Description of the condition

Neuropathic pain, unlike nociceptive pain such as gout and other forms of arthritis, is caused by nerve damage, often accompanied by changes in the central nervous system (CNS). The new (2011) definition of neuropathic pain is ‘‘pain caused by a lesion or disease of the somatosensory system’" (Jensen 2011). Fibromyalgia is a complex pain syndrome, 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 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 of fibromyalgia are not well understood, but it has features in common with neuropathic pain, including changes in the CNS. Many people with these conditions are significantly disabled with moderate or severe pain for many years. Conventional analgesics are usually not effective, although opioids may be in some individuals. Others may derive some benefit from a topical lidocaine patch or topical capsaicin. Treatment is more usually by unconventional analgesics such as antidepressants or antiepileptics.

Data for the incidence of neuropathic pain are difficult to obtain. However, a systematic review of prevalence and incidence in the Oxford Region of the UK indicates prevalence rates per 100,000 of 34 for postherpetic neuralgia, 400 for diabetic neuropathy and trigeminal neuropathy, and 2000 for fibromyalgia (McQuay 2007). Different estimates in the UK indicate incidences per 100,000 person years observation of 40 (95% CI 39 to 41) for post‐herpetic neuralgia, 27 (26 to 27) for trigeminal neuralgia, 1 (1 to 2) for phantom limb pain, and 15 (15 to 16) for painful diabetic neuropathy, with rates decreasing in recent years for phantom limb pain and post‐herpetic neuralgia and increasing for painful diabetic neuropathy (Hall 2006). The prevalence of neuropathic pain in Austria was reported as being 3.3% (Gustorff 2008).

Neuropathic pain and fibromyalgia are 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 physical or cognitive, or both, therapies being combined with pharmacological interventions.

Description of the intervention

Clonazepam is a benzodiazepine, based upon the unusual seven membered ring and aromatic ring structure that is common to all compounds in this group. Historically, the first benzodiazepine, chlordiazepoxide, was discovered accidentally in the late 1950s as a result of an unplanned reaction at the Roche laboratory, and after routine screening its unexpected pharmacological activity was recognised. Benzodiazepines bind specifically to GABA_A (gamma‐aminobutyric acid) receptors at a binding site different to that occupied by GABA, the main inhibitory neurotransmitter in the CNS. Allosteric binding to this ligand‐gated ion channel increases its affinity for GABA and therefore facilitates the opening of GABA‐activated chloride channels. This enhanced inhibitory response to GABA is thought to be the mechanism behind the main effects of benzodiazepines, namely reduced anxiety, sedation, relaxation of muscle tone and an anticonvulsant effect.

Clonazepam (trade names: Rivotril and Klonopin) is unusual because it has a very long half life (approximately 35 hours) and marked anticonvulsant effects with less marked sedation compared to other benzodiazepines. However, as with all benzodiazepines the generation of tolerance and dependence is of concern. It has also been associated with behavioural disinhibition in patients with psychiatric conditions (e.g. Binder 1987), although other studies have not demonstrated this (e.g. Rothschild 2000).

Clonazepam is indicated for the treatment of myoclonic, atypical absence, atonic and tonic epileptic seizures, as well as status epilepticus and can be administered orally (4 to 8 mg daily maintenance dose) or intravenously (1 mg/ml ampoules available). We are unaware of any license for use in neuropathic pain or fibromyalgia.

How the intervention might work

At the molecular level the pathophysiology of both neuropathic pain and fibromyalgia is unclear but both may involve changes to several neurotransmitter systems including those involving substance P, NMDA (N‐Methyl‐D‐aspartic acid), GABA and opioids. Clonazepam may have a beneficial effect in the treatment of neuropathic pain and fibromyalgia by antagonising hyperexcitability of neurotransmission through the enhancement of inhibitory GABAergic signalling pathways. However, there is no consensus as to both how and even whether clonazepam exerts analgesic effects in these conditions. An earlier Cochrane review, 'Anticonvulsants in acute and chronic pain' (Wiffen 2010), which has now been withdrawn because it is out of date and has been superseded by other reviews such as this review, found one study in temporomandibular joint dysfunction.

Why it is important to do this review

Other antiepileptic drugs have shown some efficacy in neuropathic pain and fibromyalgia (e.g. gabapentin, (Moore 2011) pregabalin, (Moore 2009a) and carbamazepine (Wiffen 2011a)), while others don't (e.g. lamotrigine (Wiffen 2011b). It is important to establish whether clonazepam has a place amongst the available treatment options for these conditions.

There have been several recent changes in how efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with the addition of new criteria on what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with "any improvement". Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be longer, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment (Moore 2010). To summarise some of the recent insights that make a new review necessary, over and above including more trials are as follows:

1. Pain results tend to have a U‐shaped distribution rather than a bell‐shaped distribution (see Moore 2005 for acute pain). This is true in acute pain and arthritis (Moore 2009b) as well as in fibromyalgia; in all cases average results usually describe the experience of almost no‐one in the actual trial. Data expressed as averages are potentially misleading, unless it can be proven that they are suitable.

2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The IMMPACT group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials shorter than 12 weeks, and especially those shorter than 8 weeks, overestimate the effect of treatment (Moore 2009b); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic‐type pain.

3. The proportion with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis, to 30% in fibromyalgia (Moore 2009b; Straube 2008; Sultan 2008). A Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009c). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.

4. Finally, presently unpublished individual patient analyses indicate that patients who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way.

This Cochrane review will therefore assess evidence in ways that make both statistical and clinical sense. 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 a minimum of 500+ participants in a comparison in which numbers needed to treat to benefit (NNTs) are four or above (Moore 1998)). This does set high standards, and marks a departure from how reviews have been conducted previously.