Basic Pharmacology: How Methadone Works by Joycelyn Woods

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!

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.

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
  absorbtion is often irregular.

• Pulmonary (through the lungs)

  Very little is known about the pulmonary absorbtion of drugs other than
  those administered as gases.

• Intravenous injection

  Avoids all the disadvantages of oral administration. More control of dosage
  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:

1. Cell Walls
2. Walls of capillary vessels of the circulatory system
3. The blood-brain barrier
4. 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.

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.

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.

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 was synthesized by German chemists in the 1930s.  There is a
myth that methadone was developed by the Nazis during WWII.  It was
not.  Pharmaceuticals have always been an important industry in Germany and
there is nothing sinister about methadone being discovered in Germany because a
great many medications were developed by German chemists.  When the Nazis
took over Germany the discovery of methadone was forgotten.  It was not
used by the Nazis 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.

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.

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.

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.

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.

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.

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!

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!

• 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. From theory to Practice. New
  York: Oxford University Press.

   

• Brecher, E.M. (1972). Licit and Illicit Drugs. The Consumers Union Report
  on Narcotics Stimulants, Depressants Inhalants, Hallucinogens, and
  Marijuana. Boston: Little, Brown and Company.

   

• Caplehorn, J.R.M. (1994). A comparison of abstinence-oriented and
  indefinite methadone maintenance treatment. International Journal of the
  Addictions 29(11): 1361-1375.

   

• Cooper, J.R. (1992). Ineffective use of psychoactive drugs: Methadone
  treatment is no exception. Journal of the American Medical Association
  267(2): 281-282.

   

• Dole, V.P. (22-29 April, 1992). Hazards of process regulations: The
  example of methadone maintenance. Journal of the American Medical
  Association 267(16): 1062-67.

   

• Dole, V.P. (1988). Implications of methadone maintenance for theories of
  narcotic addiction. Journal of the American Medical Association (November
  25) 260(20): 3025-3029.

   

• Dole, V.P. and Joseph, H. (1978). Long term outcome of patients treated
  with methadone maintenance. Annals of the New York Academy of Science 311:
  181-189.

   

• Dole, V.P. and Nyswander, M.E. (1965). A medical treatment for diacetyl
  morphine (heroin) addiction: A clinical trial with methadone hydrochloride.
  Journal of the American Medical Association 193: 646-650.

   

• Gearing, F.R. and Schweitzer, M.D. (1974). An epidemiologic evaluation of
  long-term methadone maintenance treatment for heroin addiction. American
  Journal of Epidemiology 100: 101-112.

   

• General Accounting Office (1990). Methadone Maintenance: Some Treatment
  Programs are Not Effective; Greater Federal Oversight Needed.
  GAO/HRD-90-104, 1990.

   

• Goldsmith, D.S.; Hunt, D.E.; Lipton, D.S. and Strug, D.L. (1984).
  Methadone folklore: beliefs about side effects and their impact on
  treatment. Human Organization 43(4): 330-340.

   

• Inturrisi, C.E. and Verebey, K. (1972). The levels of methadone in the
  plasma in methadone maintenance. Clinical Pharmacology and Therapeutics 13:
  633-637.

   

• Joseph, H. and Dole, V.P. (1970). Methadone patients on probation and
  parole. Federal Probation (June): 42-88.

   

• Kreek, M.J. (1978). Medical complications in methadone patients. Annals of
  the New York Academy of Science 311: 110-134.

   

• Kreek, M.J. (1973). Medical safety and side effects of methadone in
  tolerant individuals. Journal of the American Medical Association 223:
  665-668.

   

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

   

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

   

• Spence, A.P. and Mason, E.B. (1979). Human Anatomy and Physiology. Menlo
  Park, California: The Benjamin/Cummings Publishing Company.

   

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

   

• Zweben, J.E. and Payte, J.T. (1990). Methadone maintenance in the
  treatment of opioid dependence: A current perspective. Western Journal of
  Medicine 152(2): 588-599.

   

• Zweben, J.E. and Sorensen, J.L. (Jul-Sep 1988). Misunderstandings about
  methadone. Journal of Psychoactive Drugs 20(3): 275-281.

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