Lacosamide for neuropathic pain and fibromyalgia in adults

Abstract

Background: Antiepileptic drugs have been used in pain management since the 1960s; some seem to be especially useful for neuropathic pain. Lacosamide is an antiepileptic drug that has recently been investigated for neuropathic pain relief, although it failed to get approval for painful diabetic peripheral neuropathy from either the Food and Drug Administration or the European Medicines Agency.

Objectives: To evaluate the analgesic efficacy and adverse effects of lacosamide in the management of chronic neuropathic pain or fibromyalgia.

Search methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register (2011, Issue 4), CENTRAL (2011, Issue 3), MEDLINE (January 2000 to August 2011) and EMBASE (2000 to August 2011) without language restriction, together with reference lists of retrieved papers and reviews.

Selection criteria: We included randomised, double-blind studies of eight weeks duration or longer, comparing lacosamide with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.

Data collection and analysis: Two review authors independently extracted data for efficacy and adverse events and examined issues of study quality, including risk of bias assessments. Where possible, we calculated numbers needed to treat to benefit from dichotomous data for effectiveness, adverse events and study withdrawals.

Main results: We included six studies; five (1863 participants) in painful diabetic neuropathy (PDN) and one (159 participants) in fibromyalgia. All were placebo-controlled and titrated to a target dose of 200 mg, 400 mg or 600 mg lacosamide daily, given as a divided dose. Study reporting quality was generally good, although the imputation method of last observation carried forward used in analyses of the primary outcomes is known to known to impart major bias where, as here, adverse event withdrawal rates were high. This, together with small numbers of patients and events for most outcomes at most doses meant that most results were of low quality, with moderate quality evidence available for some efficacy outcomes for 400 mg lacosamide.There were too few data for analysis of the 200 mg dose for painful diabetic neuropathy or any dose for fibromyalgia.In painful diabetic neuropathy, lacosamide 400 mg provided statistically increased rates of achievement of "moderate" and "substantial" benefit (at least 30% and at least 50% reduction from baseline in patient-reported pain respectively) and the patient global impression of change outcome of "much or very much improved". In each case the extra proportion benefiting above placebo was about 10%, yielding numbers needed to treat to benefit compared with placebo of 10 to 12. For lacosamide 600 mg there was no consistent benefit over placebo.There was no significant difference between any dose of lacosamide and placebo for participants experiencing any adverse event or a serious adverse event, but adverse event withdrawals showed a significant dose response. The number needed to treat to harm for adverse event withdrawal was 11 for lacosamide 400 mg and 4 for the 600 mg dose.

Authors' conclusions: Lacosamide has limited efficacy in the treatment of peripheral diabetic neuropathy. Higher doses did not give consistently better efficacy, but were associated with significantly more adverse event withdrawals. Where adverse event withdrawals are high with active treatment compared with placebo and when last observation carried forward imputation is used, as in some of these studies, significant overestimation of treatment efficacy can result. It is likely, therefore, that lacosamide is without any useful benefit in treating neuropathic pain; any positive interpretation of the evidence should be made with caution if at all.

1

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

2

L'Abbé plot of percentage of participants achieving a moderate response with lacosamide 400 mg daily or placebo. Each circle represents one study, with size of circle proportional to size of study (inset scale).

3

Forest plot of comparison: 1 Lacosamide 400 mg versus placebo, outcome: 1.1 Moderate benefit (≥2/10 on NRS or ≥30% on VAS pain intensity reduction).

1.1. Analysis

Comparison 1 Lacosamide 400 mg versus placebo, Outcome 1 Moderate benefit (pain intensity reduction ≥2/10 on a NRS or ≥30% on VAS).

1.2. Analysis

Comparison 1 Lacosamide 400 mg versus placebo, Outcome 2 Substantial (pain intensity reduction ≥50% on a NRS).

1.3. Analysis

Comparison 1 Lacosamide 400 mg versus placebo, Outcome 3 PGIC much or very much improved.

2.1. Analysis

Comparison 2 Lacosamide 600 mg versus placebo, Outcome 1 Moderate benefit (pain intensity reduction ≥2/10 on NRS or ≥30% on VAS).

2.2. Analysis

Comparison 2 Lacosamide 600 mg versus placebo, Outcome 2 Substantial (pain intensity reduction ≥50% on NRS).

2.3. Analysis

Comparison 2 Lacosamide 600 mg versus placebo, Outcome 3 PGIC much or very much improved.

3.1. Analysis

Comparison 3 Lacosamide versus placebo, Outcome 1 At least one adverse event.

3.2. Analysis

Comparison 3 Lacosamide versus placebo, Outcome 2 Serious adverse events.

3.3. Analysis

Comparison 3 Lacosamide versus placebo, Outcome 3 All‐cause withdrawals.

3.4. Analysis

Comparison 3 Lacosamide versus placebo, Outcome 4 Lack of efficacy withdrawals.

3.5. Analysis

Comparison 3 Lacosamide versus placebo, Outcome 5 Adverse event withdrawals.