National Alliance of Methadone Advocates
The Pharmacology of Methadone
Ignorance about methadone abounds. Professionals working in the
field receive very little or no training at all about the very
medication that they will be administering. Rarely is addiction
viewed as a disease and under the domain of the medical
profession. Even the medical profession does not understand
addiction, and most physicians, nurses or other medical
professionals receive very little training about addiction.
Their education regarding methadone is usually on its use in
withdrawing an individual from opiates while its best property-
that of maintenance, is neglected. Counselors, social workers
and psychologists know even less than the medical professions.
They usually receive very little education in basic science and
even less about the biology of behavior, or the functioning of
the brain. Thus, both medical and counseling professionals have
been taught to approach addiction as a character disorder and
administer methadone as a substitute.
With such a deficiency within higher education added to the
public’s misunderstanding about addiction it is not surprising
that myths about methadone thrive. Of course, there is an
additional reason why there is so much misinformation about
methadone, and that is because methadone is the only effective
treatment for heroin addiction. Since the introduction of
methadone maintenance treatment it has been attacked by
abstinence oriented modalities attempting to denigrate methadone
and therefore improve their chances for funding. Prior to
methadone treatment the only form of treatment for heroin
addiction was the abstinence oriented modalities i.e., Project
Return, Phoenix House. Abstinence oriented modalities
controlled most state regulating agencies and many still do.
Only New York State, which has a large methadone system that
treats about one-fifth of all methadone patients in the United
States has a state agency that is supportive of methadone.
With such misunderstanding about methadone the only way for
methadone patients to deal with it and to insure adequate health
care and supportive services is to educate themselves. In this
way methadone patients can educate others about heroin addiction
and methadone treatment. That is the purpose of this paper and
although some of the topics are very technical it is not
important that you understand every word. Instead try to get
just a basic understanding of everything.
The next time you hear something “crazy” about methadone ask
that person for the scientific proof. Ask for references and
publications. You will discover that usually they have none,
instead relying on the “everybody knows” method of science!
Basics of Pharmacology
Pharmacology is the study (ology) of drugs (pharmac/y) and
psychopharmacology is the study of (ology) drugs (pharmacolog/y)
that produce their effects on the mind or brain (psycho or
psyche). There are five basic classes of psycho-active drugs:
1) the opioids (heroin and methadone), 2) the stimulants
(cocaine, nicotine), 3) the depressants (tranquilizers,
antipsychotics, alcohol), 4) hallucinogens (LSD), and 5)
marijuana and hashish.
Most compounds, including opioids exist in two forms
distinguished by levo or dextro preceding the compound (i.e.,
levo-methadone, dextro-methadone). One form is active and one
inactive. Generally speaking the active form is usually the levo
form and very often levo is dropped from the compounds name.
The best way to think of these two forms is your two hands.
Both the right and left hand have the same structures (i.e., one
thumb and four fingers) but they are mirror images of one
another. And like hands, the levo and dextro form are very
different from one another, yet similar.
Administration
An important factor in how a psychoactive drug exerts it effects
is how it is administered. Administration refers to the
mechanisms by which drugs are transmported from the point of
entry into the bloodstream. Drugs are commonly administered in
five ways: 1) orally, 2) rectally, 3) parenterally (injection),
4) the membranes of the mouth or nose, and 5) by inhalation.
Each method of administration has its advantages and
disadvantages.
- Oral
Easiest method of administration. Disadvantages include the possibility of vomiting,the differing rates of absorbtion from person to person, and the fact that some drugs are not absorbed well.
- Rectal
Easy administration, especially for children. Disadvantage is that rectal absorbtionis often irregular.
- Pulmonary (through the lungs)
Very little is known about the pulmonary absorbtion ofdrugs other than those administered as gases.
- Intravenous injection
Avoids all the disadvantages of oral administration. More control ofdosage is possible and the drug is placed in circulation with minimal delay. Also most dangerous
means because of rapidity of onset. Allergic reactions that are mild when drugs are administered
orally may be severe when administration is intravenous.
- Intramuscular injection
Same as intravenous. - Subcutaneous injection
Same as intravenous. Irritating drugs should be avoided.
After a drug is administered the next important determinant in
the drugs ability to exert its effect is how the drug is
distributed throughout the body. Once the drug reaches the
bloodstream it is distributed throughout the body. However, it
must be able to pass across various barriers in order to reach
the site of action. Only a very small portion of the total
amount of a drug in the body at any one time is in direct
contact with the specific cells that produce the pharmacological
effect of the drug. Most of the drug is found in areas of body
that are remote from the drug’s site of action. In the case of
psychoactive drugs, most of the drug is to be found outside of
the brain and is therfore not directly contributing to the
psychopharmacological effect.
Four types of membranes are most important in drug distribution:
- Cell walls
- Walls of capillary vessels of the circulatory system
- The blood-brain barrier
- The placental barrier
Cell Membranes: In order to be absorbed from the intestine or
gain access to the interior of a cell, a drug must be able to
penetrate the cell membranes. The characteristic feature of
cell membranes are fat molecules coated by a protein layer on
each surface. Like a bimolecular sandwich the fat molecules
(cheese) are sandwiched between two layers of protein (the
bread). Only drugs that are soluble in fat are permeable and
can pass through the cell membrane. The cell membrane also
contains small pores that allow water-soluble molecules to pass
through. Most drugs are too large to pass through the pores
and, thus, most water-soluble, fat-insoluble drugs cannot pass
through the cellular barrier.
Blood Capillaries: Within a minute or so of a drug entering the
bloodstream, it is distributed farily evenly through the
bloodstream. However, most drugs are not confined to the
bloodstream and are readily exchanged back and forth across the
blood capillaries. The capillary walls contain pores that are
large enough for most drugs to pass through, therefore it does
not matter whether a drug is fat-soluble or insoluble for it to
pass through capillary walls.
Blood-Brain Barrier: For drugs to enter the central nervous
system they must be able to penetrate the Blood-Brain Barrier
(BBB). The BBB decreases the permeability of the capillary
membranes thus protecting the brain from various substances that
would otherwise be harmful. Capillaries of the brain are
tightly joined and covered by a footlike sheaf structure that
arises from a nearby cell called an astrocyte. To enter the
brain, drugs must traverse not only the capillary wall but also
the membranes of the astrocytes in order to reach their target
cells.
Placential Barrier: Among all the membrane systems of the body,
the placenta is unique: it separates two distinct human beings
with differing genetic compositions, physiological resonses, and
sensitivities to drugs. The fetus obtains essential nutrients
and eliminates metabolic waste products through the placenta
without depending on its own organs, many of which are not yet
functioning. This dependnece of the fetus on the mother places
it at the mercy of the placenta when foreign substances appear
in the mother’s blood.
The Opioids
All natural and synthetic opioids exhibit a three dimensional
T-shaped configuration (Barchas, Berger, Ciaranello and Elliott,
1977). This T-shaped molecule has two broad hydrophobic
surfaces which are at right angles and a methylated nitrogen
which is usually charged at physiological pH. The charged
nitrogen is essential for activity and lies in one of the
hydrophobic planes. A hydroxyl group at carbon 3 on the other
plane is also essential. This configuration which all opioids
have is called the piperidine ring. Figure 1 is the structure
of morphine with the piperidine ring indicated by bold lines.
Endogenous Opioids
The term endorphin is used to characterize a group of endogenous
peptides whose pharmacological action mimics that of opium and
its analogs. The endogenous opioid system is complex with a
multiplicity of functions within any given organism. There
exists about two dozen known endogenous opioids which belong to
one of three endogenous opioid systems: 1) the endorphin
system, 2) the enkephalin interneuron system, and 3) the
dynorphin system.
The endogenous opioid system may play a role in a wide variety
functions such as, the production of analgesia, attention,
memory, catatonia, schizophrenia, manic depression, immune
function, endocrine function, appetite regulation, sexual
behavior, postpartum depression, release of several hormones,
locomotor activity, anticonvulsant activity, body temperature
regulation, meiosis (pin point pupils), shock, respiration,
sleep and drug dependence.
Endorphins are peptides which are biologically active substances
in the brain composed of amino acids that are produced in
neurons. Today peptides are considered to be a distinct and
separate group of psychoactive substances in the brain.
The Target of Action: The Receptor
Most psychoactive drugs exert their action at a receptor. This
can be through of as a “lock and key” with the key as the drug
opening the lock, or receptor. Opiate receptors can be broken
down further into types: the m receptor prefers morphine, heroin
and methadone, the e receptor prefers b-endorphin, the d
receptor prefers enkephalins, and the k receptor that prefers
dynorphins. Some receptors are broken down further into
subtypes as in the k1 and k2 receptors. A substance that binds
to a receptor is called a ligand, thus endorphins are the
natural ligand for the opiate receptor. The entire endogenous
opioid system is referred to as the “Endogenous Opiate Receptor
Ligand System.”
Receptors have several properties. Any substance, including the
endogenous ligand or any exogenous compound that attaches to a
receptor occurs through a process of chemical bonding. This is
referred to as binding to a receptor. Affinity refers to the
strength that a substance binds to a receptor. Some chemical
bonds are stronger than others resulting in some substances
having a greater affinity than others for a receptor. In
respect to opiate receptors and opioid analgesics the stronger
the affinity, the stronger the analgesic properties of the
substance. Therefore, morphine which is a strong analgesic has
a stronger affinity for the opiate receptor than codeine which
is a weaker analgesic.
Opiate receptors have been found in every vertebrate and even in
some invertebrate species. Therefore, opiate receptors and the
endogenous opioids are basic within the scheme of evolution.
Their vast distribution in species implies that endorphins were
important in mammalian evolution.
Methadone and Congeners
Methadone was synthesized by German chemists during Wold War II
when the United States and our allies cut off their opium
supply. And it is difficult to fight a war without analgesics
so the Germans went to work and synthesized a number of
medications in use today, including demerol and darvon which is
structurally simular to methadone. And before we go further
lets clear up another myth. Methadone, or dolophine was not
named after Adolf Hitler. The “dol” in dolophine comes from the
latin root “dolor.” The female name Dolores is derived from it
and the term dol is used in pain research to measure pain e.g.,
one dol is 1 unit of pain.
Even methadone, which looks strikingly different from other
opioid agonists, has steric forces which produce a configuration
that closely resembles that of other opiates (Figure 2).
Anotherwords, steric forces bend the molecule of methadone into
the correct configuration to fit into the opiate receptor.
An agonist is a substance that binds to the receptor and
produces a response that is similar in effect to the natural
ligand. In contrast, antagonists bind to the receptor but block
it by not allowing the natural ligand or any other compound to
bind to the receptor. Antagonists do not cause the opposite
effect. They merely fit into the receptor and block any other
substance from binding to it. For example, narcotic antagonists
such as naloxone or its’ predecessor naline are administered to
reverse a heroin or opioid overdose. This is achieved because
opioid antagonists have a greater affinity for the opiate
receptor than agonists and in fact the affinity is so strong
that narcotic antagonists can literally knock an agonist right
out of the receptor. The effect is very fast and the overdose
victim will wake up within minutes, or seconds even.
Individuals dependent on heroin, or other opioids such as
methadone can wake up in withdrawal.
Heroin, methadone and morphine are opioid agonists. Narcotic
antagonists are produced by a change on the nitrogen atom of an
opioid agonist. Thus nalorphine is produced from a change in
the nitrogen atom of the morphine molecule and naloxone is
produced from oxymorphone. Naltrexone is a long acting narcotic
antagonist which is used for maintenance treatment. It works
by binding to the receptor over a 24 hour period thus making any
injection or administration of an opioid agonist ineffective.
It must be emphasized that naltrexone does not have agonist
properties it merely blocks every opiate receptor irrespective
of that receptors function. Thus, long term treatment with
narcotic antagonists can also block important biological
functions and various side effects have been reported, including
hypersexuality.
How Methadone Works Its Miracle
When you take methadone it first must be metabolized in the
liver to a product that your body can use. Excess methadone is
also stored in the liver and blood stream and this is how
methadone works its ‘time release trick’ and last for 24 hours
or more (Inturrisi and Verebey, 1972). The higher the dose the
more that is stored. This is why 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 heroin. They are slowly loosing the blockade effect
of methadone and may begin to experience drug hunger and
craving.
Once in the blood stream metabolized methadone is slowly passed
to the brain when it is needed to fill opiate receptors. In no
way do vitamins interfere with the binding of methadone to the
opiate receptor where methadone mimics the endorphins. No other
medication has received the scrutiny and evaluations that
methadone has which continue to this day (over thirty years)
(Ball and Ross, 1991; Brecher, 1972; Caplehorn, 1994; Cooper,
1992; Dole, 1988; Dole and Joseph, 1978; Dole and Nyswander,
1965; GAO, 1990; Gearing and Schweitzer, 1974; Joseph and Dole,
1970; Kreek, 1978 and 1973; Zweben and Payte, 1990). Methadone
is perhaps one of the safest drugs known and only a few side
effects which usually subside after stabilization and the first
year of treatment. I know of no one who is allergic to
methadone.
Drugs and Conditions that Reduce the Action of Methadone
Narcotic Antagonists and Agonist-Antagonists Drugs
An important property of all narcotic antagonists is that anyone
dependent on any opiate, including methadone patients will be
extremely sensitive to them. These actions occur directly at
the opiate receptor in the brain. 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 opioids their use is contra
indicated because the individual will be thrown into withdrawal.
Talwin which is noted on the identification cards for methadone
patients is the most commonly used mixed agonist-antagonist
analgesic. Other common mixed agonist-antagonist opioids used
in obstetrics are Nubain and Stadol.
Drugs and Conditions That Impact on Metabolism
It is estimated that about 5% of methadone patients are what is
called aberrant metabolizers (Payte and Khuri, 1992).
Metabolism is necessary for methadone to be converted into a
metabolite that the body can use. A damaged liver can fail to
metabolize enough methadone for storage and the result is that
unmetabolized methadone is excreted. The result is that the
body is unable to use the methadone and the patient will begin
to experience abstinence symptoms (withdrawal). Liver disease
and alcoholism can cause a reduction of the liver’s ability to
perform normal metabolic functions, including the metabolism of
methadone to a produce that your body can use. 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. However, it is almost
impossible to keep an alcoholic methadone patient approaching
liver failure and eventual death comfortable and free of
abstinence symptoms.
Various drugs can cause the liver to speed up metabolism. When
this occurs most of the methadone is excreted before it can be
converted to a metabolite that the body can use. Drugs that
cause an increase in metabolism are rifampin for tuberculosis
(Tong et al, 1981), dilantin for epilepsy (Kreek, Gutjahr,
Garfield, Bowen and Field, 1976). Carbamazepine can speed up
the metabolism of methadone so that it is excreted unused (Payte
and Khuri, 1992). The easiest 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
regulate the liver’s metabolism. Unfortunately, most programs
do not utilize this later procedure because it is more difficult
than just raising the dose until the patient stops experiencing
symptoms of abstinence.
Cocaine Use and Opiate Receptors
A recent discovery is that cocaine use can cause an increase in
the number of brain opiate receptors. Brain receptors are not
static, rather they are compounds 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 oiate receptors in
the human brain, but 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
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 and 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 for 20-30 mgs/day to feel the same.
Barbiturates
There has been one or two reports of a barbiturate causing
abstinence in a methadone patient. While this is a rare
occurance and the causes have not been determined all methadone
patients should be aware of it.
The Myth of Vitamin C
A recent myth has surfaced about vitamin C impacting on
methadone. And as usual no data, or at least scientific data
are given. If Vitamin C did interfere with methadone it would
have been discovered years ago when methadone was administered
in orange juice. Vitamin C does not enter the brain and even if
it did it could not compete with methadone for opiate receptors
because it does not contain the right chemical machinery, namely
the piperidine ring (Figure 3). To fit into the opiate receptor
a molecule must have the proper chemical configuration. Vitamin
C has no relation to the opiate structure and therefore cannot
interfere with the process of binding to the receptor. In fact
Vitamin C has very little to do with neurological functioning.
The primary functions of Vitamin C are to promote metabolic
reactions, in particular protein metabolism and is important in
the laying down of collagen during connective tissue formation.
Methadone is not a protein or involved in connective tissue
formation. The molecular structure of the two are in no way
related and therefore have nothing to do with one another.
Nor would vitamin C impact on methadone metabolism because it
does not cause metabolism to increase or decrease. The main
impact that vitamin C has is to provide necessary vitamins that
many patients do not get in their diet. All the vitamin C myth
does is to cause fear, apprehension and raise suspictions about
methadone. Whoever has promoted this myth is anti-methadone and
therefore anti-methadone patient. Why? Because when methadone
patients are firghtened 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!
Where To Get Information
Pharmacological information about methadone and other
psychoactive drugs can be found in The Pharmacologists Bible, or
Goodman and Gillman’s The Pharmacological Basis of Therapeutics.
Goodman and Gillman is far superior to the reference book, The
Physician’s Desk Reference (PDR) that most go to for information
because it gives not only clinical information as the PDR, but
pharmacology, metabolism and the recent research findings.
NAMA produces an Education Series and provides scientific
publications. Another source is the National Clearinghouse for
Alcohol and Drug Information (1-800-SAY-NO-TO(DRUGS)) that will
do a literature search and send either a bibliography for you to
chose from or send publications directly. Sometimes the later
choice cannot be done because of the vast amount of literature.
So beware of myth-makers and “everybody knows science.”
Methadone is one of the safest and most effective procedures
that I know of, yet it is constantly denigrated by nay sayers
who do not understand methadone maintenance or heroin addiction.
Challenge the nay sayers! Ask them for proof, real science!
References
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