How Methadone Works by Joycelyn Woods

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 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.

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

• 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

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  Journal of the Addictions 29(11): 1361-1375.

• Cooper, J.R. (1992). Ineffective use of psychoactive drugs:

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• Dole, V.P. (22-29 April, 1992). Hazards of process regulations:

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• Dole, V.P. (1988). Implications of methadone maintenance for

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• Dole, V.P. and Joseph, H. (1978). Long term outcome of patients

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• Dole, V.P. and Nyswander, M.E. (1965). A medical treatment for

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• Gearing, F.R. and Schweitzer, M.D. (1974). An epidemiologic

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• General Accounting Office (1990). Methadone Maintenance: Some

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  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

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• Inturrisi, C.E. and Verebey, K. (1972). The levels of methadone

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• Joseph, H. and Dole, V.P. (1970). Methadone patients on

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• Kreek, M.J. (1978). Medical complications in methadone

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• Kreek, M.J. (1973). Medical safety and side effects of

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• Kreek, M.J.; Garfield, J.W.; Gutjahr, C.L. et al (1976).

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• Payte, J.T. and Khuri, E. (1992). Principles of methadone dose

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• Spence, A.P. and Mason, E.B. (1979). Human Anatomy and

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• Tong, T.G.; Pond, D.M.; Kreek, M.J. et al. (1981).

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• Zweben, J.E. and Payte, J.T. (1990). Methadone maintenance in

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• Zweben, J.E. and Sorensen, J.L. (Jul-Sep 1988).

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  Drugs 20(3): 275-281.

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