- methadone hydrochloride
POM: Prescription only medicine
This information is intended for use by health professionals
Adults:10 - 20mg (10 - 20ml) should be taken as an initial daily dose by oral administration. The dose should be increased cautiously by 10 - 20mg daily until no signs of withdrawal or intoxication occur. The usual dose for maintenance is 40 - 60mg daily. The dose can then be gradually decreased, when appropriate, until total withdrawal is achieved.
Elderly:Methadone mixture should be used cautiously in elderly patients.
Children:Not recommended for use in children.
Interactions potentiating the effects of methadone;Cytochrome P450 3A4 inhibitors: methadone clearance is decreased when co-administered with drugs which inhibit CYP3A4 activity, such as some anti-HIV agents, macrolide antibiotics, cimetidine, ciprofloxacin and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).Cimetidine and phenytoin may lead to potentiation of opioid activity due to displacement of methadone from protein binding sites. However, as phenytoin is also a hepatic enzyme inducer, it may lower plasma methadone levels (see below).Fluvoxamine may increase plasma concentrations of methadone.The depressant effects of methadone are likely to be enhanced by depressants of the CNS, such as other opioid analgesics, alcohol (see section 4.3), anaesthetics, antipsychotics, anxiolytics, hypnotics and sedatives, major and minor tranquilisers and phenothiazines. As well as CNS depression, there may be respiratory depression and/or hypotension. Tricyclic antidepressants may exert a similar effect.
Interactions reducing the effects of methadone;The opioid antagonists, naloxone and naltrexone, will precipitate an acute withdrawal syndrome in methadone-dependent individuals. Naloxone will also antagonise the analgesic, CNS and respiratory depressant effects of methadone.Buprenorphine and pentazocine may also rapidly precipitate withdrawal symptoms in patients addicted to methadone.The hepatic enzyme-inducing drugs, nevirapine, rifampicin (and other rifamycins), phenytoin, phenobarbital and carbamazepine may lower plasma methadone levels and produce symptoms of withdrawal in methadone dependent patients. Similar effects have been reported with efavirenz nelfinavir, ritonavir and possibly abacavir.Urinary acidifiers: Acidification of the urine will increase the rate of elimination of methadone by the kidney thereby reducing plasma concentrations.
Effects of methadone on other drugs;Methadone may increase plasma desipramine levels and increase desipramine side-effects when given concurrently. Zidovudine methadone may increase the plasma concentrations of zidovudine.Mexiletine methadone may delay mexiletine absorption.Metoclopramide and domperidone the gastrointestinal effects may be antagonised by methadone.Methadone treatment has been found to decrease the rate of absorption and decrease the bioavailability of the nucleoside reverse transcriptase inhibitors didanosine and to a lesser extent stavudine.
Other important interactions;In patients taking drugs affecting cardiac conduction or drugs which may affect electrolyte balance, there is a risk of cardiac events when methadone is taken concurrently.As serious and sometimes fatal reactions have occurred following administration of pethidine to patients receiving MAOIs, other drugs related to pethidine are contraindicated in patients taking MAOI's (including moclobemide) or within 14 days of stopping such treatment, (see section 4.3) as there is a risk of CNS excitation or depression. Cross tolerance and cross dependence can be expected between other opioids acting at the same receptors.
Pregnancy:There is no or inadequate evidence of safety in human pregnancy, but the drug has been widely used for many years without apparent ill consequence and animal studies have not shown any hazard.Methadone should only be used in pregnancy if the physician considers that the potential benefits outweigh the risks. It should be used cautiously under the close supervision of a physician if the physician considers it essential to continue or initiate (in the case of an i.v. opioid user) methadone maintenance.It may be necessary to increase the dose of methadone if withdrawal symptoms develop as increased clearance and reduced plasma levels have been reported during pregnancy.Infants of methadone-maintained mothers may experience symptoms of withdrawal in utero and following birth.Methadone should not be used during labour as the prolonged duration of action increases the risk of neonatal depression.
Lactation:Methadone is excreted in breast milk. A decision must be made whether to discontinue breastfeeding or discontinue the methadone therapy.
Blood and lymphatic system disordersLymphocytosis
Endocrine disordersAdrenal insufficiency, increased prolactin concentrations, decreased testosterone concentrations
Psychiatric disordersDependence, hallucinations, confusion, mood changes including dysphoria, decreased libido
Nervous system disordersMethadone may increase intra-cranial pressure, particularly when it is already raised. Dizziness, headache, drowsiness
Ear and labyrinth disordersVertigo
Cardiac disordersCases of QT prolongation and torsade de pointes have been rarely reported. Bradycardia, palpitations, tachycardia
Vascular disordersHypotension, facial flushing
Respiratory, thoracic and mediastinal disordersRespiratory depression, Exacerbation of existing asthma
Gastrointestinal disordersNausea, vomiting, constipation, dry mouth
Hepatobiliary disordersBiliary spasm
Skin and subcutaneous tissue disordersRashes, pruritus, urticaria, excessive sweating
Renal and urinary disordersDifficulty in micturation, ureteric spasm, antidiuretic effect
Reproductive system and breast disordersErectile dysfunction, reductions in the ejaculate volume and seminal vesicular and prostatic secretions
General disorders and administration site conditionsAbrupt cessation or reduction of the dose of methadone will result in symptoms of withdrawal. In prolonged use it should not be administered more than twice daily to avoid the risk of accumulation and overdosage.Hypothermia.
InvestigationsGlobulins increased, blood albumin increased
Reporting of suspected adverse reactionsReporting 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 at: www.mhra.gov.uk/yellowcard.
SymptomsOverdosage of methadone is characterised by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), pulmonary oedema, extreme somnolence, progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The presence and signs of drug abuse supports the diagnosis.In children, methadone overdose produces drowsiness, floppiness, constricted pupils and apnoea.In severe overdosage, particularly by the intravenous route, apnoea, circulatory collapse, cardiac arrest and death may occur.
Emergency proceduresIf ingestion is recent, gastric aspiration and lavage can be employed after acute poisoning.Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Narcotic antagonists can be used to counteract the potentially lethal respiratory depression in a nontolerant individual, especially a child. Methadone is, however, a long-acting depressant (36-48 hours) whereas the antagonists act for much shorter periods (1-3 hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and treated repeatedly with the narcotic antagonist as needed. If the respiratory depression is only due to overdosage with methadone, the use of other respiratory stimulants is not indicated.An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Intravenously administered narcotic antagonists (naloxone, nalorphine or levallorphan) can be used to reverse signs of intoxication and should be given repeatedly until the patient's status remains satisfactory.Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. The use of a narcotic antagonist in such a person should be avoided if possible. If it must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.Patients should be monitored for signs of relapse for at least 48 hours.