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Keeping patients safe from iatrogenic methadone overdoses

From the February 14, 2008 issue

Problem: Methadone, a synthetic opioid often prescribed for the detoxification and maintenance of narcotic addition, has steadily gained popularity as a treatment option for moderate-to-severe chronic pain. When used for the treatment of narcotic addiction, methadone must be prescribed by a practitioner who is registered with the DEA as participating in a Narcotic Treatment Program, and dispensed by an approved pharmacy or a state-approved maintenance program. But when used as an analgesic, methadone may be prescribed by any healthcare provider licensed to prescribe schedule II controlled substances and dispensed by any licensed pharmacy.

Methadone differs from other opioids in several important ways:

  • Interpatient variability in the drug's absorption, metabolism, and relative analgesic potency necessitates a highly individualized approach to prescribing with particular vigilance during treatment initiation and titration.1
  • Incomplete cross-tolerance between methadone and other opioids makes dosing during opioid conversion complex. A high degree of tolerance to other opioids does not eliminate the possibility of methadone overdose.1
  • While methadone's duration of analgesic action for single doses (4-8 hours) approximates that of morphine, the drug's half-life is substantially longer than that of morphine (8-59 hours vs. 1-5 hours).1
  • The half-life of methadone in an opioid-tolerant patient is approximately 24 hours; the half-life in an opioid-naïve patient is approximately 55 hours. Therefore, the duration of effect in an opioid-naïve patient is extended.2
  • With chronic use, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations.1
  • Due to the long half-life, full analgesic effects may not be attained until after 3-5 days of use; thus, the drug must be titrated more slowly than other opioids.1
  • Methadone's peak respiratory depressant effects typically occur later, and persist longer, than its peak analgesic effects.1
  • If methadone is not taken for 3 consecutive days, the patient may lose tolerance to methadone and be at-risk for an overdose if the usual dose is taken.2

Based on methadone's dosing complexities and other contributing factors, FDA, USP, ISMP, and ISMP-Canada have multiple reports of medication errors involving  methadone that have resulted in serious patient harm, including numerous fatalities.

Dosing errors. Prescribers who order methadone for pain, and patients who take this medication, may underestimate the risk of potentially harmful events associated with this drug. In November 2006 (updated in July 2007), FDA issued a Public Health Advisory3 to warn healthcare practitioners and consumers about reports of death and life-threatening adverse effects—particularly respiratory depression, QT prolongation, and Torsades de Pointes—in patients taking methadone. These adverse events occurred in patients just starting methadone for pain control and those switched to methadone after being treated for pain with other opioids. To cite several examples, ISMP is aware of two fatalities and a near-fatality that resulted from prescribing too large of a dose for patients who had previously taken high doses of daily OXYCONTIN (oxycodone controlled release) or VICODIN (hydrocodone and acetaminophen). In these cases, the accumulation of methadone during chronic administration was not considered, leading to a buildup of toxic levels. 

Errors associated with nomenclature. ISMP and FDA have received multiple reports of confusion between methadone and other medications with look-alike names, particularly methylphenidate (METADATE CD, METADATE ER), dexmethylphenidate (FOCALIN), and MEPHYTON (vitamin K). For example, ISMP received a report about a 17-year-old patient with a traumatic brain injury who received 25 mg of methadone BID instead of methylphenidate. Using the hospital's computerized prescriber order entry system, the physician had increased the patient's methylphenidate dose from 20 to 25 mg, but he accidentally selected a 2.5 mg tablet strength, which was available in the hospital (1/2 tablets of the 5 mg strength were routinely packaged by the pharmacy). During the order verification process, the pharmacist edited the order to indicate that 10 mg strength tablets should be used, but he accidentally changed the order from methylphenidate to methadone. The mnemonics for these drugs were almost identical: methadone 10 mg = METH10, and methylphenidate 10 mg = METH10T. The computer system did not alert the pharmacist that he had inadvertently changed the ordered medication, rather than the strength of tablets used to prepare the dose. The patient suffered a respiratory arrest after taking two doses of methadone; fortunately, he was resuscitated.

Confusion between mL and mg doses. 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. Prior to admission, the patient had been taking 13 mg/day of methadone, which was prepared in his community pharmacy using methadone in a 1 mg/mL concentration. The attending physician assumed that the hospital carried the same concentration and prescribed 12 mL of methadone daily without specifying the dose in mg. The order was entered into the hospital pharmacy computer system and filled by a technician using a 10 mg/mL stock solution of methadone. The checking pharmacist did not detect the error, as the hospital carried only the 10 mg/mL concentration and the patient's methadone dose did not signal a problem since doses are quite variable. The drug was sent to the nursing unit and administered to the patient. The patient received 120 mg of methadone—approximately nine times more than his usual dose. Fortunately, he vomited most of the medication. Later that day, the error was discovered when a visitor reported that the patient was more drowsy than usual.

Safe Practice Recommendations: To prevent life-threatening errors with methadone, healthcare professionals should consider the following risk-reduction actions.

Prescribing

  • Do not prescribe the drug unless you are familiar with methadone’s toxicities and unique pharmacologic properties.
  • Evaluate the patient’s risk of abusing the drug and his or her ability to comply with methadone’s administration directions. Consider alternative pain medications if the patient is deemed a risk.
  • If prescribing methadone for pain, consider designating all patients as opioid-naïve for the purposes of introducing methadone, no matter how much opioid medication they’ve previously been taking. To start, consider a conservative conversion ceiling dose of no more than 20 mg/day (10 mg/day for elderly or infirm patients).4
  • Do not adjust doses more often than weekly. Allow a steady state of methadone plasma levels to develop, and evaluate patients for untoward effects before titrating the dose upward. Be sure to ask patients about adverse effects before increasing the dose.
  • Prescribe oral liquid doses of methadone in mg, never in mL alone since several concentrations exist.
  • Include the indication for use when prescribing methadone and methylphenidate.
  • Specify the exact time(s) for administration; even daily doses, if taken in the evening one day and in the morning the next day, can lead to an overdose.
  • Avoid concomitant use of methadone with other narcotics, benzodiazepines, and sedatives, as these significantly increase the risk of an adverse event. If patients must take these medications concomitantly, the starting dose and speed of titration for methadone may need to be adjusted downward.
  • Consider restricting ordering privileges for methadone to prescribers with expertise in the management of chronic pain and narcotic addiction. 
  • Closely monitor patients who receive methadone, especially during treatment initiation and dose adjustments.

Dispensing

  • Stock only one concentration of oral liquid methadone in the pharmacy if possible. If more than one concentration is required to manage patients appropriately, prominent warning labels should be applied to distinguish the products.
  • Accept orders for methadone only when the dose is prescribed in mg.
  • Use commercially available methadone solution(s) to prevent compounding errors. If compounding is necessary, prepare the drug according to a standard, written formula, and document the preparation in a manufacturing log.
  • Require a pharmacist to verify the age of the patient, check the patient’s medication profile for other sedating drugs, and independently double-check all methadone orders and doses before they are dispensed.
  • Label all unit-doses with the exact dose (including strength and total volume if dispensing a liquid medication) and the date/time for administration.
  • Include methadone and methylphenidate on the hospital list of look-alike drug name pairs, and take steps to avoid confusion. For example, configure mnemonics in order entry systems to prevent confusion between methadone and other drugs that start with “met...,” especially those with similar strengths. 
  • Separate the storage of methylphenidate products and methadone.

Administration

  • Do not administer methadone until a pharmacist has reviewed the order. 
  • Do not stock methadone in automated dispensing cabinets or unit stock unless a patient is receiving the medication. When the patient is discharged, send the medication back to the pharmacy immediately.
  • Before administering the first dose of methadone to a patient who has been receiving the drug as an outpatient, verify when the last dose was taken by asking the patient or calling the community pharmacy where the patient has been receiving the medication. If a dose has not been taken for 3 consecutive days, contact the prescriber for a dose adjustment to prevent an overdose.
  • Adhere to standard medication administration times. If a dose is missed, check with the physician before administering it later than the scheduled time.
  • Be aware of the signs of methadone overdose (e.g., respiratory depression, lethargy, dizziness, confusion). 

What to Tell Patients

  • Pain relief from methadone does not last for as long as the drug stays in your body. Do not take more methadone than prescribed because it could build up in your body and cause death.
  • Methadone can cause life-threatening changes in breathing and the heartbeat. Seek medical attention if you experience these symptoms: lightheadedness, slow or shallow breathing, confusion, tiredness, inability to think, talk, or walk normally.
  • Take methadone exactly as prescribed. Talk to your doctor if you do not experience the desired effect from the drug after 3-5 days of use.  
  • Do not start or stop taking other medications or dietary supplements without talking to your healthcare provider. 
  • Do not drink alcoholic beverages when taking methadone. 

References: 1) Prescribing information for methadone (Dolophine), accessed at: www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf. 2) ISMP Canada. Methadone: not your typical narcotic! ISMP Canada Safety Bulletin 2003; 3(12):1-2. 3) 2006/2007 FDA Public Health Advisory about methadone, accessed at: www.fda.gov/cder/drug/advisory/methadone.htm. 4) Zero Unintentional Deaths Campaign. Prescribing methadone safely, accessed at: www.zerodeaths.org/assets/prescribing information.doc

ISMP gratefully acknowledges ISMP Canada for granting permission to use selected contents from an article previously published in the ISMP Canada Safety Bulletin (see reference 2).
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