Abstract
Perspective
Key words
General Accountability Office: Methadone-associated overdose deaths: Factors contributing to increased deaths and efforts to prevent them. Available at: http://www.gao.gov/products/GAO-09-341. Accessed January 14, 2014
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
Chou R, Weimer MB, Dana T, Pappas M, Mitchell JP: Systematic Evidence Review on 435 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
Methods
Panel Composition
Target Audience and Scope
Funding and Conflicts of Interest
Evidence Review
Chou R, Weimer MB, Dana T, Pappas M, Mitchell JP: Systematic Evidence Review on 435 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
Chou R, Weimer MB, Dana T, Pappas M, Mitchell JP: Systematic Evidence Review on 435 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
Chou R, Weimer MB, Dana T, Pappas M, Mitchell JP: Systematic Evidence Review on 435 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
Grading of the Evidence and Recommendations
Guideline Development Process
Recommendations
Patient Assessment and Selection
- •When considering initiation of methadone, the panel recommends that clinicians perform an individualized medical and behavioral risk evaluation to assess risks and benefits of methadone, given methadone's specific pharmacologic properties and adverse effect profile (strong recommendation, low-quality evidence).
- Proper patient selection is critical when considering the use of any opioid, whether for chronic pain or treatment of addiction.16This requires a comprehensive benefit-to-harm evaluation based on a thorough history, review of records, and physical examination. Opioid therapy generally is considered the mainstay in the treatment of chronic moderate or severe pain associated with active cancer or at end of life. In contrast, for other types of chronic noncancer pain, opioids are usually considered after other reasonable pain management strategies have proved ineffective. In all populations, opioids should be considered only in the context of information that weighs the potential beneficial effects of prescribed opioids against risks, including those related to their potential for abuse, addiction, diversion, overdose, relapse (for patients treated for addiction), and other adverse events. The assessment should include evaluation of biomedical, psychosocial, and cultural issues that may affect use of and adherence to methadone treatment. An American Pain Society–American Academy of Pain Medicine (APS-AAPM) Guideline provides additional details on patient assessment and selection when opioid therapy is under consideration for chronic pain.
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-13016This Guideline recommends that clinical findings or the results of specific assessment tools be used to stratify patients according to the assessed risk of substance abuse outcomes, and that this assessment be used in deciding whether to proceed with a trial of an opioid.- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130 - Once a decision is made to undertake a trial of long-term opioid therapy for pain, or to continue treatment that has provided benefit, a second analysis is needed to determine whether methadone may be an appropriate analgesic. This assessment is informed by many factors, as described below. When methadone is considered for the treatment of opioid addiction, other factors are considered, such as the level of physical dependence, presence of a structured environment, involvement in ongoing treatment and recovery activities, patient stability, prior experience with addiction treatments, concurrently prescribed medications, other drug abuse, current comorbidities, and patient preferences for opioid therapy. When treating patients with chronic pain, given the availability of alternatives, clinicians should always consider whether another opioid may be a more appropriate therapy, when an opioid is indicated.
- The necessity for additional evaluation concerning the specific use of methadone for pain and addiction is based on unique pharmacologic properties that can affect determinations of benefits relative to risks, which include a long and variable half-life, numerous drug-drug interactions (including alcohol), and effects on the electrocardiographic QTc interval and respiratory depression. For example, a patient otherwise assessed as an appropriate potential candidate for opioid treatment who is taking a medication with potential methadone interactions or has risk factors for QTc interval prolongation or known QTc interval prolongation may be more appropriately treated with an alternative opioid (see below).45,58,67,69
Patient Education and Counseling
- •The panel recommends that clinicians educate and counsel patients prior to the first prescription of methadone about the indications for treatment and goals of therapy, availability of alternative therapies, and specific plans for monitoring therapy, adjusting doses, potential adverse effects associated with methadone, and methods for reducing the risk of potential adverse effects and managing them (strong recommendation, low-quality evidence).
- As with any other opioid, clinicians should counsel patients about potential risks and benefits before initiating a trial of methadone. During treatment, clinicians should periodically review risks and benefits of therapy. An APS-AAPM guideline on opioid therapy for chronic pain provides additional details regarding suggested elements of patient education in the setting of pain management, as well as a sample informed consent form.16
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130 - In addition to common opioid-related adverse events, clinicians should discuss specific risks associated with methadone and factors that may be associated with overdose.32,
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
38These include methadone's long and variable half-life, the potential association between use of methadone and QTc interval prolongation and cardiac arrhythmia, and the potential for drug-drug interactions.General Accountability Office: Methadone-associated overdose deaths: Factors contributing to increased deaths and efforts to prevent them. Available at: http://www.gao.gov/products/GAO-09-341. Accessed January 14, 2014
45,58,67,69Patients should be specifically informed about methods for mitigating risks, including the importance of taking methadone as prescribed and adherence with recommended follow-up and monitoring. Patients seen in clinical settings other than the one in which methadone is prescribed should be informed that their receipt of methadone will not be apparent if it is not linked to the electronic medical records of that setting or to state prescription-monitoring programs, and they should be educated about the importance of disclosing its use. Patients, as well as caregivers and family members who are actively engaged in the patient's care, should be notified about the risks of respiratory depression and instructed to withhold additional doses of methadone and contact the prescribing or dispensing entity if signs of respiratory depression or somnolence are present. Patients should be instructed to never share methadone and to store methadone in a safe place, such as a locked cabinet or box if necessary, to safeguard against theft. - An opioid management plan describes how methadone will be prescribed and monitored in an individual patient. It is distinct from the informed consent process, which refers to a discussion of the potential benefit and harms of a therapy. As for all opioids, the management plan when prescribing methadone for treatment of chronic pain may include elements intended to help monitor and verify use. These may include the stipulation that methadone is obtained from one prescriber or facility, prescriptions are filled at one designated pharmacy, drug screening is performed periodically, office visits are required at a specified minimum interval, pill counts are conducted at office visits, and prescription size is limited (eg, weekly or biweekly instead of monthly amounts in higher-risk patients).16To ensure that key messages are conveyed to patients consistently, prescribers should consider the use of a written methadone management plan.
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-13016This plan may also include enumeration of behaviors that may result in discontinuation of methadone.- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130
Baseline Electrocardiograms
- •The panel recommends that clinicians obtain an ECG prior to initiation of methadone in patients with risk factors for QTc interval prolongation, any prior ECG demonstrating a QTc >450 ms, or a history suggestive of prior ventricular arrhythmia. An ECG within the past 3 months with a QTc <450 ms in patients without new risk factors for QTc interval prolongation can be used for the baseline study (strong recommendation, low-quality evidence).
- •The panel recommends that clinicians consider obtaining an ECG prior to initiation of methadone in patients not known to be at higher risk for QTc interval prolongation; an ECG within the past year with a QTc <450 ms in patients without new risk factors for QTc interval prolongation can be used for the baseline study (weak recommendation, low-quality evidence).
- Torsades de pointes is a polymorphic ventricular arrhythmia usually preceded by QTc interval prolongation22,
- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-106096that can lead to ventricular fibrillation and result in sudden death or cardiac arrest.22,- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-106084The risk of torsades de pointes increases with greater prolongation of the QTc interval. Torsades de pointes primarily occurs in patients with QTc intervals >500 ms, though risk is increased starting around QTc intervals of 450 ms.- Redfern W.S.
- Carlsson L.
- Davis A.S.
- Lynch W.G.
- MacKenzie I.
- Palethorpe S.
- Sieglf P.K.S.
- Stranga I.
- Sullivang A.T.
- Wallish R.
- Cammi A.J.
- Hammonda T.G.
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development.Cardiovasc Res. 2003; 58: 32-4522,- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-106074,80,88Although normal QTc intervals are longer in women than in men, with an average difference of 10 to 20 ms, it is unclear whether there are sex differences in risk of torsades de pointes at increased QTc intervals. Therefore, for pragmatic purposes, the panel recommends that clinicians utilize the same QTc interval parameters for men and women. Risk factors for QTc interval prolongation include22,- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-106026,31,47,93,96 - •electrolyte abnormalities such as hypokalemia or hypomagnesemia;
- •impaired liver function;
- •structural heart disease (such as congenital heart defects or a history of endocarditis or heart failure);
- •genetic predisposition such as congenital prolonged QT syndrome or familial history of prolonged QT syndrome; and
- •use of drugs with QTc-prolonging properties (Table 1).Table 1Selected Methadone Drug-Drug Interactions
Drug Effects on Methadone Levels Effects on QTc Interval Additive Sedative or Respiratory Depressant Effects Antibiotics Ciprofloxacin ↑ Clarithromycin ↑ ↑ Erythromycin ↑ ↑ Itraconazole ↑ Ketoconazole ↑ Fluconazole ↑ Rifampin ↓ Telithromycin ↑ Anticonvulsants Carbamazepine ↓ Phenytoin ↓ Antihistamines Diphenhydramine ↑ Promethazine ↑ Antipsychotics Quetiapine ↑ ↑ Barbiturates Phenobarbital ↓ ↑ Benzodiazepines Alprazolam ↑ ↑ Clorazepate ↑ ↑ Diazepam ↑ ↑ Estazolam ↑ ↑ Flurazepam ↑ ↑ Lorazepam ↑ ↑ Midazolam ↑ ↑ Triazolam ↑ ↑ Zopiclone ↑ ↑ HIV medications Abacavir ↓ Nevirapine ↓ Delavirdine ↑ Efavirenz ↓ Ritonavir-boosted lopinavir ↓ Nelfinavir ↓ Amprenavir ↓ Atazanavir ↓ Opioids ↑ Heroin ↓ ↑ Selective serotonin reuptake inhibitors Fluoxetine ↑ Fluvoxamine ↑ Nefazodone ↑ Paroxetine ↑ Sertraline ↑ Tricyclic antidepressants Amitriptyline ↑ Desipramine ↑ Imipramine ↑ Nortriptyline ↑ Protriptyline ↑ Urinary alkalinizers Bicitra ↑ Polycitra ↑ Verapamil ↑ Other Aprepitant ↑ Cimetidine ↑ Cocaine ↓ ↑ Disulfiram ↑ Ethanol ↓ ↑ Grapefruit juice or whole fruit ↑ Omeprazole ↑ St. John's wort ↓ NOTE. Most effects are predicted or expected drug interactions; in most cases direct evidence on changes in methadone levels on and off the second medication are not available. Cytochrome P450 inducers decrease methadone blood levels; inhibitors increase methadone blood levels. More comprehensive and periodically updated lists of cytochrome P450 interactions and drugs associated with QTc prolongation are available at http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx and http://QTdrugs.org.∗ Data not as strong for interaction.Leavitt63; McCance-Katz et al,72Lintzeris et al,65and Gourevitch et al.40 - Methadone use appears to be associated with risk of prolongation of the QTc interval,26,55,59,66,69,89presumably because of its potent inhibitory effects on the human ether à go-go-related gene (hERG) cardiac channel,52,95and case reports describe torsades de pointes in patients prescribed methadone.47,57,77Other medications associated with QTc interval prolongation and torsades de pointes include various antiarrhythmics, antipsychotics, citalopram, tricyclic antidepressants, fluoroquinolones, and cisapride.106The estimated risk of torsades de pointes varies widely, ranging from approximately .001% for cisapride to approximately 8% for quinidine.22In the case of cisapride, the manufacturer discontinued marketing of the drug in the United States in 2000, based on 341 cases of cardiac arrhythmias (including 80 deaths) between 1993 and 1999.
- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-106098Although estimates for the degree of risk associated with drug-induced QTc interval prolongation vary, in patients with long QT syndrome, a QTc interval >500 ms was associated with an odds ratio for syncope or sudden death (presumably due to torsades de pointes) of 4.2 (95% confidence interval [CI] 1.1–16).US Food and Drug Administration: Safety alerts. Propulsid (cisapride). Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175000.htm. Accessed January 14, 2014
8Because of potential cardiac arrhythmia risk, a baseline ECG is recommended prior to initiating a number of these medications, with periodic ECG monitoring of patients taking the medications, though evidence showing the effectiveness of ECG monitoring is lacking.- Brink P.
- Crotti L.
- Corfield V.
- Goosen A.
- Durrheim G.
- Hedley P.
- Heradien M.
- Geldenhuys G.
- Vanoli E.
- Bacchini S.
- Spazzolini C.
- Lundquist A.L.
- Roden D.M.
- George Jr., A.L.
- Schwartz P.J.
Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.Circulation. 2005; 112: 2602-26101,2,3,18,22,- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-106023Drugs.com: Propulside (Cisapride). Available at: http://www.drugs.com/pro/propulsid.html. Accessed January 14, 2014
- Similarly, in patients being considered for methadone, a baseline ECG may help clinicians assess for risk of torsades de pointes, based on the presence and degree of QTc interval prolongation prior to medication initiation. Accurate estimates on the risk of torsades de pointes or sudden cardiac death are not available. Recent data suggest that methadone is the most common drug-related cause of ventricular arrhythmias reported to the FDA.4,51However, some studies suggest that in patients on methadone for opioid addiction, attributable mortality appears low.4Although no study has evaluated the effect of ECG screening and monitoring on clinical outcomes, and the clinical opinion on the need to obtain ECGs in patients being considered for methadone varies markedly, in part because of concerns about delayed or reduced access to methadone, an ECG is the only way to detect asymptomatic QTc interval prolongation. Patients with QTc interval prolongation might benefit from efforts to address causes of QTc interval prolongation, consideration of alternative opioids or other interventions, or additional monitoring if prescribed methadone. Although no study has compared outcomes associated with different ECG strategies in this setting, the panel recommends that clinicians routinely obtain an ECG prior to initiation of methadone in patients with known risk factors for QTc interval prolongation, a prior ECG with QTc interval >450 ms, or a history suggestive of prior ventricular arrhythmia (such as prior cardiac arrest and unexplained syncope or seizure). Approximately 85% of cases of cisapride-associated cardiac arrhythmias occurred in patients with known risk factors for QTc interval prolongation.98Although data are limited, studies of methadone-associated torsades de pointes similarly indicate that a high proportion of patients had identifiable risk factors.
US Food and Drug Administration: Safety alerts. Propulsid (cisapride). Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175000.htm. Accessed January 14, 2014
47,58,77,99 - For persons not known to be at a higher risk of QTc interval prolongation, the panel found insufficient evidence to routinely recommend ECG screening. However, given that QTc interval prolongation without arrhythmia is asymptomatic and may not be associated with recognized risk factors, the panel suggests that clinicians consider obtaining an ECG prior to initiation of methadone in all patients.
- Although there is no evidence to guide recommendations on how recent an ECG should be to guide risk assessments accurately prior to initiation of methadone, the panel suggests that in patients with risk factors for QTc interval prolongation that are unchanged, an ECG within the last 3 months showing no QTc interval prolongation can be used as the baseline study and a repeat ECG is unnecessary prior to initiating methadone. In patients with no risk factors for QTc interval prolongation, an ECG within the last year showing no QTc interval prolongation can be used as the baseline study.
- The panel found extremely limited evidence to guide use of screening ECGs prior to initiation of methadone in children. Although research on long QT syndrome in families indicates a two- to fourfold increased risk of cardiac events in children with QTc intervals between 460 and 500 ms,109the panel found no reported cases of torsades de pointes in children prescribed methadone, despite relatively common pediatric use in some hospital settings. Nonetheless, given the potential for increased cardiovascular risk, the panel suggests that clinicians consider a screening ECG prior to initiating methadone in children with risk factors for prolonged QTc interval, as described above.
- •The panel recommends against use of methadone in patients with a baseline QTc interval >500 ms (strong recommendation, low-quality evidence).
- •The panel recommends that clinicians consider alternate opioids in patients with a baseline QTc interval ≥450 ms but <500 ms. If methadone is considered in a patient with a baseline QTc interval ≥450 ms but <500 ms, the clinician should evaluate for and correct reversible causes of QTc interval prolongation before initiating methadone (weak recommendation, low-quality evidence).
- •The panel recommends that clinicians consider buprenorphine as a treatment option for patients treated for opioid addiction who have risk factors for or known QTc interval prolongation when an agonist/partial agonist is indicated (weak recommendation, moderate-quality evidence).
- A QTc interval of ≥500 ms is associated with a substantially increased risk of torsades de pointes.22,
- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-106074,80,88In adults, each 10-ms increase in QTc interval is associated with an approximate 5 to 7% exponential increase in risk of torsades, so that a patient with a QTc of 540 ms has a 63 to 97% greater risk than a patient with a QTc of 440 ms.22Patients with this degree of QTc interval prolongation prior to starting methadone may experience further QTc interval prolongation on methadone, placing them at greater risk.- Drew B.J.
- Ackerman M.J.
- Funk M.
- Gibler W.B.
- Kligfield P.
- Menon V.
- Philippides G.J.
- Roden D.M.
- Zareba W.
Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-10602,3,4,5,6,7,8,- Brink P.
- Crotti L.
- Corfield V.
- Goosen A.
- Durrheim G.
- Hedley P.
- Heradien M.
- Geldenhuys G.
- Vanoli E.
- Bacchini S.
- Spazzolini C.
- Lundquist A.L.
- Roden D.M.
- George Jr., A.L.
- Schwartz P.J.
Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.Circulation. 2005; 112: 2602-26109,10,11,12,13,14,28,30,31Therefore, the panel recommends against use of methadone in adults with a QTc interval ≥500 ms at baseline. In such patients, the panel recommends that clinicians consider alternative treatments for chronic pain or opioid addiction. For patients being managed for chronic pain, a number of alternative opioids are available. Although QTc interval prolongation has been reported with oxycodone, its clinical significance is uncertain.30Other opioids have not been associated with QTc interval prolongation in clinical studies. For the treatment of opioid addiction, buprenorphine has similar efficacy to moderate doses of methadone but is associated with less QTc interval prolongation, and is one potential alternative.4,6,28,29,42,56,102A QTc interval of 450 to 500 ms in adults is also associated with increased risk of torsades de pointes.47,57,77Data from general populations of U.S. adults indicate that less than 5% of men and women have QTc intervals of >450 ms.83,111Although the risk associated with a QTc interval of 450 to 500 ms is lower than in patients with QTc intervals of >500 ms, the panel recommends that clinicians consider alternatives to methadone because there may be some additional risk. Factors to consider when deciding whether to initiate methadone include the degree of QTc interval prolongation (intervals close to 450 ms are associated with less risk than intervals closer to 500 ms) and whether there may be reversible risk factors. In patients who are prescribed other medications that prolong QTc interval or who have hypokalemia, the panel recommends that clinicians stop the other medications if clinically appropriate and correct hypokalemia. In such cases, the decision to initiate methadone would depend in part on whether the QTc interval improved after such measures. In patients with nonreversible risk factors such as structural heart disease or cirrhosis, the use of alternatives to methadone may be more strongly considered. However, the efficacy of alternative treatments, as well as the risks of inadequate or no treatment, must be considered, especially in treatment of addiction. - Patients with a QTc interval <450 ms at baseline are not considered to be at increased risk for torsades de pointes following initiation of methadone, and may be started on methadone with routine follow-up and monitoring (see below).
- The panel found insufficient evidence to determine whether QTc thresholds for use of methadone should differ in children compared with adults. As in adults, data generally indicate that <5% of children have a QTc interval >450 ms.44,79,97In addition, as noted above, studies of siblings of children with long QT syndrome found increased risk of cardiovascular events at QTc intervals of 460 to 500 ms, though reported cases of torsades de pointes in children prescribed methadone are rare. Given the potential for increased risk and the availability of alternative opioids, the panel suggests that clinicians apply similar QTc parameters for use of methadone in children as in adults, until more evidence is available.
Initiation of Methadone
- •The panel recommends that clinicians initiate methadone at low doses individualized based on the indication for treatment and prior opioid exposure status, titrate doses slowly, and monitor patients for sedation (strong recommendation, moderate-quality evidence).
- 1)When used to treat opioid addiction, the panel suggests that clinicians start methadone at no more than 30 to 40 mg once daily. The dose should be titrated based on objective signs of withdrawal and self-reported craving and methadone dose increased by no more than 10 mg/d and no more frequently than every 3 to 4 days. Methadone should be withheld if there is evidence of sedation.
- 2)When used to treat chronic pain in adults on relatively low doses of other opioids (eg, <40–60 mg/d of morphine or equivalent), the panel suggests that clinicians start methadone at 2.5 mg tid, with initial dose increases of no more than 5 mg/d every 5 to 7 days. In children, the recommended starting dose is 100 μg/kg (maximum 5 mg/dose) every 6 to 8 hours. Methadone should be withheld if there is evidence of sedation.
- 3)When used to treat chronic pain and switching to methadone from higher doses of another opioid, the panel suggests that clinicians start methadone therapy at a dose 75 to 90% less than the calculated equianalgesic dose and at no higher than 30 to 40 mg/d, with initial dose increases of no more than 10 mg/d every 5 to 7 days. Methadone should be withheld if there is evidence of sedation.
- •The panel recommends that clinicians consider those patients previously prescribed methadone, but who have not currently taken opioids for 1 to 2 weeks, opioid-naïve for the purpose of methadone reinitiation (strong recommendation, low-quality evidence).
- The panel recommends that clinicians start methadone at low doses and titrate slowly. Evidence to guide optimal methadone initiation and dose titration strategies is limited. Therefore, suggestions for practice are based on panel consensus and clinical experience, and depend on the degree to which a patient is opioid-experienced, with an overarching goal of more conservative (lower) initial dosing regimens in order to prioritize patient safety. The rationale for the panel's recommendation for careful initiation and dose titration of methadone is related to the drug's long and highly variable half-life.67Slow titration may reduce the risk of unintended accumulation that can occur as the serum concentration slowly rises toward steady state once a dose is selected. It is possible that rapid titration of the dose to a level that is efficacious for pain could be followed by toxicity over the course of the next days or even weeks as the concentration rises. In the most serious outcome, this late toxicity could take the form of respiratory depression and death. Consistent with this principle is evidence showing that the period shortly following methadone initiation appears to be associated with increased risk of overdose and other adverse events.27,37,108Although the half-life of methadone is usually assumed to be approximately 1 day, and is rarely outside a range of 15 to 60 hours, in some reports the half-life is as high as 120 hours.67By comparison, the plasma half-life of morphine, hydromorphone, oxycodone, fentanyl, and codeine range from 2 to 3.5 hours.45In a patient for whom the methadone half-life is 60 hours, it would take almost 12 days on a stable dose of methadone to approach a steady state (5 half-lives). In addition, patients with a long half-life will have more prolonged exposure to a given methadone dose, potentially increasing their risk for adverse events. Without knowing the half-life in an individual patient, risk can be minimized only by cautious titration. Clinicians should be aware that the variable half-life of methadone means that some patients may not reach steady state (5 half-lives) for over 3 weeks. Therefore, it is critical that clinicians not increase the dose solely based on preset parameters, but also evaluate patients clinically and withhold the dose if there is evidence of sedation. Once the sedation has resolved, methadone may be reinitiated at a lower dose (eg, at least 20% lower than the dose that caused sedation) and the period between dose titrations extended.
- The panel recommends particular caution when initiating methadone for pain treatment in patients with no prior exposure to opioids (“opioid-naïve”). In this situation, the panel suggests a starting dose of 2.5 mg every 8 hours (7.5 mg/d), with initial dose increases of no more than 5 mg/d every 5 to 7 days, in accordance with the APS-AAPM Guideline.16Once the dose has reached 30 to 40 mg/d and the patient has shown the ability to tolerate dose increases of 5 mg/d, clinicians may consider larger dose increases of up to 10 mg/d, though the duration between dose increases should not be shortened. Evidence indicates that the risk of overdose is increased at higher doses of opioids, suggesting that dose increases of methadone above 30 to 40 mg/d should only be done in patients who are clearly benefiting and can be monitored appropriately.
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-1307,24,39 - In children, the panel suggests a starting dose of 100 μg/kg (maximum 5 mg/dose initially) every 6 to 8 hours. Although the World Health Organization suggests a higher potential starting dose (100–200 μg/kg) with several initial loading doses (2–3 doses given every 4 hours),105the panel felt that more cautious initiation of methadone is warranted in children with chronic pain, particularly in nonhospital settings. The panel suggests use of short-acting opioids for breakthrough pain or if more rapid initial pain control is needed, rather than loading doses of methadone. As in adults, the panel recommends dose increases in children no more frequently than once every 5 to 7 days, based on the amount of breakthrough pain medications needed to maintain pain control, by no more than 50% of the current methadone dose.
World Health Organization: Guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. Available at: http://www.who.int/medicines/areas/quality_safety/guide_perspainchild/en/index.html. Accessed January 14, 2014
- For patients treated for opioid addiction and engaged in ongoing opioid use, higher starting doses and more rapid dose titration may decrease the likelihood of withdrawal and increase the likelihood of treatment success. In such patients, clinicians may consider starting at higher doses than used in opioid-naïve patients. The panel suggests initiating methadone at up to 30 to 40 mg once daily and titrating the dose based on objective signs of withdrawal and self-report of opioid craving, but by no more than 10 mg/d and with dose increases no more frequently than every 3 to 4 days.
- In patients with chronic pain on higher doses of alternative opioids, conversion to methadone should be performed carefully. Proposed equianalgesic dose ratios for conversion of other opioids (in mg morphine equivalents) to methadone are variable and range from 3:1 to 10:1 at lower doses to 8:1 to 20:1 at higher doses.78In patients on lower doses of other opioids (eg, <40–60 mg morphine equivalents/d), the panel suggests starting methadone at doses similar to those recommended for opioid-naïve patients. For patients on higher doses of other opioids, the panel suggests that clinicians start methadone at a dose 75 to 90% less than the calculated equianalgesic dose, based on more conservative dosing ratios (eg, 15:1 to 20:1) and at no higher than 30 to 40 mg/d.14Initial dose increases should be no more than 10 mg/d every 5 to 7 days.
- The panel recommends that clinicians reinitiate methadone cautiously in patients who have previously been prescribed methadone but are currently not taking an opioid. Such patients experience loss of tolerance and are at risk for accidental overdose if reinitiated at their previously tolerated methadone dose. Although there is insufficient evidence to determine with precision how quickly tolerance is lost, the panel suggests that clinicians treat patients not taking opioids for 1 to 2 weeks as opioid-naïve.
- Because of its long half-life and variable pharmacokinetics, the panel recommends that methadone not be used to treat breakthrough pain or as an as-needed medication.16
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130
Follow-Up Electrocardiograms
- •The panel recommends that for patients prescribed methadone, clinicians perform follow-up ECGs based on baseline ECG findings, methadone dose changes, and other risk factors for QTc interval prolongation (strong recommendation, low-quality evidence).
- 1)The panel suggests that for patients with risk factors for QTc interval prolongation, any prior ECG demonstrating a QTc >450 ms, or a history of syncope, clinicians perform follow-up ECG 2 to 4 weeks after initiation of methadone therapy and following significant dose increases.
- 2)The panel suggests that for all patients, clinicians perform follow-up ECG when the methadone dose reaches 30 to 40 mg/d in patients started at lower doses, and again at 100 mg/d.
- 3)The panel suggests that clinicians perform follow-up ECG for all patients prescribed methadone with new risk factors for QTc interval prolongation or signs or symptoms suggesting arrhythmia.
- •The panel recommends that clinicians switch methadone-treated adults with a QTc interval ≥500 ms to an alternative opioid or immediately reduce the methadone dose; in all such cases, the panel recommends that clinicians evaluate and correct reversible causes of QTc interval prolongation, and repeat the ECG after the methadone dose has been decreased (strong recommendation, low-quality evidence).
- •The panel recommends that clinicians consider switching methadone-treated adults with a QTc interval ≥450 ms but <500 ms to an alternative opioid or reducing the methadone dose. In patients in whom there are barriers to switching to alternative opioids, or who experience decreased treatment effectiveness with methadone dose reductions, the panel recommends that clinicians discuss with patients the potential risks of continued methadone. In all cases, the panel recommends that clinicians evaluate and correct reversible causes of QTc interval prolongation, and repeat the ECG after the methadone dose has been decreased (strong recommendation, low-quality evidence).
- Follow-up ECGs in patients prescribed methadone may be useful for identifying QTc interval prolongation that increases the risk for torsades de pointes. Although there is no evidence to guide optimal strategies for performing follow-up ECGs, the panel suggests that clinicians obtain a follow-up ECG soon after initiating methadone in patients with QTc interval prolongation at baseline and in patients on methadone with new risk factors for QTc interval prolongation of signs or symptoms suggesting ventricular arrhythmia (such as palpitations, presyncope, or syncope). In addition, some evidence suggests that the degree of QTc interval prolongation is dose dependent.13,26,29,53,57,69Therefore, follow-up ECGs should also be obtained when methadone daily doses are increased to certain threshold levels. Although there are insufficient data to determine optimal methadone dose threshold levels for ECG monitoring, the panel suggests 30 to 40 mg/d in patients started at lower doses, and again at 100 mg/d.
- The panel suggests that clinicians obtain a follow-up ECG 2 to 4 weeks after initiation of methadone in patients with a QTc interval >450 ms at baseline, a history of syncope prior to initiation of methadone, or risk factors for QTc interval prolongation, as well as when patients develop new risk factors for QTc interval prolongation or report signs or symptoms suggesting potential arrhythmia. In patients started on low doses of methadone, the panel also recommends that clinicians perform follow-up ECG when the methadone dose reaches the thresholds noted previously. The panel found insufficient evidence to suggest parameters for follow-up ECGs in patients titrated to higher methadone doses who do not experience QTc interval prolongation at doses of 100 mg/d or lower. However, a high proportion of case reports of torsades de pointes in patients prescribed methadone occurred at high doses (>200 mg/d), suggesting that additional monitoring at higher doses (eg, whenever the dose is titrated to 30–50% higher than the prior dose at which an ECG was obtained) may be warranted.47,57In patients with QTc interval prolongation on follow-up ECG, recommendations on use of methadone, consideration of alternatives, and correction of potentially reversible causes are similar to those described above for QTc interval prolongation on a baseline ECG. In addition, clinicians may consider lowering the methadone dose with follow-up to document improvement or normalization of the QTc interval.28,42,59For patients treated for opioid addiction who develop a prolonged QTc interval on methadone, buprenorphine is a potential alternative. Buprenorphine has similar efficacy to moderate doses of methadone for treatment of opioid addiction, and observational studies report normalization of prolonged QTc intervals after switching patients from methadone to buprenorphine.28,42,59For chronic pain, a number of opioids are available as alternatives to methadone. A potential limitation to use of buprenorphine is that it is a μ-opioid partial agonist and may exhibit analgesic ceiling dose effects at which further dose increases produce no additional effects.100Clinicians switching patients from methadone to buprenorphine should also follow recommended methods to avoid precipitated withdrawal due to initiation of a partial agonist.10
- •
Monitoring for and Management of Adverse Events
- •The panel recommends that patients receiving methadone be monitored for common opioid adverse effects and toxicities and that adverse effects management be considered part of routine therapy (strong recommendation, moderate-quality evidence).
- In addition to QTc interval prolongation, methadone is associated with other adverse effects typically associated with opioids, including constipation, nausea, sedation, respiratory depression, pruritus, endocrinologic effects, and others. As outlined in the APS-AAPM guideline on use of opioids for chronic noncancer pain, the panel recommends that clinicians anticipate and routinely monitor patients prescribed methadone for opioid-related adverse effects.16Adverse effects management, including proactive interventions, should be considered part of routine therapy in all patients prescribed methadone. Clinicians should routinely consider initiation of a bowel regimen to prevent or manage opioid-induced constipation. Although evidence is anecdotal, regimens including increased fluid and fiber intake, stool softeners, and laxatives are often effective. For nausea and vomiting, a number of antiemetics, in both oral and rectal forms, are available, though some are associated with QTc interval prolongation (see below). Patients should be asked about signs or symptoms of hypogonadism and appropriately tested when present. Clinicians should recognize comorbidities that may increase the risk of opioid-related adverse effects such as sleep apnea or other underlying respiratory disease, dementia, or antecedent constipation. Close monitoring is recommended in such cases.
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130 - Clinicians should periodically monitor patients for the development of substance abuse and other mental health disorders. Such patients should be managed appropriately, including referral if necessary and potential discontinuation or restructuring of methadone therapy. Clinicians should also periodically review state prescription drug monitoring program data, which are now widely available, in order to help identify patients who are obtaining opioids or other controlled substances from other providers, as such behaviors are associated with increased risk of overdose.
- Patients should be counseled on sedation after opioid initiation and with dose increases, including potential issues related to driving and work and home safety. However, most epidemiologic studies suggest that risk of motor vehicle accidents, traffic fatalities, and citations for impaired driving is not increased in patients on stable doses of opioids.34,35In the absence of signs of symptoms of impairment, the panel did not identify sufficient evidence to support restrictions in driving or most work-related activities in patients maintained on long-term opioid therapy.16
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130 - •The panel recommends face-to-face or phone assessment with patients to assess for adverse events within 3 to 5 days after initiating methadone, and within 3 to 5 days after each dose increase (strong recommendation, low-quality evidence).
- The risk of methadone-associated mortality is higher shortly after initiating methadone.9,61,73,107Although evidence is sparse on the association between methadone dose increases and serious adverse events, a similar association appears plausible. Therefore, the panel recommends that clinicians reassess patients 3 to 5 days following methadone initiation or after methadone dose increases, with particular attention to signs of respiratory depression (such as decreased respiratory rate or sedation, which may accompany respiratory depression) and arrhythmia (such as palpitations). Although there is insufficient evidence to guide recommendations on optimal methods or timing for follow-up, the panel recognizes that follow-up assessments do not necessarily require an office visit with a provider, and may be performed over the phone by an appropriately trained medical assistant or nurse or via email for reliable patients.
Urine Drug Testing
- •The panel recommends that clinicians obtain urine drug screens prior to initiating methadone and at regular intervals in patients prescribed methadone for opioid addiction (strong recommendation, low-quality evidence).
- •The panel recommends that patients prescribed methadone for chronic pain who have risk factors for drug abuse undergo urine drug testing prior to initiating methadone and at regular intervals thereafter; it recommends that clinicians consider urine drug testing in all patients regardless of assessed risk status (strong recommendation, low-quality evidence).
- One method to monitor patients prescribed opioids is urine drug testing (UDT). UDT may help identify patients engaging in aberrant drug-related behaviors and who may benefit from restructuring of their opioid therapy or treatment of underlying addiction or opioid misuse. Although no study has evaluated optimal UDT intervals in patients prescribed methadone or other opioids, the panel suggests that clinicians obtain a baseline UDT, including specific testing for methadone, in all patients prescribed methadone for opioid addiction and in all patients prescribed methadone for chronic pain that have risk factors for drug abuse. Subsequent UDT should be performed periodically if justified based on the patients' assessed risk for drug abuse or diversion. The APS-AAPM guideline on use of opioids for chronic noncancer pain suggests that clinicians use the risk assessment to help guide UDT monitoring intervals.16Patients treated for opioid addiction are at high risk for opioid abuse and misuse and generally warrant frequent monitoring. Patients prescribed methadone for chronic pain who may need more frequent or intense monitoring include those with a prior history of substance use disorder, patients with an unstable or dysfunctional social environment, and those with comorbid psychiatric conditions. In patients treated for chronic pain at low risk for adverse outcomes and on stable doses of opioids, the APS-AAPM guideline also suggests that clinicians consider UDT monitoring, as evidence indicates that a substantial minority of patients who engage in aberrant drug-related behaviors do not have identifiable risk factors.
- Chou R.
- Fanciullo G.J.
- Fine P.G.
- Adler J.A.
- Ballantyne J.C.
- Davies P.
- Donovan M.I.
- Fishbain D.A.
- Foley K.M.
- Fudin J.
- Gilson A.M.
- Kelter A.
- Mauskop A.
- O'Connor P.G.
- Passik S.D.
- Pasternak G.W.
- Portenoy R.K.
- Rich B.A.
- Roberts R.G.
- Todd K.H.
- Miaskowski C.
Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-13048,54In such patients, repeat testing every 6 to 12 months may be sufficient, though clinic follow-up every 3 to 6 months is generally suggested.
Medication Interactions
- •The panel recommends that clinicians use methadone with care in patients using concomitant medications with potentially additive side effects or pharmacokinetic or pharmacodynamic interactions with methadone (strong recommendation, low-quality evidence).
- Evidence on the magnitude of clinical harms associated with the concomitant use of methadone plus potential interacting medications is limited, and most trials were not designed to evaluate serious harms. However, several types of drug interactions can increase risk in patients using methadone and therefore require attention and care in prescribing (Table 1). These include use of drugs that
- •alter methadone absorption, metabolism, and/or excretion, thereby changing methadone blood levels;
- •have additive or synergistic sedative or respiratory suppressant effects; and/or
- •prolong QTc intervals.
- Like other opioids, methadone is primarily metabolized in the liver and gastrointestinal tract25by cytochrome P450 (CYP) enzymes including CYP2B6, CYP3A4, CYP 2C19, CYD2D6, and CYP1A2.62,
Leavitt S. Addiction Treatment Forum. Methadone-Drug Interactions, 3rd ed. November 2005 Revision/Update. Available at: http://www.atforum.com/SiteRoot/pages/addiction_resources/Drug_Interactions.pdf. Accessed February 28, 2014
104Many other medications can affect the metabolism of methadone and other opioids because they are CYP inhibitors (leading to increased opioid levels)63or CYP inducers (leading to decreased opioid levels).36CYP inhibitors may increase risk for sedation and respiratory depression at a specific opioid dose, and CYP inducers may reduce effectiveness of methadone at a specific dose or precipitate withdrawal.Flexner C, Piscitelli S: Managing drug-drug interactions in HIV disease. Available at: http://www.medscape.org/viewarticle/421137_3. Accessed January 14, 2014
- In addition, like other opioids, methadone has sedating and respiratory depressant effects that may be augmented by use of medications and drugs (such as alcohol) with similar effects. In particular, a high proportion of cases of overdoses involving methadone occurred in patients with benzodiazepines in their system at the time of death.12,37,90,94,103The panel suggests that clinicians generally avoid benzodiazepines in patients prescribed methadone because of the possible association with increased overdose risk. However, in stable patients on long-term low doses of a benzodiazepine plus methadone, the panel found insufficient evidence for or against routine discontinuation of the benzodiazepine, though a careful consideration of potential risks relative to benefits is warranted.
- Finally, care is needed when combining methadone with other drugs that may prolong QTc intervals. In spontaneously reported cases of methadone-associated arrhythmia, antiretroviral drugs for human immunodeficiency virus were the most common coadministered drugs.51The ECG should be carefully monitored and doses of methadone and/or other drugs adjusted to keep the QTc within a safe range, as discussed elsewhere in this Guideline.
- The panel recommends that clinicians review patient medications prior to initiation of methadone and consider discontinuation or dose reduction of medications with potential interactions or additive side effects (Table 1). If methadone is initiated, the panel recommends close monitoring following methadone initiation. In patients on methadone, clinicians should review new medications for potential interactions before starting them, monitor for interactions if they are used, and make appropriate methadone dose changes when a CYP inducer or inhibitor is discontinued or when the dose is adjusted. For example, discontinuation of a CYP inducer in a patient prescribed methadone could result in high methadone levels, potentially increasing the risk for overdose.
Methadone Use in Pregnancy
- •The panel recommends monitoring of neonates born to mothers receiving methadone for neonatal abstinence syndrome and treatment for neonatal abstinence syndrome when present (strong recommendation, moderate-quality evidence).
- Neonatal abstinence syndrome occurs in three-quarters or more of infants exposed to methadone prenatally.20,43,49,50,64,75,81,82,86,87,110Evidence on comparative risk of neonatal abstinence syndrome associated with different opioids is limited but may be higher with methadone than buprenorphine.33,46Although most studies have evaluated the incidence of neonatal abstinence syndrome following maternal use of methadone for treatment of opioid addiction, methadone has also become frequently used for treatment of chronic pain in women of childbearing age.
- Opioid agonist treatment with methadone is the current standard of care for opioid addiction during pregnancy in order to improve both maternal and fetal outcomes.19Detailed guidance regarding management of addiction during pregnancy is beyond the scope of this Guideline but is available from the American Congress of Obstetrics and Gynecology.19For women with chronic pain, clinicians should weigh the benefits and harms of methadone and other opioids when considering its use during pregnancy and inform women of the potential risks to the newborn, as well as the risk of opioid withdrawal with discontinuation of methadone during pregnancy. The panel recommends monitoring of all newborns born to mothers receiving methadone for neonatal abstinence syndrome and provision of appropriate treatments when it occurs.
Conclusions
Acknowledgments
Appendices
Conflicts of Interest Disclosed | |
---|---|
Cochairs | |
APS: Ricardo Cruciani, MD | Received speaking fees from Depomed Advisory Board and Speaker Bureau; Covidean Speaker Bureau; ENDO Pharmaceuticals Speaker Bureau; Ameritox consultant; grant support; Grupo Ferrer consultant (Spain). Received research funding from Ameritrox, New York State. |
CPDD: David A. Fiellin, MD | Received honoraria for serving on external advisory panels monitoring the abuse and diversion of buprenorphine for Pinney Associates and Parajuarx. |
Panel members | |
Roger Chou, MD | No conflicts disclosed. |
Peggy Compton, RN, PhD | No conflicts disclosed. |
John T. Farrar, MD, PhD | Dr. Farrar has received research grant support (through the University of Pennsylvania) and consulting fees from Purdue Pharma, Forrest Pharma, Endo Pharma, Cephalon Inc, and currently from Teva Pharma. |
Mark C. Haigney, MD | No conflicts disclosed. |
Charles Inturrisi, PhD | No conflicts disclosed. |
John R. Knight, MD | No conflicts disclosed. |
Shirley Otis-Green, MSW, ASW | No conflicts disclosed. |
Steven M. Marcus, MD | No conflicts disclosed |
Davendra Mehta, MD | Consulting fee from St. Jude's and speaker fee from Sanofi. |
Marjorie C. Meyer, MD | No conflicts disclosed. |
Russell Portenoy, MD | Honorarium received from Spanish company, Grupo Ferrer for teaching conference; honorarium from Pfizer for consulting. Conducts research on the Nabiximols project funded by Otsuka, Inc. |
Seddon Savage, MD, MS | No conflicts disclosed. |
Eric Strain, MD | Employed as medical director of a clinic that treats patients with opioid use disorders and patients with pain. Consulting for: Transcept Pharmaceuticals, Inc; The Oak Group; and Salfix Pharmaceuticals, Inc. Received National Institutes of Health funding; may receive in next 1 to 2 years pharmaceutical funding for opioid research. |
Sharon Walsh, PhD | Received research support from World Meds, Inc, and Catalyst Pharmaceuticals. Served as a paid consultant on abuse liability assessment research and medications development to pharmaceutical companies, including affiliations with Abbot Laboratories, Meda Pharmaceuticals, and Yaupon Pharmaceuticals. Received honoraria and travel support as an invited speaker for Reckitt-Benckiser. |
Lonnie Zeltzer, MD | Chair of data-monitoring committee (DMC) for buprenorphine study in children; Purdue Pharma, paid for initial take-off meeting and travel reimbursement, but no patients have completed the study yet and so no DMC reports yet. Received honoraria for lectures on chronic pain and integrative medicine in individuals with Fabry, Pompe, or Gaucher's disease sponsored by Sanofi, Inc. |
Quality of Evidence | Strength of Recommendation | |
---|---|---|
Benefits Do or Do Not Clearly Outweigh Risks | Benefits and Risks and Burdens Are Finely Balanced | |
High | Strong | Weak |
Moderate | Strong | Weak |
Low | Strong | Weak |
Insufficient evidence to determine net benefits or harms | No recommendation | No recommendation |
References
- Sudden cardiac death and antipsychotics. Part 2: Monitoring and prevention.Adv Psychiatr Treat. 2006; 12: 100-109
- What clinicians should know about the QT interval.J Am Med Assoc. 2003; 289: 2120-2127
- Treatment of patients with schizophrenia.in: APA Practice Guidelines. American Psychiatric Association, Arlington, VA2004
- Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: A mortality assessment study.Addiction. 2009; 104: 993-999
- Accuracy in equianalgesic dosing: Conversion dilemmas.J Pain Symptom Manage. 2001; 21: 397-406
- Electrocardiogram characteristics of methadone and buprenorphine maintained subjects.J Addict Dis. 2008; 27: 31-35
- Association between opioid prescribing patterns and opioid overdose-related deaths.J Am Med Assoc. 2011; 305: 1315-1321
- Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.Circulation. 2005; 112: 2602-2610
- An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam.Addiction. 2002; 97: 993-1001
- Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.(DHHS Publication No. (SMA) 40–3939)in: Treatment Improvement Protocol TIP (40). Substance Abuse and Mental Health Services Administration, Rockville, MD2004
- 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
- Gender-specific differences in susceptibility to low-dose methadone-associated QTc prolongation in patients with heroin dependence.J Cardiovasc Electrophysiol. 2012; 23: 527-533
- Dose ratios between high dose oral morphine or equivalents and oral methadone.J Palliat Med. 2013; 16: 947-950
- Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: A systematic review.J Pain Symptom Manage. 2003; 26: 1026-1048
- Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.J Pain. 2009; 10: 113-130
Chou R, Weimer MB, Dana T, Pappas M, Mitchell JP: Systematic Evidence Review on 435 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
- Setting standards for physical health monitoring in patients on antipsychotics.Psychiatrist. 2009; 33: 451-454
- Opioid abuse, dependence, and addiction in pregnancy (Committee OPinion No. 524).Obstet Gynecol. 2012; 119: 1070-1076
- Perinatal addiction: Outcome and management.Am J Obstet Gynecol. 1977; 129: 679-686
Department of Human Services: Methadone deaths (and distribution) on the rise. CD Summary 52, 2003
- Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation.Circulation. 2010; 121: 1047-1060
Drugs.com: Propulside (Cisapride). Available at: http://www.drugs.com/pro/propulsid.html. Accessed January 14, 2014
- Opioid prescriptions for chronic pain and overdose: A cohort study.Ann Intern Med. 2010; 152: 85-92
- Interindividual variability of the clinical pharmacokinetics of methadone: Implications for the treatment of opioid dependence.Clin Pharmacokinet. 2002; 41: 1153-1193
- 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
- Methadone-related deaths in Western Australia 1993-99.Aust N Z J Public Health. 2002; 26: 364-370
- Successful transition to buprenorphine in a patient with methadone-induced torsades de pointes.J Interv Card Electrophysiol. 2008; 23: 117-119
- Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen.Heart. 2007; 93: 1051-1055
- Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro.Br J Clin Pharmacol. 2009; 67: 172-179
- QTc interval prolongation for patients in methadone maintenance treatment: A five years follow-up study.Am J Drug Alcohol Abuse. 2013; 39: 235-240
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
- Methadone versus buprenorphine in pregnant addicts: A double-blind, double-dummy comparison study.Addiction. 2006; 101: 275-281
- Can patients taking opioids drive safely? A structured evidence-based review.J Pain Pall Care Pharmacother. 2002; 16: 9-28
- Are opioid-dependent/tolerant patients impaired in driving-related skills? A structured evidence-based review.J Pain Symptom Manage. 2003; 25: 559-577
Flexner C, Piscitelli S: Managing drug-drug interactions in HIV disease. Available at: http://www.medscape.org/viewarticle/421137_3. Accessed January 14, 2014
- Methadone-related deaths in Hennepin County, Minnesota: 1992-2002.J Forensic Sci. 2003; 48: 668-671
General Accountability Office: Methadone-associated overdose deaths: Factors contributing to increased deaths and efforts to prevent them. Available at: http://www.gao.gov/products/GAO-09-341. Accessed January 14, 2014
- Opioid dose and drug-related mortality in patients with nonmalignant pain.Arch Intern Med. 2011; 171: 686-691
- Interactions between methadone and medications used to treat HIV infection: A review.Mt Sinai J Med. 2000; 67: 429-436
- 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
- Ventricular arrhythmias in patients treated with methadone for opioid dependence.J Interv Card Electrophysiol. 2010; 28: 19-22
- Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome.Am J Obstet Gynecol. 1977; 129: 417-424
- Cut-offs for screening prolonged QT intervals from Fridericia's formula in children and adolescents.Circ J. 2010; 74: 1663-1669
- Clinical pharmacology of opioids for pain.Clin J Pain. 2002; 18: S3-S13
- 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
- Misuse of and dependence on opioids: Study of chronic pain patients.Can Fam Physician. 2006; 52: 1081-1087
- 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
- Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: An analysis of registry data.Ann Intern Med. 2013; 158: 735-740
- Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents.J Pharmacol Exp Ther. 2002; 303: 688-694
- QTc interval screening in an opioid treatment program.Am J Cardiol. 2013; 112: 1013-1018
- Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy.Anesth Analg. 2003; 97: 1097-1102
- Heterogeneous impact of methadone on the QTc interval: What are the practical implications?.J Addict Dis. 2008; 27: 5-9
- Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes.Pharmacotherapy. 2005; 25: 611-614
- Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes.Pharmacotherapy. 2003; 23: 802-805
- Torsade de pointes associated with very-high-dose methadone.Ann Intern Med. 2002; 137: 501-504
- Effects of methadone on QT-interval dispersion.Pharmacotherapy. 2005; 25: 1523-1529
- QTc interval screening in methadone treatment.Ann Intern Med. 2009; 150: 387-395
- Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain.Pain. 2011; 152: 1789-1795
Leavitt S. Addiction Treatment Forum. Methadone-Drug Interactions, 3rd ed. November 2005 Revision/Update. Available at: http://www.atforum.com/SiteRoot/pages/addiction_resources/Drug_Interactions.pdf. Accessed February 28, 2014
- Levy R. Thummel K.E. Trager W. Hansten P. Eichelbaum M. Metabolic Drug Interactions. Lippincott Williams & Wilkins, Philadelphia, PA2000
- Factors affecting head growth and intellectual function in children of drug addicts.Pediatrics. 1985; 75: 269-274
- Benzodiazepines, methadone and buprenorphine: Interactions and clinical management.Am J Addictions. 2009; 19: 59-72
- The effect of heroin and multiple drug abuse on the electrocardiogram.Am Heart J. 1973; 86: 663-668
- A review of the use of methadone for the treatment of chronic noncancer pain.Pain Res Manag. 2005; 10: 133-144
- The methadone epidemic: Methadone-related deaths on the rise in Vermont.Am J Forensic Med Pathol. 2011; 32: 131-135
- Impact of methadone treatment on cardiac repolarization and conduction in opioid users.Am J Cardiol. 2005; 95: 915-918
- QT interval screening in methadone maintenance treatment: Report of a SAMHSA expert panel.J Addict Dis. 2011; 30: 283-306
- Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.Cochrane Database Syst Rev. 2009; : CD002209
- Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: A review.Am J Addictions. 2009; 19: 4-16
- Factors associated with mortality in Scottish patients receiving methadone in primary care: Retrospective cohort study.BMJ. 2009; 338: b2225
- The long QT syndrome: Prospective longitudinal study of 328 families.Circulation. 1991; 84: 1136-1144
- 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
- A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia.Addiction. 2009; 104: 1541-1548
- QT prolongation and torsades de pointes among methadone users: Reports to the FDA spontaneous reporting system.Pharmacoepidemiol Drug Saf. 2005; 14: 747-753
- Morphine to methadone conversion: An interpretation of published data.Am J Hosp Palliat Care. 2011; 28: 135-140
- Baseline values from the electrocardiograms of children and adolescents with ADHD.Child Adolesc Psychiatry Ment Health. 2007; 1: 11
- Risk stratification in the long-QT syndrome.N Engl J Med. 2003; 348: 1866-1874
- 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
- Normal standards for QT and QT subintervals derived from a large ethnically diverse population of women aged 50 to 79 years (the Women's Health Initiative [WHI]).Am J Cardiol. 2006; 97: 730-737
- Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development.Cardiovasc Res. 2003; 58: 32-45
- Equianalgesic dose/ratio between methadone and other opioid agonists in cancer pain: Comparison of two clinical experiences.Ann Oncol. 1998; 9: 79-83
- 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
- Long QT syndrome in adults.J Am Coll Cardiol. 2007; 49: 329-337
- 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
- Consensus guideline on parenteral methadone use in pain and palliative care.Palliat Support Care. 2008; 6: 165-176
- Corrected QT interval during treatment with methadone and buprenorphine—relation to doses and serum concentrations.Drug Alcohol Depend. 2013; 129: 88-93
- Methadone-related deaths in New South Wales.Med J Aust. 1997; 166: 54-55
- Drug-induced torsade de pointes: From molecular biology to bedside.Jpn J Pharmacol. 2000; 83: 1-19
- Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes.Ann Intern Med. 1995; 122: 701-714
- Dispersion of QT and QTc interval in healthy children, and effects of sinus arrhythmia on QT dispersion.Heart. 1998; 801: 77-79
US Food and Drug Administration: Safety alerts. Propulsid (cisapride). Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175000.htm. Accessed January 14, 2014
- Methadone, QTc interval prolongation and torsade de pointes: Case reports offer the best understanding of this problem.Ther Adv Psychopharmacol. 2013; 3: 219-232
- Clinical pharmacology of buprenorphine: Ceiling effects at high doses.Clin Pharmacol Ther. 1994; 55: 569-580
- Drug poisoning deaths in the United States, 1980-2008.NCHS Data Brief. 2011; : 1-8
- 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
- Characterization of methadone overdose: Clinical considerations and the scientific evidence.Ther Drug Monit. 2002; 24: 457-470
World Health Organization: Guidelines on the pharmacological treatment of persisting pain in children with medical illnesses. Available at: http://www.who.int/medicines/areas/quality_safety/guide_perspainchild/en/index.html. Accessed January 14, 2014
- Drug induced QT prolongation and torsades de pointes.Heart. 2003; 89: 1363-1372
- 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
- Risk of cardiac events in family members of patients with long QT syndrome.J Am Coll Cardiol. 1995; 26: 1685-1691
- Neonatal narcotic addiction. Comparative effects of maternal intake of heroin and methadone.N Engl J Med. 1973; 289: 1216-1220
- QT-interval duration and mortality rate: Results from the Third National Health and Nutrition Examination Survey.Arch Int Med. 2011; 171: 1727-1733
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Footnotes
Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. As part of a shared decision-making approach, it may be appropriate for the clinician to inform a patient that a particular recommendation may not be applicable, after considering all circumstances pertinent to that individual.
This article is based on research conducted at the Oregon Evidence-based Practice Center (now the Pacific Northwest Evidence-based Practice Center) with funding from the American Pain Society (APS). The authors have no known or potential conflicts of interest to declare. The authors are solely responsible for the content of this article and the decision to submit for publication.
A list of authors with disclosed conflicts of interest is shown in Appendix 1.
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.
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