Addition to the List

Gabapentin

Addition to the List

Peer Feedback:

“Commonly used and studied for a variety of conditions such as neuropathic pain, hot flushes, etc. with numerous clinical trials showing some degree of benefit; since neuropathic pain is so difficult to treat, having another option seems warranted”

Literature Review Question:

What is the efficacy of gabapentin in treating neuropathic pain?

Literature Search:
eCPS - Neurologic Disorders: Neuropathic Pain
Cochrane
CPG via CMA

Pain Society Guidelines 2014

The gabapentinoids, gabapentin and pregabalin, bind to presynaptic voltage-gated calcium channels in the dorsal horn, reducing the release of excitatory neurotransmitters such as glutamate and substance P (21). These agents have been studied in large clinical trials, although mainly in the management of painful diabetic neuropathy and postherpetic neuralgia. Gabapentin has shown efficacy in three trials involving painful diabetic neuropathy and two trials involving postherpetic neuralgia (22); however, four RCTs involving gabapentin have been negative, including a trial of gabapentin in chemotherapy induced painful neuropathy (23-26). The combined NNTs for gabapentin in the management of painful polyneuropathy and postherpetic neuralgia were 6.4 and 4.3, respectively (27).

Pregabalin is an analogue of gabapentin, with the same mechanism of action, but it manifests linear pharmacokinetics and has higher affinity for the presynaptic calcium channel. Four studies have shown that pregabalin provides significant pain relief and improved quality of life in painful diabetic neuropathy (28) and an additional four trials have shown efficacy in postherpetic neuralgia (22). The combined NNTs for pregabalin in the management of painful diabetic neuropathy and postherpetic neuralgia were 4.5 and 4.2, respectively (27). Pregabalin has also been studied in chronic central NeP following spinal cord injury, with evidence of significant pain relief (29,30). However, a study investigating pregabalin in the treatment of NeP associated with chronic lumbosacral radiculopathy was negative (31), as was a recent trial involving refractory painful diabetic neuropathy (32). A study investigating the safety and efficacy of pregabalin in patients with central poststroke pain showed no significant improvement in the primary end point of pain intensity; however, there were some improvements in secondary end points including sleep and anxiety (33).

Gabapentin and pregabalin appear to be similar in their mechanisms of action and side-effect profiles, and allow for more rapid titration than antidepressant agents. Pregabalin carries the advantage of twice-daily dosing and linear pharmacokinetics relative to gabapentin. Gabapentinoids in general have few drug interactions, but are dependent on renal excretion and, therefore, require dosage reductions in patients with renal insufficiency (72).

Moulin, D. E., et al. "Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society." Pain Research & Management: The Journal of the Canadian Pain Society 19.6 (2014): 328.

Cochrane 2014

Gabapentin is a reasonably effective treatment for a variety of neuropathic pain conditions. It has been demonstrated to be better than placebo across all studies for IMMPACT outcomes of substantial and at least moderate improvement, producing almost identical results for all trials and those in parallel-group studies lasting six weeks or longer. Numbers needed to treat to benefit (NNTs) were between 5 and 7 for substantial and at least moderate improvement in PHN and PDN. Results were consistent across the major neuropathic pain conditions tested, though gabapentin was tested only in small numbers in uncommon neuropathic pain conditions and fibromyalgia. The review concentrated on doses of gabapentin of 1200 mg daily or greater, though a wide range of fixed doses and dose titration regimens were used.

Gabapentin was tested in nine different chronic pain conditions generally considered to be neuropathic in origin, and three other chronic pain conditions where the aetiology may be different (masticatory myalgia, CRPS-1, and fibromyalgia). For only three neuropathic pain conditions was there sufficient information to be confident that it worked satisfactorily, namely PHN, PDN, and mixed neuropathic pain, itself principally, though not exclusively, PHN and PDN.

Benefit was balanced by more withdrawals due to adverse events, and participants taking gabapentin experienced more adverse events, including somnolence, dizziness, peripheral oedema, and gait disturbance than did those taking placebo. Serious adverse events were no more common with gabapentin than placebo, and death was an uncommon finding in these studies.

There was no first 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 painful neuropathic pain conditions. No evidence regarding a dose-response effect was available for doses above 1200 mg daily, but limited evidence suggested that doses lower than 1200 mg daily were less effective. 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 some conditions (all except PHN, PDN, and mixed) is low, excluding any confidence that it works or does not work. The level of efficacy found for gabapentin is consistent with the efficacy estimates for other drug therapies in these conditions.

Moore, R. Andrew, et al. "Gabapentin for chronic neuropathic pain and fibromyalgia in adults." The Cochrane Library (2014).

eCPS (2014)

Chronic Peripheral Neuropathic Pain
This category of neuropathic pain conditions includes postherpetic neuralgia, diabetic neuropathy, causalgia (CRPS II), incisional neuralgias following mastectomy, thoracotomy or bypass surgery, phantom limb pain and other neuropathies. Guidelines for the treatment of chronic peripheral neuropathic pain have been developed by the Canadian Pain Society and others.2 , 3 Tricyclic antidepressants (TCAs) and GABA derivatives such as gabapentin and pregabalin are considered first-line agents (Figure 1 - Management of Chronic Peripheral Neuropathic Pain3 , Table 5).

Until more is known about the safety of gabapentin or pregabalin, avoid these agents for the treatment of neuropathic pain during pregnancy.13 , 14 Until more is known about the safety of gabapentin or pregabalin, avoid these agents for the treatment of neuropathic pain while the mother is breastfeeding.13 , 14
Table 5: Drug Therapy for Chronic Peripheral Neuropathic Pain

Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100 $$$$$ $100–125

Acute Neuropathic Pain—Herpes Zoster4

Early treatment of herpes zoster can reduce the severity of the infection; however, there is no evidence that antivirals will prevent postherpetic neuralgia.6 Oral antivirals (acyclovir, famciclovir, valacyclovir) are most effective if started within 72 hours of the onset of the rash. In addition to instituting an antiviral agent, it is important to relieve the acute pain. This may be accomplished with early treatment with amitriptyline and/or gabapentin and if necessary opioids or nerve blocks.

Neurologic Disorders: Neuropathic Pain; C. Peter N. Watson, MD, FRCPC; Date of revision: October 2014