Abstract
Methadone-associated overdose deaths have dramatically increased. In order to inform
an evidence-based clinical practice guideline to improve safety of methadone prescribing,
the American Pain Society commissioned a systematic review on various aspects related
to methadone safety. We searched Ovid MEDLINE, Cochrane Library, and PsycINFO databases
through July 2012 to identify studies that addressed 1 or more of 17 Key Questions
related to methadone safety; an update search was performed in 2014 for new studies
related to methadone-related overdose and risks related to cardiac arrhythmias. A
total of 168 studies met inclusion criteria for the review. The purpose of this article
is to highlight critical research gaps in the literature related to methadone safety.
These include lack of evidence on risk factors associated with methadone-overdose
deaths and adverse events, limited evidence to evaluate the comparative mortality
of methadone versus other opioids, insufficient evidence to fully understand the harms
associated with methadone use during pregnancy, and insufficient evidence to determine
effects of risk mitigation strategies such as electrocardiogram monitoring, strategies
for managing patients with prolonged QTc intervals on screening, urine drug testing,
alternative dosing regimens for initiation and titration of therapy, and timing of
follow-up. Therefore, most guideline recommendations are based on weak evidence. More
research is needed to guide safe methadone prescribing practices and decrease the
adverse events associated with methadone.
Perspective
This article summarizes critical research gaps in the literature related to methadone
safety, based on a systematic review commissioned by the American Pain Society. Critical
research gaps were identified in a number of areas, highlighting the need for additional
research to guide safer prescribing and risk mitigation strategies.
Key words
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References
- Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: A mortality assessment study.Addiction. 2009; 104: 993-999
- Assessment of fetal well-being in methadone-maintained pregnancies: Abnormal nonstress tests.Gynecol Obstet Invest. 1997; 43: 25-28
- Sustained attention in methadone patients.Int J Addict. 1982; 17: 1313-1327
- Digit-symbol performance in methadone-treated ex-heroin addicts.Am J Psychiatry. 1976; 133: 1337-1340
- Electrocardiogram characteristics of methadone and buprenorphine maintained subjects.J Addict Dis. 2008; 27: 31-35
- Opioid maintenance treatment during pregnancy: Occurrence and severity of neonatal abstinence syndrome. A national prospective study.Eur Addict Res. 2009; 15: 128-134
- Increase in deaths due to methadone in North Carolina.J Am Med Assoc. 2003; 290: 40
- An investigation of medical examiner cases in which methadone was detected, Harris County, Texas, 1987-1992.J Forensic Sci. 1996; 41: 442-448
- Comparing overdose mortality associated with methadone and buprenorphine treatment.Drug Alcohol Depend. 2009; 104: 73-77
- Prospective randomised comparative study of the effect of buprenorphine, methadone and heroin on the course of pregnancy, birthweight of newborns, early postpartum adaptation and course of the neonatal abstinence syndrome (NAS) in women followed up in the outpatient department.Neuroendocrinol Lett. 2008; 29: 80-86
- Methadone maintenance in pregnancy: A reappraisal.Am J Obstet Gynecol. 1998; 179: 459-463
- Methadone maintenance and male sexual dysfunction.J Addict Dis. 2005; 24: 91-106
- Methadone versus morphine as a first-line strong opioid for cancer pain: A randomized, double-blind study.J Clin Oncol. 2004; 22: 185-192
- Overdose deaths attributed to methadone and heroin in New York City, 1990-1998.Addiction. 2004; 99: 846-854
- An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam.Addiction. 2002; 97: 993-1001
- Methadone maintenance and addicts' risk of fatal heroin overdose.Subst Use Misuse. 1996; 31: 177-196
- Vital signs: Risk for overdose from methadone used for pain relief—United States, 1999-2010.MMWR Morb Mortal Wkly Rep. 2012; 61: 493-497
- Testing positive for methadone and either a tricyclic antidepressant or a benzodiazepine is associated with an accidental overdose death: Analysis of medical examiner data.Acad Emerg Med. 2006; 13: 543-547
- Perinatal addiction: The effects of maternal narcotic and nonnarcotic substance abuse on the fetus and neonate.NIDA Res Monogr. 1984; 49: 220-226
- Polydrug- and methadone-addicted newborns: A continuum of impairment?.Pediatrics. 1982; 70: 210-213
- Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: A systematic review.J Pain Symptom Manage. 2004; 26: 1026
- Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130
- Methadone safety: A clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society.J Pain. 2014; 15: 321-337
- Methadone overdose and cardiac arrhythmia potential: Findings from a review of the evidence for an American Pain Society and College on Problems of Drug Dependence clinical practice guideline.J Pain. 2014; 15: 338-365
Chou R, Weimer MB, Dana T, Pappas M, Mitchell JP: Systematic evidence review on methadone harms and comparative harms. American Pain Society, Glenview, IL, 2014. Available at http://www.americanpainsociety.org/uploads/files/FINAL_Systematic_Evidence_Review_on_Methadone_Harms.pdf. Accessed February 28, 2014
- A community-based evaluation of sudden death associated with therapeutic levels of methadone.Am J Med. 2008; 121: 66-71
- The effect of fluconazole on the clinical pharmacokinetics of methadone.Clin Pharmacol Ther. 1998; 63: 655-662
- Perinatal addiction: Outcome and management.Am J Obstet Gynecol. 1977; 129: 679-686
- A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients.Drug Alcohol Depend. 2002; 67: 177-183
- Risk of drug-related mortality during periods of transition in methadone maintenance treatment: A cohort study.J Subst Abuse Treat. 2011; 41: 252-260
- Measurement of QTc in patients receiving chronic methadone therapy.J Pain Symptom Manage. 2005; 29: 385-391
- Early switching from morphine to methadone is not improved by acetaminophen in the analgesia of oncologic patients: A prospective, randomized, double-blind, placebo-controlled study.Support Care Cancer. 2010; 18: 235-242
- Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: A dose-response study.Psychopharmacology (Berl). 2001; 154: 153-160
- Plasma testosterone in narcotic addiction.Am J Med. 1973; 55: 452-458
- Cognitive impairment among methadone maintenance patients.Addiction. 2000; 95: 687-695
- Fetal exposure to narcotics: Neonatal sleep as a measure of nervous system disturbance.Science. 1980; 209: 619-621
- Impact of maternal drug dependency on birth weight and head circumference of offspring.Am J Dis Child. 1987; 141: 1163-1167
- Hyperalgesic responses in methadone maintenance patients.Pain. 2001; 90: 91-96
- Maternal methadone use in pregnancy: Factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources.BJOG. 2009; 116: 665-671
- Drug-induced long QT syndrome in injection drug users receiving methadone: High frequency in hospitalized patients and risk factors.Arch Intern Med. 2006; 166: 1280-1287
- Abnormalities in thyroid function associated with chronic therapy with methadone.Clin Chem. 1988; 34: 2202-2204
- Methadone-related deaths in Western Australia 1993-99.Aust N Z J Public Health. 2002; 26: 364-370
- Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen.Heart. 2007; 93: 1051-1055
Fingerhut LA: Increases in poisoning and methadone-related deaths: United States, 1999–2005. Available at: http://www.cdc.gov/nchs/data/hestat/poisoning/poisoning.htm. Accessed January 14, 2014
- Comparison of methadone and slow-release morphine maintenance in pregnant addicts.Addiction. 1999; 94: 231-239
- Methadone versus buprenorphine in pregnant addicts: A double-blind, double-dummy comparison study.Addiction. 2006; 101: 275-281
- Prevalence of long QTc interval in methadone maintenance patients.Drug Alcohol Depend. 2009; 99: 327-332
- Methadone-related deaths in Hennepin County, Minnesota: 1992-2002.J Forensic Sci. 2003; 48: 668-671
- An epidemiologic evaluation of long-term methadone maintenance treatment for heroin addiction.Am J Epidemiol. 1974; 100: 101-112
- First do no harm … Reduction?.Ann Intern Med. 2009; 150: 417-418
- Physiological and psychological effects of methadone in man.Arch Gen Psychiatry. 1975; 32: 237-242
- Mortality in heroin addiction: Impact of methadone treatment.Acta Psychiatr Scand. 1990; 82: 223-227
- Grading strength of recommendations and quality of evidence in clinical guidelines: Report from an American College of Chest Physicians Task Force.Chest. 2006; 129: 174-181
- Patterns of abuse among unintentional pharmaceutical overdose fatalities.J Am Med Assoc. 2008; 300: 2613-2620
- Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment.J Sex Med. 2008; 5: 684-692
- Hypogonadism in men receiving methadone and buprenorphine maintenance treatment.Int J Androl. 2007; 32: 131-139
- Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome.Am J Obstet Gynecol. 1977; 129: 417-424
- Rates of adverse events of long-acting opioids in a state Medicaid program.Ann Pharmacother. 2007; 41 ([Erratum appears in Ann Pharmacother. 2007 Sep;41(9):1552]): 921-928
- A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.N Engl J Med. 2000; 343: 1290-1297
- Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: Effects on the neonatal abstinence syndrome.Drug Alcohol Depend. 2005; 79: 1-10
- Neonatal abstinence syndrome after methadone or buprenorphine exposure.N Engl J Med. 2010; 363: 2320-2331
- Methadone-associated torsades de pointes (polymorphic ventricular tachycardia) in opioid-dependent patients.Addiction. 2006; 101: 1333-1338
- Buprenorphine and methadone treatment of opiate dependence during pregnancy: Comparison of fetal growth and neonatal outcomes in two consecutive case series.Drug Alcohol Depend. 2008; 96: 69-78
- The narcotic-dependent mother: Fetal and neonatal consequences.Early Hum Dev. 1977; 1: 159-169
- Differential effects of maternal heroin and methadone use on birthweight.Pediatrics. 1976; 58: 681-685
- Relationship of maternal substance abuse to subsequent sudden infant death syndrome in offspring.J Pediatr. 1993; 123: 120-126
- Heterogeneous impact of methadone on the QTc interval: What are the practical implications?.J Addict Dis. 2008; 27: 5-9
- Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes.Pharmacotherapy. 2003; 23: 802-805
- Effects of methadone on QT-interval dispersion.Pharmacotherapy. 2005; 25: 1523-1529
- Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain.Pain. 2011; 152: 1789-1795
- Buprenorphine versus methadone in pregnant opioid-dependent women: A prospective multicenter study.Eur J Clin Pharmacol. 2011; 67: 1053-1059
- Prospective multicenter observational study of 260 infants born to 259 opiate-dependent mothers on methadone or high-dose buprenorphine substitution.Drug Alcohol Depend. 2006; 82: 250-257
- Neurological assessment of patients on prolonged methadone maintenance.Drug Alcohol Depend. 1976; 1: 305-311
- Factors affecting head growth and intellectual function in children of drug addicts.Pediatrics. 1985; 75: 269-274
- The effect of heroin and multiple drug abuse on the electrocardiogram.Am Heart J. 1973; 86: 663-668
- Impact of methadone treatment on cardiac repolarization and conduction in opioid users.Am J Cardiol. 2005; 95: 915-918
- Buprenorphine versus methadone maintenance therapy: A randomized double-blind trial with 405 opioid-dependent patients.Addiction. 2003; 98: 441-452
- Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.Cochrane Database Syst Rev. 2009; : CD002209
- Methadone maintenance, QTc and torsade de pointes: Who needs an electrocardiogram and what is the prevalence of QTc prolongation?.Drug Alcohol Rev. 2011; 30: 388-396
- Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.BMJ. 2009; 338: b2225
- Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home.J Clin Oncol. 1998; 16: 3656-3661
- Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management.Eur J Pain. 2008; 12: 1040-1046
- Opioid abuse and cognitive performance.Drug Alcohol Depend. 2005; 78: 225-230
- NIH consensus panel recommends expanding access to and improving methadone treatment programs for heroin addiction.Eur Addict Res. 1999; 5: 50-51
- Methadone, methadone treatment and non-fatal overdose.Drug Alcohol Depend. 2000; 58: 117-124
- Results of 313 consecutive live births of infants delivered to patients in the New York City Methadone Maintenance Treatment Program.Am J Obstet Gynecol. 1975; 121: 233-237
- AHRQ Series Paper 5: Grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program.J Clin Epidemiol. 2010; 63: 513-523
- Opioid analgesic involvement in drug abuse deaths in American metropolitan areas.Am J Public Health. 2006; 96: 1755-1757
- Increasing deaths from opioid analgesics in the United States.Pharmacoepidemiol Drug Saf. 2006; 15: 618-627
- A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia.Addiction. 2009; 104: 1541-1548
- Opioid analgesics and rates of fatal drug poisoning in the United States.Am J Prev Med. 2006; 31: 506-511
- Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: A cross-sectional study.Addiction. 2007; 102: 289-300
- A critical review of the causes of death among post-mortem toxicological investigations: Analysis of 34 buprenorphine-associated and 35 methadone-associated deaths.Addiction. 2004; 99: 978-988
- Morphine to methadone conversion: An interpretation of published data.Am J Hosp Palliat Care. 2011; 28: 135-140
- Neuropsychological functioning in opiate-dependent subjects receiving and following methadone maintenance treatment.Drug Alcohol Depend. 2006; 84: 240-247
- Acoustic cry characteristics of infants exposed to methadone during pregnancy.Acta Paediatr. 2009; 98: 74-79
- Methadone withdrawal in newborn infants.J Pediatr. 1972; 81: 523-534
- Effect of chronic maternal methadone therapy on intrapartum fetal heart rate patterns.J Soc Gynecol Investig. 2006; 13: 108-111
- Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: A naturalistic comparison of cognitive performance relative to healthy controls.BMC Clin Pharml. 2007; 7: 5
- Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: Longitudinal change in comparison to healthy individuals.Subst Abuse Treat Prev Policy. 2009; 4: 6
- Oral methadone for cancer pain: No indication of Q-T interval prolongation or torsades de pointes.J Pain Symptom Manage. 2004; 28: 301-303
- The effect of oral methadone on the QTc interval in advanced cancer patients: A prospective pilot study.J Palliat Med. 2010; 13: 33-38
- Long-term effects of prenatal methadone maintenance.NIDA Res Monogr. 1985; 59: 73-83
- Disposition of methadone and its relationship to severity of withdrawal in the newborn.Addict Dis. 1975; 2: 169-178
- Electrocardiographic effects of lofexidine and methadone coadministration: Secondary findings from a safety study.Pharmacotherapy. 2009; 29: 495-502
- The role of methadone in drug-related deaths in the west of Scotland.Addiction. 2003; 98: 995-1002
- Unintentional methadone-related overdose death in New Mexico (USA) and implications for surveillance, 1998-2002.Addiction. 2005; 100: 176-188
- Obstructive sleep apnea is more common than central sleep apnea in methadone maintenance patients with subjective sleep complaints.Drug Alcohol Depend. 2010; 108: 77-83
- Neonatal abstinence syndrome after maternal methadone treatment.Arch Dis Child Fetal Neonatal Ed. 1994; 71: F203-F205
- Fatal poisoning in methadone and buprenorphine treated patients—Are there differences?.Pharmacopsychiatry. 2006; 39: 85-87
- Cognitive-motor performance of methadone-maintained patients.Eur Addict Res. 2000; 6: 8-19
- Narcotic dependency in pregnancy. Methadone maintenance compared to use of street drugs.J Am Med Assoc. 1976; 235: 1121-1124
- Methadone maintenance during pregnancy: Pregnancy, birth, and neonate characteristics.Am J Obstet Gynecol. 1974; 120: 895-900
- Methadone-related deaths in New South Wales.Med J Aust. 1997; 166: 54-55
- Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients.Chest. 2005; 128: 1339-1347
- Doxepin as adjunctive therapy for depressed methadone maintenance patients: A double-blind study.J Clin Psychiatry. 1982; 43: 454-456
- Dose-effect relationship between overdose mortality and prescribed methadone dosage in low-threshold maintenance programs.Addict Behav. 1999; 24: 559-563
- Neonatal behavior after drug dependent pregnancy.Arch Dis Child. 1989; 64: 235-240
- A randomized study on oral administration of morphine and methadone in the treatment of cancer pain.J Pain Symptom Manage. 1986; 1: 203-207
- Methadone-related deaths associated with faulty induction procedures.J Maint Addict. 2003; 2: 57-67
- Central sleep apnea in stable methadone maintenance treatment patients.Chest. 2005; 128: 1348-1356
- Subjective daytime sleepiness and daytime function in patients on stable methadone maintenance treatment: Possible mechanisms.J Clin Sleep Med. 2008; 4: 557-562
- Opiate-related deaths in Dublin.Ir J Med Sci. 2001; 170: 35-37
- Sleep-disordered breathing and chronic opioid therapy.Pain Med. 2008; 9: 425-432
- QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.Arch Intern Med. 2007; 167: 2469-2475
- The source of methadone in overdose deaths in Western Virginia in 2004.J Addict Med. 2011; 5: 188-202
- Methadone-related overdose deaths in South Australia, 1984-1994. How safe is methadone prescribing?.Med J Aust. 1997; 166: 302-305
- Depression and anxiety in heroin addicts: A placebo-controlled study of doxepin in combination with methadone.Am J Psychiatry. 1975; 132: 447-450
- The effect of methadone treatment on the quantity and quality of human fetal movement.Neurotoxicol Teratol. 2004; 26: 23-34
- Maternal methadone dose during pregnancy and infant clinical outcome.Neurotoxicol Teratol. 2010; 32: 406-413
- Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995.Addiction. 2000; 95: 77-84
- Methadone-related deaths and mortality rate during induction into methadone maintenance, New South Wales, 1996.Drug Alcohol Rev. 2002; 21: 131-136
- Neonatal narcotic addiction. Comparative effects of maternal intake of heroin and methadone.N Engl J Med. 1973; 289: 1216-1220
Article info
Footnotes
Supported by the American Pain Society. M.B.W.'s time was partially supported by the Samuel F. Wise Trust.
The authors report no conflicts of interest.
Dear Reader,
The development of guidelines is a complex and costly enterprise. Funding is increasingly reliant on providing impact and outcome data. The American Pain Society requests your assistance in evaluating the impact of the Methadone Safety Guideline. Please follow this link (http://www.surveygizmo.com/s3/1548754/APS-Methadone-Survey) to complete a brief questionnaire before reading the guideline. The survey consists of 11 multiple-choice questions and should take no more than a few minutes.
We also seek readers willing to take a follow-up survey (see instructions at the end of this survey). These data will assist the APS in developing data on guideline impact and thus assist us in securing and determining allocation of funding in the future. We are offering a token incentive for your participation.
Thank you for your cooperation.
Clinical Practice Guidelines Committee
American Pain Society
Identification
Copyright
© 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
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- Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm SocietyThe Journal of PainVol. 15Issue 4
- PreviewMethadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain.
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- Methadone Overdose and Cardiac Arrhythmia Potential: Findings From a Review of the Evidence for an American Pain Society and College on Problems of Drug Dependence Clinical Practice GuidelineThe Journal of PainVol. 15Issue 4
- PreviewThe number of deaths associated with methadone use increased dramatically in parallel with marked increases in its use, particularly for treatment of chronic pain. To develop a clinical guideline on methadone prescribing to reduce potential harms, the American Pain Society commissioned a review of various aspects related to methadone safety. This article summarizes evidence related to unintentional overdose due to methadone and harms related to cardiac arrhythmia potential. We searched Ovid MEDLINE, the Cochrane Library, and PsycINFO databases through January 2014 for studies assessing harms associated with methadone use; we judged 70 studies to be relevant and to meet inclusion criteria.
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- Preview
