The German pharmaceutical company Grunenthal has announced the start of a human addiction potential (HAP) trial of a first-in-class analgesic called cebranopadol, described as “less addictive” than previous medications. We’ve been down this road before.

This medication is both a mu-opioid peptide and nociptin/orphanin FQ peptide (NOP) receptor agonist. I must confess I had to look up the last one. NOP receptors are a type of kappa-type 3 opioid receptor coded by the OPRL1 gene and are members of the G protein-coupled opioid receptor subfamily. This receptor is naturally bound by a neuropeptide called nociceptin. This seems to be an odd target choice as the name nociceptin should clue us in that this chemical may be related to pain. Nociception is the perception of pain.

While the mu-opioid receptor is associated with a feeling of bliss or euphoria, the kappa-opioid receptor is associated with a feeling of dysphoria, though kappa activation still produces analgesia. The hope seems to be that by balancing the mu-opioid and kappa opioid receptor activation, we can relieve pain without increasing the risk of addiction. My response would be, yes, you can, but for whom? This has been tried in the past.

Tapentadol, also called Nucynta, was developed in the 1980s, also in Germany, for the treatment of pain. It is a mu-opioid agonist and norepinephrine transporter inhibitor. Similar to the milder medication tramadol. Just like tramadol, it also lowered the seizure threshold. However, it turns out that tapentadol also binds the kappa-opioid receptor. In my experience, this dual activation of mu-opioid and kappa-opioid receptors results in patients having very divergent experiences. Some would come back saying it worked fine, and others would come back saying it made them feel terrible. This is because the human experience of pain and happiness or satisfaction is so variable as to be impossible to assess simplistically.

I think this new medication will probably work fine. For some people. And not at all for others. Let me explain why I think this way and why I believe that we need custom-made medications tailored to each individual’s unique genetic, epigenetic, and behavioral attributes.

First, we know that genetics can influence the incidence of addiction on exposure to mu-opioid agonists like heroin. I wrote an article on that study, but to summarize. A set of four genes called JUN, CEBPB, PRKCB, and ENO2 (also called CEBPG) were shown to predict the diagnosis of heroin addiction with an accuracy rate of about 85 percent. That, if it holds up to scientific scrutiny, is an amazing discovery. The fact that what has been branded a moral failing turns out to have an extremely powerful genetic component could be paradigm-shifting. For good or bad depends upon who considers this knowledge in their actions, governments, or physicians. I can see pogroms to weed out the “bad” genes in the name of the public good, but I digress.

While it has long been known that the opioid receptor system helps regulate pain perception, mood, and addiction, it also turns out that mu-opioid receptor variations are associated with the emotional reaction of frustration. In a human study of the individual differences in sensitivity to the downshift and subsequent recovery models of vulnerability and resilience in the face of loss, published in Nature, it was found that the widely prevalent A118G mutation was linked to reward loss, suggesting that carriers of this gene “exhibit vulnerability in frustration, characterized by less persistence in a frustrating task and lower recovery from a reward loss.” “The increased frustration observed in G-carriers adds to a growing literature that characterizes the A118G phenotype as having an altered opioid tone that leads to the common outcomes of differences in emotion regulation, pain sensitivity, and reward processing.” This simple single mutation, only one of thousands that need to be analyzed, is responsible for a variation in human behavior that can influence a person to give up or keep trying. This difference is fundamental to success in addiction treatment. No matter how many times you try and fail, if you keep trying, there is at least a chance of success. Once you give up, that chance is gone, and an individual’s ability to keep going in the face of adversity has been shown to be greatly influenced by this single gene.

There will undoubtedly be other genes that moderate or compensate for this gene, as human behavior is far too complicated to be reduced to a “cookbook” method of medical practice. No matter what government agencies may tell you.

Now to the crux. The FDA has approved a new test for the risk of opioid use disorder. A company called AutoGenomics has been approved to market its AvertD test to determine which patients have an increased risk for opioid use disorder. This test is supposed to be used to assess adult patients before their first use of oral opioid pain medications for acute pain. The emphasis on acute is mine. The test uses a cheek swab to check for fifteen genetic polymorphisms involved in the brain reward pathway associated with opioid use disorder. What does this mean for us and our patients? How long before a child with a broken leg, screaming in the emergency room, must wait while a test like this is being run? Determining whether or not they can get adequate pain relief? Remember that we do not have an effective replacement for opioid analgesics yet. NSAIDs inhibit bone healing and increase bleeding, while APAP is not sufficient for severe pain and can damage the liver. We need a better way to shut off pain in the emergency room, and we don’t have it right now.

In the above case, we have a patient in severe acute pain. This pain will persist for several days or even weeks. If we do not adequately treat severe acute pain, we are predisposing our patients to developing severe chronic pain. So in the above patient, you must decide between not testing at all, risking a charge of being “willfully blind,” or overriding positive test results and being prosecuted later if the patient dies of an overdose decades down the road. There is no statute of limitations on murder. You could decide to treat despite a positive test result and then be arrested for putting a patient “at risk of addiction.” A charge the DEA has been able to convict hundreds of doctors for over the last few years. If you choose not to treat because of a positive test, you could later be blamed if the patient develops severe chronic pain. Medicine is complicated, and sometimes there are no good choices. Some of you will recognize the phrase, “It is possible to commit no mistakes and still lose.” By the way, genetic tests have been deemed “unnecessary” by DEA-enforced algorithms, and ordering them helps get you labeled as a criminal doctor. I pose the argument that doctors need qualified immunity even more than police officers, to practice medicine in the political and prosecutorial minefield of modern America.

L. Joseph Parker is a distinguished professional with a diverse and accomplished career spanning the fields of science, military service, and medical practice. He currently serves as the chief science officer and operations officer, Advanced Research Concepts LLC, a pioneering company dedicated to propelling humanity into the realms of space exploration. At Advanced Research Concepts LLC, Dr. Parker leads a team of experts committed to developing innovative solutions for the complex challenges of space travel, including space transportation, energy storage, radiation shielding, artificial gravity, and space-related medical issues. 

He can be reached on LinkedIn and YouTube.