Issues for Surgery

For opioid dependence – risk of withdrawal effects and relapse if omitted.

For pain relief– risk of loss of pain control if omitted.

  Advice in the Perioperative period

Elective and Emergency Surgery


Avoid abrupt withdrawal1.

See Further Information regarding the use of methadone for opioid dependence.

Perioperative Considerations

For Opioid Dependence
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


Review methadone if patient develops a paralytic ileus1.

For Opioid Dependence
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 needed1 - 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 Interaction(s) with Common Anaesthetic Medications 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.

  Interaction(s) 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 with1, 2: -

  • 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 treatment1.

*opioids with mixed agonist / antagonist properties (e.g. pentazocine) may precipitate opioid withdrawal in patients taking pure opioid agonists, such as methadone1

CNS Depression (see also Interaction(s) 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 as1: -

  • benzodiazepines
  • inhalational anaesthetics and intravenous anaesthetics
  • local anaesthetics
  • other opioids

(Consult British National Formulary for available drugs in each class)


Methadone can increase the risk of bradycardia when used concomitantly with the following1: -

  • alfentaninl, fentanyl or remifentanyl
  • cisatracurium
  • neostigmine

  Interaction(s) with other Common Medicines used in the Perioperative Period


CNS Excitation (Serotonin Syndrome)

For a discussion of opioids see under Interaction(s) 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)2. 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 reaction2.

Other Medications
There is also an increased risk of developing serotonin syndrome when trazadone is used concurrently with the following1: -

  • 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 occurs1.

CNS Depression (also see under Interaction(s) 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 prochlorperazine1, 2.

Concurrent use need not be avoided, but patients should be monitored for adverse effects, including respiratory depression and hypotension1, 2, 3.

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)2, 3. 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 increase2.

Medicines that may be used in the perioperative period that are known to prolong the QT-interval include2: -

  • 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)


Dexamethasone and hydrocortisone may cause hypokalaemia, increasing the risk of torsades de pointes, which might be additive with the effects of methadone1.

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 accordingly2.


Opioids with mixed agonist / antagonist properties (e.g. buprenorphine, pentazocine) may precipitate opioid withdrawal in patients taking pure opioid agonists, such as methadone2, 3.

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 methadone2.


Naloxone is an opioid antagonist, and can precipitate acute withdrawal syndrome in methadone dependent individuals3.

  Further Information

Methadone for Opioid Dependence

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.

Hospitals should have local arrangements to guide the supply of methadone to patients during their inpatient stay and at discharge.


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. [Accessed on 21st May 2019]
  2. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. [Accessed on 21st May 2019]
  3. Summary of Product Characteristics – Methadone 1mg/ml Oral Solution BP – Sugar Free. Thornton & Ross Ltd. Accessed via 21/05/2019 [date of revision of the text April 2015]