Jayne E Edwards

Opioids in chronic non-cancer pain: systematic review of efficacy and safety

&NA; Opioids are used increasingly for chronic non‐cancer pain. Controversy exists about their effectiveness and safety with long‐term use. We analysed available randomised, placebo‐controlled trials of WHO step 3 opioids for efficacy and safety in chronic non‐cancer pain. The Oxford Pain Relief Database (1950–1994) and Medline, EMBASE and the Cochrane Library were searched until September 2003. Inclusion criteria were randomised comparisons of WHO step 3 opioids with placebo in chronic non‐cancer pain. Double‐blind studies reporting on pain intensity outcomes using validated pain scales were included. Fifteen randomised placebo‐controlled trials were included. Four investigations with 120 patients studied intravenous opioid testing. Eleven studies (1025 patients) compared oral opioids with placebo for four days to eight weeks. Six of the 15 included trials had an open label follow‐up of 6–24 months. The mean decrease in pain intensity in most studies was at least 30% with opioids and was comparable in neuropathic and musculoskeletal pain. About 80% of patients experienced at least one adverse event, with constipation (41%), nausea (32%) and somnolence (29%) being most common. Only 44% of 388 patients on open label treatments were still on opioids after therapy for between 7 and 24 months. The short‐term efficacy of opioids was good in both neuropathic and musculoskeletal pain conditions. However, only a minority of patients in these studies went on to long‐term management with opioids. The small number of selected patients and the short follow‐ups do not allow conclusions concerning problems such as tolerance and addiction.

Systematic review of topical capsaicin for the treatment of chronic pain

Abstract Objective To determine the efficacy and safety of topically applied capsaicin for chronic pain from neuropathic or musculoskeletal disorders. Data sources Cochrane Library, Medline, Embase, PubMed, an in-house database, and contact with manufacturers of topical capsaicin. Study selection Randomised controlled trials comparing topically applied capsaicin with placebo or another treatment in adults with chronic pain. Data extraction Primary outcome was dichotomous information for the number of patients with about a 50% reduction in pain. Outcomes were extracted at four weeks for musculoskeletal conditions and eight weeks for neuropathic conditions. Secondary outcomes were adverse events and withdrawals due to adverse events. Data synthesis Six double blind placebo controlled trials (656 patients) were pooled for analysis of neuropathic conditions. The relative benefit from topical capsaicin 0.075% compared with placebo was 1.4 (95% confidence interval 1.2 to 1.7) and the number needed to treat was 5.7 (4.0 to 10.0). Three double blind placebo controlled trials (368 patients) were pooled for analysis of musculoskeletal conditions. The relative benefit from topical capsaicin 0.025% or plaster compared with placebo was 1.5 (1.1 to 2.0) and the number needed to treat was 8.1 (4.6 to 34). Around one third of patients experienced local adverse events with capsaicin, which would not have been the case with placebo. Conclusions Although topically applied capsaicin has moderate to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain, it may be useful as an adjunct or sole therapy for a small number of patients who are unresponsive to, or intolerant of, other treatments.

Combination Analgesic Efficacy: Individual Patient Data Meta-Analysis of Single-Dose Oral Tramadol Plus Acetaminophen in Acute Postoperative Pain

The primary aims of this study were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen in acute postoperative pain and to use meta-analysis to demonstrate the efficacy of the combination drug compared with its components. Individual patient data from seven randomized, double blind, placebo controlled trials of tramadol plus acetaminophen were supplied for analysis by the R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA. All trials used identical methods and assessed single-dose oral tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) in adult patients with moderate or severe postoperative pain. Summed pain intensity and pain relief data over six and eight hours and global evaluations of treatment effect after eight hours were extracted. Number-needed-to-treat (NNT) for one patient to obtain at least 50% pain relief was calculated. NNTs derived from pain relief data were compared with those derived from pain intensity data and global evaluations. Information on adverse effects was collected. Combination analgesics (tramadol plus acetaminophen) had significantly lower (better) NNTs than the components alone, and comparable efficacy to ibuprofen 400 mg. This could be shown for dental but not postsurgical pain, because more patients were available for the former. Adverse effects were similar for the combination drugs and the opioid component alone. Common adverse effects were dizziness, drowsiness, nausea, vomiting, and headache. In sum, this meta-analysis demonstrated analgesic superiority of the combination drug over its components, without additional toxicity.

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

We assessed the quality of assessment and reporting of adverse effects in randomized, double-blind 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.

Seeking a simple measure of analgesia for mega-trials: is a single global assessment good enough?

&NA; We sought to investigate the potential of using a simple global estimation (‘How effective do you think the treatment was?’) as a measure of efficacy by comparing it with at least 50%maxTOTPAR (at least 50% of the maximum possible pain relief) in acute pain studies. One hundred and fifty randomized, double‐blind trials included in 11 systematic reviews of single dose, oral analgesics for postoperative pain were used as a source of data. The relationship between the proportion of patients reporting the top two or three values on a five‐point global scale and the proportion with at least 50%maxTOTPAR was investigated. Twenty‐six trials provided data on the proportion reporting the top two categories (very good or excellent) and 27 gave data on the top three categories (good, very good or excellent). The relationship between the percentage of patients recording the top two categories on a five‐point global scale and the proportion with at least 50%maxTOTPAR was fair (r2=0.67). That for the top three categories was less good (r2=0.57). Similar numbers‐needed‐to‐treat were calculated for aspirin 600/650 mg and ibuprofen 400 mg using at least 50%maxTOTPAR and the top two categories. No real difference was seen in the correlation for standard wording compared to non‐standard wording. Individual patient data were also used from four randomized, placebo‐controlled, double‐blind trials in postoperative pain. The frequency distribution for %maxTOTPAR was plotted for patients reporting each of the five categories on the global scale. A global assessment provides similar measures of analgesic efficacy as TOTPAR derived from hourly measurements, but the effects of adverse effects have yet to be understood.

Pain and analgesic response after third molar extraction and other postsurgical pain

&NA; There is uncertainty over whether the patient group in which acute pain studies are conducted (pain model) has any influence on the estimate of analgesic efficacy. Data from four recently updated systematic reviews of aspirin 600/650 mg, paracetamol 600/650 mg, paracetamol 1000 mg and ibuprofen 400 mg were used to investigate the influence of pain model. Area under the pain relief versus time curve equivalent to at least 50% maximum pain relief over 6 h was used as the outcome measure. Event rates with treatment and placebo, and relative benefit (RB) and number needed to treat (NNT) were used as outputs from the meta‐analyses. The event rate with placebo was systematically statistically lower for dental than postsurgical pain for all four treatments. Event rates with analgesics, RB and NNT were infrequently different between the pain models. Systematic difference in the estimate of analgesic efficacy between dental and postsurgical pain models remains unproven, and, on balance, no major difference is likely.

Statins in hypercholesterolaemia: A dose-specific meta-analysis of lipid changes in randomised, double blind trials

BackgroundStatins alter lipid concentrations. This systematic review determined the efficacy of particular statins, in terms of their ability to alter cholesterol.Review methodsPubMed, the Cochrane Library, references lists of reports, and reviews were searched (September 2001) for randomised, double blind trials of statins for cholesterol in trials of 12 weeks or longer. Mean change in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides was calculated using pooled data for particular statins, and for particular doses of a statin. Pre-planned sensitivity analyses were used to determine the effects of initial concentration of total cholesterol, study duration, the effects of major trials, and effects in placebo versus active controlled trials. Information was not collected on adverse events.ResultsDifferent statins at a range of doses reduced total cholesterol by 17–35% and LDL-cholesterol by 24–49% from baseline. Lower doses of statins generally produced less cholesterol lowering, though for most statins in trials of 12 weeks or longer there was at best only a weak relationship between dose and cholesterol reduction. Duration of treatment and baseline total cholesterol concentration did not alter the amount of the benefit attained.ConclusionsStatins are effective medicines and confer benefit to patients in terms of primary and secondary prevention of coronary heart disease. Reductions in total cholesterol of 25% or more and LDL cholesterol of more than 30% were recorded for fixed doses of simvastatin 40 mg, atorvastatin 10 mg, and rosuvastatin 5 mg and 10 mg.

Acute pain: individual patient meta-analysis shows the impact of different ways of analysing and presenting results.

&NA; Individual patient meta‐analysis using information from clinically homogeneous acute pain trials with observations over 24 h was used to investigate different ways trials can be analysed and reported. There were 13 third‐molar extraction trials, with 1,330 patients using rofecoxib 50 mg, 303 using ibuprofen 400 mg, and 570 using placebo. Pain relief scores were available at individual time points, plus time to remedication. Many more patients remedicated with placebo than ibuprofen 400 mg, and more with ibuprofen than rofecoxib 50 mg. Median time to remedication, the proportion remedicated at various times, or survival curves would be useful outcomes. In dealing with missing data points when patients remedicated, baseline observation carried forward was more conservative than last observation carried forward, resulting in higher (worse) NNTs and lower average pain scores after 12 and 24 h. Results based on both methods might be sensible for trials longer than eight hours. The distribution of pain relief was highly skewed, especially at later times, when almost no patient was average. Different cut points for pain relief (at least 25, 50 or 75% maxTOTPAR) and longer duration changed the NNT for ibuprofen compared with placebo, but less for rofecoxib, reflecting longer duration of action of rofecoxib. Reporting for each treatment group the percentage of patients with 25, 50 and 75% pain relief at various times after dose, and reporting the proportion of patients with good or complete pain relief, and inadequate pain relief, at each time point, would improve acute pain trial reporting.

Topical NSAIDs for acute pain: a meta-analysis

BackgroundA previous systematic review reported that topical NSAIDs were effective in relieving pain in acute conditions like sprains and strains, with differences between individual drugs for efficacy. More trials, a better understanding of trial quality and bias, and a reclassification of certain drugs necessitate a new review.MethodsStudies were identified by searching electronic databases and writing to manufacturers. We selected randomised double blind trials comparing topical NSAID with either placebo or another active treatment in adults with acute pain, and extracted dichotomous information approximating to a 50% reduction in pain at one week, together with details of adverse events and withdrawals. Relative benefit and number-needed-to-treat (NNT), and relative risk and number-needed-to-harm (NNH) were calculated, with sensitivity analyses where appropriate to investigate differences between individual drugs and aspects of trial design.ResultsTwenty-six double blind placebo controlled trials had information from 2,853 patients for evaluation of efficacy. Topical NSAID was significantly better than placebo in 19 of the 26 trials, with a pooled relative benefit of 1.6 (95% confidence interval 1.4 to 1.7), and NNT of 3.8 (95% confidence interval 3.4 to 4.4) compared with placebo for the outcome of half pain relief at seven days. Results were not affected by outcome reported, or condition treated, but smaller trials yielded a larger estimate of efficacy. Indirect comparisons of individual topical NSAIDs showed that ketoprofen was significantly better than all other topical NSAIDs, while indomethacin was barely distinguished from placebo. Three trials, with 433 patients, compared topical with oral NSAID (two trials compared the same drug, one compared different drugs) and found no difference in efficacy. Local adverse events, systemic adverse events, or withdrawals due to an adverse event were rare, and no different between topical NSAID and placebo.ConclusionsTopical NSAIDs were effective and safe in treating acute painful conditions for one week.

Relative efficacy of oral analgesics after third molar extraction

Objectives To compare the relative efficacy of analgesics after third molar extraction from systematic reviews of randomised, double blind studies.Data sources Dental trials from systematic reviews of randomised, double-blind studies of analgesics in acute pain.Data selection Number of patients with moderate or severe pain achieving at least half pain relief over 4 to 6 hours after a single oral dose of analgesic.Data extraction Independently by two reviewers.Data synthesis Use of dichotomous information from active and placebo treatments, first to calculate the statistical significance using relative risk, and then to evaluate the clinical relevance using number needed to treat (NNT). Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors had the lowest (best) NNTs for the outcome of at least half pain relief over 4-6 hours compared with placebo. With the best performing analgesics, 50-70 patients out of 100 had good pain relief compared with about 10 out of 100 with placebo. Only paracetamol 600/650 mg plus codeine 60 mg was associated with any significant increase in any patient experiencing an adverse event.Conclusions NSAIDs and COX-2 inhibitors have the lowest (best) NNTs. They may also have fewer adverse effects after third molar surgery, though conclusive evidence is lacking. At least 80% of analgesic prescribing by UK dentists is in line with the best available evidence on efficacy and safety.