PRESCRIBING METHADONE FOR CHRONIC PAIN*

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This module provides information about methadone as a risk factor for opioid overdose and specific risk-reduction guidance. It supplements but does not replace the general best practices for opioid prescribing presented in the “Considerations for Safe and Responsible Opioid Prescribing” module. Also, see the “Substance Use Disorder” module regarding methadone prescribed as pharmacotherapy for opioid use disorder.

 

Background

  1. Methadone is a synthetic opioid that is indicated for: a) the management of pain severe enough to require daily, around the clock, long-term opioid treatment and for which alternative opioid and non-opioid treatment options are inadequate, and b) the management of opioid withdrawal and for maintenance treatment of opioid use disorder (OUD). (See also: FDA label)

 

Methadone and opioid overdose

  1. Even at label-recommended doses, opioid analgesics carry the risk of overdose as well as misuse, abuse, OUD, and death.1
  2. Prescribing methadone is complex and requires a cautious, highly individualized approach. Methadone possesses unique pharmacokinetics with extensive inter-individual variability, making it difficult to safely titrate methadone, and increasing the risk of overdose, particularly during initiation of therapy, following dose escalation, as well as in older people, individuals on complex medication regimens, or in people with severely impaired renal or hepatic function.2-4
    1. Methadone is a very long-acting opioid with a mean elimination half-life of approximately 24-36 hours (range, 8 to 59 hours). However, methadone’s duration of analgesic action is typically 4 to 8 hours.4,5 (see also: FDA label)
    2. Steady-state plasma concentrations and full analgesic, and toxic effects are not usually attained until after 3 to 5 days of oral dosing due to slow absorption and onset of action, long half-life, and cumulative effects over time.4,5 (See also: ”” module)
    3. Methadone’s peak respiratory depressant effects typically occur later and persist longer than its peak analgesic effects, particularly in the early dosing period.6 (see also: FDA label)
      1. Tolerance to methadone-induced respiratory depression is slow to develop and may never be complete.7,8
      2. Fatal overdose has occurred due to the respiratory or cardiac effects of methadone, and too-rapid titration (including repeat self-administration by the patient due to waning analgesic effects) without appreciation for the accumulation of methadone over time. (See also: FDA label)
    4. Methadone is not a first choice for a long-acting opioid to treat chronic pain.2,9
  3. Incomplete cross-tolerance between mu-opioid agonists coupled with complex metabolic pathways makes determination of dosing during opioid conversion to, or from, methadone particularly complex.7,8
    1. Even in individuals with a high degree of opioid tolerance (i.e., those receiving long-term, high-dose treatment with other mu-agonist opioids), fatal methadone overdose has occurred during conversion to methadone or during initiation of methadone treatment of OUD. (See also: FDA label)
    2. Adults are considered opioid-tolerant if they have been receiving a total daily opioid dosage equivalent to at least 60 mg of oral morphine (60 MME/day) for one week or longer. (FDA REMS 20181, see ‘Treatment’ section 5a in the “Considerations for Safe and Responsible Opioid Prescribing” This dosage is comparable to:
      • 25 mcg transdermal fentanyl per hour
      • 30 mg oral oxycodone per day
      • 60 mg oral hydrocodone per day
      • 8 mg oral hydromorphone per day
      • 25 mg oral oxymorphone per day
    3. The risk is particularly high when a patient concurrently consumes other respiratory and CNS depressants such as alcohol or benzodiazepines. (See ‘Treatment’ section 5a in the “Considerations for Safe and Responsible Opioid Prescribing” module)
  4. Methadone undergoes hepatic N-demethylation to inactive metabolites by several cytochrome P450 (CYP) isoforms, primarily CYP2B6, CYP3A4, as well as CYP2D6, CYP2C19, and CYP2C9.10-13 (see also: FDA label)
    1. Concurrent use of methadone with drugs that inhibit its metabolism can increase plasma levels of methadone and the risk of unintentional overdose (see risk-mitigation strategies below).
  5. Methadone’s relative affordability ostensibly makes it an attractive alternative for certain patients. Yet despite representing <2% of opioid prescriptions for chronic pain (i.e., outside of opioid addiction treatment programs), methadone has been associated with approximately one-quarter to one-third of all U.S. opioid overdose deaths.14-16 Moreover, methadone was involved in twice as many single-drug deaths as any other prescription opioids.15

 

Risk-mitigation interventions to consider when prescribing methadone for management of chronic pain. 

[Beyond the general best practices for opioid prescribing described in the “Considerations for Safe and Responsible Opioid Prescribing”module. See the “Substance Use Disorder” module regarding methadone prescribed as pharmacotherapy for OUD, and refer to the full prescribing information (FDA label) for important product-specific details]

  1. Do not prescribe methadone:
    1. Unless you are knowledgeable of its complex pharmacokinetics, additional monitoring requirements, and are experienced in using it to manage chronic pain.2,9,17
    2. As a first choice for a long-acting opioid.2,9
    3. To treat acute pain or for patients with intermittent chronic pain requiring an opioid analgesic only “as needed” or for breakthrough pain.2,9
    4. With other CNS and respiratory depressant such as benzodiazepine anxiolytics, non-benzodiazepine sedatives/hypnotics, barbiturates, muscle relaxants, or alcohol.18 (see also: FDA label and the “Substance Use Disorder” module regarding concurrent use of benzodiazepines or other CNS depressants in patients receiving methadone for medication-assisted treatment of OUD)
    5. For patients who have taken monoamine oxidase inhibitors within the past 14 days. (see: FDA label)
  2. Before prescribing morphine, estimate the glomerular filtration rate using either the eGFR or creatinine clearance (ClCr) method. In patients with severe renal impairment (ClCr <10 mL/min), start with 25% to 50% of the dose that would be prescribed for patients with normal renal function.3 (see also: FDA label; see “Renal Impairment” module)
  3. In patients who are not opioid tolerant (see “Considerations for Safe and Responsible Opioid Prescribing” module), start with a low dose (e.g., 2.5 mg every 8 to 12 hours).
  4. In methadone-treated patients, certain drug interactions can lead to an increase in methadone plasma levels that may result in fatal respiratory depression (overdose). Monitor methadone-treated patients using these drugs closely for respiratory depression and over-sedation. Consider consulting a specialist in pain medicine or clinical pharmacology with expertise in opioid pharmacology and drug-drug interactions.2,11-13,20 (see also: FDA label and Drug Interactions Checker)
    1. Concomitant use of inhibitors of primarily CYP2B6 or CYP3A4, and also CYP2D6, CYP2C19, and CYP2C9, particularly when an inhibitor is added after a stable dose of methadone is achieved. Examples of inhibitors: 2B6-clopidogrel, voriconazole; 3A4-ketoconazole, clarithromycin; 2D6-paroxetine, fluoxetine, bupropion; 2C19-pantoprazole, lasoprazole; 2C9-fluconazole, amiodarone.
    2. Discontinuation of inducers of primarily CYP2B6 and CYP 3A4, and also 2D6, CYP2C19, or CYP2C9. Examples of inducers: 2B6-efavirenz; 3A4-rifampin, carbamazepine; 2D6-rifampin, dexamethasone; 2C19-ritonavir; 2C9-phenobarbital.
    3. Conversely, if an inhibitor is discontinued or an inducer is initiated, methadone plasma levels may decrease. Monitor for decreased opioid efficacy or withdrawal symptoms in patients who are physically dependent on methadone. (see: FDA label)
    4. Anti-retroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, and combination lopinavir+ritonavir are known to inhibit some CYPs, but reduce the plasma levels of methadone, possibly due to CYP induction activity.
  5. Closely monitor the patient for respiratory depression or over-sedation during methadone initiation and after dosage escalation. The risk for overdose is greatest at this time because tolerance to an opioid’s respiratory depressant effects is slower to develop and less complete than tolerance to its analgesic or euphoric effects.2,7,8,17
    1. Follow up within 1 to 3 days after initiating or increasing the dose of methadone.9,21 (AAPM 2016, SAMHSA 2012)
    2. Slowly titrate the dose of methadone if necessary to achieve effective analgesia with acceptable tolerability and minimal adverse effects. Increase the methadone dose no more frequently than once per week (five half-lives) to ensure that the full effects of the previous dose are evident.3,9
      1. Because of high variability in methadone metabolism, some patients may require substantially longer periods between dose increases (up to 12 days). (FDA label)
      2. Total daily dose increases should not exceed 5 to 10 mg per week.9
    3. If the dose of methadone is inadequate to manage the pain during a methadone dose titration, consider an immediate-release opioid as a supplemental ‘‘rescue dose.” Begin the immediate release opioid at its lowest effective dosage and prescribe no more than a 7-days’ supply.9
  1. Avoid concurrent use of other medications or substances that are central nervous system depressants, such as benzodiazepines, sedatives/hypnotics, and alcohol in morphine-treated patients. The combination can result in profound sedation, respiratory depression, coma, and death and should be restricted to the minimum required dosage and duration in patients for whom alternative treatment options are inadequate or contraindicated.2,17,23 (see also: FDA label) (See the “Considerations for Safe and Responsible Opioid Prescribing” module and the “Benzodiazepine” module)
  2. Consider prescribing take home naloxone to patients treated with methadone to reverse life-threatening respiratory depression if an overdose occurs. The long duration of action of ER/LA opioids compared with the short duration of naloxone increases the risk of recurrent respiratory and CNS depression that may require repeated doses of naloxone and prolonged surveillance. Educate the patient, family/household members, and caregivers about signs and symptoms of opioid overdose and train them to properly use naloxone if an opioid-related overdose is suspected.2,3 (See ‘Follow up’ section in the “Considerations for Safe and Responsible Opioid Prescribing“ module).

 

Special considerations: Cardiac safety

  1. Cases of QT interval prolongation and serious, potentially fatal arrhythmia (torsades de pointes) have been observed during treatment with methadone.13

    1. These cases appear to be more commonly associated with, but not limited to, patients treated for pain with large, multiple daily doses and higher total daily dose (>200 mg/day).24,25
    2. In cases treated with lower doses, contributing factors included concurrent medications and/or clinical conditions such as hypokalemia.24,25 (see also: FDA label)
  2. Obtain a baseline electrocardiogram before initiating methadone therapy in patients with risk factors for prolonged QT interval, any prior ECG demonstrating prolonged QT, or a history suggestive of prior ventricular arrhythmia.13
  3. Closely monitor patients with risk factors for developing prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a personal or family history of cardiac conduction abnormalities, family history of sudden death, and those taking medications affecting cardiac conduction.13 (see also: FDA label)
  4. Evaluate patients who develop QT prolongation while on methadone treatment for the presence of modifiable risk factors (see Credible Meds for detailed information) such as concomitant medications that are known to increase the QTc interval, cause bradycardia, other arrhythmogenic effects, drugs that might cause electrolyte abnormalities, and drugs that might inhibit methadone metabolism.13,25 (see also: FDA label)

 

Additional Resources

*The information presented in this module highlights some fundamental concepts of opioid prescribing for adult outpatients. It excludes certain populations (pediatrics, pregnancy, patients with active cancer or receiving palliative or end-of-life care) and settings (perioperative, emergency, in-patient). The information provided is intended to support safe and effective opioid therapy and minimize serious adverse outcomes, particularly overdose. It is not intended to be exhaustive nor substitute for consulting a medication’s full prescribing information for complete details and warnings. Links and references to selected, more comprehensive clinical and prescribing resources are provided to facilitate safe and effective opioid prescribing.

  1. FDA-approved drug label information: FDA Online Label Repository or Daily Med (NIH/National Library of Medicine)
  2. Flockhart Cytochrome P450 Drug Interaction Table.20
  3. Drug Interactions Checker
  4. Credible Meds – Resources focused on iatrogenic QT prolongation
  5. Opioid Milligram Morphine Equivalent (MME) Calculators:
    1. New York City Department of Health and Mental Health (online interactive and mobile app)
    2. Washington State Agency Medical Directors’ Group (online interactive and mobile app)
    3. CDC Factsheet: Calculating total daily dose of opioids for safer dosage (manual calculator and mobile app)

 

References

  1. Food and Drug Administration (FDA). Risk evaluation and mitigation strategy (REMS) for opioid analgesics. Available at: https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm
  2. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49. PMID: 26987082
  3. VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain. Veterans Health Administration, February 2017.
  4. Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone. Implications for the treatment of opioid dependence. Clin Pharmacokinet 2002;41:1153-1193. PMID: 12405865
  5. Vendramin A, Sciacchitano AM. Chapter 1.6: Pharmacology and Neurochemistry of methadone. In: Maremmani I. The principles and practice of methadone treatment.  Europad, Sept 20, 2009. Accessed at: Europad Methadone Text 2009.
  6. Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011.
  7. Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008;10:537-51. PMID: 18989788
  8. White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction 1999;94:961-72. PMID: 10707430
  9. American Academy of Pain Medicine (AAPM). The Evidence Against Methadone as a ‘Preferred’ Analgesic. 2014. http://www.painmed.org/files/the-evidence-against-methadone-as-a-preferred-analgesic.pdf
  10. Greenblatt DJ. Drug interactions with methadone: Time to revise the product label. Clin Pharmacol Drug Dev 2014;3:249-51. PMID: 27128829
  11. Turpeinen M, Zanger UM. Cytochrome P450 2B6: Function, genetics, and clinical relevance. Drug Metabol Drug Interact 2012;27:185-97. PMID: 23152403
  12. McCance-Katz EF, Sullivan L, Nallani S. Drug Interactions of Clinical Importance among the Opioids, Methadone and Buprenorphine, and Other Frequently Prescribed Medications: A Review. The American Journal on Addictions. 2010;19(1):4-16. PMID: 20132117
  13. Chou R, Cruciani RA, Fiellin DA, et al. 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 Apr;15(4):321-37. PMID: 24685458
  14. Faul M, Bohm M, Alexander C. Methadone prescribing and overdose and the association with Medicaid preferred drug list policies- United States, 2007-2014. MMWR Morb Mortal Wkly Rep. 2017;31:320-323. PMID: 28358791
  15. Paulozzi LJ, Kilbourne EM, Shah NG, et al. A history of being prescribed controlled substances and risk of overdose drug death. Pain Medicine 2012;13:87-95. PMID: 22026451
  16. Ray WA, Chung CP, Murray KT, Cooper WO, Hall K, Stein CM. Out-of-hospital mortality among patients receiving methadone for non-cancer pain. JAMA Intern Med. 2015;175(3):420-7. PMID: 25599329
  17. Washington State Agency Medical Directors’ Group (WSAMDG). Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain: An Educational Aid to Improve Care and Safety With Opioid Treatment. Corvallis, WA: Washington Department of Health, 2015. www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf
  18. FDA Drug Safety Communication. FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines. August 31, 2016. https://www.fda.gov/Drugs/DrugSafety/ucm518473.htm
  19. FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics (updated 5/2017) https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM515636.pdf
  20. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/main-table
  21. Substance Abuse and Mental Health Services Administration. Managing Chronic Pain in Adults With or in Recovery From Substance Use Disorders. Treatment Improvement Protocol (TIP) Series 54. HHS Publication No. (SMA) 12-4671. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2011.
  22. American Academy of Pain Medicine. Methadone for Pain Management: Improving Clinical Decision Making. 2016. http://www.painmed.org/files/methadone-for-pain-management-improving-clinical-decision-making.pdf  
  23. BUSSE
  24. Substance Abuse and Mental Health Services Administration. Medications to Treat Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63, Full Document. HHS Publication No. (SMA) 18-5063FULLDOC. Rockville, MD: SAMHSA Tip 63.
  25. Chou R, Weimer MB, Dana T.  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. 2014a Apr;15(4):338-65. PMID: 24685459