Authorship. Work done by junior researchers gives rise to problems.
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Authorship↗
Biomedical subjects
H J McQuay
Publications and source records attributed to H J McQuay.
Impact of covert duplicate publication on meta-analysis: a case study.
OBJECTIVE: To quantify the impact of duplicate data on estimates of efficacy. DESIGN: Systematic search for published full reports of randomised controlled trials investigating ondansetron's 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 ondansetron's antiemetic efficacy.
Antiemetics↗
Using numerical results from systematic reviews in clinical practice.
Systematic reviews summarize large amounts of information and are more likely than individual trials to describe the true clinical effect of an intervention. Traditional statistical outputs from systematic reviews cannot immediately be applied to clinical practice. The number needed to treat (NNT) has that clinical immediacy. This number can be calculated easily from raw data or from statistical outputs, and the principle involved in its calculation can be applied to different outcomes: treatment efficacy, adverse events (harm), or other end points. The NNT defines the treatment-specific effect of an intervention, and we suggest it as a currency for making decisions about individual patients. Knowing the NNT for different interventions that have the same outcome for the same disorder can help shape individual and institutional practice. Knowing or estimating the number needed to harm is also an important part of the equation. Knowing or estimating an individual patient's risk can, with the NNT, be a guide to the overall or net value of a prophylactic intervention. We advocate an approach to systematic reviews that distills information into, in effect, one number: the NNT. This is simple to remember and directly supports efforts to work with patients to make the best possible clinical decisions for their care.
Data Interpretation, Statistical↗
A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting.
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, manufacturer's 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 ondansetron's efficacy may arise because a quarter of all relevant published reports are duplicates, and reporting of study results is uncritical.
Antiemetics↗
Antidepressants and chronic pain.
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Analgesia↗
The visual analogue pain intensity scale: what is moderate pain in millimetres?
One way to ensure adequate sensitivity for analgesic trials is to test the intervention on patients who have established pain of moderate to severe intensity. The usual criterion is at least moderate pain on a categorical pain intensity scale. When visual analogue scales (VAS) are the only pain measure in trials we need to know what point on a VAS represents moderate pain, so that these trials can be included in meta-analysis when baseline pain of at least moderate intensity is an inclusion criterion. To investigate this we used individual patient data from 1080 patients from randomised controlled trials of various analgesics. Baseline pain was measured using a 4-point categorical pain intensity scale and a pain intensity VAS under identical conditions. The distribution of the VAS scores was examined for 736 patients reporting moderate pain and for 344 reporting severe pain. The VAS scores corresponding to moderate or severe pain were also examined by gender. Baseline VAS scores recorded by patients reporting moderate pain were significantly different from those of patients reporting severe pain. Of the patients reporting moderate pain 85% scored over 30 mm on the corresponding VAS, with a mean score of 49 mm. For those reporting severe pain 85% scored over 54 mm with a mean score of 75 mm. There was no difference between the corresponding VAS scores of men and women. Our results indicate that if a patient records a baseline VAS score in excess of 30 mm they would probably have recorded at least moderate pain on a 4-point categorical scale.
Double-Blind Method↗
Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials.
Anaesthetists, using basic scientific concepts of peripheral opioid activity, try to improve regional anaesthesia and postoperative analgesia by injecting opioids, with or without local anaesthetic, close to nerve trunks or nerve endings. To test the evidence that peripherally applied opioids (all except intra-articular) have an analgesic effect outside the knee joint. Systematic search for published reports of randomised controlled trials in the period 1966-1996 (MEDLINE, EMBASE, Oxford Data Base, reference lists) which compared efficacy of peripheral opioids with placebo, local anaesthetic, or systemic opioids in acute pain. Reports of pethidine or intra-articular opioids were not included. Data on intraoperative efficacy (onset, quality, duration of sensory block), and postoperative efficacy (pain intensity, analgesic consumption) were extracted. Statistical significance as indicated in the original reports and clinical relevance of differences between opioids and controls were taken into account to estimate qualitatively overall efficacy. Twenty-six trials with data from 952 patients were analysed. Opioids used were morphine (16 trials), fentanyl (8), alfentanil (1), buprenorphine (1), and butorphanol (1). Of four experimental pain trials, two reported a statistically significant difference in favour of the opioid. In 22 clinical trials efficacy of opioid injections into the brachial plexus (10), Bier's block (4), perineural (3), or other sites (5) was tested. Five of 10 clinical trials measuring intraoperative efficacy reported statistically significant efficacy with opioids compared with control; none of them were judged to be clinically relevant. Five of 17 clinical trials measuring postoperative efficacy reported a significant difference in favour of the opioid; none was judged to be clinical relevant. Trials of lower quality were more likely to report increased efficacy with opioids. Adverse events related to the route of administration were not reported. These trials provide no evidence for a clinically relevant peripheral analgesic efficacy of opioids in acute pain.
Analgesics, Opioid↗
Pain relief from intra-articular morphine after knee surgery: a qualitative systematic review.
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.
Analgesics, Opioid↗
Radiotherapy for painful bone metastases: a systematic review.
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Bone Neoplasms↗
Propofol and bradycardia: causation, frequency and severity.
As part of the development of a model for the study of adverse events, we have investigated the risk of bradycardia with propofol. A systematic search for any type of report, published and unpublished, was made to review the evidence that propofol increases the risk of bradycardia, asystole and death from bradycardic events. Quantitative and qualitative analyses of data with different strengths of evidence were performed. Sixty-five published and 187 spontaneous reports to drug monitoring centres described with different strength of evidence a biological basis for propofol-induced bradycardia, 1444 bradycardias, 86 asystoles and 24 deaths. In controlled clinical trials, propofol significantly increased the risk of bradycardia compared with other anaesthetics (number-needed-to-harm 11.3 (95% confidence interval 7.7-21)). In paediatric strabismus surgery the number-needed-to-harm was 4.1 (3-6.7). One of 660 patients undergoing propofol anaesthesia had an asystole. The risk of bradycardia-related death during propofol anaesthesia was estimated to be 1.4 in 100,000. Data from the phase IV study of propofol did not agree with data from controlled studies. Propofol carries a finite risk for brady-cardia with potential for major harm. Study of adverse events should be made with systematically searched data and, in contrast with study of efficacy, not restricted to randomized, controlled trials.
Adverse Drug Reaction Reporting Systems↗
Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials.
OBJECTIVE: The authors reviewed efficacy and safety data for ondansetron for preventing postoperative nausea and vomiting (PONV). METHODS: Systematically searched, randomized, controlled trials (obtained through MEDLINE, EMBASE, Biological Abstracts, manufacturer's database, manual searching of journals, and article reference lists) were analyzed. Relevant end points were prevention of early PONV (within 6 h after surgery) and late PONV (within 48 h) and adverse effects. Relative benefit and number-needed-to-treat were calculated. The number-needed-to-treat indicated how many patients had to be exposed to ondansetron to prevent PONV in one of them who would have vomited or been nauseated had he or she received placebo. RESULTS: Fifty-three trials were found that had data from 7,177 patients receiving 24 different ondansetron regimens and from 5,712 controls receiving placebo or no treatment. Average early and late PONV incidences without ondansetron were 40% and 60%, respectively. There was a dose response for oral and intravenous ondansetron. Best number-needed-to-treat to prevent PONV with the best documented regimens was between 5 and 6. This was achieved with an intravenous dose of 8 mg and an oral dose of 16 mg. Antivomiting efficacy was consistently better than antinausea efficacy. Efficacy in children was poorly documented. Ondansetron significantly increased the risk for elevated liver enzymes (number-needed-to-harm was 31) and headache (number-needed-to-harm was 36). CONCLUSIONS: If the risk of PONV is very high, for every 100 patients receiving an adequate dose of ondansetron 20 patients will not vomit who would have vomited had they received placebo. The antinausea effect is less pronounced. Of these 100, three will have elevated liver enzymes and three will have a headache who would not have had these adverse effects without the drug.
Antiemetics↗
Opioid use in chronic pain.
Many of the important questions for those who prescribe opioids in chronic pain, and important for those who take the drugs, still have to be answered with inadequate evidence, because we lack randomised trials on these topics. Two of the principal reasons for "failure' of opioids to relieve pain, incident pain and neuropathic pain, are discussed. Some specific adverse effect problems are addressed, and the paper concludes with a section on the vexed issue of opioid prescription in non-cancer pain.
Analgesics, Opioid↗
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
It has been suggested that the quality of clinical trials should be assessed by blinded raters to limit the risk of introducing bias into meta-analyses and systematic reviews, and into the peer-review process. There is very little evidence in the literature to substantiate this. This study describes the development of an instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research and its use to determine the effect of rater blinding on the assessments of quality. A multidisciplinary panel of six judges produced an initial version of the instrument. Fourteen raters from three different backgrounds assessed the quality of 36 research reports in pain research, selected from three different samples. Seven were allocated randomly to perform the assessments under blind conditions. The final version of the instrument included three items. These items were scored consistently by all the raters regardless of background and could discriminate between reports from the different samples. Blind assessments produced significantly lower and more consistent scores than open assessments. The implications of this finding for systematic reviews, meta-analytic research and the peer-review process are discussed.
Double-Blind Method↗
Ibuprofen compared with ibuprofen plus caffeine after third molar surgery.
OBJECTIVES: To compare the relative merits of single doses of ibuprofen and ibuprofen plus caffeine in the treatment of pain after third molar removal. DESIGN: Randomised, double-blind, placebo-controlled, single-dose parallel-group comparison of placebo, ibuprofen 200 and 400 mg with ibuprofen 200 mg plus 50, 100 or 200 mg of caffeine. SUBJECTS: 161 patients undergoing lower third molar removal. RESULTS: All active treatments produced significant analgesia and mood elevation compared with placebo. There was no significant difference in the effects of 200 and 400 mg of ibuprofen. Adding caffeine to 200 mg ibuprofen produced significantly more analgesic effect at 45 and 60 min than ibuprofen 200 mg alone. Ten patients reported 11 adverse effects, none in the highest caffeine dose group. CONCLUSIONS: Caffeine increased the analgesic effect of ibuprofen 200 mg, through an earlier onset of analgesic effect. This was achieved in this single dose context without problematic adverse effects.
Adult↗
Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain.
The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the "optimal control" group (751.2 +/- 194 nmol/L), however, were more than twice those found in the "moderate control" group (276.9 +/- 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.
Adult↗
Meta-analyses to evaluate analgesic interventions: a systematic qualitative review of their methodology.
A systematic search of the literature was performed to identify the maximum possible number of meta-analyses that evaluated analgesic interventions. Seventy-four reports were identified and retrieved and the scientific quality of 80 separate meta-analyses was assessed under blind conditions by 2 judges using Oxman and Guyatt's index. Most of the meta-analyses evaluated pharmacological interventions for chronic pain conditions and two-thirds were published since 1990. Ninety percent of the meta-analyses had methodological flaws that could limit their validity. The main deficiencies were lack of information on methods to retrieve and to assess the validity of primary studies and lack of data on the design of the primary studies. Meta-analyses of low quality produced significantly more positive conclusions. For several topics, different meta-analyses evaluating the same intervention produced conflicting results. The need to resolve these contradictions is highlighted.
Bias↗
A systematic review of antidepressants in neuropathic pain.
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.
Antidepressive Agents↗
Epidural steroids for sciatica.
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Adrenal Cortex Hormones↗