M Tramèr

A systematic review of antidepressants in neuropathic pain

&NA; The objective of this study was to review the effectiveness and safety of antidepressants in neuropathic pain. In a systematic review of randomised controlled trials, the main outcomes were global judgements, pain relief or fall in pain intensity which approximated to more than 50% pain relief, and information about minor and major adverse effects. Dichotomous data for effectiveness and adverse effects were analysed using odds ratio and number needed‐to‐treat (NNT) methods. Twenty‐one placebo‐controlled treatments in 17 randomised controlled trials were included, involving 10 antidepressants. In six of 13 diabetic neuropathy studies the odds ratios showed significant benefit compared with placebo. The combined odds ratio was 3.6 (95% CI 2.5–5.2), with a NNT for benefit of 3 (2.4–4). In two of three postherpetic neuralgia studies the odds ratios showed significant benefit, and the combined odds ratio was 6.8 (3.5–14.3), with a NNT of 2.3 (1.7–3.3). In two atypical facial pain studies the combined odds ratio for benefit was 4.1 (2.3–7.5), with a NNT of 2.8 (2–4.7). Only one of three central pain studies had analysable dichotomous data. The NNT point estimate was 1.7. Comparisons of tricyclic antidepressants did not show any significant difference between them; they were significantly more effective than benzodiazepines in the three comparisons available. Paroxetine and mianserin were less effective than imipramine. For 11 of the 21 placebo‐controlled treatments there was dichotomous information on minor adverse effects; combining across pain syndromes the NNT for minor (noted in published report) adverse effects was 3.7 (2.9–5.2). Information on major (drug‐related study withdrawal) adverse effects was available from 19 reports; combining across pain syndromes the NNT for major adverse effects was 22 (13.5–58). Antidepressants are effective in relieving neuropathic pain. Compared with placebo, of 100 patients with neuropathic pain who are given antidepressants, 30 will obtain more than 50% pain relief, 30 will have minor adverse reactions and four will have to stop treatment because of major adverse effects. With very similar results for anticonvulsants it is still unclear which drug class should be first choice. Treatment would be improved if we could harness the dramatic improvement seen on placebo in some of the trials.

Impact of covert duplicate publication on meta-analysis: a case study.

Abstract Objective: To quantify the impact of duplicate data on estimates of efficacy. Design: Systematic search for published full reports of randomised controlled trials investigating ondansetrons effect on postoperative emesis. Abstracts were not considered. Data sources: Eighty four trials (11 980 patients receiving ondansetron) published between 1991 and September 1996. Main outcome measures: Percentage of duplicated trials and patient data. Estimation of antiemetic efficacy (prevention of emesis) of the most duplicated ondansetron regimen. Comparison between the efficacy of non-duplicated and duplicated data. Results: Data from nine trials had been published in 14 further reports, duplicating data from 3335 patients receiving ondansetron; none used a clear cross reference. Intravenous ondansetron 4 mg versus placebo was investigated in 16 reports not subject to duplicate publication, three reports subject to duplicate publication, and six duplicates of those three reports. The number needed to treat to prevent vomiting within 24 hours was 9.5 (95% confidence interval 6.9 to 15) in the 16 non-duplicated reports and 3.9 (3.3 to 4.8) in the three reports which were duplicated (P<0.00001). When these 19 were combined the number needed to treat was 6.4 (5.3 to 7.9). When all original and duplicate reports were combined (n=25) the apparent number needed to treat improved to 4.9 (4.4 to 5.6). Conclusions: By searching systematically we found 17% of published full reports of randomised trials and 28% of the patient data were duplicated. Trials reporting greater treatment effect were significantly more likely to be duplicated. Inclusion of duplicated data in meta-analysis led to a 23% overestimation of ondansetrons antiemetic efficacy. Key messages Although publishing the same data more than once is strongly discouraged, there is no evidence of the impact of duplicate data on meta-analysis Re-analysing an important trial, and cross referencing to original reports (overt duplication), may be necessary and valuable in some circumstances Covert duplication, masked by change of authors, of language, or by adding extra data, causes problems. One danger is that patient data are analysed more than once in meta-analysis 17% of systematically searched randomised trials of ondansetron as a postoperative antiemetic were covert duplicates and resulted in 28% of patient data being duplicated. None of these reports cross references the original source. Duplication lead to an overestimation of ondansetrons antiemetic efficacy of 23%. Trials reporting greater treatment effect were significantly more likely to be duplicated Covert duplication of data has major implications for the assessment of drug efficacy and safety

Quantitive systematic review of topically applied non-steroidal anti-inflammatory drugs

Abstract Objective: To review the effectiveness and safety of topical non-steroidal anti-inflammatory drugs in acute and chronic pain conditions. Design: Quantitive systematic review of randomised controlled trials. Data sources: 86 trials involving 10 160 patients. Main outcome measures: Measures of treatment success approximating at least 50% reduction in pain, local and systemic adverse effects. Analysis at 1 week for acute and 2 weeks for chronic conditions with relative benefit and number needed to treat. Results: In acute pain conditions (soft tissue trauma, strains, and sprains) placebo controlled trials had a relative benefit of 1.7 (1.5 to 1.9), the number needed to treat was 3.9 (3.4 to 4.4). With analysis by drug (at least three trials), ketoprofen (number needed to treat 2.6), felbinac (3.0), ibuprofen (3.5), and piroxicam (4.2) had significant efficacy. Benzydamine and indomethacin were no different from placebo. In chronic pain conditions (osteoarthritis, tendinitis) placebo controlled trials had a relative benefit of 2.0 (1.5 to 2.7); the number needed to treat was 3.1 (2.7 to 3.8). Small trials (<40 treated patients) exaggerated effectiveness of topical non-steroidals by 33% in acute conditions but not in chronic conditions. There was no relation between trial quality and treatment effect. In both acute and chronic pain local and systemic adverse events and withdrawal from the study related to the drug had a low incidence and were no different from placebo. Conclusion: Topical non-steroidal anti-inflammatory drugs are effective in relieving pain in acute and chronic conditions. Key messages Topical non-steroidal anti-inflammatory drugs are widely thought to be ineffective, despite licensed status To evaluate their effectiveness and safety we conducted a quantitive systematic review of all relevant randomised trials In acute conditions like strains and sprains topical non-steroidals were significantly better than placebo over 1 week with a number needed to treat of 3.9 (3.4 to 4.4). For drugs with at least three placebo controlled trials ketoprofen (number needed to treat 2.6), felbinac (3.0), ibuprofen (3.5), and piroxicam (4.2) had significant efficacy In chronic conditions like arthritis and rheumatism topical non-steroidals were significantly better than placebo over 2 weeks with a number needed to treat of 3.1 (2.7 to 3.8) In both acute and chronic pain local and systemic adverse events and withdrawal related to tested drug had a low incidence and were no different from placebo

Pain relief from intra-articular morphine after knee surgery: a qualitative systematic review

Abstract Reduction of postoperative pain by injecting opioid into the knee joint is believed to support the hypothesis of peripheral opioid receptor activation in inflammation. The study design consisted of a systematic review of randomised controlled trials (RCTs). Main outcomes were pain intensity and the use of supplementary analgesics. Efficacy of intra‐articular bupivacaine against placebo was used as an index of internal sensitivity. Evidence of efficacy was sought in both early (0–6 h after intra‐articular injection) and late (6–24 h) periods. Thirty‐six RCTs in knee surgery were found. Six had both a local anaesthetic control and placebo; four showed internal sensitivity. All four sensitive studies had at least one outcome showing efficacy of intra‐articular morphine against placebo. Six studies compared intra‐articular morphine with intravenous or intramuscular morphine or with intra‐articular saline without a bupivacaine control. Four of the six studies showed greater efficacy for intra‐articular morphine. There was no dose‐response evident. No quantitative analysis of pooled data was done. We conclude that intra‐articular morphine may have some effect in reducing postoperative pain intensity and consumption of analgesics. These studies had significant problems in design, data collection, statistical analysis and reporting. Trials of better methodological quality are needed for a conclusive answer that intra‐articular morphine is analgesic, and that any analgesia produced is clinically useful.

A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting.

Abstract Objectives: To test the evidence for a dose-response with ondansetron for treatment of postoperative nausea and vomiting and to establish whether differences in efficacy between doses are of clinical relevance. Design: Quantitative systematic review of published randomised controlled trials. Data sources: Seven trials from 1991 to January 1996 retrieved from a systematic literature search (Medline, reference lists, hand searching of anaesthetic journals, manufacturers database); no restriction on language. Main outcome measures: Estimation of efficacy (incidence of complete control of further nausea and vomiting) by using odds ratios and the “number needed to treat” method for early (within 6 hours of administration) and late (within 24 hours) periods. Results: Four placebo controlled trials with 1043 patients studied intravenous ondansetron 1 mg, 4 mg, or 8 mg. All doses were more efficacious than placebo in preventing further episodes of nausea or vomiting. For combined data, the point estimates for the number needed to treat were between 3.1 (8 mg) and 3.8 (1 mg) for early efficacy and between 4.1 (8 mg) and 4.8 (1 mg) for late efficacy, without significant differences between doses. No difference was found between ondansetron and droperidol in two trials with 129 patients or between ondansetron and metoclopramide in one trial with 80 patients. Conclusions: Further nausea and vomiting could be prevented with ondansetron compared with placebo in 25% of patients who had nausea or vomiting (number needed to treat, about 4). There was no evidence of a clinically relevant dose-response between 1 mg and 8 mg or a difference between ondansetron and either droperidol or metoclopramide in a limited dataset. A false impression of ondansetrons efficacy may arise because a quarter of all relevant published reports are duplicates, and reporting of study results is uncritical. Key messages Little information exists on the efficacy of anti-emetic interventions in patients with established postoperative nausea and vomiting To evaluate the effectiveness of ondansetron in this setting we conducted a quantitative systematic review of all relevant published randomised controlled trials Four trials (1043 patients) compared intravenous ondansetron 1 mg, 4 mg, or 8 mg with placebo, two trials (129 patients) compared ondansetron with droperidol, and one trial (80 patients) compared ondansetron with metoclopramide All three tested doses of ondansetron were more efficacious than placebo. There was no evidence of a clinically relevant dose-response between 1 mg and 8 mg (number needed to treat to prevent further nausea or vomiting was about 4), or a difference between ondansetron and either droperidol or metoclopramide. Stopping further postoperative nausea and vomiting in 25% of the patients may be the best that can be achieved currently

Systemic local-anaesthetic-type drugs in chronic pain: a systematic review

Basic research indicates that systemic local‐anaesthetic‐type drugs that block sodium channels are effective in pain due to nerve damage. These drugs were first used as analgesics in the 1950s and they are still commonly used to try to relieve neuropathic pain and incident pain caused by cancer. As they are potentially toxic, these drugs should not be used without proven effectiveness. For these reasons, a systematic review of randomized controlled trials of systemically administered local‐anaesthetic‐type drugs in chronic pain was performed. Main outcomes were pain relief or pain intensity difference and adverse effects. Twenty‐one reports were found, and four publications were excluded. In the remaining 17 studies (450 patients), 10 used intravenous lignocaine, two used intranasal lignocaine, four used oral mexiletine and one used oral tocainide.

Transcutaneous electrical nerve stimulation in labour pain: a systematic review

Objective To review the effectiveness and safety of transcutaneous electrical nerve stimulation (TENS) for labour pain.

When placebo controlled trials are essential and equivalence trials are inadequate

Arguments against the use of placebo groups in clinical trials have been based on opinion rather than evidence. Ethical issues have been raised,1 but these are contentious. 2 3 Scientific requirements should not override ethical ones, but if placebo controls are not used, then active controlled trials (trials using other active drugs as controls) have to be able to determine the efficacy of an intervention and its likelihood of causing harm.nn#### Summary pointsnnWe used the antiemetic ondansetron to explore the value of active controlled trials for two reasons. Firstly, the ethics of using placebo controls in ondansetron trials has been questioned repeatedly, both in oncology 4 5 and after surgery,6 causing confusion …

Efficacy of 5-HT3 receptor antagonists in radiotherapy-induced nausea and vomiting: A quantitative systematic review

5-HT3 receptor antagonists are used to treat radiation-induced sickness. The purpose of this study was to define anti-emetic efficacy and potential for harm of these drugs in radiotherapy. A systematic search, critical appraisal and quantitative analysis of relevant data using the number-needed-to-treat or harm (NNT/H) were conducted. Acute (0 to 24h) and delayed (beyond 24 h) anti-emetic efficacy were analysed separately. Data from 1,404 patients were found in 40 trials published in 36 reports. Data from 197 patients receiving ondansetron or granisetron in five randomised trials were regarded as valid according to preset criteria. One placebo-controlled trial had 10 patients per group and in this ondansetron was not significantly different from placebo. In a larger (n = 105) placebo-controlled trial, ondansetron was significantly more efficacious than metoclopramide for complete control of acute vomiting (NNT 2.2, 95% confidence interval (CI) 1.7-3.3) and acute nausea (NNT 3.6, 95% CI 2.2-10.2). Three trials reported delayed outcomes with ondansetron or granisetron: there was no evidence of any difference compared with placebo or other anti-emetics. Two trials reported no acute or delayed but a worst day outcome; in these ondansetrons antivomiting effect was significantly better than placebo (NNT 4.4, 95% CI 2.5-23) or prochlorperazine (NNT 3.8, 95% CI 2.4-10.3), but not its antinausea effect. Constipation and headache were associated significantly with 5-HT3 receptor antagonists compared with other anti-emetics or placebo (NNH 6.4 and 17.1, respectively). Only 14% of published data enabled valid estimation of the anti-emetic efficacy of 5-HT3 receptor antagonists in radiotherapy. There was some evidence that these drugs prevent acute vomiting: 40% of treated patients will benefit (NNT approximately 2.5). The evidence for nausea was less clear. There was no evidence that these drugs are of any benefit beyond 24 h. There was evidence that they produce specific adverse effects.