New research points to a specific gene that may explain why patients show varied responses to taking methadone.
Interview with Evan D. Kharasch, MD, PhD
Prescribing safe, effective dosages of methadone can be a serious clinical challenge for practitioners. A patient’s specific genetic makeup can significantly effect how the drug is metabolized—increasing the risk of overdose and toxicity or withdrawal and inadequate analgesia.1
Now, new research points to a specific genetic subtype that can influence how a patient metabolizes methadone.2 These genetic polymorphisms seem to be more apparent when receiving the drug orally, as opposed to intravenously. Such findings could have important clinical implications in the prescribing of methadone, where genetically-guided dosing could improve pain management efficacy and possibly even save lives, noted the authors of the new study.
Methadone dosing may have just gotten safer—screen for genetic CYP2B6 alleles.
Methadone’s Uses and Dangers
Methadone is a powerful analgesic with a range of clinical uses. Besides its importance in managing acute, chronic, perioperative, neuropathic, and cancer pain, it is a valuable detoxification tool for managing opioid addiction withdrawal. It is generally considered a cheaper option to Suboxone (buprenorphine and naloxone) and more effective for recovering heavy opioid users. Over 300,000 Americans in opioid treatment programs receive the drug annually,3 with more than 5 million Americans receiving methadone prescriptions for their pain.4
However, the safe prescribing of methadone has become a source of major concern in recent years. In 2009 alone, methadone accounted for 2% of all opioid prescriptions, yet was implicated in one-third of all overdose deaths.4 Patients seem to be at highest risk during the initiation of therapy.5
While drug interactions can influence a patient’s disposition to methadone, researchers now believe that a very specific gene –cytochrome P450 [CYP]2B6 —is principally responsible for clinical methadone elimination in the body.6
Researchers are just beginning to understand how varying CYP2B6 profiles produce varying methadone clearance. The CYP2B6*6 allele, in particular, has markedly reduced hepatic expression and activity. By contrast, the CYP2B6*4 allele shows increased hepatic expression. And there are many more alleles associated with CYP2B6, 38 in total identified today.7,8
Understanding Genetic Disposition to Methadone
For years, doctors actually believed an entirely different gene – CYP3A4 – was responsible for methadone clearance in the body. Initially identified as a metabolizer of the drug in vitro, clinical guidelines and publications went on to state CYP3A4 was responsible for methadone disposition in vivo. Studies in recent years, however, have disproved that notion, stating CYP2B6 to be a principal determinant in methadone elimination.
In the new study, researchers at the Washington University School of Medicine in St. Louis, Missouri, conducted an investigation where they administered patients a single dose of simultaneous intravenous (IV) and oral methadone.2 Sixty-four patients took part in the study (34 men, 30 women; 42 Caucasians, 10 African Americans, 10 Asians, and 2 unknown), who were split into cohorts based on their CYP2B6 genotypes, stratified below:
- CYP2B6*1/*1 (n = 21)
- CYP2B6*1/*6 (n = 20)
- CYP2B6*6/*6 (n = 17)
- CYP2B6*1/*4 (n = 1)
- CYP2B6*4/*6 (n = 3)
- CYP2B6*5/*5 (n = 2)
The researchers found the CYP2B6 genotype had a noticeable influence on methadone plasma concentrations, clearance, and metabolism rates. In particular, CYP2B6*6 allele carriers, showed higher methadone concentrations and slower elimination of the drug. This could be a sign patients in this genotype are at higher risk of developing methadone toxicity. And CYP2B6*6 is a common allele found in the general population, with Africans and African-Americans showing a 33% to 50% frequency of the genotype, respectively. The allele also can be found in 62% of people from Papa New Guineans, 14% to 27% of Caucasians, and 10% to 21% of Asians.
On the other hand, the researchers reported that individuals with CYP2B6*4 showed noticeably lower methadone plasma concentrations and much faster elimination of the drug, which is in line with previous research showing CYP2B6*4 (the protein encoded by CYP2B6*4) to have significantly higher rates of N-demethylation in vitro.9 This translational connection could set a significant precedent, where in vitro analysis of other CYP2B6 variants could be utilized to help “forecast clinically significant pharmacogenetics effects,” in patients with other genotypes taking the drug, the authors described.
Oral Methadone More Dangerous Than Intravenous
CYP2B6 polymorphisms were shown to have greater differences reacting to orally ingested methadone as opposed to IV administration. This was a significant distinction considering oral methadone is far more commonly prescribed in pain management and addiction management situations. Repeat (steady state) dosing also appeared to be more consequential compared to single dosing.
“Oral drugs often show a greater influence of genetic variability and drug interactions because of the first-pass effect, whereby drugs taken orally are metabolized in the liver before they reach the circulation,” said Evan D Kharasch, MD, PhD, lead author of the study and a professor at the Washington University School of Medicine. However, since the first-pass effect does not apply to intravenously-administered drugs (typically the perioperative setting), these findings are more relevant to practitioners prescribing methadone in pill form to patients, as the drug is most commonly distributed by primary care and nonpain physicians.10
The study’s findings also could open the doors to establishing metabolizer phenotypes of methadone. For instance, CYP2B6*4 carriers, who show increased methadone metabolism and clearance, may receive inadequate pain relief from standard dosing because of their genetic disposition. Such patients ideally could benefit from increased dose requirements for pain control, or in the context of addiction management, more calibrated dosing to help limit the risk of opioid withdrawal.
According to investigators, these findings raise the important question as to whether CYP2B6 genotyping and “genetically guided methadone dosing” could be the next step towards safer standardized prescribing of methadone. “It is possible that genetic testing could have a measurable preventative effect on methadone overdose rates. However, this needs to be tested in a clinical study before any recommendations could be made,” Dr. Kharasch said.