• Summary
• Introduction
• The chemistry of methadone
• The effects of methadone
• Opiate effects on the central nervous system
• Opiate effects on the peripheral nervous system
• Histamine release-related effects
• Other reported effects
• Effects on babies
• Things that methadone does not cause
• Long-term effects
• Dental decay
• Methadone metabolism
• Tolerance
• Methadone overdose
• Treatment of methadone overdose
• Withdrawal symptoms and their causes
• Drug interactions
• Medical conditions and methadone

Summary

• Methadone is a relatively simple, synthetic compound that has similar effects to natural opiates.

• It acts on many sites in the body causing a complex range of reactions.

• Methadone is notable for its lack of long-term side effects in comparison to many prescribed drugs.

• People become tolerant to some effects of methadone, albeit usually very slowly.

• Tolerance to constipation and pin-point pupils (miosis) is rare.

• Withdrawal symptoms from methadone are mainly caused by the body reacting to the absence of opiates in the peripheral nervous system.

• Methadone does not cause congenital abnormality in babies.

• Methadone is absorbed into, and stored in, a number of sites in the body from where it is gradually released into the bloodstream.

• Methadone interacts with a number of drugs and a few medical conditions.

• Methadone overdose is a serious medical emergency requiring urgent response.

• In treating methadone overdose it must be borne in mind that it is a long-acting compound.

Introduction
Methadone, as with all opiates, is a relatively simple compound that has a powerful and complex range of effects on those who take it. But the degree of effect, and the subjective experience, can vary widely between individuals.

This section looks at the effects of methadone on the brain and body, how the body responds to the presence of methadone and how tolerance develops. There is also information on what methadone is and how it interacts with other drugs.

As the issue of how to equate methadone dose with illicit drug use is as much a matter of policy, practice, assessment and local trends as a matter of physiology and pharmacology, it is dealt with in Section 8 - Getting the starting dose right.

The chemistry of methadone
Methadone hydrochloride consists of:

• Carbon: 21 atoms
• Hydrogen: 27 atoms
• Nitrogen: 1 atom
• Oxygen: 1 atom
• Hydrochloride

The approved name of methadone hydrochloride is:

6-dimethylamino-4,4-diphenyl-3-hepatone hydrochloride.

The methadone molecule can be drawn like this:

There appear to be two separate active sites in the molecule:

• The nitrogen atom with the hydrochloride bonded to it at one end - thought to act on the peripheral nervous system
• The 2 phenyl 'rings' which are thought to be necessary for its opiate-like action on the central nervous system.

Methadone is:

• A white crystalline powder
• It melts at 233-236^oC.

It is soluble in:

• 1 in 12 of water
• 1 in 7 of ethanol
• 1 in 3 of chloroform

It does not dissolve in ether.

The effects of methadone
Until the intricate workings of the nervous system are fully understood the precise causes of all the effects of opiates cannot be explained. However extensive studies, experiments, and clinical experience together give us a clear indication of the effects of these drugs and the mechanisms that cause these effects.

Opiates appear to share some of the properties, and mimic the action of some groups of the body's naturally occurring chemicals called peptides, in particular:

• Endorphins
• Enkephalines
• Dynorphins.

Studies of the binding of opiates and these peptides to specific sites in the brain and other organs have suggested the existence of as many as 8 types of opioid receptors which, in addition, may all have sub-type receptors.⁵²

Opiates directly cause a number of actions which can be divided into the following groups:

• Opiate effects on the central nervous system (CNS)
• Opiate effects on the peripheral nervous system
• Opiate induced histamine release-related effects
• Other reported effects for which there is no identified and/or proven causal effect Effects on the unborn foetus.

The effects in each of these categories are listed below. Following the lists there are explanations, where possible, of the mechanisms involved.

Opiate effects on the central nervous system

• Euphoria
• Pleasant, warm feeling in the stomach
• Pain relief
• Drowsiness
• Sleep
• Nausea
• Vomiting
• Respiratory depression (rate and depth of breathing reduced)
• Cough reflex depression
• Arms and legs feeling heavy
• Convulsions (caused by high doses only and very rare with methadone)

Opiate effects on the peripheral nervous system

• Dryness of the mouth, eyes and nose
• Constipation
• Small pupils
• Difficulty passing urine

Histamine release-related effects

• Itching
• Sweating
• Blushing
• Flushing of the skin
• Constricting of the airways

Other reported associated effects for which there is either no identified or proven causal effect

• Reduced or absent menstrual cycle
• Altered sexual desire
• Hallucinations
• Swelling of feet and ankles
• Delayed orgasm
• Difficulty controlling orgasm
• Heart pounding
• Anxiety
• Weight gain

Effects on the foetus and young child

• Low birth weight
• Withdrawal symptoms

The mechanism thought to be responsible for each of these catagories of effects is described below.

Opiate effects on the central nervous system

Euphoria
Feelings of euphoria are not universally experienced. Heroin users often report that the euphoric effects of methadone are not nearly as pronounced as those of heroin. This is to be expected, to some extent, as heroin is smoked or injected and thus has a much quicker onset of action than oral methadone. However many drug users report that even injected methadone produces a qualitatively different euphoria to that of heroin.

The feeling 'on methadone' is often described as simply absence of withdrawal symptoms but the increase in anxiety, stress and psychological discomfort experienced by many users on detoxification programmes suggests that the methadone is contributing to a sense of relief from distress - even if this is not experienced as pronounced euphoria.

The mechanism by which opiates produce a sense of euphoria and tranquillity is not yet agreed. It may be partly via action on a part of the brain called the locus cerulus. The locus cerulus has high concentrations of opioid receptors and is thought to play a crucial role in feelings of alarm, panic, fear and anxiety.⁵²

In any event the neural systems that cause the feeling of euphoria appear to be different from the systems that cause physical dependence and pain relief.⁵³

In theory as the dose of opiates is increased the euphoric effect rises. However some long-term methadone users have taken near-fatal doses and still reported that the high was nothing like that of heroin. It is likely that some methadone overdoses are the result of people trying to achieve a heroin-like euphoria using a drug which is apparently unable to produce these same feelings.

In experiments using people who are pain free with no history of opiate use not all experience a pleasant effect. Some experience a dysphoria⁵²: uncomfortable, disorientated feelings which can be made worse by the feelings of nausea which are common.

Pleasant, warm feeling in the stomach
As with all opiates, this is a reported effect that accompanies the euphoria. The mechanisms involved are not understood.

Pain relief
Opiates reduce pain through a number of mechanisms (described below) but although the pain relief is often only partial they also alter the perception of painful stimuli and thus make pain more tolerable.

Opiates do not alter the sensitivity of nerve endings to pain, rather they interfere with the transmission of signals via the nervous system to the brain. They do this by:

• Decreasing conduction along the nerves that run between the nerve endings and the spine
• Preventing production of the chemicals that allow signals to pass between the nerves and the spinal cord
• Stimulating production of serotonin (also known as 5HT) and noradrenaline (also known as norepinephrine) which significantly reduces pain signals reaching the brain
• Mimicking the action of endorphins at their receptor sites.

Through their action in the spinal column they reduce the ability of the body to produce reflex actions to painful stimuli.

The ability of opiates to inhibit the body's response to stimuli is selective in that they do not affect touch, vibration, vision or hearing.

Drowsiness
Opiates cause some sedation, although in clients taking a dose to which they are tolerant, on a daily basis, drowsiness caused by methadone is unlikely.

Opiate users develop tolerance to the clouding of thought which may be related to drowsiness. Other related effects which are reported in studies of opiate use in volunteers with no history of opiate use are:

• Inability to concentrate
• Apathy
• Reduced physical activity
• Lethargy
• Reduced visual acuity.

It is important to look at other possible causes when these symptoms are found in long-term methadone users before they are attributed to the methadone.

At the start of methadone treatment clients should be warned that methadone causes sedation, and of the possibility that it may impair co-ordination and the ability to perform skilled tasks such as driving. This is especially marked (and can cause overdose) when other central nervous system depressants such as alcohol or benzodiazepines are also taken.⁵⁴

Sleep
Of those clients who can take their methadone home most usually take part of their methadone late in the evening to help them sleep. Many drug users lack a natural sleep pattern so they use methadone as a trigger to initiate sleep.

Methadone's action at the opioid receptors results in sedation and mood changes, which are more marked in the initial hours after dosing when the blood concentrations are marginally higher. But blood concentrations vary little in regular methadone users so the association with sleep is probably mostly psychological.

The sleep-promoting effects of methadone may be particularly important for people with underlying anxiety.

Some clients report persistent problems with sleep although how much of this is due to methadone and how much is due to:

• Drug use becoming more stable since starting methadone treatment
• Instability of drug use
• Unrealistic expectations of the sleep-inducing properties of methadone
• Previously unrecognised poor sleep pattern

Underlying anxiety or other mental health problems is often a useful topic for discussion between worker and client.

Nausea and vomiting
The feelings of nausea associated with opiates are partly due to direct stimulation of the chemo-receptor trigger zone (CTZ) in the part of the brain known as the medulla.

Not everyone is susceptible to CTZ stimulation by opiates and tolerance builds, albeit sometimes slowly, for those who are.

Vomiting caused by methadone is rare. Most in-patient methadone dose titration services rarely, if ever, encounter people who vomit their methadone dose. Services which prescribe only methadone mixture usually find that clients are able to tolerate this despite protestations to the contrary at the outset of treatment.

People who vomit methadone usually do so for reasons independent of the methadone. Far more likely causes of vomiting are:

• Excessive alcohol use
• Eating large meals
• Pre-existing eating disorder
• Pre-existing stomach problems e.g. ulcer.

All of these can be exacerbated by CTZ stimulation and the slowing of the movement of the intestine by methadone (see opiate effects on the peripheral nervous system below).

Vomiting as a side effect of methadone is often reported at assessment - usually accompanying a request for methadone in tablet or injectable form.

Even if the other causes for vomiting listed above have been excluded you must be satisfied that the nausea and vomiting are genuine before considering alternative preparations because the request for tablet form methadone may arise either from a desire to crush and inject the tablets or an intention to sell the tablets.

If treatment with an oral methadone solution is chosen it is usually best to either commence treatment in an observed environment or to start treatment with a guarantee to review in a week. Almost always the client will stabilise and not find vomiting to be as problematic as they expected.

Respiratory depression
Respiratory depression is partly caused by a direct inhibitory effect on the brain stem respiratory centres which normally increase the breathing when the level of carbon dioxide in the blood rises.

Opiates also depress the action of the centres that regulate the breathing rhythm. These effects are not normally significant other than in overdose where respiratory arrest is the most common cause of death.⁵⁵

Respiratory depression, coupled with a high incidence of smoking, can result in opiate users presenting with chronic and/or serious chest infections. Staff should be alert to this risk as early intervention can prevent extensive use of antibiotics and serious illness.

Cough reflex suppression
Opiates also have a direct suppressant effect on the cough centre in the medulla which is partly responsible for triggering a cough in response to irritation of the lower airways.¹⁹

Arms and legs feeling heavy
The cause of this subtle, but not unpleasant, effect of methadone is not understood. It may result from the effect of methadone on the nerve pathways, coupled with the increased blood flow to the peripheral blood vessels.

Convulsions
Doses far in excess of the normal therapeutic range of opiates can cause convulsions. This is therefore theoretically possible with methadone although there is no published evidence of this happening. There appear to be several mechanisms involved when convulsions occur in exciting certain groups of brain cells and in suppressing the production of chemicals that normally keep brain activity within safe limits.

Naloxone is effective in treating convulsions caused by methadone. Diazepam may also be an effective treatment. Anti-convulsants may not be effective.

See also the notes on epilepsy at the end of this section under 'Medical conditions and methadone'.

Opiate effects on the peripheral nervous system
Methadone has a powerful effect on the peripheral nervous system. This may be as a result of an inhibitory effect on some opiate receptors⁵⁵.

The effects of opiates on the peripheral nervous system seem to be more resistant to the development of tolerance than the other effects.

Dryness of the mouth, eyes and nose
All opiate drugs reduce secretion of saliva, tears and mucous in the respiratory tract by blocking the receptors that need to be stimulated for the production of these secretions.

Constipation
The waves of muscular contraction that propel the stomach contents through the large bowel can be virtually stopped by methadone. Indeed opiates are so good at slowing the passage of food through the gut that they can be used in the treatment of dysentery!

Methadone also reduces the normal stimuli to defecate and increases the tone of the anal sphincter muscle which further contributes to the constipation that is almost universal among methadone users.

A high-fibre diet and a high (non alcohol) fluid intake are the best methods for reducing constipation.

Nausea
Opiates reduce the movement of the stomach and both movement and size of the duodenum by causing the muscles to contract. This can delay the passage of food through the small bowel by as much as 12 hours. This may increase feelings of nausea (see above) by contributing to a feeling of being 'full' even several hours after eating.

Small pupils (miosis)
Opiates probably stimulate the oculomotor nerve causing the iris to contract leaving only a small hole for light to pass through. Tolerance to this effect of opiates is only partial - even after long-term use.

Because of this the degree of pupil constriction is a reliable indicator of the level of opiates in a person's blood stream⁵⁵.

Difficulty passing urine
This is a less commonly experienced effect.

Opiates can increase the tone of the sphincter muscles that allow urine to pass from the bladder thus making it more difficult to relax them in order to pass urine.

This can be aggravated by the methadone also making the bladder contract more strongly causing 'urinary urgency'.

Histamine release-related effects
In the blood, lungs, intestines, etc. there is a type of cell called a mast cell. Its function is to recognise 'invaders' in the blood and to attack them.

On encountering a substance to which the mast cell is sensitive it ruptures, releasing histamine. Histamine is the main agent in the body's allergic response. It has a number of effects, all of which are supposed to be helpful in attacking an invading substance to which the body is sensitive. Histamine triggers the opening up of the tiny blood vessels in the skin which produces:

• Blushing
• Flushing of the skin
• Itching
• Sweating.

It also causes:

• Constricting of the airways.

The opening of the blood vessels near the surface increases the number of white blood cells near a likely source of further attack. Constriction of the airway may serve some purpose in reducing the number of foreign bodies that can be inhaled. All of these effects can be exacerbated by anxiety.

Mast cell sensitivity to substances can be helpful, for instance in attacking bacteria, or unhelpful, for instance when it causes the hay fever reaction to pollen.

Methadone (and other opiate) molecules are able to enter mast cells and cause them to release histamine - with the above effects. But it is not an allergic reaction because it is caused by the molecule entering the cell rather than by the mast cell 'recognising' methadone as a foreign substance55. It is not something that people develop a tolerance to.

Sweating
Sweating is a common long-term problem in methadone users and histamine release may be partly to blame. However the fact that it can be so severe, and that it is often present in the absence of other histamine-related effects, indicates that there may well be other, not yet understood, mechanisms at work.

Other reported effects
There are a number of other effects that are associated with methadone for which there is no clear and/or proven causal mechanism. The list has been compiled from anecdotal evidence and reports in the literature.

These effects occur in people who take methadone and in the general population. Where we have found a suggested mechanism linking methadone to the effect, it is described.

Reduced or absent menstrual cycle
This is the most commonly reported experience in this category. There are other causes of amenorrhoea (absence of periods) such as stress and poor nutrition which may well contribute to the problem.

Levels of the hormones that control menstruation, follicle stimulating hormone and luteinising hormone, remain normal in women receiving long-term high doses of methadone,⁵² and amenorrhoea is not recognised as an effect of opiate treatment for other pain relief. However there are a large number of anecdotal reports of the normal menstrual cycle resuming during or post methadone detox, a time when stress levels are likely to be high and appetite poor.

All women taking methadone should be advised that even if their periods have stopped they may still become pregnant.

Altered sexual desire
All opiates are considered to reduce sexual desire. A minority of methadone users report persistent reduced sexual function. The cause of this reduced desire is not known but the sentiment 'when you've got opiates you don't need sex' is common among opiate users and may point simply to an under reporting of sexual activity - which is no longer highly valued - rather than levels of sexual activity which are less than the general population.

In a small study of 29 people dependent on methadone Cicero et al found that serum testosterone levels of those taking methadone were 43% lower than those of the heroin users and the study control group.⁵⁶

Some methadone users report increased sexual desire as a result of taking methadone. It seems likely that this has as much to do with other factors such as increased stability, reduced stress and alcohol intake, as with any direct pharmacological effect of methadone.

Delayed orgasm and difficulty controlling orgasm
Methadone may cause increased tone in the sphincter muscles that close off the urethra, having the effect, in men, of delaying orgasm. Difficulty controlling orgasm could be a result of increased sensitivity while less sedated on methadone than on heroin.

Hallucinations
The literature describing the effects of opiates in general (from which a lot of information on methadone is extrapolated) often mentions hallucinations as an effect, and heroin users describe a dream-like state when using heroin which can include perceptual alterations. But with the slower onset and reduced intensity of methadone it is very unlikely that someone who is being treated for opiate dependence, with no previous history of mental illness, would experience hallucinations due to methadone.

Swelling of feet and ankles
This is a rare transient reaction at the commencement of methadone prescribing. It usually goes within a few weeks of the start of treatment. The cause is not known.

Heart pounding
This has been reported as a transient effect when plasma levels of methadone reach a peak, about 4 hours after an oral dose.⁵⁷ The cause is not known and it is rarely problematic.

Anxiety
Again this is an effect extrapolated from the literature on other opiates as some people do not find the experience of opiates pleasant. However methadone users are a self selected group who have enjoyed the experience of taking opiates.

Increased anxiety could have a number of causes such as:

• Underlying anxiety disorder
• Insufficient methadone dose
• Benzodiazepine withdrawals
• Alcohol withdrawals
• Having more time while on methadone due to no longer having the distractions that were related to daily heroin use.

The experience of many opiate users is of reduced anxiety during methadone treatment.

Weight gain
The calorific value of methadone mixture DTF is only 1.7 kilo calories/mL.⁵⁸ This makes a dose of 50mg (85 kilo calories) equivalent to eating just a couple of biscuits so it is unlikely that the weight gain sometimes reported as linked to methadone is due to its calorific value.

Other factors could include:

• Increased appetite on methadone in relation to appetite on heroin
• Poor diet
• Client being underweight at start of treatment
• Reduced physical activity
• Reduced stress.

Effects on babies
In Section 11: Prescribing for groups with special needs, there is further discussion on:

• Care of the pregnant woman
• Other risks to the foetus (which are often greater than the risk from the methadone)
• Care of the newborn baby.

Overall risk to babies of women using prescribed methadone
No increased level of congenital abnormalities has been observed in the babies of women who have taken methadone during their pregnancy.

The problems listed below look alarming when put together but they should be read in conjunction with their explanatory notes and in the overall context of the risk assessment scale of a standard text on the subject Drugs in pregnancy and lactation: a reference guide to foetal and neonatal risk.⁵⁹

Normal methadone treatment is rated:

'Risk category B:

... no controlled studies in pregnant women or animal studies have shown an adverse effect ... in women in the first trimester and there is no evidence of risk in later trimesters.'

It has been suggested that the withdrawal syndrome from heroin in babies is less prevalent and less severe than methadone withdrawal syndrome and that it may be safer for mothers to take heroin up to delivery - particularly if they smoke the drug - than methadone. Although this may be true the current consensus is that in the vast majority of cases the other risks associated with illicit drug use such as overdose, sudden withdrawals, adulterants, crime, etc. are likely to outweigh the benefits of potentially milder withdrawals for the baby following delivery.

This is supported by Drugs in pregnancy and lactation which rates methadone treatment for 'prolonged periods' or 'in high doses at term' as:

'Risk category D:

There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk...'

If methadone substitution (either on a reducing or maintenance basis) can help alleviate the drug-related risks and improve ante-natal care (through increased contact with services) then it is a positive intervention.

Possible problems following methadone use during pregnancy
The main problems appear to be:

• Low birth weight
• Withdrawal symptoms in the baby.

Some studies have also found raised incidence of jaundice, Sudden Infant Death Syndrome and raised mortality. All of these possible problems are discussed below, and should be read in conjunction with the notes above.

Low birthweight
There is an increased incidence of low birth weight in babies born to opiate-using mothers. Johnstone⁶⁰ quotes 11 studies which together covered nearly 1200 babies delivered to mothers whose main or only drug was methadone, which show that about 25% of babies had a low birth weight.

The babies of women taking only methadone may have a higher birthweight than comparable babies of women taking only heroin⁶¹ - but whether this is due to differences in the drugs or other differences is unclear.

It has been suggested that low birth weight is due to heroin having an effect on the growth of the unborn child.⁶² Even if this is true (and there is no proof that it is) there are a number of other factors that are often present in opiate users that are known to contribute to low birth weight:

• Premature delivery
• Poor nutrition
• Poverty
• Smoking tobacco.

The neonatal withdrawal syndrome
Between 42% and 95%⁶³ of babies of opiate-using mothers may experience a withdrawal syndrome.

Neonatal withdrawal syndrome is not always directly related to the amount of opiates the mother is taking nor to the amount of opiates in the baby's blood. It normally starts within 48 hours of delivery, but in a small percentage of cases may be delayed for 7-14 days.

Withdrawal symptoms in babies
Symptoms commonly associated with neonatal opiate withdrawal are:

• Irritability and sleep disturbance
• Sneezing
• Fist sucking
• A shrill cry
• Watery stools
• General hyperactivity
• Ineffectual sucking
• Poor weight gain
• Dislike of bright lights.

Symptoms less commonly associated with opiate withdrawal are:

• Yawning
• Vomiting
• Increased mucus production
• Increased response to sound
• And, rarely, convulsions.

Other problems in the newborn that have been associated with methadone use
Other problems that have been reported by some studies as occurring more frequently in the babies of women who are methadone dependent than in the general population are:

• Infant mortality
• Sudden Infant Death Syndrome (SIDS/cot death)
• Jaundice.

Studies often caution that many of the women in their samples have used a variety of drugs during pregnancy and that it is difficult to separate the effects of methadone from the effects of these other drugs.

The modest increase in mortality of babies born to drug-using (i.e. not always just methadone-using) mothers is due to premature birth⁶⁰ and stillbirth in late pregnancy. However there are two factors which may limit the extent to which these studies are relevant: firstly most studies were carried out in the 1970s when the perinatal mortality rate was higher and many were carried out in the USA where health care is very different from that in the UK.

A link between drug addiction and Sudden Infant Death Syndrome (SIDS) has been suggested by a study of 702 infants in which 20 babies died (2.8%) but the authors could not attribute the increase to a single drug.⁵⁹ Another study of 313 babies⁶¹ found no increased prevalence of SIDS from that in the locality. These studies were carried out before the practice of laying babies on their backs to help prevent SIDS became widespread.

Jaundice is comparatively infrequent in the babies of both heroin and methadone-using mothers. It is treatable and usually passes, without harm to the baby.

Respiratory depression at birth
This is not a significant problem for babies born to opiate-tolerant mothers receiving methadone treatment. Studies consistently find that the APGAR scores (the standard measurement of physical well-being at birth) of babies born to women using methadone are comparable to the general population.

Things that methadone does not cause
There are a number of things which methadone does not do which merit listing as they are often assumed (by both drug users and professionals) to be inevitable effects of long-term opiate use.

Therapeutic doses of methadone do not cause:

• Damage to any of the major organs or systems of the body - even in high dose, long-term use
• Significant inco-ordination
• Slurred speech
• Congenital abnormalities in unborn children (see above)
• Reductions in cognitive ability in the way alcohol does.

nor does it:

• Have any anti-convulsant effect - even at high doses
• Effect levels of leuteinising and follicle stimulating hormones in women.⁵²

Long-term effects
The long-term toxic side effects of methadone (in fact all pharmaceutical opiates), if taken in hygienic conditions and in controlled doses, are few and (relative to the risks of alcohol, tobacco or illicit heroin use) benign.

Since the mid 1960s there have been about 1.5 million person years of methadone maintenance in the US alone and there have been thousands of carefully documented research cases⁶⁴ which support M J Kreek's conclusion that:

'Physiological and biochemical alterations occur, but there are minimal side effects that are clinically detectable in patients during chronic methadone maintenance treatment. Toxicity related to methadone during chronic treatment is extraordinarily rare. The most important medical consequence during chronic treatment, in fact, is the marked improvement in the general health and nutrition status observed in patients as compared with their status at the time of admission to treatment.'⁶⁵

The main long-term problems caused, as described below, are tooth decay, constipation and accidental overdose.

Dental decay
Methadone has traditionally come as a syrup-based mixture. Prolonged contact with this sugary liquid has been associated with tooth decay and dental caries, especially towards the front of the mouth.

53% of methadone users on methadone mixture report problematic side effects such as dental problems.⁶⁶ There are 3 ways that methadone mixture can contribute to decay:

• The high sugar content causes the growth of plaque
• The acidic nature of the liquid can cause direct corrosion of the enamel
• Methadone inhibits saliva production and saliva is one of the body's natural defences against plaque.

However there are other possible causes for dental problems in methadone users, such as:

• Pre-existing dental problems
• High sugar diet
• Poor oral hygiene.

Also:

• Methadone is an analgesic which can mask toothache
• Heroin is also a powerful analgesic so toothache may only start to be felt when the user is stabilised on methadone
• Cocaine users also on methadone rub cocaine into their gums to test its purity. Cocaine results in numbness and contaminants damage the surrounding teeth.

Researchers have noticed similar prevalence of dental problems in intravenous heroin users who are not on methadone. This supports the conclusion that poor dental health is endemic among opiate users and that methadone may be exacerbating pre-existing problems rather than causing new ones.⁶⁷

Prevention of tooth decay
Dentists recommend using aqueous-based, sugar-free methadone, especially in long-term methadone treatment. However, more importantly they advise informing users of methadone's potential to harm their teeth and the importance of:

• Low sugar diet
• Good dental hygiene
• Regular check-ups
• Brushing their teeth
• Rinsing the mouth immediately after taking methadone
• Taking methadone mixture through a straw.

Methadone metabolism
Methadone is soluble in body fats called lipids, so it is well absorbed from the gastrointestinal tract into the blood stream. It is primarily broken down in the liver and undergoes fairly extensive metabolism as it passes through the liver for the first time.

It binds very well to albumin and other plasma proteins and also (without causing damage) to various body tissues, especially to the:

• Lungs
• Kidneys
• Liver
• Spleen.

The concentration of methadone in these organs is much higher than in the blood.

There is then a fairly slow transfer of methadone between these stores in the tissues and the blood. For methadone to be active it must be contained in the blood so it can travel to the brain. Even if there are extensive stores elsewhere in the body a client will only feel the effects of methadone actually in the blood.

Methadone metabolites are eliminated in the urine and faeces together with unchanged methadone (about 10% of the methadone administered orally is excreted unchanged).⁷⁰ It is also secreted in sweat and saliva.

Methadone is found in high concentrations in gastric juices. During pregnancy the concentration in the placental cord blood is about half the maternal level.

Half-life
The half-life of a drug is the name given to the time it takes for blood levels of a drug to drop to 50% of the peak concentration. The half-life of diamorphine (heroin) is around 3 minutes. The half-life of methadone depends upon whether it is a first dose or a dose given as part of an ongoing programme.

Single, first dose
The apparent half-life of a single oral dose of methadone is shorter than that in extended use. This is because much of the initial dose becomes distributed into the tissue reservoirs and is therefore not available in the blood stream.

Following ingestion of oral methadone blood levels rise for about 4 hours and then begin to fall. The apparent half-life of a single first dose is 12-18 hours with a mean average of 15 hours.⁶⁸

Single dose of oral methadone

First few days of usage
Over the first 3 days of methadone consumption the 'tissue reservoirs' of methadone in the lungs, kidneys and liver gradually fills. After the first day subsequent doses start from a higher baseline and therefore reach a higher peak. The half-life of the drug reflects only clearance of the drug from the system and is therefore extended to between 13 and 47 hours with a mean average of 25 hours.⁶⁸

This graph illustrates the 3 days it takes for the 'tissue reservoirs' to fill.

First 3 days of dispensing, for oral methadone, with once-daily dosing (doses at 0, 24, 48 hours)

Regular dosing
Once in a steady state variations in blood concentration levels are relatively small. Clients may prefer to take their daily dose at a particular time each day but this makes little difference to their blood levels of methadone.

Methadone's long half-life means that once-daily dosing should theoretically be adequate for clients who have been on a constant oral methadone dose for more than 3 days.

Once-daily dosing of oral methadone at steady state

Missed dose
If one day's dose of methadone is omitted from a regular regime the blood concentration will continue to fall gradually over the 24-48 hour interval.

After 25 hours a person on a regular once-daily dosing regime will have methadone blood levels equal to around half the peak level i.e. 4 hours after dosing. The blood concentration would typically fall to 25% of the peak level after 48 hours.

3 day recovery to steady state from missed dose at day 10

Tolerance

The tolerance developing mechanisms
After daily exposure to opiates people become tolerant⁶⁹, so after a time, the same dose will have a reduced effect on the user.

Tolerance to the different effects that opiates have on the body build up separately - and at different rates - so users may develop complete tolerance to one effect, such as nausea, and virtually none to another, such as constipation.

Tolerance to methadone builds very slowly which is one of the reasons it is used in the treatment of drug dependence. The mechanisms that enable tolerance to develop are not fully understood, but we do know that the number of opiate receptors does not increase.

It seems that the brain's natural biochemical balance is altered by the constant presence of the external opiates. The production of natural opioids is suppressed since their action is reduced, and the rate at which opiates are metabolised increases.⁵⁰ The concentration of other natural neurotransmitters such as noradrenaline and serotonin rises because their effects are being masked by the high level of opiates present. As the levels increase they may begin to counteract the opiate effects.

Tolerance is a combination of three mechanisms which help the body compensate for the constant presence of opiates:

• Neuroadaption - changes at the nerve endings
• Increased metabolism of the drug
• Learning how to compensate for the effects of the drug.

The speed at which opiate tolerance develops
Tolerance to opiates rises more quickly during second and subsequent exposures to the drug.

Tolerance to opiates can develop within 2 weeks of commencement of daily opiate use. Tolerance to methadone develops more slowly than with many opiates and so is rarely a significant problem. Because it is so long-acting blood levels and response to methadone should become fairly constant.

Manifestations of withdrawal symptoms - or the client feeling that their methadone is not enough whilst on a constant dose - are not always to be related to physical tolerance. Other causes include withdrawal from additional illicit opiate use or increased psychological pressures reducing the effects of the methadone dose.

Tolerance to two of methadone's side-effects, pin-point pupils⁶⁸ (miosis) and constipation, develop very slowly indeed (if at all) and both are very often present even after years of treatment.

The speed at which tolerance goes
Tolerance may go as quickly as it develops, so within a week or two of reducing the dose of methadone (or any other opiate) it is possible that tolerance will have dropped and there may be no significant tolerance to the effects of opiates.

This means that people post detox and intermittent users of opiates are at particular risk of overdose.

Cross tolerance
Because opiates act in similar ways withdrawal symptoms can usually be avoided by substituting one for another. This phenomenon is called 'cross tolerance'. The degree of cross tolerance between any two opiate drugs is proportional to the degree of similarity in their sites of action.

An exception to this rule is buprenorphine (Temgesic) which, if substituted for heroin or methadone, can precipitate withdrawals because it excludes them from the receptor sites.

Methadone overdose
In 1992 there were 345 deaths of opiate users attributed directly or indirectly to their opiate use:

• 51 died from heroin overdose
• 131 died from methadone overdose.

Methadone is one of the strongest opiates. It has a slow onset of action and a long half-life and causes severe respiratory depression which is usually the cause of death.

Methadone is relatively available on the illicit market as there are large numbers of tolerant individuals whose daily dose is well over the lethal dose for non-tolerant individuals. This may explain why, of the fatalities above, only 25% had been previously notified to the Home Office, and why methadone overdose deaths among people in treatment are relatively rare.

Dangerous doses

Adults: For non-tolerant adults a dose of 50mg may be fatal.⁷³ The lethal dose is less if methadone is taken in conjunction with alcohol or other sedatives such as benzodiazepines.

Children: 10mg has been fatal⁷² although one child who took 60mg survived. Children are particularly susceptible to the effects of methadone in overdose. Numerous deaths have been reported world-wide.⁷² Children require treatment if they consume any amount of methadone.

Prevention of overdose
Methadone should always be supplied and stored in bottles with 'child-resistant' caps. These bottles should be clearly labelled with the risk of overdose if it is taken by anyone other than the person it is prescribed for and the quantity and strength of methadone they contain.

It is important to remember - and tell clients - that even small children can open bottles with 'child-resistant' caps. Bottles containing methadone should therefore never be left in a position where they could possibly be handled by children.

Methadone users who take their methadone home should always be made aware of the risks. The safe storage of the methadone in the home should always be part of the care plan.

Giving the following advice on the prevention of overdose to methadone users from the very beginning of their treatment can save lives:

• Make sure you are not alone for the first 2-4 hours after taking your first dose of prescribed methadone
• If moving from street drugs to a new methadone prescription beware of celebrating this by using street drugs on top of the new prescription
• Do not use other drugs in addition to your methadone on your own - ask someone to stay with you
• Do not mix methadone with alcohol
• Do not mix methadone with tranquillisers or other drugs.

Signs of methadone overdose

• Nausea and vomiting
• Constricted (pin-point) pupils
• Drowsiness
• Cold clammy blue-ish skin
• Reduced heart rate
• Reduced systolic blood pressure
• Reduced body temperature.

If the dose is large enough, and the person is left untreated, this can lead to:

• Breathlessness
• Respiratory depression with cyanosis (turning blue) and apnoea (stopping breathing)
• Pulmonary oedema (fluid gathering in the lungs)
• Possible convulsions due to hypoxia (lack of oxygen)
• Death.

Low doses of methadone mainly reduce respiratory frequency whilst higher doses also diminish tidal volume. This is because methadone blunts the natural respiratory drive mechanisms.⁶⁸

Treatment of methadone overdose

First aid
Methadone overdose is a serious medical emergency. In the event of suspected overdose call an ambulance.

If the person is losing consciousness lie them on their side in the recovery position so that they will not choke if they vomit.

Inducing people to vomit is not recommended because of the risk of rapid onset of CNS depression/unconsciousness which could lead to choking.

Medical treatment
A doctor should give 50g activated charcoal and observe for at least 24 hours.⁷²

For children give 10-15g activated charcoal. Non-tolerant adults who have consumed more than 30mg of methadone may need a stomach wash-out. Even after 4 hours a stomach wash-out may be worthwhile because of reduced gut motility caused by the methadone.

Adults who are already prescribed methadone may need a stomach wash-out if they take more than twice their daily dose - depending on their tolerance levels and response. There is anecdotal evidence of people taking in excess of four times their normal daily dose and remaining conscious.

Naloxone (Narcan)
This is a short-acting opiate antagonist used to reverse the effects of methadone in overdose. It works by competing with methadone for opiate receptors in the brain.⁷⁴

Naloxone is indicated for use in coma or bradypnoea (very slow breathing) associated with methadone overdose. Repeated increasing doses are required at intervals of 2-3 minutes if respiratory function does not improve. Alternatively an intravenous infusion may be given, the rate of administration being adjusted according to response. The British National Formulary (BNF) contains the appropriate dosage regime.

Because methadone has such a long half-life (mean average 15 hours for one-off dose or 25 hours in regular users) naloxone may be needed for prolonged periods after overdose. Even though the patient has recovered s/he may relapse once the effects of naloxone wear off. It is important to try and observe anyone who has severely overdosed for 24 hours. However any dependant opiate user who has had naloxone administered will experience acute withdrawals and will be likely to discharge themself from hospital.

Supplemental therapy
In patients with severe respiratory depression which does not improve with naloxone mechanical ventilation will be necessary.

Diazepam is the drug of choice for convulsions. Hypotension usually responds to intravenous fluids or inotropes.

Withdrawal symptoms and their causes
For discussion of the other issues related to withdrawal symptoms see also:

• Section 2 - The research basis for methadone prescribing
• Section 7 - Treatment choices
• Section 9 - Methadone detoxification.

The mind and body adjust to the constant presence of opiates, reduction in the levels of opiates can create an imbalance as the body reacts to the change. The symptoms of this imbalance are collectively called the withdrawal syndrome.

The only group of effects that this does not apply to are the histamine-release related effects - as once methadone stops entering and rupturing mast cells there is no longer excess histamine being released.

In long-term use blood concentrations are maintained by release of methadone from stores in body tissues. Therefore the withdrawal syndrome associated with methadone may not occur for 1-2 days after the dose has been lowered/stopped.

People completing in-patient detoxification are likely to experience significant withdrawal symptoms for at least 10 days after their last dose of methadone. Severity of withdrawal is affected by patients' anxiety levels, so informing patients about how their symptoms are likely to vary over time can help reduce this.

Withdrawal symptoms
During methadone treatment (or any long-term opiate use) the activity of the neurones that respond to noradrenaline is reduced. If the opiates are removed there is apparently a surge of activity in the neurones resulting in a rise in the levels of noradrenaline.

It is this physiological process together with raised anxiety levels which are largely responsible for the classic opiate withdrawal characteristics listed below:

• Weakness
• Yawning, sneezing
• Sweating
• High temperature but feeling cold
• Tremors
• Goose bumps
• Insomnia
• Irritability, aggression
• Muscle spasm and jerking (especially at night)
• Diarrhoea
• Nausea, vomiting
• Loss of appetite.

The cause of deep aches that people experience as 'painful bones' in their limbs and lower back is not known.

Reduced blood levels caused by weight gain
Dose reduction is not the only cause of withdrawal symptoms: weight gain is another possible cause of reduced methadone levels.

Methadone is fat soluble. It is stored in fats around the body. If a client's weight changes rapidly there will be simultaneous changes in the blood concentration of methadone. If the fat content of the body rises more methadone will be stored so less is active in the bloodstream. If the fat content falls methadone will be released from stores and become active.

Substantial weight changes may merit proportional dose changes in people who are receiving methadone maintenance treatment, and may need to be taken into account at the start of treatment when the initial dose is being calculated.

Drug interactions

Medical conditions and methadone
As with all opiates methadone causes no damage to any of the major organs. Prolonged use will not cause any direct physical damage other than tooth decay.

Asthma
The action of opiates in releasing histamine (which is a key factor in triggering an asthma attack) means that, in theory, methadone could worsen a pre-existing asthma condition.

This potential risk needs to be weighed against the:

• Stabilising benefits of methadone prescribing which, in reducing stress, may improve the health of someone with asthma
• Effect illicit heroin (with its high peak doses) had on the individual's asthma
• Fact that smoked heroin causes direct irritation of the airways.

Diabetes
Methadone mixture may contain glucose and this can interfere with the control of diabetes. For those clients with diabetes, pharmacists can be asked to dispense a sugar-free preparation.

Epilepsy
Methadone has no anti-convulsant properties, even at high doses.

Other opiates can cause convulsions at very high doses and it is therefore possible that methadone could do the same. If there is a risk of exacerbating existing epilepsy (and there is no evidence that there is) methadone treatment may still improve contact with services, compliance with anti-convulsant therapy as well as making dosage more predictable, and therefore safer, than heroin.

It is important to check which anti-convulsant therapy any client who is epileptic is receiving because carbamazepine and phenytoin interact with methadone (see drug interactions chart above).

Liver disease
Overall, Moore et al⁷⁷ considered that liver damage does not unduly disrupt methadone metabolism. A study by Novick et al⁷⁸ of people with chronic liver disease on long-term methadone maintenance found that dose need not be altered although they suggest that abrupt changes in liver function might require substantial dose adjustments.

However, if a client had extensive and serious liver damage methadone maintenance treatment would, because of the extra strain placed on the organ, be expected to precipitate a condition called porto-systemic encephalopathy.⁵⁵ This is a toxic confusional state caused by the liver failing to metabolise a number of products. This may be temporary and reversable or can result in permanent brain damage.

Therefore, as a precaution, when there may be impaired liver function following hepatitis B or C infection or prolonged alcohol use, methadone dose must be monitored carefully. Particular care must be taken whenever doses of over 50mg are prescribed as there have been a number of overdose deaths reported in the first 2-6 days of treatment and it has been suggested that liver function tests prior to treatment may reduce the risk of overdose.⁶⁹

Pain
Methadone is an analgesic (pain killer) and will therefore mask pain in people who are taking it. The analgesic effect of methadone may fluctuate as the duration of analgesic effect from each dose may well be shorter than its effect in terms of preventing withdrawal symptoms. This could cause pain to break through in the hours before taking the next dose.

Because the disease process may be more advanced than usual before a methadone-using client feels any pain, workers need to be alert to reports of pain. If appropriate they should be investigated promptly in case there is a treatable cause.

It is quite common for opiate users to experience pain if their methadone dose is reduced. This pain may be associated with withdrawal but other causes must be excluded as it may be pain previously masked by high opiate levels.

If not treated, pain may trigger relapse at a later stage, as many opiate users will self-medicate to relieve the discomfort.

If tolerance to opiates is a problem the use of non-opiate analgesia such as aspirin, paracetamol or Non-Steroidal Anti-Inflammatory (NSAIDs) such as ibuprofen may reduce the pain. However it is often difficult to get opiate users - who may have high expectations of analgesics - to accept other treatments.