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March 14, 2019 – Genetic predisposition may help to explain opioid based pain relief, addiction, or the combination of both. In a perfect world, and in battling the rampant opioid crises in the US and other parts of the world, doctors would be able to identify those patients who are prone to opioid addiction and prescribe them non-opioid painkillers that wouldn’t lead to dependence. To do so, they would request from pain patients genetic testing to see if they carry particular gene variants which render them susceptible for opioid addiction before deciding on a course of anti-pain treatment.
Are there currently potential candidate genes that would allow to test for such a predisposition to addiction? Research shows that indeed there are such candidates. Thus, a common variant of theµ-opioid receptor gene alters opioid sensitivity and has been linked to less pain relief and more susceptibility to addiction. Patients with this particular gene variant are more likely to experience higher levels of pain at standard opioid doses and therefore require higher concentrations for pain relief; high opioid dosages makes addiction more likely in general. This gene variant is named A118G OPRM1 for the nucleotide switch (adenine to guanine) at position 118 in the opioid receptor µ-1 gene. This gene variant leads to the synthesis of an altered µ opioid receptor protein, which loses an important amino acid (asparagine) for sugar attachment and gains an aspartic acid. This loss of the asparagine and the attached sugar chain alters the shape of the protein and likely alters its function.
There are other gene candidates linked to opioid addiction. One family of genes that has been analyzed is involved in dopamine regulation. A dopamine 2 receptor allele (called rs1800497) was compared in drug users and controls and has been linked to high heroin use and unsuccessful methadone use. Another dopamine-related gene, dopamine 4 receptor, contains a region with a variable number of nucleotide repeats; for , the gene may have a stretch with 3 repeats (ATATAT) or a stretch with 6 repeats (ATATATATATAT). People with the higher numbers of repeats (5 to 7 copies of the repeat) have the desire to try new things (called novelty-seeking behavior). Heroin users often have the dopamine 4 receptor gene variants with a higher numbers of repeats.
Besides the A118G OPRM1 gene, other opioid receptor alleles have also been found to be associated with addiction, for example the C17T OPRM1 gene variant. The combination of the G80T opioid receptor δ 1 (OPRD1) gene allele with the normal allele (G80G), as well as the C921T OPRD1 gene, was found to be more prevalent in heroin users than in controls. OPRK1 is considered a candidate gene because it is involved with the stress response and counteracts the euphoria induced through OPRM1. One allele of this gene (rs1051660) was found more frequently in heroin users.
Neurotrophins, or regulatory proteins that modulate neuronal growth, survival, and differentiation, are also candidate genes linked to addiction. Some variants of the neurexin gene are associated with increased impulsive reactions and behaviors that often lead to more drug use.
Unfortunately, most of the other analgesics are not as useful for treating severe pain and are predominantly used for mild-to-moderate pain. Tylenol (acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen are non-addictive painkillers that are available over-the-counter. Another class of pain relievers is cox-2 inhibitors (like etoricoxib); they are similar to NSAIDs but have fewer side effects.
Another type of pain reliever that is not available over-the-counter is the class of “combination drugs”, which combine addictive opioids with non-addictive analgesics. Percocet and Ultracet are mixtures of an opioid with acetaminophen, and Percodan is a mixture of oxycodone and aspirin. Fioricet is another, less common combination drug used to treat migraine pain and composed of the barbituate butalbital combined with acetaminophen and caffeine.
Knowing that a person will not experience adequate pain relief when given opiates could change surgical procedures. Sometimes patients severe pain during surgery because doctors typically use the minimum amount of drugs required to prevent the development of potential side effects. This risk for severe side effects and severe pain could be reduced if doctors knew which gene variants the patients had. Also, in regards to the management of chronic pain, knowing which patients are most inclined to addiction would allow doctors to focus greater attention on alternatives to medication.
Whatever your status relative to genetic testing might be: Never forget that genes do not dictate your actions. In the case that your genes have been sequenced and you know you carry genes that make you susceptible to addiction, don’t feel defeated and let this override your aspiration to quit. You are perfectly capable of overcoming an addiction; you just might need to work harder.
See here a short sequence on opioid dependence and opioid use disorder: