UK Clinical Pharmacy Association

Buprenorphine

(sublingual, transdermal, subcutaneous)

Issues for surgery

For pain relief

Loss of analgesic effect if omitted.

Risk of withdrawal if long-term treatment 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 if continued (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).

For opioid dependence

Risk of withdrawal, relapse and accidental overdose (if relapses) if omitted. Re-initiation would be physically painful as patient would need to withdraw from other opioids before buprenorphine could be restarted.

For Buvidal® only

Risk of QT-interval prolongation if 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 pain relief (transdermal or low-dose sublingual buprenorphine):

Continue.

Transdermal patch should be left in situ; at doses up to 70microgram/hour it is unlikely to interfere with the use of full opioid agonists for acute pain management.

For opioid dependence (sublingual or subcutaneous buprenorphine)

Continue, including combination product (see Further information for rationale).

For patient taking sublingual buprenorphine >12mg daily for opioid dependence some sources would advise tapering the dose 2 to 3 days pre-operatively following discussion with Substance Misuse team; however, a recently published clinical practice advisory indicates buprenorphine should be continued pre-operatively irrespective of the dose (see Further information).

Combination product:

Suboxone®: contains buprenorphine + naloxone. See Further information regarding the use of buprenorphine for opioid dependence.

Emergency surgery

For pain relief

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, continue.

Transdermal patch should be left in situ; at doses up to 70microgram/hour buprenorphine is unlikely to interfere with the use of full opioid agonists for acute pain management. 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 days.  

For opioid equivalence information please refer to the Faculty of Pain Medicine information ‘Dose equivalents and changing opioids’ available at https://fpm.ac.uk/opioids-aware-structured-approach-opioid-prescribing/dose-equivalents-and-changing-opioids.  

Specialist pain team input should be obtained for patients with complex pain management2 and patients with uncontrolled pain despite high opioid doses as this may indicate opioid-induced hyperalgesia or opioid tolerance (see Further Information). 

For opioid dependence

Continue, including combination product.

Combination product:

  • Suboxone®: contains buprenorphine + naloxone. See Further Information regarding the use of buprenorphine for opioid dependence.

Perioperative considerations

For pain relief

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

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

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 to overcome the binding affinity of buprenorphine.

Post-operative advice

Review buprenorphine if patient develops a paralytic ileus.

For pain relief

Transdermal buprenorphine patches are not suitable for acute pain or in those patients whose analgesic requirements are changing rapidly because the long time to steady state prevents rapid titration of the dose.

Adjunct analgesia (e.g. Non-Steroidal Anti-inflammatory Drugs [NSAIDs], paracetamol, gabapentin / pregabalin) should be first-line for post-operative pain, where appropriate. If inadequate analgesia persists additional immediate-release full agonist opioids (morphine or fentanyl) should be prescribed for post-operative surgical pain (rather than increasing the strength of the patch) but the patient’s usual buprenorphine dose should be continued. If pain is still problematic, consider reducing buprenorphine dose; in which case, monitor patient for 24 hours if receiving reduced buprenorphine dose while prescribed a full opioid agonist (see Interactions(s) with common anaesthetic agents).

Where possible, patients should be discharged on their usual medication; but if strictly necessary, they may be discharged with a limited prescription of full opioid agonist in addition to their usual / a reduced dose of buprenorphine. A clear management plan should be communicated to the GP to ensure this combination is not continued long-term.

Transdermal patches are available as 72-hourly, 96-hourly and 7-day formulations; prescribers must ensure that the correct preparation is prescribed.

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

Review opioid if patient develops a paralytic ileus. 

For opioid dependence

If prolonged Nil by Mouth (NBM) period, or problems with enteral absorption, and buprenorphine is omitted for three or more days, the patient is at risk of overdose due to loss of tolerance; dose reduction will be needed. Seek advice from the Substance Misuse Team.

Whilst opioid analgesia is not contraindicated in substance misuse patients, alternative forms of analgesia should be considered where possible. Adjunct analgesia (e.g. Non-Steroidal Anti-inflammatory Drugs [NSAIDs], paracetamol, gabapentin / pregabalin) should be first-line for post-operative pain, where appropriate. If inadequate analgesia persists additional immediate-release full agonist opioids (morphine or fentanyl) should be prescribed for post-operative surgical pain but the patient’s usual dose of buprenorphine should be continued. If pain is still problematic, consider reducing buprenorphine dose; in which case, monitor patient for 24 hours if receiving reduced buprenorphine dose while prescribed a full opioid agonist (see Interaction(s) with common anaesthetic agents).

Where possible, patients should be discharged on their usual medication, but if strictly necessary, they may be discharged with a limited prescription of full opioid agonist in addition to their usual / a reduced dose of buprenorphine. Discuss with the patient’s Substance Misuse Team as this may impact upon their usual prescription and require additional follow up in the community.

Interaction(s) with common anaesthetic agents

Central nervous system (CNS) depressant effects

(Also see under Interaction(s) with other common medicines used in the perioperative period and Opioid-induced ventilatory impairment in Further information)

Buprenorphine 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)

*Buprenorphine has mixed agonist and antagonist properties; adequate analgesia may be difficult to achieve when administering a full opioid agonist. The potential to overdose with a full agonist exists, especially when attempting to overcome buprenorphine partial agonist effects or when buprenorphine plasma levels are declining.

QT-interval prolongation (Buvidal® only)

(also see under Interactions(s) with common anaesthetics agents and Opioid-induced ventilatory impairment in Further information)

Co-administration of Buvidal® subcutaneous prolonged release injections 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.

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
  • thiopental (theoretical).

The possibility of QT-interval prolongation with concomitant administration of Buvidal® and the above listed medications is only theoretical; however, it may be prudent to 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).

Interaction(s) with other common medicines used in the perioperative period

CNS depressant effects

(Also see under Interactions(s) with common anaesthetics agents and Opioid-induced ventilatory impairment in Further information)

Buprenorphine has CNS depressant effects, which may be additive with antiemetics that also have CNS depressant effects such as:

  • antiemetics (e.g. cyclizine, droperidol and prochlorperazine)
  • gabapentinoids

Gabapentinoids

To reduce the risk of CNS depression avoid starting gabapentinoids (gabapentin, pregabalin) in gabapentinoid-naïve patients who are already taking opioids unless clinically indicated.

Macrolide antibiotics

Clarithromycin and erythromycin are predicted to increase buprenorphine concentrations (by inhibition of CYP3A4).

Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring and possibly buprenorphine dose reduction.

QT-interval prolongation (Buvidal® only)

(Also see under Interactions(s) with common anaesthetics agents and Opioid-induced ventilatory impairment in Further information)

Co-administration of Buvidal® subcutaneous prolonged release injections 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.

Anaesthetic agents that may be used in the perioperative period that are known to, or predicted to, prolong the QT-interval include:

  • ciprofloxacin
  • clarithromycin
  • domperidone
  • droperidol
  • erythromycin (especially intravenous)
  • granisetron
  • haloperidol
  • loperamide (increased risk with high doses)
  • ondansetron
  • prochlorperazine

The possibility of QT-interval prolongation with concomitant administration of Buvidal® and the above listed medications is only theoretical; however, it may be prudent to 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).

Further information

Withdrawal

Chronic use of buprenorphine may result in physical dependence so abrupt discontinuation may precipitate withdrawal. This may be delayed in onset, usually beginning after two days, and may last up to two weeks. Although generally mild, symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.

Rationale for continuing buprenorphine pre-operatively

Buprenorphine is a mixed agonist and antagonist; due to concerns about achieving satisfactory analgesia post-operatively early recommendations in the literature advised stopping pre-operatively. However, this increases the risk of withdrawal, relapse and potentially overdose if patient relapses.

Receptor binding studies show reduced but conserved availability of μ-opioid receptors in patients taking buprenorphine. Patients receiving 2mg daily have 59% of μ-opioid receptors available, this reduces to 20% at 16mg daily and 16% at 32mg. It has previously been proposed that tapering to a dose of 12mg daily will increase μ-opioid receptor availability; however, this was only recommended to start a few days prior to surgery to reduce the risk of relapse. Moreover, a recently published clinical practice advisory advocates continuing buprenorphine pre-operatively, regardless of dose. It suggests the buprenorphine dose should only be reduced post-operatively if pain cannot be managed by addition of adjunct analgesia and a full opioid agonist.

MHRA Drug Safety Update – Opioids: risk of dependence and addiction (September 2020)

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 patients:

  • 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 analgesia. 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 https://www.britishpainsociety.org/static/uploads/resources/files/pain_management_print-ready_atwork_2.pdf

Perioperative outcomes 

Pre-operative chronic opioid use for pain relief 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 complications. 

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 opioids. 

MHRA / CHM Advice – Benzodiazepines and opioids: reminder of risk of potentially fatal respiratory depression (March 2020)  

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 

Buprenorphine is are available in multiple strengths and preparations. Ensure the correct preparation is prescribed and at the appropriate frequency. 

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 dose 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 tone. 

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 present. 

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 PPOU.  

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 opioids. 

Buprenorphine for opioid dependence

It is important to confirm with the patient’s regular pharmacy / key worker their usual dose of buprenorphine and their dosing schedule i.e. daily collection / supervised consumption.

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

References

Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 7th November 2021]

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 

Goel A, Azargive S, Weissman J et al. Perioperative Pain and Addiction Interdisciplinary Network (PAIN) clinical practice advisory for perioperative management of buprenorphine: results of a modified Delphi process. British Journal of Anaesthesia. 2019; 123(2):e333-e342

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 7th November 2021]

Lembke A, Ottestad E & Schmiesing C. Patients maintained on buprenorphine for opioid use disorder should continue buprenorphine through the perioperative period. Pain Medicine. 2019; 20:425-428

Lewis N & Williams J. Acute pain management in patients receiving opioids for chronic and cancer pain. Continuing Education in Anaesthesia, Critical Care & Pain. 2005; 5(4):127-129 

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. https://doi.org/10.1111/anae.15262  

Martin Y, Pearson A, Tranchida J et al. Implications of uninterrupted preoperative transdermal buprenorphine use on postoperative pain management. Regional Anaesthesia & Pain Medicine. 2019; 44:342-347

Medicines and Healthcare products Regulatory Agency. Drug Safety Update. Gabapentin (Neurontin): risk of severe respiratory depression. Published 26th October 2017. Available at www.gov.uk [Accessed 1st August 2021] 

Medicines and Healthcare products Regulatory Agency. Drug Safety Update. Opioids: risk of dependence and addiction. Published 23rd September 2020. Available at www.gov.uk [Accessed 27th February 2022] 

Medicines and Healthcare products Regulatory Agency. Drug Safety Update. Pregabalin (Lyrica): reports of severe respiratory depression. Published 18th February 2021. Available at www.gov.uk [Accessed 1st August 2021] 

Nguyen L, Sing D & Bozic K. Preoperative Reduction of Opioid Use Before Total Joint Arthroplasty. J Arthroplasty. 2016; 31 (9 Suppl):282-287 

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. 

Simpson G & Jackson M. Perioperative management of opioid-tolerance patients. BJA Education. 2017; 17(4):124-128

Summary of Product Characteristics – Reletrans® (buprenorphine) 5 microgram/hour transdermal patch. Sandoz Limited. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text February 2019]

Summary of Product Characteristics – Buvidal® (buprenorphine) 8/16/24/32 mg prolonged-release solution for injection. Camurus AB. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text June 2019]

Summary of Product Characteristics – Suboxone® (buprenorphine + naloxone) Tablets 2mg/0.5mg. Indivior UK Limited. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text May 2018]

Summary of Product Characteristics – Subutex® (buprenorphine) 0.4 mg sublingual tablets. Indivior UK Limited. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text February 2019]

Summary of Product Characteristics – Temgesic® (buprenorphine) 200 microgram Sublingual tablets. Indivior UK Limited. Accessed via www.medicines.org.uk 07/09/2019 [date of revision of the text July 2015]