Validating speed of onset as a key component of good analgesic response in acute pain.

BACKGROUND: Previous analysis of a single data set in acute pain following third molar extraction demonstrated a strong relationship between the speed of reduction of pain intensity and overall pain relief, as well as need for additional analgesia. METHODS: Individual patient data analysis of a single randomized, double-blind trial of placebo, paracetamol 1000 mg, ibuprofen sodium 400 mg and ibuprofen-poloxamer 400 mg following third molar extraction. Visual analogue scale pain intensity (VASPI) and other measurements were made at baseline, every 5-45 min, and at 60, 90, 120, 180, 240, 300 and 360 min. RESULTS: Most patients produced consistent VASPI results over time. For placebo and paracetamol, few patients achieved low VASPI scores and maintained them. For both ibuprofen formulations, VASPI scores fell rapidly during the first hour and were then typically maintained until later re-medication. Analysis of all patients showed that rapid VASPI reduction in the first hour was strongly correlated with good overall pain relief (high total pain relief over 0-6 h), and with lesser need for additional analgesia within 6 h. Results for this analysis were in very good agreement with a previous analysis, validating the relationship between fast initial pain intensity reduction and overall good pain relief in this setting. CONCLUSIONS: In acute pain following third molar extraction, faster acting analgesic formulations provide earlier onset of pain relief, better overall pain relief and a less frequent need for additional analgesia, indicating longer lasting pain relief.

Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions.

BACKGROUND: Ibuprofen and paracetamol have long been used as analgesics in a range of acute, intermittent and chronic pain conditions. Paracetamol is often the first line analgesic recommended, without consensus about which is the better analgesic. METHODS: An overview review of systematic reviews and meta-analyses directly compares ibuprofen and paracetamol at standard doses in particular painful conditions, or uses indirect comparisons against placebo. Electronic searches for systematic reviews were sought published since 1995 using outcomes approximating to ≥50% pain intensity reduction. Painful conditions were acute post-operative pain, dysmenorrhoea, tension-type headache (TTH), migraine, osteoarthritis and rheumatoid arthritis, back pain, cancer and paediatric pain. There was no systematic assessment of harm. RESULTS: Sixteen systematic reviews and four individual patient data meta-analyses were included. Ibuprofen was consistently superior to paracetamol at conventional doses in a range of painful conditions. Two direct comparisons favoured ibuprofen (acute pain, osteoarthritis). Three of four indirect comparisons favoured ibuprofen (acute pain, migraine, osteoarthritis); one showed no difference (TTH), although there were methodological problems. In five pain conditions (dysmenorrhoea, paediatric pain, cancer pain, back pain and rheumatoid arthritis), there were limited data on paracetamol and ibuprofen. CONCLUSIONS: At standard doses in different painful conditions, ibuprofen was usually superior producing more patients with the degree of pain relief that patients feel worthwhile. Neither of the drugs will be effective for everyone, and both are needed. This overview questions the practice of routinely using paracetamol as a first line analgesic because there is no good evidence for efficacy of paracetamol in many pain conditions.

Challenges in design and interpretation of chronic pain trials.

The process of systematic review has shone a light on the methodology of randomized controlled trials. Notably, a range of potential biases hinders the interpretation of chronic pain trials. These include a consistent bias favouring active over placebo in trials that are small and of short duration. The use of the 'last observation carried forward' imputation method is known to inflate results, often generating statistically significance when adverse event withdrawals are high; in clinical practice terms, this is the wrong answer. Patients want outcomes of low pain scores, large reductions in pain and relief from associated symptoms, with improvements in ability to function and in quality of life. Some patients achieve this, but many do not. The distribution of benefit is skewed and the use of average pain scores, or change in pain, can be misleading compared with responder analysis in which withdrawal is regarded as non-response. Historically, chronic pain trials have had a simple classic or a crossover design. They have been small and short, and used inappropriate imputation and outcomes unconnected to the experiences of most patients. While these designs are useful for answering some questions, they may be insensitive for many interventions. Newer designs, like enriched enrolment randomized withdrawal (EERW) trials or clinical effectiveness trials, are potentially more interesting and informative.

A conservative method of testing whether combination analgesics produce additive or synergistic effects using evidence from acute pain and migraine.

Fixed-dose combination analgesics are used widely, and available both on prescription and over-the-counter. Combination drugs should provide more analgesia than with any single drug in the combination, but there is no evidence in humans about whether oral combinations have just additive effects, or are synergistic or even subadditive. We suggest that the measured result for the combination would be the summation of the absolute benefit increase (effect of active drug minus effect of placebo) of each component of a combination if effects were (merely) additive, and greater than the sum of the absolute benefits if they were synergistic. We tested measured effects of combination analgesics against the sum of the absolute benefits in acute pain and migraine using meta-analysis where individual components and combinations were tested against placebo in the same trials, and verified the result with meta-analyses where individual components and combinations were tested against placebo in different trials. Results showed that expected numbers needed to treat (NNT) for additive effects were generally within the 95% confidence interval of measured NNTs. This was true for combinations of paracetamol plus ibuprofen and paracetamol plus opioids in acute pain, and naproxen plus sumatriptan in migraine, but not where efficacy was very low or very high, nor combinations of paracetamol plus dextropropoxyphene. There was no evidence of synergy, defined as supra-additive effects.

Relative efficacy of oral analgesics after third molar extraction--a 2011 update.

This article provides a summary of the efficacy, and relative efficacy, of 38 different drugs or drug combinations tested in standard postoperative pain trials. It will help clinicians and patients make informed choices about analgesia based on pain relief, duration of action, and adverse events, which can then be put into context for the individual patient, depending on local availability. This article highlights the fact that no single drug is effective in all patients--even the best drugs fail to provide good levels of pain relief in at least 30%. These patients should try a different analgesic.

Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice.

BACKGROUND: Population mean changes from clinical trials are difficult to apply to individuals in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration. METHODS: The numbers of patients with pain relief over baseline (> or =15%, > or =30%, > or =50%, > or =70%) at 2, 4, 8 and 12 weeks of treatment were obtained using the WOMAC 100 mm visual analogue pain subscale score for each treatment group in seven randomised placebo-controlled trials of etoricoxib in osteoarthritis lasting > or =6 weeks. Dropouts were assigned 0% improvement from baseline from then on. The numbers needed to treat (NNTs) were calculated at each level of response and time point. RESULTS: 3554 patients were treated with placebo, etoricoxib 30 mg and 60 mg, celecoxib 200 mg, naproxen 1000 mg or ibuprofen 2400 mg daily. Response rates fell with increasing pain relief: 60-80% experienced minimally important pain relief (> or =15%), 50-60% moderate pain relief (> or =30%), 40-50% substantial pain relief (> or =50%) and 20-30% extensive pain relief (> or =70%). NNTs for etoricoxib, celecoxib and naproxen were stable over 2-12 weeks. Ibuprofen showed lessening of effectiveness with time. CONCLUSION: Responder rates and NNTs are reproducible for different levels of response over 12 weeks and have relevance for clinical practice at the individual patient level. An average 10 mm improvement in pain equates to almost one in two patients having substantial benefit.

Evaluation and registration of adverse events in clinical drug trials in migraine.

Tolerability of a drug should be regarded as important as its efficacy. In all four phases of drug development evaluation of adverse events is important. Recommendations for assessment of adverse events in acute and prophylactic clinical drug trials in migraine are given. Tolerability may be indirectly assessed using measures of general well-being and eight such tools are presented. Finally, recommendations for reporting of adverse events are given.

Acute pain: combination treatments and how we measure their efficacy.

Perioperative analgesic strategies are frequently tested using analgesic consumption as an outcome measure. This outcome measure is intuitive and superficially attractive, but has not been evaluated rigorously. Flaws in its use may be one explanation of continuing controversies surrounding the efficacy of analgesic strategies tested by this method. We contend that the analgesic consumption outcome measure is valid only when treatment groups achieve similar pain scores. A meta-analysis of perioperative gabapentin was used to test this hypothesis. Eighteen trials were identified, which were of sufficient methodological quality to include in the analysis. Trials reporting similar pain scores in treatment groups were classified as Category A and dissimilar scores as Category B. There were seven Category A trials: four reported reduced analgesic consumption with gabapentin compared with placebo, at one or more time points, and three found no difference. There were 11 Category B trials, all of which reported a decrease in analgesic consumption with gabapentin compared with placebo, at one or more time points. Analgesic consumption after gabapentin was similar for different postoperative analgesics. Sedation, dizziness, and vomiting were significant problems in pooled analysis. Analysis according to similarity of pain scores did not clarify whether perioperative gabapentin is useful in perioperative care. More rigorous examination of analgesic consumption as an outcome measure is needed, to establish whether achieving similar pain scores is as important as this paper claims and to determine those features of the analgesic delivery system, adverse effects, and other factors which may interfere with analgesic consumption as an outcome measure.

Single dose oral lumiracoxib for postoperative pain.

BACKGROUND: Lumiracoxib is a novel selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors have been developed to avoid COX-1 related gastrointestinal (GI) problems. Lumiracoxib has analgesic and anti-inflammatory activity comparable with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) in the management of post-operative pain, but with the advantage of better GI tolerability. OBJECTIVES: To review the analgesic efficacy, duration of analgesia, and adverse effects of a single oral dose of lumiracoxib for moderate to severe postoperative pain in adults and compare it with established analgesics. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to March 2007), EMBASE (1974 to 2006), and PubMed (February 2007). SELECTION CRITERIA: Single oral dose, randomised placebo controlled trials of lumiracoxib, in acute postoperative pain, in adult patients. DATA COLLECTION AND ANALYSIS: Trials were quality scored and data extracted by two review authors independently. Summed pain relief (TOTPAR) was extracted and converted into dichotomous information yielding the number of patients with at least 50% pain relief. These derived results were used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. MAIN RESULTS: Three studies (737 patients) met the inclusion criteria. In total 211 patients were treated with lumiracoxib 400 mg, 51 with lumiracoxib 100 mg, and 161 with placebo. Active comparators were naproxen 500 mg (60 patients), rofecoxib 50 mg (102), celecoxib 200 mg (101), and ibuprofen 400 mg (51). One hundred patients (48%) given lumiracoxib 400 mg had at least 50% pain relief over six hours, compared with 17 (11%) given placebo; RB 4.8 (95% CI 2.9 to 7.9), NNT 2.7 (2.2 to 3.5). Weighted median time to use of rescue medication was 7.4 hours for lumiracoxib 400 mg and 1.8 hours for placebo. Patient global assessment at study endpoint was rated as "excellent" by 71 patients (34%) given lumiracoxib 400 mg and 5 (3%) given placebo. Median time to onset of analgesia was shorter for lumiracoxib 400 mg (0.6 to 1.5 hours) than placebo (>12 hours), and use of rescue medication within 12 hours occurred in 64 patients (58%) given lumiracoxib 400 mg and 100 (91%) given placebo. Adverse events reported were generally mild to moderate in severity, with one serious adverse event reported in a patient given placebo. AUTHORS' CONCLUSIONS: Lumiracoxib 400 mg given as a single oral dose, is an effective analgesic for acute postoperative pain.

Systematic review of systematic reviews of acupuncture published 1996-2005.

Systematic reviews of acupuncture have tended to support its use, but few applied rigorous inclusion criteria. We tested the credibility of conclusions of systematic reviews of acupuncture published since 1996 by applying rigorous inclusion criteria. Reinterpretation used randomised and double blind trials with valid outcomes or design, and with information available from at least four trials or from 200 patients. Qualified support for acupuncture was originally reported in 12 out of 35 systematic reviews, and strong support was found in another six. Applying stricter inclusion criteria, however, showed that none of the 35 reviews supported acupuncture, predominantly because there were too few patients in the randomised, double blind studies. Six reviews with more than 200 patients in randomised, double blind studies had good evidence of no benefit. Systematic reviews of acupuncture have overstated effectiveness by including studies likely to be biased. They provide no robust evidence that acupuncture works for any indication.

Effect of preoperative Cox-II-selective NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized studies.

BACKGROUND: Preoperative use of coxibs has been claimed to reduce postoperative pain and analgesic consumption, and to affect other postoperative outcomes. METHODS: Systematic review of randomized trials comparing preoperative coxib with preoperative placebo, or active comparator. Searching of PubMed and Cochrane Library to August 2004. A qualitative and a quantitative analysis. RESULTS: Twenty-two included trials with 2246 patients had high reporting quality and validity scores, though treatment group sizes were small, with a median size of 30 patients. Most trials used oral preoperative rofecoxib (mainly 50 mg) or celecoxib (mainly 200 mg). Preoperative coxibs significantly reduced both postoperative pain and analgesic consumption compared with preoperative placebo in 15/20 trials. In one further trial postoperative pain was reduced and in one analgesic consumption. There was no significant difference in the incidence of postoperative nausea and vomiting in 13/17 studies or when data were pooled. Postoperative antiemetic use was significantly reduced in all five trials reporting it; the NNT to prevent one patient using postoperative antiemetic was 10 (5.5 to 66). No trial reported any significant difference in intraoperative blood loss or recovery from anaesthesia. Patient satisfaction was significantly increased with preoperative coxib use. No conclusions could be drawn from the three trials comparing preoperative coxib with preoperative NSAID. One study reported significantly improved cost-efficacy with rofecoxib. CONCLUSIONS: Preoperative coxibs had clear benefits in terms of reduced postoperative pain, analgesic consumption and patient satisfaction compared with placebo. Effects on postoperative nausea and vomiting remain uncertain, as do those on recovery from surgery or economic benefit. Future trials should be larger and more pragmatic in nature.

Incomplete evidence: the inadequacy of databases in tracing published adverse drug reactions in clinical trials.

BACKGROUND: We would expect information on adverse drug reactions in randomised clinical trials to be easily retrievable from specific searches of electronic databases. However, complete retrieval of such information may not be straightforward, for two reasons. First, not all clinical drug trials provide data on the frequency of adverse effects. Secondly, not all electronic records of trials include terms in the abstract or indexing fields that enable us to select those with adverse effects data. We have determined how often automated search methods, using indexing terms and/or textwords in the title or abstract, would fail to retrieve trials with adverse effects data. METHODS: We used a sample set of 107 trials known to report frequencies of adverse drug effects, and measured the proportion that (i) were not assigned the appropriate adverse effects indexing terms in the electronic databases, and (ii) did not contain identifiable adverse effects textwords in the title or abstract. RESULTS: Of the 81 trials with records on both MEDLINE and EMBASE, 25 were not indexed for adverse effects in either database. Twenty-six trials were indexed in one database but not the other. Only 66 of the 107 trials reporting adverse effects data mentioned this in the abstract or title of the paper. Simultaneous use of textword and indexing terms retrieved only 82/107 (77%) papers. CONCLUSIONS: Specific search strategies based on adverse effects textwords and indexing terms will fail to identify nearly a quarter of trials that report on the rate of drug adverse effects.

Reporting of adverse drug reactions in randomised controlled trials - a systematic survey.

BACKGROUND: Decisions on treatment are guided, not only by the potential for benefit, but also by the nature and severity of adverse drug reactions. However, some researchers have found numerous deficiencies in trial reports of adverse effects. We sought to confirm these findings by evaluating trials of drug therapy published in seven eminent medical journals in 1997. METHODS: Literature review to determine whether the definition, recording and reporting of adverse drug reactions in clinical trials were in accordance with published recommendations on structured reporting. RESULTS: Of the 185 trials reviewed, 25 (14%) made no mention of adverse drug reactions. Data in a further 60 (32%) could not be fully evaluated, either because numbers were not given for each treatment arm (31 trials), or because a generic statement was made without full details (29 trials). When adverse drug reactions such as clinical events or patient symptoms were mentioned in the reports, details on how they had been recorded were given in only 14/95 (15%) and 18/104 (17%) trials respectively. Of the 86 trials that mentioned severity of adverse drug reactions, only 42 (49%) stated how severity had been defined. The median amount of space used for safety data in the Results and Discussion sections was 5.8%. CONCLUSIONS: Trial reports often failed to provide details on how adverse drug reactions were defined or recorded. The absence of such methodological information makes comparative evaluation of adverse reaction rates potentially unreliable. Authors and journals should adopt recommendations on the structured reporting of adverse effects.

Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis.

OBJECTIVES: To assess the incidence of gastrointestinal haemorrhage associated with long term aspirin therapy and to determine the effect of dose reduction and formulation on the incidence of such haemorrhage. DESIGN: Meta-analysis of 24 randomised controlled trials (almost 66 000 participants). INTERVENTION: Aspirin compared with placebo or no treatment, for a minimum of one year. MAIN OUTCOME MEASURES: Incidence of gastrointestinal haemorrhage. RESULTS: Gastrointestinal haemorrhage occurred in 2.47% of patients taking aspirin compared with 1.42% taking placebo (odds ratio 1.68; 95% confidence interval 1.51 to 1.88); the number needed to harm was 106 (82 to 140) based on an average of 28 months' therapy. At doses below 163 mg/day, gastrointestinal haemorrhage occurred in 2.30% of patients taking aspirin compared with 1.45% taking placebo (1.59; 1.40 to 1.81). Meta-regression showed no relation between gastrointestinal haemorrhage and dose. For modified release formulations of aspirin the odds ratio was 1.93 (1.15 to 3.23). CONCLUSIONS: Long term therapy with aspirin is associated with a significant increase in the incidence of gastrointestinal haemorrhage. No evidence exists that reducing the dose or using modified release formulations would reduce the incidence of gastrointestinal haemorrhage.

Which exercise test variables are of prognostic importance post-myocardial infarction?

The prognostic value of parameters noted on pre-discharge exercise testing was assessed in 300 survivors of acute myocardial infarction. Exercise testing was performed at a mean of 9 days post-infarction. Each patient's data were studied for the presence of ST-segment depression or elevation greater than or equal to 0.1 mV in any of the 12 leads recorded, angina pectoris, exertional hypotension and duration of exercise. The patients were followed for a mean of 12 months and the incidence of death, reinfarction, angina pectoris, heart failure and coronary revascularization procedures was noted. All variables studied, other than the presence of exercise-induced ST-segment elevation, were significantly associated with the occurrence of subsequent cardiac events (P less than 0.001). Exercise-induced ST-segment depression identified 80% of patients who developed complications and was significantly more sensitive than any of the other variables as a prognostic marker (P less than 0.05). The finding of angina pectoris, an abnormal blood pressure response or a limited exercise tolerance in association with exercise-induced ST-segment depression heightened the prognostic implications of this variable.

Interaction of five globin gene abnormalities in a Cambodian family.

Members of a Cambodian family with an undiagnosed hypochromic, microcytic anaemia were found by haemoglobin and DNA analysis to have five interacting globin gene abnormalities. One child has Hb E and typical Hb H disease, while his mother has the form of Hb H disease associated with Hb Constant Spring interacting with Hb E. Quantitation of Hbs E and A2 by globin chain separation and triton/urea gel electrophoresis support the concept that Hb H/Constant Spring disease is a more severe form of alpha thalassaemia than Hb H disease. This family illustrates how the remarkably high prevalence of globin gene abnormalities in Southeast Asians can give rise to a series of atypical thalassaemic phenotypes, and how they can be defined by direct globin gene analysis.