Advanced Pharmacology · Topic 12 of 13

Multimodal & Non-Opioid Analgesia

Pharmacology · pain and analgesia

Multimodal & Non-Opioid Analgesia

Layer nonopioid analgesia — acetaminophen, an NSAID when safe, regional blocks, low-dose ketamine — so opioids become the add-on, not the foundation.

Key numbers

Acetaminophen maximum 4 g/day, all sources≤ 4 g/day

Acetaminophen 2–3 g/day in liver disease2–3 g/day

Low-dose ketamine infusion 0.1–0.5 mg/kg/h0.1–0.5 mg/kg/h

Ketorolac: 5 days maximum≤ 5 days

Treat LAST with 20% lipid emulsion20% lipid 1.5 mL/kg

01 · GiveAcetaminophen maximum 4 g/day, all sources

Acetaminophen maximum is 4 g/day counting every route and combination product (IV or oral 1 g every 6 hours); under 50 kg, 15 mg/kg per dose up to 75 mg/kg/day.

02 · AvoidNSAID cautions: gut, kidneys, heart, bleeding

Avoid NSAIDs with peptic ulcer or GI bleeding, renal insufficiency or hypovolemia, heart failure, after CABG and with high bleeding risk; for GI risk add a PPI or use celecoxib — coxibs are not renal-sparing.

03 · The ruleBuild analgesia on nonopioid foundations

Use multimodal analgesia for postoperative and other acute pain — acetaminophen, an NSAID when safe, regional techniques and selected adjuncts — and prefer nonopioid therapies for many acute pain conditions, adding opioids only when needed.

Management

Orders

Acetaminophen 2–3 g/day in liver disease must knowLower the ceiling to 2–3 g/day in older adults with hepatic insufficiency or alcohol misuse, and to about 2 g/day in cirrhosis, where it stays the preferred analgesic; use caution if malnourished, hypovolemic or CrCl ≤ 30.

Low-dose ketamine infusion 0.1–0.5 mg/kg/hSubanesthetic ketamine (bolus ≤ 0.35 mg/kg; infusion usually 0.1–0.5 mg/kg/h, never above 1 mg/kg/h) cuts opioid use after painful surgery and helps opioid-tolerant patients; avoid with poorly controlled cardiovascular disease, pregnancy, hepatic dysfunction or psychosis.

Ketorolac: 5 days maximumKetorolac: 5 days total at most; injection maximum 120 mg/day, or 60 mg/day at age ≥ 65, weight < 50 kg or raised creatinine. Contraindicated in advanced renal impairment, GI bleeding, bleeding risk, CABG and labor.

Regional anesthesia spares opioidsPeripheral nerve blocks and epidural local anesthetics give site-specific analgesia and reduce opioid needs; epidural analgesia with local anesthetics or opioids is particularly useful for perioperative pain.

Red flags & don'ts

Avoid harm

NSAIDs raise MI, stroke and HF risk complicationNonselective NSAIDs and coxibs are both prothrombotic, raising MI and stroke risk, and can raise blood pressure, worsen heart failure and cause sodium and water retention — caution with atherosclerosis or multiple risk factors.

Gabapentinoids plus opioids depress breathing interactionGabapentin and pregabalin can cause serious respiratory depression when combined with opioids or other CNS depressants, in COPD and in older adults (FDA 2019 warning) — start low and monitor.

Treat LAST with 20% lipid emulsion complicationFor local anesthetic systemic toxicity, secure the airway, start ACLS (epinephrine ≤ 1 mcg/kg) and give 20% lipid emulsion: 100 mL over 2–3 minutes if > 70 kg, 1.5 mL/kg if < 70 kg, then an infusion.

The rules

Know these

No routine perioperative gabapentinoidsDo not give gabapentin or pregabalin routinely for postoperative pain: a 281-trial meta-analysis found no clinically meaningful analgesia, no prevention of chronic postsurgical pain, and more dizziness and visual disturbance.

Keep baseline opioids; treat acute pain on topPatients on long-term opioids continue their baseline dose; treat superimposed acute pain with nonopioids first, adding short-acting opioids only while pain is severe, then return to baseline. Avoid abrupt discontinuation.

Acetaminophen or an NSAID?

Commonly confused

Anti-inflammatory effect	Minimal peripheral effect
Main toxicity	Hepatotoxicity above 4 g/day or with liver disease
Dose limit	4 g/day; 2–3 g/day with liver disease, ~2 g/day in cirrhosis
GI ulcer or bleeding	Spares the stomach
Kidney disease	Caution if CrCl ≤ 30 mL/min

Commonly confused

Tell apart

Older adults: NSAID GI bleeding 3–4× higherUlcer and GI bleeding risk from NSAIDs is 3–4 times higher after age 65, rising with dose and duration; protect high-risk older patients with a PPI or use a coxib (benefit lost with low-dose aspirin).

More detail

Reference

Show 5 reference facts

Acetaminophen acts centrally with minimal peripheral anti-inflammatory effect, so it spares the stomach and kidneys; hepatotoxicity — mainly above 4 g/day or with liver disease or chronic alcohol use — is its main risk.

IV acetaminophen is contraindicated with severe hepatic impairment or severe active liver disease; doses may be given every 4 hours (650 mg) or every 6 hours (1 g), never closer than 4 hours.

For opioid-tolerant patients, the ASRA/AAPM/ASA consensus supports considering ketamine during surgery (grade B, low certainty); in trials, a 0.5 mg/kg preincision bolus plus 0.6 mg/kg/h intraoperatively cut opioid use for 6 weeks after spine surgery.

LAST now often presents late — with ultrasound-guided blocks, infiltration and continuous catheters — and small body size and sarcopenia raise risk; it increasingly occurs outside the operating room.

In patients with opioid use disorder stabilized on methadone or buprenorphine, continue the treatment medication; discontinuation carries risk of return to use and overdose (see Opioid Use Disorder).

Pearl

Acetaminophen for nearly everyone (≤ 4 g/day), an NSAID when the gut, kidneys and heart allow, and opioids last.

Sources · Chou R et al. Management of Postoperative Pain: A Clinical Practice Guideline From the APS, ASRA and ASA. J Pain 2016 (abstract via Europe PMC) · Merck Manual Professional — Treatment of Pain (nonopioid analgesics, geriatrics, nerve blocks; updated Jun 2026) · Dowell D et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022. MMWR Recomm Rep 2022;71(3):1–95 · Ofirmev (acetaminophen) injection prescribing information — DailyMed · Clinical Inquiries: Alcoholic liver disease — is acetaminophen safe? J Fam Pract 2007 (AGS: ≤ 2–3 g/day in older adults with hepatic insufficiency or alcohol abuse) · Ketorolac tromethamine injection prescribing information (boxed warning) — DailyMed · Schwenk ES et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management (ASRA/AAPM/ASA). Reg Anesth Pain Med 2018;43:456–466 · Verret M et al. Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. Anesthesiology 2020 (abstract via Europe PMC) · FDA Drug Safety Communication (Dec 2019) — serious breathing difficulties with gabapentin and pregabalin in patients with respiratory risk factors · Local Anesthetic Systemic Toxicity: A Narrative Literature Review and Clinical Update on Prevention, Diagnosis, and Management. Plast Reconstr Surg 2019 (abstract: lipid bolus 100 mL if > 70 kg, 1.5 mL/kg if < 70 kg) · Neal JM et al. The Third ASRA Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017. Reg Anesth Pain Med 2018 (abstract via Europe PMC) · Rakoski M et al. Pain management in patients with cirrhosis. Clin Liver Dis (Hoboken) 2018 (acetaminophen ≤ 2 g/day preferred; avoid NSAIDs) · UCSF Pain Management Education — Local Anesthetic Systemic Toxicity (summarizes the 2020 ASRA LAST checklist: 20% lipid, 100 mL over 2–3 min if > 70 kg; epinephrine ≤ 1 mcg/kg) · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).