Basic Pharmacology: How Methadone Works?

Methadone was once considered to be pretty much the same for every patient. Thus, it was
believed that narcotic blockade began at 60 mg/day for about 90% of the patients
an adequate dose occurred at 80 mg/day. The measuring of serum methadone levels
have shown that metabolism can vary significantly for many patients.
In addition to methadone metabolism
there are a variety of conditions and medications that can impact on the
effectiveness of methadone (Leavitt, Shinderman, Maxwell, Eap, and Paris, 2000).

An important property of all narcotic antagonists is that anyone dependent on any
opiate, including methadone patients will be extremely sensitive to
them (Cooper, Bloom and Roth, 1991; Gilman, Rail, Niles and Taylor, 1990). These
actions occur directly at the opiate receptor. Some of the new analgesics are
mixed agonist-antagonists drugs which have been developed to reduce their
addiction potential. For a non dependent person these medications are pain
killers, however for methadone patients, or anyone dependent on an opioid
such as pain patients the result can be uncomfortable at the least and could in rare instances
be life threatening.

It is estimated that about 5% of methadone patients are what is called aberrant
metabolizers (Payte and Khuri, 1992). Each time methadone passes through the
liver some is lost. For the average metabolizer the loss is minimal but for fast metabolizers
the loss can be immense. Liver disease and alcoholism can cause a reduction of
the liver’s ability to perform normal metabolic functions, resulting in aberrant
metabolism. This condition is very difficult to correct and the only way to help
the liver would be to eat a low fat diet to allow the liver to rest while
increasing the dosage of methadone. Split dosing can also help to correct
aberrant metabolism.

Various drugs can cause the liver to speed up metabolism. When this occurs most of the
methadone is excreted before it can be used. Drugs that cause an increase in
metabolism are rifampin for tuberculosis (Kreek, Gutjahr, Garfield, Bowen and
Field, 1976), dilantin for epilepsy (Payte and Khuri, 1992) , carbamazepine
(Payte and Khuri, 1992) and more recently St. Johns Wort (Shinderman, 2001).
Again the best way to correct the problem is to raise the
dose and/or break the dose down into several doses throughout a 24 hour period
(Payte and Khuri, 1992). For example, a patient on 120 mgs/day might break their
dose into thirds taking one third in the morning, one third at dinner time and
one third before going to bed. In a sense this helps to maintain the long half
life of methadone. Unfortunately, most programs do not utilize this later
procedure because of over concern about diversion.

CYP-450 is a liver enzyme and drugs that speed up metabolic rate do so through this
enzyme. This is how Tegretol (carbamazepine)
and other siezure disorder medications effect methadone, by inducing CYP-450
which them speed up liver metabolism. Tegretol
is a strong inducer of hepatic CYP-450 enzyme activity in the liver. The
accelerated metabolism may eliminate methadone entirely within 24 hours causing
the abstinence syndrome. For most patients raising the dose will work, however in a few cases patients will
continue to experience the abstinence syndrome. One procedure to handle this is to rise the dose and split it and finally
adding cimetidine (Tagamet) to inhibit liver enzyme activity.

The antibiotic, Nafcillin has the same effect as rifampin (a known methadone
villain) and carbamazepine (Taylor, Pritchard, Goldstein and Fletcher, 1994;
Wells, Holbrook, Crowther and Hirsh, 1994). So it seems Nafcillin is an inducer of the same CYP-450 enzymes that
accelerate metabolism of methadone.

A recent discovery is that cocaine use can cause an increase in the number of brain opiate
receptors (Unterwald, Horne-King and Kreek, 1992). Brain receptors are not
static, rather they are chemical bonds floating along the surface of the
membrane. The number of receptors for any natural ligand can change dependent of
various conditions. As expected an increase in the number of opiate receptors
would reduce the action of methadone.

For example, lets say a patient is on 100 mgs/day. Lets use small round numbers to demonstrate
this, normally there are hundreds of thousands of opiate receptors in the human
brain. For this example when the patient is on a stable dose the number of
opiate receptors in the brain averages around 100. And 75 percent of the 100
opiate receptors, or 75 receptors remained filled throughout a 24 hour period.
Now this patient begins to use cocaine which causes an increase in the number of
opiate receptors to 150. However, only 75 receptors remain filled and active.
Now instead of 75 percent of the receptors being filled now only 50 percent are
filled. The patient complains that the cocaine is eating up their methadone and
asks for a raise. And probably the patient will need their dose to be increased
at least 20-30 mgs/day to feel the same.

There has been one
or two reports of a barbiturate causing abstinence in a methadone patient. While
this is a rare occurrence and the causes have not been determined all methadone
patients should be aware of it (Tong et al, 1981).

Some drugs can interact with methadone when it is bound to plasma proteins.
As was mentioned above most binding of methadone to plasma proteins is
non specific, and this means that many drugs with similar shapes can bind to the
same area of the blood protein and knock the methadone molecule out.

This can cause a much higher effective blood methadone level, which can
be a problem for someone who does not have tolerance or even someone on a low
dose of methadone without much of an initial tolerance.
Some drugs can knock methadone away from the blood proteins that they are
bound to causing a sudden release of methadone to them interact with the opiate
receptor. Drugs that can do this
are erythromycin, clarithromycin, Vitamin E and many of the NSAIDS (Ibuprofen
and Ketoprofen). While the danger is obvious for the individual with a low
tolerance these drugs can also have an effect on patients taking a blockade dose
with a high tolerance by causing the release of their stored methadone (or
buffer) ;and thus destabilizing them. It
would probably take a few days to build up the methadone plasma to its initial
level.

The antidepressant fluvoxamine (Luvox), used for depression and obsessive compulsive disorder, can
reduce the metabolism of methadone significantly, raising blood levels (Bertschy,
Baumann, Eap and Buettig, 1994). One
asthmatic patient almost died after a doctor prescribed the drug without knowing
that the patient was on methadone from elsewhere (Alderman and Frith, 1999).
It has also been found that fluoxetine (Prozac) also raises methadone
levels, but only of a slight order, perhaps 10% whereas fluvoxamine may do so by
50% or more. It is possible that
this effect could be used ‘therapeutically’ when higher methadone levels are
desired, but it could also be very dangerous.

Reports have surfaced about patients afraid to take Vitamin C because it would block
methadone. Vitamin C does not block methadone but it can change the pH and thus influence the bioavailability.
In an acidic environment methadone is not absorbed well and the methadone
will be excreted unused. This only occurs at extremely high doses of Vitamin C,
like 4 grams a day.

All the vitamin C myth does is to cause fear, apprehension and raise suspicions about methadone.
Whoever has promoted this myth is anti-methadone and therefore anti-methadone
patient. Why? Because when methadone patients are frightened and suspicious of
the very medication that has saved their lives they can not concentrate on the
important tasks at hand — that of changing their lives!

As more is learned about methadone metabolism the greater clinical knowledge
about the many factors can impact on its effectiveness. Unfortunately since many
medical professionals are not aware of these recent findings it will be up to
patients to insure that they are being prescribed an adequate dose. NAMA will
continue to report on new findings and the factors that can interfere with
adequate methadone dose.

Alderman, C.P. and Frith, P.A. (1999). Fluvoxamine – methadone interaction. Australia New Zealand Journal of Psychiatry 33:99-101.

Bertschy, G., Baumann, P., Eap, C.B. and Buettig, D. (1994) Probable metabolic interaction between methadone and fluvoxamine in addict patients. Therapeutic Drug Monitoring 16: 42-45.

Cooper, J.R., Bloom, F.E. and Roth, R.H. (1991). The Biochemical Basis of Neuropharmacology (6th Edition). New York: Oxford University Press.

Gilman, A.G., Rail, T.W., Niles, A.S. and Taylor, P. (eds) (1990). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (8th Edition). New York: Pergamon Press.

Kreek, M.J., Garfield, J.W., Gutjahr, C.L. et al (1976). Rifampin-induced Methadone Withdrawal. New England Journal of Medicine 294: 1104-1106.

Leavitt, S.B., Shinderman, M., Maxwell, S., Eap, C.B. and Paris, P. (2000). When enough is not enough: New Perspectives on optimum methadone maintenance dose. Mt. Sinai Journal of Medicine 67(5&6): 404-411.

Payte, J.T. and Khuri, E. (1992). Principles of methadone dose determination. In: Parrino, M.W. (Chair & Editor). State Methadone Treatment Guidelines. Rockville, MD: U.S. Department of Health and Human Services, Center for Substance Abuse Treatment.

Shinderman, M. (2001). Warning: St. Johns Wort Reduces Methadone. NAMA Talk (February).

Taylor, A.T., Pritchard, D.C., Goldstein, A. O. and Fletcher, J.L. Jr. (1994). Continuation of warfarin-nafcillin interaction during dicolxacillin therapy. Journal of Family Practice August 39(2): 182-185.

Tong, T.G., Pond, D.M., Kreek, M.J. et al. (1981). Phenytoin-induced Methadone Withdrawal. Annals of Internal Medicine 94: 349-351.

Unterwald, E.M.; Horne-King, J. and Kreek, M.J. Chronic cocaine alters brain mu opioid receptors. Brain Research 1992 584: 314-318.

Wells, P.S., Holbrook, A.M., Crother, N.R. and Hirsh, J. (1994). Interactions of warfarin with drugs and food. Annalsof Internal Medicine (November 1) 121(9): 676-83.

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