Drugs List

Therapeutic Indications

Uses

Opioid drug dependency - treatment
Pain - moderate to severe

Administration

Give by intramuscular, subcutaneous or intravenous injection only if using high strength preparation.

The intramuscular route is preferred when repeated administration is required. Volumes greater than 2 ml may need to be given in divided doses at different sites. To avoid injection of large volumes, consider higher strengths for patients requiring treatment with larger doses of methadone.

Contraindications

Children under 16 years
Risk of paralytic ileus
Within 2 weeks of discontinuing MAOIs
Acute asthma
Acute respiratory depression
Alcoholism
Coma
Head trauma
Obstetric use
Obstructive pulmonary disease
Phaeochromocytoma
Raised intracranial pressure

Precautions and Warnings

Acute alcohol intoxication
Debilitation
Elderly
Family history of long QT syndrome
Tobacco smoking
Adrenal insufficiency
Asthma
Benign prostatic hyperplasia
Biliary tract disorder
Breastfeeding
Circulatory failure
Gastrointestinal obstruction
History of torsade de pointes
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hypotension
Hypothyroidism
Inflammatory bowel disease
Labour
Long QT syndrome
Myasthenia gravis
Pregnancy
Reduced respiratory reserve
Renal impairment
Seizures
Severe hepatic impairment

May exacerbate asthma
Reduce dose in patients with moderate renal impairment
Advise patient ability to drive or operate machinery may be impaired
Advise patient not to drive until they know how the medicine affects them
Advise patient this medicine is subject to driving restrictions
Gradual titration must precede use of high concentration product
Not all available brands are licensed for all routes of administration
Not all available strengths are licensed for all indications
Reduced plasma level and efficacy in smokers
Treatment to be initiated and supervised by a specialist
Monitor ECG in patients at risk of QT prolongation
Monitor patient for signs and symptoms of respiratory depression
Neonate exposed in utero: Monitor for respiratory depression
Tolerance and dependence may occur
Neonate exposed in labour: Risk of respiratory depression
Avoid abrupt withdrawal
Dose adjustment required if patient starts/stops smoking during therapy
Alcohol may enhance side effects

Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use. Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression.

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two due to accumulation in the tissues.

Accumulation is possible due to its long half life, particularly in the elderly and debilitated. A single dose to relieve symptoms may lead to accumulation and possible death if repeated on a daily basis.

Injection site reactions may occur, inspect these sites regularly. Injections may be painful.

In patients without recognised risk factors for QT prolongation, monitor ECG before dose titration above 100 mg/day and at seven days after titration.

Pregnancy and Lactation

Pregnancy

In pregnancy methadone should only be used with caution and with monitoring of the infant.

Due to its long half-life, methadone is the first choice for substitution therapy for heroin dependency. It has been used safely for many years and is the preferred option for ensuring continuity of care during pregnancy and afterwards. It is recommended the mother should be under the care of an obstetrician and/or a midwife specializing in drug misuse and also supported by the local drug dependency service.

The main problems associated with methadone use by the mother include neonatal narcotic withdrawal syndrome and low birth weight. There is also a reported increased incidence of prematurity, jaundice, thrombocytosis, stillbirths, mortality and Sudden Infant Death Syndrome (SIDS). However methadone has not been associated with congenital malformations.

Maternal withdrawal of methadone during pregnancy should be avoided, as this appears to increase the risk of premature birth, stillbirth and neonatal mortality. The risk of spontaneous abortion is greater during the first trimester. It is therefore advisable to avoid attempts at detoxification at this time. Attempts at opiate withdrawal in the third trimester have caused premature labour. Use for prolonged periods of time, or at high doses, especially at term should also be avoided.

One study found a connection between the severity of neonatal withdrawal and SIDS. Maternal withdrawal during pregnancy has been observed to produce a significant response of the foetal adrenal glands and sympathetic nervous system. An increased stillborn and neonatal mortality rate has also been reported. The available evidence is against detoxification of the mother during gestation particularly in the first and third trimesters. Withdrawal of methadone in the first trimester may result in or be blamed for a miscarriage. Treatment should be stabilised in the first trimester. In the third trimester drug withdrawal should not normally be attempted either as evidence exists that even mild withdrawal can cause foetal stress, distress and stillbirth.

It may be necessary to increase the dose of methadone in pregnancy if withdrawal symptoms develop, in pregnancy increased clearance and reduced plasma levels have been reported.

Methadone should not be used during labour, due to the risk of gastric stasis and inhalation pneumonia in the mother, and foetal distress.

In pregnancy morning sickness may result in the woman vomiting methadone soon after swallowing, and it is essential that the prescription is replaced and a safe antiemetic is given in such circumstances.

In some cases, neonates must be closely observed for many weeks to ensure that delayed severe withdrawal symptoms can be treated. The long term effects of methadone exposure on the infant's behaviour and motor development are not known, but interuterine growth retardation can persist into childhood.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

In breastfeeding methadone should only be used with caution and with monitoring of the infant.

Methadone, like all opioids, is excreted in breast milk. The infant should be monitored for drowsiness, adequate weight gain and developmental milestones, and medical advice should be sought immediately if the infant suffers from increased sleepiness, has difficulty feeding, breathing difficulties or limpness. Particular care should be taken with children with a tendency for apnoea, due to the risk of respiratory depression, and infants should be monitored for somnolence and respiratory problems in the case of repeated doses of methadone. Maternal doses above 100 mg are particularly associated with sedation and respiratory depression in the infant, especially if the infant wasn't exposed in utero.

The studies referred to in Schaefer indicate that methadone is well tolerated during breastfeeding. Breastfeeding should be encouraged, and it is recommended that mothers should breastfeed immediately before a dose in order to avoid peak concentrations of opioid in the breast milk. The mother should be advised to monitor her infant for symptoms of both exposure to methadone and withdrawal symptoms. The evidence suggests breastfeeding infants who have been exposed in utero may decrease neonatal withdrawal symptoms. However, only small amounts are transferred in the milk, so further dosing may be required to prevent neonatal withdrawal symptoms effectively.

A study conducted where eight women breastfed their baby whilst on methadone showed no effects of methadone exposure on the infant during the duration of breastfeeding (2.5 to 21 months) or within the dose range 25 to 180 mg. The estimated mean daily methadone dose in the newborn was 0.05 mg. Other studies consider the amount secreted in breast milk to be negligible.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Amenorrhoea
Biliary spasm
Bradycardia
Confusion
Constipation
Dependence
Difficulty in micturition
Dizziness
Drowsiness
Dry eyes
Dry mouth
Dryness of nose
Dysmenorrhoea
Dysphoria
Euphoria
Facial flushing
Hallucinations
Headache
Hyperprolactinaemia
Hypothermia
Induration (injection site)
Local pain (injection site)
Local reaction at injection site
Miosis
Mood changes
Muscle rigidity
Nausea
Oedema
Orthostatic hypotension
Palpitations
Prolongation of QT interval
Pruritus
Raised intracranial pressure
Rash
Reduced libido
Respiratory depression
Restlessness
Sexual dysfunction
Sleep disturbances
Sweating
Tachycardia
Torsades de pointes
Ureteric spasm
Urinary retention
Urticaria
Vertigo
Visual disturbances
Vomiting

Presentation

Solution for injection containing methadone hydrochloride

Drugs List

Therapeutic Indications

Uses

Opioid drug dependency - treatment
Pain - moderate to severe

Dosage

Opioid dependence

The use of injectable methadone must be initiated by physicians with adequate experience and expertise in addiction therapy.

Treatment must be part of a broader treatment programme, including regular treatment reviews, and must be supervised by specialist services.

The dose of methadone should only be given once or twice a day at most, this is to avoid the risk of accumulation and overdosage.

Adults

Elderly

Patients with Renal Impairment

Patients with Hepatic Impairment

Administration

Give by intramuscular, subcutaneous or intravenous injection only if using high strength preparation.

The intramuscular route is preferred when repeated administration is required. Volumes greater than 2 ml may need to be given in divided doses at different sites. To avoid injection of large volumes, consider higher strengths for patients requiring treatment with larger doses of methadone.

Contraindications

Children under 16 years
Risk of paralytic ileus
Within 2 weeks of discontinuing MAOIs
Acute asthma
Acute respiratory depression
Alcoholism
Coma
Head trauma
Obstetric use
Obstructive pulmonary disease
Phaeochromocytoma
Raised intracranial pressure

Precautions and Warnings

Acute alcohol intoxication
Debilitation
Elderly
Family history of long QT syndrome
Tobacco smoking
Adrenal insufficiency
Asthma
Benign prostatic hyperplasia
Biliary tract disorder
Breastfeeding
Circulatory failure
Gastrointestinal obstruction
History of torsade de pointes
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hypotension
Hypothyroidism
Inflammatory bowel disease
Labour
Long QT syndrome
Myasthenia gravis
Pregnancy
Reduced respiratory reserve
Renal impairment
Seizures
Severe hepatic impairment

May exacerbate asthma
Reduce dose in patients with moderate renal impairment
Advise patient ability to drive or operate machinery may be impaired
Advise patient not to drive until they know how the medicine affects them
Advise patient this medicine is subject to driving restrictions
Gradual titration must precede use of high concentration product
Not all available brands are licensed for all routes of administration
Not all available strengths are licensed for all indications
Reduced plasma level and efficacy in smokers
Treatment to be initiated and supervised by a specialist
Monitor ECG in patients at risk of QT prolongation
Monitor patient for signs and symptoms of respiratory depression
Neonate exposed in utero: Monitor for respiratory depression
Tolerance and dependence may occur
Neonate exposed in labour: Risk of respiratory depression
Avoid abrupt withdrawal
Dose adjustment required if patient starts/stops smoking during therapy
Alcohol may enhance side effects

Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use. Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression.

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two due to accumulation in the tissues.

Accumulation is possible due to its long half life, particularly in the elderly and debilitated. A single dose to relieve symptoms may lead to accumulation and possible death if repeated on a daily basis.

Injection site reactions may occur, inspect these sites regularly. Injections may be painful.

In patients without recognised risk factors for QT prolongation, monitor ECG before dose titration above 100 mg/day and at seven days after titration.

Pregnancy and Lactation

Pregnancy

In pregnancy methadone should only be used with caution and with monitoring of the infant.

Due to its long half-life, methadone is the first choice for substitution therapy for heroin dependency. It has been used safely for many years and is the preferred option for ensuring continuity of care during pregnancy and afterwards. It is recommended the mother should be under the care of an obstetrician and/or a midwife specializing in drug misuse and also supported by the local drug dependency service.

The main problems associated with methadone use by the mother include neonatal narcotic withdrawal syndrome and low birth weight. There is also a reported increased incidence of prematurity, jaundice, thrombocytosis, stillbirths, mortality and Sudden Infant Death Syndrome (SIDS). However methadone has not been associated with congenital malformations.

Maternal withdrawal of methadone during pregnancy should be avoided, as this appears to increase the risk of premature birth, stillbirth and neonatal mortality. The risk of spontaneous abortion is greater during the first trimester. It is therefore advisable to avoid attempts at detoxification at this time. Attempts at opiate withdrawal in the third trimester have caused premature labour. Use for prolonged periods of time, or at high doses, especially at term should also be avoided.

One study found a connection between the severity of neonatal withdrawal and SIDS. Maternal withdrawal during pregnancy has been observed to produce a significant response of the foetal adrenal glands and sympathetic nervous system. An increased stillborn and neonatal mortality rate has also been reported. The available evidence is against detoxification of the mother during gestation particularly in the first and third trimesters. Withdrawal of methadone in the first trimester may result in or be blamed for a miscarriage. Treatment should be stabilised in the first trimester. In the third trimester drug withdrawal should not normally be attempted either as evidence exists that even mild withdrawal can cause foetal stress, distress and stillbirth.

It may be necessary to increase the dose of methadone in pregnancy if withdrawal symptoms develop, in pregnancy increased clearance and reduced plasma levels have been reported.

Methadone should not be used during labour, due to the risk of gastric stasis and inhalation pneumonia in the mother, and foetal distress.

In pregnancy morning sickness may result in the woman vomiting methadone soon after swallowing, and it is essential that the prescription is replaced and a safe antiemetic is given in such circumstances.

In some cases, neonates must be closely observed for many weeks to ensure that delayed severe withdrawal symptoms can be treated. The long term effects of methadone exposure on the infant's behaviour and motor development are not known, but interuterine growth retardation can persist into childhood.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

In breastfeeding methadone should only be used with caution and with monitoring of the infant.

Methadone, like all opioids, is excreted in breast milk. The infant should be monitored for drowsiness, adequate weight gain and developmental milestones, and medical advice should be sought immediately if the infant suffers from increased sleepiness, has difficulty feeding, breathing difficulties or limpness. Particular care should be taken with children with a tendency for apnoea, due to the risk of respiratory depression, and infants should be monitored for somnolence and respiratory problems in the case of repeated doses of methadone. Maternal doses above 100 mg are particularly associated with sedation and respiratory depression in the infant, especially if the infant wasn't exposed in utero.

The studies referred to in Schaefer indicate that methadone is well tolerated during breastfeeding. Breastfeeding should be encouraged, and it is recommended that mothers should breastfeed immediately before a dose in order to avoid peak concentrations of opioid in the breast milk. The mother should be advised to monitor her infant for symptoms of both exposure to methadone and withdrawal symptoms. The evidence suggests breastfeeding infants who have been exposed in utero may decrease neonatal withdrawal symptoms. However, only small amounts are transferred in the milk, so further dosing may be required to prevent neonatal withdrawal symptoms effectively.

A study conducted where eight women breastfed their baby whilst on methadone showed no effects of methadone exposure on the infant during the duration of breastfeeding (2.5 to 21 months) or within the dose range 25 to 180 mg. The estimated mean daily methadone dose in the newborn was 0.05 mg. Other studies consider the amount secreted in breast milk to be negligible.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Effects on Ability to Drive and Operate Machinery

This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988 (England and Wales). This medicine may be subject to police testing and has specified maximum blood levels for driving. When prescribing this medicine: Advise patient the medicine can affect cognitive function and is likely to affect ability to drive. Advise patient not to drive until they know how the medicine affects them. It is an offence to drive while under the influence of this medicine. However, a patient is not committing an offence (called 'statutory defence') if: 1.The medicine has been prescribed to treat a medical or dental problem and 2.The medicine has been taken according to the instructions given by the prescriber and/or in the information provided with the medicine and 3.The medicine was not affecting the ability to drive safely. For further guidance see https://www.gov.uk

Counselling

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.

Patients should be advised that alcohol may enhance the sedative and hypotensive effects of methadone, and increase respiratory depression.

Advise patients to go to their doctor if they start or wish to stop smoking as dosage adjustment may be required. Patients should be told that they may experience a reduced effect and possible withdrawal symptoms if they start smoking or increased effects and possible side effects if they stop smoking without their doctor first modifying their dose.

Advise patient that their ability to drive or operate machinery may be affected by side effects.

Side Effects

Amenorrhoea
Biliary spasm
Bradycardia
Confusion
Constipation
Dependence
Difficulty in micturition
Dizziness
Drowsiness
Dry eyes
Dry mouth
Dryness of nose
Dysmenorrhoea
Dysphoria
Euphoria
Facial flushing
Hallucinations
Headache
Hyperprolactinaemia
Hypothermia
Induration (injection site)
Local pain (injection site)
Local reaction at injection site
Miosis
Mood changes
Muscle rigidity
Nausea
Oedema
Orthostatic hypotension
Palpitations
Prolongation of QT interval
Pruritus
Raised intracranial pressure
Rash
Reduced libido
Respiratory depression
Restlessness
Sexual dysfunction
Sleep disturbances
Sweating
Tachycardia
Torsades de pointes
Ureteric spasm
Urinary retention
Urticaria
Vertigo
Visual disturbances
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: May 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com Accessed on March 24, 2014.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

Summary of Product Characteristics: Methadone 10 mg/ml solution for injection. Wockhardt UK Ltd. Revised March 2007.

Summary of Product Characteristics: Methadone Injection BP 1%. Martindale Pharmaceuticals. Revised March 2009.

Summary of Product Characteristics: Methadone Injection B.P. 10 mg/ml, 1 ml, 2 ml, 5 ml & 10 ml. Mercury Pharma International Ltd. Revised August 2012.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon

Therapeutics in Pregnancy and Lactation (2000) Lee, A., Inch, S. and Finnigan, D. Radcliffe Medical Press, Abingdon.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Methadone Last revised: January 16, 2014.
Last accessed: March 24, 2014.

Gov.uk. Government departments. Department for Transport. Publications. Drug driving and medicine: advice for healthcare professionals. Drug driving: Guidance for healthcare professionals on drug driving. Available at: https://www.gov.uk Last accessed: 6 January 2015

Specialist Pharmacy Service (SPS)
Available at: https://www.sps.nhs.uk/
What are the clinically significant drug interactions with tobacco smoking? Last revised: July 2020
Last accessed: 07 December 2020