participant’s medical record.  
Either a certified interpreter or the telephone interpreter’s service will be used 
to translate the consent information.  The process for obtaining an interpreter 
and for the appropriate use of an interpreter is outlined on the Interpreter 
Services, OHSP, and CPDMO websites. 
 


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13.0 
REFERENCES 
 
1. 
Backonja, M., A. Beydoun, et al., Gabapentin for the symptomatic treatment of 
painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. 
JAMA, 1998. 280(21): 1831-6. 
2. 
Rowbotham, M., N. Harden, et al., Gabapentin for the treatment of postherpetic 
neuralgia: a randomized controlled trial. JAMA, 1998. 280(21): 1837-42. 
3. 
van de Vusse, A.C., S.G. Stomp-van den Berg, et al., Randomised controlled trial of 
gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC 
Neurol, 2004. 4: 13. 
4. 
Ho, K.Y., T.J. Gan, and A.S. Habib, Gabapentin and postoperative pain--a systematic 
review of randomized controlled trials. Pain, 2006. 126(1-3): 91-101. 
5. 
Fink, K., D.J. Dooley, et al., Inhibition of neuronal Ca(2+) influx by gabapentin and 
pregabalin in the human neocortex. Neuropharmacology, 2002. 42(2): 229-36. 
6. 
Taylor, C.P., The biology and pharmacology of calcium channel alpha2-delta proteins 
Pfizer Satellite Symposium to the 2003 Society for Neuroscience Meeting. Sheraton 
New Orleans Hotel, New Orleans, LA November 10, 2003. CNS Drug Rev, 2004. 
10(2): 183-8. 
7. 
Field, M.J., R.J. Oles, et al., Gabapentin (neurontin) and S-(+)-3-isobutylgaba 
represent a novel class of selective antihyperalgesic agents. Br J Pharmacol, 1997. 
121(8): 1513-22. 
8. 
Feng, Y., M. Cui, and W.D. Willis, [Effect of anticonvulsant gabapentin on visceral 
nociception and its relationship with amino acid neurotransmitters released from 
spinal cord]. Beijing Da Xue Xue Bao, 2003. 35(3): 307-10. 
9. 
Matthews, E.A. and A.H. Dickenson, A combination of gabapentin and morphine 
mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model 
of neuropathy. Anesthesiology, 2002. 96(3): 633-40. 
10. 
Gilron, I., J. Biederman, et al., Gabapentin blocks and reverses antinociceptive 
morphine tolerance in the rat paw-pressure and tail-flick tests. Anesthesiology, 2003. 
98(5): 1288-92. 
11. 
Rusy, L.M., K.R. Hainsworth, et al., Gabapentin use in pediatric spinal fusion 
patients: a randomized, double-blind, controlled trial. Anesth Analg, 2010. 110(5): 
1393-8. 
12. 
Ballas, S.K., K. Gupta, and P. Adams-Graves, Sickle cell pain: a critical reappraisal. 
Blood, 2012. 
13. 
Menigaux, C., F. Adam, et al., Preoperative gabapentin decreases anxiety and 
improves early functional recovery from knee surgery. Anesth Analg, 2005. 100(5): 
1394-9, table of contents. 
14. 
Fassoulaki, A., K. Patris, et al., The analgesic effect of gabapentin and mexiletine after 
breast surgery for cancer. Anesth Analg, 2002. 95(4): 985-91, table of contents. 
15. 
Straube, S., S. Derry, et al., Single dose oral gabapentin for established acute 
postoperative pain in adults. Cochrane Database Syst Rev, 2010(5): CD008183. 
16. 
Seib, R.K. and J.E. Paul, Preoperative gabapentin for postoperative analgesia: a 
meta-analysis. Can J Anaesth, 2006. 53(5): 461-9. 


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17. 
Hurley, R.W., S.P. Cohen, et al., The analgesic effects of perioperative gabapentin on 
postoperative pain: a meta-analysis. Reg Anesth Pain Med, 2006. 31(3): 237-47. 
18. 
Peng, P.W., D.N. Wijeysundera, and C.C. Li, Use of gabapentin for perioperative 
pain control -- a meta-analysis. Pain Res Manag, 2007. 12(2): 85-92. 
19. 
Dirks, J., B.B. Fredensborg, et al., A randomized study of the effects of single-dose 
gabapentin versus placebo on postoperative pain and morphine consumption after 
mastectomy. Anesthesiology, 2002. 97(3): 560-4. 
20. 
Pandey, C.K., S. Priye, et al., Preemptive use of gabapentin significantly decreases 
postoperative 
pain 
and 
rescue 
analgesic 
requirements 
in 
laparoscopic 
cholecystectomy. Can J Anaesth, 2004. 51(4): 358-63. 
21. 
Pandey, C.K., S. Sahay, et al., Preemptive gabapentin decreases postoperative pain 
after lumbar discoidectomy. Can J Anaesth, 2004. 51(10): 986-9. 
22. 
Pandey, C.K., D.V. Navkar, et al., Evaluation of the optimal preemptive dose of 
gabapentin for postoperative pain relief after lumbar diskectomy: a randomized, 
double-blind, placebo-controlled study. J Neurosurg Anesthesiol, 2005. 17(2): 65-8. 
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thoracotomy analgesia: a randomized, double-blinded, active placebo-controlled 
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Clarke, H., K.R. Kirkham, et al., Gabapentin reduces preoperative anxiety and pain 
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Lee, J.H., H.K. Lee, et al., The prophylactic effects of gabapentin on postoperative 
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Short, J., K. Downey, et al., A single preoperative dose of gabapentin does not 
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Behdad, S., V. Ayatollahi, et al., Effect of gabapentin on postoperative pain and 
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Deniz, M.N., N. Sertoz, et al., Effects of preoperative gabapentin on postoperative 
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45. 
Panah Khahi, M., A.A. Yaghooti, et al., Effect of pre-emptive gabapentin on 
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46. 
Ucak, A., B. Onan, et al., The effects of gabapentin on acute and chronic 
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47. 
Spence, D., J. Goff, et al., Perioperative administration of gabapentin for shoulder 
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Khan, Z.H., M. Rahimi, et al., Optimal dose of pre-incision/post-incision gabapentin 
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Moore, R.A., P.J. Wiffen, et al., Gabapentin for chronic neuropathic pain and 
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Rapchuk, I.L., L. O'Connell, et al., Effect of gabapentin on pain after cardiac surgery: 
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Molokie, R.E., Z.J. Wang, and D.J. Wilkie, Presence of neuropathic pain as an 
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56. 
Wilkie, D.J., R. Molokie, et al., Patient-reported outcomes: descriptors of nociceptive 
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57. 
Brandow, A., R. Farley, and J. Panepinto. Existence of Neuropathic Pain in Patients 
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von Baeyer, C.L., L.J. Spagrud, et al., Three new datasets supporting use of the 
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Manworren, R.C. and L.S. Hynan, Clinical validation of FLACC: Preverbal patient 
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Curros-Criado, M.M. and J.F. Herrero, The antinociceptive effect of systemic 
gabapentin is related to the type of sensitization-induced hyperalgesia. J 
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Gottrup, H., G. Juhl, et al., Chronic oral gabapentin reduces elements of central 
sensitization in human experimental hyperalgesia. Anesthesiology, 2004. 101(6): 
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Haig, G.M., H.N. Bockbrader, et al., Single-dose gabapentin pharmacokinetics and 
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Nahata, M.C., Development of two stable oral suspensions for gabapentin. Pediatr 
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Farrar, J.T., What is clinically meaningful: outcome measures in pain clinical trials. 
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82. 
Farrar, J.T., J.A. Berlin, and B.L. Strom, Clinically important changes in acute pain 
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APPENDICES 
 
 
APPENDIX I: Schedule of Evaluations (required) 
 
Event 
Screen1 
Entry 
On Treatment 
24-72 hours 
after study 
drug 
Acute 
care 
setting 
3 hours 
after study 
drug  
Decision to 
discharge from 
acute care or 
admit 
Informed Consent 
X 
 
 
 
 
 
Pregnancy test 
PRN 
 
 
 
 
 
Pain assessment 
X 
X3 
PRN 
X 
X2 
 
Study drug 
 
X 
 
 
 
 
Pain intervention 
PRN 
PRN 
PRN 
PRN 
 
 
Adverse event screen  
 
 
 
X 
X 
X 
Off study  
 
 
 
 
 
X 
1Routine pain interventions may begin before study entry/administration of study drug 
2Patients who leave the ACU at the 3 hour time point will not have a fourth pain assessment captured 
3Pain score will be recorded within 30 minutes of drug administration. 
 
 
 


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APPENDIX II: 
 
TESTS PERFORMED FOR GOOD CLINICAL CARE 
 
Guidelines for pain management at St. Jude are available in the hospital Policy 
and Procedure Manual accessible via the hospital intranet or paper-based 
copies in clinical areas.   
 
Section VIII:  Pain Management 
o 8003 Guidelines for Pharmacologic Pain Management 
o 8005 Nonpharmacologic Pain Management 
o 8008 Standards of Care: Pain Management 
  
 
 
 
 
 


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Appendix III:  Recruitment Materials 
 
 
 
Sickle Cell Research:  
Pain Crisis Study 
St. Jude doctors want to know if a medicine that is helpful for some cancer pain  
and surgery pain could also help sickle cell pain in young patients. 
 
Who:  Any St. Jude patient with sickle cell disease and a new pain 
crisis, between 1-21 years old 
Where:  The study takes place only at St. Jude, in the clinic or 
medicine room during a pain crisis. 
How:  When you arrive for your pain appointment, you may be 
asked if you would like to participate.  A parent or legal guardian 
must be here to sign consent to participate. 
What:  Eligible patients will receive study drug by mouth IN 
ADDITION TO the standard pain medicines.  The rest of the pain 
crisis visit is the same as usual.  You will be asked for a pain score 3 
hours after taking the study drug, either in person or by phone. Also, 
you will receive $25 for your participation. 
 
Want to know more?  Ask your sickle cell team for more information at any time.  
You may also call 
 during business hours to talk to the 
study team for details about the study. 
Research Team:  Dr. Anghelescu, Dr. Hankins, Dr. Wang, Olivia McGregor 


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Appendix IV: Gabapentin Drug Formulation 
 
 


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Appendix V: Gabapentin Placebo Drug Formulation 


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