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In 2014, 11 million Americans were taking daily prescription opioids. However, because of widespread opioid addiction and overdose deaths, there is continuing controversy on the optimal use of opioid analgesics for chronic pain. In response to the tragic rise in opioid overdose deaths, the U.S. Centers for Disease Control and Prevention (CDC) issued the 2016Guideline for Prescribing Opioids for Chronic Pain. Subsequently, opioid prescriptions dropped by as much as 57% per year (2016-2019). By 2017, about 23% of patients taking prescribed opioids were being tapered or discontinued. Although the most common rationales for discontinuing or dose reduction were that opioids were ineffective or had unacceptable side effects, the CDC cited 2 additional reasons: first, weak evidence for opioid efficacy beyond 3 months and, second, preclinical and human studies indicating that opioid exposure could result in hyperalgesia. Additional reasons for tapering include the risk of use disorder, overdose, and diversion. Although opioid tapering was intended to improve patient safety and health by avoiding opioid use disorder, overdose and diversion, and to mitigate opioid-induced worsening of pain, outcome studies indicate that tapering introduces new risks and patient harms. Indeed, reduction or discontinuation of prescribed opioids can actually increase risks for overdose, overdose deaths, all-cause mortality, and suicide. In addition, some studies have documented increased pain, fear of pain, and mental health crises including suicidal ideation. In 2019, the American Medical Association, the CDC, the U.S. Food and Drug Administration, and others issued warnings about tapering practices that exposed patients to these iatrogenic risks. Most taper studies report that opioid dose can be reduced and, in some cases, discontinued without a worsening of pain. However, these studies were unblinded, nonrandomized, and had no nontapered control group. Most tapering studies have not differentiated voluntary vs involuntary taper methods, although limited research comparing the 2 methods has suggested no group difference for pain intensity outcomes after taper. Although seemingly promising, the authors of one of these reports cautioned against an interpretation that involuntary tapering is harmless; they noted that their outcome assessment was limited and “did not evaluate potential harms of involuntary tapering such as emotional distress, disruption of the patient-clinician relationship... and rare but serious harmssuchashospitalization and suicide” (severewithdrawal, overdose, and other mortality were also not quantified). Indeed, generalizability of the broader taper literature is limited by retrospective designs, exclusion of patients who have died during the study period or left care, and use of clinical data sets that do not capture individual patient-reported outcomes. Importantly, they do not identify conditions with enhanced patient risk. In view of significant variability in benefits and harms of taper, in its 2019 prescription opioid tapering guidance, the U.S. Department of Health and Human Services called for an individualized, patientcentered approach that accounts for potential opioid analgesic benefits and concluded that consensual tapering is ideal. Building on this foundation, we argue that the success of an opioid taper can be improved using both neuroscience-based concepts and clinical data to understand individual patient variability for opioid analgesic treatment response.We specifically describe how factors such as expectation and agency dynamically contribute to patient outcomes and offer recommendations for successful opioid tapering in patients with chronic pain. Pain is a predictive cue that signals threat of bodily harm. At any given level of stimulus intensity, anoxious stimulus that is rising is felt as more painful, whereas one that is falling is felt as less painful. Furthermore, through learning, neutral sensory cues become either pain (eg, nocebo) or relief predictive (eg, placebo). Human functional imaging studies confirm the idea that pain and relief predictive cues activate specific top–down pain modulatory circuits in the central nervous system including cortical links to spinal pain transmission neurons by striatal, mesencephalic, and pontomedullary relays to the spinal cord dorsal horn. These expectation activated descending circuits exert bidirectional control of pain by parallel descending pain modulating neurons, either suppression or facilitation. Patient expectations also robustly influence analgesic drug efficacy. One controlled study manipulated subject expectations to illustrate their impact on opioid analgesia. Healthy volunteers received experimental heat pain and intravenous administration of the opioid remifentanil under 3 conditions in which they were told they were receiving: (1) a powerful painkiller, (2) saline, or (3) a pharmacological agent that would amplify their pain (nocebo).When subjects believed that they were receiving a powerful pain reliever Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.