In Search of the Perfect Opioid

By Maximillian Stevenson, PharmD, MA

As a palliative care clinical pharmacist, I bear witness to the highs and lows of opioid analgesics: the help and the harms. But what if we could invent an opioid that eases pain without all the risks and side effects? What if we could treat our patient’s cancer pain without the awful nausea and constipation? Imagine being able to treat severe pain after a major surgery without having to worry about the risk of postoperative ileus or respiratory depression. Finding a safer opioid is the idea behind receptor-biased agonist opioids.

What is a receptor-biased opioid agonist?

First, a little pharmacology. Based on their structure and function, opioid receptors are one of the most ubiquitous receptors in the body: G-protein coupled receptors (GPCRs). Opioids work by binding to a portion of this receptor on the outside of the cell, leading to a change on the inside. When this conformational change occurs, a subunit (αγ) of the receptor dissociates and gives us the analgesia of opioids (by altering electrolyte signaling and cAMP production). This is what I will call the G-protein effect.

Once the αγ subunit works its magic, another molecule (β-arrestin) swoops in and binds to the intracellular portion of the opioid receptor. Someone had the idea that the activation of β-arrestin signals subsequent pathways that are responsible for the unwanted side effects of opioids. So, if we could bias the G-protein effects over those of the β-arrestin pathway, perhaps we could have our analgesia without the respiratory depression, constipation, and tolerance.

Did it work?

Initial animal studies were promising. Results suggested that the β-arrestin pathway could be driving the need to escalate doses to achieve similar levels of analgesia and therefore, the mechanism behind opioid tolerance. When Pre-clinical trials confirmed what the animal studies had shown, the world was introduced to oliceridine (TRV1), an intravenous opioid agonist that would activate the G-protein effects (good) without triggering the β-arrestin pathway (bad).

In a phase I trial, oliceridine was at least as effective as intravenous morphine using the cold withdrawal test (subjects hold their hands in ice water baths) in healthy male adults. In phase II trials, oliceridine was pitted against morphine or placebo to provide analgesia for adults undergoing abdominoplasty (soft tissue injury) or bunionectomy (musculoskeletal pain). While researchers highlighted that oliceridine significantly reduced pain when compared to placebo, to my eye, the important conclusions of these studies are a bit unclear. At what we consider equianalgesic doses, both morphine and oliceridine were effective for treating pain and yet, both caused typical opioid side effects like nausea, vomiting, dizziness, and constipation.

Phase III trials emphasized the comparison between morphine and oliceridine. Like phase II, these trials pitted oliceridine versus placebo or morphine in bunionectomy (APOLLO-I) and abdominoplasty (APOLLO-II). Again, oliceridine performed comparably to morphine for controlling pain and at near equianalgesic doses, both had typical adverse effect profiles. It is notable that subjects in the Oliceridine group required less antiemetics for nausea than the subjects who received morphine.

In addition to the APOLLO trials, researchers completed an open-label, “real-world” study (ATHENA) using oliceridine for acute pain in different contexts. Oliceridine worked well for moderate-to-severe pain, but this trial did not include a head-to-head comparison with other conventional opioids.

What does this all mean?

In the above trials, oliceridine performed just as well as morphine, but like morphine, shows a clear dose-dependent risk of adverse effects. In my estimation, I agree with the FDA’s thoughts in that oliceridine has a benefit-risk profile similar to other opioids that treat acute pain, and there is no evidence of a safety advantage. While receptor biased agonists are fascinating, they are not the perfect opioid.

In the quest for the perfect opioid, what does the future hold? I think it’s unlikely that we will discover an opioid that has no risk of the most common unwanted side effects (at least no time soon). This leaves us with safer options, such as buprenorphine, or in combination with dopamine-3 receptor antagonists to attenuate euphoria. Overall, the treatment of pain and the use of opioid analgesics are complicated; we ought to continue to treat pain in a holistic, safe manner while the scientific community continues its search for the perfect opioid.

Max Stevenson PharmD MA is a pain and palliative care pharmacist at MedStar Washington Hospital Center and assistant professor at Georgetown University School of Medicine. Listen to him discuss this topic on the Podcast of Pain and Palliative Care Pharmacists.