Ewan D McNicol

Bio: Ewan D McNicol is an academic researcher from Tufts Medical Center. The author has contributed to research in topics: Placebo & Randomized controlled trial. The author has an hindex of 31, co-authored 51 publications receiving 5749 citations. Previous affiliations of Ewan D McNicol include Tufts University.

Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

Abstract: Summary Background New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and E valuation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. Methods Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fi xed-eff ects Mantel-Haenszel method. Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment eff ects. Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009). T rial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2–8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5–9·4) for pregabalin; 7·2 (5·9–9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4–19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, fi nal quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These fi ndings permitted a strong recommendation for use and proposal as fi rst-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. Interpretation Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest effi cacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profi ling probably account for moderate trial outcomes and should be taken into account in future studies. Funding NeuPSIG of the International Association for the Study of Pain.

Efficacy and Safety of Opioid Agonists in the Treatment of Neuropathic Pain of Nonmalignant Origin: Systematic Review and Meta-analysis of Randomized Controlled Trials

Abstract: ContextIn the United States, an estimated 2 million persons have neuropathic pain that is often resistant to therapy. The use of opioids for neuropathic pain remains controversial, in part because studies have been small, have yielded equivocal results, and have not established the long-term risk-benefit ratio of this treatment.ObjectiveTo assess the efficacy and safety of opioid agonists for the treatment of neuropathic pain based on published randomized controlled trials (RCTs).Data SourcesWe searched MEDLINE (1966 to December 2004) and the Cochrane Central Register of Controlled Trials (fourth quarter, 2004) for articles in any language, along with reference lists of reviews and retrieved articles, using a combination of 9 search terms for RCTs with 32 terms for opioids and 15 terms for neuropathic pain.Study SelectionTrials were included in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology, pain was assessed using validated instruments, and adverse events were reported. Studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally were excluded.Data ExtractionData were extracted by 2 independent investigators and included demographic variables, diagnoses, interventions, efficacy, and adverse effects.Data SynthesisTwenty-two articles met inclusion criteria and were classified as short-term (less than 24 hours; n = 14) or intermediate-term (median = 28 days; range = 8-56 days; n = 8) trials. The short-term trials had contradictory results. In contrast, all 8 intermediate-term trials demonstrated opioid efficacy for spontaneous neuropathic pain. A fixed-effects model meta-analysis of 6 intermediate-term studies showed mean posttreatment visual analog scale scores of pain intensity after opioids to be 14 units lower on a scale from 0 to 100 than after placebo (95% confidence interval [CI], −18 to −10; P<.001). According to number needed to harm (NNH), the most common adverse event was nausea (NNH, 3.6; 95% CI, 2.9-4.8), followed by constipation (NNH, 4.6; 95% CI, 3.4-7.1), drowsiness (NNH, 5.3; 95% CI, 3.7-8.3), vomiting (NNH, 6.2; 95% CI, 4.6-11.1), and dizziness (NNH, 6.7; 95% CI, 4.8-10.0).ConclusionsShort-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrate significant efficacy of opioids over placebo for neuropathic pain, which is likely to be clinically important. Reported adverse events of opioids are common but not life-threatening. Further RCTs are needed to establish their long-term efficacy, safety (including addiction potential), and effects on quality of life.

Opioids for neuropathic pain

Abstract: Background This is an updated version of the original Cochrane review published in Issue 3, 2006, which included 23 trials. The use of opioids for neuropathic pain remains controversial. Studies have been small, have yielded equivocal results, and have not established the long-term profile of benefits and risks for people with neuropathic pain. Objectives To reassess the efficacy and safety of opioid agonists for the treatment of neuropathic pain. Search methods We searched CENTRAL, on The Cochrane Library (Issue 10 of 12, 2012), MEDLINE (1966 to Oct week 3, 2012), and EMBASE (1980 to 2012, week 42) for articles in any language, and reference lists of reviews and retrieved articles. Searches were originally run in 2005, then again in 2010 and 2012. Selection criteria We included randomized controlled trials (RCTs) in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology. Pain was assessed using validated instruments, and adverse events were reported. We excluded studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally. Data collection and analysis Two review authors independently extracted data and included demographic variables, diagnoses, interventions, efficacy, and adverse effects. Main results Thirty-one trials met our inclusion criteria, studying 10 different opioids: 23 studies from the original 2006 review and eight additional studies from this updated review. Seventeen studies (392 participants with neuropathic pain, average 22 participants per study) provided efficacy data for acute exposure to opioids over less than 24 hours. Sixteen reported pain outcomes, with contradictory results; 8/16 reported less pain with opioids than placebo, 2/16 reported that some but not all participants benefited, 5/16 reported no difference, and 1/16 reported equivocal results. Six studies with about 170 participants indicated that mean pain scores with opioid were about 15/100 points less than placebo. Fourteen studies (845 participants, average 60 participants per study) were of intermediate duration lasting 12 weeks or less; most studies lasted less than six weeks. Most studies used imputation methods for participant withdrawal known to be associated with considerable bias; none used a method known not to be associated with bias. The evidence, therefore, derives from studies predominantly with features likely to overestimate treatment effects, i.e. small size, short duration, and potentially inadequate handling of dropouts. All demonstrated opioid efficacy for spontaneous neuropathic pain. Meta-analysis demonstrated at least 33% pain relief in 57% of participants receiving an opioid versus 34% of those receiving placebo. The overall point estimate of risk difference was 0.25 (95% confidence interval (CI) 0.13 to 0.37, P < 0.0001), translating to a number needed to treat for an additional beneficial outcome (NNTB) of 4.0 (95% CI 2.7 to 7.7). When the number of participants achieving at least 50% pain relief was analyzed, the overall point estimate of risk difference between opioids (47%) and placebo (30%) was 0.17 (95% CI 0.02 to 0.33, P = 0.03), translating to an NNTB of 5.9 (3.0 to 50.0). In the updated review, opioids did not demonstrate improvement in many aspects of emotional or physical functioning, as measured by various validated questionnaires. Constipation was the most common adverse event (34% opioid versus 9% placebo: number needed to treat for an additional harmful outcome (NNTH) 4.0; 95% CI 3.0 to 5.6), followed by drowsiness (29% opioid versus 14% placebo: NNTH 7.1; 95% CI 4.0 to 33.3), nausea (27% opioid versus 9% placebo: NNTH 6.3; 95% CI 4.0 to 12.5), dizziness (22% opioid versus 8% placebo: NNTH 7.1; 95% CI 5.6 to 10.0), and vomiting (12% opioid versus 4% placebo: NNTH 12.5; 95% CI 6.7 to 100.0). More participants withdrew from opioid treatment due to adverse events (13%) than from placebo (4%) (NNTH 12.5; 95% CI 8.3 to 25.0). Conversely, more participants receiving placebo withdrew due to lack of efficacy (12%) versus (2%) receiving opioids (NNTH -11.1; 95% CI -20.0 to -8.3). Authors' conclusions Since the last version of this review, new studies were found providing additional information. Data were reanalyzed but the results did not alter any of our previously published conclusions. Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrated significant efficacy of opioids over placebo, but these results are likely to be subject to significant bias because of small size, short duration, and potentially inadequate handling of dropouts. Analgesic efficacy of opioids in chronic neuropathic pain is subject to considerable uncertainty. Reported adverse events of opioids were common but not life-threatening. Further randomized controlled trials are needed to establish unbiased estimates of long-term efficacy, safety (including addiction potential), and effects on quality of life.

Patient controlled opioid analgesia versus conventional opioid analgesia for postoperative pain.

Abstract: Background Patients may control postoperative pain by self-administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne found a strong patient preference for PCA over conventional analgesia but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, Walder's review in 2001 did not find a significant differences in pain intensity and pain relief between PCA and conventionally treated groups. Objectives To evaluate the efficacy of PCA versus conventional analgesia (such as a nurse administering an analgesic upon a patient's request) for postoperative pain control. Search methods Randomized controlled trials (RCTs) were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2004, Issue 3), MEDLINE (1966 to 2004), and EMBASE (1994 to 2004). Additional reports were identified from the reference lists of retrieved papers. Selection criteria RCTs of PCA versus conventional analgesia that employed pain intensity as a primary or secondary outcome were selected. These trials included RCTs that compared PCA without a continuous background infusion versus conventional parenteral analgesic regimens. Studies that explicitly stated they involved patients with chronic pain were excluded. Data collection and analysis Trials were scored using the Oxford Quality Scale. Meta-analyses were performed of outcomes that included analgesic efficacy assessed by a Visual Analog Scale (VAS), analgesic consumption, patient satisfaction, length of stay and adverse effects. A sufficient number of the retrieved trials reported these parameters to permit meta-analyses. Main results Fifty-five studies with 2023 patients receiving PCA and 1838 patients assigned to a control group met inclusion criteria. PCA provided better pain control and greater patient satisfaction than conventional parenteral 'as-needed' analgesia. Patients using PCA consumed higher amounts of opioids than the controls and had a higher incidence of pruritus (itching) but had a similar incidence of other adverse effects. There was no difference in the length of hospital stay. Authors' conclusions This review provides evidence that PCA is an efficacious alternative to conventional systemic analgesia for postoperative pain control.

Pharmacologic management of neuropathic pain: evidence-based recommendations.

Abstract: Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

Opioid complications and side effects.

Abstract: Medications which bind to opioid receptors are increasingly being prescribed for the treatment of multiple and diverse chronic painful conditions. Their use for acute pain or terminal pain is well accepted. Their role in the long-term treatment of chronic noncancer pain is, however, controversial for many reasons. One of the primary reasons is the well-known phenomenon of psychological addiction that can occur with the use of these medications. Abuse and diversion of these medications is a growing problem as the availability of these medications increases and this public health issue confounds their clinical utility. Also, the extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven. Lastly, the role of opioids in the treatment of chronic pain is also influenced by the fact that these potent analgesics are associated with a significant number of side effects and complications. It is these phenomena that are the focus of this review. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioid usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to under-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions.