ATHENA: AmiTritypline for the prevention of post-HErpetic NeuralgiA

Background: ~20% of people with Herpes Zoster (HZ, “shingles”) develop post-herpetic neuralgia (PHN). The pain can be difficult to treat and has a substantial impact on the quality of life of those affected. One small trial suggested that amitriptyline used prophylactically at low dose might prevent PHN.

Aim: To determine the effectiveness of prophylactic low-dose amitriptyline for the prevention of PHN in patients diagnosed with shingles.

Design: Multi-centre, individually randomised, pragmatic two arm placebo-controlled superiority trial with internal pilot, SWAT and nested qualitative study. Setting: GP surgeries in England. Participant recruitment: Adults >=50-years, with a clinical diagnosis of HZ.

Intervention: Amitriptyline 10 mg (or matched placebo tablet), increasing in 10 mg steps over two weeks as tolerated, to 30 mg maximum for up to 70 days. All participants prescribed an antiviral, as per current clinical practice. Masking: Participants, clinicians and researchers will be masked to allocation.

Primary outcome: Presence/absence of PHN at 90 days after rash onset (cut-off of =3/10 on numerical rating scale worst pain in last 24 hours, Zoster Brief Pain Inventory).

Secondary outcomes: Average/least/current pain; quality of life; mental health; frailty; side-effects and adverse events.

Sample size: Assuming 20% PHN in control and a relative risk reduction of 45%, with a 20% loss to follow-up, 846 participants will be required to detect a benefit from amitriptyline on a binary outcome for PHN (present/absent) at 90 days, with 90% power.

Nested qualitative study: We will interview clinicians and patients who do/do not refer/take part and audio-record a sample of consent encounters. The findings will support and optimise the delivery of the trial; and aid interpretation and implementation of the quantitative findings.

Study Within A Trial: During the internal pilot, GP surgeries will be cluster-randomised (1:1) to evaluate a practice-level education package, designed to facilitate early diagnosis of shingles and recruitment into the study.

Patient and Public Involvement (PPI): We will ensure meaningful PPI throughout our research, from design to dissemination, supported by a dedicated coordinator and patient co-applicant.

Dissemination: We will produce traditional academic outputs (reports, presentations and papers) and “actionable” for stakeholders and guideline developers, shared via websites, journals and professional networks.

Project timetable (months): -6 to 0 contracting, protocol and study materials development; -3 to 3 application/receipt of approvals (ethics, HRA, MHRA); 0 to 6 study database and “pop up” tool development and testing, staff and GP surgery recruitment and training; 7 to 37 participant recruitment and follow-up; 33 to 40 data cleaning, analysis and reporting.

Research team: We are an experienced group of clinicians and methodologists. We have an excellent track record of successfully delivering high-quality research in this area with expertise in primary care, herpes zoster and infection, pain, dermatology, medicines, health economics, qualitative research and PPI.