What class of medication is amitriptyline and why is this medication used as an adjuvant for pain?

This is an update of an earlier review of amitriptyline for neuropathic pain and fibromyalgia originally published in The Cochrane Library in 2012 (Moore 2012a). The effects of amitriptyline for fibromyalgia are now dealt with in a separate review (Moore 2015).

In the update we have used a template for reviews of drugs used to relieve neuropathic pain. The aim is for all reviews to use the same methods, based on current criteria for what constitutes reliable evidence in chronic pain (Moore 2010a; Appendix 1).

The 2011 International Association for the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011), and based on a definition agreed at an earlier consensus meeting (Treede 2008). Neuropathic pain is cause by injury to the nervous tissue, either peripheral or central and it can be followed by plastic changes in the central nervous system (Moisset 2007). The origin of neuropathic pain is complex (Baron 2010; Baron 2012; Tracey 2011; von Hehn 2012), and neuropathic pain features can be found in people with joint pain (Soni 2013).

Many people with neuropathic pain conditions are significantly disabled with moderate or severe pain for many years. Chronic pain conditions comprised five of the 11 top‐ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life, employment, and increased healthcare costs (Moore 2014a).

Neuropathic pain is usually divided according to the cause of nerve injury. There may be many causes, but some common causes of neuropathic pain include diabetes (painful diabetic neuropathy, PDN), shingles (postherpetic neuralgia, PHN), amputation (stump and phantom limb pain), neuropathic pain after surgery or trauma, stroke or spinal cord injury, trigeminal neuralgia (TGN), and human immunodeficiency virus (HIV) infection. Sometimes the cause is not known.

In systematic reviews, the overall prevalence of neuropathic pain in the general population is reported to be between 7% and 10% (van Hecke 2014), and about 7% in a systematic review of studies published since 2000 (Moore 2014a). In individual countries, prevalence rates have been reported as 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), and up to 8% in the UK (Torrance 2006). Some forms of neuropathic pain, such as PDN and post‐surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008). The incidence of PHN may decrease where vaccination programmes are introduced; vaccination for herpes zoster is ongoing in the UK, for example.

Estimates of incidence vary between individual studies for particular origins of neuropathic pain, often because of small numbers of cases. In primary care in the UK, between 2002 and 2005, the incidences (per 100,000 person‐years' observation) were 28 (95% confidence interval (CI) 27 to 30) for PHN, 27 (26 to 29) for TGN, 0.8 (0.6 to 1.1) for phantom limb pain, and 21 (20 to 22) for PDN (Hall 2008). Others have estimated an incidence of 4 in 100,000 per year for trigeminal neuralgia (Katusic 1991; Rappaport 1994), and 12.6 per 100,000 person‐years for TGN and 3.9 per 100,000 person‐years for PHN in a study of facial pain in the Netherlands (Koopman 2009). One systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as PDN, can be more common than other neuropathic pain conditions, with prevalence rates up to 400 per 100,000 person years (McQuay 2007).

Neuropathic pain is difficult to treat effectively, with only a minority of people experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, combining pharmacological interventions with physical or cognitive (or both) interventions. Conventional analgesics like paracetamol and nonsteroidal anti‐inflammatory drugs are not thought to be effective, but are frequently used (Hall 2013; Vo 2009). Some people may derive some benefit from a topical lidocaine patch or low‐concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012; Derry 2014). High‐concentration topical capsaicin may benefit some people with PHN (Derry 2013). Treatment is often by so‐called 'unconventional analgesics', such as antidepressants such as amitriptyline or duloxetine (Lunn 2014; Sultan 2008), or antiepileptics (gabapentin or pregabalin; Moore 2009; Moore 2014b; Wiffen 2013a).

The proportion of people who achieve worthwhile pain relief (typically at least 50% pain intensity reduction; Moore 2013a) is small, generally only 10% to 25% more than with placebo, with numbers needed to treat for an additional beneficial outcome (NNT) usually between 4 and 10 (Kalso 2013; Moore 2013b). Neuropathic pain is not particularly different from other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment (Moore 2013b).

One overview of treatment guidelines pointed out some general similarities between recommendations, but guidelines are not always consistent with one another (O'Connor 2009), nor followed (Hall 2013). The current National Institute for Health and Care Excellence (NICE) guidance in the UK suggests offering a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain (with the exception of trigeminal neuralgia), with switching if first, second, or third drugs tried are not effective or not tolerated (NICE 2013). Antidepressant drugs are also suggested as first line agents in the latest Canadian guidelines (Moulin 2014), and in updated guidance from the Neuropathic pain Special Interest Group of the International Association for the Study of Pain (Finnerup 2015).

Amitriptyline is a tricyclic antidepressant. It is not licensed in the UK for treating neuropathic pain, but is commonly used for various neuropathic pain conditions around the world, irrespective of licensed indications. The drug is available as tablets (10, 25, and 50 mg) and oral solutions. It is usually given at night time in an attempt to reduce any sedative effects during the day. There were over 11 million prescriptions for amitriptyline in England in 2013, mainly for 10 mg and 25 mg tablets (PCA 2014); some of these prescriptions would be for relief of depression. The main adverse effects are due to its anticholinergic activity, and include dry mouth, weight gain, and drowsiness.

The mechanism of action of amitriptyline in the treatment of neuropathic pain remains uncertain, although it is known to inhibit both serotonin and noradrenaline reuptake. The mechanism is likely to differ from that in depression since analgesia with antidepressants is often achieved at lower dosage than the onset of any antidepressant effect; adverse events associated with amitriptyline often wane after two or three weeks, when the benefits of the drug become apparent. In addition, there is no correlation between the effect of antidepressants on mood and pain, and antidepressants produce analgesia in people with and without depression (Onghena 1992).

Amitriptyline is an established pharmacological intervention for chronic neuropathic pain. The earlier review found some evidence of pain relief with amitriptyline compared with placebo for PDN, mixed neuropathic pain, and fibromyalgia, at the expense of increased adverse events, but this was based on small numbers of participants in studies that were susceptible to bias.

It was decided to split reviews combining neuropathic pain conditions with fibromyalgia into separate reviews, so an update was performed at the same time, to capture any new studies.

Like the earlier Cochrane review, this update assessed evidence in ways that make both statistical and clinical sense, and used developing criteria for what constitutes reliable evidence in chronic pain (Appendix 1; Moore 2010a). It followed standards set out in the PaPaS Author and Referee Guidance for pain studies of the Cochrane Pain, Palliative and Supportive Care Group (PaPaS 2012).

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Analysis

Comparison 1 Amitriptyline versus placebo, Outcome 1 Third‐tier efficacy.

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