Patients see their primary care physicians (PCPs) for a variety of medical conditions, chronic pain being one of the most common. An increased use of prescription medications (especially opioids) has led to an increase in adverse drug reactions and has heightened our awareness of the variability in response to medications.
Pharmacogenetics has improved our understanding of drug efficacy and response, opened doors to individual tailoring of medical management, and created a series of ethical and economic considerations.
Since it is a relatively new field, genetic testing has not been fully integrated into the primary care setting.
The purpose of this paper is to review the metabolism of commonly prescribed opioids, discuss the economic and ethical issues, and provide PCPs with an understanding of how to incorporate genetic testing into routine use to improve clinical practice and patient management.
With a rapidly aging population, primary care physicians (PCPs) are seeing a higher incidence of chronic pain conditions.
These patients are often plagued with multiple medical problems, which make their medication management more challenging. Pain medications are some of the most commonly prescribed drugs in the United States, with opioids continuing to be the mainstay of chronic pain management.
Adjuvant therapies such as antidepressants, benzodiazepines, anti-inflammatory agents, or anticonvulsants can also be useful in managing pain, and many (if not most) pain patients may be treated with a combination of these medications. Therefore, PCPs must be increasingly aware of the potential risk for drug-to-drug interactions
Fatal adverse drug reactions have been reported to be the fourth leading cause of death in the USA.
In addition, the “trial-and-error” approach to prescribing medicine is costly and causes delays in effective care.
As personalized medicine becomes more prevalent, these costly approaches to medical care will eventually become obsolete, and streamlined methods guiding therapeutic decisions will prevail.
One of the tools available for implementing a more personalized approach, with greater optimization of patient outcomes, is pharmacogenetic testing.
Pharmacogenetics is a type of genetic test that assesses a patient’s risk of an adverse response or likelihood of responding to a given drug, thereby informing drug selection and dosing
As the personalized medicine movement gains momentum, pharmacogenetic testing will be important across all medical specialties, with an emphasis in primary care, since a majority of all prescription drugs are written in this setting
Pharmacogenetics is a relatively new field, and as yet it is only slowly being integrated into the primary care setting. Many PCPs are still not familiar with how to test, interpret, or apply this technology in clinical practice.
This paper serves as a primer for PCPs to enhance their understanding of pharmacogenetics, with a focus on opioid pain medications.
To understand how opiates are metabolized, it is necessary to start with related terminology.
- Pharmacokinetics is the process by which the body absorbs, distributes, metabolizes, and excretes drugs, while
- pharmacodynamics describes the drug’s effects on the body at the cellular or receptor level.
Genetic polymorphism is the term for variations in the structure of genes, which includes structural changes such as deletion, duplication, and translocation.
Each of these gene alterations is called an allele of the original gene (wild-type).
Having two copies of the same allele is called a homozygous genotype, while having any combination of two different alleles is called a heterozygous genotype.
A single-nucleotide polymorphism (SNP) is the most common altered gene form.
Other Receptors and Enzymes Associated with Opioids and Analgesics
Polymorphisms in the mu opioid receptor itself may cause reduced potency of opioid medications.
For example, the mu receptor subtype OPRM1 is the primary site of action of most opioid medications as well as endogenous endorphins.
This receptor also controls the rewarding effects of nicotine and alcohol.
Whether the patient possesses the wild-type (two normal copies), heterozygous (one normal, one altered) or homozygous (two altered copies) alleles of this gene has been shown to influence postoperative opioid requirement after abdominal surgery.
One of the best-studied OPRM1 SNPs is 118A/G, with the G variant seen in 10–48% of tested patients, depending on the study. Reynolds et al. found that patients carrying the GG genotype required much higher opioid doses to achieve pain relief.
Other receptors such as catechol-o-methyl transferase (COMT) have known variants (i.e. Val/Val, Met/Met) that are associated with increased opioid requirements, fibromyalgia, and a higher risk of addictive behaviors such as gambling and drinking
Chronic pain is one of the most prevalent medical conditions, and pain medications are some of the most commonly prescribed drugs in the United States today.
Unfortunately, there is wide variability in patient response to pain and to pain medications, which may be related to
- pain origin,
- pain sensitivity,
- cultural differences,
- age, and
- prior use of opiates,
- as well as genetic polymorphisms.
The risks of long-term opioid use include death from overdose and drug interactions; the use of more objective measures (e.g. urine levels, genetic testing) rather than subjective measures (pain scores) should aid in determining efficacy, identifying diversion, ensuring patient compliance with therapy, and guiding the management of complex patients.
Over time, genetic testing has become more accessible and less expensive.
However, there are very serious and complex ethical and financial concerns regarding its use that must be addressed prior to widespread implementation of this tool.
And, while the current data are intriguing, there is still no clear evidence that genetic testing—at least for the general population—is effective.
…with the knowledge of a patient’s potential for positive response to a given pain medicine, a physician is armed with critical information that can guide therapeutic decisions in real time.
The incorporation of pharmacogenetic biomarkers holds promise as a means of assessing a patient’s risk of adverse events or likelihood of drug efficacy.
Incorporation of such biomarkers is emerging at the forefront of personalized medicine, and has the potential to improve the utility and efficacy of current strategies and to guide the development of new approaches to pain management.