Genetic Testing in Pain Medicine—The Future Is Coming – Practical Pain Management – By Steven H. Richeimer, MD and John J. Lee, MD
A patient’s response to pain and opioids is quite variable, making identifying patients who are good (risk-free) candidates for opioid therapy difficult.
Genetic studies, however, have begun to shine light on some of these questions.
This new field of medicine can potentially help physicians choose more effective treatments (similar to targeted cancer therapies), decrease iatrogenic addictions and overdoses by prescreening patients for genetic risks, and possibly even aid in the diagnosis of genetically based pain conditions. [like EDS -zyp]
Genetic testing can be used to explore the genes that encode
- the enzymes that metabolize opioid and nonopioid medications,
- the transporters, the receptors, and even
- the more cerebral aspects of perceiving and processing pain.
This review covers topics at the forefront of genetics and pain medicine, including drug metabolism, addiction risk, and pain sensitivity testing.
Genetics of Drug Metabolism Leading to Personalized Medicine
Currently, the largest area of research in pain medicine and genetics has been in the field of drug metabolism. Individuals all process and metabolize drugs to differing degrees.
Most opioid medications are metabolized by one or more of the cytochrome P450 (CYP450) isoenzymes.
A patient’s ability to metabolize medications is largely based on the type and number of copies of alleles (alternative forms of genes) he or she inherits.
On the one hand, the inhibition of a drug’s metabolism will result in an increase in the blood level of the parent drug and a decrease in its metabolite(s).
On the other hand, induction of a drug’s metabolism results in a decreased blood level of the parent drug and an increase in its metabolite(s).
People who are termed
- extensive metabolizers have 2 normal alleles;
- intermediate metabolizers have 1 normal and 1 reduced allele; \and poor metabolizers have 2 mutant alleles with limited to no activity.
- Finally, ultrarapid metabolizers can have multiple copies of functioning alleles (Table 1).
A prime example of this in pain medicine is the metabolism of codeine. Codeine is metabolized by hepatic enzymes, specifically the CYP2D6 enzyme. Codeine itself is not analgesic; it becomes effective in treating pain only when it is metabolized into morphin
Some individuals completely lack the alleles needed to produce functioning CYP2D6, and they are considered poor metabolizers
These poor metabolizers may never achieve pain relief since they cannot form the active metabolite morphine. By contrast, individuals with multiple copies of CYP2D6, ultrarapid metabolizers, can have fatally high levels of the drug on standard doses.
Other opioids that are partially dependent on CYP2D6 for metabolism include
- oxycodone, and
Approximately 7% to 10% of Caucasians are CYP2D6 deficient,
Although not all opioids depend wholly on a single enzyme for activation, their effectiveness in individuals can vary substantially based on an individual’s genetic makeup
Opioids that do not rely on CYP450 isoenzyme metabolism include
- oxymorphone, and
Patient who use opioids may be at risk for addiction. Addiction involves loss of control, continuation despite significant negative consequences, and preoccupation with obtaining, using, and recovering from the effects of the drug.
Studies of family members and twins have shown that genetic factors contribute to addictive behavior
After establishing that genetic factors contribute to risk of addiction, investigators began to search for specific genetic differences that contributed to addiction potential. Dopamine is a neurotransmitter in the human body that is responsible for a number of tasks, including movement and pleasure. Dopamine’s effect on the mesolimbic dopamine system has been shown to be associated with traits of addictive behavior.
Polymorphisms of the D2 dopamine receptor have been shown to be associated with vulnerability to addiction.
As our scope of understanding grows, we will hopefully be able to use genetic testing as a tool to identify patients at risk of opioid addiction prior to starting them on opioid medications
The focus of genetics in pain medicine pertains not only to medications but also to predicting patient response to pain
there seems to be a genetic component to an individual’s response to pain or the likelihood of developing chronic pain.
One enzyme at the forefront of pain perception, and the possible subsequent development into chronic pain, is catechol-O-methyltransferase (COMT).
COMT is an enzyme involved in degrading catecholamines such as dopamine, epinephrine, and norepinephrine. These catecholamines, when elevated throughout the body, can cause a heightened response to pain.
Inherited personality factors have also been investigated as potentially increasing a patient’s sensitivity to pain.
Life stressors and the inability to adequately cope with them can exacerbate pain for many patients. They subconsciously start catastrophizing by focusing and magnifying painful sensations.
Catastrophizing is a cognitive process characterized by a lack of confidence and control and an expectation of negative outcomes.
Pain catastrophizing is a negative cascade of cognitive and emotional responses to actual or anticipated pain—magnification, rumination, and feelings of hopelessness
In many cases, pain patients “catastrophizing” is an absolutely rational response to the devastating economic, social, and medical consequences of constant pain. See Chronic Pain IS a Catastrophe.
Other posts about catastrophizing are here: https://edsinfo.wordpress.com/tag/catastrophizing/
Now researchers are beginning to look at potential genetic roots for pain catastrophizing.
Kuhnen et al have associated the presence of the short allele in the promoter region of the serotonin transporter gene (5-HTTLPR) with certain behaviors. Patients with this short allele had an increased likelihood of having high levels of anxiety, vulnerability, and negative emotions. These patients had an increased chance of pain catastrophizing.
Genetic testing is also used to diagnose painful conditions.
The benefits gained from personalizing pain management are just beginning to be realized.
With genetic testing, patients can be placed on more effective treatments in a shorter amount of time.
The trial and error process that so often is the start of treatment can be expedited, and efficacious drugs can be ordered immediately.
Early and effective treatment of pain can lead to less time off work, improved quality of life, and potentially decreased chance of developing chronic painful conditions.
However, genetic testing for pain is still in its infancy, and physicians must be cautious when interpreting the results.
Inaccuracies will exist, and it will be possible to make assumptions and judgments of a patient’s risk of opioid addiction and pain sensitivity that would not be warranted and would raise ethical issues.
Yet, in a field where cures can be sparse and therapies can be hit or miss, genetics in pain medicine could have a profound impact in the way we practice medicine.