Learning objectives

• Definition of opioid tolerance
• Adverse effects of methadone and buprenorphine
• The pre-, peri- and postoperative management of opioid-tolerant or methadon-using patients

Definition and mechanisms

• Opioid tolerance is a process characterized by neuroadaptations that result in reduced drug effects, and more specifically, opioid tolerance is:
  • Characterized by reduced responsiveness to an opioid agonist such as morphine 
  • Usually manifested by the need to use increasing doses to achieve the desired effect
  • A common occurrence in individuals taking high doses of opioids for extended periods
• Addiction to opioids is common among recreational opioid users (heroin), but relatively rare in chronic pain patients
• The six most common clinically used opioids are morphine, oxycodone, hydromorphone, fentanyl, buprenorphine, and methadone
• Successful approaches to pharmacotherapy of opioid addiction continue to rely largely on the substitution of short-acting agonists such as heroin with oral administration of long-acting high-efficacy agonists such as methadone or partial agonists buprenorphine
• Methadone
  • Is a synthetic opioid agonist used as an analgesic for chronic pain (often in rotation with other opioids) and also for opioid dependence
  • A μ-agonist as well as an NMDA-antagonist and monoamine reuptake inhibitor
  • Relieves cravings and removes withdrawal symptoms
  • Detoxification using methadone can be accomplished in less than a month
• Buprenorphine
  • Is an opioid used to treat opioid use disorder, acute pain, and chronic pain
  • A partial agonist at μ-receptors and an antagonist at κ- and δ-receptors
  • It is used in addiction medicine to suppress opioid withdrawal and craving for 24–48 hours

Adverse effects 

Preoperative management

• Obtain a detailed medical history 
• Perform a physical exam
• Obtain pain history and medication history

Perioperative management 

• Assessment and monitoring
  • Assess the overall effectiveness of the pain management
  • Consider other important factors such as the presence of opioid-related side-effects, signs of opioid withdrawal, patient expectations, patient satisfaction, mood, and levels of physical function
• Acute pain management plan
  • Identify complex patients early
  • Adhere to a clear multi-disciplinary pain management plan
  • Consider opioid-sparing techniques
• Opioid-sparing techniques
  • Use paracetamol, NSAIDs or COX-2s
  • Use local, regional, or neuraxial anesthesia where possible
  • Administer ketamine in a low dose as a continuous i.v. or subcutaneous infusion for 1–3 days in the acute pain management of opioid-tolerant patients 
  • Consider the use of:
    • Gabapentinoids (e.g. gabapentin/pregabalin)
    • IV lidocaine infusions
• Prevention of withdrawal
  • Maintain the usual 24-hour opioid dose and continue the patient’s baseline opioid into the postoperative period
  • Convert the dose of oral morphine to i.v. morphine
  • Manage acute post-surgical pain with the addition of an appropriate dose of immediate-release opioids
  • Continue the use of a buprenorphine path (up to 70 µg/h) as this is unlikely to interfere with the use of full opioid agonists
  • The patient may need parenteral replacement if unable to take oral opioids
• Additional opioids
  • Note that opioid-tolerant patients may require a greater amount of immediate-release oral opioids than expected
  • Consider IV patient-controlled analgesia and base the size of the bolus dose on the patient’s usual 24-hour opioid requirement
• Opioid rotation
  • Switch from one opioid to another to improve pain relief and to reduce side-effects
  • Reduce the calculated equianalgesic dose by 30–50% because of the possibility of incomplete crosstolerance
• Converting back from IV to oral opioid
  • Identify the i.v. opioid consumption in the previous 24 hours and convert this to an equivalent oral dose
  • Administer 50% of this oral equivalent dose in a sustained-release form and prescribe 1/6th of the equivalent dose as an immediate-release preparation every four hours
• Opioid tolerance or opioid-induced hyperalgesia
  • Increase the opioid dose or consider an opioid rotation in opioid-tolerant patients
  • Reduce the opioid dose in opioid-induced hyperalgesia patients
• Substance abuse and substitution therapy

Postoperative management

• Methadone
  • Continue preoperative dose
  • Continue the multimodal pain management
• Buprenorphine
  • Continue preoperative dose
  • If not on the maximal dose, increase the dose to 24-32 mg/day, divide the daily dose to every 6-8 hours
  • Continue the multimodal pain management
  • Consider converting buprenorphine to methadone to prevent acute withdrawal

Suggested reading

• Srivastava, D., Hill, S., Carty, S., Rockett, M., Bastable, R., Knaggs, R., Lambert, D., Levy, N., Hughes, J., Wilkinson, P., 2021. Surgery and opioids: evidence-based expert consensus guidelines on the perioperative use of opioids in the United Kingdom. British Journal of Anaesthesia 126, 1208–1216.
• Sritapan Y, Clifford S, Bautista A. Perioperative Management of Patients on Buprenorphine and Methadone: A Narrative Review. Balkan Med J. 2020;37(5):247-252.
• Simpson, G., Jackson, M., 2017. Perioperative management of opioid-tolerant patients. BJA Education 17, 124–128.
• Rajan, J., Scott-Warren, J., 2016. The clinical use of methadone in cancer and chronic pain medicine. BJA Education 16, 102–106.
• Morgan MM, Christie MJ. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol. 2011;164(4):1322-1334. 

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