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Vol. 10 •Issue 4 • Page 43

History, Pharmacology, Outcomes, Clinical Issues & Future Trends

With the number of Americans addicted to heroin estimated to be as high as 1 million, the likelihood of primary care or specialty PAs encountering a patient with heroin addiction is ever increasing. As with other diseases, the provider has the responsibility of attaining basic knowledge of heroin addiction and the resources to ensure access to appropriate care for the patient. J. Thomas Payte, MD, a San Antonio physician who has treated opioid addiction for 40 years, issued this challenge: "It is the responsibility of physicians, psychologists, nurses, counselors and administrators to be informed and involved in this process to ensure the best possible treatment of the addict-patient toward a goal of full rehabilitation. It is no longer sufficient to take care of patients. Treatment providers must also become teachers, public relations workers, politicians and advocates for all patients who want and need treatment."1

Brain Disease

Addiction, put simply, is a brain disease. This well-documented point continues to elude many in and out of the medical field, as stigmatization and misinformation obstruct best-practice progress in the treatment of addiction. Alan I. Leshner, PhD, former director of the National Institute on Drug Abuse, described the gap between research and practice: "Just as many other diseases and disorders once thought to be caused by psychological problems or stress, such as ulcers — and schizophrenia — have been shown to have a physical origin, drug addiction also has been shown to be a disease with a physical basis. However, because of misconceptions about the brain, behavior and mind, and the resulting societal and cultural biases, there is a 'disconnect' between the scientific data and public perceptions and, in many cases, professional perceptions about the nature of addiction and it's appropriate treatment."2

Drug dependence is costly in numerous ways, with the massive impact of addiction helping to shape the public view that that drug dependence is more a social problem than a chronic illness requiring treatment and prevention. In attempting to understand the abysmally high relapse rates of drug-dependent patients after treatment in traditional programs, A. Thomas McLellan, PhD, senior scientist at the PENN/VA Center for Studies of Addiction in Philadelphia, emphasized the need to view drug dependence as a chronic illness: "Current treatment strategies and outcome expectations view drug dependence as a curable, acute condition. If drug dependence is more like a chronic illness, the appropriate standards for treatment and outcome expectations would be found among other chronic illnesses."3

Leshner shares McLellan's perspective by drawing a comparison between addiction and cardiovascular disease. In his view, patient choices may certainly play a role in both, yet once addiction and heart disease are diagnosed, their treatment paths widely diverge. Following the discovery of a patient's heart disease, a focus on treatment replaces discussion and concern over its origins. Whether a disease is initiated with excessive intake of fat or excessive ingestion of drugs, both change essential physiologic functions and both need treatment.2

Coincidentally, the identification of opiate and lipoprotein receptors both occurred between 1973 and 1976: "How different the reaction to diseases that act through these two classes of receptors! On the one hand, following a massive research effort, extraordinarily effective cholesterol-lowering drugs were developed to treat heart disease. These drugs are used extensively by physicians and accepted by the public. On the other hand, until recently there was little interest in developing medication to treat addiction and poor acceptance of those already approved," Leshner lamented.2

Within the context of this cultural discrepancy, the use of methadone as a treatment for heroin addiction since the 1960s has been commonly met with negative attitudes, even among providers. Such attitudes underscore the perception that methadone treatment is just substituting one addiction for another. This incorrect belief ignores the complexity of methadone's activity: It is not simply a replacement for heroin. While understanding of the biological mechanism involved is still incomplete, it is thought that methadone may correct a lesion in the endogenous opioid system. Such a complex function defies the logic of the pervasive "one addiction for another" saw.4 This enduring notion has been disputed by methadone pioneer Dr. Marie Nyswander, who pointed out that methadone maintenance patients who stop taking methadone do not develop craving for the its continued use. Instead, craving for heroin returns, and the patient seeks heroin, not methadone. This point demonstrates her assertion that patients do not become addicted to methadone; rather, they are ex-heroin addicts who are relieved of this addiction with the regular ingestion of methadone.5

What stands as the strongest argument in favor of the use of methadone is the exhaustive body of research that has shown, time and time again, that methadone is effective when used as an opiate replacement. Researchers have repeatedly concluded that methadone maintenance reduces heroin use, criminal behavior, HIV and hepatitis transmission, and has been shown to be a cost-effective intervention.6

Opiate Addiction's Roots

While opium use can be found in historical references dating back as far as 4,000 to 2,000 B.C., heroin was not introduced until 1874, when it was first synthesized in London. In 1898, German pharmacologist Dr. Heinrich Dreser postulated that heroin was ideal for controlling a variety of maladies, including bronchitis, emphysema, tuberculosis and asthma, and also alleged that heroin lacked problematic drug effects of morphine. Dreser proposed that heroin be used as a cure for opiate and morphine dependence, which had emerged as an area of great concern.7

The Harrison Act, passed in the United States in 1914, was the first major effort to regulate opiates. Outlawing the nonmedical use of opium products, it was not intended to deter practitioners, providing for no punishment to users and allowing opiate use for "legitimate medical purposes," "professional practice" and "good faith" prescription.1,7 Shortly after, the federal government adopted a more narrow interpretation of the law, declaring that addiction was not a disease. It followed from such an interpretation that physicians who continued to prescribe maintenance drugs were operating outside the parameters of professional practice, and physicians who continued to prescribe were indicted, prosecuted and imprisoned.7 Physicians arraigned on narcotics charges numbered up to 25,000, with 3,000 actually serving prison time.

Those addicted to opiates subsequently would have great difficulty finding physicians willing to treat them. In response to this provider prescriptive reluctance, more than 40 clinics would emerge between 1919 and 1923, designed to treat addicted patients by providing low-cost narcotics. The business of illicit drugs was growing quickly at the time, and some speculate that the closure of all such clinics by the federal government may have been tied to pressure from individuals or groups profiting from illegal drug sales, fearing that the clinics would reduce profits.1 Such prescriber nervousness continued even into the 1960s, when many working with heroin addicts did so in as inconspicuously as possible, even keeping such practice from colleagues.1

Methadone Emerges

Experiments with patients chronically addicted to heroin had begun in 1964 at New York's Rockefeller University, aimed at finding a replacement opiate that could provide a stable alternative to heroin use. Drs. Vincent Dole, Marie Nyswander and Mary Jane Kreek, regarded as the pioneers of the use of methadone maintenance as in inexpensive treatment for lengthy heroin addiction, were attempting to find an intervention that could meet their specific criteria: "It must eliminate the euphoric appeal of heroin and abstinence symptoms that draw addicts back to drug use; it must be sufficiently free from toxic dysphoric effects that patients will continue with treatment; it must be orally effective, long acting, medically safe and compatible with normal performance at work and at school and with responsible behavior in society."8,9 Methadone, which had been used primarily for analgesia and for detoxification of patients addicted to heroin, ultimately became the primary focus of their study.

What they found in methadone was a drug that would meet their original criteria, unlike their attempts to use morphine as a replacement therapy. Patients who had appeared passive and overmedicated on morphine became active, animated, and engaged with the substitution of methadone. By 1965, Dole, Nyswander and Kreek were able to report on their small trial with 22 patients, a report that was restrained and cautious. A tumultuous period would follow, filled with political battles and ill-conceived governmental regulatory attempts.

Early results were encouraging in what has been described as "the honeymoon stage," from the middle to late 1960s, although the U.S. Bureau of Narcotics continued to infiltrate and attempt to discredit methadone maintenance research. Methadone maintenance would expand quickly in the early 1970s, partly due to a continued push from the Nixon administration, but also due to continued push from inexperienced and poorly qualified interests who hoped that freely available methadone would solve a massive and complex narcotics problem. Dole advocated for rapid expansion, believing that such growth could be done in a competent fashion, pointing as evidence to the addition of 20,000 new patients to programs under the supervision of New York physician Robert Newman.1

Regulatory agencies begin to bring pressure against expansion in 1973, attempting aggressively to take charge of the expanding field. This was coupled with an unsophisticated understanding of methadone maintenance by many who hoped that such treatment would simply be quick way to get people in treatment and to keep them in treatment long enough to cure their underlying problems through psychiatry or religion. Such an approach missed the key point of methadone maintenance and its attempt to treat a chronic problem. Political and ideological intrusion had subverted the goals of treatment, making abstinence the desired outcome, instead of rehabilitation.1

A new round of acceptance would emerge in the 1980s, created in large part by the increasingly visible connection between AIDS and intravenous drug use. While the future would not be without major obstacles, methadone had achieved a higher standing. The safety and effectiveness of methadone could no longer be in question.1

Does Methadone Work?

Dating to Vincent Dole, Marie Nyswander and Mary Jane Kreek's early treatment goals, the use of methadone as a replacement for heroin has been driven and motivated by the desire to reduce crime, death, disease and drug use in a cost-effective manner. According to a 1997 research brief from the Lindesmith Center, five major claims have been validated by hundreds of scientifically sound studies:10

1. Methadone is the most effective treatment for heroin addiction. When comparing methadone to abstinence-based treatment and chemical-dependency treatment modalities, methadone has been studied more and has established superior results.

2. Methadone is effective HIV/AIDS prevention. Treatment with methadone has been proven to reduce injection and needle-sharing frequency and also provides a key point of contact between methadone patients and providers. This contact provides an excellent opportunity for providers to discuss harm-reduction techniques aimed at reducing the transmission of HIV/AIDS, hepatitis and other health problems common among intravenous drug users.

3. Methadone treatment reduces criminal behavior. Heroin addiction is extremely costly, with the current price for one gram ranging from $30 to $100 dollars, accompanying normal daily use of from one to three grams. It has been shown that drug offenses and predatory crime arrests decrease while on methadone, since patients no longer need to finance the expensive purchase of heroin. Many patients in methadone treatment are able to maintain more stable lifestyles, often including legitimate employment.

4. Methadone drastically reduces and often eliminates heroin use among addicts. The largest modern controlled drug-treatment study concluded that heroin use is drastically reduced while in methadone treatment. After just three months in treatment, fewer than 10% of patients in the study continued using heroin weekly or daily. Use of other illicit drugs also decreases with regular methadone use.

5. Methadone is cost effective. For every dollar spent in outpatient methadone treatment, there has been shown to be a $4 to $5 savings in health and social service costs. Inpatient residential treatment is up to five times more expensive than methadone maintenance treatment, and incarceration costs up to 10 times more.

Starting Patients on Methadone

Federal regulations have required patients to meet specific criteria to be admitted to methadone maintenance treatment. These have included a minimum age of 18 and a documented history of at least one year of narcotic addiction. New patients have also been required to prove a physiologic dependence on narcotics, resulting in the use of the term "sick intake" in admitting exams. In order to prove dependence, patients have been required to present in withdrawal, with typical symptoms of lacrimation, rhinorrhea, yawning, diaphoresis, piloerection, nausea and diarrhea. There have been exceptions to the sick requirement, including pregnancy and transfer from a chronic care facility, or from the care of another provider who has legitimately been prescribing methadone to a patient.11 New regulations that went into effect in May 2000 change this "sick intake" requirement and require only the meeting of diagnostic criteria for current opioid dependence.

If, in the clinician's judgment, the patient meets the federal requirements for admission, a typical oral induction dose of 30 mg/day is administered, with subsequent daily doses increasing in increments of 10 mg until reaching the a dose providing enough methadone binding to central nervous system receptors to prevent withdrawal symptoms, without overmedicating the patient. Average doses have increased to 80 to 100 mg/day, although it is essential to remember that dosing needs vary greatly among individuals and that sound dosing determination practice allows individualization of a patient's dose.

It may take anywhere from four to 10 days for methadone to reach steady state. Therefore, even an adequate methadone dose may not prevent withdrawal symptoms until the steady state has been reached. This information will assist the patient in assessing and interpreting their symptoms during the induction process. Some patients who have not yet reached steady state may present with withdrawal symptoms, even at an appropriate dose.

Dose Determination

As early as 1966, methadone trailblazers Nyswander and Dole recommended methadone maintenance doses between 80 mg and 120 mg daily. Payte describes the highly politicized nature of methadone dose determination that has developed since: "(Since 1966), methadone dose practice has been more often determined by politics and philosophy than by rational data or good clinical judgment. Studies reported by Sauna and Vaughan (1992) show that more than 50% of patients nationwide receive suboptimum methadone doses that are inadequate to prevent continued illicit narcotic use. Programs and entire states have been identified by their dose philosophy ('low dose' or 'high dose'). Low dose factions have often assumed an identity similar to that of a stern, caring, and conservative parent who would criticize the high-dose parent as permissive and enabling to the patient."11

Dosing at levels lower than what is known to be therapeutic has been common practice throughout many methadone facilities in the United States. Many states have "dose caps" determined by legislative or regulatory bodies. While studies clearly demonstrate the effectiveness of methadone, it must be at a therapeutic level to achieve full benefit. Many in the methadone field argue for the replacement of the terms "low dose" and "high dose" with "adequate dose." Many insist that adequate dosing must be individualized based on clinical and laboratory data and, like other medication dosing, should not be left to governmental agencies.11

The 'Glass Ceiling'

In numerous studies, a 100 mg daily dose has been suggested to be the upper limit of optimal dosing, a limit that has been referred to as "the impenetrable glass ceiling."12 Strain noted in a 1999 study that controversy persists in the determination of optimal dosing levels for methadone, and that by the late 1980s, surveys indicated that some methadone clinics were providing average daily doses lower than 30 mg. Even proponents of "high dose" methadone still kept average doses well below 100 mg. Federal regulations have discouraged doses higher than 100 mg/day, with rules requiring methadone clinics to receive exemptions in order to prescribe doses higher than 100 mg/day.13 With the implementation of new rules in May 2001, these regulatory prerequisites are no longer required.

Regarding the philosophical underpinnings of methadone's low-dose camp, Dole's criticism points to the problems with such a stance: "The concern of the low-dose proponents stems from a philosophy that equates addiction with moral weakness, and therefore conviction that a narcotic drug (methadone) cannot be considered legitimate for what, to them, is misuse of essentially the same kind of drug. They say that, if prescribed for treatment of heroin addiction, methadone should be given at the acceptable dose and for the shortest time needed for psychotherapists to deal with the 'fundamental problems."12 Dole asserted that with no compelling reason for prescribing only marginally adequate doses, the only prudent policy, as with antibiotics, is to supply enough medication to ensure patient success.13

Methadone and Other Drugs

Many medications also affect the P-450 system. Some medications have been found to decrease methadone blood plasma levels by increasing the rate at which methadone is metabolized and eliminated from the body. Methadone, like most other drugs, is transformed by the liver's microsomal enzyme systems. Drugs that are known to enhance the activity of these enzymes are called "inducers," increasing the pace at which methadone is metabolized. In individuals with unusually rapid rates of metabolism, this enhanced elimination of methadone can lead to otherwise puzzling signs and symptoms of withdrawal in patients being maintained on a previously adequate daily dose. Some known inducers are rifampin, ethyl alcohol and barbiturates, with anticonvulsants phenytoin and carbamazepine (Dilantin and Tegretol) particularly notorious for their propensity to induce the P-450 system.2,5

While some drugs induce the P-450 system and speed the elimination of methadone, others may do just the opposite by inhibiting the P-450 system. One such medication is the selective serotonin-reuptake inhibitor fluvoxamine, which is thought to slow the clearing of methadone, thereby increasing its activity.14 Other inhibitors are cimetidine, erythromycin and ketoconazole.1 Recently, ciprofloxacin has been suggested to be a P-450 inhibitor as well, possibly causing increased methadone levels and accompanying sedation, confusion and respiratory depression.15

Other Opiate Replacements

Methadone is joined by two drugs in the opiate-replacement therapy arena. Levo-alpha-acetyl methadol (LAAM) was initially developed in the late 1940s, and after decades of alternating clinical trials and inaction, it was approved for use in treatment of opioid dependence in 1993. LAAM's slow onset and lengthy duration result in a typical thrice-weekly dosing schedule. This decrease in required clinical attendance made it an attractive option for many patients. Problems related to Long QT syndrome, torsades de pointes cardiac arrhythmia and cardiac arrest resulted in the decision to discontinue its use in Europe. At the same time, there has been the issuance of warnings and protocol changes in the United States regarding the need for initial and serial electrocardiograms for LAAM patients and increased emphasis on more careful patient selection.4 The future of LAAM is, therefore, somewhat uncertain.

Buprenorphine, not currently available for use in opiate replacement settings, is a partial mu receptor agonist and kappa receptor antagonist.16 This mixed agonist-antagonist profile has helped to move it closer to approval for clinical use, partly due to the reduced possibility of overdose due to the mixed agonist-antagonist properties. Like LAAM, it is typically dosed three times per week. Johnson and colleagues published a high-profile comparison of LAAM, buprenorphine, and methadone in the November 2, 2000, issue of the New England Journal of Medicine, concluding that LAAM, buprenorphine, and "high-dose" (60 to 100 mg/day) methadone all reduce the use of illicit opioids, when compared to "low-dose" (20 mg/day) methadone.17 The National Institute on Drug Abuse is also currently studying the effectiveness of a combined buprenorphine/naloxone agent.

Future of Opiate Replacement

Several key issues face opiate replacement therapy in the near future. Most currently, federal oversight changed in May 2001, moving control of opioid replacement therapy from the U.S. Food and Drug Administration (FDA) to the Center for Substance Abuse Treatment. This move places opiate replacement therapy more in line with the accreditation method of oversight used in other medicine, leaving behind the more restrictive regulatory model of the FDA.

The impending addition of buprenorphine to the prescriber's armamentarium (limited to providers with training and connection to adjunctive social and health services) will add increased flexibility for patients. This addition will likely be offset, however, by the loss of LAAM if it is removed from the market. Some opiate replacement settings have moved most of their patients to LAAM and would undoubtedly face organizational difficulty with any decision to stop LAAM use.

Another trend is the movement toward the "medicalization" of methadone prescription, which is already being done on extremely limited basis. Governmental regulations have so far prohibited prescription of methadone by providers not based in methadone maintenance facilities. The foremost goal of those moving toward the loosening of regulatory constraints is to "mainstream" the most established patients into traditional clinical settings. Proponents argue that such a move would provide increased access to treatment, decrease the stigmatization of methadone treatment and open spots in more traditional methadone maintenance settings.7 This so-called "hub" model envisions clinical prescribers, working outside of traditional methadone clinics, taking over care of methadone maintenance patients who have shown a high level of clinical stability. It is speculated that many "middle class" opiate users will spurn treatment in methadone clinics, and that until treatment models are created that might be more attractive to this group, they will present to the health care system not for treatment of opiate dependence, but instead for treatment of HIV and hepatitis C.4

Insulin-Methadone Analogy

People struggling with addiction deserve to be treated like people with any other disease, but they clearly are not. Methadone maintenance portrays such medical inconsistency, with its myriad of program requirements and extensive regulation. It is not possible for patients to just drop by and pick up their medicine or go to the pharmacy on the way home for a refill. They are required to attend numerous classes, meet regularly with counselors, complete sometimes complicated treatment goals with their providers and provide regular urine samples for drug screening. Certainly the benefits of such comprehensive treatment are many, and perhaps it would be better if all illnesses were addressed with such a comprehensive approach. But they are not, and methadone patients continue with a societal spotlight burning brightly (and unfairly) on them as they attempt to achieve recovery.

In a parody of this discrepancy, Payte penned a report for a mythical two-year study about diabetes, drawing attention to the glaring inequities in our medical delivery system. In his introduction, he wrote: "The purpose of this study was to determine if the use of insulin resulted in any long-term benefit to diabetics. The concept was based on two widely accepted hypotheses: (1) that a formerly insulin-dependent diabetic could learn to live a comfortable and responsible life without insulin, and (2) that the use of any exogenous substance to replace or simply substitute for a deficient endogenous substance is conceptually unacceptable to modern scientific thinking and may be inherently evil. É It is obvious that exogenous insulin, being highly suspect at the outset, should be used in the lowest possible doses and for the shortest period of time."18

Alluding to the extensive program requirements standard in methadone treatment: "All patients were required to endure one hour of individual or group counseling each week, which addressed such subjects as meal planning, hygiene for the feet, pancreatic imagery and dietary assertiveness. É Avoiding the bothersome, time-consuming and costly process of individualized treatment also served to reduce the risk of enabling patients' maladaptive behaviors by what could seem to be a reward system. The resulting uniformity of service assured that the needs of no one were met. It was hoped that by making the treatment unpleasant that motivation for recovery would be enhanced." Finishing with an unsmiling wave to the substituting-one-addiction-for-another crowd, Payte concluded his report from the make-believe study: "As the patients approached the two-year period, the insulin doses were tapered over the final two months. All subjects were showing active insulin-dependent diabetes. The obvious conclusion is that insulin does not help insulin-dependent diabetics and is not effective in treatment. The high mortality rate of post-treatment patients suggests that insulin may have had some delayed, deadly toxic effects. This concept should be the subject of future research."18

As Payte pointed out in his more serious-toned addendum at the conclusion of the 1991 faux study, the humor of his piece is blunted by the high stakes involved in methadone treatment. The continuing loss of life associated with the shortage of methadone treatment slots is sobering indeed and is exacerbated by negative attitudes about methadone treatment, both from the general public and the medical community.18

The stigmatization of methadone continues, and challenging this stigma, as well as moving toward more progressive and fair treatment models, can be assisted by methadone advocates from the opiate replacement therapy community as well as primary-care and specialty providers.

Jim Anderson is a physician assistant at Evergreen Treatment Services in Seattle.


1. Payte JT. A brief history of methadone in the treatment of opioid dependence: a personal perspective. J Psychoactive Drugs. 1991;23:103-107.

2. Leshner AI. What we know: drug addiction is a brain disease. In: Graham AW, Schultz TK, eds. Principles of Addiction Medicine. 2nd ed. Chevy Chase, Md: American Society of Addiction Medicine; 1998: xxix-xxxvi.

3. McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000;284:1689-1695.

4. Payte JT, Zweben JE. Opioid maintenance therapies. In: Graham AW, Schultz TK, eds. Principles of Addiction Medicine. 2nd ed. Chevy Chase, Md: American Society of Addiction Medicine; 1998:557-570.

5. Schaffer Library of Drug Policy Web page. The Consumers Union Report on Licit and Illicit Drugs. Chapter 17. Why methadone maintenance works. Available at: Library/studies/cu/CU17.html. Accessed February 13, 2002.

6. Ward J, Mattick RP, Hall W, eds. Methadone Maintenance Treatment and Other Opioid Replacement Therapies. Amsterdam, Netherlands: Harwood Academic Publishers; 1998.

7. Fiellin DA, Storti SA, Schottenfeld RS, Briscoe JD, Pantalon MV, O'Connor PG. Methadone Medical Maintenance: A Training and Resource Guide for Office-Based Physicians. Substance Abuse Center and the Department of Internal Medicine, Yale University School of Medicine and the Addiction Technology Transfer Center of New England, located at the Brown University Center for Alcohol and Addiction Studies; 2000. Available at: ATTC-NE/pubs/. Accessed February 13, 2002.

8. Methadone 101. National Alliance of Methadone Advocates Web page. Available at: m101.html. Accessed February 13, 2002.

9. Parrino MW. Overview: current treatment realities and future trends. In: Parrino MW, ed. State Methadone Treatment Guidelines. Rockville, Md: US Dept of Health and Human Services; 1993:1-9.

10. The Lindesmith Center Drug Policy Foundation Web page. Research Brief: Methadone Maintenance Treatment. 1997. Available at: Accessed February 13, 2002.

11. Payte JT, Khuri ET. Principles of methadone dose determination. In: Parrino MW, ed. State Methadone Treatment Guidelines. Rockville, Md: US Dept of Health and Human Services; 1993:47-58.

12. MMT & beyond–the 100 mg/d methadone glass ceiling. Addiction Treatment Forum. 2000;9(4). Available at: Accessed February 13, 2002.

13. Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P. When "enough" is not enough: new perspectives on optimal methadone dose. Mt Sinai J Med. 2000;67:404-411.

14. Drugdex Drug Evaluations. Methadone. Available at: Accessed July 11, 1999.

15. Herrlin K, Segerdahl M, Gustafsson LL, Kalso E. Methadone, ciprofloxacin, and adverse drug reactions. Lancet. 2000;356:2069-2070.

16. Office of Alcoholism and Substance Abuse Services, State of New York. OASAS FYI page. Available at Accessed February 13, 2002.

17. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer M, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290-1297.

18. Payte JT. The use of insulin in the treatment of diabetes: an analogy to methadone maintenance. J Psychoactive Drugs. 1991;23:109-110.

Higher-Dose Research

Disagreement abounds within the methadone maintenance field regarding proper dosing. One piece of the dosing controversy relates to the use of serum methadone levels (SMLs) in determining adequate dose. While some in the field believe that therapeutic drug monitoring using SMLs should be routine, others have proposed that the correlation between SMLs and clinical signs of optimal dose is questionable, raising doubt about the usefulness of SMLs.1

One reason that SMLs may not be as valuable as once thought has to do with metabolic nuance. Racemic methadone, the formulation available in the United States, contains a 50:50 mixture of R and S stereoisomers of methadone. Also called "enantiomers," these methadone molecules are mirror images of one another. R and S methadone stereoisomers can be metabolized at significantly different rates. Traditional SML assessment measures only the sum of both stereoisomers, because the R isomer is 50 times more biologically active than the S isomer. An apparently adequate SML (the sum or the R and S stereoisomers) may not contain enough of the R enantiomer, the stereoisomer that gives methadone the ability to prevent withdrawal.2

According to Maxwell and Shinderman, a patient with an inadequate serum level of the active R enantiomer may have what appears on paper to be an adequate, or even toxic SML, while in fact his dose in not adequate for maintenance.

Testing for serum R:S enantiomer (stereoisomer) ratios could address this problem, but such testing is relatively costly and not readily available.2 Their recommendation, in light of such lack of reliability of SMLs, is increased emphasis on medical evaluation of objective and subjective signs and no use of SMLs in determining dose, with some rare exceptions. Methadone dose in their clinics average 130 mg, and currently range to 1,400 mg/day.

–Jim Anderson, PA-C


1. Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P. When "enough" is not enough: new perspectives on optimal methadone dose. Mt Sinai J Med. 2000;67:404-411.

2. Maxwell S, Shinderman M. Optimizing response to methadone maintenance treatment: use of higher-dose methadone. J Psychoactive Drugs. 1999;31(2):95-102.

Pharmacology of Methadone

While opioids act in numerous ways, two of their most profound actions are analgesia and euphoria, altering an individual's pain perception. One of their attractive features is that this alteration can occur in doses that do not significantly alter other central nervous system functions.1 The brain's three primary types of narcotic receptors, identified as mu, delta and kappa, interact with endogenous and exogenous opiates in a "lock and key" fashion.1

It's important to distinguish the pharmacology of compulsive self-administration behavior from the actions that govern physical dependence, because they occur in different parts of the brain. Repetitive self-administration, motivated by a psychological need for primary reinforcement from the repeated use of an opiate, occurs in the brain's ventral tegmental area (located below the pons), activating the release of dopamine and creating this reinforcement.2

In contrast, withdrawal symptoms originate in the periaqueductal gray matter, part of the midbrain's periaqueductal gray region that surrounds the third ventricle. As noted by Goldstein, this is an important point, because "this anatomic separation of opiate effects emphasizes an important point about all the addictive drugs: The primary cause of compulsive self-administration is the reinforcing property, manifested in specific brain pathways that are quite different from those mediating other pharmacologic effects of the development of physical dependence. Confusion over this distinction led to misunderstanding about whether of not certain drugs (e.g., nicotine, cannabis), which did not display a florid opiate-like withdrawal syndrome, were addictive. Indeed they are, with addiction being defined as compulsive self-administration, resulting from stimulation of a brain reward system."2

Opiates can also be categorized based on their type of action as they bind to a CNS receptor. Full agonists bind and activate certain receptors; partial agonists also bind, yet only cause partial receptor activation; antagonists bind to the receptor without any activation. Heroin, methadone and morphine are all agonists, with naloxone being the best-known narcotic antagonist, chasing agonist substances off of mu receptors and temporarily halting the opiate agonist effect. Naloxone is primarily used to reverse opiate overdoses, although it has been experimented with in maintenance trials. Because it lacks addictive properties, some patients may be more likely to discontinue self-administration, while other highly motivated patients may not need the dependence-production of agonists to ensure compliance.

Compliance has been shown to be much less of an issue with methadone, due in part to its ability to produce dependence. While euphoria and analgesia are the significant actions mediated through receptors, accompanying effects also include respiratory depression, constipation and miosis. The physical dependence and withdrawal syndrome associated with extended use of mu-binding opiates results from removal of the mu-binder (drug cessation), culminating in well-known withdrawal symptoms of heroin addiction.1

One of methadone's unique benefits is its long action (26 to 36 hours), unlike the shorter-acting heroin and morphine. Methadone also has a stronger affinity for the mu receptors than heroin does; if heroin is administered while methadone is present at an effective dose, methadone will prevail in competition with heroin for the same receptor sites, denying heroin an opportunity to bind with already occupied mu receptors. Not only can this discourage heroin users from use, but also it can reduce the likelihood of overdose should heroin be used in addition to methadone.3 Methadone's oral effectiveness also adds to its usefulness, eliminating the numerous dangers inherent in the intravenous administration of heroin. Another of methadone's proven qualities it the proven lack of long-term side effects, particularly when compared with other drugs also used over extended periods of time.4

–Jim Anderson, PA-C


1. Fiellin DA, Storti SA, Schottenfeld RS, Briscoe JD, Pantalon MV, O'Connor PG. Methadone Medical Maintenance: A Training and Resource Guide for Office-Based Physicians. Substance Abuse Center and the Department of Internal Medicine, Yale University School of Medicine and the Addiction Technology Transfer Center of New England, located at the Brown University Center for Alcohol and Addiction Studies; 2000. Available at: Accessed February 13, 2002.

2. Goldstein A. Heroin addiction: neurobiology, pharmacology, and policy. J Psychoactive Drugs. 1991;23:123-133.

3. Woods J. How Methadone Works. National Alliance of Methadone Advocates Web page. Available at: Accessed February 13, 2002.

4. Drugtext Libraries Full Text Books. Physiology and Pharmacology of Methadone. Available at: Accessed February 13, 2002.

DSM-IV Interview Questions for Establishment of Criteria for Opioid Dependence

1. Have you needed to markedly increase your (drug name) dose to achieve your desired high or have you found that the same dose has markedly diminished effect?

2. Did you experience any withdrawal symptoms after reducing or stopping (drug name) use or did you take additional (drug name) or a similar drug to reduce or avoid withdrawal symptoms?

3. Do you often take (drug name) in larger amounts or over a longer period of time than you intended?

4. Have you had a persistent desire or unsuccessful efforts to cut down or control your (drug name) use?

5. Have you found that you spend a great deal of time obtaining, using, or recovering from (drug name) effects?

6. Have you reduced or given up important social, occupational, or recreational activities because of your (drug name) use?

7. Have you had any persistent or recurrent physical or psychological problems that were probably caused or aggravated by (drug name), and have you continued to use despite these problems?

Opioid dependence = answering "yes" to three or more questions

Courtesy of Evergreen Treatment Services, Seattle


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