Acute Pain in Opioid-Tolerant Patients

Acute pain management in opioid-tolerant patients — those already receiving long-term opioid therapy for chronic pain or as part of an opioid treatment programme (OTP) — represents one of the most complex challenges in acute and perioperative medicine. These patients present with acute pain from surgery, trauma, acute illness, or exacerbations of their underlying condition, yet their baseline opioid consumption means that standard analgesic regimens are frequently inadequate.

In Australia, an estimated 3.1 million Australians were dispensed at least one opioid prescription in 2021–22, with approximately 150,000–200,000 on long-term opioid therapy (defined as ≥90 days of continuous use). Additionally, around 55,000 Australians are enrolled in opioid treatment programmes receiving methadone or buprenorphine for opioid dependence. These populations routinely present to emergency departments (EDs) and require hospital-based care for acute conditions, yet evidence consistently shows they receive suboptimal pain management due to clinician misconceptions, stigma, and inadequate training.

The Australian Institute of Health and Welfare (AIHW) reports that opioid-related hospitalisations have risen significantly over the past decade, and the Pharmaceutical Benefits Scheme (PBS) dispensing data show that codeine, oxycodone, tramadol, and tapentadol remain the most commonly dispensed opioids. Since the 2018 upscheduling of codeine to prescription-only, patterns have shifted, but long-term opioid use remains prevalent.

This article provides a comprehensive, evidence-based guide to managing acute pain in opioid-tolerant patients within the Australian healthcare context, covering patients on chronic opioid therapy, those with diagnosed opioid use disorder, and the specific pharmacological considerations around buprenorphine and methadone maintenance therapy.

Chronic opioid therapy (COT) is generally defined as the use of opioid analgesics for ≥90 days, typically for chronic non-cancer pain (CNCP). In Australia, COT is prescribed predominantly in primary care, with oxycodone, tramadol, codeine (pre-2018), tapentadol, and morphine being the most frequently used agents. Patients on COT develop both pharmacological tolerance and, in many cases, physiological dependence.

Tolerance vs Dependence vs Addiction

Assessment of the Chronic Opioid Patient

• Determine the exact current opioid regimen: drug name, dose, frequency, route, and duration of use.
• Obtain corroborating information: My Health Record, state real-time prescription monitoring (RTPM) systems (e.g., SafeScript VIC, QScript QLD, ScriptCheckWA, SafeScript NSW, NT CARA), community pharmacy records, or contact the prescriber.
• Assess for signs of opioid withdrawal using the Clinical Opiate Withdrawal Scale (COWS) if opioid use history is unclear or abrupt cessation has occurred.
• Screen for opioid-induced hyperalgesia (OIH): worsening pain despite dose escalation, diffuse allodynia, or pain disproportionate to the clinical stimulus.
• Do not equate tolerance or dependence with drug-seeking behaviour; treat pain first, address dependence as a parallel issue.

Equianalgesic Dosing Reference

Note: Equianalgesic conversions are estimates only. Cross-tolerance is incomplete — reduce the calculated equianalgesic dose by 25–50% when switching opioids to avoid overdose. Individual variation is significant.

Opioid use disorder (OUD) is a chronic relapsing condition characterised by compulsive opioid use, loss of control, and continued use despite significant psychosocial and physical harm. In Australia, OUD affects an estimated 75,000–100,000 people, with the burden falling disproportionately on younger adults, people experiencing socioeconomic disadvantage, and Aboriginal and Torres Strait Islander communities.

Diagnostic Criteria (DSM-5)

OUD is diagnosed when ≥2 of the following criteria are met within a 12-month period:

• Opioids taken in larger amounts or over a longer period than intended
• Persistent desire or unsuccessful efforts to cut down
• Excessive time spent obtaining, using, or recovering from opioids
• Craving for opioids
• Failure to fulfil role obligations at work, school, or home
• Continued use despite social or interpersonal problems
• Important activities given up or reduced
• Use in physically hazardous situations
• Continued use despite awareness of physical or psychological problems
• Tolerance (as defined by the clinician — not applicable when opioids are taken as prescribed)
• Withdrawal (as defined by the clinician — not applicable when opioids are taken as prescribed)

Managing Acute Pain in OUD

• Patients with OUD have typically developed significant tolerance and may require substantially higher opioid doses than opioid-naïve patients.
• Continue the patient's maintenance pharmacotherapy (buprenorphine or methadone) — do not stop it for acute pain management.
• Use multimodal analgesia aggressively to minimise opioid requirements.
• Involve the addiction medicine team, pain service, or the patient's OTP prescriber early.
• Use observed dosing for additional opioids if there are concerns about diversion; this is standard practice, not punitive.
• Communicate with the patient's treating team (GP, OTP prescriber, community pharmacy) to ensure continuity.

Buprenorphine is a semi-synthetic opioid with unique pharmacology — a partial μ-receptor agonist, κ-receptor antagonist, and very high receptor affinity with slow dissociation. It is used both as an analgesic and, at higher doses, as maintenance pharmacotherapy for OUD (buprenorphine-naloxone: Suboxone®, or buprenorphine monoproduct: Subutex®). In Australia, buprenorphine is available in multiple formulations and is listed on the PBS.

Key Pharmacological Challenges with Buprenorphine

• Receptor blockade: Buprenorphine's very high μ-receptor affinity means it competitively blocks other full μ-agonist opioids (morphine, oxycodone, fentanyl). Standard doses of these agents will be ineffective or greatly reduced in effect at maintenance doses ≥8 mg/day sublingual.
• Slow dissociation: Buprenorphine dissociates slowly from the μ-receptor (half-life of receptor binding ≈ 2–5 hours post-dissociation), meaning the blocking effect persists even after the drug's plasma levels fall.
• Ceiling effect on respiratory depression: Buprenorphine has a ceiling effect on respiratory depression, making it inherently safer than full agonists in overdose, but also meaning it cannot easily be titrated upward for severe pain.

Strategies for Acute Pain Management in Patients on Buprenorphine Maintenance

Option A — Continue buprenorphine + multimodal adjuncts (preferred for most acute pain):

• Continue the patient's usual buprenorphine dose.
• Maximise non-opioid analgesia: IV paracetamol (1 g QDS), IV ketorolac (15–30 mg stat), ketamine infusion (0.1–0.3 mg/kg/hr), gabapentinoids, regional anaesthesia / nerve blocks.
• If parenteral opioid is required, consider splitting the buprenorphine dose to TDS (for opioid effect) and adding short-acting opioids in higher-than-usual doses titrated to effect — evidence suggests some analgesic benefit is achievable despite partial blockade.
• IV fentanyl PCA may provide some analgesia through high-receptor-occupancy dosing, though responses are variable.

Option B — Reduce buprenorphine dose (moderate–severe pain, e.g., major surgery):

• Reduce sublingual buprenorphine to 4–8 mg/day (or 2–4 mg/day for lower maintenance doses) for the duration of acute pain requiring parenteral opioids.
• Supplement with short-acting full μ-agonist opioids titrated to effect (may require higher doses than standard equianalgesic calculations).
• Restart full maintenance dose once parenteral opioids are weaned — typically within 2–5 days.
• Requires close coordination with OTP prescriber.

Option C — Cease buprenorphine temporarily (severe, major surgery):

• Cease buprenorphine 24–72 hours pre-procedure if planned surgery allows.
• Manage acute pain with full μ-agonist opioids (PCA morphine or fentanyl) + multimodal analgesia.
• Restart buprenorphine once acute opioid requirements are reducing and stable (typically ≥24 hrs after last full-agonist dose to avoid precipitated withdrawal).
• Higher risk of relapse — only appropriate when surgical pain is expected to be severe and prolonged, and when addiction medicine input is available.

Buprenorphine for Analgesic Use (non-OUD)

Low-dose buprenorphine (transdermal patches 5–20 μg/hr, or sublingual 0.2–0.4 mg) is used as an analgesic in patients with chronic pain. These patients do not typically have the same degree of μ-receptor occupancy as those on OUD-maintenance doses, and conventional opioid strategies for acute pain escalation are generally more straightforward. Transdermal patches should be removed if parenteral opioids are required, as the combination may cause unpredictable receptor interactions.

Methadone is a synthetic full μ-opioid agonist and NMDA receptor antagonist used as maintenance pharmacotherapy for OUD (typically at doses of 20–120 mg/day in Australian OTPs) and, less commonly, for chronic pain. Methadone has unique pharmacokinetics — a long and highly variable half-life (15–60+ hours), NMDA antagonism (which may attenuate opioid tolerance and hyperalgesia), and potentiation of serotonergic and noradrenergic pathways.

Critical Principles for Methadone Patients with Acute Pain

• Maintain the methadone dose: The patient's usual methadone dose should be continued throughout the hospital admission. This does not provide sufficient analgesia for acute pain — it prevents withdrawal and maintains OUD stability.
• Add short-acting opioids: Supplement with IV morphine, IV fentanyl, or oral oxycodone. Patients on methadone are tolerant; they will require higher doses than opioid-naïve patients. Start at 50–100% of the standard dose and titrate upward.
• QTc monitoring: Methadone prolongs the QT interval (particularly at higher doses >100 mg/day and in combination with other QT-prolonging agents). Obtain a baseline ECG and repeat if high-dose methadone or concomitant QT-prolonging drugs.
• Drug interactions: Methadone is metabolised by CYP3A4, CYP2B6, and CYP2D6. Co-administration of CYP inducers (rifampicin, carbamazepine, phenytoin, St John's wort) can precipitate withdrawal. CYP inhibitors (fluconazole, fluoxetine, erythromycin) can increase levels and toxicity.
• Respiratory depression risk: Methadone's long and variable half-life (15–60+ hrs) means accumulation can occur with repeated dosing. While the maintenance dose is stable, the addition of other sedating agents (benzodiazepines, gabapentinoids, other opioids) increases respiratory depression risk. Monitor respiratory rate, sedation score, and SpO₂.
• OTP dispensing on discharge: Ensure the patient can access their usual OTP dose on the day of discharge. Arrange a take-away dose if needed, coordinated with the dispensing pharmacy and OTP prescriber.

Perioperative Methadone Use

In the perioperative setting, some Australian hospitals use methadone as a perioperative analgesic at doses of 0.2–0.3 mg/kg IV (max 20–30 mg) intra-operatively, leveraging its NMDA antagonist properties and long duration of action. This is distinct from the patient's OUD maintenance dose and should be managed by the anaesthetist in consultation with the acute pain service. Post-operatively, the patient's maintenance methadone is resumed and supplemented with short-acting opioids as above.

Opioid Tolerance

Opioid tolerance develops through multiple mechanisms:

• Receptor desensitisation: Chronic μ-receptor activation leads to receptor phosphorylation, β-arrestin recruitment, and internalisation, reducing the cell's responsiveness to subsequent opioid binding.
• Receptor downregulation: Prolonged exposure reduces the total number of surface μ-receptors on dorsal root ganglion neurons and central pain processing neurons.
• Counter-regulatory mechanisms: Upregulation of NMDA receptor activity, dynorphin/κ-opioid systems, and descending facilitatory pathways partially oppose opioid analgesia.
• Neuroimmune activation: Opioids activate glial cells (microglia, astrocytes) via toll-like receptor 4 (TLR4), releasing pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) that counteract analgesia.

Clinically, tolerance manifests as a reduced duration of analgesia (loss of "duration tolerance" before "potency tolerance"), requiring dose escalation or more frequent dosing to maintain effect.

Opioid-Induced Hyperalgesia (OIH)

OIH is a paradoxical state in which opioid exposure itself increases pain sensitivity. It is distinct from tolerance: in tolerance, more opioid produces more analgesia (albeit at higher doses); in OIH, more opioid actually worsens pain.

• Central sensitisation: Chronic opioid use enhances NMDA receptor-mediated excitatory neurotransmission in the spinal cord dorsal horn.
• Descending facilitation: Activation of descending pain facilitatory pathways from the rostral ventromedial medulla.
• Glial activation: TLR4-mediated release of pronociceptive mediators (glial-derived neurotrophic factor, BDNF, chemokines).
• Clinical clues: Diffuse allodynia, pain that is disproportionate to the inciting stimulus, worsening pain despite dose escalation, and improvement with opioid dose reduction.

Opioid-tolerant patients present with acute pain from the same range of conditions as any patient — surgical, traumatic, medical, or procedural. The key difference is that standard analgesic approaches are likely to be inadequate without modification.

Initial Assessment Framework

Oral Morphine Equivalent Daily Dose (OMEDD) Conversion

Calculating the OMEDD helps quantify tolerance. Multiply the patient's daily opioid dose by the conversion factor:

Investigations are directed by the acute presentation, not by opioid-tolerant status per se. However, the following are relevant:

Risk stratification in opioid-tolerant patients considers both the adequacy of analgesia and the safety risks of escalation:

The foundation of acute pain management in opioid-tolerant patients is multimodal analgesia — combining agents with different mechanisms to achieve additive or synergistic analgesia while minimising opioid-related adverse effects.

Step 1: Continue Baseline Opioid

• Continue the patient's usual opioid at the same dose and frequency.
• If the patient is NPO (nil per os), convert to an equianalgesic IV or transdermal regimen.
• For patients on long-acting opioids (e.g., MS Contin®, OxyContin®, Targin®), convert to IV opioid infusion if prolonged NPO status expected.

Step 2: Multimodal Non-Opioid Analgesia

Step 3: Supplemental Short-Acting Opioid

In addition to the patient's baseline opioid, provide a short-acting opioid for breakthrough acute pain:

When standard multimodal analgesia and opioid dose escalation are inadequate, targeted therapies address specific pathophysiological mechanisms:

Low-Dose Ketamine

Rationale: Ketamine is an NMDA receptor antagonist that directly addresses the central sensitisation and OIH mechanisms driven by chronic opioid use. In opioid-tolerant patients, low-dose ketamine can reduce opioid consumption by 25–50% while improving pain scores. It is particularly effective in patients with suspected OIH or neuropathic components to their pain.

Regional Anaesthesia & Nerve Blocks

Regional anaesthesia (peripheral nerve blocks, epidural, fascial plane blocks) is a critical component of the analgesic strategy for opioid-tolerant patients, particularly in the perioperative setting. Australian hospitals increasingly employ ultrasound-guided regional techniques, and the availability of catheter-based continuous blocks allows prolonged analgesia.

• Perform nerve blocks where clinically appropriate (e.g., TAP block for laparotomy, femoral/sciatic block for lower limb fracture, erector spinae plane block for rib fractures).
• Continuous epidural analgesia should be strongly considered for major thoracic and abdominal surgery in opioid-tolerant patients.
• Local anaesthetic systemic toxicity (LAST) — ensure lipid emulsion (Intralipid® 20%) is available wherever blocks are performed.

Adjuvant Agents for Specific Pain Mechanisms

Opioid-tolerant patients receiving supplemental opioids for acute pain require enhanced monitoring, particularly in the first 24–48 hours of dose escalation.

Monitoring Parameters

Pasero Opioid-Induced Sedation Scale (POSS)

Naloxone for Respiratory Depression

• Naloxone ampoule: 400 μg/mL — dilute 1:10 (40 μg/mL) for titrated use.
• Start with 40–80 μg IV every 2–3 min until RR ≥10 and patient responsive.
• Monitor closely — naloxone's duration (30–90 min) may be shorter than the opioid's duration, risking re-narcotisation.
• Ensure naloxone is readily accessible on the ward. PBS-listed naloxone (Nyxoid® nasal spray 1.8 mg) is available for take-home use and is available on the PBS as an Authority Required item for patients on high-dose opioids or those at risk of overdose.

Discharge planning for opioid-tolerant patients must begin at admission. Poor transitions of care contribute to pain crises, opioid overdose, and relapse of OUD.

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