Abstract:The pharmacological effects of the opioid analgesics are derived from their complex interactions with three opioid receptor types (, ␦, and ; morphine is an agonist at the opioid receptor). These receptors are found in the periphery, at presynaptic and postsynaptic sites in the spinal cord dorsal horn, and in the brain stem, thalamus, and cortex, in what constitutes the ascending pain transmission system, as well as structures that comprise a descending inhibitory system that modulates pain at the level of the spinal cord. The cellular effects of opioids include a decrease in presynaptic transmitter release, hyperpolarization of postsynaptic elements, and disinhibition. The endogenous opioid peptides are part of an endogenous pain modulatory system. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxymorphone, methadone, meperidine, oxycodone, and fentanyl, and their advantages and disadvantages for the management of pain are discussed. An understanding of the pharmacokinetic properties, as well as issues related to opioid rotation, tolerance, dependence, and addiction are essential aspects of the clinical pharmacology of opioids for pain.
In recent years, the observation that the response of patients to opioid drugs may be influenced by properties inherent in the pain or pain syndrome, such as its pathophysiology, has evolved into the belief that certain types of pain, e.g., neuropathic pains, may be unresponsive to these drugs. This concept has important implications for both clinical practice and basic understanding of opioid mechanisms. We critically evaluate opioid responsiveness, particularly as it relates to neuropathic pain, and propose a clinically relevant definition and a paradigm for its investigation. The paradigm is illustrated by analgesic responses to opioid infusion in 28 patients with neuropathic pains and by a detailed presentation of the pharmacokinetic and pharmacodynamic relationships in one of these patients, whose central pain responded promptly to an infusion of hydromorphone. From this analysis, we hypothesize that (1) opioid responsiveness in man can be defined by the degree of analgesia achieved during dose escalation to either intolerable side effects or the occurrence of 'complete' or 'adequate' analgesia; (2) opioid responsiveness is a continuum, rather than a quantal phenomenon; (3) opioid responsiveness is determined by a diverse group of patient characteristics and pain-related factors, as well as drug-selective effects; and (4) a neuropathic mechanism may reduce opioid responsiveness, but does not result in an inherent resistance to these drugs. Given the complexity of factors contributing to opioid responsiveness and the observation that outcome cannot be reliably predicted, opioids should not be withheld on the assumption that pain mechanism, or any other factor, precludes a favorable response. Both the clinical use of opioids and paradigms to investigate opioid responsiveness should include dose escalation to maximally tolerated levels and repeated monitoring of analgesia and other effects.
Methadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain. As part of the guideline development process, the American Pain Society commissioned a systematic review of various aspects related Clinical practice guidelines are ''guides'' only and may not apply to all patients and all clinical situations. As part of a shared decision-making approach, it may be appropriate for the clinician to inform a patient that a particular recommendation may not be applicable, after considering all circumstances pertinent to that individual. This article is based on research conducted at the Oregon Evidence-based Practice Center (now the Pacific Northwest Evidence-based Practice Center) with funding from the American Pain Society (APS to safety of methadone. After a review of the available evidence, the expert panel concluded that measures can be taken to promote safer use of methadone. Specific recommendations include the need to educate and counsel patients on methadone safety, use of electrocardiography to identify persons at greater risk for methadone-associated arrhythmia, use of alternative opioids in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation, careful dose initiation and titration of methadone, and diligent monitoring and follow-up. Although these guidelines are based on a systematic review, the panel identified numerous research gaps, most recommendations were based on low-quality evidence, and no recommendations were based on high-quality evidence.Perspective: This guideline, based on a systematic review of the evidence on methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge in use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias. M ethadone is a synthetic opioid used for the treatment of opioid addiction and for treatment of chronic pain. 15,61 The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths.38 This increase appears largely related to the dramatic rise in the use of methadone for chronic pain, though a small proportion of deaths occur in patients treated for opioid addiction. 21,37,68,76,91,103 Methadone poisoning deaths in the United States increased steadily from about 800 in 1999 to a high of about 5,500 in 2007; th...
To determine the importance of the NMDA receptor (NMDAR) in pain hypersensitivity after injury, the NMDAR1 (NR1) subunit was selectively deleted in the lumbar spinal cord of adult mice by the localized injection of an adenoassociated virus expressing Cre recombinase into floxed NR1 mice. NR1 subunit mRNA and dendritic protein are reduced by 80% in the area of the virus injection, and NMDA currents, but not AMPA currents, are reduced 86-88% in lamina II neurons. The spatial NR1 knock-out does not alter heat or cold paw-withdrawal latencies, mechanical threshold, or motor function. However, injury-induced pain produced by intraplantar formalin is reduced by 70%. Our results demonstrate conclusively that the postsynaptic NR1 receptor subunit in the lumbar dorsal horn of the spinal cord is required for central sensitization, the central facilitation of pain transmission produced by peripheral injury.
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