The latest epidemic in America isn’t a virus, you won’t catch it from a friend. However, your doctor might give it to you. This epidemic is opioid addiction. Almost two million Americans are opioid dependent[1], and many of these dependencies begin with medically prescribed opioids. Despite the increasing amount of opioid addicts and opioid-related deaths, opioid prescription has increased over the past 20 years.[2]These realizations have caused a push in the medical and pharmaceutical communities for a change in opioid culture. There’s a push for opioid alternatives, less addictive opioids, and better methods of opioid prescription and pain management to combat the growing opioid crisis.

           Combating the opioid crisis requires an understanding of opioid function and how it relates to human pain tolerance. The human body has four neurological opioid receptors, kappa (KOP), delta (DOP), mu (MOP), and nociceptin (NOP), that all stimulate a pain relieving response. However, not every opioid receptor binds the same drugs, and each receptor causes different side effects, making some a more desirable target than others. The most commonly targeted receptor is MOP, which is targeted by opioids like heroin and morphine. It is effective at providing pain relief, but causes side effects such as nausea, respiratory depression, tolerance, and hyperalgesia.[3]

           Opioid tolerance is the result of a patient’s opioid receptors becoming accustomed to the drug, so that more and more of the drug must be administered to illicit the same pain relieving response, while hyperalgesia is along the same lines, it’s actually an increased sensitivity to pain, which can be caused by opioid use, which make pain receptors ultra sensitive. The problem with tolerance and opioid induced hyperalgesia (OIH) is that they require more opioids in order to treat, which is the driving force behind addiction.

           One study suggests specifically targeting KOP, a receptor that is less-studied, and therefore not currently used for treatment. Che, et al, at the University of North Carolina, Chapel Hill, purified and obtained the crystal structure of KOP, and found that its binding site is different than MOP, and that it could potentially be a safer receptor to target as it might have less side effects causing addiction. Also by obtaining the crystal structure, the drugs designed to target the receptor can be more specifically designed to better fit the binding site.[4]

           Another study, by Ding, et al, at Wake Forest University, shows that a dual-receptor targeting drug, AT-121, which targets MOP and NOP worked as a strong pain killer in primates, but without the common MOP side effects. The primates treated with AT-121 did not experience reinforcing effects after multiple rounds of treatment, suggesting lower abuse risk than current opioids. Being administered at 10 times the dosage of normal analgesics, AT-121 impairs respiratory or cardiovascular function.[5]Thus, AT-121 is still in experimental phase, but  has potential to be used for treatment in those who have opioid addictions as it is less addictive, causes less tolerance, and because it inhibits cardiovascular and respiratory rates less than traditional opioids, there is less chance of accidental death by overdose.

           While targeting different receptors may be the future of less addictive opioids, non-opioid analgesics are also a major focus, along with more regulations on how much and how often opioids are prescribed, to help mitigate the epidemic. The development of less addictive analgesics and anesthetics are paramount to not only the medical community, but society as a whole.


REFERENCES

[1]Delara Brandal; Michelle S. Keller; Carol Lee; Tristan Grogan; Yohei Fujimoto; Yann Gricourt; Takashige Yamada; Siamak Rahman; Ira Hofer; Kevork Kazanjian; Jonathan Sack; Aman Mahajan; Anne Lin; Maxime Cannesson. Impact of Enhanced Recovery After Surgery and Opioid-Free Anesthesia on Opioid Prescriptions at Discharge From the Hospital: A Historical-Prospective Study.International Analgesia Society. 2017

[2]Delara Brandal; Michelle S. Keller; Carol Lee; Tristan Grogan; Yohei Fujimoto; Yann Gricourt; Takashige Yamada; Siamak Rahman; Ira Hofer; Kevork Kazanjian; Jonathan Sack; Aman Mahajan; Anne Lin; Maxime Cannesson. Impact of Enhanced Recovery After Surgery and Opioid-Free Anesthesia on Opioid Prescriptions at Discharge From the Hospital: A Historical-Prospective Study.International Analgesia Society. 2017

[3]Ding Huiping, Norikazu Kiguchi, Dennis Yasuda, Pankaj R. Daga, Willma E. Polgar, James J. Lu, Paul W. Czoty, Shiroh Kishiok, Nurulain T. Zaveri, and Mei-Chuan Ko. Department of Physiology and Pharmacology, Wake Forest School of Medicine. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Science Translational Magazine. August 2018.

[4]Tao Che, Susruta Majumdar, Saheem A. Zaidi, …, Vsevolod Katritch, Daniel Wacker, Bryan L. Roth. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine. Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell. 2018.[5]Ding Huiping, Norikazu Kiguchi, Dennis Yasuda, Pankaj R. Daga, Willma E. Polgar, James J. Lu, Paul W. Czoty, Shiroh Kishiok, Nurulain T. Zaveri, and Mei-Chuan Ko.Department of Physiology and Pharmacology, Wake Forest School of Medicine. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Science Translational Magazine. August 2018.

[5]Ding Huiping, Norikazu Kiguchi, Dennis Yasuda, Pankaj R. Daga, Willma E. Polgar, James J. Lu, Paul W. Czoty, Shiroh Kishiok, Nurulain T. Zaveri, and Mei-Chuan Ko.Department of Physiology and Pharmacology, Wake Forest School of Medicine. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Science Translational Magazine. August 2018.

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