Gabapentin for Chronic Neuropathic Pain and Fibromyalgia

This review is an update of a review published in 2011, itself a major update of previous reviews published in 2005 and 2000, investigating the effects of gabapentin in chronic neuropathic pain (pain due to nerve damage). Antiepileptic drugs are used to manage chronic neuropathic pain and fibromyalgia.

What are the signs and symptoms of fibromyalgia?
What are the signs and symptoms of fibromyalgia?

OBJECTIVES:

To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain and fibromyalgia.

SEARCH METHODS:

We identified randomised trials of gabapentin for chronic neuropathic pain or fibromyalgia by searching the databases MEDLINE (1966 to March 2014), EMBASE (1980 to 2014 week 10), and CENTRAL in The Cochrane Library (Issue 3 of 12, 2014). We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched Clinicaltrials.gov. Searches were run originally in 2011 and the date of the most recent search was 17 March 2014.

SELECTION CRITERIA:

Randomised, double-blind studies reporting the analgesic and adverse effects of gabapentin in neuropathic pain or fibromyalgia with assessment of pain intensity, pain relief, or both, using validated scales. Participants were adults.

DATA COLLECTION AND ANALYSIS:

Three review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.For efficacy, we calculated the number needed to treat to benefit (NNT), concentrating on at least 50% pain intensity reduction, and Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) definitions of at least moderate and substantial benefit. For harm we calculated number needed to treat for harm (NNH) for adverse effects and withdrawal. Meta-analysis was undertaken using a fixed-effect model. We emphasised differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, complex regional painsyndrome type 1 (CRPS-1), and fibromyalgia.

MAIN RESULTS:

Seven new studies with 1919 participants were added. Another report (147 participants) provided results for a study already included, but which previously had no usable data. A further report (170 participants) used an experimental formulation of intrathecal gabapentin. Thirty-seven studies (5633 participants) studied oral gabapentin at daily doses of 1200 mg or more in 12 chronic pain conditions; 84% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy or mixed neuropathic pain. There was no first tier evidence.Second tier evidence for the outcome of at least 50% pain intensity reduction, considered valuable by patients with chronic pain, showed that gabapentin was significantly better than placebo in postherpetic neuralgia (34% gabapentin versus 21% placebo; NNT 8.0, 95% CI 6.0 to 12) and painful diabetic neuropathy (38% versus 21%, NNT 5.9, 95% CI 4.6 to 8.3). There was insufficient information in other pain conditions to reach any reliable conclusion. There was no obvious difference between standard gabapentin formulations and recently-introduced extended-release or gastro-retentive formulations, or between different doses of gabapentin.Adverse events occurred significantly more often with gabapentin. Persons taking gabapentin could expect to have at least one adverse event (62%), withdraw because of an adverse event (11%), suffer dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (9%). Serious adverse events (3%) were no more common than with placebo.There were insufficient data for direct comparisons with other active treatments, and only third tier evidence for other painful conditions.

AUTHORS’ CONCLUSIONS:

There was no top tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with some painful neuropathic pain conditions. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. About 35% achieved this degree of pain relief with gabapentin, compared with 21% for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in neuropathic pain conditions except postherpetic neuralgia and painful diabetic neuropathy, and in fibromyalgia, is very limited.The levels of efficacy found for gabapentin are consistent with those found for other drug therapies in postherpetic neuralgia and painful diabetic neuropathy.

Gabapentin for Chronic Neuropathic Pain and Fibromyalgia

Study Population: Adults with postherpetic neuralgia or diabetic neuropathy

Efficacy Endpoints: 50% pain intensity reduction

Harm Endpoints: Dizziness, somnolence, ataxia, edema

Narrative: Neuropathic pain, when the pain generator is the nerve itself, occurs in a variety of conditions including diabetes mellitus and postherpetic neuropathy. The exact mechanism of action for these conditions is unclear. Some speculate that aberrant nerve signal modulation may be a culprit, which would explain why neuropathic pain rarely responds adequately to traditional analgesics, and why an effective treatment has proven elusive. Further complicating matters for patients, neuropathic pain typically is chronic in nature. Given the chronic nature and the poorly understood etiology, neuropathic pain is a challenge to treat and to study.

Patients generally consider a 50% reduction in their chronic pain a useful outcome because it has been associated with important beneficial effects on sleep interference and depression.1 Physicians have tried a variety of medicines off-label including opiates, antidepressants, and antiepileptics to relieve patients’ neuropathic pain. One such drug, gabapentin (Neurontin), received approval by the U.S. Food and Drug Administration (FDA) in 1993 as an adjunct medicine for partial seizures and additional FDA approval in 2002 for the treatment of postherpetic neuralgia.2 Gabapentin remains off-label when used to treat diabetic neuropathy.

This summary uses a Cochrane review, updated in 2014, to address the efficacy of gabapentin compared with placebo to palliate neuropathic pain.3 The Cochrane review includes 37 trials enrolling more than 5,600 patients. Overall, there were limited quality data to permit analysis of other neuropathic indications other than postherpetic neuralgia and diabetic neuropathy. Oral gabapentin dosed at 1,200 mg or more daily demonstrated a 50% reduction in pain intensity, with a number needed to treat (NNT) of eight for postherpetic neuralgia and an NNT of six for diabetic neuropathy. Gabapentin treatment was associated with several adverse effects including dizziness (number needed to harm [NNH] = 8), somnolence (NNH = 11), ataxia (NNH = 13), and edema (NNH = 21). There were no obvious differences in patient response with doses greater than 1,200 mg. The NNT for gabapentin is similar to a recent meta-analysis that demonstrated an NNT of seven.4

Caveats: The Cochrane reviewers indicated that high-quality evidence was lacking, which limits the strength of the conclusions and the resulting NNTs in this analysis. Moreover, only postherpetic neuralgia and diabetic neuropathy had been studied adequately to generate numerical estimates for the purposes of this review. Although patients with other neuropathic conditions were included in the Cochrane review, specifically fibromyalgia, the efficacy of gabapentin could not be evaluated in the treatment of these conditions because of a lack of quality data.

The regulatory and research history of gabapentin is important and relevant in any attempt to understand how related data should be applied or extrapolated. There are a number of peer-reviewed publications,5,6,7 publicly available court documents,8 investigative lay press reports,9 and high-profile scientific editorials10 that all strongly suggest that available data on gabapentin cannot be comfortably extrapolated or applied to practice. For this reason, we have rated gabapentin for chronic neuropathic pain yellow, meaning we believe that a proper answer is not yet available. In the future, we hope to see high-quality, randomized, non–industry-funded data that may offer reliable and valid answers to the question of the efficacy of gabapentin for neuropathic pain and other conditions.

There are patients who appear to benefit from gabapentin. This is particularly important in the case of postherpetic neuralgia, which can severely impact quality of life, and psychological and physical well-being.11,12 The challenge is identifying the minority of patients who derive benefit and finding the proper dose,13 both of which seem to depend on patients’ clinical response to a trial of therapy.

Notably, few guidelines exist for the treatment of neuropathic pain. One, from the National Institute for Health and Care Excellence in the United Kingdom, includes the use of gabapentin as a first-tier treatment for all neuropathic pain.14 Similarly, the European Federation of Neurological Societies includes gabapentin as a first-tier agent in its guideline for neuropathic pain, specifically including painful polyneuropathy and postherpetic neuralgia.15 The American Academy of Neurology with other organizations issued a joint guideline in 2011 indicating only that gabapentin should be considered for the treatment of painful diabetic neuropathy.16

The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the U.S. Air Force medical department or the U.S. Air Force at large.

The original manuscript was published in Medicine by the Numbers, American Family Physician as part of the partnership between TheNNT.com and AFP.

 

Geriatric Use and Pediatric Use of Gabapentin for Neuropathic Pain

The total number of patients treated with Neurontin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. Totally 80% Gabapentin patients are seniors.

There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage.

Gabapentin
Gabapentin

Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients ≥ 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse events were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age.

Clinical studies of Neurontin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and dose should be adjusted based on creatinine clearance values in these patients

Pediatrics: The safety and efficacy in patients under the age of 18 have not been established.

Safety data in 39 patients between the ages of 12 and 18 years included in the double-blind, placebo-controlled trials showed that, at doses of 900 to 1200 mg/day, the incidence of adverse events in this group of patients was similar to that observed in older individuals.

In controlled clinical trials involving patients, 3 to 12 years of age (N=323), psychiatric adverse events such as emotional lability, hostility, hyperkinesia and thought disorder were reported at a higher frequency in patients treated with gabapentin compared to placebo.

Geriatrics: Systematic studies in geriatric patients have not been conducted. Adverse clinical events reported among 59 patients over the age of 65 years treated with Neurontin did not differ from those reported for younger individuals. The small number of individuals evaluated and the limited duration of exposure limits the strength of any conclusions reached about the influence of age, if any, on the kind and incidence of adverse events associated with the use of Neurontin.

Gapapentin for Neuropathic Pain

Gabapentin (Neurontin) has FDA indication to treat postherpetic neuralgia and partial onset seizures.  Controlled clinical trials in diabetic neuropathy and postherpetic neuralgia show that gabapentin at 2400-3600 mg/day has a similar efficacy to tricyclic antidepressants and carbamazepine.  Consistent, though less compelling clinical evidence supports its use for neuropathic cancer pain, pain associated with HIV infection, chronic back pain and others (readers wanting more in depth research findings are urged to consult Reference 1).  Due to this emerging evidence, it is widely used for the treatment of neuropathic pain.  The exact mechanism and site of action of gabapentin is unknown.   Gabapentin is generally well-tolerated, easily titrated, has few drug interactions, and does not require laboratory monitoring.  However, cost may be a limiting factor for some patients.  Patients suitable for gabapentin should have a clear neuropathic pain syndrome, characterized by sharp, shooting, lancinating and/or burning pain, in a nerve root (radicular) or stocking/glove distribution. See Fast Fact #289 for a comparison of gabapentin with pregabalin a similar neuropathic analgesic.

Adult Dosing    Gabapentin is started at low doses (100 mg to 300 mg total daily) and increased by 100 – 300 mg every 1-3 days to effect.  A typical schedule might be: day 1-2: 300 mg nightly; day 3-4: 300 mg twice daily; day 5-7: 600 mg twice daily; day 8 onwards: 600 mg three times a day.  The usual effective total daily dose is 900-3600 mg, administered in three divided doses per day.  Titration should proceed more slowly in elderly patients. If gabapentin is discontinued, it should be done over a minimum of a week to prevent withdrawal seizures.

Pediatric Use    There is limited data available assessing its effectiveness in neuropathic pain in children. The American Pain Society recommends that gabapentin be considered for pediatric neuropathic pain especially when concurrent analgesics are found to be too sedating.  Their recommended initial dose is 2 mg/kg/day with a usual dosage range of 8 to 35 mg/kg/day divided into 3 daily doses.

Dosing in Renal Failure   Gabapentin doses must be reduced for patients with renal insufficiency.

  • Creatinine Clearance (CrCl) 30-60 ml/min: maximum daily dose is 1400 mg, divided.
  • CrCl 16-30 ml/min: maximum daily dose is 700 mg, given once daily.
  • CrCl 15ml/min: maximum daily dose is 300 mg, once daily.  Doses should decrease proportionally for CrCl less than 15 ml/min (e.g. 300 mg every other day for a CrCl of ~7.5 ml/min).
  • For patients on hemodialysis a supplemental dose is usually given after dialysis (usually 100-300 mg).

Adverse Reactions    Sedation, confusion, dizziness, and ataxia are the most common side effects, especially with rapid dose titration.  Tolerance to these effects appears to develop within a few days if the dose is held at the highest tolerated dose until symptoms improve or stabilize.

Dosage Formulations    Gabapentin is available in 100 mg, 300 mg, and 400 mg capsules, 600 mg and 800 mg tablets, and as a liquid (250mg/5mL).

Cost    Gabapentin is more expensive than older agents used for neuropathic pain (tricyclic antidepressants and older anti-epileptic drugs such as carbamazepine).  Generic gabapentin is available, although can cost ~$100 for 90 600 mg tablets.

Other Palliative Care Uses of Gabapentin    Small scale published trials have shown efficacy in the treatment of severe chronic hiccups, pruritus, postoperative pain and delirium, restless leg syndrome and hot flashes. Perhaps more compelling is its potential efficacy for chronic cough for which a randomized double-blind placebo controlled trial demonstrated significant improvement in cough-specific quality of life, cough frequency, and cough severity. See Fast Fact #200.

Summary    Gabapentin is a safe and effective adjuvant analgesic for neuropathic pain.  Physicians should become comfortable using and titrating gabapentin in patients with neuropathic pain syndromes.

References
  1. Moore R, Wiffen PJ, Derry S, Toelle T, Rice AS C. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007938. DOI: 10.1002/14651858.CD007938.pub3
  2. Mishra S, Bhatnagar S, et al.  A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: a prospective randomized double-blind placebo-controlled study. American Journal of Hospice and Palliative Medicine 2012;29:177-182.
  3. Caraceni A, et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the gabapentin cancer pain study group. J Clin Onc. 2004; 22:2909-2917.
  4. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 6th ed, Glenview, IL: American Pain Society, 2008.
  5. Micromedex Drug Database. Thompson Reuters. http://www.micromedex.com.
  6. Giampiero P, Aielli F, et al.  Gabapentin in the treatment of hiccups in patients with advanced cancer: a 5-year experience. Clin Neuropharm 2010; 33:179-180.
  7. Anand S, Gabapentin for pruritus in palliative care. Am J of Hospice and Pall Med 2012; 30:192-196.
  8. Dauri M, Faria S, Gatti A, et al. Gabapentin and Pregabalin for the Acute Post-operative Pain Management. A Systematic-Narrative Review of the Recent Clinical Evidences. Curr Drug Targets 2009, 10(8):716-33.
  9. Leung JM, Sands LP, et al.  Pilot clinical trial of gabapentin to decrease postoperative delirium in older patients.  Neurology. 2006; 67:310-314.
  10. Saletu M, Anderer P, Saletu-Zyhlarz GM, et al. Comparative Placebo-Controlled Polysomnographic and Psychometric Studies on the Acute Effects of Gabapentin Versus Ropinirole in Restless Legs Syndrome. J Neural Transm 2010, 117(4):463-73.
  11. Butt DA, Lock M, Lewis JE, et al. Gabapentin for the Treatment of Menopausal Hot Flashes: A Randomized Controlled Trial. Menopause 2008; 15(2):310-8.

Version History:  This Fast Fact was originally edited by David E Weissman MD.   2nd Edition published August 2005; 3rd Edition May 2015. Version re-copy-edited April 2009; then again May 2015; renal dosing information adjusted to reflect current recommendations, and updated cost information added.

Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.

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