Millions of Americans remain dependent on opioid analgesics despite mounting evidence that neuroadaptive changes render these medications ineffective for chronic pain management, wrote Jane C. Ballantyne, MD, of the Department of Anesthesiology and Pain Medicine at the University of Washington School of Medicine in Seattle, and George F. Koob, PhD, of the National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health in Bethesda, in a perspective published in Annals of Internal Medicine. They described a recent household survey that identified 3 million patients who were taking opioids exactly as prescribed but still reported struggles with use.
Neuroadaptation represented the central mechanism underlying opioid tolerance, extending beyond simple receptor desensitization to encompass enduring changes in brain motivational circuits. These adaptations affected regions that regulate motivation, affect, reward, and stress responses, and produce hyperalgesia, hyperkatifeia (intensified withdrawal symptoms), reward deficiency, and heightened stress reactivity. These neuroadaptive changes decreased activity in dopamine and opioid peptide systems and increased activity in stress systems including dynorphin, corticotropin-releasing factor, norepinephrine, hypocretin, and neuroimmune pathways. The opponent process framework challenges conventional clinical interpretations of breakthrough pain. "Worsening pain in the presence of opioids is often recognized as breakthrough pain, suggesting an inadequate dose of opioids," the authors wrote. "Yet, escalation stimulates opponent process–like neuroadaptations, which lead to declines in analgesia, mood, and quality of life."
Patients prescribed opioids for pain management underwent identical neuroadaptive processes as patients with opioid use disorder. "There is no reason to believe that the neuroadaptations that develop with opioids prescribed for pain would differ from those produced by any other continuous opioid use or misuse," Dr. Ballantyne and Dr. Koob wrote. Both populations experienced negative reinforcement—continuing drug use to avoid withdrawal's aversive effects rather than to achieve positive effects. These neuroadaptations persisted well beyond acute withdrawal into protracted withdrawal, which is characterized by continuing brain changes that opposed opioid effects. The adaptations remained even after drug discontinuation. They complicated tapering efforts and explained why patients reported difficulty reducing opioid dosages despite inadequate pain control.
Current federal guidelines from the Centers for Disease Control and Prevention and the US Department of Health and Human Services emphasize self-management approaches for chronic pain and reserve opioids for situations in which alternative treatments prove insufficient or infeasible. The researchers recommended initiating tapering conversations whenever patients receive long-term opioid therapy. They noted that "nothing is lost by having the conversation, which helps patients understand what is happening to their brain while receiving opioids." Some patients may benefit from switching to buprenorphine if they started opioid treatment for acute pain or began treatment before its limitations were understood, Drs. Ballantyne and Koob added.
Their perspective article suggested that neuroscience education regarding opponent processes may facilitate patient acceptance of tapering protocols. "Those in the middle can be persuaded by understanding that there is no free ride in the brain, and continuous long-term opioid therapy will always be met with tolerance and the adverse effects of neuroadaptation," the researchers concluded.
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Source: Annals of Internal Medicine