Multimodal Analgesia — Principles
Multimodal analgesia combines drugs with different mechanisms of action to achieve superior pain control while minimising opioid requirements and their associated adverse effects. PROSPECT, ERAS, ASA, and ESRA guidelines all recommend multimodal opioid-sparing strategies as the standard of care for perioperative pain management.
Core principle: No single analgesic is adequate alone. Combining agents that act at different points in the pain pathway — peripheral, spinal, supraspinal — produces additive or synergistic analgesia with reduced side effects from any single agent.
Quick Reference — All Drug Classes
| Drug Class | Mechanism | PROSPECT | Opioid Sparing | Key Caution |
|---|---|---|---|---|
| Paracetamol | Central COX inhibition, endocannabinoid, serotonergic | A | ✓ 20–30% | Hepatic impairment, weight <50 kg |
| NSAIDs / COX-2 | Peripheral & central COX-1/2 inhibition → ↓PGE2 | A | ✓ 30–50% | Renal, GI, cardiovascular, bleeding |
| Dexamethasone | Glucocorticoid → ↓PGE2, cytokines, nerve sensitisation | A | ✓ + block prolongation | Diabetes, immunosuppression, infection |
| Ketamine | NMDA receptor antagonist → ↓central sensitisation | B | ✓ 25–40% | Psychomimetic effects, hypertension |
| Gabapentinoids | α2δ calcium channel subunit → ↓presynaptic glutamate | C | ~ Variable | Sedation, dizziness, elderly, OSA, renal |
| α2-Agonists | α2 adrenergic → ↓noradrenaline release, spinal inhibition | B | ✓ 20–30% | Bradycardia, hypotension, sedation |
| IV Lidocaine | Sodium channel blockade → ↓peripheral & central sensitisation | B | ✓ Abdominal surgery | Narrow therapeutic window, cardiac toxicity |
| Opioids | μ/κ/δ opioid receptors → ↓ascending pain transmission | Rescue | — First-line avoided | Dependence, OIRD, OIH, constipation, PONV |
Paracetamol (Acetaminophen)
Paracetamol is the cornerstone of multimodal analgesia — recommended by PROSPECT for virtually all surgical procedures. Its exact mechanism remains incompletely understood but involves central COX inhibition (particularly COX-3), enhancement of descending serotonergic inhibition, and endocannabinoid system modulation. When combined with NSAIDs, additive analgesia is achieved.
Dosing
IV vs PO: Evidence does not support superiority of IV over oral in patients who can take medications by mouth. Use PO where possible — significantly cheaper with equivalent efficacy.
PROSPECT Recommendation
Regular (not PRN) paracetamol throughout perioperative period unless contraindicated. Contributes to opioid sparing of approximately 20–30% when used as part of multimodal regimen.
Contraindications
- Severe hepatic impairment (Child-Pugh C)
- Known hypersensitivity
- Chronic alcohol use disorder (relative)
Dose Reductions
- Weight <50 kg → 500–750 mg per dose
- Hepatic impairment → 500 mg per dose, max 2 g/24h
- Malnutrition / fasting >24h — use with caution
NSAIDs & COX-2 Inhibitors
NSAIDs provide the greatest opioid-sparing effect of any systemic analgesic class — reducing opioid consumption by 30–50% and improving pain scores. PROSPECT recommends them for virtually all surgical procedures when not contraindicated. COX-2 selective agents (celecoxib, etoricoxib, parecoxib) offer equivalent analgesia with reduced GI and platelet effects, making them preferable in higher-risk patients.
Key Agents & Dosing
| Drug | Class | Dose | Route | Frequency | Duration |
|---|---|---|---|---|---|
| Celecoxib | COX-2 | 200 mg | PO | BD | ≤5 days |
| Etoricoxib | COX-2 | 60–90 mg | PO | OD | ≤5 days |
| Parecoxib | COX-2 | 40 mg | IV/IM | BD | ≤3 days IV |
| Ibuprofen | Non-selective | 400 mg | PO | TDS | ≤5 days |
| Diclofenac | Non-selective | 75 mg | PO/IM | BD | ≤5 days |
| Ketorolac | Non-selective | 15–30 mg | IV/IM | QDS | ≤5 days |
| Naproxen | Non-selective | 500 mg | PO | BD | ≤5 days |
Use at lowest effective dose for shortest duration (≤5 days). Always consider GI protection (PPI) with non-selective NSAIDs. COX-2 inhibitors preferred in elderly, high GI risk, or anticoagulated patients. Avoid in renal impairment (eGFR <30), active peptic ulcer, decompensated heart failure, post-CABG, and in the third trimester of pregnancy.
Non-selective vs COX-2 — Key Differences
- COX-1 + COX-2 inhibition
- ↑GI risk (PPI needed)
- Antiplatelet effect
- Cheaper
- Avoid with anticoagulants
- COX-2 inhibition only
- ↓GI risk
- No antiplatelet effect
- ↑CV risk at high doses
- Safer with anticoagulants
Contraindications
- eGFR <30 mL/min — avoid; eGFR 30–60 — use with caution
- Active peptic ulcer / GI bleed
- Decompensated heart failure
- Post-CABG (COX-2 inhibitors)
- NSAID/aspirin-exacerbated respiratory disease (AERD)
- Third trimester pregnancy
- Severe hepatic impairment
Dexamethasone
Dexamethasone is a highly versatile perioperative drug with three simultaneous benefits: analgesia, PONV prophylaxis, and prolongation of peripheral nerve block duration. A single intraoperative IV dose of 4–8 mg is now standard in most ERAS protocols. Evidence is strong across multiple surgical specialties.
Dosing
IV vs perineural dexamethasone: Systematic reviews (Desmet 2017, Rahangdale 2024) show IV dexamethasone is non-inferior to perineural for block prolongation. IV is preferred — simpler, avoids off-label injection, same effect. 8 mg IV is as effective as 4 mg in most studies.
Effects Summary
| Effect | Magnitude | Evidence |
|---|---|---|
| Opioid reduction (24h) | ~30–40% | A |
| Pain score reduction (0–24h) | Moderate | A |
| PONV prophylaxis | ~50% risk reduction | A |
| Block duration prolongation (IV) | +6–8 hours | A |
| Block duration prolongation (perineural) | +6–8 hours | A |
Cautions
- Diabetes: Single dose 8 mg causes transient blood glucose elevation (~2–4 mmol/L for 8–12h) — monitor and manage. Not a contraindication but requires awareness.
- Infection / sepsis: Use with caution in active untreated infection.
- Immunosuppressed patients: Relative caution in severely immunocompromised.
- Perineal/anorectal surgery: Some evidence of impaired wound healing with repeated doses — not a concern for single intraoperative dose.
Ketamine
Sub-anaesthetic ketamine is most valuable in high-pain procedures, opioid-tolerant patients, and surgery with significant wind-up risk. NMDA receptor blockade prevents central sensitisation and opioid-induced hyperalgesia (OIH) — making it particularly useful in chronic pain patients and those on pre-existing opioids. Evidence is strongest for abdominal, thoracic, and complex orthopaedic surgery.
Dosing Regimens
| Setting | Dose | Route | Timing | Notes |
|---|---|---|---|---|
| Intraoperative bolus | 0.3–0.5 mg/kg | IV | Induction | Standard sub-anaesthetic dose |
| Intraoperative infusion | 0.1–0.3 mg/kg/h | IV | Throughout surgery | Stop 30 min before end to ↓emergence effects |
| Postoperative infusion | 0.05–0.2 mg/kg/h | IV | PACU / ward | ≤48h; requires monitoring |
| OIH prevention | 0.5 mg/kg bolus + 0.25 mg/kg/h | IV | Intra-op | Opioid-tolerant / chronic pain patients |
| Single bolus (ED/ED analgesia) | 0.1–0.3 mg/kg | IV slow | PRN | "Sub-dissociative" dose — analgesic, not anaesthetic |
When to Use Ketamine
Strong indications: Major abdominal surgery · thoracic surgery · complex spine surgery · opioid-tolerant patients · chronic pain patients · procedures expected to cause significant central sensitisation · ERAS protocols where opioid minimisation is prioritised
Caution / consider avoiding: Uncontrolled hypertension · active psychosis / schizophrenia · raised ICP (controversial — evidence now reassuring at low doses) · history of ketamine misuse · ischaemic heart disease (relative)
Side Effects
- Psychomimetic effects (hallucinations, dysphoria) — rare at sub-anaesthetic doses; mitigated by co-administration of midazolam 1–2 mg or low-dose benzodiazepine
- Hypertension and tachycardia — sympathomimetic effect; usually mild at analgesic doses
- Hypersalivation — co-administer glycopyrrolate if needed
- Emergence phenomena — rare with low doses; allow calm, quiet recovery
Gabapentinoids
Gabapentin and pregabalin have been widely adopted in multimodal protocols, but enthusiasm has been tempered by more recent evidence. Meta-analyses show modest opioid-sparing in certain populations, but at the cost of sedation, dizziness, and — in vulnerable groups — significant harm. PROSPECT 2024 does not recommend gabapentinoids in elderly patients (e.g. hip fracture) due to delirium and sedation risk. Their role is now considered procedure- and patient-specific.
FDA warning (2019): Serious respiratory depression with gabapentinoids, particularly when combined with opioids, benzodiazepines, or other CNS depressants. Increased monitoring required in elderly, OSA, and respiratory disease.
Dosing
| Drug | Preoperative | Postoperative | Max | Renal adjustment |
|---|---|---|---|---|
| Pregabalin | 75–150 mg PO 1–2h pre-op | 75–150 mg BD | 300 mg/day | ↓dose if eGFR <60; avoid if <15 |
| Gabapentin | 300–600 mg PO 1–2h pre-op | 300 mg TDS | 1800–2400 mg/day | ↓dose if eGFR <60 |
When to Consider / When to Avoid
Consider in
- Chronic pain patients / opioid-tolerant
- Procedures with high neuropathic pain component
- Major spine / thoracic surgery (selected patients)
- Younger patients without sedation risk factors
Avoid in
- Elderly patients (≥70) — delirium, falls risk
- Obstructive sleep apnoea + opioid co-administration
- Renal impairment (eGFR <30) without dose adjustment
- Ambulatory patients (dizziness, driving)
α2-Agonists — Clonidine & Dexmedetomidine
Alpha-2 agonists provide opioid-sparing analgesia and sedation. Dexmedetomidine (highly selective α2) is preferred intraoperatively and in ICU settings. Clonidine (less selective) is used as a perineural or neuraxial adjuvant. Both reduce opioid requirements and attenuate sympathetic stress responses but carry risk of bradycardia and hypotension.
Dosing
| Drug | Route | Dose | Indication | Notes |
|---|---|---|---|---|
| Dexmedetomidine | IV loading | 0.5–1 mcg/kg over 10 min | Pre/intra-op sedation-analgesia | Give slowly — hypotension/bradycardia if fast |
| Dexmedetomidine | IV infusion | 0.2–0.7 mcg/kg/h | Intraoperative / ICU | Titrate to sedation; stop >24h before extubation |
| Dexmedetomidine | Perineural | 0.5–1 mcg/kg | Block adjuvant | Extends block duration 4–6h; systemic effect likely |
| Clonidine | Neuraxial | 75–150 mcg | Spinal/epidural adjuvant | Prolongs block; hypotension risk |
| Clonidine | Perineural | 75–150 mcg | Block adjuvant | Modest duration extension; sedation possible |
| Clonidine | PO | 100–200 mcg | Premedication | Reduces anxiety, attenuates stress response |
Key Adverse Effects
- Bradycardia — most common; usually responds to atropine; avoid rapid bolus
- Hypotension — particularly with loading doses; have vasopressor available
- Sedation — therapeutic at low doses; excessive with high doses or combinations
- Rebound hypertension — with abrupt clonidine withdrawal after prolonged use
IV Lidocaine Infusion
IV lidocaine infusion is increasingly used as part of multimodal analgesia in abdominal and colorectal surgery, where evidence is strongest. Benefits include opioid sparing, earlier return of bowel function, reduced PONV, and anti-inflammatory effects. Evidence outside abdominal surgery is limited and inconsistent.
Narrow therapeutic window. IV lidocaine toxicity manifests as tinnitus, perioral numbness, metallic taste, dysarthria, seizures, and cardiac arrhythmias. Mandatory: cardiac monitoring throughout, trained personnel, resuscitation facilities including Intralipid 20% immediately available. Never give as IV bolus without dilution.
Dosing
Best Evidence For
- Open and laparoscopic colorectal surgery — PROSPECT recommended
- Open abdominal surgery where epidural is not used
- Bariatric surgery
- Opioid-tolerant patients in major abdominal surgery
Contraindications
- Known allergy to amide local anaesthetics
- Severe hepatic impairment (↓lidocaine metabolism)
- Pre-existing cardiac arrhythmias (AV block, severe bradycardia)
- Epilepsy — use with caution
Opioids — Rescue & Titrated Use
Opioids remain essential for rescue analgesia and in procedures where non-opioid strategies are insufficient. However, PROSPECT and ERAS guidelines consistently position opioids as rescue agents, not routine first-line analgesics. Minimising opioid exposure reduces PONV, ileus, respiratory depression, OIH, tolerance, and the risk of persistent postoperative opioid use.
Perioperative Opioid Dosing Reference
| Drug | Route | Dose | Frequency | Notes |
|---|---|---|---|---|
| Morphine | IV | 1–2 mg titrated | PRN q4–6h | Active metabolite (M6G) accumulates in renal impairment |
| Oxycodone | PO | 5–10 mg | PRN q4–6h | Predictable PK; preferred oral option |
| Fentanyl | IV | 25–50 mcg titrated | PRN | Short-acting; preferred in renal impairment |
| Hydromorphone | IV | 0.2–0.4 mg | PRN q3–4h | 5× more potent than morphine IV |
| Tramadol | PO/IV | 50–100 mg | TDS–QDS | Avoid elderly Serotonin syndrome risk; seizures |
| Codeine | PO | 30–60 mg | QDS | Prodrug — poor/ultra-rapid metabolisers; avoid in children |
Opioid-induced respiratory depression (OIRD): Monitor SpO₂ and respiratory rate. Risk highest in opioid-naïve patients, elderly, OSA, concurrent CNS depressants. Have naloxone immediately available (0.1–0.2 mg IV titrated, may repeat every 2–3 min). Note: naloxone duration shorter than most opioids — repeated doses or infusion may be required.
Special Populations
| Population | Recommendation |
|---|---|
| Elderly (≥70) | Start low, go slow. Fentanyl preferred (no active metabolites). Reduce dose 25–50%. Frequent reassessment. Avoid tramadol. |
| Renal impairment | Fentanyl or hydromorphone preferred. Avoid morphine (M6G accumulation). Reduce doses and frequency. Monitor carefully. |
| Hepatic impairment | Reduce all opioid doses. Morphine and oxycodone affected most. Fentanyl relatively safer. |
| Opioid tolerant | Continue baseline opioid + supplement for surgical pain. Consider ketamine, regional techniques. Coordinate with pain team. |
| OSA | Minimise opioids strongly. Regional preferred. Mandatory SpO₂ monitoring. Elevate head of bed. CPAP if available. |
References
- ESRA PROSPECT Working Group. Procedure-specific postoperative pain management recommendations. esraeurope.org/prospect ↗
- Elvir-Lazo OL et al. Multimodal analgesia, current concepts, and acute pain considerations. Curr Pain Headache Rep. 2017;21(1):3.
- Mulier JP et al. Perioperative multimodal analgesia: a review of efficacy and safety. Anesth Perioper Sci. 2024. DOI ↗
- Desmet M et al. Intravenous dexamethasone and nerve block duration. Br J Anaesth. 2017;117(6):799–807.
- Laskowski K et al. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58(10):911–923.
- Fabritius ML et al. Gabapentin for post-operative pain management — a systematic review. Acta Anaesthesiol Scand. 2016;60(9):1188–1208.
- Weibel S et al. Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis. Cochrane Database Syst Rev. 2020;10:CD012859.
- Kaba A et al. Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy. Anesthesiology. 2007;106(1):11–18.
- Levy N et al. Opioid-free anaesthesia — why and how? Anaesthesia. 2021;76(S1):171–183.
- Puntillo F et al. Personalized multimodal and opioid-sparing analgesia. J Pain Res. 2026. PMC13094574 ↗