Alejandro R. Jadad

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.

Assessing the quality of randomized controlled trials: An annotated bibliography of scales and checklists

Assessing the quality of randomized controlled trials (RCTs) is important and relatively new. Quality gives us an estimate of the likelihood that the results are a valid estimate of the truth. We present an annotated bibliography of scales and checklists developed to assess quality. Twenty-five scales and nine checklists have been developed to assess quality. The checklists are most useful in providing investigators with guidelines as to what information should be included in reporting RCTs. The scales give readers a quantitative index of the likelihood that the reported methodology and results are free of bias. There are several shortcomings with these scales. Future scale development is likely to be most beneficial if questions common to all trials are assessed, if the scale is easy to use, and if it is developed with sufficient rigor.

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.

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 Guyatts 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.

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.

Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design

&NA; The aim was to compare the analgesic effectiveness and adverse effect incidence of oral dextromethorphan (DM) with placebo in patients with neuropathic pain. The first 10‐day treatment period was a multiple‐dose double‐blind randomised controlled cross‐over comparison of 13.5 mg of DM 3 times a day (t.d.s.) with placebo t.d.s.: 5 treatment pairs, each pair 1 day DM and 1 day placebo. The second 10‐day treatment period used 27 mg of DM t.d.s. vs. placebo, with the same design. The study incorporated a 5 pair n‐of‐1 design for each of the 2 doses of DM. Patients took the study medication in addition to any pre‐existing analgesic regime. Patients who reported benefit could continue with DM after the study. Nineteen patients with chronic neuropathic pain were studied over two 10‐day treatment periods. Outcome measures were pain intensity, pain relief, adverse effects, mood, sleep and global rating of treatment. These were recorded by daily patient diaries and by clinic assessments before and after each treatment period. There were no significant differences between DM and placebo on any of the clinic assessment outcome measures. Two patients had significantly better analgesia on more than one outcome measure on within‐patient testing. One had better analgesia with DM. The other had better analgesia with placebo. Ten patients had no adverse effects on either dose of DM. Two patients withdrew during the first treatment period because of adverse effects (which included increased pain intensity), and 5 during the second period. Five patients continued with DM after the study for 1–3 months. No long‐term clinical benefit was apparent in those who continued with open DM. Dextromethorphan at either 40.5 or 81 mg daily did not relieve neuropathic pain.

Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: A systematic review and a randomized, double-blind crossover study

The first aim was a systematic review of intravenous regional sympathetic blocks (IRSBs) in patients with reflex sympathetic dystrophy (RSD). Randomized controlled trials (RCTs) of IRSBs in patients with RSD were identified by MEDLINE search (1966 to May 1993) and by hand search of 30 journals (1950 to May 1993). Authors of eligible trials were asked for information on additional trials and for unpublished data. Seven RCTs of IRSBs in RSD were found. Four used guanethidine; none showed significant analgesic effect in IRSBs to relieve pain due to RSD. Two reports, one using ketanserin and one bretylium, with 17 patients in total, showed some advantage of IRSBs over control. RCT results were not combined because of the variety of different drugs and outcome measures and because of methodological deficiencies in most of the reports. The second aim was a randomized, double-blind, crossover study to assess the effectiveness of IRSBs with guanethidine. Patients fulfilling diagnostic criteria for RSD and who had reported pain relief after an open IRSB with guanethidine received IRSBs with guanethidine high dose, guanethidine low dose, and normal saline. Pain intensity and relief, adverse effects, mood, duration of analgesia, and global scores were recorded. Sixteen patients with diagnosis of RSD were recruited, but only nine entered the double-blind phase. The trial was stopped prematurely because of the severity of the adverse effects. No significant difference was found between guanethidine and placebo on any of the outcome measures.(ABSTRACT TRUNCATED AT 250 WORDS)

Opioid sensitivity of chronic pain: a patient-controlled analgesia method

Twenty‐two patients with chronic pain of malignant or nonmalignant origin were given intravenous morphine by patient‐controlled analgesia. A prestudy judgment was made from the characteristics of the pain as to whether it was nociceptive or neuropathic. Analgesic efficacy was assessed by a nurse‐observer; adverse events were noted and plasma morphine and metabolitie concentrations measured. Three categories of opioid response were distinguished. Good responders obtained > 70 mm relief on the visual analogue scale, with minimal or manageable adverse events. Moderate responders obtained < 70 but > 30 mm relief with more problematic adverse events, and poor responders had < 30 mm relief with troublesome adverse events. This method for the study of opioid sensitivity allowed a wide dosage range to be studied. The simultaneous analgesic and adverse event measurements showed that the spectrum of observed response was wide, and response category could be judged for the majority by 4 h. In those with poor or moderate response, adverse event severity limited further dose increment. The relationship between pain characteristics and response showed that some pains judged to be neuropathic had a good response to opioid (5/13), and some pains judged to be nociceptive did not (5/14). The study suggests that the pattern of response is not as black and white as the prediction of good response from nociceptive pain and poor from neuropathic pain would suggest, although nociceptive pain was more likely than neuropathic pain to show a good response. For the moderate responders opioid titration may, in the absence of other effective treatments, be useful, but the analgesic endpoint may not be totally satisfactory. The method provides an operational definition of opioid sensitivity.