EDUCATIONAL COMMENTARY METHADONE

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1 EDUCATIONAL COMMENTARY METHADONE Educational commentary is provided through our affiliation with the American Society for Clinical Pathology (ASCP). To obtain FREE CME/CMLE credits see the Continuing Education menu on the left side of the screen. Learning Outcomes Upon completion of this exercise the participant will be able to: discuss the use of methadone for addiction treatment and pain management. explain why urine drug testing of methadone and its metabolite 2-ethylidene- 1, 5-dimethyl-3, 3-diphenylpyrrolidine (EDDP) is used to monitor treatment of addiction and pain. interpret the results of urine drug testing for methadone and its metabolite EDDP. Methadone Use Methadone, a synthetic opioid originally developed by German scientists prior to World War II, was introduced into the United States in 1947 as an analgesic. By the 1960s, it was primarily used as a treatment for heroin (and other opioids) dependence. By the mid-1990s, guidelines from various painrelated organizations included the use of methadone for cancer-related pain. In the late 1990s, the use of methadone for chronic non-cancer pain relief increased dramatically, partly due to concerns about the abuse potential of the opioid pain reliever oxycodone. Approximately 30% of the US population suffers from chronic pain, and an estimated 90% of patients who present to pain centers are prescribed opioids. Methadone is relatively inexpensive compared with other opioids, and by 2008 the number of patients taking methadone for pain was three times the number of patients taking it for addiction treatment. This increased use of methadone was followed by a dramatic rise in the number of methadone-related hospitalizations and deaths. From 1999 to 2006, deaths due to methadone increased sevenfold, and methadone demonstrated the largest percentage increase (400%) in hospitalization-related prescription drug poisonings for that time period. Thirty percent of opioid-related deaths involve methadone, but only 5% of the nation s opioid prescriptions are for methadone. This disproportionate increase in methadone use and consequences has led to an increased emphasis on monitoring patients who are treated with methadone for either addiction or pain. Pharmacology The pharmacokinetics of methadone are highly variable. Even clinicians familiar with its use and risks should prescribe methadone cautiously whether for addiction or chronic pain. Methadone is available as a liquid, a solid tablet (5 and 10 mg), a rapidly dissolving wafer or diskette (40 mg), or a powder. Liquid methadone is most commonly used for addiction treatment, while the 5 and 10 mg tablets are most often prescribed for pain management. After oral administration, the onset of action is 30 to 60 minutes and the stated elimination half-life ranges from 2 to 60 hours, with reports of individual cases as high as 120 hours. The primary enzymes involved in methadone metabolism are CYP3A4 and CYP2B6, and the multiple metabolites are all inactive. The main metabolite is 2-ethylidene- 1,5-dimethyl-3,3

2 diphenylpyrrolidine (EDDP), and the primary route of excretion is through the kidneys. The metabolizing enzymes also act on numerous other drugs thereby increasing the possibility of drug-drug interaction due to concomitant administration of methadone and other drugs that either induce or inhibit CYP3A4 and/or CYP2B6. The genetic variability of these metabolizing enzymes adds to the pharmacokinetic variability and makes interpretation of urine drug levels difficult. Excretion of unmodified methadone in urine is ph dependent, with increased excretion observed when the urine is acidic. Approximately 5% to 50% of a dose is eliminated as methadone and 3% to 25% as EDDP. Methadone Maintenance Treatment (MMT) Although methadone s structure is different from that of morphine or heroin, it interacts with opioid receptors in a similar way. When used in opioid treatment programs, daily doses of methadone reduce cravings and prevent symptoms of opiate withdrawal while blocking their euphoric effects. A daily oral dose suppresses narcotic withdrawal for 24 to 36 hours. The patient remains physically dependent on an opioid (methadone) but does not experience the extreme highs and lows leading to the compulsive and disruptive behavior often seen in addicts. When used for addiction treatment, methadone must be dispensed by an opioid treatment program (OTP) that is certified by the Substance Abuse and Mental Health Services Administration (SAMHSA). The treatment process is usually long-term and typically includes three phases: an initial early stabilization period of up to 2 weeks when patients take their initial methadone dose of 10 to 30 mg (often in orange juice) under direct observation; a late stabilization period of 2 to 6 weeks during which the dosage is increased to an optimal dose of 50 to 120 mg for most patients, and an extended maintenance phase. The ultimate goal is to gradually taper the dosage to the point of complete withdrawal from methadone. At some point during maintenance, patients may earn the privilege of take-home doses for up to 6 days. Urine drug testing is the most objective technique for patient monitoring in an OTP and is used for several purposes. The SAMHSA requirement of eight drug tests per year for patients in long-term maintenance is considered a minimal requirement, and some states require more frequent testing. An initial drug screen can be used to confirm and determine the primary opioid and any other drugs that may be abused. Thereafter urine drug testing can be used to verify compliance (methadone) and detect abuse of drugs other than methadone. Results can be used as part of a program of positive or negative reinforcement to reward compliance or reduce privileges due to noncompliance. Drug-testing results are commonly used by OTPs as a performance improvement tool required for accreditation. For example, the percent positive and negative drug test results on patients in long-term maintenance can be monitored. In guidelines developed for OTPs, a consensus panel recommended that if the positive rate for drugs other than methadone exceeds 20%, the OTP should develop new measures to improve outcomes. 1 The positive rate for methadone should be nearly 100% because a lower percentage could indicate noncompliance and/or diversion. Federal regulations require that OTPs maintain diversion control plans (investigation and corrective-action plan) as part of their quality assurance efforts. Another possible use of drug test results is that other agencies concerned with patient

3 progress (e.g., child welfare and criminal justice agencies) may request and use these results with the patient s informed consent. Methadone for Pain Management Unlike methadone s use in addiction treatment where it must be dispensed by OTPs, methadone when used to treat pain may be prescribed by an appropriately licensed and registered practitioner and dispensed by licensed and registered retail pharmacies. Standardized dosing of methadone for pain is difficult and treatment should be individualized. Methadone generally relieves pain for only 4 to 8 hours in contrast to the 24 to 36 hours for suppression of opioid withdrawal symptoms. It may take up to 5 days to achieve full pain relief, so dosage increases should be done slowly. In patients taking other opioids, conversion to methadone should be performed cautiously. Several algorithms for converting from other opioids to methadone are available, and the dose ratios, typically expressed in morphine equivalents, are variable. Factors such as variability in methadone s absorption, metabolism, drug-drug interactions, and relative pain relief potency among patients make prescribing methadone a highly individualized process. The use of urine drug testing as part of a comprehensive patient-monitoring program for pain management is an effective method of detecting misuse of opioids. There is no mandated requirement for periodic drug testing when methadone is used for pain management, but the Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain recommends periodic drug screens in patients at high risk of misuse, abuse, and diversion (sale). 2 Laboratory Testing for Methadone Methadone and its metabolites are detected in urine by several different techniques including immunoassays, high-performance liquid chromatography (HPLC), or gas chromatography coupled with mass spectrometric detection (GCMS). Detection of both methadone and its primary metabolite, EDDP, should be included when using urine drug testing to monitor methadone treatment for addiction or pain management. Immunoassays for methadone and EDDP are the most commonly used method for this urine drug testing. Two separate assays are required because the immunoassays for methadone and EDDP demonstrate little or no cross-reactivity to each other. The most frequently used cutoff concentration is 300 ng/ml for the methadone immunoassay and 100 ng/ml for the EDDP immunoassay. Methadone immunoassays with cutoff concentrations of 200 and 250 ng/ml are also available. The variable pharmacokinetics and potential drug-drug interactions associated with methadone contribute to a range of methadone and EDDP concentrations in patient urine. Interpretation of methadone and EDDP results is shown in the Table. In patients who are compliant, the expected results are: positive for both methadone and EDDP, or possibly negative for methadone and positive for EDDP in those patients who are rapid metabolizers. Negative results for both methadone and EDDP typically indicate that methadone was not ingested but could result from bingeing. These negative results could also occur if levels of both methadone and EDDP are below the cutoff concentrations, which can occur in a dilute urine sample. A technique known as spiking has been used by patients to mimic compliance when diverting

4 methadone for sale, a positive test for methadone is achieved by adding a small amount of the methadone dose to the urine prior to testing, but in this case the EDDP result is negative. TABLE. Interpretation of Urine Test Results for Methadone and EDDP. Methadone EDDP Interpretation Positive Positive Methadone ingested, normal situation Negative Negative No methadone ingested, bingeing, or levels below detection limit Negative Positive Fast metabolism, interaction with other drugs Positive Negative Methadone added to sample ( spiker ) EDDP indicates 2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine. Chromatographic methods and some immunoassays provide concentrations of methadone and EDDP. The ratio of EDDP to methadone can be helpful when interpreting the results. Ratios of EDDP to methadone of >0.60 indicate compliance whereas a ratio of <0.090 strongly suggests spiking. The variable dilution in urine excretion may be corrected by normalizing the EDDP concentration to the creatinine concentration (dividing the EDDP result by the creatinine result). These normalized values could be compared to a reference range to actually indicate overuse or underuse of methadone, and a patent for this application has been issued. 3 In addition to monitoring methadone compliance, urine drug testing is also used to determine use/abuse of other substances including both prescription medication and illegal drugs. Comprehensive drug screening capable of detecting many drugs is desirable, but at a minimum opioids, cocaine, and benzodiazepines should be included in a drug panel used for compliance monitoring. 1 Other drugs such as amphetamines (methamphetamine) should be considered based on regional prevalence or patient history. Testing for alcohol and marijuana is sometimes included. Laboratories should be aware of the analytic parameters (sensitivity, specificity, cross-reactivity, etc.) of the assays used. Immunoassay cross-reactivity to other drugs is of particular concern when interpreting drug-testing results. For example, opioid immunoassays do not detect all opioids, particularly oxycodone, and different immunoassays may have different reactivities. Up-to-date cross-reactivity data is typically listed in immunoassay package inserts or may be obtained from each manufacturer. Ideally laboratories should perform cross-reactivity studies of the most common interfering substances on their reagent/instrument system. At a minimum, they should contact the manufacturer to verify that they have the most recent applicable cross-reactivity information. Unexpected immunoassay positive results should be verified by a confirmatory method such as GCMS because several instances of false positives due to cross-reacting drugs have been reported. A drug-testing panel should include ph and creatinine measurement in order to validate specimen integrity and help interpret results. Creatinine values provide an indication of relative dilution of the sample and as previously mentioned may also be used to normalize concentrations of methadone and

5 EDDP. Measurement of the ph of the urine specimen is used to detect one type of adulteration but because the amount of methadone parent drug in the urine is ph dependent, it can also help explain inappropriate negative methadone results on a patient who is taking methadone as prescribed. Summary Urine drug testing to monitor compliance in methadone treatment programs is mandatory. The highly variable metabolism and excretion of methadone, its increased use for pain management, and the subsequent increase in methadone-related deaths have resulted in an awareness of the need for drug testing in these patients. Monitoring compliance for either addiction or pain management treatment should include detection of methadone and its primary metabolite EDDP. Interpretation of methadone and EDDP results must take into consideration the variable pharmacology of methadone and the analytic characteristics of the assays used for testing. References 1. Treatment Improvement Protocol (TIP) Series 43 Consensus Panel. Guideline: Medication-assisted treatment for opioid addiction in opioid treatment programs: drug testing as a tool. National Guideline Clearinghouse, Available at: Accessed September 2, Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009,10: Larson ME, Richards TM. Quantification of a methadone metabolite (EDDP) in urine: assessment of compliance. Clin Med Res. 2009,7: Available online at: Patent information available online at: &db_query=0%3a%3a0%3a%3a0%3a&markuptype=all. Accessed September 2, ASCP 2010