CONTEMPORARY SUBJECT
`
`Examination of the Evidence for Off-Label Use of Gabapentin
`
`ALICIA MACK, PharmD
`
`ABSTRACT
`
`OBJECTIVES: (1) Describe the relevance of off-label use of gabapentin to man-
`aged care pharmacy; (2) summarize recent FDA warnings and media reports
`related to off-label gabapentin use; (3) review medical information pertaining
`to the off-label use of gabapentin; (4) outline alternatives to off-label use of
`gabapentin in an evidence-based fashion, where literature exists to support such
`alternatives; and (5) encourage key clinicians and decision makers in managed
`care pharmacy to develop and support programs that restrict the use of
`gabapentin to specific evidence-based situations.
`
`SUMMARY: Gabapentin is approved by the U.S. Food and Drug Administration
`(FDA) for adjunctive therapy in treatment of partial seizures and postherpetic
`neuralgia. Various off-label (unapproved) uses have been reported, and the use
`of gabapentin for off-label purposes has reportedly exceeded use for FDA-
`approved indications. Pharmaceutical marketing practices and physician dissat-
`isfaction with currently available pharmacological treatment options may be key
`factors that contribute to this prescribing trend.
`Recently, the media has focused on these issues, noting that many cases of
`reported safety and effectiveness of gabapentin for off-label use may have been
`fabricated. A thorough review of the medical and pharmacy literature related to
`off-label use of gabapentin was performed, and a summary of the literature for the
`following conditions is presented: bipolar disorder, peripheral neuropathy, diabetic
`neuropathy, complex regional pain syndrome, attention deficit disorder, restless
`legs syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep,
`migraine headaches, and alcohol withdrawal syndrome. A common theme in the
`medical literature for gabapentin is the prevalence of open-label studies and a lack
`of randomized controlled clinical trials for all but a small number of indications.
`
`CONCLUSIONS: In the majority of circumstances where it has reported potential
`for "off-label" use, gabapentin is not the optimal treatment. The off-label use of
`gabapentin for indications not approved by the FDA should be reserved for cases
`where there is solid research support (e.g., diabetic neuropathy and prophylaxis
`of frequent migraine headaches). Managed care pharmacists should develop
`programs to restrict the use of gabapentin to these specific evidence-based situ-
`ations, and key decision makers in managed care practice should feel confident
`in supporting these use restrictions for gabapentin.
`
`KEYWORDS: Neurontin, Gabapentin, Off-label, Comparison, Bipolar, Restless legs,
`Trigeminal neuralgia, Migraine, Peripheral neuropathy, Diabetic neuropathy,
`Complex regional pain syndrome, Attention deficit disorder, Periodic limb move-
`ment disorder of sleep, Alcohol withdrawal syndrome
`
`J Managed Care Pharm. 2003;9(6):559-68
`
`!lutlwr
`AU CIA MACK, PharmD, is clinical pharmacy coordinator, Three Rivers
`Administrative Services, Il.C, Monroeville, Pennsylvania, and adjunct clinical
`instructor, Department of Pharmacy and Therapeutics, University of Pittsburgh
`School of Pharmacy, and Duquesne University, Mylan School of Pharmacy,
`Pittsburgh.
`
`AU1HOR CORRESPONDENCE: Alida Mack, PharmD, Oinical Pharmacy
`Coordinator, Three Rivers Administrative Services, Il.C, 300 Oxford Dr.,
`Monroeville, PA 15146. Tel: (412) 856-5108; Fax: (412) 457-1622;
`E-mail: amack@trhp.com
`
`Copyright© 2003, Academy of Managed Care Pharmacy. All rights reserved.
`
`G abapentin (Neurontin) was approved by the U.S. Food
`
`and Drug Administration (FDA) on December 30,
`1993, for adjunctive therapy in the treatment of partial
`seizures, with and without secondary generalization, in patients
`above the age of 12 years. The FDA approved the indication for
`adjunctive therapy for partial seizures in children aged 3 to
`12 years in October 2000 and the indication for postherpetic
`neuralgia in adults in May 2004. 1
`Gabapentin is an amino acid that is structurally related to the
`inhibitory neurotransmitter gamma-amino butyric acid (GABA);
`however, its antiepileptic activity appears unrelated to any direct
`effects on the GABAergic system. 2 The mechanism of action of the
`drug has led to tremendous scientific speculation as to the poten-
`tial merits of the drug in other clinical conditions.
`Since its introduction to the market in 1993, gabapentin has
`gained widespread use, and a significant portion of this use has
`been for non-FDA approved uses (Figure 1). A retrospective
`iiiCJII:JMi Reported Off-Label (Unapproved)
`Uses of Gabapentin
`l. Bipolar disorder
`2. Neuropathic pain
`3. Diabetic neuropathy
`4. Complex regional pain syndrome
`5. Attention deficit disorder
`6. Restless legs syndrome
`7. Trigeminal neuralgia
`8. Periodic limb movement disorder of sleep
`9. Migraine
`10. Drug and alcohol withdrawal seizures
`
`review of one managed Medicaid plan demonstrated that 95%
`of patients were using gabapentin for off-label diagnoses. 3
`Gabapentin has also garnered unfavorable publicity because of
`accusations that the manufacturer illegally promoted the agent
`for at least 10 "off-label" medical conditions4•5 (Figure l). The
`FDA has issued various warning statements to the manufactur-
`er as a result of these marketing practices. 67
`While various summaries of these issues are accessible in the
`public domain, a more thorough evaluation of the issues from a
`clinical standpoint is warranted. The intent of this review is to
`tie the media concerns to clinical evidence obtained from a
`thorough literature review so that managed care pharmacists
`and physicians will be better prepared to address the subject of
`appropriate use of gabapentin.
`
`• Media Issues
`The manufacturer of gabapentin has been accused of illegal pro-
`motion of the drug to prescrib Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1055
`
`]MCP J
`
`www.amcp.org Vol. 9, No. 6 November/December 2003
`
`

`
`C O N T E M P O R A RY S U B J E C T
`
`Examination of the Evidence for Off-Label Use of Gabapentin
`
`ALICIA MACK, PharmD
`
`ABSTRACT
`
`OBJECTIVES: (1) Describe the relevance of off-label use of gabapentin to man-
`aged care pharmacy; (2) summarize recent FDA warnings and media reports
`related to off-label gabapentin use; (3) review medical information pertaining
`to the off-label use of gabapentin; (4) outline alternatives to off-label use of
`gabapentin in an evidence-based fashion, where literature exists to support such
`alternatives; and (5) encourage key clinicians and decision makers in managed
`care pharmacy to develop and support programs that restrict the use of
`gabapentin to specific evidence-based situations.
`
`SUMMARY: Gabapentin is approved by the U.S. Food and Drug Administration
`(FDA) for adjunctive therapy in treatment of partial seizures and postherpetic
`neuralgia. Various off-label (unapproved) uses have been reported, and the use
`of gabapentin for off-label purposes has reportedly exceeded use for FDA-
`approved indications. Pharmaceutical marketing practices and physician dissat-
`isfaction with currently available pharmacological treatment options may be key
`factors that contribute to this prescribing trend.
`Recently, the media has focused on these issues, noting that many cases of
`reported safety and effectiveness of gabapentin for off-label use may have been
`fabricated. A thorough review of the medical and pharmacy literature related to
`off-label use of gabapentin was performed, and a summary of the literature for the
`following conditions is presented: bipolar disorder, peripheral neuropathy, diabetic
`neuropathy, complex regional pain syndrome, attention deficit disorder, restless
`legs syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep,
`migraine headaches, and alcohol withdrawal syndrome. A common theme in the
`medical literature for gabapentin is the prevalence of open-label studies and a lack
`of randomized controlled clinical trials for all but a small number of indications.
`
`CONCLUSIONS: In the majority of circumstances where it has reported potential
`for “off-label” use, gabapentin is not the optimal treatment. The off-label use of
`gabapentin for indications not approved by the FDA should be reserved for cases
`where there is solid research support (e.g., diabetic neuropathy and prophylaxis
`of frequent migraine headaches). Managed care pharmacists should develop
`programs to restrict the use of gabapentin to these specific evidence-based situ-
`ations, and key decision makers in managed care practice should feel confident
`in supporting these use restrictions for gabapentin.
`
`KEYWORDS: Neurontin, Gabapentin, Off-label, Comparison, Bipolar, Restless legs,
`Trigeminal neuralgia, Migraine, Peripheral neuropathy, Diabetic neuropathy,
`Complex regional pain syndrome, Attention deficit disorder, Periodic limb move-
`ment disorder of sleep, Alcohol withdrawal syndrome
`
`J Managed Care Pharm. 2003;9(6):559-68
`
`Author
`
`ALICIA MACK, PharmD, is clinical pharmacy coordinator, Three Rivers
`Administrative Services, LLC, Monroeville, Pennsylvania, and adjunct clinical
`instructor, Department of Pharmacy and Therapeutics, University of Pittsburgh
`School of Pharmacy, and Duquesne University, Mylan School of Pharmacy,
`Pittsburgh.
`
`AUTHOR CORRESPONDENCE: Alicia Mack, PharmD, Clinical Pharmacy
`Coordinator, Three Rivers Administrative Services, LLC, 300 Oxford Dr.,
`Monroeville, PA 15146. Tel: (412) 856-5108; Fax: (412) 457-1622;
`E-mail: amack@trhp.com
`
`Copyright© 2003, Academy of Managed Care Pharmacy. All rights reserved.
`
`G
`
`abapentin (Neurontin) was approved by the U.S. Food
`and Drug Administration (FDA) on December 30,
`1993, for adjunctive therapy in the treatment of partial
`seizures, with and without secondary generalization, in patients
`above the age of 12 years. The FDA approved the indication for
`adjunctive therapy for partial seizures in children aged 3 to
`12 years in October 2000 and the indication for postherpetic
`neuralgia in adults in May 2004.1
`Gabapentin is an amino acid that is structurally related to the
`inhibitory neurotransmitter gamma-amino butyric acid (GABA);
`however, its antiepileptic activity appears unrelated to any direct
`effects on the GABAergic system.2 The mechanism of action of the
`drug has led to tremendous scientific speculation as to the poten-
`tial merits of the drug in other clinical conditions.
`Since its introduction to the market in 1993, gabapentin has
`gained widespread use, and a significant portion of this use has
`been for non-FDA approved uses (Figure 1). A retrospective
`
`FIGURE 1
`
`Reported Off-Label (Unapproved)
`Uses of Gabapentin
`
`1. Bipolar disorder
`2. Neuropathic pain
`3. Diabetic neuropathy
`4. Complex regional pain syndrome
`5. Attention deficit disorder
`6. Restless legs syndrome
`7. Trigeminal neuralgia
`8. Periodic limb movement disorder of sleep
`9. Migraine
`10. Drug and alcohol withdrawal seizures
`
`review of one managed Medicaid plan demonstrated that 95%
`of patients were using gabapentin for off-label diagnoses.3
`Gabapentin has also garnered unfavorable publicity because of
`accusations that the manufacturer illegally promoted the agent
`for at least 10 “off-label” medical conditions4,5 (Figure 1). The
`FDA has issued various warning statements to the manufactur-
`er as a result of these marketing practices.6,7
`While various summaries of these issues are accessible in the
`public domain, a more thorough evaluation of the issues from a
`clinical standpoint is warranted. The intent of this review is to
`tie the media concerns to clinical evidence obtained from a
`thorough literature review so that managed care pharmacists
`and physicians will be better prepared to address the subject of
`appropriate use of gabapentin.
`
`II Media Issues
`The manufacturer of gabapentin has been accused of illegal pro-
`motion of the drug to prescribing physicians for at least 10 off-
`
`www.amcp.org Vol. 9, No. 6 November/December 2003 JMCP Journal of Managed Care Pharmacy 559
`
`Exh. 1055
`
`

`
`Examination of the Evidence for Off-Label Use of Gabapentin
`
`TABLE 1
`
`Summary of Open-Label Trials and Case Reports With Gabapentin in Bipolar Illness
`
`Population
`21 outpatients meeting DSM-IV
`criteria for bipolar spectrum
`disorder (type I, type II, NOS
`cyclothymia) who were treated
`with gabapentin
`
`Results
`Alone, or as adjunct, gabapentin
`appeared moderately effective in
`treating depression. Using the CGI-
`BP, gabapentin was moderately to
`markedly effective in 43% of patients
`for overall bipolar illness, 38% for
`depressive symptoms, and 25% for
`manic symptoms.
`28 bipolar patients, 5 experiencing As adjunctive therapy, gabapentin
`manic symptoms, 5 experiencing appears to have acute antimanic and
`depressive symptoms, and 5
`antidepressant properties. Fourteen
`experiencing rapidly cycling
`of the 18 (78%) mania or hypo-
`symptoms refractory to at least
`mania patients had a positive response.
`1 mood stabilizer
`All of the patients treated for depression
`had positive response. (Positive response
`was a CGI response of much or very
`much improvement.)
`A positive response to therapy was
`observed with subsequent improvement
`of psychopathological conditions, particularly
`for anxiety and depressive symptoms.
`
`10 patients with intellectual
`disability and demonstrable
`increases in symptomatology
`during significant life events
`that had interfered with or
`induced interruption of their
`rehabilitation programs
`10 bipolar patients with mixed
`symptoms who had previously
`demonstrated only partial
`treatment responses
`
`Reference
`J Affect Disord.
`2001;65(2):167-71.
`
`Bipolar Disord.
`1999;1(1):61-65.
`
`J Intellect Disabil Res.
`2001;45(pt 2):I39-45.
`
`Ann Clin Psychiatry.
`1999; 11(4):217-22.
`
`J Affect Disord.
`1999;55(1):73-77.
`
`Eur. Neuropsychopharma.
`1999;9(3):257-9.
`
`J Psychiatr Res.
`1998;32(5):261-64.
`
`J Child Adolesc
`Psychopharmacol.
`1998;8(1):81-85.
`
`Decreases in Hamilton depression
`(P<0.05) and Bech mania ratings
`(P<0.01) were evident in the first week
`of treatment and were sustained.
`Potent early improvements were noted
`in early, middle, and late insomnia.
`Using HamD and YMS scales, mood symptoms
`were assessed and both depressive and manic
`symptoms were found to be significantly reduced
`with gabapentin.
`After 2 weeks of treatment, a moderate
`improvement of both patients was observed.
`
`The study suggested that gabapentin
`monotherapy may be useful in treating
`modest but not severe manic states. In
`conjunction with other mood stabilizers
`such as lithium or depakote, it may be
`useful. Of note, there was not a comparison
`arm to the mood stabilizers alone, so any
`advantage of the combination over mono-
`therapy with these agents remains unproven.
`Patient remained euthymic 7 months
`after gabapentin was added. Young
`Mania Rating Scale (YMRS) score
`was 27 when gabapentin was added,
`9 after 1 month, 15 after 4 months,
`and 6 after 7 months.
`
`Study
`Ghaemi SN,
`Goodwin FK.
`Open, prospective
`chart review
`
`Treatment
`8 patients
`received
`gabapentin
`monotherapy;
`13 received
`adjunctive therapy
`
`Altshuler LL, Keck PE, Adjunctive
`McElroy SL, et al.
`therapy with
`Open
`gabapentin
`600 mg-3,600 mg/
`day
`
`Carta MG,
`Hardoy MC, Dessi I,
`et al.
`Open
`
`Adjunctive
`therapy with
`gabapentin
`300 mg-900 mg
`
`Sokolski KN,
`Green C, Maris DE,
`et al.
`Open label
`
`Adjunctive
`therapy for
`1 month
`
`Young LT, Robb JC,
`Hasey GM, et al.
`Open
`
`Adjunctive
`treatment for
`up to 6 months
`
`37 patients with bipolar type I
`or II with or without rapid
`cycling course
`
`Hatzimanolis J,
`Lykouras, L,
`Oulis P, et al.
`Case report
`Erfurth A,
`Kammerer C,
`Grunze H, et al.
`Open label
`
`Monotherapy
`for 2 weeks
`
`2 patients with acute mania
`
`14 patients with acute mania
`
`6 add-on cases
`and 8 high-dose
`monotherapy
`cases; dose
`range of 1,200 mg-
`4,800 mg/day;
`treatment for
`up to 21 days
`
`Soutullo CA,
`Casuto LS, Keck PE.
`Case report
`
`Add-on to
`carbamazepine
`
`One boy, aged 13 years,
`with bipolar disorder,
`manic episode, and ADHD
`
`label conditions; company medical science liaisons were also
`alleged to have been involved in this practice.4 The authors of
`one news article noted that many reported cases of safety and
`effectiveness with unapproved use of the drug appeared to be
`fabricated by the manufacturer.
`
`A follow-up story in January 2003 about a “whistle-blower”
`lawsuit related to allegedly illegal marketing practices included
`an explanation of some of the issues, with particular emphasis
`on the clinically inappropriate promotion of gabapentin for
`bipolar disorder.4 The lawsuit involves charges made by a for-
`
`560 Journal of Managed Care Pharmacy
`
`JMCP November/December 2003
`
`Vol. 9, No. 6 www.amcp.org
`
`Exh. 1055
`
`

`
`Examination of the Evidence for Off-Label Use of Gabapentin
`
`TABLE 2
`
`Summary of Selected Primary and Tertiary References
`Using Gabapentin in Management of Neuropathic Pain
`
`Publication Type
`
`Treatment or Method
`
`Population
`
`Results
`
`Randomized,
`double-blind,
`placebo-
`controlled trial
`
`Symptom-based, 8-week
`study design of patients
`receiving gabapentin in
`doses up to 2,400 mg/day
`or placebo
`
`153 patients patients
`randomized to gabapentin
`and 152 patients
`randomized to placebo
`
`Pilot study
`
`Gabapentin was administered
`orally in gradually increasing
`doses up to a maximum of
`2,400 mg/day
`
`18 patients with
`peripheral nerve injuries
`or central lesions
`
`Retrospective
`chart review
`
`Patients receiving
`gabapentin for
`at least 30 days
`were studied.
`
`122 patients divided into
`3 groups based on pain
`diagnosis of low back,
`myofascial, or neuropathic
`pain
`
`Meta-analysis
`
`35 papers involving
`Extensive search of
`727 patients with
`several electronic
`multiple neuropathic
`databases for controlled
`pain conditions
`and uncontrolled studies.
`Efficacy was assessed through met inclusion
`meta-analyses of randomized
`criteria
`controlled trials (RCTs).
`Effectiveness of gabapentin
`in uncontrolled studies was
`assessed via a novel system of
`dichotomous classification of
`bad versus good results.
`
`Randomized
`controlled
`clinical trial
`
`Gabapentin 3,600 mg/day
`(forced max) 67% achieved
`max dose
`
`Randomized
`controlled
`clinical trial
`
`Gabapentin 3,600 mg/day
`(65% achieved max dose)
`versus placebo
`
`Uncontrolled
`diabetes
`(75% type 2)
`n=84 gabapentin,
`n=81 placebo
`
`Postherpetic
`neuralgia
`n=113 gabapentin,
`n=112 placebo
`
`Over the study, the average daily pain
`diary score improved by 1.5 (21%) in
`gabapentin-treated patients and by
`1.0 (14%) in placebo-treated patients.
`(P=0.048, rank-based analysis of
`covariance). Significant differences
`were shown in favor of gabapentin
`(P<0.05) for the clinician and patient
`global impression of change and some
`domains of the Short-Form McGill
`Pain Questionnaire.
`
`Gabapentin induced a moderate and
`statistically significant relief of
`ongoing or spontaneous pain and was
`particularly effective in reducing
`paroxysmal pain. A striking finding
`was the significant effect on brush-
`induced cold allodynia. In contrast,
`no effects were observed on detection
`of pain thresholds to static mechanical
`and hot stimuli.
`
`Significant decrease in pain scores
`with gabapentin in the neuropathic
`pain group but not in the low-back-
`pain group. Patients with postherpetic
`neuralgia had the greatest decrease in
`pain scores. Patients who were taking
`opiates had significantly less benefit
`with gabapentin in terms of pain score.
`
`The meta-analysis of the 2 high-
`quality placebo-controlled randomized
`trials showed positive effect of
`gabapentin in diabetic neuropathy
`and postherpetic neuralgia. Addition
`of 2 low-quality PC, RCTs did not
`alter the magnitude or duration of the
`observed effect. The uncontrolled
`studies demonstrated positive effect
`on pain in different neuropathic
`syndromes as well as benefit for
`different types of neuropathic pain;
`highest dose administered and rate of
`dose escalation showed wide variability
`between prescribers. Fewer and less-
`severe side effects were reported in the
`uncontrolled studies.
`
`Gabapentin versus placebo:
`difference in mean pain score at
`endpoint = -1.2 (P<0.001);
`difference in mean sleep
`interference score = -1.47 P<0.001).
`
`Decrease in average daily pain score
`= 33% gabapentin, 7% placebo
`(P<0.001).
`
`Reference
`
`Serpell MG. Pain.
`2002;99(3):557-66.
`
`Brasseur AN, Parker F,
`Chauvin M, et al.
`Eur Neurol. 1998;40(4):
`191-200.
`
`Rosenberg JM, Harrell C,
`Ristic H, et al. Clin J Pain.
`1997;13(3):351-55.
`
`Mellegers MA, Furlan AD,
`Mailis A. Clin J Pain.
`2001;17(4):284-95.
`
`Backonja M, Beydoun A,
`Edwards K, et al.
`JAMA. 1998;280: 1831-36.
`
`Rowbotham M, Harden N,
`Stacey B, et al.
`Ann Pharmacother.
`2000;34:802-07.
`
`www.amcp.org Vol. 9, No. 6 November/December 2003 JMCP Journal of Managed Care Pharmacy 561
`
`Exh. 1055
`
`

`
`Examination of the Evidence for Off-Label Use of Gabapentin
`
`TABLE 3
`
`Price Comparisons for Gabapentin Versus Various Tricyclic Antidepressants
`Used in the Management of Neuropathic Pain
`
`Drug
`Gabapentin
`
`Amitriptyline
`
`Nortriptyline
`
`Dose for Management of
`Neuropathic Pain†*
`300 mg/day up to
`1,800 mg/day
`
`FDA Approval
`No
`
`10 mg-25 mg orally
`at bedtime, up to
`150 mg-200 mg/day
`
`10 mg/day orally,
`increase by 10 mg/day
`every 3 to 5 days as needed;
`doses up to 60 mg/day
`have been reported
`
`No
`
`No
`
`Cost per Unit†
`100 mg cap ($0.51 ea)
`300 mg ($1.23 ea)
`400 mg ($1.47 ea)
`600 mg ($1.98 ea)
`800 mg ($2.38 ea)
`10 mg tab ($0.09 ea)
`25 mg ($0.12 ea)
`50 mg ($0.09 ea)
`75 mg ($0.12 ea)
`100 mg ($0.13 ea)
`10 mg cap ($0.14 ea)
`25 mg cap ($0.21 ea)
`50 mg cap ($0.25 ea)
`75 mg cap($0.28 ea)
`
`Tablet or Capsules
`per Month
`up to 540
`up to 180
`up to 135
`up to 90
`up to 68
`up to 600
`up to 240
`up to 120
`up to 90
`up to 60
`up to 180
`up to 60
`up to 30
`up to 30
`
`Maximum Average
`Cost per month
`$275.40
`$221.98
`$199.48
`$178.98
`$162.44
`$54.00
`$28.80
`$10.80
`$10.80
`$7.80
`$25.20
`$12.60
`$7.50
`$8.40
`
`† Gelman CR, Rumack BH, eds. DRUGDEX Information System. Denver, CO: Micromedex, Inc.; 1994.
`‡ http://www.drugstore.com. Accessed September 7, 2003. Cost per unit based on 90 unit/month pricing.
`
`mer salesman that the company used a systematic strategy to
`promote gabapentin for various off-label uses. The extension of
`potential uses of gabapentin contributed to the drug’s tremen-
`dous financial success, essentially creating a “blockbuster” drug
`in terms of sales. In 2000 alone, gabapentin earned $1.3 billion
`in sales, and as much as 78% of these sales were for uses with-
`out clinical evidence of safety or effectiveness.4
`
`II Review of the Clinical Literature
`Off-label use of gabapentin has been reported in bipolar disor-
`der, peripheral neuropathy, diabetic neuropathy, complex
`regional pain syndrome, attention deficit disorder, restless legs
`syndrome, trigeminal neuralgia, periodic limb movement disor-
`der of sleep, migraine headaches, and drug and alcohol with-
`drawal syndrome. A recurring theme in the literature, with the
`exception of neuropathic pain and migraine, is a prevalence of
`open-label studies with a lack of randomized controlled clinical
`trials. It is important to consider that an inherent problem with
`open-label trial design is the potential for introduction of bias
`because the treatment assignment is known.
`
`Gabapentin in the Treatment of Bipolar Disorder
`Extensive review confirms that current published literature on
`gabapentin is primarily based on open-label trials that evaluate
`small numbers of patients (Table 1).8-15 The few randomized
`controlled trials designed to investigate the efficacy of
`gabapentin in treating bipolar disorder have concluded that
`there is no significant difference in the effects of the drug com-
`pared with placebo.16,17 This supports the likelihood of bias in
`the various open-label studies since these results have not been
`confirmed in the randomized controlled trials. Various authors
`
`of medical reviews on this subject have concluded that
`gabapentin should not be recommended for treatment of bipo-
`lar disorder and that double-blind, randomized controlled trials
`are needed to confirm any true efficacy of the drug in manage-
`ment of this condition.18-21
`Real-life practice involves instances of refractory bipolar disorder
`that exhaust the current treatment options. The Texas Medication
`Algorithm Project (TMAP) lists lamotrigine or gabapentin only as
`salvage therapy. Therefore, these 2 agents should be reserved for
`unstable patients at the seventh stage of treatment
`in
`hypomanic/manic episodes.22 In all other forms of bipolar disorder,
`gabapentin is not recommended at any phase of therapy.
`Although limited comparative data are available on the sub-
`ject, results from a cross-over study suggest that lamotrigine
`may be superior to gabapentin as well as placebo for the man-
`agement of refractory mood disorders.23 The investigators stud-
`ied 31 patients who had either bipolar I, bipolar II, or unipolar
`disorder and failures of other mood stabilizing agents.
`Lamotrigine was titrated to 300 mg–500 mg by weeks 5 and 6,
`and gabapentin was titrated to 4,800 mg daily by week 6.
`At week 6, based on the Clinical Global Impression Score, 52%
`of patients responded to
`lamotrigine, 26% responded
`to gabapentin, and 23% responded to placebo (P=0.011,
`lamotrigine versus gabapentin). The results of this study suggest
`that lamotrigine might be considered in cases of treatment
`refractory to first-line agents in bipolar disorder.
`
`Gabapentin in the Treatment of Pain Syndromes,
`Peripheral Neuropathy, and Diabetic Neuropathy
`The exact mechanism of action of gabapentin in managing neu-
`ropathic pain is unknown; however, it is speculated to work via
`
`562 Journal of Managed Care Pharmacy
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`JMCP November/December 2003
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`Vol. 9, No. 6 www.amcp.org
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`Exh. 1055
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`
`Examination of the Evidence for Off-Label Use of Gabapentin
`
`TABLE 4
`
`Published Reports Related to Use of Gabapentin
`in Complex Regional Pain Syndrome I
`
`the
`In the Morello study,34
`agents were proven comparable
`in clinical efficacy. In fact, these
`authors suggested a slight advan-
`tage to using amitriptyline over
`gabapentin, although the differ-
`ence was not statistically signifi-
`cant. Comparing prices of the
`agents given in doses for the man-
`agement of neuropathic pain,
`amitriptyline and nortriptyline cost
`only a small fraction of the signifi-
`cant direct drug cost associated
`with gabapentin
`(Table 3).35
`Therefore, the tricyclics appear to
`offer a lower-cost therapeutically equivalent alternative to
`gabapentin in many situations.
`
`Study
`
`Treatment
`
`Population
`
`Results
`
`Case study
`
`Gabapentin
`
`1 child
`
`Satisfactory pain relief
`was reported.
`
`Reference
`
`Wheeler DS, Vaux KK , Tam DA.
`Use of gabapentin in the treatment
`of childhood reflex sympathetic
`dystrophy. Pediatr Neurol. 2000;
`22(3):2201-11.
`
`Case study
`
`Gabapentin
`
`6 patients, aged
`42-68 years,
`with severe,
`refractory RSD
`
`Satisfactory pain relief was Mellick GA, Mellick LB. Reflex
`obtained in all patients.
`sympathetic dystrophy treated
`with gabapentin. Arch Phys Med
`Rehabil. 1997;78(1):98-105.
`
`voltage-activated calcium ion channels at the postsynaptic dor-
`sal horn, thereby interrupting the series of events that leads to
`the sensation of neuropathic pain. Review of the various
`hypotheses concerning these pharmacologic theories is beyond
`the scope of this article but may be found elsewhere.24-26
`While the clinical literature in support of gabapentin use for
`conditions of neuropathic pain is more favorable than that con-
`cerning its use in various other disease states, there remain
`issues concerning its merits in clinical practice. These involve
`variable doses, few direct comparisons to other agents, and,
`again, a number of open-label studies with the potential
`for bias. Nonetheless, gabapentin does have proven efficacy for the
`treatment of diabetic neuropathy and postherpetic neuralgia.32,33
`A summary of selected published studies on this subject
`appears in Table 2.27-33
`Morello et al. demonstrated that there is no statistically sig-
`nificant difference between amitriptyline and gabapentin in the
`treatment of diabetics with peripheral neuropathic pain, as
`measured by pain scales and global pain scores.34 In this study,
`21 diabetic patients with stable glycemic control received either
`gabapentin or amitriptyline for 6 weeks and then crossed over
`to the other arm of therapy for 6 additional weeks, with a
`1-week wash-out period between therapies. Dosage was adjust-
`ed based on the patient’s response, with a mean gabapentin dose
`of 1,565 mg and a mean amitriptyline dose of 59 mg. Both
`medications were found to significantly decrease pain scores
`from baseline (P<0.001). Sixty-seven percent of amitriptyline
`patients reported moderate or greater pain relief, and 52% of
`gabapentin patients reported such relief (P=0.26).
`Current treatment guidelines favor using amitriptyline, nor-
`triptyline, or gabapentin for the management of painful neuro-
`pathic conditions. It is recognized that, in specific clinical cir-
`cumstances, the adverse-effect profile of the tricyclics may
`prove unacceptable, thus warranting consideration of therapeu-
`tic alternatives. However, in cases without tricyclic contraindi-
`cations, cost should also be considered when selecting an initial
`option for treatment.
`
`Gabapentin in the Treatment of
`Complex Regional Pain Syndrome
`There are no reports that confirm efficacy of gabapentin in
`management of complex regional pain syndrome, also known
`as reflex sympathetic dystrophy (RSD). The literature is sparse
`and primarily anecdotal in nature, composed of 2 reports
`involving a total of 7 patients in addition to 2 letters (Table 4)
`that offer little scientific value.36-40 From an evidence-based
`standpoint, the available information is insufficient to support
`use of gabapentin in this condition. Recognized medical treat-
`ments for RSD include adrenergic blockers, nonsteroidal anti-
`inflammatory drugs, calcium channel blockers, phenytoin, opi-
`oids, and calcitonin.39
`
`Gabapentin in the Treatment of Attention Deficit Disorder
`There are 3 published reports related to behavioral disturbances
`and the use of gabapentin, none of which were clinical trials.
`One case report is specific to the use of the drug in attention
`deficit hyperactivity disorder (ADHD). A second case report
`involved 7 patients who experienced behavioral side effects
`with gabapentin. The third citation was a letter (Table 5).41-43
`Thus, the evidence related to the use of gabapentin in ADHD is
`insufficient to warrant its use for this condition.
`Stimulants have been the mainstay of ADHD therapy for
`decades, but there is a rising trend in pediatric polypsy-
`chopharmacy with little or no research to support this phe-
`nomenon.44 Since there is no evidence to support the use of
`gabapentin in ADHD, alternative clinically appropriate and sup-
`portable treatment options should be given primary considera-
`tion when formulating treatment plans for cases refractory to
`stimulants in ADHD. Current treatment guidelines suggest a
`trial with a stimulant along with diet, behavior management,
`special education, and perhaps psychotherapy in ADHD disease
`management. 43
`
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`Exh. 1055
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`
`Examination of the Evidence for Off-Label Use of Gabapentin
`
`TABLE 5
`
`Study type
`Case report
`
`Published Reports of Gabapentin and Behavior in Children
`Treatment
`Population
`Results
`Gabapentin 200 mg/day added
`1 boy, aged 12 years, with
`Within 3 weeks, mother,
`to methylphenidate 30 mg/day
`ADD, reading disorder, mixed
`teacher, and clinician noted
`receptive and expressive
`improvement and stabiliz-
`language disorder,
`ation of mood symptoms as
`encopresis, and
`remarkable; it remained so for
`bipolar disorder II
`6 months of follow-up.
`
`Case report
`
`Gabapentin as adjunct
`
`7 children with baseline
`ADD and developmental
`delay
`
`Children consequentially
`developed behavioral side
`effects, including tantrums,
`aggression toward others,
`hyperactivity, and defiance.
`All behavioral changes were
`reversible and were managed
`by dose reduction or discon-
`tinuation of gabapentin.
`
`Reference
`Hamrin V, Bailey K. Gabapentin
`and methylphenidate treatment
`of a preadolescent with attention
`deficit hyperactivity disorder and
`bipolar disorder. J Child Adolesc
`Psychopharmacol. 2001;11(3):
`301-09.
`Lee DO, Steingard RJ, Casena M,
`et al. Behavioral side effects of
`gabapentin in children. Epilepsia.
`1996;3(1):87-90.
`
`Gabapentin in the Treatment of Restless Leg Syndrome
`Restless leg syndrome (RLS) is an awake phenomenon charac-
`terized by an intense, irresistible urge to move the legs, usually
`associated with sensory complaints, motor restlessness, worsen-
`ing of symptoms at rest and relief with motor activation, and
`incre