CE Article: (ACCME, CMI, ACFEI) 1 CE credit for this article Increasing use of Methadone as a pain killer may be fueling a disturbing increase in deaths related to this potent drug. eath and morbidity associated with methadone treatment has increased dramati- cally in recent years, largely in the population prescribed this drug for pain control rather than addiction maintenance. Inadvertent overdose is becoming increasingly common, likely in part because the drug’s acute pain-relieving effect lasts only 4 to 6 hours, yet it has a very long and variable plasma half-life of 24 to 36 (in some studies 15 to 55) hours, is stored in body tissues, and toxic accumulation occurs with too-frequent consump- tion. Adverse effects are most common in patients treated with methadone in combination with other drugs. Both cardiac and respiratory systems are vulnerable targets for the drug’s toxic actions, and other co-administered drugs can interactively increase the risk of death through a variety of mechanisms including direct central nervous system depression of respiration, idiosyncratic respiratory vulnerabilities, and lethal cardiac arrhythmias. Idiosyncratic fac- “ tors also play a part in methadone’s cardiac toxicity, and risk factors are well characterized, though perhaps not sufficiently widely known and understood by key stakeholders. The re- cent change in FDA labeling requirements for the drug—and the November 2006 post- ing of a government warning regarding its use in pain treatment—has not yet reduced morbidity and mortality associated with methadone as reported in the MedWatch database for the first quarter of 2007. Methadone at high doses, or in naive users or idiosyncratically “ at much lower doses, depresses Joshua Perper, chief medical examiner for Broward County, displays a bottle respiration and may interfere with of methadone collected in a possible drug overdose death. KRT PHOTO BY cardiac function, either or both ANASTASIA WALSH/SOUTH FLORIDA of which can lead to death.” SUN-SENTINEL (800) 423-9737 Summer 2008 THE FORENSIC EXAMINER 39 Forensic Relevance on the effect of methadone on psychomotor netics have been reached and before the user Methadone is a synthetic morphine-type (opi- impairment and neuropsychological func- has subjectively adjusted to, and learned to oid) drug developed in Germany in 1937 and tion are complicated by the fact that the compensate for, the effects of the drug. introduced to the United States in 1947 by methadone-using population suffers from the Eli Lilly company under the trade name multiple co-morbidities, and impairments Adverse Outcomes: Lethal Toxicity Dolophine®. It is now classified and restrict- may be due in part to other factors including Methadone at high doses, or in naïve us- ed as a Schedule II drug. Methadone has two chronic pain, psychiatric problems, sequelae ers or idiosyncratically at much lower doses, principal legitimate clinical uses: [1] substi- of chronic alcohol abuse, and invariably, too, depresses respiration and may interfere with tution treatment of opiate drug dependency, traffic accidents involve other drugs in addi- cardiac function, either or both of which and [2] analgesia for chronic pain. In addition, tion to methadone. can lead to death. An additional complica- methadone is also subject to diversion and il- Methadone maintenance patients, addicts tion is that of co-morbid illness, which in licit consumption as a drug of abuse. taking stable supervised doses to the effects the methadone maintenance population in- Methadone-related cases come under fo- of which they are tolerant (see below), tend cludes a disproportionately large proportion rensic review for a number of reasons, now to have automobile driving accidents at a rate of HIV/AIDS patients and viral hepatitis pa- more than in the past. Methadone toxicity not greatly dissimilar to the general popula- tients who acquired their addiction from IV may be sub-lethal (affecting behavior and tion (reviewed by Stout & Farell, 2002). opiate abuse and their illness from needle- mental condition) or lethal. Both forms of Correlating driving performance deficits sharing. In this tragic population, the second- toxicity are forensically relevant. Accordingly, with neuropsychological performance defi- ary treatment of drug-abuse-related illnesses reasons underlying forensic interest in meth- cits proves more complicated: Some stud- greatly increases the risk of drug interaction adone are similar to reasons underlying fo- ies find no difference between methadone with methadone. rensic interest in any potentially toxic drug maintenance patients and control groups that has both therapeutic and abuse poten- (Maddux, Williams, & Ziegler, 1977) while Cardiac system. Cardiac problems associ- tial. More specifically: others find between 50% to 80% of chronic ated with methadone toxicity and the heart’s methadone maintenance patients to be neu- underlying vulnerability to these can be de- [1] Methadone may adversely affect the behav- ropsychologically impaired (Darke, Sims, scribed in terms of the electrocardiogram ior and/or culpable mental states of criminal McDonald, & Wickes, 2000; Dittert, Naber, (ECG): The QT interval of the ECG, mea- defendants or victims or witnesses to crime. & Soyka, 1999) with deficits in information sured from the beginning of the QRS com- processing, memory, attention, and prob- plex to the end of the T wave (see Fig. 1), [2] Methadone may affect the mental and/or lem solving ability. Yet other studies have represents the duration of activation and re- physical condition of civil litigants and may concluded that the performance of patients covery of the heart in a single beat as mea- play a role as an element of disability deter- stabilized on methadone for 3 months and sured by the electrocardiogram. QT intervals mination, liability, and/or damages. Liability tested in driving simulators is similar to com- corrected for heart rate (QTc) longer than could be an issue in a motor vehicle accident munity-equivalent control patients (Lenne, 0.44 seconds are generally considered abnor- caused by a methadone-impaired driver or in Dietze, Rumbold, Redman, & Triggs, 2003). mal, though a normal QTc can be slightly a medical malpractice case involving negli- It would seem on balance that the neurobe- prolonged in some otherwise normal females gent prescription. Damages could be an issue havioral deficits of the majority of chronic, (up to 0.46 sec). Torsade de Pointes (TdP, or in a case where negligent prescription results stable, methadone-treated patients are usu- “torsades”) is defined as a polymorphous ven- in death by overdose, or where tortiously- ally not of a degree to cause accidents, or such tricular tachycardia in which the morphology, caused injuries result in a need for methadone patients avoid circumstances in which their the shape, of the electrocardiogram’s QRS maintenance treatment for chronic pain. impairments may contribute to driving ac- complexes varies from beat to beat. The ven- cidents. tricular rate in TdP can range from 150 beats [3] Illicit use, possession, and/or distribu- In non-addicted subjects given metha- per minute (bpm) to 250 bpm. TdP usually tion of methadone itself constitutes a crime. done, however, measurable and dose-relat- starts with a prolonged QT interval. Moreover, when distribution leads to harm to ed impairments typical of opiate drug ef- At high doses, methadone, even in oth- third parties, there may be additional crimi- fects are seen in choice reaction time and erwise normal subjects, is associated with nal consequences (e.g., homicide charges continuous performance test measures an increased risk for QT prolongation and against a drug supplier when a recipient dies (Rothenberg, Schottenfeld, Meyer, Krauss, TdP, especially at very high doses. The risk from overdose). & Gross, 1977); in attention, perception, of QT prolongation appears to be dose-re- and learning tasks (Gritz et al., 1975); and lated. Laboratory studies, both in vivo and in [4] As a toxic substance, methadone may be in tests for visual vigilance (Rothenberg, vitro, have demonstrated that prolongation an instrument for homicide or suicide, or its Schottenfeld, Gross, & Selkoe, 1980), al- of the QT interval operates through metha- therapeutic or recreational use may result in though these impairments are less severe than done’s inhibition of cardiac potassium chan- accidental death. Sorting among these possi- are seen with diazepam or alcohol (Chesher, nels (Islander & Vinge, 2000). Most cases bilities is of obvious forensic relevance. Lemon, Gomel, & Murphy, 1995). involve patients being treated for pain with Problems of neurobehavioral impairment large, multiple, daily doses of methadone, al- Adverse Outcomes: due to methadone, thus, typically occur in though cases have been reported in patients Sub-lethal Toxicity the early stages of treatment or when a dose- undergoing maintenance treatment of opi- Methadone is commonly associated with adjustment has been made, as blood levels oid addiction (Krantz, Kutinsky, Robertson, automobile driving accidents, yet studies are rising and before stable plateau-like ki- & Mehler, 2003; Walker, Klein, & Kasza, 40 THE FORENSIC EXAMINER Summer 2008 www.acfei.com pressants are also included among the drugs which prolong the heart’s QT interval. Table 1: Drugs that pro- Pulmonary edema is also a common manifes- long the heart’s QT inter- tation of opiate, including methadone, toxicity val (see text for abbrevi- (Gottlieb & Boylen, 1974). A white