Susceptibility to fraud in systematic reviews: lessons from the Reuben case.

BACKGROUND: Dr. Scott Reuben allegedly fabricated data. The authors of the current article examined the impact of Reuben reports on conclusions of systematic reviews. METHODS: The authors searched in ISI Web of Knowledge systematic reviews citing Reuben reports. Systematic reviews were grouped into one of three categories: I, only cited but did not include Reuben reports; II, retrieved and considered, but eventually excluded Reuben reports; III, included Reuben reports. For quantitative systematic reviews (i.e., meta-analyses), a relevant difference was defined as a significant result becoming nonsignificant (or vice versa) by excluding Reuben reports. For qualitative systematic reviews, each author decided independently whether noninclusion of Reuben reports would have changed conclusions. RESULTS: Twenty-five systematic reviews (5 category I, 6 category II, 14 category III) cited 27 Reuben reports (published 1994-2007). Most tested analgesics in surgical patients. One of 6 quantitative category III reviews would have reached different conclusions without Reuben reports. In all 6 (30 subgroup analyses involving Reuben reports), exclusion of Reuben reports never made any difference when the number of patients from Reuben reports was less than 30% of all patients included in the analysis. Of 8 qualitative category III reviews, all authors agreed that one would certainly have reached different conclusions without Reuben reports. For another 4, the authors' judgment was not unanimous. CONCLUSIONS: Carefully performed systematic reviews proved robust against the impact of Reuben reports. Quantitative systematic reviews were vulnerable if the fraudulent data were more than 30% of the total. Qualitative systematic reviews seemed at greater risk than quantitative.

Gabapentin and postoperative pain: a qualitative and quantitative systematic review, with focus on procedure.

BACKGROUND: Gabapentin is an antiepileptic drug used in a variety of chronic pain conditions. Increasing numbers of randomized trials indicate that gabapentin is effective as a postoperative analgesic. This procedure-specific systematic review aims to analyse the 24-hour postoperative effect of gabapentin on acute pain in adults. METHODS: Medline, The Cochrane Library and Google Scholar were searched for double-blind randomized placebo controlled trials of gabapentin for postoperative pain relief compared with placebo, in adults undergoing a surgical procedure. Qualitative analysis of postoperative effectiveness was evaluated by assessment of significant difference (P < 0.05) in pain relief using consumption of supplemental analgesic and pain scores between study groups. Quantitative analyses of combined data from similar procedures, were performed by calculating the weighted mean difference (WMD) of 24-hour cumulated opioid requirements, and the WMD for visual analogue scale (VAS) pain, (early (6 h) and late (24 h) postoperatively), between study groups. Side-effects (nausea, vomiting, dizziness and sedation) were extracted for calculation of their relative risk (RR). RESULTS: Twenty-three trials with 1529 patients were included. In 12 of 16 studies with data on postoperative opioid requirement, the reported 24-hour opioid consumption was significantly reduced with gabapentin. Quantitative analysis of five trials in abdominal hysterectomy showed a significant reduction in morphine consumption (WMD - 13 mg, 95% confidence interval (CI) -19 to -8 mg), and in early pain scores at rest (WMD - 11 mm on the VAS, 95% CI -12 to -2 mm) and during activity (WMD -8 mm on the VAS; 95% CI -13 to -3 mm), favouring gabapentin. In spinal surgery, (4 trials), analyses demonstrated a significant reduction in morphine consumption (WMD of - 31 mg (95%CI - 53 to -10 mg) and pain scores, early (WMD - 17 mm on the VAS; 95 % CI -31 to -3 mm) and late (WMD -12 mm on the VAS; 95% CI -23 to -1 mm) also favouring gabapentin treatment. Nausea was improved with gabapentin in abdominal hysterectomy (RR 0.7; 95 % CI 0.5 to 0.9). Other side-effects were unaffected. CONCLUSION: Perioperative use of gabapentin has a significant 24-hour opioid sparing effect and improves pain score for both abdominal hysterectomy and spinal surgery. Nausea may be reduced in abdominal hysterectomy.

Quantitative sensory examination of epidural anaesthesia and analgesia in man: effects of pre- and post-traumatic morphine on hyperalgesia.

The objectives of the study were: (1) comparison of hypoalgesic effects of pre- and post-traumatic epidural morphine (EM) on primary and secondary hyperalgesia, and (2) comparison of EM hypoalgesia in normal and injured skin. Burn injuries (25 x 50 mm rectangular thermode, 47 degrees C, 7 min) were produced on the calves of healthy volunteers, at 2 different days at least 1 week apart. In randomized order, the subjects received 4 mg of EM administered via the L2-L3 intervertebral space on one day and no treatment on the other day. One calf was injured 30 min prior to and the other calf 2.5 h after administration of morphine. Hence, the calf injured prior to morphine administration was a model of postinjury treatment, and the calf injured after morphine administration, a model of pretraumatic treatment. The timing of injuries was identical on the morphine treatment and control days. The injuries induced decrease in heat pain detection and tolerance thresholds within the area of injury (area of primary hyperalgesia) as well as reduction of areas of allodynia for brush and pinprick surrounding the injury (area of secondary hyperalgesia). Both pre- and post-traumatic administration of EM increased heat pain detection and tolerance thresholds, and decreased by approximately 50% the areas of secondary hyperalgesia 2.5 h postinjury. The effects of morphine were naloxone (NAL)-reversible (0.1 mg/kg, i.v.). There was no significant difference between pre- and post-traumatic administration of morphine on the effect of either primary or secondary hyperalgesia. EM increased the heat pain detection threshold more within the injury than at a corresponding non-injured site. There was no significant difference in the effect of morphine on heat pain tolerance in injured and non-injured skin. Following NAL, the areas of secondary hyperalgesia expanded beyond control size. It is suggested that the major effect of EM on secondary hyperalgesia is inhibition of C fibre-mediated activity which maintains the altered response properties of central neurons responsible for secondary hyperalgesia. Possible mechanisms of action of NAL in enhancement of hyperalgesia are discussed.

Pre-emptive analgesia.

Transmission of pain signals evoked by tissue damage leads to sensitization of the peripheral and central pain pathways. Pre-emptive analgesia is a treatment that is initiated before the surgical procedure in order to reduce this sensitization. Owing to this 'protective' effect on the nociceptive system, pre-emptive analgesia has the potential to be more effective than a similar analgesic treatment initiated after surgery. Theoretically, immediate postoperative pain may be reduced and the development of chronic pain may be prevented. Although some clinical studies have demonstrated significant effects on acute postoperative pain, no major clinical benefits of pre-emptive analgesia have been documented. The only way to prevent sensitization of the nociceptive system might be to block completely any pain signal originating from the surgical wound from the time of incision until final wound healing. Other pharmacological interventions, including 'antihyperalgesic' drugs such as NMDA-receptor antagonists and gabapentin, may interfere with the induction and maintenance of sensitization. Future studies will investigate the analgesic effect of prolonged multimodal combinations of different classes of 'traditional' analgesics and 'antihyperalgesics' on postoperative pain.

Mechanisms of postoperative pain: clinical indications for a contribution of central neuronal sensitization.

BACKGROUND: The relative importance of different nociceptive mechanisms for the intensity, duration, and character of postoperative pain is not well established. It has been suggested that sensitization of dorsal horn neurones may contribute to pain in the postoperative period. We hypothesized that wound hyperalgesia in postoperative patients and experimentally heat-induced secondary hyperalgesia share a common mechanism, sensitization of central neurones, and consequently, that the short-acting opioid remifentanil would have comparable effects on hyperalgesia in both conditions. METHODS: In a randomized, controlled, double-blind trial, we assessed mechanical hyperalgesia in skin bordering the surgical wound, and an area of experimentally heat-induced secondary hyperalgesia on the thigh, in 12 patients who underwent abdominal hysterectomy within 5 days prior to the investigation. Observations were made before and during a drug challenge with remifentanil, which has been demonstrated to reduce the area of heat-induced secondary hyperalgesia in volunteers. RESULTS: The area of skin with surgically-induced mechanical hyperalgesia, the area of heat-induced secondary hyperalgesia, and pain during cough, were significantly reduced during remifentanil infusion compared with placebo (P = 0.008, P = 0.006, and P = 0.002, respectively). The relative reduction (% of baseline) of the area of skin with surgically-induced hyperalgesia and heat-induced secondary hyperalgesia during infusion of remifentanil was significantly associated (R2 = 0.72, P = 0.001). CONCLUSIONS: Although remifentanil is not a highly targeted "antihyperalgesic," these results support the hypothesis that both wound hyperalgesia in postoperative patients and experimentally heat-induced secondary hyperalgesia may share common mechanisms, and that central neuronal sensitization may contribute to some aspects of postoperative pain. Antihyperalgesic drugs should be further developed and evaluated in clinical trials of postoperative pain.

Nonsteroidal antiinflammatory drugs and the risk of operative site bleeding after tonsillectomy: a quantitative systematic review.

UNLABELLED: The use of nonsteroidal antiinflammatory drugs (NSAIDs) for analgesia after tonsillectomy is controversial because NSAIDS, through platelet inhibition, may increase the risk of perioperative bleeding. We systematically searched for randomized, controlled trials that reported on the incidence of perioperative bleeding attributable to the use of NSAIDs in patients undergoing tonsillectomy. As secondary outcome measures, we analyzed the quality of pain relief and the incidence of postoperative nausea and vomiting. Twenty-five studies with data from 970 patients receiving a NSAID and 883 receiving a non-NSAID treatment or a placebo were analyzed. Data were combined using a fixed-effect model. Of four bleeding end points (intraoperative blood loss, postoperative bleeding, hospital admission, and reoperation because of bleeding), only reoperation happened significantly more often with NSAIDs: Peto-odds ratio, 2.33 (95% confidence interval [CI], 1.12-4.83) and number-needed-to-treat, 60 (95% CI, 34-277). Compared with opioids, NSAIDs were equianalgesic, and the risk of emesis was significantly decreased (relative risk, 0.73; 95% CI, 0.63-0.85; numbers-needed-to-treat, 9; 95% CI, 5-19). IMPLICATIONS: The evidence for nonsteroidal antiinflammatory drugs to increase the risk of bleeding after tonsillectomy is equivocal, and the risk-benefit ratio is not straightforward. There is some evidence for an increased likelihood of reoperation because of bleeding. The agenda must be one of further research rather than of clinical recommendations.