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Three Part Question

In [adult patients] does [amitriptyline] reduce [acute pain]?

Clinical Scenario

You are working in the Emergency Department and a patient presents in acute pain. They have tried simple analgesics and are keen to avoid opiate medications. You are aware of Amitriptyline use in patient's with chronic pain. You wonder if there is any evidence supporting the use of Amitriptyline for symptom control in acute pain.

Search Strategy

Using the NICE HDAS interface on the worldwide web we searched AMED, BNI, CINAHL, EMBASE, EMCARE, HMIC, Medline, PsycINFO and Pubmed databases.
Literature searches were carried out by 2 reviewers independently.
Search terms were amended to
Search terms used: (((amitriptyline OR amitriptiline OR amitryptiline OR amytriptiline OR amitriptilyne) AND (acute OR emergency)) AND pain)

708 results following initial search.

Abstracts were then screened and duplicates removed. Non-human studies, studies on chronic pain (>6 months), studies not available in English, and studies of prophylaxis treatment were excluded.

References of the remaining papers were then screened for further relevant studies.

Search Outcome

33 relevant papers were identified, majority of these were single case reports or case series of less than 10 patients. 5 were randomised control trials.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kerrick J, Fine P, Lipman A, Love G March 1993 USA	28 postoperative patients following hip or knee arthroplasty.	Randomised to placebo or amitriptyline 50mg orally once daily on day 1,2 and 3 post-op, whilst also using morphine or meperidine patient controlled analgesia. Twice daily numerical visual analogue pain scores, sedation scores and sleep quality and quantity scores were recorded on days 1,2 and 3 post-surgery. Hourly opioid PCA use was also recorded.	Patients in the amitriptyline group reported higher pain scores and no difference in opioid usage		This is a pilot study so the sample size is small and there is no power calculation.
Jan-Feb 1996 Israel		Randomised double blinded control trial. 39 patients presenting to the emergency service of a single centre with acute lower back pain over 6 month period. Randomised to 150mg oral amitriptyline or 2000mg acetaminophen per day for 5 weeks. 4 psychometric tests administered and analysed for differences between the treatment and control arms	79% of patients receiving amitriptyline and 75% of patients receiving acetaminophen reported reported significant reduction in pain intensity, but there was no statistically significant difference between the 2 groups.		2000mg/day is less than the normal maximum therapeutic dose of paracetamol, which limits the validity of the comparison.There is no power calculation and the measurement of multiple outcomes limits the statistical validity of any findings.
June 1997 USA	Healthy adult volunteers	Injections of capsaicin were administered to 6 volunteers to demonstrate the reproducibility of capsaicin injection. 40 volunteers were then randomised to receive injections of either midazolam plus saline, alfentanil plus saline, amitriptyline plus saline or alfentanil plus amitriptyline. Numerical pain scores, hyperalgesia and allodynia were recorded at intervals up to 60 minutes after each injection.	Amitriptyline did not reduce pain scores, hyperalgesia or allodynia compared to placebo or compared to alfentanil alone when administered in combination with alfentanil		There is no reference to how the study was powered or how the volunteers were recruited. This is not an applied clinical trial and a non-clinical outcome.
Gerner P, Kao G, Srinivasa V, Narang S, Wang G July- August 2003 USA	14 healthy volunteers	Gauze soaked in 10, 50 and 100 ml solution of amitriptyline or placebo were applied as a dressing to 4 areas of skin on volunteers arms for 1 hour. A blunt 16g needle was subsequently used to test painful sensation in each area using a numerical analogue score.	There was a statistically significant reduction in pain scores between solutions greater than 50 and 100 ml solutions compared to solutions of 10 ml or less, which was diminished with time.		There is a power calculation mentioned but it is not clear what difference the study was intended to be powered for. This is a small study, which did not measure a clinical outcome. Measurement of multiple outcomes at multiple times also reduces the validity of the statistically significant finding reported
April 2008 France	Healthy male volunteers	Double blinded RCT. 16 volunteers had transcutaneous solutions containing 25, 50 and 100 mm amitriptyline solution, saline, solution without amitriptyline and EMLA applied to randomised areas of their back and dressing applied for 1 hour. Areas were tested for touch, mechanical nociception, cold, warm, and heat at 1, 2, 4, 6, 8 hours	There was a statistically significant difference between the threshold for tactile and mechanical nociception with amitriptyline compared to placebo at 2 and 4 hours after treatment only. There was a statistically significant difference between the threshold for cold and heat sensation with amitriptyline compared to placebo at 1,2 and 4 hours.		This is a small study, which did not take place in clinical setting or with an applicable outcome. The study is powered to detect a difference in mechanical nociception but measurement of this outcome at multiple time points reduces the validity of the findings.

Comment(s)

There is no single study that answers this question. The small studies available offer conflicting results.

Clinical Bottom Line

Currently there is insufficient evidence to recommend or refute the use of amitriptyline as a treatment in acute pain

References

1. Kerrick J, Fine P et al Low dose amitriptyline as an adjunct to opioids for postoperative orthopedic pain: a placebo-controlled trial
2. Stein D, Tuvia P et al The Efficacy of Amitriptyline and Acetaminophen in the Management of Acute Low Back Pain
3. Eisenach J, Hood D, Curry R, Tong C Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans
4. Gerner P, Kao G, Srinivasa V, Narang S, Wang G Topical amitriptyline in healthy volunteers
5. Duale C, Daveau J et al Cutaneous Amitriptyline in Human Volunteers: Differential Effects on the Components of Sensory Information