This protocol is based on a template for reviews of drugs used to relieve neuropathic pain. The aim is for all reviews to use the same methods, based on new criteria for what constitutes reliable evidence in chronic pain (Moore 2010a; Appendix 1).
Description of the condition
Neuropathic pain, unlike nociceptive pain such as toothache and osteoarthritis, is caused by nerve damage, often accompanied by changes in the central nervous system (CNS) (Iannetti 2005). It is by nature chronic and may be present for months or years. The 2011 definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011). Many people with neuropathic pain are significantly disabled, with 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% confidence interval (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). The prevalence of neuropathic pain was reported as being 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008) and as high as 8% in the UK (Torrance 2006). Some forms of neuropathic pain, such as diabetic neuropathy and post-surgical chronic pain (which is often neuropathic in origin) are increasing (Hall 2008). Although incidence rates for neuropathic pain have not been accurately reported in Ireland, recent results from the PRIME study (Prevalence, Impact and Cost of Chronic Pain) suggest a prevalence of 36% for chronic pain in the community setting (Raftery 2011). It is likely that a significant proportion of these patients suffer from pain of neuropathic origin.
Neuropathic pain is known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. Thus it constitutes a significant burden on healthcare systems and society at large, as well as being distressing for individual patients (Moore 2013). A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Conventional analgesics are usually not effective, although opioids may be in some individuals. Others may derive some benefit from topical lidocaine patches or topical capsaicin. Treatment is more usually by so-called 'unconventional' analgesics, such as antidepressants or antiepileptics.
Description of the intervention
The antidepressant agent venlafaxine is a serotonin reuptake inhibitor and weak noradrenaline reuptake inhibitor, but is not considered to affect other receptor systems. It is used in the treatment and prevention of recurrence of major depressive disorder, as well as in the treatment of generalised anxiety disorder, social anxiety disorder, panic disorder and agoraphobia. Although not licensed in Ireland (or the UK) for the treatment of chronic or neuropathic pain, it is commonly used for these indications. The drug is available as prolonged-release capsules (37.5 mg, 75 mg, 150 mg) suitable for once daily dosing. For the treatment and prevention of depression, the recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur as a side effect of venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system. Suicide-related behaviours, mydriasis (dilated pupils) and dose-related increases in blood pressure and heart rate have also been reported with venlafaxine. Other, more common, side effects include nausea, dizziness, drowsiness and dry mouth.
How the intervention might work
Venlafaxine is a chimeric compound and both R- and S-enantiomers, and their O-desmethylated metabolites, are reported to mediate inhibition of serotonin and noradrenaline reuptake (Bolden-Watson 1993; Muth 1986; Muth 1991). Its relatively clean pharmacological profile means that venlafaxine has a favourable adverse effect profile in comparison to other antidepressants used in pain management, especially the tricyclic antidepressants such as amitriptyline. The major metabolite, R-O-desmethylvenlafaxine, has been reported as the most potent inhibitor of both noradrenaline and serotonin reuptake (Muth 1991). Recently, this metabolite (desvenlafaxine) has been approved by the US Food and Drug Administration as a treatment for major depressive disorder (Seo 2010). Relating steady-state concentration of venlafaxine to in vitro reuptake inhibitory concentration suggests that serotonin reuptake is maximal at low doses (< 100 mg daily), whereas noradrenaline reuptake increases over the dose range of 100 mg to 375 mg/day. Inhibition of both serotonin and noradrenaline reuptake is thought to be important for the antidepressant activity of venlafaxine. However, the mechanism of action of venlafaxine in the treatment of neuropathic pain remains uncertain and is likely to differ from the mechanisms underlying its antidepressant effect. In animal experiments, venlafaxine-induced analgesia was reported to be mediated via adrenergic mechanisms and via the κ and δ opioid receptors (Schreiber 1999). It is important to note that there tends to be little or no correlation between the effect of antidepressants on mood and pain in humans and that antidepressants can produce analgesia in patients with and without depression (Onghena 1992). Furthermore, antidepressant-induced pain relief typically emerges more rapidly and at a lower dose than the antidepressant effect, which often takes up to six weeks.
Why it is important to do this review
Venlafaxine is a well-tolerated antidepressant and an established pharmacological intervention for chronic neuropathic pain. In a recent update to an earlier Cochrane review of antidepressants for neuropathic pain, preliminary evidence for the effectiveness of venlafaxine in relieving pain in polyneuropathy was reported (Saarto 2007). In animal studies, thermal hyperalgesia in rats with an induced mononeuropathy was relieved by venlafaxine (Lang 1996). Similarly in human experimental studies, the threshold at which repetitive electrical stimulation shows pain summation was reduced by venlafaxine (Enggaard 2001). Taken together, there is good justification for conducting a comprehensive systematic review to establish whether an evidence base exists for the clinical use of venlafaxine in neuropathic pain management. This review will be one of several updates to the Saarto 2007 review of antidepressants in neuropathic pain. It will apply more stringent criteria for validity and may include new studies that have emerged since the 2007 update by Saarto and Wiffen.
The standards used to assess evidence in chronic pain trials have changed substantially since 2008, because of an improved awareness of quality issues and the emergence of new recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT; Dworkin 2008). Particular attention is now being paid to trial duration, withdrawals and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using average pain scores, or average change in pain scores, to the number of patients who have a large decrease in pain (by at least 50%); this level of pain relief has been shown to correlate with improvements in comorbid symptoms, function and quality of life. These standards are set out in the reference guide for pain studies (AUREF 2012).
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 number needed to treat for an additional beneficial outcome (NNTB) is four or above (Moore 1998)). This sets high standards and marks a departure from how reviews have been done previously.