Genetic Predisposition May Help to Explain Opioid Addiction

In a perfect world, doctors would be able to identify patients who are prone to opioid addiction and prescribe them non-opioid painkillers that wouldn’t lead to dependence.

For years, researchers have been trying to advance care to this point by looking for genes that contribute to addiction. There are currently a number of potential candidates, so patients may request genetic testing to see if the carry one or two copies of susceptibility gene variants before deciding on a course of treatment.


What Are Opioids?

Opioids are a group of sleep inducing pain relievers that specifically interact with an opioid receptor. There are three opioid receptors – µ (pronounced mu), κ (kappa), and δ (delta) – and opioids predominantly bind to the µ receptor. Binding at this receptor can alter respiration, gastrointestinal tract motility, physical dependence, euphoria, and pain relief. Opioids are typically used to relieve acute and severe chronic pain.

Commonly prescribed opioids include: Dolophine (methadone), codeine, hydrocodone, OxyContin (oxycodone), Duramorph (morphine), propoxyphene, Duragesic (fentanyl), Ultram (tramadol), Dilaudid (hydromorphone), Levo-Dromoran (levorphanol), or Demerol (meperidine).


Opioids on a blue background


What Are the Other Types of Pain Relievers?

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.


Gene Variant Alters Opioid Sensitivity

A common gene variant of the µ-opioid receptor gene has been linked to less pain relief and more susceptibility to addiction. Patients with this gene 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 A118G OPRM1 is named for the nucleotide switch (adenine to guanine) at position 118 in the gene opioid receptor µ-1. 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. Researchers originally thought that this altered protein structure led to opioids not attaching to the µ-receptor; however, that was later proved wrong. Now researchers think that receptor function after opioid attachment is altered.




Genetic Testing

Doctors want to test patients for the presence of this gene (A118G OPRM1) and genes like it so they can make better-informed treatment decisions.

Knowing that a person will not experience adequate pain relief when given opiates could change surgical procedures. Sometimes patients experience 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.


Other Gene Candidates Linked to Opioid Addiction

Researchers have suggested that a number of gene variants might be responsible for 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 example, 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.


Gene Variants Associated With Increased Opioid Susceptibility

Just as gene alleles might make you more susceptible to drug addiction, some may make you less susceptible. For example, the A118G OPRM1 gene variant was associated with better response to fentanyl in pregnant women. People who carried two copies of the nerve growth factor B responded better on methadone.


Pills isolated


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.

Sources: combination drugs


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