Can taking amitriptyline tablets stop long-term pain from shingles?

ISRCTN	ISRCTN14490832
DOI	https://doi.org/10.1186/ISRCTN14490832
EudraCT/CTIS number	2021-001101-78
IRAS number	1003967
Secondary identifying numbers	CPMS 50893, IRAS 1003967

Submission date: 17/01/2022
Registration date: 27/01/2022
Last edited: 15/04/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

Background and study aims
Shingles is a viral infection that causes a painful rash. This study aims to find out whether taking a low dose of amitriptyline soon after getting shingles can prevent the long-term pain associated with shingles

Who can participate?
Patients aged over 50 years who have been diagnosed by their GP with shingles.

What does the study involve?
Participants take tablets nightly for 10 weeks: half will be given low-dose amitriptyline and the other half will get placebo (dummy) tablets. Pain is assessed at 90 days after rash onset.

What are the possible benefits and risks of participating?
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 tablets. This study is needed so doctors can be sure that any benefits outweigh any harm.

Where is the study run from?
1. University of Bristol (UK)
2. Southampton University (UK)
3. Oxford University (UK)

When is the study starting and how long is it expected to run for?
July 2021 to July 2025

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
athena-study@bristol.ac.uk

Study website

Contact information

Dr Sian Wells
Scientific

Centre for Academic Primary Care
Bristol Medical School
University of Bristol
Canynge Hall
39 Whatley Rd
Bristol
BS8 2PS
United Kingdom

Phone	+44 (0)117 9287308
Email	athena-study@bristol.ac.uk

Prof Matthew Ridd
Scientific

Centre for Academic Primary Care
Bristol Medical School
University of Bristol
Canynge Hall
39 Whatley Rd
Bristol
BS8 2PS
United Kingdom

Phone	+44 (0)117 33 14557
Email	m.ridd@bristol.ac.uk

Study information

Study design	Randomized; Interventional; Design type: Treatment, Drug
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	GP practice
Study type	Treatment
Participant information sheet	https://athena-study.blogs.bristol.ac.uk/files/2022/01/ATHENA-PIL.pdf
Scientific title	Amitriptyline for the prevention of post-herpetic neuralgia
Study acronym	ATHENA
Study hypothesis	Prophylactic low-dose amitriptyline will reduce post-herpetic neuralgia in patients diagnosed with herpes zoster (shingles).
Ethics approval(s)	Approved 18/10/2021, South West- Central Bristol Research Ethics Committee (Ground Floor, Temple Quay House, 2 The Square, Bristol, BS1 6PN, UK; +44 (0)207 104 8029, +44 (0)207 104 8068, +44 (0)207 104 8375; centralbristol.rec@hra.nhs.uk), REC ref: 21/SW/0130
Condition	Shingles
Intervention	Amitriptyline 10 mg tablets (or matched placebo tablet), increasing in 10 mg steps over 2 weeks as tolerated, to 30 mg maximum per day, for 70 days. Total follow-up is 12 months, with participant surveys at baseline and 30, 60, 90, 120, 180 and 360 days after rash onset. Randomisation: Trial participants will be allocated in a 1:1 ratio to receive amitriptyline or placebo. Randomisation will be stratified by centre and minimised on age deciles, gender at birth, pain in the last 24 hours and shingles vaccination history. The randomisation sequence will be generated by the company Sealed Envelope™ using their online randomisation system, which will allocate the participant to a treatment arm. The person undertaking the randomisation and the participant will remain masked as to which treatment group this code refers.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Amitriptyline
Primary outcome measure	Presence/absence of postherpetic neuralgia measured using a cut-off of ≥3/10 on numerical rating scale average pain in last 24 hours; Timepoint(s): 90 days after rash onset
Secondary outcome measures	1. The safety, tolerability and acceptability of amitriptyline assessed using patient-completed medication use, problems and hospitalisation sections of questionnaire at 30, 60 and 90 days, and by direct report by participant or clinician 2. Masking of participants assessed using the bang binding index in patient questionnaires at 30, 60 and 90 days post rash onset 3. Shorter and longer-term outcomes of pain, quality of life, mental well-being and frailty, assessed using the Zoster Brief Pain Inventory (ZBPI), 9-item patient health questionnaire (PHQ-9), 7-item general anxiety disorder questionnaire (GAD-7) and Tilburg Frailty Indicator, at 0, 90, 180 and 360 days post rash onset 4. The cost-effectiveness of low dose amitriptyline to placebo for the prevention of PHN using EQ-5D-5L and patient-completed healthcare resource use questions at 0, 90, 180 and 360 days post rash onset, and GP electronic medical records for the 12-month study period 5. Use of healthcare resources and analgesics assessed using patient-completed medication and healthcare resource use questions at 90, 180 and 360 days post rash onset, and GP electronic medical records for the 12-month study period
Overall study start date	01/07/2021
Overall study end date	31/07/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	50 Years
Sex	Both
Target number of participants	Planned Sample Size: 846; UK Sample Size: 846
Participant inclusion criteria	1. Adults aged ≥50 years 2. Clinical diagnosis of herpes zoster (HZ) 3. Rash onset <144 hours
Participant exclusion criteria	1. Inability to give informed consent 2. Third or more episode of herpes zoster 3. Known adverse reaction to amitriptyline or contraindications (monoamine oxidase inhibitors) 4. Current/recent (within previous two weeks) use of a tricyclic antidepressant 5. Prolonged QT interval or concomitant drugs that prolong the QT interval 6. Suicidal ideation 7. Heart block 8. Recent myocardial infarction (<4 weeks) 9. Immunosuppression 10. Significant bradycardia 11. Uncompensated heart failure 12. Hyperthyroidism 13. Severe liver disease 14. Phaeochromocytoma 15. Urinary retention 16. If female; current or planned (in next 3 months) pregnancy or breastfeeding 17. Currently (or recently, within the previous 4 months) enrolled in another CTIMP
Recruitment start date	30/03/2022
Recruitment end date	30/04/2025

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

University of Bristol

Senate House
Tyndall Avenue
Bristol
BS8 1TH
United Kingdom

University of Oxford

University Offices
Oxford
OX1 2JD
United Kingdom

University of Southampton

University Road
Southampton
SO17 1BJ
United Kingdom

Sponsor information

University of Bristol
University/education

1 Cathedral Square
Trinity Street
College Green
Bristol
BS1 5DD
England
United Kingdom

Phone	+44 (0)117 394 0177
Email	research-governance@bristol.ac.uk
Website	http://bristol.ac.uk/
"ROR"	https://ror.org/0524sp257

Funders

Funder type

Government

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: NIHR129720

No information available

Results and Publications

Intention to publish date	30/04/2027
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in non-publicly available repository
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal in approximately 2025. The researchers will publish a protocol in due course.
IPD sharing plan	The final anonymised trial data set will be stored as restricted data on the data.bris research data repository for at least 5 years after the end of the study. Data will be made available after the end of the study to approved bona fide researchers only after their host institution has signed a data access agreement. Details of how to request access are available at the University of Bristol’s data repository website.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Other publications	Qualitative interviews	31/07/2024	01/08/2024	Yes	No

Editorial Notes

15/04/2025: The overall study end date was changed from 30/04/2026 to 31/07/2025.
01/10/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 31/12/2024 to 30/04/2025.
2. The overall study end date was changed from 31/03/2025 to 30/04/2026.
3. The intention to publish date was changed from 31/12/2025 to 30/04/2027.
01/08/2024: Publication reference added.
03/07/2024: The recruitment end date was changed from 30/09/2024 to 31/12/2024.
21/06/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 30/11/2023 to 30/09/2024.
2. The overall study end date was changed from 30/06/2024 to 31/03/2025.
3. The intention to publish date was changed from 30/06/2025 to 31/12/2025.
13/09/2023: The recruitment start date was changed from 01/01/2022 to 30/03/2022.
05/09/2023: The recruitment end date was changed from 30/09/2023 to 30/11/2023.
15/06/2023: The recruitment end date was changed from 30/06/2023 to 30/09/2023.
23/02/2022: Internal review.
28/01/2022: Internal review.
17/01/2022: Trial's existence confirmed by the NIHR.