Keywords: shingles, post-herpetic neuralgia, prophylaxis, treatment

Background:

Post-herpetic neuralgia (PHN) is one of the most common and troublesome complication of herpes zoster (HZ) but there are no treatments that prevent it. A previous small, single centre RCT from 1997 reported that amitriptyline could reduce the incidence of PHN by 45% (Bowsher, 1997, J Pain Symptom Management) but the generalisability of this has never been assessed.

Research questions:

Does prophylactic low dose amitriptyline started soon after HZ onset prevent PHN?

Method:

Adults ≥50 years old, diagnosed with HZ within 6 days of rash onset were recruited via 331 GP surgeries in England. Participants were randomised 1:1 to self-titrated amitriptyline 10-30 mg or matched placebo, for 70 days. Primary outcome was presence/absence of PHN (“worst pain in last 24 hours” ≥3/10) at 90 days after rash onset on Zoster Brief Pain Inventory (ZBPI). Target sample size was 846 participants for 90% power, assuming 20% PHN in the control group, relative risk reduction of 45% with amitriptyline, and 20% loss to follow-up. Modified primary intention-to-treat and safety analyses were undertaken. Trial registration ISRCTN14490832.

Results:

Between 30 March 2022 and 30 April 2025, 4941 patients were screened of whom 878 were randomly assigned (441 [50.2%] to amitriptyline and 437 [49.8%] to placebo). Among the 790 participants with worst pain scores at baseline and 90 days included in the primary analysis, the prevalence of PHN was 8.9% in the placebo group and 11.8% in the amitriptyline group (adjusted OR 1.35, 95% 0.84 to 2.18, p=0.217).

Conclusions:

In this large, robust, pragmatic, placebo-controlled RCT in primary care, we did not find any evidence that low-dose amitriptyline prevents PHN at 90 days in adults diagnosed with HZ within 6 days of rash onset.

Points for discussion: