Symptoms:
Similar to those for morphine.
Respiratory depression, extreme somnolence progressing to stupor or coma, cyanosis, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension are observed.
In severe overdosage, apnoea, circulatory collapse, pulmonary oedema, cardiac arrest and death may occur.
Management:
Treatment is supportive. Patients should be kept conscious wherever possible.
A patent airway must be established with assisted or controlled ventilation. Narcotic antagonists may be required if there is evidence of significant respiratory or cardiovascular depression. However, treatment with these antagonists must be repeated as necessary because of the longer duration of depressant activity of methadone (36 to 48 hours) compared to the antagonists (1 to 3 hours). Nalorphine or Levallorphine should be given intravenously as soon as possible and repeated every 15 minutes if necessary. In a person addicted to narcotics, administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. In such cases, use of an antagonist should be avoided unless there is serious respiratory depression when they should be administered with great care.
Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.
-
- Patients with respiratory depression and obstructive airways disease.
- Use during an acute asthma attack.
- Concurrent administration with monoamine oxidase inhibitors, or within 2 weeks of discontinuation of treatment with them.
- Phaeochromocytoma. Opiates may induce the release of endogenous histamine and stimulate catecholamine release.
- Risk of paralytic ileus.
- Comatose patients.
No major incompatibilities known
Methadone is associated with undesirable effects similar to other opioid analgesics. There are no modern clinical studies available that can be used to determine the frequency of undesirable effects. Therefore, all the undesirable effects listed are classed as “frequency unknownâ€.
Endocrine Disorders:-
Hyperprolactinaemia.
Psychiatric Disorders:-
Dependence, confusion, mood change including euphoria and dysphoria, hallucinations, restlessness, sleep disturbances.
Nervous System Disorders:-
Drowsiness, dizziness, vertigo.
Eye Disorders:-
Dry eyes, visual disturbances such as miosis.
Cardiac Disorders:-
Bradycardia, tachycardia, palpitations, QT prolongation, torsades de pointes.
Vascular Disorders:-
Orthostatic hypotension.
Respiratory, Thoracic & Mediastinal Disorders:
), dry nose.Gastrointestinal Disorders:-
Nausea, vomiting (particularly at the start of treatement), constipation, biliary spasm, dry mouth.
Skin & Subcutaneous tissue Disorders:-
Sweating, facial flushing, rashes (urticaria, pruritus), oedema.
Musculoskeletal, Connective Tissue & Bone Disorders:-
Muscle rigidity
Renal & Urinary Disorders:-
Micturition difficulties, urinary retention, ureteric spasm
Reproductive System & Breast Disorders:-
Decreased libido, dysmenorrhoea, amenorrhoea, sexual dysfunction
General & Administration Site Disorders:-
Hypothermia
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard).
No additional data of relevance to the prescriber.
The treatment of opioid drug addiction as a narcotic abstinence syndrome suppressant ( substitution or maintenance therapy).
This should be part of a broader treatment programme including regular treatment reviews and must be supervised by specialist services
Treatment of moderate to severe pain as an alternative to morphine
Pharmacotherapeutic group: Diphenylpropylamine derivatives. ATC code N07BC02.
Methadone is a drug of addiction and repeated administration can result in dependence and tolerance. Cross-tolerance with other opioids can occur.
It is a synthetic opioid analgesic similar to morphine although less sedative. It acts on the CNS system and smooth muscles via the peripheral nervous system.
The analgesic effect of methadone occurs about 10 to 20 minutes following parenteral administration. Miosis and respiratory depression can occur for more than 24 hours after a single dose. Methadone also reduces heart rate, systolic blood pressure and body temperature. Sedation is seen in some patients receiving repeated doses and sudden cessation of treatment can result in withdrawal symptoms.
Like morphine, it also has effects on bowel motility, biliary tone and secretion of pituitary hormones as well as on cough suppression. Methadone also causes the release of histamine from mast cells resulting in a number of allergic-type reactions.
Absorption
Methadone is rapidly absorbed following intramuscular or subcutaneous injection, however there are wide inter-individual variations.
Distribution
Methadone is widely distributed in the tissues, diffuses across the placenta and is excreted in breast milk. It is extensively protein bound.
Biotransformation
It is metabolised in the liver (forming inactive metabolites) and excreted via the bile and urine.
Elimination
Urinary excretion is pH-dependent, the lower the pH the greater the clearance.
Methadone has a prolonged half-life (15 to 40 hours) and can accumulate on repeated administration.
In the case of elderly or ill patients, repeated doses should only be given with extreme caution. Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2).
It has a long half-life and can therefore accumulate. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.
Tolerance and dependence may occur as with morphine.
Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.
Withdrawal
Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to those with morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.
Respiratory depression
Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two.).
Cardiac effects
Cases of QT interval prolongation and torsade de points have been reported during treatment with methadone, particularly at high doses (>100 mg/d). Methadone should be administered with caution to patients at risk for development of prolonged QT interval, e.g. in case of:
- history of cardiac conduction abnormalities,
- advanced heart disease or ischaemic heart disease,
- liver disease,
- family history of sudden death,
- electrolyte abnormalities, i.e. hypokalaemia, hypomagnesaemia
- concomitant treatment with drugs that have a potential for QT-prolongation,
- concomitant treatment with drugs which may cause electrolyte abnormalities,
- concomitant treatment with cytochrome P450 CYP 3A4 inhibitors.
In patients with recognised risk factors for QT prolongation, or in case of concomitant treatment with drugs that have a potential for QT-prolongation, ECG monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilisation.
ECG monitoring is recommended, in patients without recognised risk factors for QT prolongation, before dose titration above 100 mg/d and at seven days after titration.
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Female addicts who discover they are pregnant will require specialised care from obstetric and paediatric staff with experience in such management. Methadone should not be withdrawn abruptly and infants require careful monitoring for signs of respiratory depression and/or opioid withdrawal.
Hepatic impairment
Special care should be taken with patients with severe liver damage, as there is a risk that methadone might precipitate porto-systemic encephalopathy or precipitate coma.
Renal impairment
Reduce doses to avoid increased and prolonged effect, increased cerebral sensitivity.
Other warnings
Methadone should be used with great caution in patients with acute alcoholism, convulsive disorders and head injuries.
Methadone, as with other opiates, has the potential to increase intracranial pressure especially where it is already raised.
Children (under 16): Even at low doses, methadone is a special hazard to children if ingested accidentally. Children under 6 months, particularly neonates, may be more sensitive to respiratory depression than adults.
The drug should be used with caution in elderly or debilitated patients due to its long half-life. It should also be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, biliary tract disorders, inflammatory or obstructive bowel disorders or myasthenia gravis.
Local reactions at the site of injection can occur and therefore these sites should be inspected regularly. Injections may be painful.
Patients should not drive or use machines while taking methadone.
Methadone may cause drowsiness and reduce alertness and the ability to drive after the administration of methadone.
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
- The medicine is likely to affect your ability to drive
- Do not drive until you know how the medicine affects you
- It is an offence to drive while under the influence of this medicine
- However, you would not be committing an offence (called 'statutory defence') if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
It was not affecting your ability to drive safely
Posology
Adults
In the treatment of opioid drug addiction.
Initially 10- 20mg/day, increasing by 10 - 20mg/day until there is no sign of withdrawal or intoxication. The usual dose is 40 - 60mg/day. The dose is adjusted according to the degree of dependence, with the aim of gradual reduction. Providing a dosage schedule is difficult as it is largely subjective based on the addict's reported drug use and a clinical assessment of their dependence. A cautious approach is usually adopted starting at a low dose and following with incremental increases as judged appropriate bearing in mind the general health of the patient.
In the treatment of moderate to severe pain
Usually 5 - 10mg every 6 - 8 hours although doses should be adjusted according to response. In prolonged use it should not be administered more than twice daily.
Elderly and debilitated patients
In the case of the elderly or ill patients, repeated doses should be given with extreme caution due to the long plasma half-life. There may be a greater risk of respiratory depression, with or without any associated renal or hepatic impairment in this age group.
Paediatric population
As methadone has not been studied in children, it should not be used in children under the age of 16 years until further data becomes available
Hepatic impairment
In patients with severe liver damage, the dose of methadone should be carefully controlled as there is a risk that methadone might precipitate porto-systemic encephalopathy.
Method of administration
Sterile solution for subcutaneous or intramuscular injection. If repeated doses are required the intramuscular route should be used.
The intramuscular route is preferred when repeated administration is required. Volumes greater than 2ml (20mg) may need to be given in divided doses at different sites.
Methadone is controlled under the Misuse of Drugs Act 1971 (Schedule 2).Any unused medicinal product or waste material should be disposed of in accordance with local requirements
