Series Number 5.1
2001 (Revised)
2 continued
Figure 3 The Methadone Molecule.
The two dimensional representation of the methadone
molecule is very different from that of morphine. However, molecules are three
dimensional and the methadone molecule bends into a structure that is very
similar to morphine and the
piperdine ring. The is probably how methadone is able to fit into the opiate
receptor. From Gilman, Rail, Niles, Taylor, Goodman and Gilmans The
Pharmacological Basis of Therapeutics (1990).
Methadone
looks strikingly different from other opioid agonists, however it has steric
forces which produce a configuration that closely resembles that of other
opiates (Figure 3). In other words, steric forces Bend the molecule of methadone
into the correct configuration to fit into the opiate receptor.
How
Methadone Works Its Miracle
Methadone
has a long half life in comparison to other opiates averaging about 28 hours and
is active without first passing through the liver. As the dose is increased over
time excess methadone is stored in body tissue and blood stream. This is how
methadone works its ‘time release trick’ and can last for 24 hours or more (Inturrisi
and Verebey, 1972). The higher the dose the more that is stored. As
stabilization is reached so the patient is in a steady state then narcotic
blockade is achieved. Basically narcotic blockade is tolerance but with special
properties. A patient at narcotic blockade will not experience drug craving and
they are also protected from overdose should they attempt to take an illicit
drug or opiate that was not prescribed.
Once
in the blood stream methadone is slowly passed to the brain when it is needed to
fill opiate receptors. Methadone has a higher affinity for the opiate receptor
than other opiates. Thus, the long half life along with storage and methadones
high affinity for the opiate receptor creates a steady state and the narcotic
blockade (see Figure 4). This is why some patients on blockade doses (70 mg/day
or more) are able to go for a day or two without their medication. Of course the
down side to this is that when a patient misses a dose they will begin to
destabilize” which places them at risk of overdose should they attempt
to administer other opiates. They are slowly loosing the narcotic blockade and
may begin to experience drug hunger and craving. No other medication has
received the scrutiny and evaluations that methadone has which continue to this
day (over thirty years) (Ball and Ross, 1991; Caplehorn, 1994; Cooper, 1992;
Dole, 1988; Dole and Joseph, 1978; Dole and Nyswander, 1965; GAO, 1990; Gearing
and Schweitzer, 1974; Joseph and Dole, 1970; Zweben and Payte, 1990).
Methadone
is perhaps one of the safest drugs known with only a few side effects which
usually subside after stabilization or adjustment of dose
during the first year of
treatment. There are no reports of anyone being
allergic to methadone.
The
current theory of why methadone delays the onset of opiate abstinence syndrome
for 24-48 hours, but is only effective for pain relief for 4-6 hours, appears to
be because these two phenomena involve two different part s of the brain each
with slightly different m receptors. Pleasure, and much of the pain relief
associated with opiates, occurs in the Nucleus Accumbens (NA) and the Ventral
Tegmental Area (VTA); however, withdrawal appears to be localized in the
Periaquaductal Gray (PAG). It appears that some of the products of methadone
biotransformation bind better to the PAG than in the VTA and NA. The phenomenon
is responsible for methadones ability to delay the onset of withdrawal for
extended periods of time.
When
a drug is in your bloodstream, it is not always just a free drug roaming around
waiting to interact with a receptor. Virtually
all drugs, depending on their lipophilicity (attraction to lipids or fat) and
hydrophilicity (attraction to water), bind to some extent with plasma (blood)
proteins. Recall that when a ligand
or drug binds to a receptor this kind of binding is called specific.
The binding to a receptor occurs because of specific chemical bonds and
the strength of the bonding depends of the affinity. Chemical bonds are common
to all substances whether your body produces the substance or it is a drug that
you take. In this way substances can attach to cell membranes or plasma
proteins but the binding is not very strong.
This kind of binding is called non specific.
And
in fact this was the fact that Candice Pert solved when she located the opiate
receptor (Pert and Snyder, 1973). Both Dole and Goldstein could not
differentiate between specific binding to a receptor and non specific binding to
membranes (Ingolia and Dole, 1970). In
simple terms Pert theorized that she should be able to wash away the non
specific binding because the bonds are not strong.
And that was what she did, after applying the radioactive opiate drug to
the tissue sample, she washed it. What was left was specific binding to the
opiate receptor.
When
methadone is bound to the plasma proteins it kind of works like a time release
capsule. The methadone is kept in
the blood stream until you need it. Typically methadone is almost 80% bound to
plasma proteins. However, since t his binding is non specific the bond can be
easily broken which releases the methadone.
The methadone is then free to interact with the receptor.
Bioavailability
Drugs
that are taken orally do not always get completely in to the blood stream like a
drug taken intravenously (see Part1, Administration). Many are poorly absorbed
when taken orally, like methadone. Heroin and morphine are about 85-90%
inactivated by the liver before getting into the blood stream. This is known as
the first-pass effect. Methadone has an average bioavailability of 0.5 or
50%, which means that half of the methadone gets into the blood stream and half
of it just passes through the GI tract, without being utilized. Many things can influence the bioavailability and of the
major influences it is the pH. Food
that you have eaten can change your
pH to acidic or basic (sugar). When methadone is in an acid environment, much
less of it gets absorbed. This
means that a glass of juice can
hinder absorption (acidic) and an anti-ulcer medication can increase absorption
(basic).
Bioavailability:
The
Mystery of the Diskette vs Liquid!
Many
patients will swear that the diskettes (biscuits) are stronger and last longer
that the liquid methadone. The
diskettes are designed to stay bound to an insoluble matrix until the acid in
your stomach hydrolyzes it (frees it). Thus,
the insoluble matrix helps to keep methadone around longer in your stomach, in
comparison to the liquid version which could pass right through without being
used depending upon your pH. Also,
eating before dosing can definitely decrease bioavailability, whereas eating
right after a dose appears to increase it.
Many
people in treatment think that the powder at the bottom is talc.
It is not; it is the actual methadone bound to the matrix.
- Methadone
Serum Levels (MSL):
- Helpful
Tool or Malevolence Science
In
the past ten years the ability to measure the level of methadone in the blood
has become available. MSLs have been more useful in helping clinicians
understand methadone metabolism rather than as a clinical tool. Methadone blood levels are measured in nanograms per
milliliter (ng/mL). After taking a
dose MSLs will peak at 3 to 4 hours followed by a slow decline over the
next 24 hours or trough. Researchers
have confirmed an MSL of 150-600 ng/mL in order to suppress drug craving and a
trough level above 400 ng/mL to achieve narcotic blockade
(Dole, 1988; Payte and Khuri,
1992).
Unfortunately
measuring MSLs only tells the clinician what is occurring at the time that the
blood sample was taken. Attempting to take peak and tough levels can be
intrusive to the patient, costly and unnecessarily time consuming. Recent
studies have found no correlation between a patients dose and MSL and that a
group of patients taking the same methadone dose can vary significantly
(Bradbury and Paris 1998). Thus
MSLs are more useful in helping the clinician to confirm inadequate
doses that for determining optimum dose (Leavitt, Shinderman, Maxwell,
Eap and Paris, 2000).
Unfortunately
many clinicians have begun to use MSL as an excuse to withhold an adequate dose
from patients. Some clinics now require that a patient have blood levels done
before they can get an increase instead of relying on patient reports, continued
opiate use, clinical observation and expertise. Thus often patients have to wait
for weeks for an increase because they must make an appointment to have blood
levels done and then wait for the laboratory results.
And since blood levels do not tell the full story of what may be occuring
some patients may have normal MSLs and yet still experience abstinence symptoms.
Typically these patients are denied their much needed increase.
Dole
(1988) has stressed that the use of MSLs are not necessary and that adequate
dosing can be achieved by listening and evaluating the patients report
along with other clinical
variables.
References
-
- Anon (1994). Conversation with
Vincent Dole. Addiction
89: 239
-
- Ball, J.C. and Ross, A. (1994). The
Effectiveness of Methadone Maintenance Treatment. New York: Springer-Verlag.
-
- Barchas, J.D., Berger, P.A.,
Ciaranello, R.D. and Elliot, G.R. (1977). Psychopharmacology.
From Theory to Practice. New York: Oxford University Press.
