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Applying Legal Risk Management To the Clinical Use of Methadone
Methadone is an old drug, first introduced in the U.S. in 1947 by Eli Lilly & Company as an analgesic.1 It works by occupying the brain receptor sites affected by heroin and other opioids.2 In the early 1960s, methadone was developed as an alternative to heroin in so-called methadone maintenance treatment (MMT) programs.3 Today, there has been renewed interest in pain management associated with various chronic disorders, especially cancer, and end-of-life care. This column explores clinical risk-management and P&T committee considerations regarding methadone analgesia and presents two real-world scenarios that illustrate these topics.
METHADONE IN THE TREATMENT OF CHRONIC PAIN
Methadone is a potent, long-acting opioid analgesic.4 Its use was once limited almost exclusively to the treatment of narcotic addicts who had voluntarily submitted to detoxification. This restriction was removed in 1976; physicians with appropriate Drug Enforcement Agency registration may now prescribe methadone for analgesia.3
The unique pharmacokinetic and pharmacodynamic characteristics of methadone make it a valuable option for the management of chronic pain both as a first-line agent and as a replacement opioid.1,4 Even though methadone may be administered by several routes––oral, rectal, intravenous, intramuscular, subcutaneous, epidural, and intrathecal––it is most commonly given orally in either tablets or solution.1,5
Numerous evaluations of methadone, including placebo-controlled clinical trials, have shown that it is an effective analgesic in cancer pain and in chronic non-cancer pain.1 Its pharmacological properties, however, demand greater precautions than are necessary with other opioids.6
Methadone has a long-elimination half-life (8–59 hours),7–9 which might not correlate with its duration of analgesic efficacy (typically 8–12 hours with repeated dosing).4 This pharmacokinetic property necessitates careful management and titration of effective dosing schedules, because the mismatch of half-life and duration of analgesia is potentially life-threatening.10
Day-to-day monitoring is essential when chronic methadone therapy is initiated or when patients are switching from another opioid to methadone for pain relief.1
METHADONE AS A THERAPY FOR OPIOID DEPENDENCE
Methadone is the most commonly used medication for substitution therapy of opioid addiction (morphine or morphine-like drugs).5 Substitution therapy has been defined as “the administration under medical supervision of a prescribed psychoactive substance, pharmacologically related to the one producing dependence, to people with substance dependence, for achieving defined treatment aims.”5 Substitution maintenance therapy with methadone (MMT) has been shown to reduce illicit drug use, mortality rates and criminality associated with drug use, and the risk of the spread of human immuno deficiency virus (HIV) infection associated with opiate injection.2,3,5 MMT also improves physical and mental health as well as social functioning in patients with opioid addiction.2,3,5 Methadone is useful in substitution therapy for the following reasons; namely, it:2
- blocks the euphoric and sedating effects of opiates.
- relieves the cravings for opiates that is a major factor in relapse.
- relieves symptoms that are associated with withdrawal from opiates.
- does not cause euphoria or intoxication at stable doses.
In the U.S., methadone products may be dispensed only by opioid treatment programs that have been certified by the Substance Abuse and Mental Health Services Administration (SAMHSA) and approved by the designated state authority.8,9 Medical practitioners who do not have this special license are prohibited from treating a patient with methadone to maintain an addiction to any controlled substance.
An exception is a patient who requires acute medical care, for whom the interruption of opiate maintenance treatment would create a medical complication (i.e., withdrawal). This is a common situation in acute-care hospitals, which admit addicted patients and must treat these individuals both for pain and for the prevention of withdrawal.
CLINICAL–LEGAL RISK MANAGEMENT
All mu-opiate receptor agonists, including methadone, carry the risk of potentially fatal respiratory depression.7,11,12 Methadone carries an exceptionally high risk because of its unique kinetics (i.e., a long elimination half-life but a substantially shorter duration of analgesic action). After administration, methadone can remain in the liver and in other tissues, including fat cells, from which it is slowly released back into the circulation.7 If this slow release from tissues occurs while the patient is taking additional doses of methadone, the drug may reach toxic levels and may have a depressive effect on neurons in the brain’s respiratory center, located in the medulla.11 Importantly, methadone reabsorption from the tissues may continue for weeks after drug administration has ceased.4
Because methadone’s half-life is much longer than its duration of action, the drug’s peak respiratory-depressant effects typically occur later and persist longer than its peak analgesic effects, particularly in the early dosing period.1,7
The titration of methadone dosing must be performed by individuals with experience using this agent, and it is best monitored in chronic-pain clinics with multidisciplinary observation.
As mentioned, it is possible to underestimate the potency of methadone when patients are undergoing a transition from another opioid, such as controlled-release morphine (e.g., MS-Contin, Purdue Pharma) or oxycodone (OxyContin, Purdue Pharma). The available equianalgesic dosing tables provide only general guidelines.1,13–15 The previous use of high-dose morphine may lead clinicians to overestimate the correct replacement dose when patients are switching to methadone.1 In addition, the metabolism of methadone can vary considerably among patients;16 therefore, each patient must be evaluated individually.
The transition to methadone is further complicated by the fact that patients who are tolerant to other mu-opioid agonists may not be tolerant to methadone. It is critical that clinicians understand the pharmacokinetics of methadone when converting patients from other opioids. A high degree of opioid tolerance does not eliminate the possibility of a methadone overdose, iatrogenic or otherwise.8,9
Methadone dosing should be conservative, in accordance with the adage “start low and go slow.”1 Incremental changes in dosing should be made infrequently, and the dosing interval should not be too short. Until a stable pattern of effective dosing has been established, frequent monitoring is vitally important for all patients undergoing the transition to methadone therapy.
Methadone is metabolized almost exclusively by the liver;17 the main step consists of N-demethylation of methadone by cytochrome P450 (CYP) enzymes (principally CYP3A4, CYP2B6, and CYP2D6) to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), an inactive metabolite.8,9 Interindividual differences in the activity of the various CYP enzymes may explain some of the variation in methadone metabolism observed among patients. For example, the amount of the CYP3A4 enzyme in the intestine can vary up to 11-fold, which may account for individual differences in the breakdown and absorption of methadone.18
During methadone therapy, treatment with other agents may be necessary because of the comorbidities that are frequently encountered in drug addicts and in patients with chronic pain. These additional treatments (e.g., psychotropic drugs, antibiotics, anticonvulsants, and antiretroviral drugs) can precipitate a wide range of pharmacokinetic interactions. Some drugs, such as verapamil (e.g., Calan, Pfizer) and quinidine, may alter the absorption of methadone; others, such as propranolol (e.g., Inderal, Akrimax) and tricyclic antidepressants, may influence the protein binding of methadone.19
Several agents displace methadone from mu-opioid receptors, thereby blocking the effects of methadone. These drugs include buprenorphine (Subutex, Reckitt Benckiser), pentazocine (Talwin, Hospira), nalbuphine (Nubain, Endo), and butorphanol (Stadol, Bristol-Myers Squibb).4,6 Of particular concern are agents that potentiate the respiratory depression associated with opiates, such as alcohol and benzodiazepines.20
In drug addicts undergoing MMT, the known drug–drug interactions associated with methadone do not have life-threatening consequences, but they usually result in decreased concentrations of the drug, which in turn can cause symptoms of withdrawal and increase the risk of relapse into heroin abuse.21
It has been well established, through both animal and human studies, that methadone has the potential to cause cardiac arrhythmias––specifically, QT prolongation and torsades des pointes.22,23 Therefore, the coadministration of other medications that increase the risk of QT prolongation and torsades des pointes, such as the antibiotics clarithromycin (Biaxin, Abbott) and erythromycin and the antidepressants fluoxetine (Prozac, Eli Lilly) and venlafaxine (Ef fexor, Wyeth/Pfizer), may result in additive effects and an increased risk of ventricular arrhythmias and sudden cardiac death.
Patients receiving methadone should be advised to seek medical attention if they experience symptoms that indicate the occurrence of torsades des pointes, such as dizziness, palpitations, or syncope. If patients are taking drugs that also cause central nervous system (CNS) or hypotensive effects (e.g., psychotropic agents, such as tricyclic antidepressants, phenothiazines, and neuroleptic drugs), they should be made aware of the possibility of additive effects with methadone and should be counseled to avoid activities that require mental alertness until they know how these agents will affect them.
High-dose methadone monotherapy has been associated with QT prolongation and torsades des pointes in drug addicts undergoing MMT.24 High doses of methadone are also used to treat chronic pain at pain-management centers. Patients with chronic pain, therefore, are at risk of QT prolongation and torsades des pointes from methadone treatment even in the absence of coadministered drugs.
UNINTENTIONAL METHADONE-RELATED DEATHS
In July 2007, a conference on methadone mortality rates, sponsored by the SAMHSA, concluded that the distribution of all forms of methadone (tablets, diskettes, and solution) continues to grow, with the greatest expansion coming from tablets distributed through pharmacies.25 At the same time, the number of methadone-related deaths has increased substantially.
A review of data from the National Vital Statistics System found that poisoning deaths attributed to methadone rose from 786 in 1999 to 4,462 in 2005, for an increase of 468% (
In November 2006, a public health advisory issued by the FDA included the following statement:27
… the FDA has received reports of death and life-threatening side effects in patients taking methadone. These deaths and life-threatening side effects have occurred in patients newly starting methadone for pain control and in patients who have switched to methadone after being treated for pain with other strong narcotic pain relievers. Methadone can cause slow or shallow breathing and dangerous changes in heartbeat that may not be felt by the patient.
The advisory urged physicians to use caution when prescribing methadone to patients who are not accustomed to the drug, and it emphasized that patients should take the drug exactly as directed.
As with any medication that can be fatal in large doses, methadone must be taken properly and with due care. As discussed previously, accumulation of the drug in tissues can reach toxic levels if the dose is too high or if the user’s metabolism of the drug is too slow. In such situations, a patient who fared well after the first few doses of methadone could experience high levels of the drug without taking more than was prescribed. For this reason, it is important that patients and their families be made aware of the symptoms that are characteristic of an opiate overdose.
LEGAL CASE SCENARIOS
The following scenarios provide examples of cases that have been brought against practitioners and their practices for deaths related to the use of methadone. These cases were settled out of court under seal, which is commonly done to avoid a costly and public trial.
A 35-year-old mother of two was being treated by a pain-management physician in a midwestern state. She had a long history of low back pain and had undergone a laminectomy a few years earlier, which did not improve her condition. She was being maintained on oxycodone 20 mg every 12 hours for pain. She informed her physician that her husband had recently lost his job and that they no longer had health insurance. Her physician prescribed methadone 10 to 15 mg every 8 hours. The more expensive oxycodone was discontinued.
The woman and her husband went to a local chain pharmacy to fill the prescription for methadone. She took three 15-mg tablets that night, two tablets in the morning, two tablets at mid-day, and three tablets at bedtime. The husband found her unresponsive on the floor the following morning. An ambulance was called, and Emergency Medical Services (EMS) technicians declared her dead at the scene.
A 35-year-old male school teacher and wrestling coach in a southwestern state was seen by a sports-medicine specialist. The patient was taking hydrocodone/acetaminophen (e.g., Vicodin, Abbott) for chronic low back pain. The sports specialist was concerned about potential acetaminophen toxicity. He prescribed “low-dose” methadone, 10 mg twice daily, and discontinued the hydrocodone/acetaminophen combination.
The next day, the patient stayed at his parent’s home. He was very drowsy, sleeping on and off most of the day, and went to bed early. On the morning of the third day, his mother was unable to awaken him. He was declared dead by EMS technicians.
In both cases, the medical examiner cited methadone intoxication as the cause of death. Both of the physicians, along with their practices (one a local hospital, the other a specialty group), were sued for wrongful death. Both physicians testified that the methadone dose was “equivalent” to that of previously used opiates. They considered their patients to be opiate-tolerant and considered the methadone prescriptions to be safe. Neither physician was aware of the unusual (and cumulative) kinetics of methadone, and neither of them recognized the need to start with a low dose, gradually discontinue existing opiates, and regularly reassess the patients’ tolerance to methadone.
Methadone is commonly used as a substitute for morphine or morphine-like drugs in addicted patients undergoing MMT, and it provides a low-cost option for patients with chronic pain, especially those who have lost their prescription-drug insurance. The clinical use of methadone, however, must be governed by prescribing guidelines that inform physicians, pharmacists, and especially patients about vitally important safety issues. Clear warnings and usage data, including serious adverse events, must be included in prescribing guidelines. Such information should be made available to clinical staff members (e.g., physicians, nurses, and pharmacists) involved in the risk-management aspects of clinical care and should be embedded in electronic ordering and patient record systems.
P&T committees can promote these initiatives through medical-staff or multidisciplinary departmental education. In addition, guideline compliance can be incorporated into the institution’s electronic medical record and prescribing systems. Partnering with hospital clinical or risk-management teams can also help P&T committees promote safe and appropriate patient care.
Medical-care delivery organizations (hospitals, clinics, and medical groups) and their clinical staff not only are on the front line of care for patients; they are also at the leading edge for exposure to malpractice claims, with the potential for significant financial loss as well as serious damage to the institution’s reputation if the claims go to court. Individual practitioners along with key institutional operating committees, such as P&T and quality improvement, share the need to protect both their patients and their institutions from harm that is avoidable. The safe clinical use of methadone is a case in point.
The ubiquitous use of a drug like methadone illustrates the risk–benefit equation that applies to both old and new oral drugs. The real risk of patient harm along with legal exposure requires greater attention by P&T committees and the care delivery system itself.
Poisoning and methadone-related poisoning deaths in the U.S., 1999–2005. (From Fingerhut LA, 2008.
- Toombs JD. Oral Methadone Dosing for Chronic Pain: A Practitioner’s Guide Glenview, Ill.: Pain Treatment Topics. March 2008;Available at: http://updates.pain-topics.org/pdf/OralMethadoneDosing.pdf. Accessed October 31, 2011.
- CDC. Methadone maintenance treatment. IDU HIV Prev February 2002;Available at: www.cdc.gov/idu/facts/methadonefin.pdf. Accessed October 31, 2011.
- Joseph H, Stancliff S, Langrod J. Methadone maintenance treatment (MMT): A review of historical and clinical issues. Mt Sinai J Med 2000;67:347–364.
- Toombs JD, Kral LA. Methadone treatment for pain states. Am Family Phys 2005;71:1353–1358.
- World Health Organization, United Nations Office on Drugs and Crime, and Joint United Nations Programme on HIV/AIDS. WHO/UNODC/UNAIDS Position Paper: Substitution Maintenance Therapy in the Management of Opioid Dependence and HIV/AIDS Prevention Geneva: 2004;Available at: www.who.int/substance_abuse/publications/en/PositionPaper_English.pdf. Accessed November 2, 2011.
- Terpening CM, Johnson WM. Methadone as an analgesic: A review of the risks and benefits. W V Med J 2007;103:14–18.
- Substance Abuse and Mental Health Services Administration (SAMHSA). Knowledge Application Program. Emerging issues in the use of methadone. Substance Abuse Treatment Advisory 2009;8:1–8.Pub. No. (SMA) 09-4368. Available at: http://kap.samhsa.gov/products/manuals/advisory/pdfs/Methadone-Advisory.pdf. Accessed October 31, 2011.
- Dolophine HCl (methadone HCl tablets, USP), prescribing information. Columbus, Ohio.: Roxane. October 2006;Available at: www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM142842.pdf. Accessed October 31, 2011.
- Diskets Dispersible Tablets (methadone HCl, USP) prescribing information. Birmingham, Ala.: Cebert Pharmaceuticals, Inc.. October 2006;Available at: https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=3711. Accessed October 31, 2011.
- Säwe J. High-dose morphine and methadone in cancer patients: Clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokinet 1986;11:87–106.
- McCrimmon DR, Alheid GF. On the opiate trail of respiratory depression. Am J Physiol Regul Integr Comp Physiol 2003;285:R1274–R1275.
- Santiago TV, Edelman NH. Opioids and breathing. J Appl Physiol 1985;59:1675–1685.
- Cunningham G, Bodley S, Chaiet A, et al. Methadone for Pain Guidelines Toronto: College of Physicians and Surgeons of Ontario. November 2004;Available at: www.cpso.on.ca/uploadedFiles/policies/guidelines/methadone/Methadone_or_PainGUIDE.pdf. Accessed November 4, 2011.
- Shaiova L, Berger A, Blinderman CD, et al. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care 2008;6:165–176.
- Trescot AM, Helm S, Hansen H, et al. Opioids in the management of chronic non-cancer pain: An update of the American Society of Interventional Pain Physicians Guidelines. Pain Physician 2008;11;(2 Suppl):S5–S62.
- 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.
- Nilsson MI, Meresaar U, Anggard E. Clinical pharmacokinetics of methadone. Acta Anaesthesiol Scand 1982;74:66–69.
- In: Levy RH, Thummel KE, Trager WF, et al. Metabolic Drug Interactions Philadelphia: Lippincott Williams & Wilkins. 2000;
- Brown R, Kraus C, Fleming M, Reddy S. Methadone: Applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad Med J 2004;80:654–659.
- Corkery JM, Schifano F, Ghodse AH, Oyefeso A. The effects of methadone and its role in fatalities. Hum Psychopharmacol Clin Exp 2004;19:565–576.
- Ferrari A, Coccia CPR, Bertolini A, Sternieri E. Methadone: Metabolism, pharmacokinetics, and interactions. Pharmacol Res 2004;50:551–559.
- George S, Moreira K, Fapohunda M. Methadone and the heart: What the clinician needs to know. Curr Drug Abuse Rev 2008;1:297–302.
- Schmittner J, Krantz MJ. QTc prolongation in methadone maintenance: Fact and fiction. Heroin Addict Relat Clin Probl 2006;8:41–52.
- Justo D, Gal-Oz J, Paran Y, et al. Methadone-associated torsades des pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction 2006;101:1333–1338.
- Substance Abuse and Mental Health Services Administration. Summary Report of the Meeting: Methadone Mortality—A Reassessment Washington, D.C.: Department of Health and Human Services. July
202007;Available at: www.dpt.samhsa.gov/pdf/Methadone_Report_10%2018%2007_Brief%20w%20attch.pdf. Accessed November 3, 2011.
- Fingerhut LA. Increases in poisoning and methadone-related deaths: United States, 1999–2005. Hyattsville, Md: National Center for Health Statistics. February 2008;Available at: www.cdc.gov/nchs/data/hestat/poisoning/poisoning.pdf. Accessed November 3, 2011.
- FDA. Public health advisory: Methadone use for pain control may result in death and life-threatening changes in breathing and heart beat. November
272006;Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm124346.htm. Accessed November 3, 2011.