Background: Postherpetic neuralgia (PHN) is the most common chronic complication of herpes zoster (HZ), and current treatment regimens often fail to effectively control the pain.

Objective: The purpose of this study is to compare the efficacy and tolerability of duloxetine combined with pregabalin and amitriptyline combined with pregabalin in the treatment of PHN, as well as their impact on sleep and quality of life in patients with PHN.

Methods: This is a double-blind, randomized, crossover trial involving PHN patients. About 220 participants were randomly assigned (1:1) to either the duloxetine combined with pregabalin or the amitriptyline combined with pregabalin. The patient takes duloxetine or amitriptyline orally before bedtime for 6 weeks each time. Perform a 2-week single-blind placebo washout between the two treatments, and a 2-week single-blind placebo washout at the end of the treatment period. In the last week of the treatment cycle, evaluate the 7-day average daily pain, Pittsburgh Sleep Quality Index, 17-item Hamilton Depression Rating Scale, 36-Item Short Form Health Survey, and record the occurrence of major adverse events. A median reduction of 50%, 25%-50%, and 25% in pain score is considered good, moderate, and mild improvement, respectively.

Results: Both treatment methods can significantly improve the baseline pain value (p < 0.001 for both). The combination of duloxetine and pregabalin resulted in good, moderate, and mild pain relief of 52%, 24%, and 7%, respectively. The combination of amitriptyline and pregabalin resulted in good, moderate, and mild pain relief of 48%, 21%, and 9%, respectively. There was no significant difference in the measurement of various results between the two groups. In the reported adverse events, patients in the amitriptyline group had significantly more dry mouth compared to the duloxetine group (26% vs. 11%; p = 0.008).

Conclusions: Duloxetine and amitriptyline have similar analgesic effects, and the difference is not statistically significant. The combination of pregabalin has good tolerability and better pain relief in PHN patients, thus providing clinically relevant benefits. Background: Chinese Clinical Trial Registry: ChiCTR2100054831.