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Reference: Table of Drug Interactions developed from the National Policy on Methadone Treatment – National Drug Strategy, Australian Government
Abstract: Defining the Nature of the Problem – Induction and Stabilization of Patients onto Methadone, Drummer and Zador (1999)
The article by Drummer and comments by Zador (1999) relate to the epidemiological findings of a series of national and international studies that examined death rates among opioid-dependent patients who were receiving treatment in methadone maintenance programs. Methadone is the most widely prescribed form of long-acting oral replacement therapy used by physicians to treat opioid addiction, particularly heroin abuse.
The epidemiological studies reviewed have shown that the risk of death from all causes is reduced significantly by three to four times for opioid addicted patients treated in methadone maintenance programs compared with those that are not. The studies reviewed were conducted in the 1990’s in Britain, Switzerland, Australia, Italy, Denmark and the United States. They allow the following conclusions:
The postmortem concentrations of methadone are not good predictors of opioid toxicity because a number of mitigating factors play a role in contributing to drug toxicity. For example:
The published studies reviewed by Drummer indicate that initial methadone dosage above 40mgs of methadone can be toxic (one study claimed a starting dose of 25mgs, and one of 30mgs, was associated with death). In her discussion of Drummer’s report, Zabor concludes that a safe and efficacious approach to prescribing methadone is to give "a starting dose of 20-30mg with dose increments of 5-10mg no more than every 4th day."
Most of the deaths of patients in methadone maintenance programs that occur during the induction phase of treatment are related to poly-drug use. Patients should be warned of the risk associated with drug abuse during their initiation into the treatment program. A thorough drug and alcohol pre-treatment clinical assessment screening should be done before methadone is prescribed.
The majority of methadone related fatalities are diversion-related and usually occur among patients who have access to a take away dose of the drug. Children of opioid addicted parents in treatment represent a vulnerable group of opioid naïve individuals who may be at risk of inadvertent unintentional consequences of a take away dose of methadone. There is a need for service providers to develop a better surveillance system to monitor methadone-related deaths in treatment programs and to design a standardized classification scheme with variables that will allow for the uniform collection of data on these type of fatalities.
Drummer, Olaf H ("Trigger Paper") and Zador, Deborah ("Discussion Paper") Proceedings of 1999 Expert Workshop on the Induction and Stabilization of Patients onto Methadone, National Drug Strategy Research Report Series, Monograph No 39. Commonwealth Department of Health and Aged Care, Australia, 2000.
The pharmacology of methadone is so straightforward, so unequivocal, so
simple, that its discussion in a website aimed at medical professionals inevitably
will appear patronizing. However, we know that most doctors and other healthcare
providers are unfamiliar with even the most basic aspects of what methadone
is and how it works. Indeed, even physicians who themselves prescribe methadone
to opioid addicts often provide patients with inadequate dosages, and pursue
goals that are simply not applicable to this treatment of the disease of
addiction. Accordingly, the following is presented with apologies to those
for whom it is patronizing, in the hope that it will give others reason to
reconsider their therapeutic principles and practices.
Methadone is a narcotic medication, which merely means that it has a series of actions similar to those of the prototypical narcotic, morphine. Table 1 provides a partial listing of these actions. There are obviously many drugs that produce one or more of the individual effects listed, but unless they elicit the entire spectrum, they are not classified as narcotics.
Although nausea and vomiting are among the pharmacological effects of narcotics, it is obvious that if addicts experienced these unpleasant consequences each time they inject heroin we would not be faced with a problem of narcotic addiction! But why does the addict not experience these effects, since they are listed - appropriately - among the pharmacological actions of narcotics? The answer is a simple one: repeated use produces a tolerance to the drug's effects. Clinically, this is known to physicians and patients alike who treat pain, and find that a tolerance to the analgesic properties of even the most potent narcotics develops quite quickly.
Several characteristics of tolerance must be stressed. First, tolerance does not develop to the same degree or with the same speed for each of the various actions of the drug. Thus, the addict soon develops tolerance to the adverse effects of nausea and vomiting, but is still able to achieve euphoria, and risks overdose due to the central nervous system depressant effect.
Secondly, although tolerance develops as a result of repeated exposure to a specific drug, it applies to all drugs in the same class. Thus, a patient whose pain has been treated exclusively with morphine, and who develops tolerance as a result, also is unable to get analgesic relief from codeine, demerol or any other narcotic. Similarly, although the street addict's exclusive drug may have been heroin, he or she develops a tolerance to morphine, methadone and all other narcotics as well.
And thirdly, although tolerance is defined as a level of drug concentration
in the body which must be exceeded before the pharmacological effect can
be experienced (as shown in Figure 1), that level may be unreachable regardless
of the amount of drug taken. A non-narcotic example of this phenomenon is
the common decongestant nose drop: Tolerance quickly develops, and to such
an extent that even an endless flow of the medicine will produce no effect
whatsoever. As mentioned previously, precisely the same phenomenon precludes
sustained analgesia through the administration of narcotics, even if they
are given in progressively higher and higher dosages.
Along with tolerance there is another consequence of repeated exposure to
narcotics, and that is dependence. Dependence also refers to a level of drug
concentration in the body, but it has nothing to do with the pharmacological
actions of the drug. Rather, it is the level which must be exceeded in order
to avoid the symptoms associated with the absence of the drug. As Figure
2 indicates, when the concentration of narcotics in the body falls below
the dependence level, withdrawal symptoms result, while when the concentration
is above this level there are no such symptoms.
As in the case of tolerance, dependence - even when a consequence of exposure
to only a single specific drug - is in fact a dependence on the entire class
of drugs. This means that withdrawal symptoms in an addict who has never
taken anything but heroin can be treated effectively by the administration
of any narcotic.
Critical to the understanding of the use of methadone in the treatment of
addiction is that a range exists between the dependence level and the tolerance
level. As indicated in Figure 3, as long as the concentration of narcotics
in the body falls below the tolerance level (thus precluding experiencing
narcotic effects), and yet is above the dependence level (thus precluding
withdrawal symptoms), the patient will look and feel completely normal. The
most astute clinical observer will be unable to distinguish the addict from
the non-addict under these circumstances. Of course, the heroin-dependent
individual, if unable to obtain another fix, will experience withdrawal symptoms
in a matter of hours as the drug from previous injections is metabolized
and the concentration falls below the dependence level.
Figure 4
In the chemotherapeutic treatment of addiction, whether the goal is short-term
detoxification or long-term maintenance, the objective is obvious: to maintain
the patient in a state of physiological normalcy by keeping the narcotic
concentration in the body in the range between the tolerance level and the
dependence level. Theoretically, one could try to "stabilize" a
patient with heroin or morphine, but this would require the administration
of the drug by injection, at least four or five times each day (Figure 4).
Obviously, such a treatment regimen would be exceedingly difficult. With methadone, on the other hand, this objective is relatively easy to achieve: Methadone has a very predictable effectiveness even when taken by mouth, and the duration of effectiveness is in the neighborhood of 24 to 36 hours, while that of virtually all other narcotics is no more than three to six hours (Figure 5).
In countries throughout the world it has been demonstrated that an initial
dose of methadone of 30 to 40 mgs. will prevent withdrawal symptoms without
producing any significant untoward effects. This is true regardless of the
amount of heroin being consumed by the individual addict, the purity of the
drug or the route of administration. Once treatment has begun, the body quickly
adjusts to the starting dosage such that the concentration of the narcotic
in the body is maintained at approximately the mid-level between the dependence
and the tolerance levels.
Since we are dealing with a range between the two levels, and a relatively broad range at that, it is possible to increase or decrease the dosage by five or ten milligrams of methadone without crossing either of the two levels. In detoxification treatment, a decrease of five milligrams will not be accompanied by withdrawal symptoms, and after several days at the new reduced level, the dosage can be lowered once more, and this process can be repeated until methadone administration has been discontinued altogether (Figure 6). In this way, generally in no more than 14 days, physical dependence on narcotics can be eliminated successfully without the patient experiencing withdrawal symptoms.
The benefits of such short-term addiction treatment with methadone are substantial.
It is a safe, effective, relatively inexpensive (particularly when provided
on an outpatient basis) medical intervention in the chronic problem of heroin
addiction. It lends itself to very rapid and large-scale implementation -
to the extent that virtually unlimited numbers of patients can be accommodated
promptly. In this way, it can ease significantly the unconscionable situation
in which addicts who desperately want treatment must remain on "waiting
lists" because long-term rehabilitation programs are filled to capacity.
In addition, we know from the experience in many parts of the world that
no other form of treatment generates as much demand among the addict population.
For example, in New York City, a network of only five ambulatory detoxification
clinics admitted over 22,000 individuals yearly in the early 1970s.
On the other hand, there is a major limitation of detoxification treatment: Once withdrawal from physical dependence has been accomplished, the former heroin user almost invariably reverts to illicit drug use. This might occur after a matter of days or, in some cases, many months, but sooner or later relapse is the rule rather than the exception. For this reason, there is another application of methadone in the treatment of heroin addiction: as a maintenance medication for patients who are motivated to give up heroin use and the life style associated with it.
"Maintenance" is really a relative term, and does not denote any specific duration of treatment. It should be clear from the pharmacological description above that any patient can be maintained - with any amount of methadone - indefinitely. Constant doses will maintain the concentration of methadone in the range between the dependence and the tolerance levels, and thus neither withdrawal symptoms nor narcotic effects will be experienced. It also should be obvious that any patient can be detoxified from methadone through a gradual reduction of dosage, in precisely the manner described previously, regardless of the dose and duration of methadone treatment.
A fundamental question is: Why maintain a patient on methadone? The answer is simple: empirically, it has been demonstrated that individuals are able to give up illicit heroin use and to resume (and in many instances assume for the first time) a normal, productive, healthy, socially acceptable and self-fulfilling life style while maintained on constant doses of methadone. Surely this is a compelling rationale for methadone maintenance!
Another question commonly raised is how long this treatment should continue? The response, again, is both simple and empirical: as long as it is effective! As in any other form of medical treatment, the success of the treatment regimen is determined by how the patient responds, and the favorable assessment of a therapeutic outcome is not diminished in the slightest by the fact that the patient continues to receive medication.
What underlies the response to both of the above questions is the reality that heroin addicts, following treatment, have a tendency to relapse to illicit drug use. This is true regardless of the form of care which has been provided, its duration or its apparent effectiveness. This being the case, the conservative approach - and the common sense approach - is to continue treatment which is effective.
Some have rejected as nihilistic the notion that a persistent risk of recidivism is inevitable. Such rejection ignores the experience of all addiction treatment specialists, regardless of their individual techniques, and regardless of their locale. It is worth considering the field of alcoholism, which in many respects is analogous. Alcoholics Anonymous, the most respected voice in the field of alcoholism treatment, has as the cornerstone of its philosophy the premise that no alcoholic is ever cured, and that the illness of alcoholism persists even after a decade or more of total abstinence. The universal experience with narcotic addiction suggests most strongly that precisely the same premise applies to that form of substance abuse as well.
Finally, a word about dosages. One of the greatest challenges in the field of addiction treatment is the perception that there is inherent goodness in prescribing the lowest possible dose of methadone. In fact, the only consideration that matters is the effectiveness of the medication; if the patient is comfortable at a particular dosage, reports no drug craving and clinically is doing well, it is inconsequential what dosage of medication contributes to this outcome. Thus, the answer to the question of "optimal" dosage is once again an empirical one: whatever dosage is effective! Here, too, the conservative approach is to give more rather than less, as long as no side effects occur, and indeed there are no significant side effects which have been associated with constant administration of methadone in either low or high dosages.
But there is a pharmacological rationale for relying, in general, on relatively higher amounts of medication. As demonstrated in Figure 7, the tolerance level does not rise in parallel with the methadone dosage which is administered. The individual who is maintained at 30 or 40 mgs. of methadone has little difficulty, through supplemental narcotics (methadone, heroin or any other drug in this class), in reaching and exceeding the tolerance level and thereby experiencing euphoria, and risking overdose. As the maintenance dose increases, however, the proportionate increase in the tolerance level is much greater, so that it takes steadily more and more supplemental narcotics to achieve any effect. Ultimately, at a maintenance dose of approximately 80 to 120 mgs, the tolerance level is so exceedingly high that for practical purposes it is impossible for the patient to achieve euphoria or other central nervous system effects of narcotics, regardless of the amount of additional narcotics which is taken. The sole exception is with respect to the analgesic effect; patients are tolerant to the analgesic action of the methadone dosage being taken, but this tolerance level can be exceeded by normal pain-killing doses of any narcotic medication. But again, with regard to euphoria, the patient is pharmacologically unable to achieve euphoria through misuse of narcotics, and ultimately will not be tempted to do so regardless of the circumstances or opportunities which might arise.
It must be stressed once more that none of the above pharmacological phenomena are speculative or theoretical or the focus of controversy among knowledgeable individuals. They will be familiar to every doctor, nurse and medical student who has prescribed narcotics for pain medication or for any other purpose. To summarize: methadone maintenance is associated with no euphoria, and at appropriate dosages renders the patient pharmacologically unable to achieve euphoria even with supplemental narcotics. It is safe, effective and in tremendous demand by addicts throughout the world who are motivated to give up illicit narcotic addiction and the associated life style, even though they will also give up the euphoria which they once enjoyed.