Non-Addictive Opioid Alternatives: A Step Closer?

An excessive reliance on opioid analgesics for treating acute and chronic pain has contributed to the current global opioid epidemic. The lessons learned from this epidemic are many, starting with the need to develop efficacious, less addictive alternatives for people coping with pain. Another dimension of this argument is the need to limit prescribing opioids in emergency rooms, post-surgery and in doctor’s offices. Research studies have focused on these topics, as well as analyzing the complex role of pain and opioid receptors in the brain. The goal of the latter is to gain greater understanding of the effects of opioids on brain receptors involved in suppression of pain, as well as unwanted side effects including addiction. Statistics indicate people who receive prescription opioids after surgery are more likely to still use them a year later. Of course, this poses a risk of abuse, dependence and addiction. Interestingly, studies have not demonstrated that prolonged opioid use offers long-term benefits.

  • A review of 11 million patients undergoing elective surgery from 2002-2011 found opioid overdoses and dependence increased over time.
  • According to the Centers for Disease Control and Prevention, the likelihood of still using an opioid a year after surgery increased with the length of the initial prescription. One-day: 6%, two-day: 10% and 40-day: 45%.
  • A retrospective study was conducted on more than 390,000 individuals over 66 years of age who underwent minor ambulatory surgical procedures. Those who received a prescription opioid analgesic within seven days of discharge were 44% more likely to continue using opioids one year after surgery.
  • A large study on opioid-naïve individuals undergoing abdominal surgery indicated they were still using opioid analgesics 3-6 months post-surgery and the adjunctive use of an epidural local analgesia was not protective against persistent opioid use in this population.

The Efficacy of Opioid Alternatives

Several studies have already shown opioid alternatives (including ibuprofen and acetaminophen) can be as effective at treating pain as hydrocodone, oxycodone, fentanyl and other potentially deadly prescription painkillers. Morphine for end-of-life cases of cancer and other highly painful diseases are generally not part of this discussion. The following alternatives have been the subject of research studies:

Medical Cannabis

A 2011 study confirmed cannabinoids and opioids share many similar therapeutic and pharmacodynamics properties including analgesic effects. Cross-sectional and population-level research indicated introducing cannabis into the treatment of chronic pain may result in a reduction or complete cessation of opioid use, thereby greatly reducing the potential for dependence or overdose. A recent systematic review of medical cannabis and mental health suggested possible barriers to using cannabis therapeutically in people with psychotic disorders, and those at increased genetic risk of developing these disorders. While this approach is not for everyone (e.g., pregnant women) and bureaucratic, legal and ideological obstacles unquestionably prevent this intervention in some jurisdictions, medical cannabis shows promise as an alternative to opioids.


Positive allosteric modulators precisely target receptors in the body that amplify natural processes, rather than turning them on or off altogether. A mouse model study analyzed the use of PAM to amplify production of the two pain-relieving brain chemicals, anandamide and 2-arachidonoylglycerol on the CB1 brain receptor, the receptor that responds to tetrahydrocannabinol (THC) in marijuana. Researchers found PAM enhanced the pain-relieving power of anandamide and 2-arachidonoylglycerol without causing the side effects associated with marijuana (e.g., impaired motor function and tolerance). Researchers theorize PAM’s effectiveness is associated with cuing the body’s natural painkillers to hit a limited number of targets at the right time, rather than flooding many receptors throughout the body.

Research on Kappa Opioid Receptor Provides Hope

In order to create better opioids, it’s necessary to understand the structure of their four primary brain receptors: delta, kappa, mu and nociceptin. Research has shown most of the negative side effects of opioids are tied to the mu opioid receptor. Recently, scientists at the University of North Carolina School of Medicine and collaborators solved the crystal structure of the activated kappa opioid receptor (KOR) bound to a morphine derivative. Based on this knowledge, they created a new drug-like compound that only activated the KOR, a key step in developing new pain medications. Although drugs targeting KOR are not associated with addiction risk, they can cause hallucinations and dysphoria. Now the goal is to produce a drug solely targeting the pain-relieving parts of the KOR structure. While this research holds promise, the drug-like compound has only been tested in cell cultures, so it’s a long road ahead before this type of painkiller will be available to humans.

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