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Editorial
November 2018

Modulation of Nociception in Multiple Brain Systems—The Strain in Pain

Author Affiliations
  • 1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
JAMA Neurol. 2018;75(11):1309-1310. doi:10.1001/jamaneurol.2018.1752

The strain in pain lies mainly in the brain. Pain experience is always a combination of sensory pathway input and brain processing of that information. The key questions are where it is and what can we do to modulate it. Can alterations in top-down processing of pain signals reduce pain, even if the ascending pain signals themselves are largely unaltered?

This has become an increasingly pressing problem as the opiate crisis unfolds,1 with the annual number of drug overdose deaths tripling since 19992 to a total of 50 000 per year, a third of them from use of prescription medications.3 This is more than the annual number of deaths from firearms (33 000, two-thirds of them suicides),4 or automobile crashes (40 000).5 Findings from the 2015 National Survey on Drug Use and Health showed that more than one-third of US adults took an opioid drug in the previous year.3 Prescription deaths are supplemented by increasingly powerful and cheaper opiates found on the street. The introduction of the potent μ-opioid agonist fentanyl and the much more highly potent carfentanyl in prescriptions and street drugs is increasing that danger substantially. The number of overdose deaths in the United States from drugs such as fentanyl and tramadol doubled in a single year, from 3.1 per 100 000 in 2015 to 6.2 in 2016.2 As much as 90% of the opioid overdose deaths are thought to be unintentional.1 The danger of unintentional fatal overdose is especially great, because tolerance develops much more rapidly in μ1 opioid receptors that mediate analgesia than in μ2 receptors that produce respiratory depression.6 Thus unintentional death through respiratory depression occurs easily, because the drug user thinks they can handle more of the drug because they need it to maintain analgesia. I remember being taught in medical school that people who used opiates for real pain would not become addicted.7 We now know that, if anything, the opposite is the case, because withdrawal hyperalgesia arises from hyperexcitability of neurons in the periaqueductal gray and locus coeruleus.8 Those taking opiates for chronic pain are doubly trapped, first by addiction withdrawal and then by pain sensitization. So there is a pressing need to understand pain pathways in the brain and the effect of nonpharmacological pain interventions that may be real but different, and are certainly less dangerous, than opiate use. In this context, it is sobering to remember that heroin was developed to treat morphine addiction.

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