Identifying Patients Who Need Higher Methadone Doses

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According to opioid dependency treatment programs, African American patients are more likely to report methadone under-dosing than European Americans.
According to opioid dependency treatment programs, African American patients are more likely to report methadone under-dosing than European Americans.

The variation in response to pharmacological agents between individuals has been recognized for decades. However, the underlying genetic basis that provides a rational explanation for the observation that different individuals can display widely different responses to the same pharmacological agent came to light with the sequencing of the human genome, which allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphisms (SNPs).1,2

Polymorphism at the level of drug receptors, transporters, or other proteins involved in drug metabolism or action may have an impact on the effect of a drug, eg, by dampening its efficacy, or by increasing its toxicity. Genetic polymorphisms for many drug targets and enzymes involved in drug metabolism have been identified, particularly for anti-cancer drugs.3 Experts estimate that genetic factors account for 20% to 95% of patient variability in response to individual drugs.4 As a result, despite significant advances in pharmacotherapy, challenges related to patient subpopulations experiencing  serious to fatal adverse events or not responding to standard therapy remain.

The impact of genetic polymorphism is evident in many clinical areas, including pain management. Evidence is accumulating that supports the notion that an individual's specific response to pain or pain treatments may be affected by particular gene polymorphisms.

Cytochrome P450 2D6 (CYP2D6) genotype has been implicated in the response to opioid analgesics that depend on its metabolism for bio-activation. Variations in the CYP2D6 genotype may determine how well an individual responds to opioid analgesics.5,6 For example, “poor CYP2D6 metabolizers” (PMs) have lower concentrations of active metabolites of codeine (morphine), tramadol (O-desmethyltramadol), oxycodone (oxymorphone), and hydrocodone (hydromorphone), compared with “extensive metabolizers” of CYP2D6 (EMs), for similar treatment doses. PMs may therefore fail to  achieve pain relief with these opioids compared with EMs.

The role of genetic polymorphism on postoperative pain and its response to treatment was highlighted in a study investigating the impact of several genetic variants on pain, opioid consumption, and opioid side effects. Results from this study indicated that the A118G allele variant of OPRM1 has the greatest impact on inter-individual differences in response to opioids in the postoperative patients studied.8,9

Morphine and other µ-opioid agonists are among the most commonly prescribed narcotic analgesics in the management of moderate-to-severe pain. While effective, these analgesics have highly addictive properties. The  well-documented challenges resulting from opioid use and abuse10 prompted the Centers for Disease Control and Prevention to publish a guideline and checklist for prescribing opioids in the management of chronic pain.11,12

Methadone – because it reduces opioid-associated craving, withdrawal symptoms, and risk of relapse – is the treatment of choice to wean individuals off opioids.13 Titrating methadone to determine the effective maintenance dose in each patient is critical and can prove challenging. Underdosing methadone increases the risk of relapse in patients, while overdosing may lead to respiratory depression.

Opioid dependency treatment programs indicate that African-American patients are more likely to report methadone under-dosing than European-American patients, but it is unclear whether this observation reflects differences in responses to medication.14,15 Evidence is accumulating that points to genetic variants in African-Americans that influence opioid sensitivity.

Mu-opioids receptors are encoded by the OPRM1 gene, and a common missense SNP, rs1799971, has attracted attention as it plays a significant role in determining the response to opiate analgesics.

A genome-wide association study found  a significant association between the therapeutic dose of methadone and another SNP, rs73568641 in African-Americans (n = 383, P =2.8 x10-8).16 A similar association was not observed in the cohort of European-Americans studied (n = 1027). In addition, a correlation between rs1799971 and the requirement of higher doses of morphine was also reported in opioid-naïve African-American children being treated for postsurgical pain.16

Commenting on the study, Joel Gelernter, MD, professor of genetics and neuroscience at Yale University School of Medicine, and lead author of this study, told Clinical Pain Advisor: “in African-American subjects, this [rs73568641] variant could identify subjects who will need a higher dose of methadone (or morphine)… We suppose that from time to time people on methadone say they are not getting enough of an effect. If a person with 1, or especially 2, effect alleles made such a complaint, one might reasonably be less skeptical about their complaint.”

While acknowledging the limitations of the current study, Dr  Gelernter added: “We do think the paper suggests a role for genotyping to predict dose requirements [for example, of methadone] in the relatively near term.”

Summary and Clinical Applicability

Polymorphism of enzymes involved in drug metabolism may underlie inter-individual differences in response to medication and adverse drug reactions. Although still in its infancy, the field of pharmacogenetics already provides useful clinical information to improve patient care.


According to Professor Gelernter, the main limitation of the study is its limited sample size. In addition, the replication sample included in the study was for morphine, not methadone. This is due to the fact that there are few individuals of African ancestry diagnosed with opioid dependence.



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