Methadone

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METHADONE

OFFICIAL NAMES: Methadone, Dolophine

STREET NAMES: Fizzies, dollies, dolls

DRUG CLASSIFICATIONS: Schedule II, opioid narcotic analgesic

OVERVIEW

Methadone is a synthetic opioid narcotic, discovered in Germany in 1939. Its original name was Amidon, and it was used mainly as a pain reliever. After the conclusion of World War II, Eli Lilly and other American pharmaceutical companies began clinical trials of the medication, renamed methadone, and also began commercial production. Its original uses in the United States were for pain control and as a component of cough medicine.

While methadone works well as a pain control medication, its main use today is in the treatment of heroin addiction. Methadone itself is an addicting drug; its effects are much longer acting than heroin. Easier to administer on a once-daily basis, it is effective orally, which protects addicts from acquiring diseases such as HIV/AIDS, hepatitis B, and hepatitis C, obtained when they use dirty needles. Tolerance and dependence on methadone may develop in long-term users, and withdrawal symptoms, while less severe than among heroin users, are generally longer lasting.

CHEMICAL/ORGANIC COMPOSITION

Methadone is an odorless, white powder that dissolves easily in water and alcohol. In methadone treatment programs, it is often mixed with an insoluble matrix to form what are known as methadone biscuits. These biscuits stay in the stomach longer because it takes awhile for the stomach acids to break down the matrix. This is important because it allows more of the methadone to be absorbed, rather than passing quickly through the stomach when in liquid form.

INGESTION METHODS

Methadone is manufactured as tablets, diskettes (also known as biscuits), and liquid. People who use the drug illegally often inject either the liquid form or crushed and dissolved tablets. Methadone is detectable in a person's bloodstream seven to 10 days after use.

When used as a cough suppressant, methadone is taken in a liquid or tablet form in very small (1–2 mg) doses every four to six hours. For relief of moderate to severe pain, it is generally given as a tablet or as an intramuscular injection, 2.5–20 mg every three to four hours. When used in heroin detoxification and methadone maintenance programs, it is given as oral tablets, biscuits, or liquid, 20–120 mg every 24–48 hours.

THERAPEUTIC USE

The most well-known use of methadone is for treating heroin addiction. It is calculated that between 500,000 and one million Americans are addicted to heroin. Along with the obvious infectious risks to heroin users such as HIV/AIDS and hepatitis, heroin addicts often engage in criminal activity to obtain heroin, an illegal drug, to support their addiction. Methadone is an agonist, which means it fits into the brain's opiate receptors and blocks heroin. It reduces the intense cravings addicts experience when they try to give up heroin and enables them to participate in therapy and other aspects of their treatment. Methadone also reduces the need for addicts to commit crimes to obtain heroin and protects them from disease. Recent studies have found that persons in a methadone maintenance program were three to six times less likely than heroin users to become infected with HIV, even if they continue to use illegal drugs.

Methadone generally lasts about one day in the body, meaning that a person in a maintenance program has to take methadone at least once a day. Federal regulations require that to be eligible for enrollment in a methadone maintenance program, potential patients must be at least 18 years of age and demonstrate that they have had at least a one-year history of heroin (or other opiate) addiction. An exception is made for patients between the ages of 16 and 18 who can document a history of at least two unsuccessful detoxification trials.

Methadone maintenance programs are generally managed through methadone clinics, which also provide counseling and rehabilitation services. There are currently 42 states that have methadone maintenance programs, along with the District of Columbia, Puerto Rico, and the U.S. Virgin Islands.

The goal of a methadone maintenance program for people who are just coming off heroin is to decrease their withdrawal symptoms and their desire to use heroin. Initially, people starting in a methadone maintenance program will be given 30–40 mg of methadone a day, although there are addiction specialists who recommend higher initial doses such as 60–80 mg a day. In fact, most programs today are switching to the larger dose because research shows the larger dose is required for methadone to work effectively. Further into a methadone maintenance program, the dosages of the drug will be adjusted so that a person will not have cravings for heroin but also will not have any side effects from the methadone, such as sedation or euphoria.

Besides its use in treating illegal opiate addiction, methadone is occasionally used in other areas of medicine. All of the opiates, including methadone, are powerful pain control medications. Since pain is one of the most frequent, and least well-managed, aspects of cancer care, physicians often use multiple medications to try to control cancer pain. Methadone can be given in 20 mg tablets or by intramuscular injection every four to six hours to control moderate to severe cancer pain. Methadone is often used when there is a desire to let the patient sleep because of its high sedating properties.

Methadone can also be used to treat a common condition called restless leg syndrome. This condition generally affects middle-aged to older adults, although it is occasionally seen in adolescents. In restless leg syndrome, people complain of a strong, almost uncontrollable desire to move their legs, especially at night. In people who are unable to sleep because of this disorder, 10 mg of methadone, given at bedtime, often is effective at slowing or stopping the leg movements.

USAGE TRENDS

Scope and severity

The number of people entering methadone treatment programs to help them fight their heroin habit has steadily increased since methadone was first approved to treat heroin addiction. The latest statistics show that there are 170,000 admissions to methadone treatment programs throughout the United States every year.

Several major studies have been undertaken to gather data on opiate drug abusers who enter methadone treatment programs. The first of these was the Drug Abuse Reporting Program (DARP), which gathered data between 1969 and 1973. The second study, which examined patient characteristics of heroin addicts entering a methadone maintenance program, was the Treatment Outcomes Prospective Study (TOPS), which ran from 1979 to 1981. The most recent nationwide research, known as the Drug Abuse Treatment Outcomes Study (DATOS), collected data from 1991 to 1993.

There were many significant changes noted between the studies. In DARP, the earliest study, the patients entering methadone treatment programs had been, on average, addicted to heroin for at least nine years. In the 1990s, that number had increased to 13 years. Furthermore, the number of patients who had received previous treatment for heroin addiction increased from 50% in the 1960s to 75% in the 1990s. The proportion of addicts that had at least three prior treatment attempts increased from 13% in the 1960s study to 40% for the 1990s study. Use of other drugs such as cocaine among people entering methadone treatment programs increased from approximately 30% in the 1960s to 50% in the 1990s.

Age, ethnic, and gender trends

Based on data from these studies, there has been a significant change in the past three decades in the age, ethnic, and gender composition of methadone users. The proportion of women entering methadone treatment programs increased from 22% in the early studies to 39% in the most recent studies. The proportion of African Americans entering methadone programs decreased from 58% in the 1960s to only 28% in the 1990s, while the percentage

of Hispanics rose from 10% to 24% over that same time period. The percentage of whites entering methadone programs increased from 29% in the 1960s to 38% in the 1990s. Forty-six percent of the methadone program participants were between the ages of 35 and44. Only 20% were below the age of 30.

MENTAL EFFECTS

Methadone and all other opiates produce multiple effects on a user's psychological and mental status. These effects are generally dose-related, with more powerful effects seen at higher doses.

In order to influence a person's mental state, methadone, along with any other drug or substance, must first be able to cross what is known as the blood-brain barrier. The blood-brain barrier is an actual physical barrier, made up of tightly interspaced blood vessels that protect the brain from substances that might be harmful. The more effective a substance is at getting through the blood-brain barrier, the greater the effect it has on the person's mental status. Methadone and other opiates cross the blood-brain barrier quite easily.

Most users of methadone, especially new users, report feelings of well being and tranquility after taking the drug. How methadone produces these feelings is still being researched. Some scientists think that methadone and other opiates cause these effects by acting on a part of the brain known as the locus cerulus. This area of the brain is known to play a major role in feelings of pain, panic, fear, and anxiety. It is thought that by dampening the action of the locus cerulus, methadone and other opiates cause thoughts and feelings of tranquility and ease.

Methadone and opiates were first used for pain relief, and are still chiefly used in that area of medicine. It is important to remember that methadone and other opiates do not exert their pain control by altering a person's sensitivity to pain. Rather, methadone and other opiates interfere with the transmission of pain impulses from the nervous system to the brain. They accomplish this by a variety of methods. First, they decrease the transmission of nerve signals that conduct pain messages from various parts of the body to the spine. Secondly, they prevent production of neurochemicals that transfer this pain information to the spine. Finally, they mimic the actions of endorphins, which are the body's own pain-controlling chemicals. While methadone and other opiates work quite well to control pain, they do not affect touch, vision, or hearing.

Methadone also produces clouding of thoughts, drowsiness, and sleep in people who use it. It is thought that psychological effects seen in people who use methadone, including the inability to concentrate, apathy, and lethargy are related to methadone's pro-drowsiness effects, although researchers have yet to pinpoint the way in which methadone causes these effects. Methadone is often used by clinicians who specialize in addictive disorders to help heroin addicts resume a normal sleep cycle, since it is a powerful trigger at inducing sleep.

There are some reports by users that methadone use may cause hallucinations. While it is well known that heroin users often describe a dream-like mental state when using heroin, this effect is rarely seen in people who use methadone. The reason behind this is probably due to methadone's slower onset of action and reduced level of intensity. Likewise, while users of heroin and other harder narcotics sometimes report feelings of acute anxiety, especially when first using the drug, users of methadone rarely report these psychological effects.

PHYSIOLOGICAL EFFECTS

Methadone, like all opiates, is a chemically simple compound that has a variety of effects on those who take it. But while other opiates exert powerful euphoric effects on a person by acting very much like chemicals called endorphins and enkephalins, methadone produces only a mild (or no) euphoria, to which patients quickly become tolerate. Endorphins and enkephalins are naturally produced inside the brain. When released in the brain's reward system, they produce a mind reward and users feel good as a result. Methadone and other opiates mimic these natural brain chemicals, which is why they are so addicting.

Scientific research has shown that methadone and other opiates have specific areas, or sites, that they attach to in order to exert their influence on the brain and body. These sites, called receptors, are classified as mu, delta, and kappa, depending on what body functions they influence. Opiate activation of mu and delta receptors seems to influence mood, respiration, pain, blood pressure, and gastrointestinal functions. Kappa receptors appear to be more involved in the perception and aversion to pain. The degree of methadone's effect on these receptors can vary widely between individuals, however, there are certain effects that are almost universal.

Nausea is a side effect of all opiates. People who take opiates, including methadone, for a long period of time generally develop a tolerance for its nauseating effects. Vomiting, while common with other opiates such as heroin, is actually a rare side effect of methadone. These side effects are due to the stimulation by opiates of the part of the brain called the medulla, which controls nausea and vomiting.

Another important side effect of all opiates on the central nervous system is respiratory depression. This is caused by an inhibitory effect on the brain stem, which is the part of the brain that controls breathing and other involuntary bodily systems such as heart beat, etc. Like nausea and vomiting, people who take methadone and other opiates normally develop a tolerance to this side effect. However, even people who have taken methadone for a long period of time can develop major respiratory depression.

Cough suppression is another side effect of opiates. In fact, some opiates such as codeine are specifically marketed as cough suppressants. Other less common side effects of methadone include convulsions with very high doses, and a heavy feeling in the arms and legs. While not fully understood, it is thought that this side effect is due to the methadone causing increased blood circulation to the peripheral blood vessels of the body, especially to the arms and legs.

One of the most annoying physiological side effect of methadone use is a feeling of dryness in the mucous membranes of the mouth, eyes, and nose. This is caused by methadone reducing the secretion of saliva, tears, and mucous. Regular users of methadone refer to the dryness of the mouth as "cotton mouth," since the feeling is akin to having one's mouth stuffed full of cotton.

Methadone and all other opiates also have the unwanted physiological side effect of producing constipation. Generally, involuntary movements, or waves, of the muscles in the small and large intestines propel fecal matter through the intestines and out of the body. However, methadone and other opiates significantly slow these involuntary movements, and result in constipation. Even after long usage, many users of methadone will continue to report continued constipation.

A very visible physiological effect of methadone and all other opiates is the constriction of a person's pupils. The pupils, which are the black center of the eye, can be likened to lens on a camera. When pupils are wide open, then more light can pass through. When the pupils are constricted, very little light can pass through. Persons who are on methadone often have pupils that are quite small, making it very difficult for the person to see in anything but bright light.

There are other physiological effects of methadone for which there is no known mechanism. In women who use methadone, there can be changes seen in their menstrual cycle. It has been hypothesized that these changes are due to methadone's effect on the hormones that regulate menstruation, but this has not yet been proven.

Another side effect of methadone is a change in a user's sexual desire and function. One theory is that opiates decrease testosterone levels in both men and women; one small study of 29 methadone users found testosterone levels to be decreased by 40%. Methadone also inhibits sexual function by increasing the tone in the muscles surrounding the urethra and therefore causing a delay in orgasm in men.

It is generally thought that methadone is extremely dangerous for women who are pregnant. The fact is that there are no well-researched studies showing any adverse physiological effects for pregnant women who are using methadone for heroin withdrawal. However, while the risk for pregnant women may be minimal, there are very real physiological risks for their babies.

The first problem for the baby of a woman who is using methadone is a higher risk of low birth rate. Most studies show that babies born to women who are using methadone for heroin detoxification have a 25% greater risk of low birth weights than babies whose mothers were not using methadone. It is thought by some researchers that methadone itself somehow causes babies to be born underweight, but the majority of drug addiction specialists feel that the higher incidence of low birth weight seen among methadone users is due in fact to social factors such as poor nutrition, smoking, and poverty.

Babies who are born to mothers who are using methadone are at high risk of experiencing a syndrome known as the methadone withdrawal syndrome. This syndrome usually occurs within 48 hours of birth, but can be seen anytime during the first two weeks of birth. Symptoms are quite variable, but generally include irritability and sleep disturbances; prolonged sneezing; loud, shrill cries; watery stools; hyperactivity; poor weight gain; and aversion to bright lights.

Besides the classical withdrawal signs, there are other reported physiological problems in babies born to mothers who are using methadone. Some studies have reported that there is a higher rate of infant mortality and SIDS (sudden infant death syndrome) in babies who are born to methadone-using mothers. However, these studies were done in the 1970s, when there was a generally higher rate of infant mortality. Subsequent studies have failed to prove a definitive relationship between methadone use by pregnant women and a subsequent increase in death rates in their infant offspring.

Many physicians who do not treat opiate addicts on a regular basis believe that methadone inhibits and interferes with the functioning of a person's immune system. While it is true that some of the shorter acting opiates like heroin do inhibit a person's immune system, and thus make them more prone to infections, methadone does not inhibit the immune system. This is an important fact, especially in light of the fact that many ex-heroin users have HIV and AIDS. There are even some researchers who believe that methadone, by ways still unknown, may even help restore the functioning of the immune system in patients with HIV.

Harmful side effects

The harmful side effects of methadone, if taken in controlled conditions of a heroin detoxification program, are actually very small. The three main side effects of methadone use are tooth decay, constipation, and accidental overdose. Over half the users of methadone report problems with their teeth related to their methadone usage. Methadone use makes users more prone to tooth decay because methadone in a treatment clinic is generally given as a syrup-based mixture that has a high-sugar content, and is also acidic. Also, methadone itself inhibits the production of saliva in the mouth, which indirectly promotes the production of plaque. To help prevent tooth decay in methadone users, researchers are formulating water-based, sugar-free solutions of methadone, and promoting a low-sugar diet along with regular dental checkups for long-term users of methadone.

Chronic constipation is also another troublesome side effect of prolonged methadone use. As discussed previously, methadone significantly slows the involuntary movements of the small and large intestines. By consuming a high-fiber diet and plenty of water, chronic users of methadone can reduce, but not eliminate, the occurrence of constipation.

The third and most serious side effect of long-term methadone use is the danger of an overdose. Methadone is one of the most powerful opiates, and with its slow onset of action and long half-life, that is, the time it stays active in the body, it can cause overdose, even in chronic users. Early signs of methadone overdose include nausea and vomiting, drowsiness, reduced heart rate, and pinpoint pupils. Signs of a more severe overdose include breathlessness and convulsions, which may result in death. To help prevent a methadone overdose, people should follow the advice of the physician or treatment specialist who provides methadone to them, and they should not mix methadone with other drugs, especially tranquilizers or alcohol. All suspected cases of methadone overdose should immediately be taken to the nearest hospital emergency room.

Long-term health effects

The long-term health effects of methadone, if taken in the controlled conditions of a methadone maintenance program, are minimal. Through the study of thousands of patients, researchers have shown that while some physiological changes do occur in people taking methadone, problematic long-term health effects during prolonged treatment are very rare. In fact, the most important long-term side effect seems to be that there are significant improvements in the general health of heroin addicts who enter a methadone maintenance program.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

Methadone is mainly broken down, or metabolized, in the liver. Therefore, any other medications or substances that affect the functioning of the liver can change the rate of metabolism of methadone, either increasing or decreasing the amount in a person's bloodstream.

There are many drugs that increase the rate of the liver's metabolism. More commonly used medications that fall into this category include rifampin, which is used to treat tuberculosis, and dilantin, phenytoin, and carbamazepine, which are medications commonly used to treat seizures and epilepsy. Chronic alcohol abuse also speeds up the metabolism of the liver. Since all of these substances cause the liver to break down methadone faster then it normally would, one way to correct the problem would be to increase the dose of methadone or break down the dose into several smaller doses given throughout the day. This should only be done on a physician's advice.

Other medications that can slow down the metabolism of the liver, thereby causing a person to get a higher dose of methadone than they normally would, include Cimetidine, commonly used for upset stomachs, diazepam, a commonly used anti-anxiety medication, and fluvoxamine, a recently introduced antidepressant medication. Interestingly, alcohol, when used only occasionally, increases methadone levels as compared to decreasing methadone levels when it is used and abused on a chronic basis.

There are other well-known medications that can increase the level of a methadone in a person's bloodstream. Medications, including the common antibiotics, erythromycin and clarithromycin, along with vitamin E and the pain reliever ibuprofen, can all cause an increase in methadone levels by affecting the way methadone is carried in the bloodstream by plasma proteins. All the mentioned medications cause methadone to be "knocked away" from its plasma protein carriers, causing a great surge of methadone in the bloodstream. As with medications and substances that slow the metabolism of the liver, patients who are taking any other medications should discuss this with all the specialists involved in treating them for various problems so that they do not overdose on methadone.

Besides being affected by medications and substances that affect the liver's metabolism, methadone itself affects the liver's metabolism of certain substances. A significant number of people who are taking methadone for heroin addiction also are HIV positive and are taking anti-HIV medications such as Desipramine (DMI) and zidovudine (AZT). Through its actions on the liver, methadone decreases the metabolism of these medications. Because of this, certain troublesome side effects of DMI and AZT, including nausea, vomiting, and fatigue, can increase when a person is on both methadone and these anti-HIV medications.

TREATMENT AND REHABILITATION

Getting people off methadone, referred to as methadone detoxification, is a complex process. People who are on methadone to combat their heroin addiction often decide to stop using methadone when they and their counselors have decided that they are ready to live without drugs. However, there are times when, even though the patient is not truly ready to stop methadone, they feel they must stop for a variety of reasons such as getting a new job, moving to a new area, the societal stigma of being on methadone, or an upcoming or actual prison sentence. Whatever the reason, methadone detoxification must be done carefully.

Almost all people on methadone who decide to go off of it will have withdrawal symptoms such as anxiety, depression, nausea/vomiting, and difficulty sleeping. To help minimize these effects of methadone detoxification, a gradual reduction in the dose of methadone is done over a long period of time to help the person adjust to not having methadone in their body.

For short-term detoxification, a person would decrease and stop methadone in less then a month. It should be noted that people in short-term detoxification programs have a higher likelihood of returning to heroin abuse than do people in a long-term methadone detoxification program.

In a long-term detoxification program, people on methadone may spend up to six months gradually cutting back on the amount of methadone that they use. The entire detoxification program would take four months.

PERSONAL AND SOCIAL CONSEQUENCES

The personal and social consequences of drug abuse are wide-reaching. Consequences of drug abuse affect all people and all ages. The impact of drug abuse is a complete societal problem that leaves no person in this country, either directly or indirectly, untouched.

Opiate abuse, mainly heroin abuse, is the main reason people turn to methadone treatment programs. The consequences of opiate abuse can be staggering. People who are addicted to opiates generally have a variety of psychiatric, medical, and social problems. As compared to other persons their own age and sex, opiate addicts have a significantly higher incidence of anxiety, depression, schizophrenic-like symptoms, and other serious psychiatric disorders. Opiate abusers frequently suffer from multiple medical problems. Due to their high rate of injecting heroin to get high, opiate addicts have a very high rate of hepatitis B, hepatitis C, and HIV/AIDS.

People who are addicted to opiates also have a number of societal problems. Maintaining meaningful employment is almost impossible for a person addicted to opiates. Likewise, maintaining stable relationships or marriage, making and keeping friends, and functioning as a caring and dependable parent are almost impossible tasks for someone whose life revolves around the next high. Most opiate addicts have to steal in order to maintain their habit, so they are at very high risk of being jailed for drug-related crimes.

LEGAL CONSEQUENCES

The penalties for illegally using and distributing methadone are severe. Methadone is classified as a Schedule II substance. For illegal possession of methadone, the penalty (for first offenders) for possession of greater than 100 g is a fine of not more than four million dollars. The penalty for a second offense is a fine of no more than eight million dollars.

The penalties for trafficking illegal methadone are even more severe. For a first offense, the penalty can be up to 20 years in prison. For a second offense, the penalty can be up to 30 years in prison.

Legal history

Methadone began to be used as a treatment for heroin addiction in the 1960s. In 1963, Dr. Vincent Dole, an expert in metabolic disorders, and Dr. Marie Nyswander, a psychiatrist who had worked in the U.S. Public Health facility for heroin addicts in Lexington, Kentucky, began experimenting with several drugs to help addicts recover from their addiction. The doctors discovered that when heroin addicts were given methadone, their behavior radically changed. Suddenly, instead of focusing on getting more heroin, the focus of the addict's attention turned away from drugs and to pursuits in life they had had before they were addicted to heroin. Dr. Dole and Dr. Nyswander realized that once a heroin addict was given an adequate treatment dose of methadone, that person could remain on the same dose for a long period of time and function almost as well as they did when they were not addicts.

Within a year, Nyswander and Dole had developed a methadone maintenance treatment program. They based their program on the idea that heroin addicts suffer from a metabolic disorder much as a person with diabetes suffers from a metabolic disorder. They reasoned that just as insulin stabilizes a person with diabetes, methadone could stabilize a person with a heroin addiction. However, even though Nyswander and Dole viewed their program as a physical treatment for a physiological disorder, they also used intense psychological counseling services to help their patients get over their addiction. This new form of treatment for heroin addiction spread rapidly over the next few years, and by 1972 there were more than 800 methadone maintenance programs in the United States.

Federal guidelines, regulations, and penalties

Since the passage of the Harrison Narcotic Act in 1914 by the U.S. Congress, the federal government has been involved in the control of narcotics and the treatment of addicts. In terms of treatment of narcotic addicts, the federal government opened facilities in Lexington, Kentucky, and Fort Worth, Texas, between 1936 and 1939 to help deal with the rising number of opiate addicts in the United States.

After the development of methadone maintenance programs in the mid-1960s, the federal government, through the action of the 1966 Narcotic Addiction Rehabilitation Act, authorized the civil commitment of narcotic addicts, as well as giving federal finanical assistance to states and local authorities to develop a local system of drug treatment programs. The act required that these treatment programs include mandatory three-times-a-week counseling sessions; weekly urine tests; restorative dental services; and psychological counseling and vocational training.

In 1970, the Comprehensive Drug Abuse Prevention and Control Act was enacted into federal law. One purpose of the act was to clarify the ways in which medical personnel could legally dispense methadone to heroin addicts. In order to further clarify heroin treatment parameters, the Narcotic Addict Treatment Act of 1974 was passed, which set forth minimum standards for all methadone treatment facilities, as well as setting standard definitions for addicts. In the 1980s, these regulations were amended to allow younger patients (ages 16–18) to legally enter treatment programs. The regulations passed in the 1980s are still in effect today.

See also Heroin