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doi: 10.1097/ALN.0b013e318164937c
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Understanding Methadone Metabolism: A Foundation for Safer Use

Clark, J David M.D., Ph.D.

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METHADONE has become one of the darling drugs of the pain management community and is used in a variety of situations. Far from being restricted to use in addiction treatment centers, the drug is now frequently prescribed for the management of pain related to malignancies and even more frequently for nonmalignant types of pain. One review found the number of population-adjusted methadone prescriptions increased 727% from 1997 to 2004, and that this increase was due in general to an increase in prescriptions for pain.1 The readers of this journal may also be familiar with the drug’s use perioperatively when a sustained base of analgesia is desired as part of the anesthetic plan or perioperative pain management scheme. Indeed, this drug has many properties making it useful in these settings. It is potent and has high efficacy, excellent absorption from the gastrointestinal tract, no known active metabolites, very low cost, and both oral and intravenous formulations. The weak noncompetitive N-methyl-d-aspartate receptor antagonism possessed by methadone may further enhance the analgesia of the drug. The name of one of the first formulations, Dolophine, in fact, comes from dolor (“pain”) and fin (“end”). What could possibly be the problem with this pain-ending drug? As explained by Totah et al. in the introduction to their article, “Role of CYP2B6 in Stereoselective Human Methadone Metabolism,” the drug has an exceedingly variable but generally slow hepatic clearance.2 The variable but usually very long half-life governed by this slow clearance has raised serious concerns over this drug’s safety.
The chief serious hazard associated with this opioid when used for pain management is respiratory depression. What makes this particular opioid more problematic than most is that accumulation to steady state can take a week or more. This slow approach to steady state levels brings with it the possibility that side effects can also appear slowly. In the majority of cases, the drug is administered to outpatients; therefore, the patients are unmonitored as the drug accumulates. Specific populations such as the elderly or those prone to abuse of medications may be at particular risk for delayed respiratory depression caused by methadone. Data strongly support the notion that methadone’s slow accumulation can have lethal consequences. For example, Sims et al.1 found that the number of methadone deaths increased 1,770% from 1997 to 2003. Appalachian states once hard hit by OxyContin abuse now seem to be particularly hard hit by methadone-related problems as well.3 Many other articles have commented on methadone’s particular problem with slow accumulation and toxicity and have generally recommended a “start low, go slow” approach.4,5 It is quite rational, then, to focus studies on methadone’s metabolism to predict who might be particularly prone to methadone-related toxicity, and under what circumstances toxicity might be seen.
Investigators have for some time been interested in methadone’s hepatic clearance. The cytochrome P450 (CYP) enzyme system has long been known to play a major role in first phase methadone metabolism. The more important unanswered question has been, “Which isoform?” The hepatic CYP enzyme family has approximately 50 members expressed in humans. Many are concentrated in the liver, although CYP-mediated metabolism occurs in many other organs, including the gut, lungs, and brain. Far from drug specific, individual drugs can be substrates for multiple CYPs. Making matters more complex, the predominant metabolizing isoform may depend on which isomer of a racemic mixture of drug is being followed. With respect to methadone metabolism, several isoforms including the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 have been implicated. This might prompt the reader to ask what the value of further study would be if there are so many enzymes known to be involved. The goal of the studies of Totah et al. was therefore not necessarily to ask which enzymes are able under some set of conditions to metabolize the drug, but to assess which isoforms really do dominate human metabolism, thus providing us a more clinically useful metabolic characterization. The answer in this case was not entirely expected. Using a series of pharmacologic tools and a rigorous analytical strategy, the authors were able to implicate the CYP2B6 enzyme as that responsible for the bulk of methadone metabolism in humans, particularly the S-methadone isomer. Therefore, not only overall plasma levels but also the ratio of plasma methadone isomers is controlled by CYP2B6.2
Of special note are genetic factors impacting metabolism through the CYP enzyme system, particularly the CYP2B6 and CYP3A4 isoforms the authors conclude are likely important for hepatic methadone metabolism. Both genes are polymorphic in humans, and the polymorphic nature of both genes has been demonstrated to affect the rates or clearance, production of metabolites, and probability of reaching clinical endpoints for various drugs, including methadone. Crettol et al.,6 for example, attempted to associate CYP2B6, CYP2C9, and CYP2C19 polymorphisms with methadone plasma levels in 209 patients in methadone maintenance with positive associations found for only the CYP2B6 variants. The predominant effects were on S-methadone levels, which is consistent with the findings of Totah et al.2 In a follow-up study by the same group involving 245 patients in methadone maintenance, these authors reproduced their initial genetic associations with S-methadone metabolism and CYP2B6 variants, although CYP3A4 activity was also linked to plasma methadone levels in this study.7 Zanger et al.8 have demonstrated the CYP2B6 enzyme to be highly polymorphic, and more detailed studies will be required to determine which haplotypes of the more than 100 single nucleotide polymorphisms are associated with altered enzymatic activity. Other studies have associated CYP3A4 activity with total methadone plasma concentrations, and possibly with the rare methadone-related complication of prolonged QT interval and torsade de pointes.9 The genetics and impact on disease have been far more carefully studied for CYP3A4, and many publications are dedicated to variants of the gene for this enzyme as they impact drug disposition of opioids, benzodiazepines, chemotherapeutics, and other drugs as well as susceptibility to diseases, particularly cancers.
The field of medicine is experiencing growing interest toward individualizing medical care. This approach to therapy takes into account multiple aspects of a patient’s makeup when selecting and implementing treatments. Determinants of drug metabolism figure prominently in this approach. Methadone is an effective treatment option for many patients but has a clear record of at least one severe complication, respiratory arrest. Better understanding the process of clearance of this drug stands a reasonable chance of improving the safety and outcomes of methadone use in patients, particularly if genetic or other types of profiling could be shown to accurately predict plasma drug levels. Understanding the control of individual isomer levels for racemic drugs in which the isomers have different pharmacologic properties needs to be taken into account. With their expertise in the investigation of drug disposition, laboratories like those of Totah et al.2 are in excellent position to help anesthesiology and its related fields take a lead position in this emerging area of medicine.
J. David Clark, M.D., Ph.D.
Department of Anesthesia, Stanford University School of Medicine, Stanford, California, and Veterans Affairs Palo Alto Healthcare System, Palo Alto, California. djclark@stanford.edu
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References

1. Sims SA, Snow LA, Porucznik CA: Surveillance of methadone-related adverse drug events using multiple public health data sources. J Biomed Inform 2007; 40:382–9

2. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED: Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology 2008; 108:363–74

3. Terpening CM, Johnson WM. Methadone as an analgesic: A review of the risks and benefits. W V Med J 2007; 103:14–8

4. Carroll IR, Angst MS, Clark JD: Management of perioperative pain in patients chronically consuming opioids. Reg Anesth Pain Med 2004; 29:576–91

5. Toombs JD, Kral LA: Methadone treatment for pain states. Am Fam Physician 2005; 71:1353–8

6. Crettol S, Déglon JJ, Besson J, Croquette-Krokkar M, Gothuey I, Hämmig R, Monnat M, Hüttemann H, Baumann P, Eap CB: Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 2005; 78:593–604

7. Crettol S, Déglon JJ, Besson J, Croquette-Krokar M, Hämmig R, Gothuey I, Monnat M, Eap CB: ABCB1 and cytochrome P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006; 80:668–81

8. Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann HM, Schwab M: Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 2007; 8:743–59

9. Routhier DD, Katz KD, Brooks DE: QTc prolongation and torsades de pointes associated with methadone therapy. J Emerg Med 2007; 32:275–8

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