Issues for surgery
Risk of withdrawal effects and relapse if omitted.
Risk of QT-interval prolongation if continued (see Interactions with common anaesthetic agents and Interactions with other common medicines used in the perioperative period).
Advice in the perioperative period
Elective and emergency surgery
Continue.
Avoid abrupt withdrawal.
It is important to confirm with the patient’s regular pharmacy / key worker their usual dose of methadone and their dosing schedule, i.e. daily collection / supervised consumption. Consideration may need to be given to patients being able to obtain their usual dose if they are on a daily collection schedule.
Perioperative considerations
Consider multi-modal analgesia and regional anaesthesia for pain management. If prescribing opioids patients will need higher doses than opioid naïve patients.
Post-operative advice
Continue.
Review methadone if patient develops a paralytic ileus.
If prolonged Nil by Mouth (NBM) period, or problems with enteral absorption, and methadone is omitted for 3 or more days patient is at risk of overdose due to loss of tolerance; dose reduction will be needed - seek advice from substance misuse team.
Whilst opioid analgesia is not contraindicated in substance misuse patient, alternative forms of analgesia should be considered where possible (see Interactions with common anaesthetic agents below for information on interactions with other opioids). If pain is difficult to manage post-operatively and patient-controlled analgesia or epidural anaesthesia is required seek advice from pain team.
Interactions with common anaesthetic agents
Central nervous system (CNS) excitation (serotonin syndrome)
Some opioids act as weak serotonin reuptake inhibitors (SRIs) and can precipitate serotonin syndrome in conjunction with other serotonergic medication e.g. methadone. Symptoms of serotonin syndrome may occur if methadone is given concomitantly with:
- fentanyl
- pentazocine*
- pethidine
- tapentadol
- tramadol
Patients should be monitored closely and the possibility of serotonin toxicity considered if patients experience altered mental state, autonomic dysfunction or neuromuscular adverse effects with concomitant treatment.
*opioids with mixed agonist/antagonist properties (e.g. pentazocine) may precipitate opioid withdrawal in patients taking pure opioid agonists, such as methadone.
CNS depression
See also Interactions with other common medicines used in the perioperative period.
Methadone has CNS depressant effects which may be additive with other medicines that also have CNS depressant effects such as:
- benzodiazepines
- inhalational anaesthetics and intravenous anaesthetics
- local anaesthetics
- other opioids
(Consult British National Formulary for available drugs in each class).
Bradycardia
Methadone can increase the risk of bradycardia when used concomitantly with the following:
- alfentaninl, fentanyl or remifentanyl
- neostigmine
- propofol
- suxamethonium
QT-interval prolongation
See also Interactions with other common medicines used in the perioperative period.
Cases of QT-interval prolongation and torsades de pointes have been reported during treatment with methadone, particularly at high doses (> 100mg/day). Co-administration with other medicines known to prolong the QT-interval must be based on careful assessment of the potential risks and benefits for each patient.
Anaesthetic agents that may be used in the perioperative period that are known to, or predicted to, prolong the QT-interval include:
- desflurane, isoflurane, sevoflurane – avoid
- thiopental (theoretical)*
*monitor ECG with concurrent use if risk factors for QT-prolongation are also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia).
Interactions with other common medicines used in the perioperative period
CNS excitation (serotonin syndrome)
Opioids
For a discussion of opioids, see Interactions with common anaesthetic agents above.
Methylthioninium chloride (methylene blue)
The MHRA advise that methylthioninium chloride should be avoided in patients taking drugs that enhance serotonergic transmission (e.g. methadone). If concurrent use is necessary the lowest possible dose of methylthioninium chloride should be given and the patients should be closely monitored for signs of CNS toxicity for 4 hours after administration. However, this advice is contested in one report which suggests even doses as low as 1mg/kg may be sufficient to inhibit monoamine oxidase-A, thus causing a reaction.
Other medications
There is also an increased risk of developing serotonin syndrome when trazadone is used concurrently with the following:
- granisetron (also see QT-interval prolongation below)
- ondansetron (also see QT-interval prolongation below)
- linezolid
Monitor patients for symptoms of serotonin syndrome such as fever, tremors, diarrhoea, and agitation. Concurrent treatment should be stopped if serotonin syndrome occurs.
CNS Depression
See also Interactions with common anaesthetic agents.
Methadone has CNS depressant effects, which may be additive with antiemetics that also have CNS depressant effects such as cyclizine, droperidol and prochlorperazine.
Concurrent use need not be avoided, but patients should be monitored for adverse effects, including respiratory depression and hypotension.
QT-interval prolongation
Cases of QT-interval prolongation and torsades de pointes have been reported during treatment with methadone, particularly at high doses (> 100mg/day). Co-administration with other medicines known to prolong the QT-interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase.
Medicines that may be used in the perioperative period that are known to prolong the QT-interval include:
- ciprofloxacin*
- clarithromycin* (also see Macrolides below)
- domperidone – avoid
- droperidol – avoid
- erythromycin (especially intravenous)* (also see Macrolides below)
- granisetron – avoid if risk factor present (see below)
- haloperidol – avoid
- loperamide (increased risk with high doses)*
- ondansetron – avoid
- prochlorperazine*
*monitor ECG with concurrent use if risk factors for QT-interval prolongation also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia).
Corticosteroids
Dexamethasone and hydrocortisone may cause hypokalaemia, increasing the risk of torsades de pointes, which might be additive with the effects of methadone.
Macrolide antibiotics
Clarithromycin, and to a lesser extent erythromycin are inhibitors of cytochrome P450 3A4; methadone is partly metabolised via this pathway therefore clearance of methadone may be decreased. No case reports have been noted, however, it would be prudent to monitor patients for increased and prolonged sedation with concurrent use and adjust methadone dose accordingly.
Opioids
Opioids with mixed agonist / antagonist properties (e.g. buprenorphine, pentazocine) may precipitate opioid withdrawal in patients taking pure opioid agonists, such as methadone.
Methadone might reduce the efficacy of codeine – bare the possibility of an interaction in mind in case of reduced codeine efficacy with concurrent use of codeine and methadone.
Naloxone
Naloxone is an opioid antagonist and can precipitate acute withdrawal syndrome in methadone dependent individuals.
Further information
Hospitals should have local arrangements to guide the supply of methadone to patients during their inpatient stay and at discharge.
References
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 21st May 2019]
Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 21st May 2019]
Summary of Product Characteristics – Methadone 1mg/ml Oral Solution BP – Sugar Free. Thornton & Ross Ltd. Accessed via www.medicines.org.uk 21/05/2019 [date of revision of the text April 2015]