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
The approved name of methadone hydrochloride is:
The methadone molecule can be drawn like this:
There appear to be two separate active sites in the molecule:
It is soluble in:
It does not dissolve in ether.
The effects of methadone
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:
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:
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
Opiate effects on the peripheral nervous system
Histamine release-related effects
Other reported associated effects for which there is either no identified or proven causal effect
Effects on the foetus and young child
The mechanism thought to be responsible for each of these catagories of effects is described below.
Opiate effects on the central nervous system
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
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:
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.
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:
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
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:
Underlying anxiety or other mental health problems is often a useful topic for discussion between worker and client.
Nausea and vomiting
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:
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.
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
Arms and legs feeling heavy
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
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
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.
Small pupils (miosis)
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
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
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:
It also causes:
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.
Other reported effects
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
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
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
Swelling of feet and ankles
Increased anxiety could have a number of causes such as:
The experience of many opiate users is of reduced anxiety during methadone treatment.
Other factors could include:
Effects on babies
Overall risk to babies of women using prescribed methadone
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:
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:
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
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.
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:
The neonatal 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 less commonly associated with opiate withdrawal are:
Other problems in the newborn that have been associated with methadone use
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
Things that methadone does not cause
Therapeutic doses of methadone do not cause:
nor does it:
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:
The main long-term problems caused, as described below, are tooth decay, constipation and accidental overdose.
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:
However there are other possible causes for dental problems in methadone users, such as:
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
It binds very well to albumin and other plasma proteins and also (without causing damage) to various body tissues, especially to the:
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.
Single, first dose
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
First few days of usage
This graph illustrates the 3 days it takes for the 'tissue reservoirs' to fill.
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.
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.
The tolerance developing mechanisms
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:
The speed at which opiate tolerance develops
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
This means that people post detox and intermittent users of opiates are at particular risk of overdose.
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 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.
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
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:
Signs of methadone overdose
If the dose is large enough, and the person is left untreated, this can lead to:
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
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.
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 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.
Diazepam is the drug of choice for convulsions. Hypotension usually responds to intravenous fluids or inotropes.
Withdrawal symptoms and their causes
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.
It is this physiological process together with raised anxiety levels which are largely responsible for the classic opiate withdrawal characteristics listed below:
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
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.
Medical conditions and methadone
This potential risk needs to be weighed against the:
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).
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
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.