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The University of Southampton

Research project: ATHENA: Amitriptyline for the prevention of post-herpetic neuralgia

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Shingles is caused by the same virus that causes chickenpox. It “sleeps” in the nerve cells for decades. When it “wakes up”, it can make people feel generally unwell, cause tingling or pain in one part of the body, followed a few days later by a rash. The rash can take up to 4 weeks to heal. Antiviral medicine helps reduce initial pain and rash severity.   Some people can have “nerve pain” months after the shingles rash has gone. Called post-herpetic neuralgia, we don’t have any treatments to prevent this. Patients buy, and GPs prescribe, painkillers such as paracetamol, but they often don’t help. Amitriptyline is an old medicine, originally used at high doses (75-150 mg) to treat depression but now used at low dose for nerve pain. A small study published in 1997 suggested that taking a low dose (25 mg) of amitriptyline early on may help prevent post-herpetic neuralgia. We want to do a larger study to find out if using amitriptyline when the rash first appears really prevents pain later.   The only way to find this out is by doing a clinical trial. We will recruit 846 people aged 50 years or older who have been diagnosed by their GP with shingles, within 144 hours of the rash appearing. We will ask everyone to take tablets nightly for 10 weeks: half will be given amitriptyline and the other half will get placebo (or “dummy”) tablets. Neither patients nor their doctors will be able to choose which group they’re in. This will be done by a computerised process called “randomisation” – a bit like rolling a dice to decide. This way the results cannot be affected by anyone’s beliefs about amitriptyline. All other care will be the same – this includes GPs prescribing antivirals and painkillers if needed. We will use questionnaires to find out what happens to everyone over the following 12 months, especially whether they still have pain related to shingles at 3 months.   If starting amitriptyline early on does help, it is a cheap medicine that would prevent prolonged, difficult to treat pain for thousands of people. However, amitriptyline commonly causes side-effects such as dizziness, dry mouth and constipation. It can also cause problems when used together with some other medications. This study is needed so we can be sure that any benefits outweigh any harms. We have met with people with experience of shingles, with one person joining us as a co-applicant. We discussed the trial with them, and they identified potential barriers to taking part, such as lack of understanding about the condition; difficulty accessing GP appointments; and wrong information online about the risks of taking amitriptyline. While some people felt that any side-effects were offset by the potential benefits, others wanted more information first. We have carefully considered and addressed these issues in the design of the trial. Patient and Public Involvement will be built into the study set-up, running and sharing of the results.   We are a group of researchers from three of the UK’s leading primary care research universities. We have expertise in pain, post-herpetic neuralgia and running clinical trials in GP surgeries on skin problems and infections. We are uniquely placed to run the trial that is needed to answer the long-standing and important question of whether early use of amitriptyline in shingles prevents long-term pain.


Background: Approximately 20% of people with Herpes Zoster (“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: ~120 GP surgeries in England. 
Participant recruitment: Adults >=50 years, with a clinical diagnosis of HZ presenting <72 hours of rash onset.

Intervention: Amitriptyline 10 mg (or matched placebo tablet), increasing in 10 mg steps over two weeks as tolerated, to 30mg maximum for 70 days. All participants prescribed aciclovir 800 mg five times a day for seven days, as per current clinical practice. 
Allocation: Individual randomisation (1:1 ratio), stratified by centre and minimised on age, sex and pain.

Masking: Participants, clinicians and researchers will be masked to allocation. 
Primary outcomes: Presence/absence of PHN at 90 days after rash onset (cut-off of =3/10 on numerical rating scale average pain in last 24 hours, Zoster Brief Pain Inventory). 
Secondary outcomes: Worst/least/current pain; quality of life; mental health; frailty; medication use; NHS resource use; 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.

Internal pilot: By month six of participant recruitment, we aim to have recruited 225 patients.

Nested qualitative study: We will interview ~65 clinicians and patients who do/do not refer/take part and audio-record ~20 consent encounters. 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.

Local Investigators: Professor Hazel Everitt 

Study team: Chief investigator Dr Matt Ridd, University of Bristol


  • Professor Tony Pickering, Professor of Neuroscience and Anaesthestia, University of Bristol
  • Dr Robert Johnson Honorary Senior Research Fellow (Pain Medicine), University of Bristol
  • Dr Stephanie MacNeill Lecturer in Medical Statistics, University of Bristol
  • Dr Ioana Fodor Pharmacist University of Bristol
  • Dr Vikki Wylde Senior Lecturer University of Bristol
  • Dr Rebecca Kandiyali Research Fellow Healthcare resource University of Bristol
  • Dr Alison Heawood Senior Research Fellow University of Bristol
  • Professor Alastair Hay Primary Care University of Bristol
  • Dr Oliver van Hecke NIHR Clinical Lecturer University of Oxford
  • Professor Hazel Everitt Professor of Primary Care Research University of Southampton
  • Ms Lorelei Hunt Patient with lived experience of HZ/PHN
  • Dr Julie Clayton PPI coordinator Lead for Public University of Bristol

Funder: NIHR HTA (reference 129720)

Duration: 1st July 2021 to 31/10/2024 (40 months)

ContactsProfessor Hazel Everitt;

This study is being led by Population Health Sciences at University of Bristol with Southampton hub recruitment conducted by the Primary Care Research Centre at the University of Southampton.

Website: ATHENA | Centre for Academic Primary Care | University of Bristol


Related research groups

Primary Care, Population Sciences and Medical Education
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