Since gabapentin was approved by the US Food and Drug Administration (FDA) for treatment of partial-onset seizures and postherpetic neuralgia, it has been used in many different ways, many off-label indications, and with several recent safety warnings.
Early Problems
After FDA approval in 1993 (for partial seizures), gabapentin was promoted by its maker (Park-Davis) for off-label indications, especially for pain. There was no FDA approval for that indication and the studies the company had done were deemed to have been manipulated in a subsequent lawsuit.1 Gabapentin became the nonopioid go-to medication for treatment of pain despite underwhelming evidence.
Studies on Neuropathy
In the largest trial of gabapentin for diabetic peripheral neuropathy, Rauck and colleagues found no significant difference in pain relief between gabapentin and placebo.2 A Cochrane review of gabapentin for neuropathic pain concluded that about 30%-40% of patients taking gabapentin for diabetic neuropathy achieved meaningful pain relief with gabapentin use, with a number needed to treat (NNT) of 6.6.3 The review also concluded that for postherpetic neuralgia (an FDA-approved indication) 78% of patients had moderate to substantial benefit with gabapentin (NNT 4.8 for moderate benefit).
Dr. Douglas S. Paauw
Side Effects of Gabapentin
From the Cochrane review, the most common side effects were: dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%). The number needed to harm for gabapentin was 7.5 The two side effects listed here that are often overlooked that I want to highlight are peripheral edema and gait disturbance. I have seen these both fairly frequently over the years. A side effect not found in the Cochrane review was weight gain. Weight gain with gabapentin was reported in a meta-analysis of drugs that can cause weight gain.4
New Warnings
In December 2019, the FDA released a warning on the potential for serious respiratory problems with gabapentin and pregabalin in patients with certain risk factors: opioid use or use of other drugs that depress the central nervous system, COPD, and other severe lung diseases.5 Rahman and colleagues found that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation (hazard ratio, 1.39; 95% confidence interval, 1.29-1.50).6
Off-Label Uses
Primary care professionals frequently use gabapentin for two off-label indications that are incorporated into practice guidelines. Ryan et al. studied gabapentin in patients with refractory, unexplained chronic cough.7 In a randomized, placebo-controlled trial, gabapentin improved cough-specific quality of life compared with placebo (P = .004; NNT 3.58). Use of gabapentin for treatment of unexplained, refractory cough has been included in several chronic cough practice guidelines.8,9
Gabapentin has been studied for the treatment of restless legs syndrome and has been recommended as an option to treat moderate to severe restless legs syndrome in the American Academy of Sleep Medicine Guidelines.10
Pearl of the Month:
Gabapentin is used widely for many different pain syndromes. The best evidence is for postherpetic neuralgia and diabetic neuropathy. Be aware of the side effects and risks of use in patients with pulmonary disease and who are taking CNS-depressant medications.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.
References
1. Landefeld CS, Steinman MA. The Neurontin legacy: marketing through misinformation and manipulation. N Engl J Med. 2009;360(2):103-6.
2. Rauck R et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485-96.
3. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938.
4. Domecq JP et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.
5. 12-19-2019 FDA Drug Safety Communication. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).
6. Rahman AA et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: A population-based cohort study. Ann Intern Med. 2024 Feb;177(2):144-54.
7. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 2012;380(9853):1583-9.
8. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016 Jan;149(1):27-44.
9. De Vincentis A et al. Chronic cough in adults: recommendations from an Italian intersociety consensus. Aging Clin Exp Res 2022;34:1529.
10. Aurora RN et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults — an update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039.