Reporting of Adverse Effects in Clinical Trials Should Be Improved: Lessons from Acute Postoperative Pain

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1 Vol. 18 No. 6 December 1999 Journal of Pain and Symptom Management 427 Original Article Reporting of Adverse Effects in Clinical Trials Should Be Improved: Lessons from Acute Postoperative Pain Jayne E. Edwards, BSc, Henry J. McQuay, DM, R. Andrew Moore, DSc, and Sally L. Collins, BSc Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, Oxford, UK Abstract We assessed the quality of assessment and reporting of adverse effects in randomized, doubleblind clinical trials of single-dose acetaminophen or ibuprofen compared with placebo in moderate to severe postoperative pain. Reports were identified by systematic searching of a number of bibliographic databases (e.g., MEDLINE). Information on adverse effect assessment, severity and reporting, patient withdrawals, and anesthetic used was extracted. Compliance with former guidelines for adverse effect reporting was noted. Fifty-two studies were included; two made no mention of adverse effects. No method of assessment was given in 19 studies. Twenty trials failed to report the type of anesthetic used, eight made no mention of patient withdrawals, and nine did not state the severity of reported adverse effects. Only two studies described the method of assessment of adverse effect severity. When all adverse effect data were pooled, significantly more adverse effects were reported with active treatment than with placebo. For individual adverse effects, there was no difference between active (acetaminophen 1000 mg or ibuprofen 400 mg) and placebo; the exception was significantly more somnolence/drowsiness with ibuprofen 400 mg. Ninety percent of trials reporting somnolence/drowsiness with ibuprofen 400 mg were in dental pain. All studies published after 1994 complied with former guidelines for adverse effect reporting. Different methods of assessing adverse effects produce different reported incidence: patient diaries yielded significantly more adverse effects than other forms of assessment. We recommend guidelines for reporting adverse effect information in clinical trials. J Pain Symptom Manage 1999;18: U.S. Cancer Pain Relief Committee, Key Words Adverse effects, randomized trials, postoperative pain, acetaminophen, ibuprofen Address reprint requests to: Jayne E. Edwards, BSc, Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Oxford OX3 7LJ, UK. Accepted for publication: February 4, Introduction Clinical trials concentrate on efficacy 1 and adverse effects are reported almost as an afterthought, even though good information is likely to have been collected. Adverse effects are, however, the usual reason patients stop taking a drug or cannot tolerate an effective dose. They are a major factor in drug compliance. U.S. Cancer Pain Relief Committee, /99/$ see front matter Published by Elsevier, New York, New York PII S (99)

2 428 Edwards et al. Vol. 18 No. 6 December 1999 When assessing adverse effects, multiple-dose studies are desirable, as they are more representative of clinical practice and can yield dose response relationships for both efficacy and adverse effects. 2 There are few multiple-dose analgesic trials, however, and statistical power in the more common single-dose analgesic trials is calculated for efficacy, not adverse effects. Indeed, adverse effects of any severity are rare in these trials. Pooling of adverse effect data in a meta-analysis, rather than studying data from single trials, may provide the extra power required to more reliably interpret single-dose adverse effect data. Another problem encountered when assessing adverse effect data is that different methods of assessment are frequently used. There are some obvious distinctions between the various methods of assessing adverse effects, perhaps the most important being whether or not a checklist is used. A checklist could be presented verbally or on paper, and of course begs the question of how extensive it is. The alternative is more open questioning, such as Have you had any problem with the drugs?. The open question might result in lower reported adverse effect incidence than the checklist, and verbal report may lead to a lower incidence than a written checklist. 3,4 These complexities are often forgotten. In 1994, the Standards for Reporting in Trials (SORT) Group published recommendations for reporting information in clinical trials; these guidelines included adverse effects. 5 Their recommendation was that trialists should define what constituted adverse events and how they were monitored by intervention group. At a similar time, guidelines were also proposed by the Working Group on Recommendations for Reporting of Clinical Trials in the Biomedical Literature, 6 though no specific reference to adverse effects was made. More recently, these two groups collaborated to produce the CONSORT (Consolidated Standards for Reporting Trials) statement 7 : a template for use by authors when producing reports of trials. Unfortunately, the CONSORT statement does not refer to adverse effects directly, stating only that the author should state the estimated effect of the intervention on primary and secondary outcome measures, including a point estimate and measure of precision (confidence interval). This could refer to adverse effects, but does not do so specifically. Considering the implications adverse effects may have in clinical practice, and the limitations of both the former and more recent guidelines, we wanted to determine how authors currently present adverse effect information in reports of analgesic trials. As adverse effects are uncommon with single doses of analgesics, large data sets are required in order to conduct any analyses. We used systematically searched randomized comparisons of singledose acetaminophen or ibuprofen with placebo in moderate to severe postoperative pain, extracting the details of adverse effect assessment, severity, and reporting, including information on anesthetic used and patient withdrawals. We also noted compliance with the recommendations for adverse effect reporting put forward in the former SORT guidelines. We hoped meta-analysis would increase the yield of adverse effect information from these abundant single-dose studies, allowing reliable interpretation of the retrieved data. Methods Acetaminophen Randomized controlled trials of single oral doses of acetaminophen in postoperative pain (post dental extraction, postsurgical, or postpartum pain) were sought. A number of different search strategies were used to identify eligible reports in MEDLINE (1966 May 1996), EMBASE ( ), the Cochrane Library (March 1996), and the Oxford Pain Relief Database ( ). 8 The words paracetamol, acetaminophen, and trial were used in a free text search, including combinations of these words, and without restriction to language. Additional reports were identified from reference lists of retrieved reports, review articles (including a recent systematic review of acetaminophen plus codeine 9 ) and textbooks. Efficacy analysis, including trial quality assessment, has been published previously. 10 Ibuprofen Randomized controlled trials of single oral doses of ibuprofen in postoperative pain (post dental extraction, postsurgical, or postpartum pain) were sought. A number of different search strategies were used to identify eligible reports from MEDLINE (1966 Aug. 1996), EMBASE ( ), the Cochrane Library

3 Vol. 18 No. 6 December 1999 Reporting Adverse Effects in Clinical Trials 429 (Aug. 1996), Biological Abstracts (Jan Sept. 1996) and the Oxford Pain Relief Database ( ). 8 The words Ibuprofen, Brufen, propionic acid, isobutylphenyl propionic acid, clinical trial, trial, study, random*, analgesi*, and pain were used in a broad free text search, including combinations of these words, and without restriction to language. Additional reports were identified from the reference lists of retrieved reports, review articles, and textbooks. Efficacy analysis, including trial quality assessment, has been conducted previously. 11 Inclusion Criteria The inclusion criteria used were full journal publication, acute postoperative pain, standard methods of measuring pain intensity or relief, oral administration, adult patients, baseline pain of moderate to severe intensity, blinded design, and randomized allocation to treatment groups which included acetaminophen or ibuprofen and placebo. We excluded reports for the relief of other pain conditions, combination with other drugs, and trials where the number of patients per treatment group was fewer than 10. Neither pharmaceutical companies nor authors of papers were contacted for unpublished reports. Abstracts and review articles were not considered. Trial quality was assessed using a validated five-point scale; 12 studies were included if they achieved at least 2 points on this scale for randomization and double-blinding. Data extracted from the reports included whether or not adverse effects were reported, the number of patients treated, and the number of patients with adverse effects. The form of adverse effect assessment (direct questioning, use of patient diaries, or spontaneous reporting) was noted. For patient diaries we sought information on whether checklists of adverse effects had been used, and how questions were phrased. We also sought information on the type of anesthetic used (general, local, or combination of general and local), the methods of assessing adverse effect severity, the severity of reported adverse effects, and information on patient withdrawals. The type of pain model (dental or postoperative) was also noted. Compliance with the 1994 SORT 5 recommendations for adverse effect reporting was noted. For adverse effect reporting we categorized reporting methods as: 1. Adverse effects not mentioned in the report. 2. Statement that no adverse effects occurred. 3. Statement that there was no difference between active treatment and placebo. 4. Statement that adverse effects occurred but with no detail of frequency or type. 5. Full description of type and frequency of the individual adverse effects. Analysis Relative risk was calculated from these numbers with 95% confidence intervals using a fixed effects model. 13 Number-neededto-harm (NNH) was calculated as for numberneeded-to-treat with 95% CI. 14 A statistically significant difference from control was assumed when the 95% CI of the relative risk did not include 1. Results Thirty trials (18 in dental pain, 12 in postoperative pain) with 2424 patients examined different doses of acetaminophen and placebo. Of these, 10 (33%) used patient diaries, five (17%) used spontaneous reporting, and two (7%) used direct questioning (Table 1). Twenty-two trials (19 in dental pain, three in postoperative pain) with 2152 patients examined different doses of ibuprofen and placebo. Of these, six (27%) did not state the method of assessment, eight (36%) used patient diaries, two (9%) used spontaneous reporting, and four (18%) used direct questioning. References for the included reports are given in the Appendix. Only two studies from the 52 trials made no mention of adverse effects. 15,16 In the 50 studies that provided information on adverse effects, the total number of patients affected by adverse effects was significantly greater for acetaminophen compared with placebo, relative risk 1.3 (95% CI 1.02 to 1.6), and for ibuprofen, relative risk 1.4 (1.1 to 1.8) (Table 2). The numbersneeded-to-harm were high (adverse effects were uncommon), at 25 (13 to 139) for acetaminophen and 26 (15 to 97) for ibuprofen.

4 430 Edwards et al. Vol. 18 No. 6 December 1999 Table 1 Adverse Effect Assessment and Reporting Methods Acetaminophen (30 trials) Ibuprofen (22 trials) No. Percent No. Percent Method of assessment Spontaneous Patient diaries Direct questioning Not stated Adverse effects not reported Reporting of adverse effects Adverse effect information not reported No adverse effects occurred No difference as only mention No details on frequency and type Full details on frequency and type Total Adverse Effects Adverse effect data for all available doses of ibuprofen and acetaminophen compared with placebo were pooled. Full details of the frequency and type of adverse effects were reported in the majority of studies, 18/30 (60%) for acetaminophen and 16/22 (73%) for ibuprofen. A statement that adverse effects occurred but with no detail of frequency or type was less common, occurring in 5/30 (17%) studies for acetaminophen and 3/22 (14%) for ibuprofen. A definite statement that no adverse effects occurred was uncommon (17% for acetaminophen and 5% for ibuprofen) (Table 1). In less than 10% of studies was there no description of adverse effects or a statement which said only that there was no difference between active treatment and placebo. Method of Assessment The total number of adverse effects reported was influenced by the method of assessment. For both acetaminophen and ibuprofen significantly higher adverse effect incidence overall was reported with patient diaries than with other methods of assessment, and significantly higher incidence with active than with placebo (Table 2; Figure 1). No diary used a checklist, but questions were generally of the type, Have the tablets upset you in any way? or Have you experienced any side effects?. Where the assessment was by direct questioning, by spontaneous reporting, or where the method was not stated, there was no significant difference between the method of assessment, and no significant difference between active and placebo (Table 2). Method of assessment Table 2 Patients Reporting Any Adverse Effect-Influence of Method of Assessment Number of trials Harmed on acetaminophen Harmed on placebo Relative risk NNH Acetaminophen Total / / (1.02 to 1.6) 25 (13 to 139) Spontaneous 5 9/216 15/ (0.2 to 1.2) 27 (103 to 12) Patient diaries 10 89/387 43/ (1.2 to 2.4) 10 (7 to 25) Direct questioning 2 7/100 8/ (0.4 to 2.5) 183 (15 to 13) Not stated 13 47/578 36/ (0.8 to 1.8) 79 (23 to 54) Ibuprofen Total / / (1.1 to 1.8) 26 (15 to 97) Spontaneous 2 8/104 11/ (0.3 to 1.7) 33 (20 to 9) Patient diaries 8 62/417 31/ (1.05 to 2.4) 18 (10 to 126) Direct questioning 4 31/256 13/ (0.8 to 2.7) 25 (10 to 52) Not stated 6 30/304 22/ (0.7 to 2.0) 58 (16 to 34) NNH number-needed-to-harm.

5 Vol. 18 No. 6 December 1999 Reporting Adverse Effects in Clinical Trials 431 Individual Adverse Effects and Pain Model Details of the incidence of commonly reported adverse effects with acetaminophen 1000 mg and ibuprofen 400 mg (the most common doses) and placebo are given in Table 3. For individual adverse effects, there was no difference between active and placebo except for drowsiness/somnolence which had a higher incidence with ibuprofen 400 mg than with placebo. The relative risk was 3.1 (1.7 to 5.7) and the number-needed-to-harm was 19 (12 to 41). The higher incidence of drowsiness/somnolence with ibuprofen 400 mg was consistent across trials (Figure 2), being higher for ibuprofen than placebo in 9 of 10 trials. Nine of the 10 trials were in dental studies. Fig. 1. Percentage of patients with adverse effects: method of assessment. Severity of Adverse Effects Descriptions of and the amount of information on the severity of adverse effects varied between trials (Table 4). All reports on ibuprofen provided some information on the severity of adverse effects, whereas a third of reports on acetaminophen did not. Of those studies which did report adverse effect information, only two described how information on the severity of adverse effects was collected; both stated that patients had been questioned whether their adverse effects were mild, moderate, or severe in nature (Table 4). The majority of reports provided a statement about adverse effects such as none were severe or none were serious (27% for acetaminophen and 75% for ibuprofen), or all were transient in nature (13% for acetaminophen and 15% for ibuprofen). A full description of adverse effects by severity, type, frequency, and drug was uncommon (13% for acetaminophen and 5% for ibuprofen; Table 4). One study which assessed ibuprofen reported one patient to have experienced severe vomiting with ibuprofen 400 mg. 17 One acetaminophen study 18 reported one patient on placebo to have severe headache. Patient Withdrawals Details of patient withdrawals are shown in Table 4. Eight (8/52) reports provided no information on patient withdrawals, two stated that no patients withdrew from the study, and Adverse effect Table 3 Individual Adverse Effect Analysis (Acetaminophen 1000 mg, Ibuprofen 400 mg) Number of trials Harmed on acetaminophen Harmed on placebo Relative risk NNH Nausea 4 23/201 13/ (0.5 to 1.9) 49 (11 to 22) Vomiting 3 16/164 4/ (0.7 to 5.4) 18 (9 to 145) Dizziness 5 8/223 8/ (0.2 to 1.8) 70 (36 to 18) Drowsiness/somnolence 4 12/172 19/ (0.4 to 1.4) 78 (25 to 15) Headache 6 16/339 14/ (0.3 to 1.2) 54 (46 to 17) Adverse effect Number of trials Harmed on ibuprofen Harmed on placebo Relative risk NNH Nausea 5 13/367 8/ (0.5 to 3.2) 96 (28 to 66) Vomiting 2 1/79 1/ (0.1 to 5.2) 241 (25 to 20) Dizziness 6 3/250 5/ (0.2 to 2.5) 152 (62 to 35) Drowsiness/somnolence 11 35/446 12/ (1.7 to 5.7) 19 (12 to 41) Headache 9 12/353 11/ (0.5 to 2.5) 233 (33 to 46)

6 432 Edwards et al. Vol. 18 No. 6 December 1999 nine provided a statement that no patient withdrew because of adverse effects. The majority of studies (25/52) provided reasons for patient withdrawals of which none were related to adverse effects. Five studies reported patients to have been withdrawn due to vomiting of the study medication within 30 minutes of ingestion. Three studies reported patient withdrawals due to adverse effects. One ibuprofen trial reported a patient withdrawal due to headache with ibuprofen, 19 and two acetaminophen trials reported patient withdrawals due to nausea (two patients on acetaminophen and one on placebo) and severe headache (one patient on placebo). 20,21 Fig. 2. Ibuprofen 400 mg: somnolence/drowsiness. Anesthetic The type of anesthetic used, when reported, is shown in Table 4. Anesthetic was categorized as either local or general anesthetic though it may have been used in a variety of ways or combinations in the individual trials. The type of anesthetic used was not provided in 50% of acetaminophen and 23% of ibuprofen trial reports. Insufficient information was available to assess whether the type of anesthetic used had any influence on the reported incidence of adverse effects. Table 4 Reporting of Adverse Effect Severity, Patient Withdrawals, and Anesthetic Used Acetaminophen Ibuprofen Number of trials Number of trials reporting adverse effect information Number Percent Number Percent Method of assessment of adverse effect severity Method (scale/wording/questioning) described Reporting of the severity of reported adverse effects Adverse effect information not reported No adverse effects occurred No mention of adverse effect severity None were severe/none were serious All were transient in nature Full details of severity of adverse effects provided including frequency, type, and study drug Reporting of patient withdrawals No mention of patient withdrawals Statement that no patients withdrew from study Statement that no patients withdrew because of adverse effects Reasons for patient withdrawal provided none related to adverse effects Patient(s) withdrawn because vomited study medication within 30 minutes of ingestion Adverse effect related withdrawals occurred details provided (frequency, type, and drug) Reporting of the type of anesthetic used No mention of the type of anesthetic used Local anesthetic only General anesthetic only Local or general anesthetic Mixture of local and general anesthetic

7 Vol. 18 No. 6 December 1999 Reporting Adverse Effects in Clinical Trials 433 Quality of Adverse Effect Reporting No meaningful assessment of the quality of adverse effect reporting with time, other than compliance with the SORT guidelines 5 of 1994 could be established due to the variation in reporting techniques and the failure of current guidelines to specifically mention adverse effects. Nineteen (19/52; 36%) studies did not meet the criteria recommended by SORT for reporting adverse effects: 43% (13/30) of reports on acetaminophen and 27% (6/22) of reports on ibuprofen did not state either the method of adverse effect assessment or the frequency of adverse effects by treatment group. These 19 studies were all published before 1994 and all subsequent studies did meet the SORT recommendations for adverse effect reporting. Discussion The randomized double-blind controlled trial is the gold standard for assessing treatment efficacy because it is relatively free from bias. 22,23 We wanted to examine adverse effect assessment and reporting in high-quality studies, and the 52 studies included were searched for systematically meeting the criteria that they were randomized, double-blind, and examined placebo and acetaminophen or ibuprofen in single oral doses in moderate or severe postoperative pain. As such, they represent the published quality literature on the subject. Fifty of the 52 studies made an assessment and/or reported adverse effects. The method by which adverse effects were assessed was often not stated (in 19/52 reports (37%, Table 1). The commonest method was patient diaries or questionnaires, and the excess of adverse effect reports occurred in studies that used these methods (Table 2, Figure 1). Direct questioning or spontaneous reporting was used rarely. None of the diaries used a checklist, so the only obvious difference between a diary without a checklist and direct questioning is paper presentation versus verbal presentation. When checklists are used, adverse effects are more likely to be elicited, and this has been suggested as reducing the chance of relevant adverse effects being detected. 3 Certainly, the mention of particular adverse effects in consent forms leads to many more patients discontinuing treatment. 4 The suspicion must be that different methods elicit different incidences of adverse effects. The unanswered question, though, is whether the higher adverse effect incidence with patient diaries (Figure 1) is more accurate than the lower incidence seen with other assessment methods. We can think of no way of judging this. Even a clinical trial with adverse effects as the primary outcome and patients randomized to different methods of assessment cannot answer this question, but can only indicate the method of assessment that produces the highest incidence of adverse effects. For both acetaminophen and ibuprofen the overall result was that a greater proportion of patients reported adverse effects with active than with placebo. The number-needed-toharm for both was about 25. This means that for every 25 patients given either acetaminophen or ibuprofen for treatment of moderate or severe pain, one will report an adverse effect who would not have done so with placebo. When individual adverse effects were examined in studies using the common standard doses of acetaminophen 1000 mg or ibuprofen 400 mg, only drowsiness/somnolence occurred significantly more frequently with ibuprofen (Table 3, Figure 2). The number needed to harm was 19, which means that for every 19 patients treated with ibuprofen 400 mg, one would experience drowsiness or somnolence who would not have done so with placebo. Is drowsiness with a nonsteroidal anti-inflammatory drug (NSAID) plausible, because there is no biological explanation and the absolute number of events was small (Table 3)? The effect was not due to general anesthesia because nine of the 10 trials used local anesthetic. More frequent drowsiness or somnolence occurred in nine out of the 10 trials (Figure 2). Central nervous system effects of single-dose ibuprofen have been reported before. 24,25 Somnolence was more common with naproxen, another NSAID, compared with placebo 26 again primarily in dental studies, where the overall somnolence rates (7200 patients) were 2.1% for placebo and 4.1% with naproxen. Similar increased incidence of somnolence (and other central nervous system adverse effects) was described in 3500 patients for tramadol (a weak opioid) and combinations of aspirin or acetaminophen with weak opioids, again in dental but not postoperative pain models. 27

8 434 Edwards et al. Vol. 18 No. 6 December 1999 We cannot provide a final answer on the influence of the type of pain, dental versus other postoperative pain, on adverse effect incidence, despite a total of 52 studies and 4366 patients. Most of the studies were in dental pain, and any analysis of dental versus other postoperative pain was confounded by the different methods of adverse effect assessment. The suspicion must be that studies in dental pain are more sensitive to adverse effects, but we do not know whether the higher incidence reported is a better predictor of real adverse effect incidence in normal multiple dose prescribing. Reporting of information varied considerably between trials. Of the 50 trials that mentioned adverse effects, only two described the way in which information regarding the severity of adverse effects had been collected, although most studies did make some mention of the severity of reported events. Few reports provided full details of adverse effects by severity, type, frequency, and drug (13% acetaminophen and 5% ibuprofen; Table 4). Disappointingly, almost 40% of studies failed to report whether local or general anesthetic had been used and so, any association between the anesthetic and the incidence of reported adverse effects could not be elicited. The quality of reporting with time could not be assessed in any way, other than compliance with the SORT guidelines of 1994: 19 studies published before the guidelines did not meet these basic recommendations. These results all show that there is room for improvement when reporting adverse effect information in clinical trials. More information on adverse effects, particularly common effects, can be provided by clinical trials if authors make the data available. We propose an extension of the current CON- SORT guidelines 7 to specifically mention adverse effects, and ask that reports of trials should provide: details of the type of anesthetic used (if relevant); a description of the format of questions and/or checklists used in the assessment of adverse effects; details of how the severity of adverse effects was assessed; full details of the type and frequency of adverse effects reported for active drug and for placebo; details of the severity of the reported adverse effects; full details of adverse effect related patient withdrawals; and, where possible, the likely relationship between the adverse effect and the study drug. We propose that the above recommendations be used as a model for the reporting of adverse effects in future clinical trials. Acknowledgments This study was supported by grants from the Biotechnology and Biological Sciences Research Council, SmithKline Beecham Consumer Healthcare, European Union Biomed 2, NHS R&D Health Technology Evaluation Programmes, and Pain Research Funds. References 1. Beaver WT. Measurement of analgesic efficacy in man. In: Bonica JJ, Lindblom U, Iggo A, eds. Advances in pain research and therapy, Vol. 5. New York: Raven Press; 1983: McQuay HJ, Carroll D, Guest PG, Robson S, Wiffen PJ, Juniper RP. A multiple dose comparison of ibuprofen and dihydrocodeine after third molar surgery. Br J Oral Maxillofac Surg 1993;31: Huskisson EC, Wojtulewski JA. Measurement of side effects of drugs. BMJ 1974;2: Myers MG, Cairns JA, Singer J. The consent form as a possible cause of side effects. Clin Pharmacol Ther 1987;42: The Standards of Reporting Trials Group (SORT). A proposal for structured reporting of randomized controlled trials. JAMA 1994;272: Working Group on Recommendations for Reporting of Clinical Trials in the Biomedical Literature. Call for comments on a proposal to improve reporting of clinical trials in the biomedical literature. Ann Intern Med 1994;121: Begg C, Cho M, Eastwood ELS, Horton R, Moher D, Olkin I, Pitkin R, Rennie D, Schulz KF, Simel D, Stroup D. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996;276: Jadad AR, Carroll D, Moore A, McQuay H. Developing a database of published reports of randomised clinical trials in pain research. Pain 1996; 66: De Craen AJM, Di Giulio G, Lampe-Schoen-

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