Treatment of Postherpetic Neuralgia

Results

Searching identified 186 potential trials, of which 92 were excluded as irrelevant on the basis of titles and abstracts alone. Of the 94 citations reviewed in greater detail, 64 were excluded for the following reasons: not describing a trial (10), not describing a trial of treatment for PHN (10), describing an uncontrolled trial (7), no randomization (7), evaluation period limited to 24 hours or less (13), duplicate publication (4), language other than English (7), not providing results specifically for patients with PHN (3), and available only in abstract form (3). One unpublished trial of mexiletine was identified through a review by Hanania and Brietstein; Dr Hanania informed us, however, that this trial had been stopped early because the treatment group had experienced serious side effects. One controlled trial was excluded because correspondence with the investigator did not confirm that it had been randomized. One trial was excluded because it included only 6 patients with PHN. (A list of excluded studies is available in Table W1.)

Of the remaining 27 trials reviewed for methodologic quality, most (16) received a Jadad score of 4. The 2 authors had substantial agreement on quality ratings ( = 0.75). Table W2 provides details of treatment regimens, quality ratings, ages of subjects, and duration of PHN. One trial with a Jadad score of 1 was excluded.⁸ Most subjects were elderly and had had PHN for longer than 6 months.

Topical therapies

Topical therapies evaluated were lidocaine, capsaicin, and benzydamine (Table 1). Lidocaine patch therapy is the only agent with a specific FDA indication for PHN. We found few trials supporting the FDA approval. The only published RCT of relatively unselected patients with PHN (n = 35) showed significant benefit versus placebo but was excluded because evaluation sessions had been limited to 12 hours.⁹ We reviewed a report of an unpublished RCT comparing lidocaine patch with vehicle placebo used in the application for FDA approval.¹⁰ This trial found a large, statistically significant reduction in pain scores with placebo throughout the 3- to 4-week trial. This trial found a similar statistically significant reduction in pain scores with lidocaine patch and no significant difference comparing lidocaine patch with placebo.

Three findings in the unpublished trial were used to support arguments for efficacy: (1) a statistically significant difference in the pain relief score at the final visit; (2) differences in allodynia (based on investigators’ sensory skin testing, described as stroking the maximally painful area with a foam brush and recording the pain scale rating) at the beginning of the trial; and (3) a greater increase in pain scores among lidocaine subjects upon trial conclusion (ie, after stopping study medication). The clinical relevance of these 3 findings is unclear.

The FDA declined to approve lidocaine patch therapy on the basis of these 2 studies and required an additional trial to demonstrate benefit. An “enriched enrollment study” involved subjects who had used lidocaine patch for at least 1 month and received at least moderate relief but had pain without the patch.¹¹ Lidocaine patch was clearly effective in this highly selected cohort.

Capsaicin 0.075% cream was effective in 2 trials of patients with severe refractory PHN.^12,13 The benefit appeared modest in the larger trial (pain was eliminated or nearly eliminated in less than 20% of capsaicin patients) and greater in the smaller trial. Blinding had limited efficacy because of the stinging effect of capsaicin.

Benzydamine cream, an antiprostaglandin, was not effective in a 2-week crossover trial.¹⁴ The cream showed a nonsignificant trend for pain reduction in an earlier 2-week crossover trial.¹⁵

TABLE 1