Best Evidence Analyses and Commentary

Effective dosing of gabapentin for diabetic peripheral neuropathy
Rebekah Stoner, Kimberly Clifton, PharmD Candidates; Marcus W. Campbell, PharmD BC-ADM
February 6, 2015

Diabetic peripheral neuropathy (DPN) is a common long-term complication of type 2 diabetes and occurs in up to 50% of patients with long-standing disease.1 DPN and its complications cost between $4.6 and $13.7 billion dollars in the United States annually.2 Gabapentin, an anticonvulsant first approved in the U.S. in 1994 for the treatment of epilepsy, is widely used off-label for the treatment of DPN. Although the exact mechanism of action is unknown, gabapentin is thought to disrupt excitatory neurotransmitter release through blockade of voltage-dependent calcium channels.3'

 

Studies evaluating the maximum effective dose of gabapentin to treat DPN are conflicting and are generally limited by small population sizes and short study durations. In a small randomized, placebo-controlled study, Backonja and colleagues evaluated the efficacy of gabapentin in 165 patients with DPN using doses initiated at 900 mg per day and titrated up to a dose of 3,600 mg per day. Following 8 weeks of therapy, patients receiving gabapentin showed significant reductions in mean pain scores compared with placebo (p<0.001) as measured on an 11-point Likert scale. Gabapentin also improved sleep interference scores (p<0.05), reduced total mean pain (p<0.01), reduced mean visual analog scale (p<0.01) and present pain intensity scores (p<0.05) when compared to placebo. The most frequently reported adverse effects were dizziness and somnolence.4 Backonja and colleagues also performed a review of five randomized controlled trials evaluating the efficacy of gabapentin for the treatment of DPN and other neuropathic pain syndromes. Gabapentin was shown to be effective in the treatment of DPN at doses of 900 mg/day, with greater efficacy achieved at doses of 1,800 to 3,600 mg/day. Backonja and colleagues concluded that gabapentin should be initiated at 300 mg on day 1 and then titrated to 600mg on day 2, and then 900 mg on day 3.6

In a randomized crossover study evaluating the efficacy of gabapentin 900 mg daily in 40 patients with DPN, there were no significant differences in mean change of visual analog pain scale and present pain intensity scores compared with placebo. However, statistically significant improvements were seen in the McGill pain questionnaire (p=0.03). The most common side effects were drowsiness, fatigue and ataxia.5

At present, the recommended starting dose of gabapentin for diabetic neuropathy is 900 mg per day in 3 divided doses.3 According to 2011 guidelines published by the American Academy of Neurology (AAN) and based on the previously mentioned studies, gabapentin is regarded as “probably effective” at daily doses between 900 and 3,600 mg.7

 

Summary

There is moderate clinical literature supporting modest effectiveness of gabapentin for the treatment of DPN at daily doses up to a maximum 3,600 mg given in 3-4 divided doses.5  There is no evidence to support efficacy of doses less than 900 mg/day and doses between 1800 mg/day and 3600 mg/day have demonstrated superior efficacy to doses of 900 mg/day. In a patient with adequate renal function, therapy should be initially titrated to a minimum of 900 mg/day given in 3 divided doses and gradually increased as tolerated to treatment effect. Do not exceed 3,600 mg of gabapentin per day. Consider increased monitoring for adverse effects such as somnolence, dizziness and ataxia in patients undergoing dose escalations. Gabapentin is primarily eliminated through the kidneys and in advanced stages of diabetes, the majority of  patients have some degree of renal dysfunction. Dose adjustments are required in patients with reduced creatinine clearance to avoid accumulation of drug and subsequent adverse effects (Table 1).8 There is no clinical trial data assessing effectiveness of gabapentin for the treatment of DPN in patients with advanced renal disease.

References

1.     Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ 3rd, Service FJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 43 : 817-824,1993

2.     Gordois, A., Scuffham, P., Shearer, A., et al. The health care costs of diabetic peripheral neuropathy in the U.S. Diabetes Care 2003 26: 1790-95.

3.     Lexi-Comp, Inc. (Lexi-DrugsTM). Lexi-Comp, Inc.; August 3, 2014.

4.     Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. A randomized controlled trial. JAMA. 1998; 280: 1831–1836.

5.     Gorson KC, Schott C, Herman R, et al. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry.1999; 66:251.

6.     Backonja, M., Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clinical Therapeutics 2003 Jan; 25(1): 81-104.

7.     Bril V, England J, Franklin GM, et al. Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology, 2011, 76(20):1758-65.

8.     Lexi-Comp OnlineTM , Pediatric & Neonatal Lexi-Drugs OnlineTM , Hudson, Ohio: Lexi-Comp, Inc.; June 2014.

 


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