The journal of pain : official journal of the American Pain Society
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The number of deaths associated with methadone use increased dramatically in parallel with marked increases in its use, particularly for treatment of chronic pain. To develop a clinical guideline on methadone prescribing to reduce potential harms, the American Pain Society commissioned a review of various aspects related to methadone safety. This article summarizes evidence related to unintentional overdose due to methadone and harms related to cardiac arrhythmia potential. We searched Ovid MEDLINE, the Cochrane Library, and PsycINFO databases through January 2014 for studies assessing harms associated with methadone use; we judged 70 studies to be relevant and to meet inclusion criteria. The majority of studies on overdose and cardiac arrhythmia risk are observational and provide weak evidence on which to base clinical guidelines. In patients prescribed methadone for treatment of opioid dependence, data suggest that mortality benefits related to reduction in illicit drug use outweigh harms. Despite epidemiologic data showing marked increases in the numbers of methadone-related deaths that have been primarily attributed to increased use of methadone for chronic pain, evidence on methadone and mortality risk in this population has been somewhat contradictory. There is some evidence that recent initiation of methadone, psychiatric admissions, and concomitant use of benzodiazepines are associated with a higher risk for overdose. Evidence on cardiac risks is primarily limited to case reports of torsades de pointes, primarily in patients on high doses of methadone, and to studies showing an association between methadone use and prolongation of QTc intervals. Research is needed to understand the effectiveness of dosing methods, electrocardiogram monitoring, and other risk mitigation strategies in patients prescribed methadone. ⋯ This systematic review synthesizes the evidence related to methadone use and risk for overdose and cardiac arrhythmia. Findings regarding the association between methadone use and QTc interval prolongation and risk factors for methadone-associated overdose suggest potential targets for risk mitigation strategies, though research is needed to determine the effectiveness of such strategies at reducing adverse outcomes.
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Methadone-associated overdose deaths have dramatically increased. In order to inform an evidence-based clinical practice guideline to improve safety of methadone prescribing, the American Pain Society commissioned a systematic review on various aspects related to methadone safety. We searched Ovid MEDLINE, Cochrane Library, and PsycINFO databases through July 2012 to identify studies that addressed 1 or more of 17 Key Questions related to methadone safety; an update search was performed in 2014 for new studies related to methadone-related overdose and risks related to cardiac arrhythmias. A total of 168 studies met inclusion criteria for the review. The purpose of this article is to highlight critical research gaps in the literature related to methadone safety. These include lack of evidence on risk factors associated with methadone-overdose deaths and adverse events, limited evidence to evaluate the comparative mortality of methadone versus other opioids, insufficient evidence to fully understand the harms associated with methadone use during pregnancy, and insufficient evidence to determine effects of risk mitigation strategies such as electrocardiogram monitoring, strategies for managing patients with prolonged QTc intervals on screening, urine drug testing, alternative dosing regimens for initiation and titration of therapy, and timing of follow-up. Therefore, most guideline recommendations are based on weak evidence. More research is needed to guide safe methadone prescribing practices and decrease the adverse events associated with methadone. ⋯ This article summarizes critical research gaps in the literature related to methadone safety, based on a systematic review commissioned by the American Pain Society. Critical research gaps were identified in a number of areas, highlighting the need for additional research to guide safer prescribing and risk mitigation strategies.
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Previous research describes an inconsistent relation between temporal changes in transversus abdominis or lumbar multifidus and temporal changes in clinical outcomes. Unfortunately, a relevant systematic review is unavailable. As a result, this systematic review was designed to summarize evidence regarding the association between temporal changes in muscle morphometry and activity in response to treatment, and temporal changes in clinical outcomes. Candidate publications were identified from 6 electronic databases. Fifteen articles were included after scrutinization by 2 reviewers using predetermined selection criteria. The methodological quality of these articles was appraised using a standard tool. These methods revealed strong evidence that temporal alterations in transversus abdominis thickness change during contraction (as measured by B-mode or M-mode ultrasound) or feedforward activation of transversus abdominis (assessed via electromyography, tissue Doppler imaging, or M-mode ultrasound) were unrelated to temporal changes in low back pain (LBP)/LBP-related disability. There was limited evidence that temporal changes in transversus abdominis lateral sliding or lumbar multifidus endurance were unrelated to temporal changes in LBP intensity. Conflicting evidence was found for the relation between temporal changes in lumbar multifidus morphometry and temporal changes in LBP/LBP-related disability. This review highlights that temporal changes in transversus abdominis features tend to be unrelated to the corresponding LBP/LBP-related disability improvements, whereas the relation between multifidus changes and clinical improvements remains uncertain. ⋯ This systematic review highlighted that changes in morphometry or activation of transversus abdominis following conservative treatments tend not to be associated with the corresponding changes in clinical outcomes. The relation between posttreatment changes in characteristics of lumbar multifidus and clinical improvements remains uncertain.
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The purpose of this study was to investigate possible racial differences in opioid prescriptions among primary care patients with chronic noncancer pain receiving care in the Veterans Affairs health care system. This was a retrospective cohort study of 99,903 veterans with diagnoses of low back, neck, or joint pain selected to participate in the Veterans Affairs Survey of the Healthcare Experiences of Patients in fiscal year 2006. The outcome was prescription of opioids in the year following the first pain diagnosis, obtained through electronic medical record data. Analyses incorporated fixed effects for race, most recent pain intensity rating, new or established primary care patient status, and an interaction between race and most recent pain intensity rating, together with random effects for health care facility and race within facility. The association between patient race and prescription of opioids was moderated by baseline level of pain intensity scores (assessed on a 0-10 scale) and patient age. Among patients under 65 years of age, blacks with moderate (4-6) or high (7-10) levels of pain were less likely to receive opioids than whites (P = .0025, P = .0011); however, there were no significant differences between black and white patients with low levels of pain intensity (1-3) and those with pain intensity ratings of 0 (no pain). Among patients 65 and older with pain intensity ratings of zero, blacks were more likely than whites to receive opioid prescriptions (P = .0087), but there were no significant racial differences in opioid prescriptions in those with low to high levels of pain. ⋯ Among veterans under age 65 reporting moderate to high levels of chronic noncancer pain, blacks were less likely to be prescribed opioids than whites, even after controlling for clinical and system-level factors. Results underscore the challenges of eliminating racial differences in pain treatment, despite comprehensive systemwide improvement initiatives.
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Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 μM). A-1264087 was also shown to inhibit the release of the pronociceptive calcitonin gene-related peptide from rat dorsal root ganglion neurons. Oral administration of A-1264087 produces robust antinociceptive efficacy in monoiodoacetate-induced osteoarthritic, complete Freund adjuvant-induced inflammatory, and chronic constrictive injury of sciatic nerve-induced, neuropathic pain models with ED50 values of 3.0, 5.7, and 7.8 mg/kg (95% confidence interval = 2.2-3.5, 3.7-10, and 5.5-12.8 mg/kg), respectively. Further analysis revealed that A-1264087 also suppressed nociceptive-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation, which are biochemical markers of engagement of pain circuitry in chronic pain states. Additionally, A-1264087 inhibited both spontaneous and evoked neuronal activity in the spinal cord dorsal horn in complete Freund adjuvant-inflamed rats, providing a neurophysiological basis for the observed antihyperalgesia. A-1264087 produced no alteration of body temperature or motor coordination and no learning impairment at therapeutic plasma concentrations. ⋯ The present results demonstrate that the neuronal Ca(2+) channel blocker A-1264087 exhibits broad-spectrum efficacy through engagement of nociceptive signaling pathways in preclinical pain models in the absence of effects on psychomotor and cognitive function.