Background: Population mean adjustments from clinical tests are difficult to apply

Background: Population mean adjustments from clinical tests are difficult to apply to individuals in clinical practice. 200 mg, naproxen 1000 mg or ibuprofen 2400 mg daily. Response rates fell with increasing pain relief: 60C80% experienced minimally important pain relief (?15%), 50C60% moderate pain relief (?30%), 40C50% substantial pain relief (?50%) and 20C30% extensive pain relief (?70%). NNTs for etoricoxib, celecoxib and naproxen were stable over 2C12 weeks. Ibuprofen showed lessening of performance with time. Summary: Responder rates and NNTs are reproducible for different levels of response over 12 weeks and have relevance for medical practice at the individual patient level. An average 10 mm improvement in pain buy 1000787-75-6 equates to almost one in two individuals having substantial benefit. Medical trials are performed usually for regulatory purposes, with outcomes typically reported as statistical comparisons between treatment group population means. The results of clinical trials can be difficult to translate into clinical practice. A report that an intervention shows an average 10 mm reduction more than placebo on a 100 mm visual analogue scale has little immediate impact. Moreover, few of us are average. Most drugs provide a good response in half or fewer of the patients treated,1 2 true in postoperative pain,3 neuropathic pain,4 5 6 migraine7 and tumour necrosis factor antagonists in rheumatoid arthritis.8 An 80/20 rule seems to apply in osteoarthritis, with 80% of buy 1000787-75-6 patients experiencing 20% pain relief but only 20% experiencing 80% relief; about half have their pain halved.9 Genetic influences help determine the clinical response to analgesic drugs for non-specific anti-inflammatory drugs (NSAIDs),10 opioids11 and more generally,12 as well as the clinical response to methotrexate.13 Pain is driven by complex pathways of neural mechanisms which are likely to be different between individuals.14 Imaging reveals loss of grey matter in chronic pain above that found with age alone.15 16 Average data from skewed distributions can produce misleading results.17 Dichotomous responder analyses have been reported previously for acute18 and chronic pain.5 6 19 The validity of a buy 1000787-75-6 dichotomous measure should be established before being widely used.20 An added factor contributing to differences in treatment response observed in clinical practice compared with a clinical trial is the handling of dropouts. Commonly, a last observation carried forward technique is used in clinical trials, where data from patients with buy 1000787-75-6 good pain control but intolerable adverse events will still be included in efficacy calculations using the population mean. In clinical practice, this same patient would be considered a treatment failure. We used individual patient data from seven randomised placebo-controlled trials in osteoarthritis to investigate the effects of different levels of pain relief assessed at various time points on estimates of efficacy. Methods Merck Research Laboratories provided Tagln pain response data from seven randomised placebo-controlled trials of etoricoxib in osteoarthritis lasting ?6 weeks (protocols 007, 018, 019, 071, 073, 076 and 077).21 22 23 24 25 26 PDF copies of the company clinical trial reports were also available. We calculated the number of patients in each treatment group in each trial achieving various Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) thresholds of pain relief over baseline of ?15% (minimal benefit), ?30% (moderate), ?50% (substantial)27 and ?70% which we defined as extensive improvement. These were assessed at 2, 4, 8 and 12 weeks. All trials lasted 12 weeks except protocol 007 which lasted 6 weeks. In each study patients were asked, During the last 48 hours, how much pain do you have (1) walking on a flat surface; (2) going up or down stairs; (3) at night while in bed; (4) sitting or lying; (5) standing upright?. On a 100 mm visual analogue scale, patients placed an x ranging from 0 (no pain) to 100 (extreme pain). The Western Ontario and McMasters Universities (WOMAC) 100 mm visual analogue pain subscale score was calculated as the average of the responses to the five questions. Criteria used in defining responders included: For patients who did not drop out, only actual measured values were used for calculations. Last observation carried forward was not used. For patients who withdrew for any reason, measurements made within 7 days of the last dose were used to calculate the response. Thereafter, patients were assigned 0% improvement. We calculated the number and percentage of responders for each level of response for each drug and time point and the number needed to treat (NNT) compared with placebo (with 95% CI).28 The relative risk with 95% CI was calculated using the fixed effects model29 and considered statistically significant when the 95% CI did not include 1. Statistically significant differences between NNTs were established using the z test,30 comparing different drug/dose combinations only in the trials in which they were used together..