Codeine, Dihydrocodeine, Dipipanone, Fentanyl [transdermal], Hydromorphone, Meptazinol, Morphine, Oxycodone, Pentazocine, Pethidine, Tapentadol, Tramadol


[For methadone and buprenorphine see individual monographs]

  Issues for Surgery

Loss of analgesic effect if omitted.

For codeine use in high output stoma – loss of control of stoma output if omitted.

Risk of withdrawal if long-term treatment is abruptly discontinued (see Further Information).

Risk of opioid-induced hyperalgesia and tolerance, secondary to chronic opioid use, if continued (see Further Information).

Risk of worse perioperative outcomes if continued (see Further Information).

Risk of opioid-induced ventilatory impairment (OIVI) if continued.

Risk of persistent post-operative opioid use (PPOU) in both opioid sensitive and opioid naïve patients (see Further Information).

Risk of serotonin syndrome if fentanyl, pentazocine, pethidine, tapentadol or tramadol are continued (see Interaction(s) with Common Anaesthetic Agents and Interaction(s) with other Common Medicines used in the Perioperative Period).

  Advice in the Perioperative period

Elective Surgery

Continue1 (including combination products).

Consideration should be given to reducing the patient’s opioid dose pre-operatively to improve post-operative outcomes (see Further Information).

Specialist pain team input should be obtained for patients with uncontrolled pain despite high opioid doses as this may indicate opioid-induced hyperalgesia or opioid tolerance (see Further Information).

Combination Products: -

  • Co-codamol – contains codeine + paracetamol
  • Remedeine® / Remedeine Forte® – contains dihydrocodeine + paracetamol
  • Dipipanone with cyclizine
  • Migraleve Pink® – contains paracetamol + buclizine hydrochloride + codeine phosphate
  • Skudexa® – contains tramadol + dexketoprofen (also see NSAIDs monograph)
  • Tramacet® – contains tramadol + paracetamol


Consideration should be given to prescribing the components of combination products as separate medicines perioperatively, to facilitate review of their appropriateness and encourage deprescribing.

Emergency Surgery



Perioperative Considerations

Consider multi-modal analgesia and regional anaesthesia as pain management options to reduce the need for further opioids2.

Absorption from a transdermal patch can be increased by heat, e.g. perioperative warming devices, whereas absorption may be reduced if poor perfusion or reduced temperature2.

Post-operative Advice

Opioid Sensitive Patients

  • Continue the patient’s usual baseline opioid including transdermal and modified release preparations2.
  • Additional immediate-release opioids should be prescribed for acute post-operative surgical pain for a short period e.g. 5 days (opioid-tolerant patients may require a greater amount of immediate-release oral opioids than is usually expected2).
  • Utilise multimodal analgesia to reduce reliance on opioids.
  • Regular modified release preparations can be continued with Patient Controlled Analgesia (PCA) but should not be given with epidurals unless on specific advice of Pain Team.
  • Consider intravenous alternatives if patients who usually take oral opioids are not able to take medication orally or if there are concerns regarding absorption2.

Opioid Naïve Patients

  • Immediate release preparations should be used if opioids are required for acute post-operative pain3 (avoid modified release preparations and transdermal preparations)
  • Opioid naïve patients are still at risk of PPOU (see Further Information): -
  • preferably avoid use of oxycodone (as it is more addictive)4.
  • preferably avoid use of tramadol (as it is an independent risk factor for PPOU)5.
  • preferably limit use of immediate release opioids to 5 days.

Ensure adequate laxatives are prescribed to prevent opioid-induced constipation.

Review opioid if patient develops a paralytic ileus6.

Prior to Discharge

Good opioid stewardship is necessary to reduce the risk of PPOU and opioid addiction.

To reduce the risk of misuse, patients should not be prescribed excessive quantities of opioids on discharge5, 7; in addition, they should be advised to return any unused medication to a community pharmacy for safe disposal7. Discharge prescriptions should explicitly state that opioids should not be continued as repeat prescriptions unless reviewed clinically.

Opioid Sensitive Patients

  • Patients should be given advice on weaning any additional opioid analgesia with a view to reducing to their usual opioid dose as soon as possible post-operatively.
  • Once the patient’s baseline opioid dose is reached the need for on-going opioid analgesia should be reviewed; if the surgery has addressed the cause of the pain opioid analgesia should be further weaned with a view to stopping completely1.

Opioid Naïve Patients

  • Opioid naïve patients should NOT be discharged with modified release opioid preparations3.
  • Use of immediate release opioid preparations should be limited to a short supply e.g. 5 days.

  Interaction(s) with Common Anaesthetic Agents


Central Nervous System (CNS) Depression (also see under Interaction(s) with other Common Medicines used in the Perioperative Period and Opioid-Induced Ventilatory Impairment in Further Information)

Opioids have CNS depressant effects which may be additive with other medicines that also have CNS depressant effects such as 6, 8: -

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

*meptazinol and pentazocine have mixed agonist and antagonist properties; adequate analgesia may be difficult to achieve when administering a full opioid agonist.

CNS Excitation (Serotonin Syndrome)

Some opioids act as weak serotonin reuptake inhibitors (SRIs) and can precipitate serotonin syndrome in conjunction with other serotonergic medication. Symptoms of serotonin syndrome may occur if two of the following opioids with serotonergic activity are given concomitantly6, 8: -

  • fentanyl
  • methadone
  • 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.

*meptazinol and pentazocine have mixed agonist and antagonist properties; adequate analgesia may be difficult to achieve when administering a full opioid agonist.


Fentanyl can increase the risk of bradycardia when used concomitantly with the following6: -

  • alfentanil or remifentanil
  • cisatracurium
  • neostigmine

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


CNS Excitation (Serotonin Syndrome)

Methylthioninium chloride (methylene blue)
Some opioids (e.g. fentanyl, pentazocine, pethidine, tapentadol and tramadol) act as weak serotonin reuptake inhibitors (SRIs)6. The MHRA advise that methylthioninium chloride should be avoided in patients taking drugs that enhance serotonergic transmission. 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 reaction8.

Other medications
There is also an increased risk of developing serotonin syndrome when opioids that act as weak serotonin reuptake inhibitors (e.g. fentanyl, pentazocine, pethidine, tapentadol and tramadol) are used concurrently with the following6: -

  • granisetron
  • ondansetron
  • linezolid

Monitor patients for symptoms of serotonin syndrome such as fever, tremors, diarrhoea, and agitation. Concurrent treatment should be stopped if serotonin syndrome occurs6.

CNS Depression (also see under Interaction(s) with Common Anaesthetic Agents and Opioid-Induced Ventilatory Impairment in Further Information)

Opioids have CNS depressant effects which may be additive with antiemetics that also have CNS depressant effects such as cyclizine, droperidol and prochlorperazine6, 8.

Macrolide Antibiotics

Clarithromycin and erythromycin are predicted to increase the exposure to fentanyl and oxycodone6. Whilst single surgical prophylactic doses should not pose a problem, monitor and adjust opioid dose accordingly if a course of macrolide antibiotic is necessary.

  Further Information


After long-term opioid treatment physical dependence occurs; opioids should be withdrawn gradually to avoid abstinence symptoms6 including malaise, abdominal cramps, yawning and perspiration9.

Perioperative Outcomes

Pre-operative chronic opioid use has consistently been associated with worsened perioperative outcomes including higher levels of pain and opioid consumption, worsened post-operative function, prolonged recovery, increased length of stay and higher incidence of complications10.

Patients with a history of chronic opioid use who successfully decreased their use of opioids by at least 50% before arthroplasty surgery had substantially improved clinical outcomes which were comparable to patients not taking opioid10.

Opioid Tolerance and Opioid-induced Hyperalgesia (OIH) 

Opioid tolerance and OIH usually develop after chronic use, but occasionally have been reported after short-term use, and negatively impact upon analgesia. Tolerance means increasing doses of opioid are needed to obtain the same effect; this can often be overcome by rotating opioids. OIH is thought to result from the opioid sensitising the patient to nociception; this results in diffuse and widespread pain and sensitivity which does not respond to an increase in the dose of opioid. Patient’s experiencing OIH should be managed by a reduction in their opioid dose2.

Opioid-Induced Ventilatory Impairment (OIVI)

OIVI may result from depression of respiratory drive with a reduction in respiratory rate or depth of breathing, depression of consciousness and / or depression of supraglottic airway muscle tone11.

Risk factors for OIVI include obesity, sleep-disordered breathing, chronic obstructive pulmonary disease, renal disease, cardiac disease, neurological disorders, patients with ASA status of 3 or 4 and patients aged >65. Risk is further increased by external factors including concomitant administration of other medications with CNS depressant effects (see Interaction(s) with Common Anaesthetic Agents and Interaction(s) with Other Common Medicines used in the Perioperative Period), inadequate monitoring, continuous infusions of opioids and administration of opioids by multiple routes. However, in many cases no identifiable comorbidities are present11.

OIVI continues to cause patient harm in the acute pain setting, including death and hypoxic brain damage but the majority of events are considered preventable with better assessment and monitoring of all patients, not just those with risk factors11.

Persistent Post-operative Opioid Use (PPOU)

New persistent opioid use after surgical interventions is common, with one study finding 5.9% of patients who had minor surgery and 6.5% of patients who had major surgery developed PPOU; this incidence doubled in patients who had received an opioid in the 30 days before surgery12. The similar incidence between minor and major surgery indicates this is unrelated to surgical pain. Risk factors for developing PPOU include tobacco use, alcohol and substance abuse disorders, anxiety, depression, and a history of back pain, arthritis or other pain conditions12.

PPOU can occur with any opioid, not just ‘strong opioids’; indeed, tramadol use has been associated with a higher risk of PPOU than other short-acting opioids5.



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  2. Simpson G & Jackson M. Perioperative management of opioid-tolerance patients. BJA Education. 2017; 17(4):124-128
  3. Levy N & Mills P. Controlled-release opioids cause harm and should be avoided in management of postoperative pain in opioid naïve patients. British Journal of Anaesthesia. 2019; 122(6):e86-e90
  4. Wightman R, Perrone J, Portelli I et al. Likeability and Abuse Liability of Commonly Prescribed Opioids. J. Med. Toxicol. 2012; 8:335-340
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  10. Nguyen L, Sing D & Bozic K. Preoperative Reduction of Opioid Use Before Total Joint Arthroplasty. J Arthroplasty. 2016; 31 (9 Suppl):282-287
  11. Australian and New Zealand College of Anaesthetists. Position statement on the use of slow-release opioid preparations in the treatment of acute pain (2018). Available at: [Accessed on 28th September 2019]
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