New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double-blind, placebo-controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross-over and large parallel group trials, remain as limitations.

Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.

Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline. Trials were classified according to the aetiological condition. All class I and II controlled trials (according to EFNS classification of evidence) were assessed, but lower-class studies were considered in conditions that had no top level studies. Only treatments feasible in an outpatient setting were evaluated. Effects on pain symptoms/signs, quality of life and comorbidities were particularly searched for. Most of the randomized controlled trials included patients with postherpetic neuralgia (PHN) and painful polyneuropathies (PPN) mainly caused by diabetes. These trials provide level A evidence for the efficacy of tricyclic antidepressants, gabapentin, pregabalin and opioids, with a large number of class I trials, followed by topical lidocaine (in PHN) and the newer antidepressants venlafaxine and duloxetine (in PPN). A small number of controlled trials were performed in central pain, trigeminal neuralgia, other peripheral neuropathic pain states and multipleaetiology neuropathic pains. The main peripheral pain conditions respond similarly well to tricyclic antidepressants, gabapentin, and pregabalin, but some conditions, such as HIV-associated polyneuropathy, are more refractory. There are too few studies on central pain, combination therapy, and head-to-head comparison. For future trials, we recommend to assess quality of life and pain symptoms or signs with standardized tools. Background and objectives

Tricyclic antidepressants and carbamazepine have become the mainstay in the treatment of neuropathic pain. Within the last decade, controlled trials have shown that numerous other drugs relieve such pain. We identified all placebo-controlled trials and calculated numbers needed to treat (NNT) to obtain one patient with more than 50% pain relief in order to compare the efficacy with the current treatments, and to search for relations between mechanism of pain and drug action. In diabetic neuropathy, NNT was 1.4 in a study with optimal doses of the tricyclic antidepressant imipramine as compared to 2.4 in other studies on tricyclics. The NNT was 6.7 for selective serotonin reuptake inhibitors, 3.3 for carbamazepine, 10.0 for mexiletine, 3.7 for gabapentin, 1.9 for dextromethorphan, 3.4 for tramadol and levodopa and 5.9 for capsaicin. In postherpetic neuralgia, the NNT was 2.3 for tricyclics, 3.2 for gabapentin, 2.5 for oxycodone and 5.3 for capsaicin, whereas dextromethorphan was inactive. In peripheral nerve injury, NNT was 2.5 for tricyclics and 3.5 for capsaicin. In central pain, NNT was 2.5 for tricyclics and 3. 4 for carbamazepine, whereas selective serotonin reuptake inhibitors, mexiletine and dextromethorphan were inactive. There were no clear relations between mechanism of action of the drugs and the effect in distinct pain conditions or for single drug classes and different pain conditions. It is concluded that tricyclic antidepressants in optimal doses appear to be the most efficient treatment of neuropathic pain, but some of the other treatments may be important due to their better tolerability. Relations between drug and pain mechanisms may be elucidated by studies focusing on specific neuropathic pain phenomena such as pain paroxysms and touch-evoked pain.

SummaryPainful diabetic peripheral neuropathy (DPN) is common, is associated with significant reduction in quality of life and poses major treatment challenges to the practising physician. Although poor glucose control and cardiovascular risk factors have been proven to contribute to the aetiology of DPN, risk factors specific for painful DPN remain unknown. A number of instruments have been tested to assess the character, intensity and impact of painful DPN on quality of life, activities of daily living and mood. Management of the patient with DPN must be tailored to individual requirements, taking into consideration the co-morbidities and other factors. Pharmacological agents with proven efficacy for painful DPN include tricyclic anti-depressants, the selective serotonin and noradrenaline re-uptake inhibitors, anti-convulsants, opiates, membrane stabilizers, the anti-oxidant alpha-lipoic acid and topical agents including capsaicin. Current first-line therapies for painful DPN include tricyclic antidepressants, the serotonin and noradrenaline re-uptake inhibitor duloxetine and the anti-convulsants pregabalin and gabapentin. When prescribing any of these agents, other co-morbidities and costs must be taken into account. Second-line approaches include the use of opiates such as synthetic opioid tramadol, morphine and oxycodone-controlled release. There is a limited literature with regard to combination treatment. In extreme cases of painful DPN unresponsive to pharmacotherapy, occasional use of electrical spinal cord stimulation might be indicated. There are a number of unmet needs in the therapeutic management of painful DPN. These include the need for randomized controlled trials with active comparators and data on the long-term efficacy of agents used, as most trials have lasted for less than 6 months. Finally, there is a need for appropriately designed studies to investigate non-pharmacological approaches.

In neuropathic pain it has been suggested that pain phenotype based on putative pain mechanisms may predict response to treatment. This was a randomised, double-blind, placebo-controlled, and phenotype-stratified study with 2 6-week treatment periods of oxcarbazepine (1800-2400mg) and placebo. The primary efficacy measure was change in median pain intensity between baseline and the last week of treatment measured on an 11-point numeric rating scale, and the primary objective was to compare the effect of oxcarbazepine in patients with and without the irritable nociceptor phenotype as defined by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing. Ninety-seven patients with peripheral neuropathic pain due to polyneuropathy, surgical or traumatic nerve injury, or postherpetic neuralgia were randomised. The intention-to-treat population comprised 83 patients: 31 with the irritable and 52 with the nonirritable nociceptor phenotype. In the total sample, oxcarbazepine relieved pain of 0.7 points (on a numeric rating scale 0-10; 95% confidence interval [CI] 0.4-1.4) more than placebo (P=0.015) and there was a significant interaction between treatment and phenotype of 0.7 (95% CI 0.01-1.4, P=0.047). The number needed to treat to obtain one patient with more than 50% pain relief was 6.9 (95% CI 4.2-22) in the total sample, 3.9 (95% CI 2.3-12) in the irritable, and 13 (95% CI 5.3-∞) in the nonirritable nociceptor phenotype. In conclusion, oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype.

Tramadol inhibits norepinephrine reuptake, stimulates serotonin release, and acts with mu-opioid receptors by way of its metabolite (+)-M1. Formation of M1 seems to depend on the genetic polymorphic CYP2D6. The analgesic effect of 2 mg/kg tramadol was evaluated in 15 extensive and 12 poor metabolizers of sparteine in two parallel, randomized, double-blind, placebo-controlled crossover studies that used experimental pain models. In extensive metabolizers, tramadol increased pressure pain detection (p = 0.03) and tolerance (p = 0.06) thresholds, as well as thresholds for eliciting nociceptive reflexes, after single (p = 0.0002) and repeated (p = 0.06) stimulation of the sural nerve. Peak pain and pain area in the cold pressor test were reduced (p = 0.0006 and 0.0009). In poor metabolizers, only thresholds to pressure pain tolerance (p = 0.02) and nociceptive reflexes after single stimulation (p = 0.04) were increased and the reflex threshold was less increased in poor metabolizers than in extensive metabolizers (p = 0.02). The serum concentration of (+)-M1 2 to 10 hours after tramadol ranged from 10 to 100 ng/L in extensive metabolizers, whereas in poor metabolizers serum concentrations of (+)-M1 were below or around the detection limit of 3 ng/ml. It is concluded that formation of (+)-M1 by way of CYP2D6 is important for the effect of tramadol on experimental pain.

Animal experiments have shown that the nociceptive reflex can be used as an indicator of central temporal integration in the nociceptive system. The aim of the present study on humans was to investigate whether the nociceptive reflex, evoked by repetitive strong electrical sural nerve stimuli, increased when summation was reported by the volunteers. The reflexes were recorded from the biceps femoris and rectus femoris muscles in eight volunteers following a series of stimulations at 0.1, 1, 2, and 3 Hz. Each series consisted of five consecutive stimuli. Using 0.1- and 1-Hz stimulation, the reflex was not facilitated in the course of the five consecutive stimuli. Following 2- and 3-Hz stimulation, the reflex size (root mean square amplitude) increased significantly during the course of the fifth stimulus. This reflex facilitation was followed by a significant increase (summation) in the pain magnitude when compared with 1- and 0.1-Hz stimulation. Furthermore, the threshold for psychophysical summation could be determined. This threshold (stimulus intensity) decreased when the stimulus frequency (1-5 Hz) of the five consecutive stimuli was increased. The nociceptive reflex and the psychophysical summation threshold might be used to clarify and quantify aspects of temporal summation within the human nociceptive system.