Genetic Marker Helps Explain Opioid Sensitivity

Not every patient responds to opioids the same way, some patients simply do not get the same pain relief from typical doses. Chances are, these patients may possess a specific genetic variation, which could also increase their chances of becoming addicted to opioids.

By Thomas G. Ciccone and Priyank Kumar, PhD

As useful as opioids can be for managing pain, not everyone responds to these drugs the same way. Researchers are learning more about the genetics behind drug metabolism, and in recent years, studies have shown some patients are less sensitive to opioids and more prone to addiction than others.

Opioids act on the μ-opioid receptors (MORs) to produce analgesic effects useful for managing acute and chronic pain. But a common polymorphism found in the μ-opioid receptor (OPRM1) gene – A118G – could make a patient less sensitive to the drug’s effects.

This could present clinical problems for someone being pharmaceutically treated for pain. While there are standard dosages set for different opioid medications, patients with the A118G polymorphism may not receive adequate pain relief from those typical dosages.

“Some people don’t seem to respond as well, and doses need to be raised in order to have adequate pain control, but that increases the risks of side effects, including addiction,” said Priyank Kumar, PhD, an assistant professor and head of laboratory research at the Touro College of Pharmacy in New York, New York.

Dr. Kumar recently teamed up with colleagues Drs. Zvi Loewy and Maureen Sullivan to conduct a timely literature review exploring how this gene mutation could influence drug metabolism and addiction.¹ Their review gleaned numerous insights about the implications of A118G, and they suggest screening patients before receiving opioid-based pharmacotherapy could be a significant way to improve patient response to opioid-based pain therapies.

A118G: Implicated in Reduced Opioid Efficacy

Dr. Kumar and his colleagues looked over about 60 studies published through a 10-year period, all of which concerned A118G. They found numerous studies reporting the A118G single nucleotide polymorphism (SNP) associated with diminished analgesic response to opioids.

In various clinical scenarios, patients with the A118G SNP – rather than the standard A118A SNP –appeared less sensitive to opioid medications. It is trait that negatively could affect patient outcomes, especially post-surgery, considering researchers have found G-allele carriers require a higher mean opioid dose following surgery, compared to AA counterparts.²

This worrisome trend could serve to explain interpatient variability in postsurgical analgesia, which typically shows a noticeable incidence of central side effects, particularly respiratory depression. One of the most common adverse events associated with post-surgical pain management, respiratory depression occurs in about 41% of post-op patients.^3-5

Due to its potential for hypoxic brain injury or even fatality,⁶many G-allele carriers could go undertreated due to medical fears of such consequences now associated with morphine overuse.⁷ Indeed, sub-optimal pain management has been seen in various pain groups containing G-allele carriers, such as adolescents undergoing spine fusion, who showed higher pain scores and less susceptibility to respiratory depression compared to their wild-type (AA) counterparts.⁸

The G-allele is not an anomaly in patient populations, though. One study in the literature review reported 64.7% of a cohort of Caucasian female patients suffering from migraine with aura had tested for the polymorphism, and another study found 85% of Caucasians had associated with the genetic variant, Dr. Kumar told Practical Pain Management.

A Prime Marker for Addiction

Unfortunately, patients with the A118G polymorphism also appear to be more susceptible to addiction, another example of how genetic (and epigenetic) factors could help determine whysome patients seem more vulnerable to addiction than others.

A118G is found on exon 1 of OPRM1, an SNP that exchanges adenine to guanine, leading to asparagine substitution for aspartic acid. This subsequently causes an N-glycosylation site in the extracellular region of the receptor to be lost.⁹  There are 3 different genotypes that exist at this locust.

• AA (homozygous wild type)
• AG (heterozygous)
• GG (homozygous minor allele)

GG mice consistently show reduced morphine reward, associated with a decreased dopamine release in the nucleus accumbens, as well as fewer MOR-binding sites.¹⁰ While GG mice show similar developed tolerance to morphine compared to wild-type mice, the GG allele uniformly blunts morphine-induced hypothermia and hotplate antinociception, and GG mice show marked signs of addictive potential for opioids, including increased place preference, higher NEO-Neuroticism scores, and more pronounced mood disturbances after administering a placebo in place of the narcotic.^11-13

Scanning for A118G and Optimizing Pain Control

Knowing which patients have this genetic variation could be useful for making more precise, effective treatment decisions and practicing caution with long-term opioid use. For instance, one meta-analysis found pregnant women carrying the G allele (AG or GG) actually required less fentanyl doses to achieve effective labor analgesia.¹⁴

“Genetic testing is done routinely when treating illnesses like cancer, and many medications are designed based on this information. But for pain medications, such genetic testing is not popular,” said Dr. Kumar.

And despite the fact that researchers have been finding increasing evidence of the clinical implications associated with the A118G SNP, the costs associated with genetic testing have been a prohibitive factor. But this has not stopped pain management from starting to incorporate more precision methods.

Genetic tests are now examining metabolic effects related to Cytochromes P450 (CYPs) proteins, an area of research also important to understanding how patients react to opioid drugs. It is a topic Dr. Kumar and his students currently are exploring, as well.

The hope is that as genetic testing for these patient traits becomes more accessible and applicable to clinical practice, enhancing pain management options for vulnerable patient groups will optimize pain management therapies and methodologies in the years to come.

“It will help us in designing a better pain management regime for the patients with A118G polymorphism. Genetic testing may explain and predict many of the clinical responses seen with opioids medications, and may help the clinician identify those patients at genetic risk of opioid misuse and addiction,” Dr. Kumar said.

1. Pokotylyuk I, Sullivan M, Loewy Z, et al. (May, 2016).Assessment of the effect of µ-opioid receptor A118G polymorphism in analgesia. Poster presented as part of the Touro College Research Day, Harlem, New York.

2. Hwang IC, Park JY, Myung SY, et al. OPRM1 A118G gene variant and postoperative opioid requirement: A systematic review and meta-analysis.Anesthesiology. 2014;121(4):825-834.

3. Overdyk FJ, Carter R, Maddox RR, et al. Continuous oximetry/capnometry monitoring reveals frequent desaturation and bradypnea during patient-controlled analgesia.Anesth Analg. 2007;105:412-418.

4. Voepel-Lewis T, Marinkovic A, Kostrzewa A, et al. The prevalence of and risk factors for adverse events in children receiving patient-controlled analgesia by proxy or patient-controlled analgesia after surgery.Anesth Analg. 2008;107:70-75.

5. Sadhasivam S, Boat A, Mahmoud M. Comparison of patient-controlled analgesia with and without dexmedetomidine following spine surgery in children.J Clin Anesth. 2009;21:493-501.

6. Lotsch J, Dudziak R, Freynhagen R, et al. Fatal respiratory depression after multiple intravenous morphine injections.Clin Pharmacokinet. 2006;45:1051-1060.

7. Brennan F, Carr DB, Cousins M. Pain management: A fundamental human right.Anesth Analg. 2007;105:205-221.

8. Chidambaran V, Mavi J, Esslinger H, et al. Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents.Pharmacogenomics J. 2015;15(3): 255-262.

9. Huang P, Chen C, Mague SD, et al. A common single nucleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and protein stability.Biochem J. 2012;441:379-386.

10.Robinson JE, Vardy E, DiBerto JF, et al. Receptor reserve moderates mesolimbic responses to opioids in a humanized mouse model of the OPRM1 A118G polymorphism.Neuropsychopharmacology. 2015;40(11):2614-2622.

11. Henderson-Redmond AN, Yuill MB, Lowe TE, et al. Morphine-induced antinociception and reward in ‘humanized’ mice expressing the mu opioid receptor A118G polymorphism.Brain Res Bull. 2016;123:5-12.

12. Peciña M, Love T, Stohler CS, et al. Effects of the Mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects, and associated personality trait measures.Neuropsychopharmacology. 2015;40(4):957-965.

13. Zhang Y, Picetti R, Butelman ER, et al. Mouse model of the OPRM1 (A118G) polymorphism: Differential heroin self-administration behavior compared with wild-type mice.Neuropsychopharmacology. 2015;40(5):1091-1100.

14. Song Z, Du B, Wang K, et al. Effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor: A meta-analysis.Genet Test Mol Biomarkers. 2013;17(10):743-749.