Sunday, December 16, 2012

Amitriptyline for neuropathic pain

Note: One of the difficulties in treating pain is that scientists have yet
to develop an accurate "blood test" for pain making it difficult to
objectively measure pain and thus pain relief. And no one drug (or other
treatment) is a miracle for every single person who tries it regardless of
the condition or disease but particularly in areas where there is
diagnostic confusion and overlap.

Cochrane Database Syst Rev. 2012 Dec 12;12:CD008242. doi:
Amitriptyline for neuropathic pain and fibromyalgia in adults.
Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ.

Pain Research and Nuffield Department of Clinical Neurosciences, University
of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, UK,
OX3 7LE.

Amitriptyline is a tricyclic antidepressant that is widely used to treat
chronic neuropathic pain (pain due to nerve damage) and fibromyalgia, and
is recommended in many guidelines. These types of pain can be treated with
antidepressant drugs in doses below those at which the drugs act as

To assess the analgesic efficacy of amitriptyline for chronic neuropathic
pain and fibromyalgia.To assess the adverse events associated with the
clinical use of amitriptyline for chronic neuropathic pain and fibromyalgia.

We searched CENTRAL, MEDLINE, and EMBASE to September 2012, together with
reference lists of retrieved papers, previous systematic reviews, and other
reviews; we also used our own handsearched database for older studies.

We included randomised, double-blind studies of at least four weeks'
duration comparing amitriptyline with placebo or another active treatment
in chronic neuropathic pain or fibromyalgia.

We extracted efficacy and adverse event data, and two study authors
examined issues of study quality independently. We performed analysis using
two tiers of evidence. The first tier used data meeting current best
standards, where studies reported the outcome of at least 50% pain
intensity reduction over baseline (or its equivalent), without the use of
last observation carried forward (LOCF) or other imputation method for
dropouts, reported an intention-to-treat (ITT) analysis, lasted 8 to 12
weeks or longer, had a parallel-group design, and where there were at least
200 participants in the comparison. The second tier used data that failed
to meet this standard and were therefore subject to potential bias.

Twenty-one studies (1437 participants) were included; they individually
involved between 15 and 235 participants, only four involved over 100
participants, and the median study size was 44 participants. The median
duration was six weeks. Ten studies had a cross-over design.

Doses of amitriptyline were generally between 25 mg and 125 mg, and dose
escalation was common.

There was no top-tier evidence for amitriptyline in treating neuropathic
pain or fibromyalgia.

Second-tier evidence indicated no evidence of effect in cancer-related
neuropathic pain or HIV-related neuropathic pain, but some evidence of
effect in painful diabetic neuropathy (PDN), mixed neuropathic pain, and

Combining the classic neuropathic pain conditions of PDN, postherpetic
neuralgia (PHN) and post-stroke pain with fibromyalgia for second-tier
evidence, in eight studies and 687 participants, there was a statistically
significant benefit (risk ratio (RR) 2.3, 95% confidence interval (CI) 1.8
to 3.1) with a number needed to treat (NNT) of 4.6 (3.6 to 6.6).

The analysis showed that even using this potentially biased data, only
about 38% of participants benefited with amitriptyline
and 16% with
placebo; most participants did not get adequate pain relief.

Potential benefits of amitriptyline were supported by a lower rate of lack
of efficacy withdrawals; 8/153 (5%) withdrew because of lack of efficacy
with amitriptyline and 14/119 (12%) with placebo.More participants
experienced at least one adverse event; 64% of participants taking
amitriptyline and 40% taking placebo.

The RR was 1.5 (95% CI 1.4 to 1.7) and the number needed to treat to harm
was 4.1 (95% CI 3.2 to 5.7). Adverse event and all-cause withdrawals were
not different.

Amitriptyline has been a first-line treatment for neuropathic pain for many
years. The fact that there is no supportive unbiased evidence for a
beneficial effect is disappointing, but has to be balanced against decades
of successful treatment in many patients with neuropathic pain or

There is no good evidence of a lack of effect; rather our concern should be
of overestimation of treatment effect.
Amitriptyline should continue to be
used as part of the treatment of neuropathic pain or fibromyalgia, but only
a minority of patients will achieve satisfactory pain relief.

Limited information suggests that failure with one antidepressant does not
mean failure with all.It is unlikely that any large randomised trials of
amitriptyline will be conducted in specific neuropathic pain conditions or
in fibromyalgia to prove efficacy.

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