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When “Enough” Is Not Enough:New Perspectives on Optimal Methadone Maintenance Doses

STEWART B. LEAVITT, PH.D.1, MARC SHINDERMAN, M.D.2,SARZ MAXWELL, M.D.2, CHIN B. EAP, PH.D.3, AND PHILIP PARIS, M.D.4

.Abstract

Some methadone maintenance treatment (MMT) programs prescribe inadequate daily methadone doses. Patients complain of withdrawal symptoms and continue illicit opioid use, yet practitioners are reluctant to increase doses above certain arbitrary thresholds.

Serum methadone levels (SMLs) may guide practitioners’ dosing decisions, especially for those patients who have low SMLs despite higher methadone doses. Such variation is due in part to the complexities of methadone metabolism. The medication itself as a racemic (50:50) mixture of 2 enantiomers: an active “R” form and an essentially inactive “S” form. Methadone is metabolized primarily in the liver, by up to five cytochrome P450 isoforms, and individual differences in enzyme activity help explain wide ranges of active R-enantiomer concentrations in patients given identical doses of racemic methadone.

Most clinical research studies have used methadone doses of less than 100 mg/day [d] and have not reported corresponding SMLs. New research suggests that doses ranging from 120 mg/d to more than 700 mg/d, with correspondingly higher SMLs, may be op-timal for many patients.

Each patient presents a unique clinical challenge, and there is no way of prescribing a single best methadone dose to achieve a specific blood level as a “gold standard” for all patients. Clinical signs and patient-reported symptoms of abstinence syndrome,and continuing illicit opioid use, are effective indicators of dose inadequacy. There does not appear to be a maximum daily dose limit when determining what is adequately “enough” methadone in MMT.

Key Words: Methadone, therapeutic dose, serum methadone levels, pharmacokinetics, metabolism, clinical implications

INTRODUCTION — SHAPING CLINICAL INTUITION

Patients in Methadone Maintenance Treatment  programs frequently complain of withdrawal symptoms and continue their high-risk behaviors. They protest, “My dose isn’t holding me”; “I have drug cravings at night”; or “I wake up sick every morning” (1). Yet practitioners may be reluctant to increase methadone doses above certain thresholds, believing patients are already receiving “enough” of the medication (1).Payte and Khuri (2) have defined “enough”methadone as “the amount required to produce the desired response for the desired duration off time, with an allowance for a margin of effectiveness and safety.” However, the issue of optimal methadone dosing during maintenance therapy —what is “enough” under various circumstances —still seems unresolved.

Vincent Dole, a co-developer of MMT in the mid-1960s, advised that (3) “there is no compelling  reason for prescribing doses that are only marginally adequate. As with antibiotics, the prudent policy is [to] give enough medication to ensure success.” However, MMT programs may prescribe inadequate daily doses of methadone more for philosophical, moral, or psychological reasons than for sound pharmacological and clinical ones (4). Many clinicians also assume that lower doses automatically prevent toxicity and eventually engender opioid abstinence (5). Some researchers have recommended routine therapeutic drug monitoring using serum methadone levels (SMLs) as a diagnostic tool for guiding dosing decisions (4), and have noted a correlation between “poor performance” in MMTand lower methadone serum levels (6). Others haveconcluded that the determination of such serum levels is not likely to be of practical value in MMT programs (7),  and that many patients have  subtherapeutic  SMLs despite "high" methadone doses (7,8).

There are indications that SMLs can be useful when the clinical picture does not agree with the typical or expected response to a given dose of methadone (1), but they must be used and interpreted cautiously. Regardless of a particular serum level reading, the patient may not be getting enough daily methadone (9). Clinical signs and patient-reported symptoms of abstinence syndrome and illicit opioid use can often be the most effective indicators of dose inadequacy.

For several reasons discussed in this paper, higher methadone dosing and correspondingly higher SMLs than previously considered necessary or advantageous may be desirable. An understanding of methadone’s pharmacokinetics and pharmacodynamics can enhance clinical intuition and assist practitioners in prescribing reliablyeffective and safe doses that will result inbetter MMT outcomes.

         ---------------------------------------- Table 1------------------------------------------

            Signs/Symptoms of opioid Withdrawal (Abstinence Syndrone)                                   and Overmedication (2, 3, 9-12 ) 

Overmedication-Signs/Symptoms

     Somnolence (nodding off,*drowsy), miosis (pinpoint pupils),                                                                            

     itching/scratching, hypotension, respiratory depression (in severe

    overdose), depressed mental status, flushing and spasticity.

_________________________________________________________________________

                         No Illicit Opioid Use

               No Withdrawal or Overmedication Signs

                      ¦ Therapeutic Serum Methadone Level ¦

                                              ( ng/ml ) 

_________________________________________________________________________

Continued Withdrawal – Subjective Symptoms

     Drug craving, anxious feelings, depression, dysphoria, irritability,

     fatigue, insomnia, hot/cold flashes, nausea, myalgia/arthralgia

    (aching muscle/joints) anorexia, nausea, restlessness.

_________________________________________________________________________

Severe Withdrawal- Objective Signs

     Illicit opioid use, mydriasis (dilated pupils)), piloerection (‘goose

    flesh , diaphoresis (perspiring), muscle tremors/ twitching

    (shaking), diarrhea, vomiting, lacrimation, rhinorrhea, sneezing,

   yawning, anxiety (outward signs), fever, hypertension.

_________________________________________________________________________

0     2     4       6     8      10      12      14        16        18          20         22          24                                                           

  HOURS

________________________________________________________________________

SML + serum methadone level

As the serum methadone level rises, the objective signs of abstinence syndrome disappear and the clinician uses subjective symptoms as a guide for further dose increases.  At the optimal dose, the serum methadone level stays in the therapeutic range throughout the 24 hour period.  If the methadone dose is too high, signs/ symptoms of overmedication appear.    


Traversing Peaks and Troughs

Methadone, administered daily at a steady dose, should be present in the blood at levels sufficient to maintain an asymptomatic state over a 24-hour period, with no periods of opioid overmedication or withdrawal (1, 4). As with any opioid, methadone withdrawal (abstinence syndrome) involves a constellation of clinical signs and symptoms (2, 3, 9, 10 – 12) (see Table 1).  It is important to note that patients may experience subjective symptoms in the absence of observable signs (3), and the onset and severity of withdrawal in methadone-maintained patients are variable,depending on the patient’s metabolism of the medication, among other factors.

The elimination half-life of methadone averages 28 hours or less, but may range from as lowas 4 hours to a high of 91 hours. The clearance rate of methadone from the body can vary from individual to individual by a factor of almost 100 (5, 13). Measuring levels of methadone inthe blood via SMLs — in nanograms per milliliter(ng/mL) — is helpful in determining just how much of the medication is circulating in the patient’s system at the time of testing. Typically, the blood level reaches a high point, or “peak,”about 3 to 4 hours after taking the dose, and there is a gradual decline over the remainder ofthe 24-hour period to a low point or “trough” level before the next dose (1). Although a strong correlation between methadone dose and concentrations in plasma (r = 0.82, p < 0.001)
has been noted (14), the relationship may not be linear. Moreover, there is a need to account for the high degree of inter-individual variation (5, 15 – 17).

Payte and Zweben have suggested (1) that thepeak SML at 3 to 4 hours post-dosing should beno more than twice the trough level, giving anideal peak/trough ratio of 2 or less. A troughSML alone, although of some use, does not indicatethe rate at which the serum level changesover the time-course of a dose (1). However, in everyday clinical practice, measuring peak and trough levels can be time-consuming and invasive,due to necessary multiple phlebotomies (5).In lieu of this, physically evaluating patients for signs/symptoms of overmedication (Table 1) about 3 hours after a dose increase can help to assess whether the peak/trough ratio is appropriate 9).

Researchers have affirmed the need for a trough SML of 150 – 600 ng/mL to suppress drug craving (1, 3, 4), and a trough level at or above 400 ng/mL to provide adequate opioid cross-tolerance which makes ordinary doses of IV heroin ineffective (non-inforcing) during MMT (1, 2). Today, many practitioners consider an SML of 400 ng/mL (trough) as adequate therapy for stabilized methadone maintenance. However, Eap etal. (13) have observed that “no study so far has clearly demonstrated the existence of such a threshold [i.e., minimally adequate SML],” and Hiltunen and colleagues (10) noted that recommended SML ranges have not been validatedagainst self-reported clinical symptoms inpatients. An optimal trough SML may range from 400 mg/mL to values much higher, and efforts to set methadone ceiling doses and commensurate
SMLs by policy or regulation are not based oncientific, clinical, or laboratory evidence (1).
  

                                                                                                                        

BROAD SML RANGES                                       

Patients taking the same methadone doses have SMLs which vary significantly. Bradbury and Paris reported on 55 patients evaluated for ongoing problems with their methadone dose and opiate withdrawal signs/symptoms (15). Average
patient time in treatment was 46 months and mean methadone dose was 98 mg/d (range 30 – 160 mg; mode 100 mg). Trough methadone plasma levels were obtained for all patients upon entry into the study (Table 2).

SMLs ranged from 10 – 530 ng/mL, with some patients well below adequate trough levels at each methadone dose. Moreover, as Table 2 demonstrates, there was no apparent correlation between methadone dose and SML. More than a third ofthe patients also were being prescribed psychotropic medications — e.g., ntipsychotics, antidepressants,benzodiazepines, anticonvulsants — and this was positively correlated with continued opioid abuse. The authors speculated that there may be limitations in the psychosocial coping mechanisms in such patients influencing continuedopioid abuse (15). However, as others have found, there could also have been metabolic interactions of methadone with the prescribed psychotropic medications, and SMLs below therapeutic thresholds for those particular patients (1, 9, 13, 18).

SMLs are generally more appropriate for confirming inadequate dose than for determining the optimum dose, and they should be interpreted within the context of the patient’s overall clinical presentation. Bradbury and Paris provide some telling examples (15):A woman transferred from an MMT program where she was having difficulties but was told that her 100 mg/d dose was “enough.” At the

Table 2

             MMT Patients Evaluated for Dose/Withdrawal Problems (15)

n        Dose mg/d;                  SML — mean ± (SD)                  ML — range        
                                                  mg/ml                                       ng/mL
_________________________________________________________________________

2             30                               70 (42.4)                                    40 – 100

1             40                               20                                                   —

1            50                               320                                                   —

4            60                               95 (65.6)                                     10 – 170

4            70                              132.5 (58.5)                                 100 – 120

4            80                              332.5 (205.7)                               150 – 530

1           90                               350                                                    —

20        100                             236.4 (122.4)                                  90 – 520

2         110                             115 (134.4)                                     20 – 210

10       120                             212.4 (142.4)                                  10 – 440

3         140                             271.2 (123.6)                                 130 – 360

3         160                             243.3 (181.5)                                    50 – 510

_________________________________________________________________________


new clinic her dose was raised to 120 mg/d but the plasma level was still fairly low (130ng/mL). The dose was titrated upward to 180mg/d, relieving her withdrawal symptoms.

A patient taking several psychiatric medications and 80 mg/d of methadone was experiencing severe withdrawal symptoms. Her trough SML was non-detectable. However, at 140 mg/d she experienced sedation soon after taking her methadone, and opiate withdrawal at night (peak/trough ratio apparently high)splitting the dose — 70 mg in the morning  and 70 mg at night — eliminated both sedation and withdrawal symptoms.

A male patient was stable and free of illicit drugs at 100 mg/d, but insisted on a dose reduction. At a lower dose he soon developed withdrawal symptoms. His blood level tested at 100ng/mL, convincing him he needed to return to the original dose.

As in the last example, many patients have concerns about needing higher methadone doses and may minimize reported withdrawal symptoms or deny the extent of continued opioid abuse. SMLs can be used as a tool to address those fears, objectively demonstrating when the dose is too low to provide an adequate therapeutic blood level of the medication. And for patients taking co-medications or with organic dysfunctions such as liver or kidney disease, which might interact with methadone metabolism, SMLs can help confirm a need for higher dosing or split doses to achieve desired therapeutic levels (15).

Nuances of Methadone Metabolism

Methadone’s peak-trough-average SMLs and its rate of elimination (half-life) may be influenced by several factors, such as poor absorption, metabolism, changes in urinary pH, concomitant medications or drug abuse, diet, physical condition,pregnancy, and even vitamins (1, 15, 18).  Considerable flexibility in dosing is required to stabilize patients whose methadone pharmacokinetics may be affected by so many factors.

Methadone itself is a more complex substance than many appreciate. The formulation universally used in MMT is a 50:50 racemic mixture of two molecular forms, or enantiomers , specified as“R” (also called) have the same chemical composition but different spatial arrangements and kinetics: only Rmethadone has clinically significant mu-receptoragonist activity, while the S form is essentially inactive as an opioid agonist. R-methadone also has a higher clearance rate (13).

These differences in methadone structure and action have been known since the earliest days of MMT. In their original 6 patients, Dole (3) tried switching from the usual racemic R/S mixture to S-methadone and noted the gradual appearance of abstinence sybstinence symptoms. Unaware of the switch,patients reported that they “seemed to be gettingthe flu.” When returned to a mixture also containing the R-enantiomer, the patients again became functionally normal.

Methadone metabolism is largely a functionof liver enzyme activity involving cytochrome P450 isoforms (CYP450 enzymes). Drugs that induce these enzymes can accelerate methadone metabolism, abbreviate the duration of its effect,lower the SML, and precipitate abstinence syndrome..Other drugs can inhibit this enzymeactivity and slow the rate of methadone metabolism,thereby raising the SML, and extending th eduration of methadone’s effects (1, 13)..

Recent research has demonstrated that several CYP450 isoforms — CYP3A4, CYP2D6, and to a smaller extent CYP1A2, and also possiblyCYP2C9 and CYP2C19 — are involved inmethadone metabolism (13, 19). Eap and colleagues have reported on genetic and environmental factors acting on these enzymes, leadingto a high degree of inter-individual variation inmethadone pharmacokinetics (13).First, the CYP2D6 isoform selectively metabolizes the R-methadone enantiomer. A genetic polymorphism has been described for this enzyme, which is virtually absent in a small portion of the population, resulting in decreased metabolism of methadone. Another segment ofthe population has very high CYP2D6 activity due to duplication or multiplication of the CYP2D6 gene, and such persons might requirevery high SMLs of methadone for optimal effect,since there is an increased metabolism of theactive R-enantiomer (13).

Second, there is more than a 40-fold interindividualvariation in activity of the CYP1A2isoform, although it is not genetically polymorphicCYP1A2 appears to be involved in metabolizing both R- and S-methadone but, overall,plays a relatively minor role. Of interest, tobacco smoking enhances the enzyme’s activity, leading  to faster methadone metabolism (13, 17).

Third, CYP3A4, the most abundant CYP isoform in the liver, is also expressed in the gut. While there is no genetic polymorphism, there is up to a 30-fold inter-individual variability of its existence and activity in the liver, and up to an 11-fold variability in the gut. CYP34 is also ininvolved in the metabolism of many medications, such as selected benzodiazepines, antidepressants,anticonvulsants, antibiotics, and antivirals (including interferon and HIV protease inhibitors), that MMT patients may be taking. These and others can interact to raise or lower the methadone SML (see Table 3). In some cases,such as when MMT is initiated, methadone itself may induce increased CYP3A4 activity (13).

Finally, a very recent in vitro study suggests that two other CYP enzymes — CYP2C9 and CYP2C19 — may be involved in methadone metabolism (19).
However, their relative clinical importance still needs confirmation by in vivo investigations.

In sum, individual differences in the activity of CYP1A2 and CYP3A4, in addition to the genetic polymorphism of CYP2D6 and the possibleinvolvement of CYP2C9 and CYP2C19, help account for wide variances in methadone metabolism.
As a result, in patients given exactly the same dose of racemic methadone, corrected for body weight, concentrations of the active R-enantiomer can vary from 1- to 17-fold even in the absence of /potentially interacting co-medications (13). Such phenomena help explain clinical cases of so-called "fast metabo-lizers"  who repeatedly complain, “My methadone dose is not enough to hold me.”


Past research over the years raises the question:  How high is a “high” methadone dose? Dole observed long ago (3) that 100 mg/d may fail to hold methadone blood levels within a therapeutic range for many patients.   Despite this, a 100-mg dose has become accepted as a “glass ceiling” of sorts, rarely to be penetrated, and in
practice much lower thresholds are maintained.  

An extensive survey conducted in 1988 by the University of Michigan Institute for Social Research found that nearly 70% of U.S. clinics maintained patients at an average dose of 50 mg/d or less (20). This was well below an 80 – 120 mg/d
range recommended by Dole and others (1 – 3, 21), which would average about 100 mg/d, with significant numbers of patients above and below the range. This situation seems to have improved only slightly since 1990, as informal surveys found that the U.S. average methadone dose was 56.6 mg/d in 1993 and 69.4 mg/d in 1998 (22).

Clinical researchers continue to evaluate low methadone doses.  Although several often-quoted studies found that “higher” doses were more beneficial
in terms of less continued opioid abuse, the doses studied averaged only in the 40 – 50 mg/d range (23 – 25). One randomized trial explored the relative merits of 50, 20, and 0 mg/d, predictably finding that opiate-positive urines increased as
dose decreased (26). None of the studies explored doses exceeding the 100 mg/d barrier, even though opioid addicts who are not receiving adequate
doses of methadone might be expected to respond poorly to treatment, just as would any patients prescribed deficient pharmacotherapy for any other chronic medical condition (20).

Strain et al. (27) recently reported a trial enrolling 192 MMT patients randomized to receive daily methadone in a defined “moderate” dose range of 40 – 50 mg/d or a “high” dose of 80 – 100 mg/d. Over the course of 30 weeks, the “high-dose” group had statistically significant lower rates of opioid-positive urines than the
“moderate-dose” group (53% vs. 61.9% respectively, p = 0.047).  However, this difference in illicit opioid use outcomes between the two dosage levels, with an absolute risk reduction of only 8.9%, was remarkably modest.

In this study (27), both the “moderate” dose (mean 45.8 mg/d) and the “high” dose (mean 89.5mg/d) were clearly subtherapeutic for many patients. The authors conceded that “it is possible that dosages in excess of 100 mg/d may be
required for optimal benefit in some patients.”


           Some Drugs That Affect Methadone Metabolism* (1, 2, 18)¯
_________________________________________________________________________

Reduce SML **                                                                       Increase SML _________________________________________________________________________
Phenytoin                                                                               Cimetidine

Carbamazepine                                                                       Ketoconazole

Rifampin                                                                                 Fluconazole

Barbiturate sedatives/hypnotics                                              Amitriptyline

Certain antivirals                                                                     Diazepam

Urinary acidifiers, ascorbic acid                                          Fluvoxamine Maleate 

Ethanol (chronic use)
_________________________________________________________________________
Contraindicated Drugs — Precipitate Opioid Withdrawal

Opioid antagonists
(naloxone, nalmefene, naltrexone),

tramadol, buprenorphine, butorphanol, dezocine, nalbuphine,

pentazocine

*Note:  List is not inclusive of all drugs that may interact with methadone

SML = Serum Methadone Level

As a further example, Magura et al. prospectively followed for up to three years in treatment more than 1000 patients newly admitted to New York City MMT clinics (28). Three groups were identified in terms of dosing levels established
within the first 3 months: 42% were at “low dosage” (mean = 34 mg/d); 39.4% received“medium dose” (mean = 58 mg/d); 18.4% were considered “high dose” (mean = 84 mg/d). Nei
ther health status and concurrent use of prescribed
medications nor SMLs were assessed.

This investigation found no association between methadone dose level and continued heroin abuse. The authors noted that continued heroin use resulted in patients receiving increased methadone doses, although they acknowledged that “it may be that such upward dosage adjustments [were] simply not high enough to achieve their aim.” Indeed, the average methadone dose level for the entire sample population was 52mg/d (±20 SD) with only 3% of patients averaging 90 mg/d or higher.

To explore the question of just what might constitute more appropriately “high” methadone dosing, Maxwell and Shinderman (9) identified a group of 164 patients who, despite methadone doses of up to 100 mg/d, had high rates (87%) of continuing illicit opioid use. These patients, assigned to a “high dose” (HD) condition, received clinically guided dose increases, resulting in a mean dose of 211 mg/d (range 120 – 780mg). This cohort was compared to a randomly selected control group receiving an average dose of 69 mg/d (range 10 – 100 mg), drawn from a clinic population of 1100 patients.

Group characteristics differed in two significant ways. Prescription psychotropic medications were being taken by 63% of the HD group compared to only 28% of the control patients (p < 0.001). Also, the HD group reported taking larger amounts of daily heroin, spending more money on their addictions, than control subjects prior to entering treatment (mean $153/day vs. $87/day; p < 0.001).

The fraction of opioid-positive urine samples decreased from 87% to 3% in the HD group compared to a decrease from 55% to 36% in the control group. Further-more, the one year or more retention-in-treatment rate for the HD group was
86%, compared to 35% for the general clinic population, a 51% absolute risk difference in favor or higher doses.

SMLs were performed on most of the HD group patients; when the trough levels were less than 200 ng/mL, patients exhibited objective signs of abstinence syndrome. As methadone dose was increased and the SML rose, objective
signs disappeared, but some patients still reported subjective symptoms of withdrawal. This is consistent with a report by Loimer and Schmid (4)
which calculated that even patients with trough plasma levels exceeding 600 ng/mL may complainof withdrawal symptoms. Further increases in methadone dose, reaching a therapeutic SML range,alleviated all symptoms and continued
heroin abuse abated (see Table 1).

Maxwell and Shinderman noted (9) that SMLs were somewhat helpful in confirming inadequate methadone dose, but were not useful for determining optimal dose. “Although 400 ng/mL is the lowest SML that is usually considered effective in alleviating objective signs and subjective symptoms of [abstinence syndrome],” they wrote, “some HD group patients had SMLs of 800 – 1200 ng/mL when titrated to doses resulting in no signs of opioid [overmedication], no symptoms of withdrawal, and no illicit substance use.”

The higher-than-expected SMLs necessary for optimal dose in the HD group might have been predicted from their larger heroin habits prior to MMT and their greater intake of prescription psychotropic medicines, some of which might have
interacted to accelerate methadone metabolism overall or to selectively reduce levels of the active R-enantiomer. Testing for serum R/S-enantiomers would have been enlightening, but this test is not yet available in most laboratories. In lieu of this, Maxwell and Shinderman proposed that (9) “medical evaluation of  objec-tive signs and subjective symptoms is a sensitive, reliable, and cost-effective method of dose titration.” Furthermore, this study concludes that (provided the

clinical picture does not suggest opioid overmedication) there does not appear to be a maximum limit for optimal methadone dose.


There is no way of prescribing a single best methadone dose to achieve a specific blood level as a “gold standard” for all patients. In clinical practice, when faced with continued illicit drug use or patient-reported withdrawal or craving complaints, serum levels may confirm what is happening to methadone in the patient’s system.  SMLs can be an educational aid for encouraging a
fearful patient to accept a more adequate methadone dose or for assuring a less experienced colleague, a wary relative, a reluctant insurance company, or a circumspect regulatory agency, that a dose increase is justified.

Since SML results are not reliable for determining optimal dose, clinical symptoms and signs become particularly important as a dosing guide, as this final example illustrates: 

A 33-year-old woman was initially titrated to a methadone dose of 100 mg/d (trough SML 680 ng/mL), but she continued heroin use. After 6 weeks at that dose and ongoing psychotherapy in the MMT program, her heroin use continued and a repeat trough SML was performed.  At the time of phlebotomy, the patient was aphoretic, restless, yawning, pupils 7 mm, and complaining of severe drug cravings — the SML was 810 ng/mL. Her dose was titrated upward to 400 mg/d, at which time she reported abstinence from illicit opioids and relief from cravings, with no clinical signs of opioid overmedication. After 5 months of continued opioid abstinence and patient-reported feeling [of] “normal” at this dose, her trough SML measured 1800 ng/mL; peak SML was 3400 ng/mL. The patient has been successfully maintained on 400 mg/d of methadone with continued illicit drug abstinence for more than three years.

In this case, the final peak/trough ratio of 1.9 (3400/1800) was within a desirable range (1), although the SMLs might seem excessive. Given the inter-individual variances of methadone metabolism observed by Eap et al. ([13] described
above), only a fraction of this woman’s serum methadone might have been the active Rmethadone enantiomer; however, enantioselective testing was unavailable to establish this. 
Although this case may seem a rare example, it
strongly demonstrates the importance of being guided by clinical signs and symptoms in dosing decisions. The first SML reading of 680 ng/mLmistakenly suggested the patient was getting “enough” methadone, but a 400 mg/d methadone dose and very much higher SML proved necessary to achieve optimal therapy.

Dole has stressed (3), even when the means for repeated measurements of SMLs are available, that any rigid set of dosing guidelines would be misleading. “Fortunately, this laboratory support is not needed,” he wrote. “An experienced cliniciancan judge the adequacy of the dose from [the] effects.” He advised, as did Maxwell and Shinderman, that adequate methadone dosing can be readily identified by listening to patient reportedsymptoms, considering their timing in
relation to daily dose, noting the patient’s response to a change in dose, and evaluating his or her emotional stability.

Dole believed (3) that “the patient’s clinical state is correlated reliably with the blood level and the degree of tolerance.” Similarly, Hiltunen and colleagues found (10) thatpatient-reported subjective withdrawal symptoms correlated significantly with SMLs, and that patients may still experience and complain of such symptoms in theabsence of any objective signs.

Dole’s classic advice of “listen to the patient” seems all the more apropos in view of recent discoveries about the individual differences in methadone metabolism discussed above. However, pharmacokinetics do not explain everything, and there may be interacting pharmacodynamic host factors, such as the potential role of psychosocial influences (15). In addition, new research suggests genetic variations at the opioid or the dopamine receptors in the brain (29).

Finally, environmental factors also need consideration, as the drug scene has greatly changed.  Over the years, the street heroin has become purer in qual-       ity and lower in price making it more economically  accessible.  A report of the U.S. Drug Enforcement Agency noted that from 1980 to 1995, the price of a           
milligram of street heroin decreased from $3.90 to $1.04, while its purity  in-    creased from 3
.6% to 39.7% (30). Purity levels exceeded 60% in New York, Philadelphia, and Newark (31). 

Higher-purity street heroin has led to itsincreased use, since it can be smoked, snorted, or otherwise inhaled without the need for hypodermic injection.  This has attracted many new users among young, working, white, and middle-class
populations (31). Those who snort or smoke heroin increased from 55% of users in 1994 to 82% in 1996 (32). All of this suggests that today’s increasing numbers of opioid addicts often have more refractory drug dependencies, which will
require higher doses of methadone during MMT.

There have been cases of patients requiring in excess of 2000 mg of daily methadone, possibly due to the metabolic interactions with other medications
or organ dysfunction. However, in this era of HIV/AIDS, hepatitis C, tuberculosis, and other widespread infectious diseases among substance- abusing populations, the “exceptional” MMT patient requiring exceptionally high doses
may become more of a “rule” than presently imagined.


There is no scientific rationale for maintaining patients at lower than optimal methadone doses, yet some MMT practitioners and researchers seem philoso-phically committed to dosing regimens that expose countless patients to
unnecessary abstinence syndrome and illicit opioid use each day. Dole (3) has written “the results are generally poor, [since] limiting or withholding medication that reduces drug hunger increases the need for illicit narcotics.” Therapeutic drug monitoring tests can play auseful role in MMT programs. However, a basic
precept of sound medical practice is to trust clinical findings — withdrawal signs/symptoms, drug craving, and continuing opioid abuse----as indicators of inadequate versus adquate dose.  Each patient presents a unique clinical chal-lenge.  Practitioners are cautioned against making the mistake of " treating test results" or dogmatically adhering to biased preconception s of what is "enough" methadone, and thereby ignoring patients' needs for optimal methadone doses.


The authors thank J. Thomas Payte, M.D. San Antonio, TX; Andrew Byrne, M.D., Redfern NSW, Australia; and Herman Joseph Ph.D., New York, NY, for their reviews and comments during developement of this paper.

   


1.Payte JT, Zweben JE. Opioid maintenance therapies. In: Graham

AW, Schultz TK, editors. Principles of addiction medicine.

2nd ed. Chevy Chase (MD): American Society of Addiction

Medicine; 1998. pp. 557 – 570.

2. Payte JT, Khuri ET. Principles of methadone dose determination.

In: Parrino MW, editor. CSAT state methadone treatment

guidelines. Rockville (MD): Center for Substance

Abuse Treatment: Treatment Improvement Protocol (TIP)

Series 1, U.S. Department of Health and Human Services;

1993:47 – 58. USPHS Publication (SMA): 93-1991.

3. Dole VP. Implications of methadone maintenance for theories of

narcotic addiction. JAMA 1988; 260(20):3025 – 3029.

4. Loimer N, Schmid R. The use of plasma levels to optimize

methadone maintenance treatment. Drug Alcohol Depend

1992; 30(3):241 – 246.

5. Kell JM. Utilization of plasma and urine methadone concentrations

to optimize treatment in maintenance clinics: I. Measurement

techniques for a clinical setting. J Addict Dis 1994; 13(1):5 – 26.

6. Tennant FS, Jr, Rawson RA, Cohen A, et al. Methadone plasma

levels and persistent drug abuse in high dose methadone

patients. NIDA Res Monogr 1984; 49:262 – 268.

7. Horns WH, Rado M, Goldstein A. Plasma levels and symptom

complaints in patients maintained on daily dosage of methadone

hydrochloride. Clin Pharmacol Ther 1997; 17(6):636 – 649.

8. Tennant FS, Jr. Inadequate plasma concentrations in some highdose

methadone maintenance patients. Am J Psychiatry

1987; 144(10):1349 – 1350.

9. Maxwell S, Shinderman M. Optimizing response to methadone

maintenance treatment: Higher-dose methadone. J Psychoactive

Drugs 1999(Apr–Jun); 31(2):95-102.

10. Hiltunen AJ, Lafolie P, Martel J, et al. Subjective and objective

symptoms in relation to plasma methadone concentration in

methadone patients. Psychopharmacology 1995;

118:122 – 126.

11. O’Connor PG, Kosten TR. Management of opioid intoxication

and withdrawal. In: Graham AW, Schultz TK, editors. Principles

of addiction medicine. 2nd ed. Chevy Chase (MD):

American Society of Addiction Medicine; 1998: pp. 457 – 464.

12. Beers MH, Berkow R, editors. The Merck manual of diagnosis

and therapy. 17th ed. Whitehouse Station (NJ): Merck

Research Laboratories; 1999. pp. 1585, 2637.

13. Eap CB, Déglon J-J, Baumann P. Pharmacokinetics and pharmacogenetics

of methadone: Clinical relevance. Heroin Add Rel

Clin Probl 1999; 1(1):19 – 34.

14. Wolff K, Hay A. Methadone concentrations in plasma and their

relationship to drug dosage. Clin Chem 1992; 38:438 – 439.

15. Bradbury M, Paris P. Exploring serum methadone levels as a

tool to enhance methadone treatment efficacy. Presented at:

American Methadone Treatment Association Conference;

Sep 1998; New York.

16. Byrne A. Use of serum levels for optimising doses in methadone

maintenance treatment. J Maint Addict 1998; 1(3):13 – 14.

17. Eap CB, Finkbeiner T, Gastpar M, et al. High inter-individual

variability of methadone enantiomer blood levels to dose

ratios [letter]. Arch Gen Psychiatry 1988; 55:89 – 90.

18. Leavitt SB, editor. Methadone at work. Addiction Treatment

Forum. [serial online] Spring 1997; 4(2):1 – 6. Available

from: http://www.atforum.com/ Accessed: Jan 23, 2000.

19. Foster DJR, Somogyi AA, Bochner F. Methadone N-demethylation

in human liver microsomes: Lack of stereoselectivity

and involvement of CYP3A4. Br J Clin Pharmacol 1999;

47:403 – 412.

20. D’Aunno T, Vaughn TE. Variations in methadone treatment

practices. JAMA. 1992; 267(2):253 – 258.

21. Dole VP, Nyswander ME. Rehabilitation of heroin addicts after

blockade with methadone. N Y State J Med 1966;

66(15):2011 – 2017.

22. Leavitt SB, editor. Dosage survey ‘98: Changes for the better.

Addiction Treatment Forum. 1998; 7(3):1. Available from:

http://www.atforum.com/ Accessed: Jan 23, 2000.

23. Ball JC, Ross A. The effectiveness of methadone maintenance

treatment: Patients, programs, services, and outcomes. New

York: Springer-Verlag; 1991. p. 248.

24. Caplehorn JRM, Reilly DK, Wodak A. Detected heroin use in an

Australian methadone maintenance program. J Subst Abuse

Treat 1993; 10:553 – 559.

25. Hartel DM, Schoenbaum EE, Selwyn PA, et al. Maintenance

treatment: The importance of methadone dose and cocaine

use. Am J Public Health 1995; 85(1):83 – 88.

26. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Methadone

dose and treatment outcome. Drug Alcohol Depend 1993;

33:105 – 117.

27. Strain EC, Bigelow GE, Liebson IA, Stitzer ML. Moderate- vs

high-dose methadone in the treatment of opioid dependence:

A randomized trial. JAMA 1999; 281(11):1000 – 1005.

28. Magura S, Kang S, Nwakeze PC, Demsky S. Temporal patterns

of heroin and cocaine use among methadone patients. Subst

Use Misuse 1998; 33(12):2441 – 2467.

29. Noble EP, Lawford BR, Ritchie T, et al. The D2 dopamine

receptor (DRD2) gene and methadone treatment outcome of

opioid-dependent patients [abstract]. Presented at: 1998

Annual Meeting of the Society for Neuroscience; 1998 Nov

7 – 12; Los Angeles (CA).

30. O’Dea P. Domestic monitor program. Presented at: Heroin: It

never went away: The National Heroin Conference. Feb

1997. Washington (DC): U.S. Department of Justice, Drug

Enforcement Administration.

31. Nadelman E, McNeely J. Doing methadone right. Public Interest

1996; 123:83 – 93.

32. Office of National Drug Control Policy (ONDCP). Policy Paper:

Opioid agonist treatment. Washington, DC: Office of

National Drug Control Policy; March 1999.

Updated:  3 July 2005

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