Current concepts - Methadone Dose Debate

Medical practitioners rarely deny patients adequate medication for their disorders. Yet, this has not always been the case with methadone maintenance treatment (MMT).

Some MMT patients have had their methadone doses taken away or reduced as punishment for disobeying instructions.. Perhaps worse, many patients have been undermedicated with methadone and then personally blamed for not avoiding illicit drugs and/or remaining in treatment.

Should such practices be allowed to continue?

Basic Observations
A common theme in Addiction Treatment Forum is the urgent need for science to outweigh stigma, prejudice, and misunderstanding. And, the scientific advantages of MMT, discovered more than 35 years ago, are straightforward.

A large number of research studies have demonstrated that adequate doses of oral methadone ward off withdrawal symptoms and relieve opioid cravings for 24 hours or more, without making the person feel "high" or drugged. Unfortunately, even after all this time, what constitutes an "adequate" dose of this medication is still being debated by practitioners, patients, researchers, and regulators.

During the past several years, this topic has been discussed by a series of articles in A.T. Forum [1-8] and other sources.[9] Research, spanning many years, has consistently and unquestionably demonstrated the following:

patients receiving inadequate methadone doses will continue to use heroin, alcohol, and other addictive substances;
these patients will not be responsive to behavioral therapies or remain in MMT for extended lengths of time;
conversely, when methadone doses are raised to individually-determined adequate levels, patients vastly improve on all measures of treatment success.

Given these basic observations, why would there be continuing debate about methadone dosing policies and practices?

Individual Differences
Methadone prescribing practices have followed philosophical, moral, or psychological rationales, rather than available scientific evidence.[9] The stigma, prejudices, and controversies surrounding MMT seem to have diverted attention from the fact that it is nothing more than a medicine, following well-established principles of pharmacology such as noted in Goodman & Gilman's; The Pharmacological Basis of Therapeutics, a classic text on the subject:

"Optimal treatment will result only when the physician is aware of the sources of variation in response to drugs and when the dosage regimen is designed on the basis of the best available data about the diagnosis, severity and stage of the disease, presence of concurrent disease or drug treatment, and predefined goals of acceptable efficacy and limits of acceptable toxicity. If objectively assessable expectations of drug therapy are not set before therapy is initiated, therapy is likely to be ineffective…."[10]

Individuals differ in how any drug affects them. Absorption, digestion, and excretion of a drug may account for half or more of the differences in how people eventually respond to the therapy. There are many factors that can influence the potency and effect of oral methadone, as with any drug, and some of these are listed in the table.[11,12]

Given the many factors potentially affecting individual response to methadone, research suggests that there can be a 17-fold difference between individual patients. That is, whereas 60 mg/d may be adequate for one patient, another individual might require more than 1000 mg/d for optimum effect. The notion of a particular dose range, or upward limit on dose, being suitable for all patients is scientifically implausible.

Arbitrary Limitations
The first patients treated during the early 1960s required 150 to 180 mg of daily oral methadone to avert abstinence syndrome and achieve normal functionality. By 1968, more than 1000 patients had been treated and daily methadone doses averaging between 80 mg and 120 mg appeared to be optimum for most patients, although some required more or less than that amount.[5] It should be noted, however, that heroin was less potent and more costly in those days than it is today; consequently, opioid dependence was likely less severe in those early patients.

During the 1970s, regulatory constraints and stigmatization of MMT led to dosing practices that had no basis in science.[5] A methadone dose ceiling of 100 mg/d was imposed, without any justification from research data, and exceptions to that required special permission from regulatory agencies. In an apparent overreaction to regulations, by the early 1980s, more than 40% of MMT patients were administered maintenance doses less than 40 mg/d. Even the most recent survey in year 2000 showed that 13% were still receiving less than 40 mg/d and more than a third of patients were receiving less than 60 mg/d. [13]

Although average methadone dose levels slowly moved upward during the 1990s, the latest data from 2000 indicate that only about a third of MMT patients receive doses at or above the 80 mg/d lower threshold established by Dole and his colleagues in the 1960s.[13] However, it is unknown how many receive greater than 100 mg/d and the upcoming A.T. Forum dosing survey results may shed light on this (see the feedback card in this issue or visit www.atforum.com to respond).

The Value of SMLs
Appropriate concentrations of medications in blood serum are critical for therapeutic success and patient safety. However, the limited research testing serum methadone levels (SMLs) demonstrates that there is no way of prescribing a single best dose to achieve an optimal SML as a "gold standard" for all patients.

Methadone serum level is usually described in nanograms per milliliter (ng/ml) and available evidence suggests that a trough SML (at the low point just prior to the next methadone dose) of about 400 ng/ml blocks effects of heroin and prevents opioid withdrawal or drug craving. However, some patients may require higher SMLs for stabilization.

Due to individual differences, the methadone dose to achieve an optimal serum level can vary quite widely across patients,[2] and recent data illustrate this (see figure).[14] In an examination of 69 MMT patients with methadone doses ranging from 10 to 270 mg/d (mean 134 mg/d), there was a positive relationship between dose and trough SML. However, at each methadone dose there were patients with widely differing serum concentrations, including one SML measurement greater than 1000 ng/ml So, it would be improper to conclude that a particular dose "causes" a specific methadone serum concentration; other factors might be more important in many patients.

Many patients may have inadequate SMLs despite what some might consider "high" daily methadone doses. For example, the figure shows that many patients even at doses well above 100 mg/d had relatively low (subtherapeutic) SMLs [14] and past research has found this can negatively affect performance in MMT programs.[9]

Measuring methadone serum levels may be most useful for analyzing cases of seemingly sufficient doses of methadone that are still not benefiting a patient. If, for example, a patient prescribed 150 mg/d is still complaining of the dose "not holding," a blood test might reveal a trough SML of only 100 ng/ml, which should indicate to both the practitioner and patient that a dose increase is appropriate and necessary.

New Research Directions
Clinical trials over the years have compared and contrasted differing methadone doses. Earlier trials had serious limitations in their methods and the range of doses examined.[4]

First and foremost, none of those trials examined methadone doses above 100 mg/d. Probably as a consequence of this, the studies reported disappointingly high rates of continued illicit-substance abuse and low rates of retention. None of the trials included measurements of SMLs as a verification of dose adequacy.

Some of the researchers conceded that the doses tested were likely inadequate for a great many patients, who no doubt suffered through part of each day in opioid withdrawal. Therefore, this body of evidence says more about the negative effects of methadone undermedication than helping to define the dimensions of truly adequate dosing practices. The one consistent observation coming from the trials is that those patients receiving relatively higher doses did better in terms of drug abstinence and retention in treatment.

Newer research has examined the potential benefits and dimensions of higher, adequate methadone doses. In the largest, long-term study,[6] researchers identified 164 patients with excessive rates of continued opioid dependence, despite methadone doses of up to 100 mg/d. Using clinically-guided criteria, methadone doses were increased to an average of 211 mg/d (range 120-780 mg/d).

Quite dramatically, illicit-opioid-positive urinalysis rates in this "high dose" group decreased by 84% (from 87% to 3%). Moreover, the one-year retention-in-treatment was 86%. This compared with only 35% retention and 19% reduction in illicit-opioid use in a control group of patients randomly drawn from the clinic population (mean dose in this group was 69 mg/d; range 10-100 mg/d).

A recently reported 152-week follow-up of the "high dose" patients found that average doses had been increased to 285 mg/d (ranging up to 1100 mg/d).[15] Retention in treatment was 61% and only 16% exhibited opioid-positive urinalyses, which are exceptionally favorable long-term outcomes.

To date, only a handful of limited-scope studies have examined higher dosing levels – all producing very positive results. Hopefully, this line of clinical research will continue, with sufficient funding and on a larger scale.

How Much Methadone is "Adequate"?
Since there are so many factors that can influence individual responses to methadone, the clinical presentation of the patient can be the best guide for dosing decisions.[7,9] For any drug, there is a zone of clinical efficacy, bordered by regions of either undermedication or overmedication.[10] A challenge with methadone is that this effective "comfort" zone can be rather narrow, and it differs across individual patients.

Looking for clinical signs, listening to patient-reported symptoms, considering the timing of these in relation to daily dose, and noting patient response to dose changes can help achieve more favorable outcomes. Indicative signs and symptoms are outlined in the chart.[9]

As the SML increases with more adequate dosing, signs and symptoms of opioid withdrawal (abstinence syndrome) vanish. If the methadone dose becomes too high, the patient will exhibit signs of opioid overmedication. At the optimally adequate methadone dose, peak and trough SMLs stay well within the therapeutic "comfort zone" throughout a 24-hour dosing period.

Special circumstances need to be taken into account. Research has found that patients with psychiatric diagnoses, in addition to substance dependence, may need more than a 50% increase in methadone dose. Similarly, for reasons still under investigation, patients with hepatitis C have been found to require up to 50% increases in methadone dose for stabilization.[9,15]

In sum, thinking of "high dose" as being above a certain threshold is misleading. Patients differ widely when considering "adequate" dose ranges, and enlightened outlooks avoid value judgments of what is too high.

Methadone dosing practices may be changing. The most recent survey data indicates that accredited MMT clinics are less likely to provide low doses to their patients.[13] Although accreditation agencies do not dictate dosing practices, this suggests that "best practices" are closely associated with outcomes achievable with more adequate methadone dosing. It is something to consider.

1. Optimal methadone dose? Research needs careful interpretation. Addiction Treatment Forum. 1997;6(1).*
2. Why measure methadone blood levels? Addiction Treatment Forum. 1999 (Summer);8(3).*
3. Reader survey – why measure methadone blood levels? Addiction Treatment Forum. 1999 (Fall);8(4).*
4. Shifting paradigms & slippery slopes. Addiction Treatment Forum. 2000(Summer);9(3).*
5. The 100 mg/d methadone glass ceiling. Addiction Treatment Forum. 2000(Fall);9(4).*
6. Redefining "adequate" methadone dose. Addiction Treatment Forum. 2001(Winter);10(1).*
7. Overcoming obstacles to optimum methadone dose. Addiction Treatment Forum. 2001 (Summer); 10(3).*
8. Reader survey - MMT attitudes. Addiction Treatment Forum. 2001(Fall);10(4).*
9. Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P. When "enough" is not enough: new perspectives on optimal methadone maintenance dose. MT Sinai J Med. 2000;67(5-6):404-411. Available online at: www.mssm.edu/msjournal.
10. Hardman JG, Limbird LE, eds. Goodman & Gilman's; The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill;1996:47-55.
11. Berkow R, Beers MH, eds. Merck Manual. 17th ed. Chapter 301: Factors affecting drug response. Whitehouse Station, NJ: Merck Research Laboratories; 1999.
12. Piscitelli SC, Rodvold kA, eds. Drug Interactions in Infectious Diseases. Totowa, NJ: Humana Press; 2001.
13. D'Aunno T, Pollack HA. Changes in methadone treatment practices: results from a national panel study, 1988-2000. JAMA. 2002;288(7):850-856.
14. Okruhlica L, Devinsk F, Valentova J, Klempova D. Does therapeutic threshold of methadone concentration in plasma exist? Heroin Add & Rel Clin Probl. 2002;4(1):29-36.
15. Maxwell S, Shinderman MS. Optimizing long-term response to methadone maintenance treatment: a 152-week follow-up using higher dose methadone. J Addict Dis. 2002:21(3):1-12.
*All articles from Addiction Treatment Forum are available online at http://www.atforum.com.

traduzione di R. Nardini

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