A Potential Solution to Opioids' Adverse Effects

As computational techniques become more sophisticated, the idea of targeted therapeutic treatments sans adverse effects could become reality.

Our understanding of pain, including its pathogenesis and treatment, is constantly evolving.

Despite having several validated objective assessment scales, pain is often subjective in the sense of being based on what the patient reports. As a result, treating patients appropriately and effectively is challenging and not well defined.

Opioids are commonly prescribed for both acute and chronic pain because of their high potency and patient-perceived analgesic effect. Unfortunately, they’re associated with several adverse effects that can significantly impact a patient’s functional status and well-being. They include constipation and respiratory depression, among others.

Luckily, researchers may have found a way to achieve opioid analgesia while avoiding these adverse effects.

When opioid agonists bind to μ-opioid receptors on neurons, it activates the G-protein signaling pathway and the β-arrestin pathway. The former produces analgesia, while the latter results in constipation, respiratory depression, and other physiologic manifestations.

Using computational analyses, researchers have identified a molecule with affinity for the G-protein pathway that doesn’t affect the β-arrestin one.

Essentially, they screened a library database of more than 3 million chemical structures, focusing on structures distinctly different from existing opioid analgesic molecules. To accomplish this, they used molecular docking, which computationally analyzes the physical ligand-receptor interaction between all screened chemical structures and the crystal structure of the μ-opioid receptor.

In doing so, they identified a chemical structure, which they named “PZM21”. In vitro studies revealed PZM21 is a selective agonist of μ-opioid receptor G-protein activation lacking appreciable β-arrestin recruitment.

To test the molecule’s therapeutic properties, the researchers injected mice with either 10 mg/kg morphine or 20 mg/kg PZM21 and recorded time to hind paw reflexive withdraw after the mice were placed on a 52.5 oC hotplate. They noticed mice receiving PZM21 achieved 87% maximal possible effect at just 15 minutes, while those receiving morphine plateaued at 92% maximal possible effect at 30 minutes.

They also observed a prolonged analgesic effect in mice receiving PZM21, evidenced by an 8% metabolism of the molecule after an hour of administration. At 120 minutes, maximal dose PZM21 still provided approximately 60% maximal possible effect, while maximal dose morphine only provided less than 20% maximal possible effect.

Although PZM21’s analgesic profile appears promising, its adverse effect profile is more interesting. Compared with mice injected with morphine, those injected with PZM21 had a significantly lower constipating effect, although PZM21 still reduced defecation.

Using a plethysmograph, the researchers measured the mice’s respirations after administering equianalgesic doses of morphine and PZM21 to 2 separate groups. Although respiratory frequency was significantly reduced in the morphine group, between PZM21 and placebo, it was nearly indistinguishable. Interestingly, the respiratory depression effects of morphine lasted significantly longer than its analgesic effects, further supporting the dual cellular pathway of μ-opioid receptor agonism.

These findings may advance the way we think about and manage pain. As computational techniques become more sophisticated, the idea of targeted therapeutic treatments sans adverse effects could become reality.

It’s still unknown whether PZM21 has opioids’ addictive properties, but it will certainly be interesting to follow this molecule’s progress.

The views expressed in this article are those of the author and should not be attributed to Mayo Clinic.


Manglik A, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature. 2016 Aug 17:1-22.