R. Andrew Moore

Evidence in chronic pain--establishing best practice in the reporting of systematic reviews.

‘‘Evidence” in chronic pain – establishing best practice in the reporting of systematic reviews R. Andrew Moore *, Christopher Eccleston , Sheena Derry , Phillip Wiffen , Rae F. Bell , Sebastian Straube , Henry McQuay , for the ACTINPAIN writing group of the IASP Special Interest Group (SIG) on Systematic Reviews in Pain Relief and the Cochrane Pain, Palliative and Supportive Care Systematic Review Group editors

Vitamin D and chronic pain.

A number of studies have suggested a link between low levels of vitamin D and higher incidence of chronic pain [4,7,22]. There is a well-established link between low vitamin D and pain due to osteomalacia. There is no clear biological mechanism of how low vitamin D might be causally related to other types of chronic pain, though vitamin D is thought to be involved in regulating inflammatory cytokine synthesis [17], and might be implicated in some chronic pain conditions. Associations of pain with latitude and season of the year offer circumstantial evidence that vitamin D may be involved. These associations have been suggested for such diverse types of pain as headache, abdominal pain, knee pain and back pain; but the evidence is far from convincing [24,29,34]. This paper undertakes an assessment of the relationship between vitamin D and chronic pain. Before vitamin D supplementation can be advocated for chronic pain, evidence for health benefits and adverse effects needs to be assessed rigorously. Vitamin D and its roles in health and disease have been of interest in the scientific community [17] and the general media [20]. Many tissues express vitamin D receptors, and it is not surprising that a physiological role beyond the skeleton has been proposed. Vitamin D deficiency has been implicated in conditions like autoimmune and cardiovascular diseases, cancers, and chronic pain [17]. A recent meta-analysis even suggested reduced all-causemortality with vitamin D supplementation [5]. This contrasts with antioxidant vitamins A and E, where a review suggested a possible increase in mortality rates [8]. Some experts advocate limited and sensible sun exposure and vitamin D supplementation [17] in order to ensure adequate blood levels. Excessive dietary supplementation can lead to vitamin D intoxication [1], and excessive sun exposure increases the risk of skin cancers, already a substantial health problem. Although cases of vitamin D intoxication have been reported infrequently, they could become more common with widespread use of vitamin D supplements. If there is a link between vitamin D deficiency and chronic pain, a systematic review of the evidence would be expected to uncover two things: firstly, an inverse association between pain and 25-OH

Pregabalin in fibromyalgia--responder analysis from individual patient data.

BackgroundPopulation mean changes are difficult to use in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration. A consensus group has defined what constitutes minimal, moderate, and substantial benefit based on pain intensity and Patient Global Impression of Change scores.MethodsWe obtained individual patient data from four randomised double blind trials of pregabalin in fibromyalgia lasting eight to 14 weeks. We calculated response for all efficacy outcomes using any improvement (≥ 0%), minimal improvement (≥ 15%), moderate improvement (≥ 30%), substantial improvement (≥ 50%), and extensive improvement (≥ 70%), with numbers needed to treat (NNT) for pregabalin 300 mg, 450 mg, and 600 mg daily compared with placebo.ResultsInformation from 2,757 patients was available. Pain intensity and sleep interference showed reductions with increasing level of response, a significant difference between pregabalin and placebo, and a trend towards lower (better) NNTs at higher doses. Maximum response rates occurred at 4-6 weeks for higher levels of response, and were constant thereafter. NNTs (with 95% confidence intervals) for ≥ 50% improvement in pain intensity compared with placebo after 12 weeks were 22 (11 to 870) for pregabalin 300 mg, 16 (9.3 to 59) for pregabalin 450 mg, and 13 (8.1 to 31) for pregabalin 600 mg daily. NNTs for ≥ 50% improvement in sleep interference compared with placebo after 12 weeks were 13 (8.2 to 30) for pregabalin 300 mg, 8.4 (6.0 to 14) for pregabalin 450 mg, and 8.4 (6.1 to 14) for pregabalin 600 mg. Other outcomes had fewer respondents at higher response levels, but generally did not discriminate between pregabalin and placebo, or show any dose response. Shorter duration and use of any improvement over-estimated treatment effect compared with longer duration and higher levels of response.ConclusionsResponder analysis is useful in fibromyalgia, particularly for pain and sleep outcomes. Some fibromyalgia patients treated with pregabalin experience a moderate or substantial pain response that is consistent over time. Short trials using any improvement as an outcome overestimate treatment effects.

Enriched enrolment with randomised withdrawal (EERW): Time for a new look at clinical trial design in chronic pain.

Conventional clinical trials tell us about the average performance of a therapy. While chronic pain patients may have symptoms in common, and clearly have pain in common, the origin and the mechanism of the pain may vary widely. Different mechanisms not surprisingly can lead to different responses to therapy. Although individual patient effects have to be considered sensibly [13], we have scientific explanations for differences in individual response, including genetic polymorphisms for opioids [6], cyclooxygenase inhibitors [4], and more generally for analgesics [10]. Average performance is just what it says – the average of good performance in patients who respond and poor performance in nonresponders. Adverse effects deemed tolerable when there is at least some efficacy will be deemed intolerable when there is none. Drugs that are clearly analgesic in some patients may have very limited efficacy in others; even in the simplest example of acute postoperative pain individual patient meta-analysis showed some patients to have very limited response while others did very well, but few had the ‘‘average” response [11]. There are also examples of drugs with equivalent average efficacy in clinical trials benefiting completely different groups of patients in clinical practice. In depression, a randomised trial showed that three similarly effective antidepressants each benefited only a minority of patients, with switching or stop-

Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use.

BackgroundSome people who suffer an upper gastrointestinal bleed or perforation die. The mortality rate was estimated at 12% in studies published before 1997, but a systematic survey of more recent data is needed. Better treatment is likely to have reduced mortality. An estimate of mortality is helpful in explaining to patients the risks of therapy, especially with NSAIDs.MethodsA systematic review of studies published before 1997, and between 1997 and 2008. Any study architecture was acceptable if it reported on cases who died from any cause of upper gastrointestinal bleed or perforation. Analyses were conducted separately for all cases, and those prescribed NSAID or aspirin.ResultsInformation was available for 61,067 cases (81% published since 1997) of whom 5,001 died. The mortality rate in all cases fell significantly, from 11.6% (95% confidence interval, 11.0 to 12.2) in pre-1997 studies to 7.4% (7.2 to 7.6) in those published since 1997. In 5,526 patients taking NSAID or aspirin, mortality increased, from 14.7% (13.6 to 15.8) before 1997 to 20.9% (18.8 to 22.9) since 1997.ConclusionUpper gastrointestinal bleed or perforation still carries a finite risk of death. Differences in study architecture, population characteristics, risk factors, definition of mortality, and reporting of outcomes impose limitations on interpreting effect size. Data published since 1997 suggest that mortality in patients suffering from an upper gastrointestinal bleed or perforation has fallen to 1 in 13 overall, but remains higher at about 1 in 5 in those exposed to NSAID or aspirin.

Systematic review of dexketoprofen in acute and chronic pain

BackgroundDexketoprofen, an NSAID used in the management of acute and chronic pains, is licensed in several countries but has not previously been the subjected of a systematic review. We used published and unpublished information from randomised clinical trials (RCTs) of dexketoprofen in painful conditions to assess evidence on efficacy and harm.MethodsPubMed and Cochrane Central were searched for RCTs of dexketoprofen for pain of any aetiology. Reference lists of retrieved articles and reviews were also searched. Menarini Group produced copies of published and unpublished studies (clinical trial reports). Data were abstracted into a standard form. For studies reporting results of single dose administration, the number of patients with at least 50% pain relief was derived and used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief compared with placebo.ResultsThirty-five trials were found in acute pain and chronic pain; 6,380 patients were included, 3,381 receiving dexketoprofen. Information from 16 trials (almost half the total patients) was obtained from clinical trial reports from previously unpublished trials or abstracts. Almost all of the trials were of short duration in acute conditions or recent onset pain.All 12 randomised trials that compared dexketoprofen (any dose) with placebo found dexketoprofen to be statistically superior. Five trials in postoperative pain yielded NNTs for 12.5 mg dexketoprofen of 3.5 (2.7 to 4.9), 25 mg dexketoprofen of 3.0 (2.4 to 3.9), and 50 mg dexketoprofen of 2.1 (1.5 to 3.5). In 29/30 active comparator trials, dexketoprofen at the dose used was at least equivalent in efficacy to comparator drugs. Adverse event withdrawal rates were low in postoperative pain and somewhat higher in trials of longer duration; no serious adverse events were reported.ConclusionDexketoprofen was at least as effective as other NSAIDs and paracetamol/opioid combinations. While adverse event withdrawal was not different between dexketoprofen and comparator analgesics, the different conditions and comparators studies precluded any formal analysis. Exposure was limited, and no conclusions could be drawn about safety in terms of serious adverse events like gastrointestinal bleeding or cardiovascular events.

Topical Agents in the Treatment of Rheumatic Pain

In rheumatic pain there is good evidence that topical nonsteroidal anti-inflammatory drugs are about as effective as oral nonsteroidal anti-inflammatory drugs, but are probably safer and more tolerable because of much less systemic absorption and lower plasma concentrations. The best information is for topical diclofenac. For topical capsaicin, evidence of efficacy is trivial. For topical rubefacients there is no evidence of efficacy.

Improving the quality and reporting of systematic reviews.

Establishing the evidence for any treatment offered to patients suffering from chronic pain is a primary goal of clinical pain research. Understanding how confident to be about the claims made by individual researchers in individual trials has been greatly enhanced by developments in systematic review and meta-analysis. However, systematic reviews are themselves subject to bias and can sometimes be dangerously wrong (Derry et al., 2006; Gerber et al., 2007). In this issue of the European Journal of Pain Van de Wetering et al. (2010) report a systematic review that falls foul of some of the common pitfalls and problems in the undertaking and reporting of systematic reviews in pain (Moore et al., in press). The evidence synthesis they offer is, unfortunately, flawed. This paper raises the opportunity to consider issues of quality in systematic reviews that are submitted for publication in the European Journal of Pain. Here we discuss the common problems faced by authors in trying to manage the biases inherent in primary studies that can undermine the credibility and utility of any review. Further, we focus on the particular problems posed by reviews of non-pharmacological interventions, and last we address the specific problems of this particular study.

Studies on morphine disposition: Plasma concentrations of morphine and its metabolites in anesthetized middle-aged and elderly surgical patients

The effects of aging on the disposition of morphine and its metabolites have been investigated in 10 middle-aged patients (36 to 55 years of age) undergoing lower abdominal or body surface surgery, and compared with 10 elderly patients (65 to 83 years of age) undergoing similar surgery. All patients received 10 mg morphine sulphate pentahydrate IV over 30 seconds as part of a balanced anesthetic technique. Peripheral venous blood samples were collected to 180 min, and plasma concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were assayed by differential radioimmunoassay. There were no differences between the two groups for morphine elimination half-life (middle-aged patients, 129 min; elderly patients, 162 min), mean residence time (154 and 207 min), and apparent volume of distribution at steady state (116 and 107 l). However, clearance was significantly greater in the younger patients (853 vs. 559 ml/min; p less than 0.02). The area under the curve (AUC0-180) for M3G and M6G were similar in the two patient groups, as were the peak metabolite concentrations and times to peak concentrations. M6G has been shown in both animals and humans to exert analgesic properties. Despite the reduced clearance of the parent drug, there was an unaltered AUC for M6G, presumed due to the greater decrease in glomerular filtration rate seen during anesthesia in the elderly patient. This phenomenon may result in enhanced analgesic efficacy from a given dose of morphine in the elderly patient.

آسپرین برای درمان حاد سردرد اپیزودیک فشاری در بزرگسالان

BACKGROUNDnTension-type headache (TTH) affects about 1 person in 5 worldwide. It is divided into infrequent episodic TTH (fewer than one headache per month), frequent episodic TTH (two to 14 headache days per month), and chronic TTH (15 headache days per month or more). Aspirin is one of a number of analgesics suggested for acute treatment of episodic TTH.nnnOBJECTIVESnTo assess the efficacy and safety of aspirin for acute treatment of episodic tension-type headache (TTH) in adults compared with placebo or any active comparator.nnnSEARCH METHODSnWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Oxford Pain Relief Database from inception to September 2016, and also reference lists of relevant published studies and reviews. We sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers websites.nnnSELECTION CRITERIAnWe included randomised, double-blind, placebo-controlled studies (parallel-group or cross-over) using oral aspirin for symptomatic relief of an acute episode of TTH. Studies had to be prospective, with participants aged 18 years or over, and include at least 10 participants per treatment arm.nnnDATA COLLECTION AND ANALYSISnTwo review authors independently assessed studies for inclusion and extracted data. For various outcomes (predominantly those recommended by the International Headache Society (IHS)), we calculated the risk ratio (RR) and number needed to treat for one additional beneficial outcome (NNT), one additional harmful outcome (NNH), or to prevent one event (NNTp) for oral aspirin compared to placebo or an active intervention.We assessed the evidence using GRADE and created a Summary of findings table.nnnMAIN RESULTSnWe included five studies enrolling adults with frequent episodic TTH; 1812 participants took medication, of which 767 were included in comparisons of aspirin 1000 mg with placebo, and 405 in comparisons of aspirin 500 mg or 650 mg with placebo. Not all of these participants provided data for outcomes of interest in this review. Four studies specified using IHS diagnostic criteria; one predated commonly recognised criteria, but described comparable characteristics and excluded migraine. All participants treated headaches of at least moderate pain intensity.None of the included studies were at low risk of bias across all domains considered, although for most studies and domains this was likely to be due to inadequate reporting rather than poor methods. We judged one study to be at high risk of bias due to small size.There were no data for aspirin at any dose for the IHS preferred outcome of being pain free at two hours, or for being pain free at any other time, and only one study provided data equivalent to having no or mild pain at two hours (very low quality evidence). Use of rescue medication was lower with aspirin 1000 mg than with placebo (2 studies, 397 participants); 14% of participants used rescue medication with aspirin 1000 mg compared with 31% with placebo (NNTp 6.0, 95% confidence interval (CI) 4.1 to 12) (low quality evidence). Two studies (397 participants) reported a Patient Global Evaluation at the end of the study; we combined the top two categories for both studies to determine the number of participants who were satisfied with treatment. Aspirin 1000 mg produced more satisfied participants (55%) than did placebo (37%) (NNT 5.7, 95% CI 3.7 to 12) (very low quality evidence).Adverse events were not different between aspirin 1000 mg and placebo (RR 1.1, 95% CI 0.8 to 1.5), or aspirin 500 mg or 650 mg and placebo (RR 1.3, 95% CI 0.8 to 2.0) (low quality evidence). Studies reported no serious adverse events.The quality of the evidence using GRADE comparing aspirin doses between 500 mg and 1000 mg with placebo was low or very low. Evidence was downgraded because of the small number of studies and events, and because the most important measures of efficacy were not reported.There were insufficient data to compare aspirin with any active comparator (paracetamol alone, paracetamol plus codeine, peppermint oil, or metamizole) at any of the doses tested.nnnAUTHORS CONCLUSIONSnA single dose of aspirin between 500 mg and 1000 mg provided some benefit in terms of less frequent use of rescue medication and more participants satisfied with treatment compared with placebo in adults with frequent episodic TTH who have an acute headache of moderate or severe intensity. There was no difference between a single dose of aspirin and placebo for the number of people experiencing adverse events. The amount and quality of the evidence was very limited and should be interpreted with caution.