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 gastrointestinal stoma output if omitted.

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

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

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

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

Risk of worse perioperative outcomes if continued (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
For Analgesia
Consideration should be given to reducing the patient’s opioid dose pre-operatively to improve post-operative outcomes(see Further Information).

If this is not possible, continue1 (including non-aspirin containing combination products – see below). Escalation of doses prior to surgery should be avoided.

Confirm brand, dose and frequency with patient and consult British National Formulary to confirm appropriateness of dosing schedule (see Further Information).

Patients should be screened for chronic pain and opioid use pre-operatively and the Oral Morphine Equivalent per 24 hours (OME) of prescribed opioids should be recorded. Opioid tolerance is likely at 60mg OME for ≥ 7 days2.  

For opioid equivalence information please refer to the Faculty of Pain Medicine information ‘Dose equivalents and changing opioids’ available at

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

Combination Products: -


Consideration should be given to prescribing the components of combination products as separate medicines perioperatively, to facilitate review of their appropriateness and encourage deprescribing. See also Post-operative Advice below.

Codeine for Management of High Output Stoma (HOS)

Emergency Surgery
Bear in mind that the dose of aspirin in combination products with codeine is usually > 150mg and may present an increased risk of bleeding (see Non-Steroidal Anti-inflammatory Drugs (NSAIDs) including Cyclo-oxygenase-2 (COX-2) Selective Inhibitors (Oral) monograph for relevance of this).

Perioperative Considerations
Consider multi-modal analgesia and regional anaesthesia as pain management options to reduce the need for further opioids3.

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 temperature3.

Post-operative Advice
For Analgesia
Post-operative use of oral opioids should only be considered if post-operative pain is expected to be moderate or severe or where patients are opioid tolerant (see below). Where indicated, administer an oral opioid as soon as the person can eat and drink after surgery. The dose should be adjusted to help the person achieve functional recovery (such as coughing and mobilising) as soon as possible4. Dosing of opioids should be based on patient age, not weight2.

Patients who cannot take oral opioids, should be offered a choice of patient-controlled analgesia (PCA) or a continuous epidural to relieve pain after surgery, where clinically indicated4.

Combination analgesics such as tablets containing paracetamol with an opioid (e.g. co-codamol) should be avoided post-operatively as the fixed doses do not allow for titration to patient need, or the flexibility required for weaning5.

Opioid Tolerant Patients

  • Consider Acute Pain Team input in the post-operative pain management of opioid tolerant patients2.
  • Continue the patient’s usual baseline opioid including transdermal and long-acting preparations3, 6.
  • Additional immediate-release opioids should be prescribed on a ‘when required’ basis for acute post-operative surgical pain for a short periode.g. 5 days (opioid-tolerant patients may require a greater amount of immediate-release oral opioids than is usually expected3).
  • Utilise multimodal analgesia to optimise pain management4, 6.
  • Caution should be exercised when patient’s regular long-acting opioid preparations are continued with PCA. Modified-release opioids should not be given with epidurals unless on specific advice of the Acute 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 absorption3

Opioid Naïve Patients

  • Immediate-release preparations should be used if opioids are required for acute post-operative pain, with liquid oral morphine being the first line choice2, 6, 7 (avoid long-acting preparations and transdermal preparations6 – see Further Information).
  • Opioid naïve patients are still at risk of PPOU (see Further Information): -
    • preferably avoid use of tramadol (as it is an independent risk factor for PPOU)8.
    • preferably limit opioid use to the duration of pain severe enough to require an opioid.

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

Review opioid if patient develops a paralytic ileus9.

Patients undergoing Gastrointestinal (GI) Stoma Reversal
For patients taking codeine for management of high output stoma (HOS) who undergo GI stoma reversal surgery, review continued need post-operatively.

Prior to Discharge
Good opioid stewardship is necessary to reduce the risk of PPOU and opioid addiction. To reduce the risk of misuse, the quantity prescribed should be based on the expected duration of pain which is severe enough to require an opioid6. Patients and carers should be given appropriate education on safe management of opioid medication2, 5 (see Further Information – an example leaflet can be found at Discharge prescriptions should explicitly state that opioids should not be continued as repeat prescriptions unless clinically indicated.

Opioid Tolerant 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-operatively2.
  • Once the patient’s baseline opioid dose is reached the need for on-going opioid analgesia should be reviewed.
  • De-escalation of opioids (weaning the dose with a view to completely stopping) should occur / be encouraged if the surgery has addressed the cause of the pain2.

Opioid Naïve Patients

  • Opioid naïve patients should NOT be discharged with long-acting opioid preparations7.
  • Use of immediate-release opioid preparations should be limited to a short supply, usually 5 days and no more than 7 days of opioids (including tramadol)2.

  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 as9, 10

  • 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.

** benzodiazepines (and benzodiazepine-like drugs) and opioid medicines (opioids) can both cause respiratory depression; when used together, additive effects on the central nervous system increase the risks of sedation, respiratory depression, coma, and death11 (see Further Information).

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 concomitantly9, 10: -

  • 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 following9: -

  • alfentanil or remifentanil
  • neostigmine
  • propofol
  • suxamethonium

  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)9. 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 reaction10.

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 following9: -

  • 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 occurs9.

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 other medicines that also have CNS depressant effects such as9, 10: -

  • antiemetics (e.g. cyclizinem droperidol and prochlorperazine)
  • gabapentinoids

Gabapentin and Pregabalin
To reduce the risk of CNS depression avoid starting gabapentinoids in gabapentinoid-naïve patients who are already taking opioids unless clinically indicated.

Consider adjusting the dose of gabapentin / pregabalin for patients who are prescribed opioid-containing medication in the post-operative period12, 13 – see also Gabapentin monograph and Pregabalin monograph

Macrolide Antibiotics
Clarithromycin and erythromycin are predicted to increase the exposure to fentanyl and oxycodone9. 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

MHRA Drug Safety Update – Opioids: risk of dependence and addiction (September 2020)11
Following a review of the risks of dependence and addiction associated with prolonged use of opioid medicines (opioids) for non-cancer pain new safety recommendations have been published.

Before prescribing opioids, the following should be discussed with patients2, 5, 11: -

  • the risks and features of tolerance, dependence, and addiction
  • the risk of potentially fatal unintentional overdose, including the signs and symptoms of opioid overdose to be aware of
  • agreement of a treatment strategy, including a plan for end of treatment
  • safe storage and disposal of opioid medication

There should be appropriate pre-operative education for patients providing realistic expectations regarding their pain relief post-operatively. Information should be provided about multimodal analgesia, including non-pharmacological techniques and non-opioid analgesia2, 5. Patients should be provided with written information to advise them and their relatives / carers on the risks of dependence and addiction. A leaflet is available from

MHRA / CHM Advice – Benzodiazepines and opioids: reminder of risk of potentially fatal respiratory depression (March 2020)9 
When opioids are prescribed with benzodiazepine and benzodiazepine-like drugs there is potential for additive CNS depressant effects, thereby increasing the risk of sedation, respiratory depression, coma and death. Co-prescription is advised only if there is no alternative and, if necessary, the lowest possible doses should be given for the shortest duration. Patients should be closely monitored.

Safe prescribing
Some opioids may be available as multiple preparations (e.g. short acting, 12-hour modified release, 24-hour modified release) and / or multiple strengths. Ensure the correct preparation is prescribed9.

MHRA / CHM Advice – Dihydrocodeine with paracetamol (Co-Dydramol): Prescribe and dispense by strength to minimise risk of medication error (January 2018)9
When prescribing dihydrocodeine with paracetamol, the strength and dose must be clearly indicated. The British Pharmacopeia defines Co-Dydramol Tablets as containing dihydrocodeine tartrate 10mg and paracetamol 500mg.

After long-term opioid treatment physical dependence occurs; opioids should be withdrawn gradually to avoid abstinence symptoms9 including malaise, abdominal cramps, yawning and perspiration14.

Long-Acting Opioids
Long-acting opioids (e.g. modified release preparations) have shown no benefit in the management of post-operative pain, and they increase the risk of opioid-induced ventilatory impairment11. Newly prescribed opioids should only be given as immediate-release formulations for post-operative pain, both in hospital and at discharge5.

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 complications15.

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 opioids15.

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 gradual reduction in their opioid dose3 and conversion to an alternative treatment if required.

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 tone6.

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 years. 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 present6.

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 factors6.

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 surgery16. 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 conditions16. An oral morphine equivalent dose of 60mg per day or higher has been associated with an 80% probability of PPOU5.

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 opioids8


  1. Carroll I, Angst M & Clark J. Management of Perioperative Pain in Patients Chronically Consuming Opioids. Regional Anaesthesia and Pain Medicine. 2004; 29(6):576-591
  2. Faculty of Pain Medicine 2021. Surgery and Opioids: Best Practice Guidance 2021. March 2021. Available at
  3. Simpson G & Jackson M. Perioperative management of opioid-tolerance patients. BJA Education. 2017; 17(4):124-128
  4. National Institute for Health and Care Excellence. Perioperative care in adults. NICE Guideline 180. Accessed via 17/08/2021 Published 19th August 2020
  5. Levy N, Quinlan J, El-Boghdadly K et al. An international multidisciplinary consensus statement on the prevention of opioid-related harm in adult surgical patients. Anaesthesia. 2020; 76(4): 520-536.
  6. Schug SA, Palmer GM, Scott DA, Alcock M, Halliwell R, Mott JF; APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine (2020), Acute Pain Management: Scientific Evidence (5th edition), ANZCA & FPM, Melbourne.
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  9. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. [Accessed on 13th February 2022)
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  12. Medicines and Healthcare products Regulatory Agency. Drug Safety Update.  Gabapentin (Neurontin): risk of severe respiratory depression. Published 26th October 2017. Available at [Accessed 1st August 2021]
  13. Medicines and Healthcare products Regulatory Agency. Drug Safety Update.  Pregabalin (Lyrica): reports of severe respiratory depression. Published 18th February 2021. Available at [Accessed 1st August 2021]
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  15. Nguyen L, Sing D & Bozic K. Preoperative Reduction of Opioid Use Before Total Joint Arthroplasty. J Arthroplasty. 2016; 31 (9 Suppl):282-287
  16. Brummett CM, Waljee JF, Goesling J et al. New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg. 2017; 152(6):e170504