An estimated 2,452 overdose deaths were attributed to methadone in 2003, up from 623 in 1999. The increase in mortality associated with methadone is primarily related to the use of methadone for pain management and not in methadone treatment settings. A recent SAMHSA report “A National Assessment of Methadone-Associated Mortality: Background Briefing Report” highlights three primary scenarios that have been seen in Methadone associated deaths:
- Accumulations to toxic levels during the start of Opioid Detoxification or beginning methadone maintenance (i.e. the induction period to methadone steady-state and tolerance development) or in pain management with legitimately dispensed methadone;
- Misuse of diverted methadone by essentially Opioid naïve persons or by those who have diminished Opioid tolerance; who also may take excessive and/or repetitive doses in an attempt to achieve euphoric effects;
- Additive or synergistic effects of other CNS-depressant agents, e.g., benzodiazepines, alcohol, heroin or other agents taken in conjunction with methadone (primarily taken for abuse) by either Opioid-naïve or Opioid-tolerant individuals, although the amounts fostering toxicity and death vary across individuals.
Part of the problem is that prescribers may not be aware that while methadone’s duration of analgesic action, which is typically 4 to 8 hours in the setting of single-dose studies, approximates that of morphine, methadone’s plasma elimination half-life is substantially longer than that of morphine; typically 8 to 59 hours (some studies have it to 120 hours) vs. 1 to 5 hours. Methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. With repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. Steady state plasma levels are not usually attained until 3 to 5 days of dosing. Signs of methadone overdose include trouble breathing or shallow breathing; extreme tiredness or sleepiness; blurred vision; inability to think, talk or walk normally; and feeling faint, dizzy or confused. Patients require immediate medical attention If these signs occur.
In the selection of an initial dose of methadone, attention should be given to the following:
- The total daily dose, potency and specific characteristics of the opioid the patient has been taking previously.
- The relative potency estimate used to calculate an equianalgesic starting methadone dose.
- Is the dosing intended for acute or chronic methadone dosing?
- The patient’s degree of opioid tolerance.
- The age and general medical condition of the patient.
For the initiation of pain control using oral methadone in the non-tolerant patient, the usual oral dose starts at 2.5 mg to 10 mg every 8 to 12 hours, slowly tolerated to effect.
More frequent administration may be required to maintain adequate analgesia, but extreme caution is necessary to avoid overdosage, taking into account methadone’s long elimination half-life.
When converting from parenteral methadone to oral methadone, one should use a 1:2 ratio (for example, 10 mg parenteral methadone to 20 mg oral methadone).
Switching a patient from another chronically administered opioid to methadone requires caution due to the uncertainty of dose conversion ratios and incomplete cross-tolerance. The conversion rations in many tables do not apply to repeated dosing of methadone, but were set up for only single - one time dosing. This is an area where deaths have occurred.
The oral morphine to oral methadone conversion for chronic administration can be found in the following table. Be aware that the total daily methadone dose derived from the table may then be divided so as to give a greater than once daily dose (for administration every 8 hours, divide the total daily dose of methadone by 3). Also, be aware that equianalgesic methadone dosing varies not only between patients, but also within the same patient, depending on the baseline morphine, or other opioid dose.
|Total Daily Baseline Oral Morphine Dose||Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Dose|
< 100 mg
20% to 30%
100 to 300 mg
10% to 20%
300 to 600 mg
8% to 12%
600 to 1000 mg
5% to 10%
> 1000 mg
What should healthcare professionals tell patients when prescribing methadone for pain?
- Pain relief from methadone does not last as long as methadone stays in your body, therefore, do not to take more methadone than prescribed because methadone could build up in your body and cause death.
- Methadone can cause life-threatening changes in breathing (it may slow or stop).
- Methadone can cause life-threatening changes to the heart beat that may not be felt.
- Seek medical attention right away if you experience symptoms suggestive of an arrhythmia such as palpitations, dizziness, lightheadedness, or fainting or if you experience symptoms suggestive of a methadone overdose such as slow or shallow breathing; extreme tiredness or sleepiness; blurred vision; inability to think, talk or walk normally; and feeling faint, dizzy or confused.
- Directions you should follow if your pain is not controlled after taking the prescribed amount of methadone.
- Pain relief from methadone should last longer after you have taken it for awhile.
- Tell your doctor if you start or stop other medicines because other medicines can interact with methadone and possibly cause death or life threatening side effects, or result in less pain relief from methadone.
- Tell your doctor if you are breastfeeding because methadone is secreted into human milk. Babies can experience the same serious side effects from methadone as the mother.
Specific Addiction Settings
In the pregnant patient, methadone clearance may be increased, so that lower trough methadone plasma levels and shorter methadone half-lives may be seen. The pregnant woman may need to have her dose increased, or the dosing interval decreased.
In the patient who is to be treated in a detox setting with methadone for the treatment of opioid withdrawal, an initial dose of 20 to 30 mg of methadone will usually suppress withdrawal symptoms. It is important to perform frequent opioid withdrawal assessments. If the initial dose needs further adjustment in the same day, the patient should be asked to wait at least 2 to 4 hours for the peak levels to be reached. An additional dose of 5 to 10 mg can be given, but the total daily dose should ordinarily not exceed 40 mg on the first day and frequent nursing assessments are mandatory as deaths have occurred in early treatment due to the cumulative effects of the first several days of dosing.
In the MTP setting, a study by Caplehorn and Drummer in Australia found the risk of fatal accidental drug toxicity for patients in the first 2 weeks of methadone induction was 6.7 times higher than that of heroin users not in treatment and 98 times higher than long-term MTP patients.
Srivastava and Kahan in their Journal of Addictive Diseases article (Vol 25-3 2006) suggested that patients be divided in high risk and low risk for induction problems. A patient could be considered high risk if he/she was over 65 years old; had respiratory disease; had severe hepatitic dysfunction or was under treatment with a sedating medication along with the methadone.
It was suggested that the initial maximum dose of methadone should be 30 mg and only 10-20 mg in the high risk patient. The dose could be increased by 5-15 mg every 3-5 days in both groups, but the maximum increase in the high risk patient was no greater than 20 mg per week.
What should physicians do?
- Read and follow the prescribing information for methadone.
- Carefully weigh methadone’s risks with its potential benefits before prescribing methadone.
- Avoid prescribing methadone 40 mg dispersible tablets for pain. This product is only FDA-approved for detoxification and maintenance treatment of narcotic addition.
- Closely monitor patients who receive methadone, especially during treatment initiation and dose adjustments.
- FDA Public Health Advisory, 11//06.
- FDA Information for Healthcare Professionals, 11/06.
- SAMHSA TIP # 43.
- Roxane Laboratories Medication Insert – revised 10/2006
- Goodman F., Jones W., Glassman P. Methadone Dosing Recommendations for Treatment of Chronic Pain, Pharmacy Benefits Management Strategic Healthcare Group, United States Department of Veterans Affairs, December 2001
- Pain Management at the End of Life. A Physician's Self-Study Packet. For physicians with prescribing privileges. A Collaborative Project of the Main Hospice Council, Maine Pain Initiative, University of Southern Maine, Muskie School of Public Service, 2006.
- Pereira J, Lawlor P, Vigano A, Dorgan M, Bruera E. Equianalgesic dose ratios for opioids. a critical review and proposals for long-term dosing. J Pain Symptom Manage. 2001 Aug;22(2): 672-87.
- Srivastava A and Kahan M. Methadone Induction Doses: Are our Current Practices Safe? J Addictive Dis. 2006 Vol 25 (3): 5 – 13.
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