FRCA Notes

Pain Management in the Opioid-Tolerant Patient

The curriculum asks for knowledge on "techniques for the management of acute pain in those on background large dose opioids", including in "long term opiate users and substance misuse".

A CRQ on pain & opioid tolerance (September 2025) was well answered although marks were dropped on the risk factors for opioid tolerance (dose and duration) and the definition of opioid-induced hyperalgesia.

A CRQ on opioid stewardship (February 2024) showed poor knowledge of opioid equivalence and the perioperative management of fentanyl patches.

Resources

  • The number of patients taking long-term opioids for chronic non-cancer pain, cancer pain or as substitution therapy is increasing
  • Standard post-operative analgesic regimens are designed for the opioid-naïve patient and are often inadequate in this group

  • Compared with opioid-naïve patients, opioid-tolerant patients:
    • Report higher rest and dynamic pain scores
    • Use 2 - 3x more opioid via PCA
    • Need more frequent reviews and prescription changes
  • Staff may be apprehensive about giving large opioid doses
  • Under-treatment, however, can lead to opioid-seeking behaviour which is misperceived as 'manipulative', damaging the doctor-patient relationship

  • The three aims of perioperative management are to:
    1. Prevent opioid withdrawal
    2. Provide effective analgesia
    3. Ensure continuity of care in the community after discharge
  • No attempt should be made to withdraw opioids during the perioperative period

Definitions

  • Tolerance: exposure to a drug results in a reduced effect, or a higher dose is needed to maintain the same effect; predictable and physiological
  • Physical dependence: stopping, reducing or reversing the drug causes a withdrawal syndrome; predictable and physiological
  • Cross-tolerance: tolerance to one drug causes tolerance to structurally similar drugs of the same class; this is often incomplete between opioids
  • Opioid-induced hyperalgesia (OIH): a state of nociceptive sensitisation secondary to opioid exposure, often with a more diffuse and widespread pattern of pain
  • Further definitions (addiction, pseudoaddiction) are covered on the substance misuse page

Tolerance vs. opioid-induced hyperalgesia

  • Both present as inadequate analgesia, and can be difficult to distinguish from each other or from progression of the underlying disease
  • Tolerance: analgesia improves with an increased dose or opioid rotation
  • OIH: pain is not improved by increasing the dose; treatment paradoxically requires an opioid dose reduction
  • Both are thought to involve NMDA receptor activation, glial cell activation and altered intracellular opioid signalling (see opioid-induced hyperalgesia)

Risk factors for tolerance

  • The key factors are the dose and duration of opioid use
  • Tolerance, dependence and withdrawal may occur in patients taking strong opioids, or high doses of weak opioids (e.g. codeine >120mg/day, tramadol >400mg/day), for more than 2 weeks pre-operatively
  • Two-thirds of patients taking >120mg/day oral morphine equivalent, or treated for >3 months, will continue their opioids for years
  • Tolerance can also develop with short-term use of high-potency opioids (e.g. remifentanil), although evidence is conflicting

Risk of harm

  • Compared with <20mg/day oral morphine equivalent, doses of >50mg/day and >100mg/day carry a 3.7x and 8.9x greater risk of overdose respectively
  • Wider opioid-related harms are covered on the opioid-related harm page

Equianalgesic conversion

  • Equianalgesic tables are based on small, single-dose studies in healthy opioid-naïve volunteers; they do not reflect complex clinical situations and should be used with caution
  • A full table of conversions between different opioids is on the substance misuse page
  • Conversions between routes for morphine and diamorphine are shown below

Drug and route Dose equivalent to 10mg oral morphine
IV morphine 3.3mg (oral:IV ratio 2 - 3:1)
IM or SC morphine 5mg
SC diamorphine 2.5mg
Epidural morphine 1mg
Intrathecal morphine 0.1mg

Opioid rotation

  • Describes switching from one opioid to another and is common in chronic and cancer pain
  • Useful when there are intolerable side-effects or inadequate analgesia despite escalating doses
  • Tolerance to side-effects (itch, nausea, sedation) develops at a different and unpredictable rate to tolerance to analgesia
  • Because cross-tolerance is incomplete, an alternative opioid may give better analgesia with fewer side-effects
  • For the same reason, reduce the calculated equianalgesic dose by 30 - 50% when rotating, with IR opioid available for breakthrough pain

Perioperative Management of the Opioid-Tolerant Patient


Planning

  • Early identification by surgeons and pre-operative assessment staff allows time for planning
  • Agree a clear, documented multidisciplinary plan wit§h the patient, involving anaesthetists, acute and chronic pain teams, palliative care, GP, psychology and physiotherapy
  • Assess the effectiveness of current analgesia and treat any unrelieved pain pre-operatively where possible
  • Plan post-operative care in an HDU or similar monitored setting where large doses are anticipated

History

  • Establish the total daily opioid intake and convert to an oral morphine equivalent
  • Drug, dose, route (oral, SC, transdermal, intrathecal), formulation (modified or immediate release) and duration of use
  • Reason for opioid use: chronic non-cancer pain, cancer pain or substitution therapy
  • Co-prescribed adjuvants (e.g. gabapentinoids, antidepressants)

Continuing baseline opioids

  • Continue oral opioids (immediate and modified release) up to and including the day of surgery
  • Transdermal patches (fentanyl, buprenorphine up to 70mcg/hr) should be continued at their baseline dose
    • Older manufacturer advice was to remove patches pre-operatively and use immediate release oral opioids; current practice is to continue them
    • Ensure the patch is not placed where heat (e.g. warming devices) will increase absorption, or over poorly perfused or cold skin which will reduce it
  • Intrathecal opioids via implanted pumps should be continued throughout, rather than upsetting a finely balanced regimen

Substitution therapy

  • Methadone: continue the usual dose although if unable to take orally rotate to an IV fentanyl or morphine PCA
  • High-dose sublingual buprenorphine: continue the usual dose, maximise opioid-sparing techniques and use full agonists for acute pain
  • Naltrexone: stop 72hrs before surgery; patients become very sensitive to opioids once it is stopped
  • See substance misuse for further detail on these agents

Baseline requirement

  • If the oral route will be unavailable or gut absorption is unreliable, the baseline requirement must be replaced parenterally to prevent withdrawal
  • Expect higher than usual intra-operative opioid requirements

Opioid-sparing techniques

  • Regular paracetamol and NSAIDs or COX-2 inhibitors unless contraindicated
  • Local anaesthetic techniques wherever possible: wound infiltration, regional and neuraxial blocks
    • Catheter techniques extend the benefit well into the post-operative period
  • Ketamine
    • Attenuates both tolerance and OIH, and reduces post-operative opioid use and pain scores
    • Low-dose IV or SC infusion for 1 - 3 days; a suggested starting dose is 100 - 200mg/24hrs
  • Clonidine
  • IV lidocaine infusion in selected cases

Principles

  • Continue the baseline opioid and manage acute pain with additional immediate release opioid
  • Requirements may be higher or lower than predicted:
    • Surgery may increase requirements (20% or more above baseline has been reported)
    • Surgery may reduce requirements, e.g. tumour removal in cancer pain
    • Only a relatively small dose (<50% of the pre-operative dose) is needed to prevent withdrawal
  • The calculated dose is an approximation - start at 50 - 100% of it and titrate to effect

Factors affecting post-operative opioid requirements

Pre-operative Intra-operative Post-operative
Unrelieved pain Type and location of surgery Pain scores
Opioid drug and dose Regional anaesthesia and nerve blocks Tolerance
Route and formulation Adjuvant analgesics Physical dependence
Duration of use Level of sedation
Medical condition

Oral route available

  • Continue the usual modified release preparation
  • PRN immediate release opioid dose is traditionally 1/6 of the total 24hr dose, 4-hourly
  • The dose needed may not correlate with this and starting with standard doses then titrating is reasonable

Oral route unavailable

  • IV PCA: allows individual titration and reduces staff workload
    • The baseline requirement can be met with a background infusion, or with a larger bolus dose alone
    • Bolus size can be based on the patient's usual 24hr requirement; e.g. 1.5 - 2mg morphine rather than the standard 1mg, or 50% of the hourly background rate
  • Alternatively, a continuous IV morphine or SC diamorphine infusion with 1/6 of the daily dose available PRN
  • Epidural analgesia:
    • Standard local anaesthetic and opioid mixtures have been used successfully in opioid-tolerant patients
    • Alternatively, a plain local anaesthetic epidural with the baseline opioid given as an IV or SC infusion

Adjuncts

  • Consider continuing ketamine as an infusion
  • Gabapentinoids are not routinely recommended but could be considered if all other avenues explored
    • They have sedative properties and the potential for abuse too

Returning to oral analgesia

  • Calculate the IV opioid used over the previous 24hrs and convert to an oral equivalent
  • Give 50% of this as a modified release preparation, with 1/6 of the total oral equivalent as IR PRN 4-hourly

Assessment and monitoring

  • Pain scores are consistently higher in opioid-tolerant patients, so assess overall effectiveness of analgesia:
    • Function: ability to cough, deep breathe, mobilise and engage with physiotherapy
    • Opioid side-effects and signs of withdrawal
    • Mood, patient expectations and satisfaction
  • Monitor for both under-treatment (pain, withdrawal) and over-treatment (sedation, respiratory depression); see OIVI

Opioid withdrawal

  • Occurs if the opioid is stopped, reduced too quickly, reversed (e.g. naloxone, mixed agonist/antagonists) or fails to reach its site of action
  • Features: adrenergic hyperactivity, malaise, abdominal cramps, yawning and sweating

Discharge

  • Agree and communicate an onward plan with the patient, GP and pharmacist
  • The discharge letter should emphasise reducing and stopping any opioids or adjuvants that are ineffective or no longer required
  • Some patients may already have agreed arrangements with their GP (e.g. weekly or daily prescriptions)
  • See opioid-related harm for strategies to reduce persistent post-operative opioid use

Oral morphine to IV PCA

  • A patient taking modified release morphine 200mg bd needs an emergency laparotomy and will be nil by mouth
    1. Total oral morphine: 400mg/24hrs
    2. Convert to IV using a 3:1 ratio: 133mg/24hrs
    3. Background infusion: 133 ÷ 24 = 5.5mg/hr
    4. Bolus: 50% of the hourly background rate = 2.5 - 3mg, 5min lockout

Oral methadone to IV morphine

  • A patient taking methadone 100mg/day needs an emergency laparotomy and will be nil by mouth
    1. Convert to oral morphine using a 1:3 ratio: 300mg/24hrs
    2. Convert to IV morphine (3:1): 100mg/24hrs
    3. Reduce by 50% for incomplete cross-tolerance: 50mg/24hrs
    4. Deliver via PCA with either a larger bolus (1.5 - 2mg), or a standard 1mg bolus with a 2mg/hr background infusion

IV morphine back to oral

  • A patient has used 60mg IV morphine in the last 24hrs
    1. Oral equivalent (× 2 - 3): 120 - 180mg/24hrs
    2. 50% as modified release: 60 - 90mg/day, i.e. 30 - 45mg bd
    3. PRN: 1/6 of 120 - 180mg = 20 - 30mg IR, 4-hourly