Keeping patients safe from methadone overdoses.

Problem: Methadone (e.g., Dolophine, Roxane), a synthetic opioid often prescribed for the detoxification of and maintenance therapy for patients with narcotic addiction, has steadily gained popularity as a therapy for moderate-to-severe chronic pain. When used for narcotic addiction, methadone must be prescribed by a practitioner who is registered with the U.S. Drug Enforcement Administration and who is participating in a narcotic treatment program. The drug must also be dispensed by an approved pharmacy or a state-approved maintenance program. However, when methadone is used as an analgesic, any health care provider licensed to prescribe Schedule II controlled substances may prescribe it and any licensed pharmacy may dispense it. Methadone differs from other opioids in several important ways: Variability in the drug’s absorption, metabolism, and relative analgesic potency among patients calls for a highly individualized approach to prescribing. Particular vigilance is necessary during treatment initiation and titration.1 Incomplete cross-tolerance between methadone and other opioids makes dosing complex when patients are switched from one opioid to another. A high degree of tolerance to other opioids does not eliminate the possibility of a methadone overdose.1 Although methadone’s duration of analgesic action for single doses (four to eight hours) approximates that of morphine, methadone’s half-life is substantially longer than that of morphine (eight to 59 hours vs. one to five hours).1 The half-life of methadone in an opioid-tolerant patient is approximately 24 hours; its half-life in an opioid-naive patient is approximately 55 hours. Therefore, the duration of effect is extended in opioid-naive patients.2 Owing to methadone’s long half-life, full analgesic effects might not be attained until after three to five days of use. Therefore, the dose must be titrated more slowly than that of other opioids.1 Methadone’s peak respiratory depressant effects typically occur later and persist longer than its peak analgesic effects.1 As a result of methadone’s dosing complexities and other contributing factors, the FDA, the Institute for Safe Medication Practices (ISMP), and ISMP Canada have received multiple reports of medication errors involving methadone that have resulted in serious patient harm, including fatalities. Methadone represents fewer than 5% of total opioid prescriptions dispensed but one-third of opioid-related deaths nationwide.3 Dosing errors. Prescribers who order methadone for pain, as well as patients who take this medication, may underestimate the risk of potentially harmful events associated with this drug. In November 2006, the FDA issued a Public Health Advisory (which was updated in July 2007) to warn health care practitioners and consumers about reports of death and life-threatening adverse effects (AEs) in patients taking methadone.4 These AEs occurred in patients who were just starting to use methadone for pain control and in those who switched to methadone after using other opioids for pain. For example, the ISMP had learned of two fatalities and a near-fatality that resulted from prescribing too large of a dose for patients who had previously taken high daily doses of oxycodone controlled release (OxyContin, Purdue Pharma) or hydrocodone/acetaminophen (Vicodin, Abbott). In these cases, the accumulation of methadone during chronic administration was not considered, consequently leading to a buildup of toxic levels. Confusion between mL and mg units. ISMP Canada received several reports of dosing errors with the oral liquid form of methadone. In one report, a hospitalized patient received a large overdose of methadone. Before admission, the patient had been taking 13 mg/day, which was prepared as a 1-mg/mL concentration in his community pharmacy. Assuming that the hospital carried the same concentration, the attending physician prescribed 12 mL of methadone daily without specifying the dose in milligrams. The order was entered into the hospital pharmacy computer system and was then filled by a technician who used a 10-mg/mL stock solution of metha done. The checking pharmacist did not detect the error. The hospital carried only the 10-mg/mL concentration, and the patient’s methadone dose did not signal a problem (doses can be quite variable). The drug was sent to the nursing unit, and the patient received 120 mg—approximately nine times more than his usual dose. Fortunately, most of the medication was eliminated by emesis. Later that day, the error was discovered when a visitor reported that the patient was drowsier than usual. Safe Practice Recommendations: To prevent life-threatening errors with methadone, health care professionals should consider the following risk-reduction actions:

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