Gabapentin (Neurontin) in Diabetic Neuropathy
Abstract & Commentary
Synopsis: This multicenter, randomized, parallel design, double-blind, placebo-controlled clinical trial demonstrates that gabapentin (up to 3600 mg/d) is effective in decreasing pain associated with diabetic neuropathy.
Source: Backonja M, et al. For the Gabapentin Diabetic Neuropathy Study Group. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA 1998;280:1831-1836.
Gabapentin’s use as a monotherapy analgesic for patients with moderate to severe pain from diabetic neuropathy is described in this report. As in the report abstracted above, a multicenter, randomized, parallel design, double-blind, placebo-controlled clinical trial design was performed. Subjects were included if they had diabetes (type I or II) and symptoms of painful diabetic neuropathy for at least one, but no more than five years. To be included in the study, pain intensity at the time of screening had to be at least moderate (score of 4 of 10 on a Likert [visual analog] scale for pain). After a one-week screening period, subjects received gabapentin (up to 3600 mg/d) or matching placebo in a titration period lasting four weeks, followed by another four weeks at the maximum tolerated dosage. The only analgesics permitted were acetaminophen (up to 3 g/d) and low-dose aspirin (for cardiac indications). Subjects could also be maintained on a fixed dosage of a selective serotonin reuptake inhibitor if they were receiving this antidepressant prior to study entry. Other inclusion and exclusion criteria were appropriate. Subjects maintained a daily pain log, and returned for several follow-up visits, where standard rating scales for pain, mood, functioning, and quality of life were performed.
Eighty-four subjects received gabapentin (70 [83%] completed the study), and 81 were randomized to placebo (65 [80%] completed the study). The mean age for study participants was 53 years. For the primary outcome measure in this study, gabapentin was shown to significantly reduce the intensity of the pain from diabetic neuropathy. In addition, gabapentin outperformed placebo across multiple secondary measures, including quality of life, mood, and functioning. Adverse effects were much more common in the gabapentin group when compared to placebo, yet as in the study described above, drop-outs from adverse events were similar in the two groups. Backonja and colleagues conclude that gabapentin is an effective monotherapy analgesic for diabetic neuropathy.
Comment by Andrew L. Stoll, MD
Gabapentin is currently approved for add-on therapy in partial epilepsy. However, for several years, anecdotal accounts of the efficacy of gabapentin in various neuropathic pain states have been reported. These two large multicenter trials (sponsored by gabapentin’s manufacturer Parke-Davis) are the first placebo-controlled studies of the efficacy of gabapentin in two common, and often intractable, neuropathic pain conditions. Both studies were well-designed and implemented, and both confirmed the generally accepted clinical impression that gabapentin is safe and effective for neuropathic pain, at least from diabetes or recent herpes zoster infection. It is likely that gabapentin is effective in other neuropathic pain states, but this remains to be proven in controlled studies. Despite the convincing efficacy demonstrated in these studies, it is clear that the gabapentin-treated patients were not, on average, pain-free at the end of the studies. Thus, more work is needed to improve our treatment of these conditions.
Gabapentin was generally well-tolerated, although typical dose-related adverse effects were observed in both studies. These studies pushed the gabapentin dosage to the maximum tolerated level, and it is possible that patients, particularly the elderly, would respond to lower, presumably better tolerated, dosage levels.
Gabapentin appears to have several other potential indications, in addition to epilepsy and neuropathic pain. There is anecdotal evidence and growing use of gabapentin to treat primary and secondary insomnia (e.g., from selective serotonin reuptake inhibitors), various anxiety disorders (e.g., social phobia), and possibly bipolar disorder. Beyond the multiple indications, the beauty of gabapentin lies in its pharmacokinetic and side-effect profile. Gabapentin does not undergo biotransformation, and is excreted unchanged in the urine. This is an advantage in patients with hepatic disease. Due to its structural similarity to amino acids, and unlike other drugs, gabapentin is absorbed via the neutral amino acid pathway in the gut. This transport protein is saturable, which means that a fatal overdose is next to impossible. Gabapentin also does not bind to plasma protein and does not interact with the cytochrome P450 system. Thus, the potential for pharmacokinetic drug interactions is low. However, due to gabapentin’s sedative effects, there is the potential for pharmacodynamic drug interactions with other sedative drugs, producing additive or synergistic sedation or ataxia. Rarely, some sensitive patients will develop intolerable sedation or ataxia on low-dose gabapentin monotherapy.
All in all, gabapentin is a valuable addition to our armamentarium to treat neuropathic pain and possibly several other conditions. Because of its apparent efficacy, combined with a generally benign side-effect profile, low toxicity, and lack of drug interactions, gabapentin should be considered a first-line treatment for neuropathic pain.
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