Background: Chronic noncancer pain (CNCP) is a major health problem, for which opioids provide one treatment option. However, evidence is needed about side effects, efficacy, and risk of misuse or addiction. Methods: This meta-analysis was carried out with these objectives: to compare the efficacy of opioids for CNCP with other drugs and placebo; to identify types of CNCP that respond better to opioids; and to determine the most common side effects of opioids. We searched MEDLINE, EMBASE, CENTRAL (up to May 2005) and reference lists for randomized controlled trials of any opioid administered by oral or transdermal routes or rectal suppositories for CNCP (defined as pain for longer than 6 mo). Extracted outcomes included pain, function or side effects. Methodological quality was assessed with the Jadad instrument; analyses were conducted with Revman 4.2.7. Results: Included were 41 randomized trials involving 6019 patients: 80% of the patients had nociceptive pain (osteoarthritis, rheumatoid arthritis or back pain); 12%, neuropathic pain (postherpetic neuralgia, diabetic neuropathy or phantom limb pain); 7%, fibromyalgia; and 1%, mixed pain. The methodological quality of 87% of the studies was high. The opioids studied were classified as weak (tramadol, propoxyphene, codeine) or strong (morphine, oxycodone). Average duration of treatment was 5 (range 1–16) weeks. Dropout rates averaged 33% in the opioid groups and 38% in the placebo groups. Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or neuropathic pain or fibromyalgia. Strong, but not weak, opioids were significantly superior to naproxen and nortriptyline, and only for pain relief. Among the side effects of opioids, only constipation and nausea were clinically and statistically significant. Interpretation: Weak and strong opioids outperformed placebo for pain and function in all types of CNCP. Other drugs produced better functional outcomes than opioids, whereas for pain relief they were outperformed only by strong opioids. Despite the relative shortness of the trials, more than one-third of the participants abandoned treatment.

Objective: The authors hypothesized that central factors may underlie sensory deficits in patients with nondermatomal somatosensory deficits (NDSD) and that functional brain imaging would reveal altered responses in supraspinal nuclei. Background: Patients with chronic pain frequently present with NDSD, ranging from hypoesthesia to complete anesthesia in the absence of substantial pathology and often in association with motor weakness and occasional paralysis. Patients with pain and such pseudoneurologic symptoms can be classified as having both a pain disorder and a conversion disorder (Diagnostic and Statistical Manual of Mental Disorders–IV classification). Methods: The authors tested their hypothesis with functional MRI (fMRI) of brush and noxious stimulation-evoked brain responses in four patients with chronic pain and NDSD. Results: The fMRI findings revealed altered somatosensory-evoked responses in specific forebrain areas. Unperceived stimuli failed to activate areas that were activated with perceived touch and pain: notably, the thalamus, posterior region of the anterior cingulate cortex (ACC), and Brodmann area 44/45. Furthermore, unperceived stimuli were associated with deactivations in primary and secondary somatosensory cortex (S1, S2), posterior parietal cortex, and prefrontal cortex. Finally, unperceived (but not perceived) stimuli activated the rostral ACC. Conclusions: Diminished perception of innocuous and noxious stimuli is associated with altered activity in many parts of the somatosensory pathway or other supraspinal areas. The cortical findings indicate a neurobiological component for at least part of the symptoms in patients presenting with nondermatomal somatosensory deficits.

To assess the efficacy/effectiveness and side effects of gabapentin for the treatment of neuropathic pain. Systematic review of the literature. Extensive search of several electronic databases located both controlled and uncontrolled studies. Efficacy was assessed through meta-analysis of randomized controlled trials (RCTs), whereas the effectiveness of gabapentin in uncontrolled studies was assessed via a novel system of dichotomous classification of “bad” versus “good” results. Thirty-five papers involving 727 patients with multiple neuropathic pain conditions met the inclusion criteria. The meta-analysis of the 2 high-quality, placebo-controlled RCTs showed positive effect of gabapentin in diabetic neuropathy and post-herpetic neuralgia. The addition of 2 low-quality, placebo-controlled RCTs did not alter the magnitude or direction of observed effect. The uncontrolled studies demonstrated positive effect on pain in different neuropathic syndromes, as well as benefit on different types of neuropathic pain; highest dose administered and rate-of-dose escalation showed wide variability between prescribers. Fewer and less severe side effects were reported in the uncontrolled studies. Gabapentin seems to be effective in multiple painful neuropathic conditions. The variable prescribing patterns of the uncontrolled studies raise the suspicion that effectiveness may be reduced if one limits administration of the drug to very low doses, whereas rapid dose escalation may be associated with increased central nervous system side effects. Well-designed controlled trials may provide insight into differential symptom sensitivity to the drug.

Limited research suggests that there may be Warm complex regional pain syndrome (CRPS) and Cold CRPS subtypes, with inflammatory mechanisms contributing most strongly to the former. This study for the first time used an unbiased statistical pattern recognition technique to evaluate whether distinct Warm vs Cold CRPS subtypes can be discerned in the clinical population. An international, multisite study was conducted using standardized procedures to evaluate signs and symptoms in 152 patients with clinical CRPS at baseline, with 3-month follow-up evaluations in 112 of these patients. Two-step cluster analysis using automated cluster selection identified a 2-cluster solution as optimal. Results revealed a Warm CRPS patient cluster characterized by a warm, red, edematous, and sweaty extremity and a Cold CRPS patient cluster characterized by a cold, blue, and less edematous extremity. Median pain duration was significantly (P < 0.001) shorter in the Warm CRPS (4.7 months) than in the Cold CRPS subtype (20 months), with pain intensity comparable. A derived total inflammatory score was significantly (P < 0.001) elevated in the Warm CRPS group (compared with Cold CRPS) at baseline but diminished significantly (P < 0.001) over the follow-up period, whereas this score did not diminish in the Cold CRPS group (time × subtype interaction: P < 0.001). Results support the existence of a Warm CRPS subtype common in patients with acute (<6 months) CRPS and a relatively distinct Cold CRPS subtype most common in chronic CRPS. The pattern of clinical features suggests that inflammatory mechanisms contribute most prominently to the Warm CRPS subtype but that these mechanisms diminish substantially during the first year postinjury.

An enriched enrollment randomized withdrawal (EERW) trial design has been advocated to be useful for the study of drugs that are beneficial to only a fraction of the individuals who take them. Some investigators defend the use of enrichment designs for opioids in chronic noncancer pain (CNCP), reasoning that opioids may appear to underperform in clinically heterogeneous contexts, ie, that substantial efficacy in a particular patient subgroup may be diluted or masked by poor efficacy in another subgroup. The authors previously published a systematic review of opioids for CNCP in 2006; however, at that time, there were only a few EERW trials available for comparison. This more exhaustive, updated review compares the results between EERW and non‐EERW trials of opioids for a variety of CNCP conditions.BACKGROUND: An enriched enrollment randomized withdrawal (EERW) design excludes potential participants who are nonresponders or who cannot tolerate the experimental drug before random assignment. It is unclear whether EERW design has an influence on the efficacy and safety of opioids for chronic noncancer pain (CNCP).OBJECTIVES: The primary objective was to compare the results from EERW and non‐EERW trials of opioids for CNCP. Secondary objectives were to compare weak versus strong opioids, subgroups of patients with different types of pain, and the efficacy of opiods compared with placebo versus other drugs.METHODS: MEDLINE, EMBASE and CENTRAL were searched up to July 2009, for randomized controlled trials of any opioid for CNCP. Meta‐analyses and meta‐regressions were conducted to compare the results. Treatment efficacy was assessed by effect sizes (small, medium and large) and the incidence of adverse effects was assessed by a clinically relevant mean difference of 10% or greater.RESULTS: Sixty‐two randomized trials were included. In 61 trials, the duration was less than 16 weeks. There was no difference in efficacy between EERW and non‐EERW trials for both pain (P=0.6) and function (P=0.3). However, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness and dry skin/itching compared with non‐EERW. Opioids were more effective than placebo in patients with nociceptive pain (effect size=0.60, 95% CI 0.49 to 0.72) and neuropathic pain (effect size=0.56, 95% CI 0.38 to 0.73).CONCLUSION: EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta‐analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin.