Dawn Carroll

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.

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.

Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review.

Abstract Objective: To quantify the antiemetic efficacy and adverse effects of cannabis used for sickness induced by chemotherapy. Design: Systematic review. Data sources: Systematic search (Medline, Embase, Cochrane library, bibliographies), any language, to August 2000. Studies: 30 randomised comparisons of cannabis with placebo or antiemetics from which dichotomous data on efficacy and harm were available (1366 patients). Oral nabilone, oral dronabinol (tetrahydrocannabinol), and intramuscular levonantradol were tested. No cannabis was smoked. Follow up lasted 24 hours. Results: Cannabinoids were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride: relative risk 1.38 (95% confidence interval 1.18 to 1.62), number needed to treat 6 for complete control of nausea; 1.28 (1.08 to 1.51), NNT 8 for complete control of vomiting. Cannabinoids were not more effective in patients receiving very low or very high emetogenic chemotherapy. In crossover trials, patients preferred cannabinoids for future chemotherapy cycles: 2.39 (2.05 to 2.78), NNT 3. Some potentially beneficial side effects occurred more often with cannabinoids: “high” 10.6 (6.86 to 16.5), NNT 3; sedation or drowsiness 1.66 (1.46 to 1.89), NNT 5; euphoria 12.5 (3.00 to 52.1), NNT 7. Harmful side effects also occurred more often with cannabinoids: dizziness 2.97 (2.31 to 3.83), NNT 3; dysphoria or depression 8.06 (3.38 to 19.2), NNT 8; hallucinations 6.10 (2.41 to 15.4), NNT 17; paranoia 8.58 (6.38 to 11.5), NNT 20; and arterial hypotension 2.23 (1.75 to 2.83), NNT 7. Patients given cannabinoids were more likely to withdraw due to side effects 4.67 (3.07 to 7.09), NNT 11. Conclusions: In selected patients, the cannabinoids tested in these trials may be useful as mood enhancing adjuvants for controlling chemotherapy related sickness. Potentially serious adverse effects, even when taken short term orally or intramuscularly, are likely to limit their widespread use. What is already known on this topic Requests have been made for legalisation of cannabis (marijuana) for medical use Long term smoking of cannabis can have physical and neuropsychiatric adverse effects Cannabis may be useful in the control of chemotherapy related sickness What this study adds Oral nabilone and dronabinol and intramuscular levonantradol are superior to conventional antiemetics (such as prochlorperazine or metoclopramide) in chemotherapy Side effects are common with cannabinoids, and although some may be potentially beneficial (euphoria, “high,” sedation), others are harmful (dysphoria, depression, hallucinations) Many patients have a strong preference for cannabinoids

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

Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review.

Abstract Objective: To establish whether cannabis is an effective and safe treatment option in the management of pain. Design: Systematic review of randomised controlled trials. Data sources: Electronic databases Medline, Embase, Oxford Pain Database, and Cochrane Library; references from identified papers; hand searches. Study selection: Trials of cannabis given by any route of administration (experimental intervention) with any analgesic or placebo (control intervention) in patients with acute, chronic non-malignant, or cancer pain. Outcomes examined were pain intensity scores, pain relief scores, and adverse effects. Validity of trials was assessed independently with the Oxford score. Data extraction: Independent data extraction; discrepancies resolved by consensus. Data synthesis: 20 randomised controlled trials were identified, 11 of which were excluded. Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. No randomised controlled trials evaluated cannabis; all tested active substances were cannabinoids. Oral delta-9-tetrahydrocannabinol (THC) 5-20 mg, an oral synthetic nitrogen analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg were about as effective as codeine 50-120 mg, and oral benzopyranoperidine 2-4 mg was less effective than codeine 60-120 mg and no better than placebo. Adverse effects, most often psychotropic, were common. Conclusion: Cannabinoids are no more effective than codeine in controlling pain and have depressant effects on the central nervous system that limit their use. Their widespread introduction into clinical practice for pain management is therefore undesirable. In acute postoperative pain they should not be used. Before cannabinoids can be considered for treating spasticity and neuropathic pain, further valid randomised controlled studies are needed. What is already known on this topic Three quarters of British doctors surveyed in 1994 wanted cannabis available on prescription Humans have cannabinoid receptors in the central and peripheral nervous system In animal testing cannabinoids are analgesic and reduce signs of neuropathic pain Some evidence exists that cannabinoids may be analgesic in humans What this study adds No studies have been conducted on smoked cannabis Cannabinoids give about the same level of pain relief as codeine in acute postoperative pain They depress the central nervous system

Postoperative orthopaedic pain — the effect of opiate premedication and local anaesthetic blocks

&NA; The postoperative analgesic effect of opiate premedication and local anaesthetic blocks was studied in 929 patients having orthopaedic surgery. The median time to first request for postoperative analgesia was less than 2 h when neither opiate premedication nor block was used; opiate premedication increased the time significantly to more than 5 h; local anaesthetic block produced a further significant increase to 8 h and opiate premedication used with local anaesthetic block extended the median time further to more than 9 h. Women requested analgesia significantly earlier than men, independent of treatment. Age had no significant effect. Prolonging the time before more pain relief is required may be worthwhile for both patients and staff.

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.

Morphine responsiveness of chronic pain: double-blind randomised crossover study with patient-controlled analgesia.

There is controversy about whether the lack of response of some chronic pain to opioid treatment is absolute or relative. It is widely believed that nociceptive pain is responsive to opioids whereas neuropathic pain tends not to be. We have used a method of patient-controlled analgesia (PCA) with simultaneous nurse-observer measurement of analgesia, mood, and adverse effects to address these issues. Ten patients with chronic pain were given morphine at two concentrations (10 and 30 mg/ml) by PCA in two separate sessions in a double-blind randomised crossover study. Before the study a clinical judgment was made as to whether each pain was nociceptive or neuropathic. Seven patients showed good analgesic responses (more than 70 mm pain relief on a visual-analogue scale) of pain at rest, two patients poor responses (less than 30 mm pain relief), and one a moderate response with both concentrations (30-70 mm pain relief). The response to morphine was consistent (greater and faster relief with the higher concentration) in nine patients. Two patients had pain on movement that responded moderately to low-concentration morphine and well to the higher concentration. All patients with pains judged to be nociceptive showed good analgesic responses compared with half of those with neuropathic pain. There was no evidence that analgesic responses in patients with neuropathic pain were due to changes in mood. This PCA method is a quick and efficient tool to determine the consistency of the analgesic response. Such consistency can guide the clinician as to whether continued or higher-dose opioid treatment will produce good analgesia. An inconsistent response points to the use of other pain-relieving strategies.

Developing a database of published reports of randomised clinical trials in pain research

&NA; A database of randomised clinical trials (RCTs) in pain research published from 1950 to 1990 was created following an extensive literature search. By applying a refined MEDLINE search strategy from 1966 to 1990 and by hand‐searching more than 1 000 000 pages of a total of 40 biomedical journals published during the period 1950–1990, more than 8000 RCTs were identified. The RCTs were published in more than 800 journals and over 85% appeared between 1976 and 1990. If the trend of the last 15 years persists, a total of more than 15 000 RCTs will be published in pain relief by the year 2000. A detailed description of methods to ensure efficient use of resources during the identification, retrieval and management of the information in pain relief and other fields is given. Emphasis is made on the importance of refining MEDLINE search strategies, on the use of volunteers to hand‐search journals and on careful monitoring of each of the steps of the process. The potential uses of the database to guide clinical and research decisions are discussed.

Paracetamol with and without codeine in acute pain: a quantitative systematic review.

Abstract In order to assess the analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in postoperative pain, we conducted a systematic review of randomised controlled trials. We found 31 trials of paracetamol against placebo with 2515 patients, 19 trials of paracetamol plus codeine against placebo with 1204 patients and 13 trials of paracetamol plus codeine against the same dose of paracetamol with 874 patients. Pain relief information was extracted, and converted into dichotomous information (number of patients with at least 50% pain relief). Wide variations in responses to placebo (0–72%) and active drug (3–89%) were observed. In postoperative pain states paracetamol 1000 mg alone against placebo had an number‐needed‐to‐treat (NNT) of 3.6 (3.0–4.4) and paracetamol 600/650 mg alone an NNT of 5.0 (4.1–6.9). Paracetamol 600/650 mg plus codeine 60 mg against placebo had a better NNT of 3.1 (2.6–3.8), with no overlap of 95% confidence intervals with paracetamol 600/650 mg alone. In direct comparisons of paracetamol plus codeine with paracetamol alone the additional analgesic effect of 60 mg of codeine added to paracetamol was 12 extra patients in every 100 achieving at least 50% pain relief. In indirect comparisons of each with placebo it was 14 extra patients per 100. This was an NNT for adding codeine 60 mg of 9.1 (5.8–24). The results confirm that paracetamol is an effective analgesic, and that codeine 60 mg added to paracetamol produces worthwhile additional pain relief even in single oral doses.