This protocol is based on a template for reviews of drugs used to relieve neuropathic pain and fibromyalgia. Imipramine is a tricyclic antidepressant that is sometimes used to treat chronic neuropathic pain (pain due to nerve damage or changes in the central nervous system (CNS)) and fibromyalgia. Its use is recommended in some guidelines though this is an unlicensed indication.
Description of the condition
The 2011 International Association of the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011) based on an earlier consensus meeting (Treede 2008). Neuropathic pain may be caused by nerve damage, but is often followed by changes in the central nervous system (CNS) (Moisset 2007). It is complex (Apkarian 2011; Tracey 2011), and neuropathic pain features can be found in patients with joint pain (Soni 2013).
Fibromyalgia is defined as widespread pain for longer than three months with pain on palpation at 11 or more of 18 specified tender points (Wolfe 1990), and is frequently associated with other symptoms such as poor sleep, fatigue, and depression. More recently, a definition of fibromyalgia has been proposed based on symptom severity and the presence of widespread pain (Wolfe 2010). The cause, or causes, are not well understood, but it has features in common with neuropathic pain, including changes in the CNS. Moreover, neuropathic pain and fibromyalgia patients experience similar sensory phenomena (Koroschetz 2011). Many people with these conditions are significantly disabled by moderate or severe pain for many years.
In primary care in the UK the incidences, per 100,000 person years observation, have been reported as 28 (95% CI 27 to 30) for postherpetic neuralgia, 27 (95% CI 26 to 29) for trigeminal neuralgia, 0.8 (95% CI 0.6 to 1.1) for phantom limb pain, and 21 (95% CI 20 to 22) for painful diabetic neuropathy (Hall 2008). Estimates vary between studies, often because of small numbers of cases. The incidence of trigeminal neuralgia has been estimated at 4 in 100,000 per year (Katusic 1991; Rappaport 1994), while more recently, a study of facial pain in The Netherlands found incidences per 100,000 person years of 12.6 for trigeminal neuralgia and 3.9 for postherpetic neuralgia (Koopman 2009). A systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as painful diabetic neuropathy, can be more common, with prevalence rates up to 400 per 100,000 person years (McQuay 2007) illustrating how common the condition was as well as its chronicity. The prevalence of neuropathic pain was reported as being 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), as high as 8% in the UK (Torrance 2006), and about 7% in a systematic review of studies published since 2000 (Moore 2013a). Some forms of neuropathic pain, such as diabetic neuropathy and post surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008). Fibromyalgia is common, especially in women, with an all-age prevalence of 12%, and a female to male ratio of 6:1 (McNally 2006).
Neuropathic pain and fibromyalgia are known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Conventional analgesics are usually not effective. Some patients may derive some benefit from a topical lidocaine patch or low concentration topical capsaicin, though evidence about benefits is uncertain (Derry 2012; Khaliq 2007). High concentration topical lidocaine may benefit some patients with postherpetic neuralgia (Derry 2013). Treatment is more usually by so-called unconventional analgesics such as antidepressants like duloxetine and amitriptyline (Lunn 2009; Moore 2012a; Sultan 2008) or antiepileptics like gabapentin or pregabalin (Moore 2009a; Moore 2011). An overview of treatment guidelines points out some general similarities, but also differences in approach (O'Connor 2009). The proportion of patients who achieve worthwhile pain relief (typically at least 50% pain intensity reduction (Moore 2013b)) is small, generally 10% to 25% more than with placebo, with the number needed to treat for an additional beneficial outcome (NNT) usually between 4 and 10.
Chronic painful conditions comprise 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 health costs (Moore 2013a).
Description of the intervention
Imipramine is a tricyclic antidepressant (TCA), most commonly used to treat depressive illness and nocturnal enuresis in children. It is partially converted in the body to an active metabolite, desipramine, another TCA. Imipramine is not licensed in the UK for treating neuropathic pain or fibromyalgia but is commonly used for these conditions. It is also used around the world for neuropathic pain, irrespective of licensing.
Imipramine is available as tablets (10 mg and 25 mg). For treating neuropathic pain, typical starting dosages are between 10 mg and 25 mg daily, usually taken at night, increasing to 75 mg daily if necessary. The main adverse effects are due to its anticholinergic activity and include dry mouth, weight gain and drowsiness (although it is less sedating than amitriptyline).
How the intervention might work
The mechanism of action of imipramine in the treatment of neuropathic pain and fibromyalgia remains uncertain, though it is known to be a strong reuptake inhibitor of serotonin and, to a lesser extent, norepinephrine (Watson 2013). Its active metabolite, desipramine, is conversely a very strong reuptake inhibitor of norepinephrine, and to a lesser extent, serotonin. The mechanism is likely to differ from that in depression since analgesia with TCAs is often achieved at lower doses than are needed for antidepressant effects. An alternative mechanism is likely to involve its action (as with many other analgesics) in blocking sodium channels in nerve membranes.
Why it is important to do this review
The earlier review of antidepressants for neuropathic pain (Saarto 2007) is being updated with separate reviews for individual drugs due to the large amount of data now available. These separate reviews will use more stringent criteria of validity, which include the level of response obtained, the duration of study and method of imputation of missing data (Moore 2012b). The individual reviews will be included in an overview of antidepressant drugs for neuropathic pain and fibromyalgia. Appendix 1 gives details of recent changes to the thinking about chronic pain and evidence.
This Cochrane review will assess evidence in ways that make both statistical and clinical sense, and will use developing criteria for what constitutes reliable evidence in chronic pain (Moore 2010a). Trials included and analysed will need to meet a minimum of reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc) and size (ideally at least 500 participants in a comparison in which the NNT is four or above (Moore 1998)). This sets high standards and marks a departure from how reviews have been done previously.