When I heard about the new AvertD genetic test, pronounced like “averted,” I was compelled to contact the CEO of SOLVD Health, the maker of AvertD, and ask him to answer some of my questions. To my surprise, he was willing to do so, and here is what I learned from the training documents that will be mandatory for all prescribing MDs.
First, AvertD is not for use in patients receiving treatment for chronic pain, period. This was good to hear because my greatest fear was that patients stable on their treatment would be thrown off their medications because they were deemed to be “at risk.” Every patient is at risk. Doctors understand this even if the DEA does not.
Second, the test results should not be used alone to make any decisions regarding treatment. The results should be combined with a complete clinical evaluation and used to inform the physician and patient of the potential for increased risk. A potential risk is not absolute or even determinative.
Third, an elevated genetic risk is not synonymous with a determination that the patient will or will not develop OUD, nor does it provide any information about the genetic risk of the patient’s relatives, as the test is based on fifteen genetic variants that work in concert to increase risk.
Fourth, the test should only be used on someone over the age of 18 with the patient’s informed consent prior to receiving a first prescription for oral opioids. This last is critical to me. If it does not apply to patients already on opiates, that changes everything.
What the test results do tell you is whether or not you are in the 20 percent of the population that carries an increased risk of developing opioid use disorder if exposed to these medications. What it does not do is tell you absolutely that it is safe to use opioids or that they should be contraindicated. Due to factors like epigenetic expression and life experience.
The test’s performance was established based on clinical studies involving 381 patients, of whom 174 had a clinical diagnosis of opioid use disorder according to DSM-5 criteria, while the other 207 did not. Looking for genes or combinations of genes predominantly found in those suffering from this condition. From these scans, the scientists identified fifteen single nucleotide polymorphisms (SNPs) associated with the OUD diagnosis.
A look at these SNPs is informative about the complicated way that opiate addiction works. One gene coded for the serotonin 2A receptor (5-HTR2A). The SNP is (5-HTR2A C>T), which means that a thymine molecule has been replaced by a cytosine in the DNA, a single DNA change or polymorphism. 5-HT2A is associated with neuroplasticity and is targeted by hallucinogens like LSD, mescaline, and psilocybin. Interestingly, these chemicals have been found to help some people struggling with addiction.
There are dopamine receptor gene variants coding for D1, D2, and D4, with another SNP being a variant of the dopamine transporter. How long a neurotransmitter stays in the synaptic cleft is directly related to the strength of its effects. We use selective serotonin reuptake inhibitors to treat depression and acetylcholine esterase inhibitors to treat Alzheimer’s. And one for beta-hydroxylase, which turns dopamine into epinephrine and norepinephrine, reducing the amount of dopamine on hand.
Not surprisingly, of the fifteen genes found to be associated with an increased risk of OUD, twelve are heavily expressed in the nucleus accumbens itself. This is the brain’s reward-targeting center, where the feeling of euphoria seems to be generated and where addiction happens. Dopaminergic pathways from the ventral tegmental area to the nucleus accumbens are responsible for dopamine release in the nucleus accumbens and are critical to the development of addiction.
How much of a neurotransmitter is released and how rapidly it undergoes reuptake or degradation can affect our risk of addiction. One illustrative example is alcoholism. Alcohol is seen by the body as a toxin and is broken down by an enzyme called alcohol dehydrogenase. This enzyme is coded by the ADH1B gene. If you inherit the ADH1B2 variant (also called ADH1B*2), then you will process alcohol at a faster rate than those who carry other variants.
People with this variant experience unpleasant effects from alcohol, such as facial flushing, nausea, and an elevated heart rate. In short, you won’t feel good, so this allele is associated with a lower risk of alcoholism. On the other hand, a slow metabolizer usually won’t have these uncomfortable reactions and will be at a higher risk of alcoholism. The gene that codes for aldehyde dehydrogenase, the next step in detoxifying alcohol, is important, too, because if it is too slow, a severe flush reaction can occur.
Most people find this unpleasant, and this almost immediate aversive reaction usually creates a lower risk for alcoholism. The medication disulfiram (Antabuse) works in a similar way to inhibit the aldehyde dehydrogenase enzyme, giving someone the same effect as the protective genetic variant would, causing nausea, vomiting, headache, rapid heartbeat, and facial flushing. This treatment can help people stop using alcohol. A test for these gene variants could help warn someone that they are vulnerable.
One of the other alleles codes for Catechol-O-Methyltransferase (COMT), which is related to the processing of epinephrine, norepinephrine, and dopamine. The gene is carried on chromosome 22, and the Val158Met polymorphism is an SNP of particular interest. The Val/Val genotype is associated with high cognitive performance under stress, while the Met/Met variant may have a higher sensitivity to stress with enhanced emotional processing and seem to be more prone to anxiety disorders.
Four of the SNPs are related to opioid receptor variants: two for the mu opiate receptor, the target for endorphin, one for the dynorphin-targeted kappa receptor, and the other for the enkephalin-targeted delta receptor variant. Activation of the mu receptor is associated with a feeling of euphoria, while activation of kappa can generate dysphoria. A more responsive mu receptor variant combined with a less responsive kappa variant could influence a stronger reinforcing euphoric effect.
The next SNPs in the panel relate to GABA, the brain’s major inhibitory neurotransmitter, and galanin. Galanin is a neuropeptide found in the hypothalamus, hippocampus, amygdala, and spinal cord, where it modulates other neurotransmitters’ activity. It is related to pain perception, stress and anxiety response, appetite regulation, and neuroprotection. The third one relates to the gene coding for methylene tetrahydrofolate reductase, which is critical for DNA synthesis and repair. Finally, we come to ATP Binding Cassette Transporter I gene, associated with interindividual differences in drug response.
So, how should this test be used? When a patient is scheduled for an elective procedure, and you inform them of the risks and benefits related to the procedure and their treatment afterward, the test can be performed using a buccal swab and sent to the lab. About 72 hours later, the patient and physician will know if the patient carries the 15 allele variants that put them at a genetically increased risk of addiction. With this knowledge, they can make an informed decision about post-surgical care.
This is the future of medicine and not just for addiction. Tests like these could dramatically change the practice of medicine. Instead of guessing whether your patient is one of the tens of thousands helped by post-MI/CVA aspirin or one of the hundreds killed by it, we may soon know before we give it. We also may not have to find out if someone is deathly allergic to an antibiotic after we give it. Knowing more about your patient helps a physician make better decisions about their health care.
What about insurance companies using your genetic information to discriminate against you? Using this test to restrict your access to the only effective medications for severe chronic pain? Will you be left in agony because some government or corporate functionary has decided you are too “at risk” of effective treatment? As the DEA is blatantly doing all over this country right now? While nothing can prevent the federal government from breaking the law, there are special protections for genetic information.
These protections fall under the Genetic Information Nondiscrimination Act (GINA), which was enacted in 2008 and prohibits discrimination by health insurance companies and employers based on genetic information. Employers cannot make hiring, firing, or promotion decisions based on genetic information, and health insurance companies cannot deny coverage, adjust premiums, or impose preexisting condition exclusions. The Americans with Disabilities Act also provides some protection.
I think that genetic information should fall under the same protections as psychological counseling records, which are held in separate files not generally released without a specific subpoena. The CEO of SOLVD Health, Dr. Keri Donaldson, agrees. Patients have the right to be heard and have their autonomy protected and respected when it comes to their medical treatment. This test is just one factor that will need to be considered when deciding whether or not to start someone on opiates.
But it is information the patient has a right to know. So why all the backlash against the test? I have noticed that the most vociferous voices against this objective opioid risk test are coming from the purveyors of proprietary, subjective tests that use secret algorithms to determine opioid risk. The rise of oxycodone overdose and fentanyl poisoning deaths, as well as the billion-dollar lawsuits against pharmaceutical manufacturers and distributors, has come to an entire industry based on addiction.
This industry, for the most part, is composed of people who can fit mainly into three categories. The first is what I will call opioid prohibitionists; these are the true believers that opioids are poison and anyone who prescribes them is a drug dealer. Some of these people have lost loved ones to overdose and, like the alcohol prohibitionists of the early 1900s, are determined to stamp out this threat. The DEA uses these people to propagate that viewpoint as it helps them get funding and power.
The next group, sadly, is my addiction science colleagues. Many of these providers, because they witness the consequences of addiction daily and do not see the agony suffered by chronic pain patients, have come to believe that all opioid use is a disorder, with prescription opioid use disorder actually being put forward as a potential diagnosis by some. Arguing, contrary to the DSM-5, that physical dependence and withdrawals are signs of addiction in persons on chronic opioid therapy.
It is these unproven, non-evidence-supported opinions that are being presented to juries as the standard by which opiate treatment should be judged. The ever-changing secret and proprietary algorithms that the pain-treating physician failed to follow are being sold to the federal government to aid its efforts to dictate the practice of medicine in this country. The biggest threat to these subjective unsupported tests is an objective, evidence-based test.
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.
