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Analgesia and sedation for the critically ill patient

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CONTENTS

[1/5] pure analgesics

[2/5] analgosedatives (analgesia > sedation)

[3/5] sedalgesics (sedation > analgesia)

[4/5] pure sedatives 

[5/5] antipsychotics / anti-agitation

miscellaneous

underlying concepts & construction of regimens

general schema for the intubated patient

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core sedation: propofol and/or dexmedetomidine

propofol gtt ⚡️ (ideally low-dose to avoid hypertriglyceridemia & over-sedation; perhaps ≦~40 mcg/kg/min)

  • Disadvantages:
    • ⚠️ Hypertriglyceridemia.
    • ⚠️ Excessive suppression of brain activity at high doses may cause or prolong delirium.
  • Advantages:
    • [1] May achieve deeper sedation (if this is the goal, which it usually isn't).
      • Suppression of respiratory drive may improve ventilator synchrony.
    • [2] Ease of titration:
      • Propofol's shorter half-life may make it easier to titrate (especially easier to rapidly achieve adequate sedation).
    • [3] Niche neurologic indications:
      • [i] Antiepileptic activity.
      • [ii] May reduce ICP (intracranial pressure).
      • [iii] May treat alcohol withdrawal.

dexmedetomidine gtt ⚡️

  • Disadvantages & contraindications:
    • ⚠️ Higher rate of bradycardia as compared to propofol.
    • ⚠️ Sympatholytic effects may be poorly tolerated among patients with systolic heart failure.
    • ⚠️ Cannot achieve deep sedation (e.g., dexmedetomidine isn't a good choice for ARDS or COPD if you're trying to suppress the respiratory drive).
    • ⚠️ High-dose dexmedetomidine may eventually cause tachyphylaxis and subsequent withdrawal.
  • Advantages:
    • [1] Beneficial for delirium:
      • Promotes physiological, restorative sleep.
      • Reduces the rate of delirium.
      • Avoids deep sedation that may occur with high-dose propofol.
    • [2] Facilitates extubation:
      • May decrease the duration of mechanical ventilation.
      • Helps bridge agitated patients through extubation (may be continued after extubation).
    • [3] Promotes analgesia:
      • Directly provides some adjunctive analgesia.
      • Synergizes well with ketamine.
    • [4] If dexmedetomidine is well tolerated and helpful, it can be transitioned to enteral clonidine or guanfacine.

problems with binary dexmedetomidine vs. propofol studies

  • [1] This is a false dichotomy. Some patients may do best with a multimodal combination of low-dose propofol plus low-dose dexmedetomidine.
  • [2] Propofol is a fundamentally different drug at different dose ranges:
    • Low-dose propofol functions as a sedative (e.g., patients may be arousable and relatively intact).
    • High-dose propofol functions as a general anesthetic (e.g., the EEG is silent and patients are deeply comatose). Use of high-dose propofol probably promotes delirium.
remainder of the regimen

analgesia

  • More useful:
    • Acetaminophen ⚡️:
      • Usually 1,000 mg q6hr scheduled.
      • In compensated cirrhosis, severe EtOHism, or <50 kg: 650 mg q8hr.
    • IV fentanyl PRN pain ⚡️ (avoid infusion if at all feasible).
    • Pain-dose ketamine gtt ⚡️ (basal analgesia; ~0.1-0.3 mg/kg/hr).
      • Useful for patients with difficult-to-treat pain.
      • The risk of psychomimetic side effects is minimized by coadministration with dexmedetomidine or propofol.
  • Also consider:
    • Methocarbamol ⚡️ for musculoskeletal pain or muscle spasm.
    • Pregabalin ⚡️ for neuropathic pain (including major trauma/surgery with nerve damage).

adjunctive sedation

  • More useful:
    • Quetiapine 📖: 50-100 mg PO q12hr.
    • Hydroxyzine 📖: 50-100 mg PO Q6hr.
    • Melatonin ⚡️: 3 mg PO QHS.
  • Also consider:
    • Haloperidol IV PRN ⚡️ (use if tempted to give IV lorazepam).
    • (Valproic acid) ⚡️ may be helpful in refractory agitation.
    • (Dissociative ketamine infusion): If all else fails, another option is a dissociative-dose ketamine infusion (e.g., 1-5 mg/kg/hour). (33068459) This may be necessary for patients with profound hypotension, which limits the ability to give sedatives (e.g., propofol, alpha-2 agonists, or phenobarbital). After the patient is fully dissociated with ketamine, other sedatives and analgesics should be discontinued.

acetaminophen

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drug interactions, side effects 👎

contraindications

  • Discussed in the section below on dosing.

drug-drug interactions

  • Warfarin: Acetaminophen may potentiate warfarin's effect.
  • CYP450 inducers: may increase NAPQI formation via CYP2E1 (e.g., chronic alcohol use, isoniazid, phenytoin, carbamazepine, rifampin).
  • Cholestyramine may decrease the oral bioavailability of acetaminophen (doses should be separated by >2 hours).

side effects

  • Rash, urticaria.
  • Hypotension can occur with the IV infusion.
indications, advantages 👍
  • Analgesia:
    • Acetaminophen is a mild-to-moderately effective analgesic with an outstanding safety profile. It forms the first level of the analgesic ladder due to its safety, rather than its efficacy. Acetaminophen is often overlooked because it isn't very potent. However, scheduled acetaminophen may nonetheless play a useful role in multi-modal analgesia. RCTs and meta-analyses demonstrate that acetaminophen is an effective analgesic in a variety of contexts, with benefits which may include reduced opioid requirements, reduced delirium, and avoidance of nausea/vomiting. (20189753, 30726545, 30305124, 30778597)
    • Acetaminophen is a centrally acting, non-competitive, reversible inhibitor of cyclooxygenase (COX) enzymes, with analgesic and antipyretic effects. (30845871) However, the mechanism is not entirely clear. Acetaminophen may prevent prostaglandin production at the cellular transcriptional level, independent of COX activity. (Paw and Shulman 2025)
  • Antipyretic.
dosing
  • Max 4 grams/day in most patients (650-1,000 mg q6hr).
  • Max 2 grams/day in at-risk patients (650 mg q8hr). (25477978)
    • [1] Severe alcoholism.
    • [2] Stable cirrhosis.
    • [3] Malnutrition.
    • [4] Weight <50 kg.
  • Avoid entirely in:
    • [1] Acute liver injury or decompensated cirrhosis.
    • [2] Neutropenia (may blunt detection of a neutropenic fever).
  • Acetaminophen should be scheduled for patients with ongoing pain to provide a baseline level of analgesia.
  • Route:
    • Acetaminophen may be given PO, PR, or IV.
    • PO is preferred over IV due to cost. Available RCTs have found no difference in efficacy between the IV and oral routes.
    • PR is not preferred; it's dubious whether the benefits of acetaminophen are worth the invasiveness of scheduled q6hr PR medication administration.
  • Renal failure: No dose adjustment.
pharmacology
  • Absorption:
    • Oral bioavailability is ~70-90%.
    • Rectal bioavailability may be as low as 24%. (Scarth & Smith 2016)
  • Distribution:
    • Vd of ~0.9 L/kg.
    • Protein binding is low (10-25%).
    • Acetaminophen does penetrate the blood-brain barrier.
  • Metabolism occurs via three pathways:
    • [1] Glucuronidation (~60%) by UGT1A1 and UGT1A6.
    • [2] Sulfation (30-35%) by SULT1A1 and SULT1A3.
    • [3] Oxidation (mostly via CYP2E1) to a toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is detoxified by conjugation with glutathione. Fomepizole inhibits CYP2E1, so it may be used to treat massive acetaminophen intoxication.
  • Elimination:
    • Renal elimination of metabolites.
  • Half-life & duration of action:
    • Half-life is ~2-3 hours in healthy adults.

methocarbamol

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contraindications, drug interactions, side effects 👎

contraindications

  • Contraindications for IV methocarbamol:
    • [1] Hypotension or tenuous hemodynamics (IV methocarbamol tends to cause hypotension, particularly if infused rapidly).
    • [2] Intravenous methocarbamol is contraindicated in renal failure (due to polyethylene glycol 300 in the vehicle).
  • Myasthenia gravis.

drug-drug interactions

  • Methocarbamol may reduce the levels of pyridostigmine.

side effects

  • Common side effects may include sedation and dizziness (although methocarbamol may be less sedating than most other muscle relaxants).
  • Less frequent side effects may include seizure, leukopenia, and cholestatic jaundice. (33351427)
indications, advantages 👍
  • Methocarbamol is generally utilized as an adjunct for acute musculoskeletal pain, including:
    • Muscle spasm with associated pain (especially due to herniated intervertebral discs).
    • Rib fractures or painful chest tube sites.
    • Perioperative pain (orthopedic surgery, cardiothoracic surgery). (Jung H, Chae HK)
  • Methocarbamol is ineffective for muscle spasms due to upper motor neuron injury. (33351427)
dosing
  • There is a roughly  1:1 conversion between PO and IV methocarbamol.
  • PO methocarbamol:
    • The usual dose is 1,000-1,500 mg PO Q6hr.
  • IV methocarbamol:
    • A typical regimen is 1,000 mg IV Q8hr.
    • ⚠️ Renal dysfunction: IV formulation is contraindicated due to the polyethylene glycol excipient. Unfortunately, there isn't a clear definition of exactly what constitutes renal dysfunction.
  • Cirrhosis: consider dose reduction (not well defined).
pharmacology
  • Chemical properties:
    • Molecular weight: 241 g/mol
    • LogP: 0.8
  • Absorption:
    • Gastrointestinal absorption is rapid, with onset within 30 minutes and peak effect at two hours. (33351427)
    • Absorption appears to be high (perhaps ~90%), consistent with a 1:1: conversion between PO and IV methocarbamol.
  • Distribution:
    • Protein binding is 50%.
    • It is widely distributed throughout the body (including penetration of the blood-brain barrier).
  • Metabolism:
    • Hepatic metabolism via dealkylation and hydroxylation.
  • Elimination:
    • Urinary elimination of metabolites (only 10-15% is excreted unchanged in the urine).
  • Half-life & duration of action:
    • The half-life is 1-2 hours (potentially longer in elderly patients or hepatic dysfunction).

NSAIDs

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candidates for receiving NSAIDs in the ICU

  • 🛑 NSAIDs are generally not preferred in the ICU due to risks of gastrointestinal hemorrhage, platelet dysfunction, or (especially) renal failure.
  • NSAIDs may be considered selectively for patients at low risk of complications:
    • [1] Low risk for AKI:
      • [a] Chronic dialysis patient with anuria (further renal injury is impossible).
      • -or-
      • [b] Robust kidney function without other nephrotoxic medications or impaired perfusion.
    • [2] Reasonably low risk for GI hemorrhage:
      • Absence of cirrhosis or inflammatory bowel disease.
      • No history of GI ulceration/bleeding.
      • On PPI to prevent GI hemorrhage.
    • [3] No active hemorrhage or severe coagulopathy (especially, no platelet dysfunction).
    • [4] No history of aspirin or NSAID sensitivity (i.e., aspirin-exacerbated respiratory disease 📖). AERD may be suggested by Samter's triad of asthma, nasal polyposis, and sensitivity to aspirin/NSAIDs.
    • [5] No cirrhosis.
    • [6] No inflammatory bowel disease (may cause flare).

relative risk

  • Risk of acute kidney injury:
    • 🏆 COX-2 selective NSAIDs (especially celecoxib) have a lower risk of AKI as compared to nonselective NSAIDs. (16941030, 19585463, 10826459, 17005625)  
    • Ibuprofen might possibly have a somewhat lower risk compared to other nonselective COX inhibitors. (33910887) However, the risk seems to be relatively uniform among nonselective COX inhibitors. Risk of chronic renal insufficiency among outpatients may not translate perfectly into the risk of acute kidney injury among inpatients.
  • Risk of gastrointestinal hemorrhage:
    • COX-2 selective NSAIDs (e.g., celecoxib) have lower GI bleeding risks than nonselective NSAIDs.
    • Rough relative risks for GI hemorrhage (sources vary somewhat):
      • Celecoxib: ~1.5
      • Diclofenac: ~3.3
      • Ibuprofen: ~1.8
      • Indomethacin: ~4
      • Ketorolac: ~11.5
      • Meloxicam: ~3.5
      • Naproxen: ~5.6
  • Risk of myocardial infarction: Meta-analyses suggest the relative risks: (28487435)
    • Celecoxib: 1.2 (95% CI 0.91-1.82)
    • Diclofenac 1.5 (95% CI 1.06-2.04)
    • Ibuprofen: 1.5 (95% CI 1 – 2.26)
    • Indomethacin: 1.4
    • Ketorolac: 2.1
    • Meloxicam: 1.3
    • Naproxen: 1.5 (95% CI 1.07-2.33)

dose ceiling 

  • The key principle of NSAID dosing is the concept of the dose ceiling. Above a certain dose, further increases will only increase toxicity (without increasing efficacy). Recent evidence demonstrates that the dose ceiling is often lower than was previously thought. This is useful because it reveals that we can obtain the same efficacy while using smaller, safer doses.
  • 🛑 Don't give a dose higher than the dose ceiling! Doses below the dose ceiling may still remain useful, however (e.g., 300 mg of ibuprofen).

COX-1 vs. COX-2

  • COX-1 (constitutive form) roles:
    • Prostaglandins that control renal blood flow.
    • Prostaglandins that protect the gastric mucosa.
    • Thromboxane synthesis (affects platelets and coagulation).
  • COX-2 (inducible form) roles:
    • Inflammatory response to tissue damage.
    • Production of prostacyclin (PGI2) in vascular endothelium (blockade may promote platelet aggregation, vasoconstriction, and thromboembolism).

NSAID chemical families

  • Propionic acids:
    • Ibuprofen (nonselective COX inhibitor).
    • Naproxen (nonselective COX inhibitor).
  • Acetic acid derivatives:
    • Diclofenac (COX 2 > COX 1).
    • Ketoralac (nonselective COX inhibitor).
    • Indomethacin (nonselective COX inhibitor).
  • Oxicams (meloxicam). Inhibit COX2 >> COX1.
  • COX-2: Celecoxib.
celecoxib
  • Contraindications:
    • Class contraindications are discussed above; unique contraindications:
    • [1] Sulfonamide allergy.
    • [2] CYP2C9 inhibitors.
    • [3] Perioperative pain following CABG.
  • Drug-drug interactions:
    • Inhibitors of CYP2C9 increase exposure.
    • Celecoxib is a moderate inhibitor of CYP2D6.
  • Dosing for analgesia:
    • Acute pain: 400 mg loading dose followed by 200 mg BID.
    • Osteoarthritis: 200 mg daily (or 100 mg BID) provides maximal benefit.
    • Limit the dose to ≦400 mg/day.
    • Moderate hepatic impairment: reduce the dose by 50%.
  • Absorption:
    • Peak level within 2-4 hours of administration.
    • Elderly patients may have greater peak concentrations and AUC.
  • Distribution:
    • Protein binding is 97% (mostly to albumin).
    • Vd is ~5.7 L/kg. (Peck 2021) 
  • Metabolism:
    • ~90% is metabolized via CYP2C9 into inactive metabolites.
    • Minor roles for CYP3A4 and CYP2C8.
  • Elimination:
    • <3% of the drug is excreted unchanged.
  • Half-life & duration of action:
    • The half-life is 11 hours in healthy adults, but may extend to 13 hours in the elderly or those with hepatic impairment.
diclofenac
  • Contraindications:
    • [1] Class contraindications are discussed above.
    • [2] Celecoxib or ibuprofen is safer.
  • Drug-drug interactions:
    • CYP2C9 inhibitors or inducers.
    • CYP3A4 inducers may reduce diclofenac levels.
    • Methotrexate (increases methotrexate levels).
    • Aspirin (may impair aspirin effectiveness; may increase risk of bleeding).
  • Dosing:
    • Usual dose: 50 mg PO 2-3 times daily.
    • The maximal dose for analgesia is ~150 mg/day. (Peck 2021)
    • Renal failure: No dose adjustment, but NSAIDs are generally inadvisable in renal dysfunction (see discussion above regarding who are good candidates to receive NSAIDs in the ICU).
  • Absorption:
    • Rapidly and completely absorbed, but first-pass metabolism reduces bioavailability to 50%.
    • Peak plasma concentrations occur within about half an hour. However, enteric-coated tablets may delay absorption by about an hour.
  • Distribution:
    • Vd ~0.15 L/kg.
    • Protein binding is >99% (mostly albumin).
    • Substantial levels achieved in synovial fluid.
  • Metabolism:
    • Extensive hepatic metabolism, primarily via CYP2C9 (also CYP2C8, CYP3A4, and UGT2B7).
  • Elimination:
    • Little to no unchanged drug is excreted.
  • Half-life & duration of action:
    • Terminal half-life is ~2 hours (but synovial fluid concentrations may last longer).
  • Mechanism of action:
    • Nonspecific COX inhibitor.
    • It may also inhibit the lipo-oxygenase pathway by acting on hydroperoxy fatty acid peroxidase. (Scarth & Smith 2016)
ibuprofen
  • Contraindications:
    • Class contraindications are discussed above.
  • Drug-drug interactions:
    • CYP2C9 inhibitors and inducers.
  • Indications/advantages
    • Among nonspecific COX inhibitors, ibuprofen might have the best safety profile.
    • Lower doses (e.g., 400 mg TID) aren't associated with prothrombotic events. (Peck 2021)
  • Dosing for analgesia:
    • 400 mg is considered the ceiling for analgesic effect, as higher doses don't provide superior pain relief. (31383385)
    • Typical dose: 200-400 mg Q4-8hrs PRN.
    • Maximal daily dose: 2,400 mg/day (400 mg Q4hr).
    • Renal failure doesn't affect pharmacokinetics (but avoid ibuprofen due to risk of exacerbating nephrotoxicity, except in anuric end-stage renal failure on hemodialysis). (Wellington 3e)
  • Absorption:
    • Rapidly and almost completely absorbed (85% bioavailability).
    • Peak levels are achieved within ~1-2 hours.
  • Distribution:
    • Vd is ~0.15 L/kg.
    • Protein binding is >99% (mostly to albumin).
    • Substantial concentrations are achieved in the synovial fluid.
  • Metabolism:
    • Extensive hepatic metabolism via oxidation, mostly by CYP2C9 (75%), also CYP2C8 (15%) and CYP3A4 (7%).
  • Elimination:
    • Nearly no drug is eliminated unchanged.
  • Half-life & duration of action:
    • Half-life is 1.8-2 hours.
indomethacin
  • Contraindications:
    • Class contraindications are discussed above.
  • Drug-drug interactions:
    • CYP2C9 inhibitors or inducers.
  • Dosing for acute pain:
    • For mild-moderate acute pain: 20-25 mg TID, or 40-50 mg BID-TID.
    • Higher doses may be considered to treat inflammation.
    • The total daily dose shouldn't exceed 150-200 mg.
  • Absorption:
    • Bioavailability is ~100%.
    • Peak levels are reached after ~2 hours.
  • Distribution:
    • Protein binding is ~99%.
  • Metabolism:
    • Mostly metabolized via CYP2C9. Some metabolism via UGT enzymes.
    • Enterohepatic recirculation may cause plasma levels to be somewhat erratic.
  • Elimination:
    • Urine and feces (inactive metabolites).
  • Half-life & duration of action:
    • Half-life is ~4.5 hours.
ketorolac
  • Contraindications:
    • Class contraindications are discussed above.
    • ⚠️ Ketorolac is one of the most toxic NSAIDs (in terms of gastrointestinal bleeding and myocardial infarction). It is commonly utilized because it is available in an intravenous formulation. For patients able to take oral medication, there seems to be little reason to use oral ketorolac.
  • Drug-drug interactions:
    • CYP2C8/9 inhibitors or inducers.
  • Dosing:
    • For patients <65 years old, without renal impairment, and weight >50 kg: 10-15 mg IV Q6hr PRN.
    • For patients >65 years old, with renal impairment, or weight <50 mg: 7.5 mg q6hrs or the drug should be avoided entirely.
    • Limit therapy duration to <5 days.
    • Although 30-mg doses are often recommended, a dose ceiling exists around 10-15 mg. Therefore, 30-mg doses are unnecessarily high. (37178102)
    • Renal failure: Avoid ketorolac, as it is nephrotoxic and also cleared by the kidneys.
  • Absorption:
    • Oral bioavailability: 80-100%, with peak level 20-60 minutes after administration.
  • Distribution:
    • Vd 0.25 L/kg.
    • Protein binding is >99% (mostly albumin).
  • Metabolism:
    • Hydroxylation via CYP2C8 and CYP2C9.
    • Glucuronidation via UGT2B7.
  • Elimination:
    • 92% excreted in the urine (60% as unchanged drug, 40% as metabolites).
    • 6% excreted in the feces.
    • Renal impairment causes accumulation and requires dose reduction (unlike most NSAIDs, wherein renal impairment causes accumulation of inactive metabolites).
  • Half-life & duration of action:
    • S-ketorolac (which is responsible for therapeutic effects): 2.5 hours.
    • R-ketorolac: 5 hours.
meloxicam 
  • Contraindications:
    • Class contraindications are discussed above.
    • Perioperative period after CABG surgery.
    • Severe hepatic impairment (may worsen hepatic injury).
  • Drug-drug interactions:
    • CYP2C9 inhibitors or inducers.
    • CYP3A4 inducers.
  • Advantages/general comments:
    • Meloxicam is 3-50 times more effective on COX-2 than COX-1.
    • Clinically, it functions similarly to nonselective COX inhibitors.
  • Dosing:
    • 5-10 mg/day.
    • Hemodialysis: maximum dose 5 mg/day (although not renally cleared, an increased free drug level may occur).
    • Maximal dose: 10 mg/day.
  • Absorption:
    • Bioavailability is ~95% with peak levels after 2 hours (fasting) or 5-6 hours (with food).
  • Distribution:
    • Vd is ~0.3 L/kg.
    • Protein binding is >99% (mostly to albumin).
  • Metabolism:
    • Extensively metabolized in the liver.
    • CYP2C9 (major) and CYP3A4 (minor).
    • CYP2C9 genetic polymorphisms can significantly affect exposure.
    • Significant enterohepatic circulation occurs (e.g., cholestyramine reduces exposure by ~50%).
  • Elimination:
    • Virtually no drug is excreted unchanged.
  • Half-life & duration of action:
    • Half-life varies between ~15-24 hours.
naproxen
  • Contraindications:
    • Class contraindications are discussed above.
    • Avoid in GFR <30 ml/min due to accumulation of conjugates as well as nephrotoxicity.
    • Status post CABG surgery.
  • Drug-drug interactions:
    • CYP2C9 inhibitors may increase exposure.
  • Dosing:
    • Over-the-counter dosing: 220-225 mg q8-q12 PRN (max daily dose ~750 mg).
    • For acute pain: the usual dose is 500 mg q12hr or 250 mg PRN q6-8 hours.
    • The maximal dose is 1250 mg on the first day and 1000 mg/day subsequently.
  • Absorption:
    • Oral bioavailability is ~95%.
  • Distribution:
    • Vd is ~0.15 L/kg.
    • Protein binding is >99% (mostly to albumin).
  • Metabolism:
    • Extensive hepatic metabolism involving CYP1A2, CYP2C8, and CYP2C9.
    • CYP2C9 polymorphisms may reduce clearance, increasing toxicity.
  • Elimination:
    • <1% is eliminated as unchanged drug.  However, in renal insufficiency, metabolites can accumulate, necessitating dose adjustment or avoidance.
  • Half-life & duration of action:
    • Half-life is 12-17 hours.

opioids

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The choice of opioid depends largely on your hospital and unit's usual practices. Below are some preferences. Overall, however, by far the most important aspect is to titrate the dose correctly. Most opioids will work fine if they are dose-titrated correctly.  

selection of a PRN IV opioid for intubated patients

  • General principles of opioid selection on the ventilator:
    • Respiratory suppression isn't a problem (and might help improve ventilator synchrony).
    • A little sedation is potentially beneficial.
    • Short duration of activity is helpful to facilitate extubation (allows you to hold opioid and have it wear off quickly).
  • 1st line = PRN IV fentanyl:
    • Rapid onset (allows dose-titration without dose-stacking).
    • Lack of histamine release promotes hemodynamic stability.
    • Lower risk of nausea/vomiting as compared to morphine. (30418234)
    • Renal failure doesn't cause accumulation of active metabolites.
  • 2nd line = PRN IV hydromorphone:
    • Lack of histamine release promotes hemodynamic stability.
    • May be utilized for longer-lasting effects (if patients require very frequent IV fentanyl).
  • 3rd line = PRN IV morphine:
    • It may be the least desirable due to its longer half-life.
    • ⚠️ Contraindicated in renal failure (GFR <30 ml/min/1.73m2).

selection of an IV opioid for nonintubated patients

  • General principles of opioid selection off the ventilator:
    • Respiratory suppression is more problematic (not intubated).
    • Higher priority on avoiding more euphorogenic and habit-forming opioids (patients are awake and involved in requesting additional opioids).
  • 1st line = IV nalbuphine (for patients without contraindications):
    • Fewer side effects than morphine (less nausea/vomiting, less respiratory suppression, less pruritus).
    • Lowest abuse potential.
    • A ceiling on respiratory suppression provides safety in the event of dose stacking.
    • ⚠️ Contraindicated in patients with opioid tolerance, chronic opioid use, or extremely severe pain with high expected opioid requirement.
  • 2nd line = IV morphine:
    • Effective.
    • Less habit-forming than most other opioids.
    • Reasonable duration of activity.
    • ⚠️ Contraindicated in renal failure (GFR <30 ml/min/1.73m2).
  • 3rd line = IV hydromorphone:
    • Fewer side effects than morphine, but it is more habit-forming.
    • ⚠️ Contraindicated in severe renal failure (GFR << 30 ml/min/1.73m2).

selection of an oral opioid for non-intubated patients

  • 1st line = Oral morphine 🏆:
    • Minimal drug-drug interactions.
    • Not euphorogenic, so it has the least abuse potential and tends not to be over-utilized as a sedative.
    • ⚠️ Contraindicated in renal failure (GFR <30 ml/min/1.73m2).
  • 2nd line = Oral HYDROmorphone:
    • Minimal drug-drug interactions.
    • ⚠️ Contraindicated in severe renal failure (GFR << 30 ml/min/1.73m2).
  • 3rd line = Oral oxycodone:
    • It might have the highest abuse potential.
    • Subject to CYP3A4 and CYP2D6 interactions (but not as dependent on CYP2D6 as hydrocodone).
    • ⚠️ Contraindicated in hepatic dysfunction.
  • 4th line = Oral hydrocodone-acetaminophen:
    • The fixed combination makes titration challenging.
    • Subject to CYP3A4 and CYP2D6 interactions.
    • The only advantage over oxycodone is its somewhat lower abuse potential.
    • ⚠️ Contraindicated in hepatic dysfunction.
fentanyl (IV)
  • Disadvantages/Contraindications:
    • ⚠️ Contraindicated in serotonin syndrome.
    • ⚠️ Continuous fentanyl infusions are often problematic. When infused, fentanyl accumulates in fat, and its half-life is extended (may cause delayed awakening). CYP3A4 inhibitors may reduce metabolism. (Further discussion: 🌊)
    • ⚠️ If high doses of fentanyl are utilized for prolonged periods, the fat tissues may become saturated with fentanyl, leading to a prolonged (context-dependent) half-life.
  • Drug-drug interactions:
    • CYP3A4 inducers and inhibitors.
    • Serotonergic drugs (increased risk of serotonin syndrome).
  • Side effects:
    • High doses may cause chest rigidity (rare with the doses discussed here).
    • Discussion of opioid side-effects & their management is below.
  • Indications/advantages:
    • General advantages of PRN fentanyl are discussed in the section above on opioid selection..
    • Procedural sedation: Rapid onset of action with a relatively limited duration of effect makes fentanyl useful for procedural sedation.
  • Dosing:
    • Typical dose for nurse-driven PRN dosing
      • Bolus: ~50–100 mcg q30–60 min.
      • Infusion: ~ 25–100 mcg/hour (but please avoid if possible: 🌊).
    • Initial PCA dosing 
      • Demand 20–50 mcg.
      • Lockout 5–10 minutes.
    • Onset & duration of action
      • Onset ~1–2 minutes.
      • Peak ~6–15 minutes.
      • Duration: ~0.5–2 hours (longer in liver failure or after prolonged infusion).
    • Roughly equianalgesic doses
      • 5 mg IV morphine
      • 15 mg PO morphine (1/3 as strong as IV).
      • 50 mcg IV fentanyl (10x morphine dose in mg).
      • 0.75 mg IV HYDROmorphone (7x more potent than IV morphine).
      • 6 mg IV nalbuphine.
      • 3.75 mg PO HYDROmorphone (4x more potent than PO morphine).
      • 10 mg oxycodone (1.5x stronger than PO morphine).
      • 15 mg HYDROcodone (1.5x weaker than PO oxycodone).
      • 150 mg tramadol (10x less potent than PO morphine).
  • Absorption:
    • IV administration.
  • Distribution:
    • Initially, there is rapid distribution to highly perfused tissues (e.g., brain, heart, lungs, and kidneys). Subsequently, fentanyl redistributes to the muscle and fat.
    • Protein binding is high (80-85%), mostly to alpha-1-acid glycoprotein.
    • Vd is ~4 L/kg.
    • LogP is 2.9 (much higher than morphine's LogP of 0.88).
  • Metabolism:
    • Primarily metabolized by CYP3A4 to norfentanyl (an inactive metabolite).
  • Elimination:
    • Inactive metabolites (mostly norfentanyl) are renally cleared.
  • Half-life & duration of action:
    • Terminal elimination half-life is ~5-12 hours.
nalbuphine (IV)
  • Disadvantages/Contraindications:
    • The primary contraindicates relate to opioid use disorder:
      • Risk of precipitated withdrawal: Nalbuphine is a partial μ-receptor agonist, so it may precipitate withdrawal similar to buprenorphine.
      • Active opioid withdrawal: Nalbuphine has inadequate μ-receptor agonism to work well here. (29733100)
    • Substantial opioid tolerance: Nalbuphine may be unable to overcome opioid tolerance due to limited efficacy at μ-receptors.
    • (Extremely severe pain that is expected to have a high opioid requirement. However, if nalbuphine fails to work, then a traditional full μ-receptor agonist can be subsequently added to control the pain. A somewhat higher dose might be required, but nalfphine won't block the full μ-receptor agonist from working.)
  • Drug-drug interactions:
    • Nalbuphine has minimal pharmacokinetic drug-drug interactions.
    • Serotonergic medications & MAO inhibitors: may increase the risk of serotonin syndrome.
    • Traditional opioids (full μ-receptor agonists): nalbuphine may reduce their efficacy and also reduce their side-effects (especially respiratory depression and pruritus). The combination of nalbuphine and traditional opioids can be used together to good effect, but this needs to be done with intention and thoughtfulness.
  • Side effects:
    • Usual opioid side effects (e.g., sedation, nausea/vomiting, constipation).
    • Sweating.
    • Serotonin syndrome.
    • Dysphoria can occur (but not at higher levels than with morphine). (9067299) Dysphoria and hallucinations may be more likely at higher doses, due to overstimulation of kappa opioid receptors and/or beta-arrestin-2 receptors.
    • (General discussion of opioid side-effects & their management is below.)
  • Indications & advantages compared to conventional opioids:
    • 🏆 Lower incidence of respiratory depression. Due to partial agonism at the μ-receptor, nalbuphine exhibits a ceiling effect for respiratory suppression (similar to buprenorphine). Beyond a moderate dose of nalbuphine, additional doses won't increase respiratory suppression. Compared with morphine, a meta-analysis shows that nalbuphine causes less respiratory depression (pooled odds ratio of 0.27; 95% confidence interval of 0.12-0.57). (26039709)  Indeed, nalbuphine might actually be able to treat respiratory depression caused by full μ-opioid agonists (by knocking the full agonists off the μ-receptors). There are case reports of using 10-20 mg IV nalbuphine to reverse respiratory suppression caused by full opioid agonists, without loss of analgesia. (6150248, 6465575, 3277486) 
    • 🏆 Lower incidence of nausea/vomiting. A meta-analysis found that, compared with morphine, nalbuphine is less likely to cause emesis (pooled odds ratio of 0.65; 95% confidence interval of 0.5-0.85). (26039709)
    • 🏆 No active metabolite accumulation in renal failure: Nalbuphine is metabolized primarily into an inactive metabolite (nalbuphine-6-glucuronide). This metabolite accumulates in renal failure but remains inactive, so its accumulation is irrelevant. In contrast, both morphine and hydromorphone have active metabolites that may accumulate in renal failure, leading to toxicity.
    • 🏆 Lower potential for dependence and abuse. Similar to buprenorphine's mixed agonist/antagonist effect, nalbuphine appears to have a relatively low potential for dependence or abuse. Indeed, nalbuphine is the only opioid that isn't a federally controlled substance in the USA. (29649890)
    • 🏆 Lower incidence of pruritus: Meta-analysis shows that, as compared to morphine, nalbuphine has a reduced likelihood of causing pruritus (pooled odds ratio of 0.17; 95% confidence interval of 0.09-0.34). (26039709) Nalbuphine can actually be used to treat pruritus caused by uremia. (29733100) Low doses of nalbuphine may also be effective to treat opioid-induced pruritus (e.g., 2.5-5 mg). (29733100, 41255954)
    • 🏆 Hemodynamic stability: Even enormous doses (e.g., 5 mg/kg) have been used after cardiac surgery without causing hemodynamic perturbations. (29733100)
    • 🏆 Effective for shivering: Nalbuphine exhibits anti-shivering activity comparable to meperidine. (10072029) 
  • Dosing:
    • The conversion from morphine: nalbuphine is roughly 0.8:1 (i.e., 8 mg of IV morphine is equivalent to 10 mg of IV nalbuphine). (340643, 38496295) Nalbuphine is well supported in the literature as being an effective analgesic, but an adequate dose needs to be given.
    • A typical regimen is 5-10 mg IV, administered up to every 3 hours as needed. If 10 mg IV is inadequate, an additional 10 mg may be given after >3 minutes. (15107384)
    • The maximal dose is 20 mg IV every 3 hours PRN (maximal total daily dose of 160 mg IV).
    • Renal or hepatic impairment: Caution, dose reduction may be necessary; monitor closely.
    • Roughly equianalgesic doses
      • 5 mg IV morphine
      • 15 mg PO morphine (1/3 as strong as IV).
      • 50 mcg IV fentanyl (10x morphine dose in mg).
      • 0.75 mg IV HYDROmorphone (7x more potent than IV morphine).
      • 6 mg IV nalbuphine.
      • 3.75 mg PO HYDROmorphone (4x more potent than PO morphine).
      • 10 mg oxycodone (1.5x stronger than PO morphine).
      • 15 mg HYDROcodone (1.5x weaker than PO oxycodone).
      • 150 mg tramadol (10x less potent than PO morphine).
  • Chemical properties:
    • Molecular weight 394 g/mol.
    • LogP of 2 (moderately lipophilic).
  • Absorption:
    • IV administration is generally utilized (although SC and IM are also possible).
    • The onset of analgesia occurs within 2-5 minutes after IV administration, with peak effects typically occurring at ~30 minutes.
  • Distribution:
    • Protein binding is 25-40%.
    • Vd is large (100-200 L).
    • Readily crosses the blood-brain barrier.
  • Metabolism:
    • Metabolism in the liver:
      • 75% cleared by glucuronidation (mainly UGT2B7, UGT1A3, UGT1A9).
      • 25% cleared by CYP2C9 and CYP2C19.
    • The primary metabolite (nalbuphine-6-glucuronide) is inactive.
  • Elimination:
    • Elimination is via the bile and urine (mostly of metabolites).
    • Enterohepatic recirculation may occur, but doesn't seem clinically significant.
  • Half-life & duration of action:
    • The plasma elimination half-life is ~2-5 hours after IV administration. (29733100)
    • The half-life may be prolonged by 50-100% in moderate/severe hepatic dysfunction.
    • Renal failure increases systemic exposure by 50-85%. (29649890) Nalbphine metabolites are inactive, but they may potentiate back-inhibition of hepatic metabolism of nalbuphine. Additionally, renal failure may down-regulate hepatic CYP enzymes. Finally, renal failure impairs hepatic uptake transports, especially organic anion transport polypeptides (OATPs). Nalbuphine isn't dialyzed, so post-dialysis pain exacerbation isn't a problem. (29733100)
  • Mechanism of action:
    • Basics:
      • Nalbuphine acts largely as a kappa opioid agonist in the spinal cord. This inhibits pain transmission and is involved in nalbuphine's antipruritic effects.
      • Nalbuphine is a partial agonist at the mu opioid receptors in the brain (similar to buprenorphine). Partial agonism at the mu receptor explains the ceiling effect for respiratory suppression and also why nalbuphine has a lower abuse potential (as compared to full mu opioid agonists). Please note that there is some controversy surrounding this, with some older sources stating that nalbuphine is simply a mu antagonist.
      • Nalbuphine is also an agonist at 6 transmembrane (TM) mu receptors and a partial beta-arrestin agonist.
    • Nalbuphine causes minimal histamine release (probably not clinically significant at usual analgesic doses).
    • Nalbuphine causes fewer side effects that are mediated by the μ-opioid receptor, specifically:
      • Respiratory depression.
      • Pruritus.
      • Nausea/vomiting (which seems to result from stimulation of μ-opioid receptors in the chemoreceptor trigger zone of the area postrema of the medulla).
HYDROmorphone (IV/PO)
  • Contraindications/Disadvantages:
    • [1] Renal failure: The accumulation of HYDROmorphone-3-glucuronide may cause seizure, myoclonus, or agitation. However, this is generally not a significant problem (it occurs primarily in a palliative context with high doses). HYDROmorphone-3-glucuronide is less toxic than morphine-3-glucuronide. Consequently, morphine should typically be avoided when GFR <30 ml/min/1.73m2, but hydrophone can often be continued cautiously. There is no specific GFR cutoff below which hydromorphone should be discontinued. In severe renal failure (GFR <<30 ml/min/1.73m2), better options may be fentanyl, nalbuphine, or oxycodone.
    • [2] Relatively euphorogenic and sedating (especially IV administration). This may cause HYDROmorphone to be misused for anxiety or agitation (rather than pain). However, these properties may be helpful for palliative therapy.
  • Drug-drug interactions:
    • Minimal CYP involvement decreases drug-drug interactions as compared to other opioids.
    • UGT enzyme inducers: Rifampin reduces exposure.
    • Serotonergic medications (potential risk of serotonin syndrome).
  • Side effects:
    • Discussion of opioid side-effects & their management is below.
  • Indications/advantages:
    • Compared to fentanyl, a longer duration of action may be helpful for some patients who require frequent dosing.
    • HYDROmorphone may remain effective in patients who have become tolerant of morphine or fentanyl (opioid rotation).
    • HYDROmorphone causes relatively little histamine release, which may allow it to be better tolerated in some patients than morphine or oxycodone.
  • Dosing:
    • IV: Typical dose for nurse-driven PRN dosing
      • Bolus: ~0.4–1 mg q1-2 hours.
      • Infusion: ~0.4–3 mg/hour.
    • IV: Initial PCA dosing 
      • Demand 0.2–0.5 mg.
      • Lockout 10–15 minutes.
    • IV: Onset & duration of action
      • Onset: ~5–15 minutes.
      • Peak: ~10–20 minutes.
      • Duration: ~2–4 hours (longer in liver failure or advanced renal failure).
    • PO: Dosing
      • Oral HYDROmorphone is ~4x more potent than oral morphine (this is different from the IV conversion due to variation in bioavailability). (Critical Care Pharmacotherapy 2e)
      • Typical dosing:
        • Opioid naive: 2-4 mg PO q4hr PRN.
        • Opioid tolerant: 4-8 mg PO q4hr PRN.
    • Renal failure: Discussed above under the contraindications section.
    • Hepatic impairment: Reduced metabolism increases exposure; reduce the dose.
    • Roughly equianalgesic doses
      • 5 mg IV morphine
      • 15 mg PO morphine (1/3 as strong as IV).
      • 50 mcg IV fentanyl (10x morphine dose in mg).
      • 0.75 mg IV HYDROmorphone (7x more potent than IV morphine).
      • 6 mg IV nalbuphine.
      • 3.75 mg PO HYDROmorphone (4x more potent than PO morphine).
      • 10 mg oxycodone (1.5x stronger than PO morphine).
      • 15 mg HYDROcodone (1.5x weaker than PO oxycodone).
      • 150 mg tramadol (10x less potent than PO morphine).
  • Absorption:
    • IV: 100% bioavailable.
    • PO: Oral bioavailability is ~60% due to first-pass metabolism. Peak levels occur within 30-60 minutes.
  • Distribution:
    • Protein binding is low (~15%).
    • Vd is large (4 L/kg).
    • High lipid solubility causes rapid penetration of the blood-brain barrier.
    • LogP is 1.23
  • Metabolism:
    • Hepatic metabolism via glucuronidation via UGT2B7 yields an active metabolite (HYDROmorphone-3-glucuronide). This metabolite lacks analgesic properties, but it may cause neurotoxic effects (e.g., myoclonus).
  • Elimination:
    • The active metabolite, HYDROmorphone-3-glucuronide, is renally cleared.
  • Half-life & duration of action:
    • Half-life is ~2.5 hours.
morphine (IV/PO)
  • Contraindications/Disadvantages:
    • GFR <30 ml/min: Metabolites (M3G and M6G) accumulate; should be avoided.
    • Histamine release may cause pruritus, bronchospasm, and/or vasodilation.
    • The relatively longer duration of action makes titration difficult (as compared to IV fentanyl or HYDROmorphone). However, this could be beneficial for a morphine PCA.
  • Drug-drug interactions:
    • Serotonergic drugs (may increase risk of serotonin syndrome).
    • Oral P2Y12 inhibitors: morphine delays and reduces absorption.
  • Side effects:
    • Morphine causes more histamine release than most other opioids listed here.
    • Discussion of opioid side-effects & their management is below.
  • Indications/advantages:
    • It is the least euphorogenic agent (aside from perhaps nalbuphine, although one study found that morphine and nalbuphine were similar in this regard). (9067299) This may tend to avoid inappropriate use of morphine as a sedative agent and may reduce the likelihood of causing opioid use disorder.
  • Dosing:
    • IV: Typical dose for nurse-driven PRN dosing
      • Bolus: ~4–8 mg q1-2 hours.
      • Infusion: ~2–30 mg/hour (palliative care utilization only).
    • IV: Initial PCA dosing 
      • Demand 1–3 mg.
      • Lockout 10–20 minutes.
    • IV: Onset & duration of action
      • Onset ~5–10 minutes.
      • Peak ~15–30 minutes.
      • Duration ~3–5 hours (longer in liver failure or advanced renal failure).
    • PO Dosing:
      • PO morphine is ~1/3 as potent as IV morphine.
      • Typical dosing:
        • Opioid naive: 10-15 mg PO q4hr PRN.
        • Opioid tolerant: 15-30 mg PO q4hr PRN.
    • Cirrhosis: Increased exposure to PO morphine and prolonged half-life; dose reduction required.
    • Renal failure: Accumulation of M3G and M6G increases neurotoxicity risk; morphine is contraindicated if GFR <30 ml/min.
    • Roughly equianalgesic doses
      • 5 mg IV morphine
      • 15 mg PO morphine (1/3 as strong as IV).
      • 50 mcg IV fentanyl (10x morphine dose in mg).
      • 0.75 mg IV HYDROmorphone (7x more potent than IV morphine).
      • 6 mg IV nalbuphine.
      • 3.75 mg PO HYDROmorphone (4x more potent than PO morphine).
      • 10 mg oxycodone (1.5x stronger than PO morphine).
      • 15 mg HYDROcodone (1.5x weaker than PO oxycodone).
      • 150 mg tramadol (10x less potent than PO morphine).
  • Absorption:
    • IV: 100%.
    • PO:
      • ~30% bioavailability due to first-pass metabolism.
      • Morphine is a weak base (pKa=8) that is ionized in the acidic stomach. It is only absorbed when it reaches the small intestine. (Peck 2021)
      • Peak plasma concentration occurs after about 90 minutes.
    • Subcutaneous: 100% bioavailable, sometimes used for palliative care. However, subcutaneous absorption is slow. (Peck 2021)
  • Distribution:
    • Vd ~4 L/kg (reduced in the elderly, causing higher peak plasma levels). (Peck 2021)
    • Protein binding is ~33%.
    • Morphine's ability to penetrate the blood-brain barrier is middling.
    • LogP is 0.88
  • Metabolism:
    • Morphine is primarily metabolized via glucuronidation (UGT2B7) to:
      • 50% morphine-3-glucuronide (M3G), which can cause neurotoxicity (e.g., myoclonus) and hyperalgesia (mu receptor antagonist!).
      • 10% morphine-6-glucuronide (M6G), which has opioid activity that is 13 times more potent than morphine. Accumulation of M6G may cause sedation and respiratory suppression.
    • Metabolism predominantly occurs in the liver, but also in the kidneys. (Peck 2021)
  • Elimination:
    • M3G and M6G are renally excreted.
    • ~10% of morphine is excreted unchanged in the urine.
  • Half-life & duration of action:
    • Half-life is ~2-3 hours (prolonged to 4 hours in cirrhosis).
  • Mechanism of action:
    • Agonist at mu and kappa opioid receptors.
oxycodone (PO)
  • Contraindications:
    • Oxycodone is OK for cautious use in severe renal failure (this is its niche).
  • Drug-drug interactions:
    • CYP3A4 inhibitors increase therapeutic effects, whereas inducers decrease them.
    • CYP2D6 inhibitors may reduce oxymorphone formation, thereby decreasing analgesia.
    • Serotonergic medications (may increase risk of serotonin syndrome).
    • CYP3A4 and CYP2D6 inhibited: substantial increase in exposure and toxicity.
  • Side effects:
    • Discussion of opioid side-effects & their management is below.
  • Indications/advantages:
  • Dosing:
    • Typical dosing:
      • Opioid naive: 5-10 mg PO q4hr PRN.
      • Opioid tolerant: 10-30 mg PO q4hr PRN.
    • Renal impairment: Accumulation of noroxycodone and oxymorphone may increase therapeutic effects. Therefore, clinical effects may be longer-lasting and more pronounced. However, oxycodone lacks neurotoxic metabolites. Consequently, oxycodone may be used PRN for patients with GFR >10 ml/min. (Wellington 3e) 
    • Hepatic impairment: Decrease dose to half of the usual dose and titrate cautiously PRN (avoid scheduled doses).
    • Roughly equianalgesic doses
      • 5 mg IV morphine
      • 15 mg PO morphine (1/3 as strong as IV).
      • 50 mcg IV fentanyl (10x morphine dose in mg).
      • 0.75 mg IV HYDROmorphone (7x more potent than IV morphine).
      • 6 mg IV nalbuphine.
      • 3.75 mg PO HYDROmorphone (4x more potent than PO morphine).
      • 10 mg oxycodone (1.5x stronger than PO morphine).
      • 15 mg HYDROcodone (1.5x weaker than PO oxycodone).
      • 150 mg tramadol (10x less potent than PO morphine).
  • Absorption:
    • Bioavailability is 60-87%, which is higher and less variable than morphine.
    • Peak plasma level usually occurs within 1-2 hours.
  • Distribution:
    • Vd is ~2.6 L/kg.
    • Protein binding is ~45%.
    • LogP is 0.7
  • Metabolism:
    • ~45% of oxycodone is metabolized by CYP3A4 to noroxycodone (weak analgesic activity). Noroxycodone is then metabolized by CYP2D6 into noroxymorphone.
    • ~20% of oxycodone is metabolized by CYP2D6 to oxymorphone. Oxymorphone is then metabolized by either CYP2D6 or CYP2D6 into noroxymorphone.
    • Oxymorphone has 30-40 times the opioid receptor affinity as compared to oxycodone and may contribute to clinical efficacy. It seems to be the most valuable player here.
    • CYP2D6 genetic variability may affect exposure to oxymorphone. However, since CYP2D6 is involved in both the generation and metabolism of oxymorphone, CYP2D6 genetics may have a less powerful impact on the efficacy of oxycodone as compared to hydrocodone or tramadol.
    • (Further discussion: Huddard et al.)
  • Elimination:
    • ~10% of oxycodone is excreted as the unchanged drug in the urine.
    • Metabolites are also renally excreted.
  • Half-life & duration of action:
    • Half-life is ~3.5-4 hours.
  • Mechanism of action:
    • Affinity for mu, kappa, and delta-opioid receptors.
HYDROcodone (PO)
  • Contraindications/drawbacks:
    • Compared to oxycodone, HYDROcodone may be more affected by CYP2D6 inhibition.
    • HYDROcodone is often formulated in combination with acetaminophen, which makes it difficult to maximize the acetaminophen dose.
  • Drug-drug interactions:
    • CYP3A4 inhibitors increase exposure.
    • CYP2D6 inhibitors reduce hydromorphone formation (limiting analgesic efficacy).  CYP2D6 inhibition is more problematic for HYDROcodone, since it is more dependent on HYDROmorphone formation to achieve efficacy.
  • Side effects:
    • Discussion of opioid side-effects & their management is below.
  • Indications/advantages:
    • The only advantage of HYDROcodone over oxycodone is that it may cause less euphoria, and therefore, HYDROcodone has less abuse potential.
  • Dosing:
    • Roughly equianalgesic doses
      • 5 mg IV morphine
      • 15 mg PO morphine (1/3 as strong as IV).
      • 50 mcg IV fentanyl (10x morphine dose in mg).
      • 0.75 mg IV HYDROmorphone (7x more potent than IV morphine).
      • 6 mg IV nalbuphine.
      • 3.75 mg PO HYDROmorphone (4x more potent than PO morphine).
      • 10 mg oxycodone (1.5x stronger than PO morphine).
      • 15 mg HYDROcodone (1.5x weaker than PO oxycodone).
      • 150 mg tramadol (10x less potent than PO morphine).
  • Absorption:
    • Estimated to be moderate/high (hard to quantify without an IV formulation).
  • Distribution:
    • Vd is ~400 L.
    • Protein binding is 36%.
    • LogP is 2.
    • Moderate blood-brain penetration.
  • Metabolism:
    • Primary pathway: CYP3A4 to norhydrocodone (relatively inactive).
    • Minor pathway: CYP2D6 to hydromorphone (active metabolite with five times more potency).
  • Elimination:
    • Urinary excretion, primarily as metabolites.
  • Half-life & duration of action:
    • Half-life is 4-9 hours.
tramadol (PO)
  • ⚠️ Initiation of tramadol in the ICU is not recommended (opioids listed above are superior). However, for patients who are chronically maintained on tramadol prior to admission, it is often sensible to continue this.
  • Contraindications/Drawbacks:
    • Seizure disorder.
    • Risk of serotonin syndrome.
    • Erratic pharmacokinetic effect depending on CYP2D6 genetics.
  • Drug-drug interactions:
    • CYP2D6 inhibitors: Reduce M1 formation, decreasing efficacy.
    • CYP3A4 inducers: Accelerate clearance, reducing efficacy.
    • Serotonergic medications: risk of serotonin syndrome.
  • Side effects:
    • Serotonin syndrome.
    • Opioid intoxication.
    • Seizure.
    • (Further discussion of opioid side-effects & their management is below.)
  • Indications/advantages:
    • At equi-analgesic doses to morphine, tramadol causes less respiratory depression and constipation. (Peck 2021) 
  • Dosing:
    • Initial dose: 50-100 mg q4-6 hrs PRN.
    • Roughly equianalgesic doses
      • 5 mg IV morphine
      • 15 mg PO morphine (1/3 as strong as IV).
      • 50 mcg IV fentanyl (10x morphine dose in mg).
      • 0.75 mg IV HYDROmorphone (7x more potent than IV morphine).
      • 6 mg IV nalbuphine.
      • 3.75 mg PO HYDROmorphone (4x more potent than PO morphine).
      • 10 mg oxycodone (1.5x stronger than PO morphine).
      • 15 mg HYDROcodone (1.5x weaker than PO oxycodone).
      • 150 mg tramadol (10x less potent than PO morphine).
    • Renal or hepatic impairment: dose reduction required.
  • Absorption:
    • Bioavailability is 75%.
    • Peak plasma level in 1-2 hours.
  • Distribution:
    • Vd of ~4 L/kg. (Peck 2021)
    • Protein binding of 20%.
    • LogP of 1.35
  • Metabolism:
    • Competing metabolic pathways:
      • CYP2D6 metabolizes tramadol to M1 (O-desmethyltramadol), which is 200-times more potent than the parent drug.
      • CYP3A4 metabolizes tramadol to NDT (N-desmethyltramadol, an inactive metabolite.
    • CYP2D6 poor metabolizers produce less M1, resulting in reduced analgesia.
    • CYP2D6 ultra-rapid metabolizers experience toxicity due to excessive M1.
  • Elimination:
    • 90% excreted in the urine (30% unchanged tramadol, 60% as metabolites).
    • 10% excreted in feces.
  • Half-life & duration of action:
    • Tramadol: 5-6 hours.
    • Half-life is doubled in patients with hepatic or renal impairment. (Scarth & Smith 2016)
    • M1 active metabolite: 7-8 hours, contributing to prolonged analgesia.
  • Mechanism of action:
    • Agonist properties at all opioid receptors (especially mu-receptors, but also kappa and delta receptors).
    • Inhibits the reuptake of norepinephrine and serotonin.
    • Stimulate presynaptic serotonin release (may provide an alternative pathway for analgesia involving descending inhibitory pathways). (Peck 2021)
opioid patient-controlled analgesia (PCA)

Patient-controlled analgesia (PCA) may be useful for severe pain in a patient who is awake enough to understand how to use the PCA.

general concepts behind a PCA

  • Small doses of opioids provided on demand may allow for finer dose titration against the patient's pain requirements. This may lead to reduced opioid consumption over time.
  • Small doses are provided, with a defined lock-out interval between doses (during which time, activating the PCA will not result in delivering additional medication). Using a lock-out interval prevents multiple doses from accumulating (“stacking”) and thereby leading to intoxication.
  • Also, to ensure safety, a patient who becomes mildly intoxicated will fall asleep and stop activating the PCA. For this safety mechanism to function optimally, the PCA should ideally have no basal rate (more on this below).

how to order & titrate a PCA

  • [1] The selection of an agent is very similar to the selection of an IV opioid in general (discussed above ⚡️). Morphine is generally a good choice (it causes less euphoria, making it less prone towards inappropriate reinforcement).
  • [2] Discontinue all other opioid orders. Also, remove potentially sedating medications if possible (e.g., benzodiazepines).
  • [3] Initial orders are as follows:
    • Fentanyl PCA:
      • Demand 20-50 mcg.
      • Lockout 5-10 minutes.
      • Basal rate: zero.
    • HYDROmorphone PCA:
      • Demand 0.2-0.5 mg.
      • Lockout 10-15 minutes.
      • Basal rate: zero.
    • Morphine PCA:
      • Demand 1-3 mg.
      • Lockout 10-20 minutes.
      • Basal rate: zero.
  • [4] If pain control is inadequate:
    • Consider increasing the demand dose and/or reducing the lockout interval.
    • Do not add a basal rate (discussed further below).
    • Consider augmenting with non-opioid multimodal analgesia.

common PCA mistakes

  • [1] The PCA is designed to maintain analgesia, not to rescue the patient from uncontrolled pain. If the patient has severe, uncontrolled pain, then this should be treated immediately by clinician-titrated boluses of opioids. Patients often require loading with a moderate dose of opioids before initiation of the PCA. The PCA delivers only small doses of opioids, so it's not adequate to “catch up” to entirely uncontrolled pain.
  • [2] Never use a continuous (basal) infusion in a patient who isn't on chronic opioids.
    • The basal (continuous) rate of the PCA should always be set to zero unless the patient has been on chronic opioids. For patients who were previously on chronic opioids, their chronic dose may be converted into an appropriate basal rate using various calculators (e.g., this one). This can be a bit tricky though, so when in doubt err on the low side.
    • In the case of PCAs, it has been shown explicitly that adding a basal rate doesn't improve analgesia – but it does increase toxicity! (16334492, 21074739)
  • [3] Ensure that only the patient activates the PCA (and not, for example, relatives or friends). A safety mechanism of PCAs is that as patients become sedated, they will stop activating the PCA.
  • [4] Pumps can malfunction, rarely leading to opioid intoxication. If the patient is demonstrating features of opioid intoxication, then disconnect the PCA and treat the patient appropriately.
avoiding opioid infusions

the use of continuous infusions of opioids for days on end lacks a strong evidentiary basis. For example:

  • No prospective, high-quality study has demonstrated a benefit from using a continuous opioid infusion. It's often assumed that more is better, but a continuous exposure to opioid may merely blunt the brain's responsiveness to it (rather than improving efficacy).
  • Among patients being treated with patient-controlled analgesia (PCA) for acute pain, the addition of a continuous opioid infusion has been shown to increase complications, without improving pain control! (21074739)
  • Replacing fentanyl infusions with methadone was shown to accelerate extubation, implying that fentanyl infusions prolong intubation. (22420584)

major reasons to avoid opioid infusions include the following:

  • Continuous exposure to opioids rapidly causes tolerance, which may eventually lead to problems with withdrawal and dependence.
  • Infusions will be up-titrated with the patient is in pain, but less aggressively down-titrated when the patient isn't in pain. This will inevitably increase opioid exposure, compared to a PRN-only strategy (which only provides opioid when the patient has pain).
  • High cumulative opioid exposure from infusions (especially fentanyl) may cause opioid-induced hyperalgesia leading to a vicious spiral.
  • Continuous infusions of fentanyl will lead to drug accumulation in the fat tissue, which makes it impossible to rapidly withdraw the opioid when the patient is otherwise ready for extubation.

strategies to avoid problems with opioid infusions:

  1. Avoid infusions whenever possible (favoring a bolus-only strategy, even if that involves using relatively generous opioid boluses).
  2. If an infusion is necessary, use a rational dose (e.g., 25-50 mcg/hour fentanyl). Note that 100 mcg/hr fentanyl infusion is roughly equivalent to ~400 mg of oral oxycodone daily.
  3. Aggressively wean down the infusion at least once daily (but optimally more often).
  4. It takes an infusion 4-5 half-lives to reach steady state. Therefore, for severe uncontrolled pain the first line therapy is PRN boluses of opioid, combined with up-titration of opioid infusion. Merely up-titrating the infusion without PRN doses is the wrong approach here, because it will lead to delayed and excessive opioid dosing.
  5. Pay attention to how much opioid is being used as PRN doses vs. infusion. Ideally at least a moderate fraction of the total opioid given should be given as PRN doses. Alternatively, if the patient is receiving no PRN doses, then that suggests that the infusion rate is excessively high.
  6. Ketamine may reduce the development of tolerance and opioid induced hyperalgesia. Thus, co-infusion of pain-dose ketamine with an opioid may limit opioid dose and toxicity.

opioid infusions may be beneficial in the following situations:

  1. Among intubated patients with profound respiratory failure with a need to suppress the respiratory drive (e.g., severe status asthmaticus), opioid infusions may be beneficial. Use of an opioid infusion to suppress respiratory drive may allow for avoidance of paralysis, thereby constituting the lesser of two evils.
  2. For patients on chronic opioids prior to admission, some basal amount of opioid may be necessary to prevent withdrawal.
opioid side-effects and their management

complications of greatest concern in the ICU

  • Respiratory suppression: Patients at greatest risk are those with chronic hypercapnia and a blunted respiratory drive (e.g., obesity hypoventilation syndrome or chronic hypercapnic respiratory failure due to COPD). Among intubated patients, respiratory suppression can be beneficial by facilitating ventilator synchrony. However, persistent respiratory suppression may delay extubation.
  • Gastrointestinal failure:
    • Opioids are a major risk factor for nausea/vomiting, gastroparesis, ileus, and colonic pseudo-obstruction. In severe cases, the latter can cause colonic perforation and death.
    • An aggressive bowel regimen is indicated.
    • The use of specific opioid antagonists to specifically antagonize the effects on the bowel is discussed here.
  • Urinary retention – increased tone of the bladder detrusor and vesical sphincter.
  • Opioid dependence and withdrawal: The brain very rapidly adapts to continuous opioid exposure, leading to dependence. When the opioid dose is reduced, this may cause withdrawal and rebound analgesia. Opioid withdrawal may be an under-recognized factor that contributes to pain and depression after critical illness. Ongoing use of opioids throughout the patient's hospital course may lead to chronic outpatient opioid use, which exposes the patient to a host of long-term problems.
  • Delirium: The appropriate use of opioids to treat pain probably doesn't cause delirium. However, misutilization of opioids to treat agitation (taking advantage of their sedative properties) probably does promote delirium.
  • Nausea/vomiting: Appears to be predominantly related to the stimulation of mu opioid receptors in the chemoreceptor trigger zone.
  • Histamine release (primarily with morphine):
    • Some opioids stimulate the MRGPRX2 receptor on mast cells, leading to the release of histamine. (36344690)
    • Clinical consequences of mast cell stimulation with histamine release may include:
      • Hypotension due to vasodilation.
      • Urticaria, flushing, and wheal-and-flare reactions.
      • Pruritus.
      • Bronchospasm.
    • Opioids associated with histamine release:
      • High histamine-releasing opioids: Morphine, codeine, meperidine.
      • Variable & generally lower histamine-releasing: Hydromorphone, buprenorphine, nalbuphine.
      • Opioids that don't release histamine: Fentanyl, tramadol.
  • Bradycardia: Occurs via stimulation of central mu-opioid receptors in regions controlling vagal tone, leading to increased parasympathetic outflow to the heart. Bradycardia may be more notable with high doses and rapid IV administration (especially higher doses of fentanyl).
  • Pruritus: Isolated pruritus (without a rash) doesn't seem to be caused by histamine release. (Peck 2021)

the dose makes the poison 

  • PRN bolus-dose opioids will often be required for the management of critically ill patients. Opioid toxicity increases substantially with the use of a continuous opioid infusion, so these should be avoided whenever possible.
  • A series of studies in Europe has demonstrated that critically ill, intubated patients can be maintained on extremely low doses of opioids or no opioids at all. ( 20116842, 32068366) This implies that many ICUs are using vastly more opioids than are necessary.
  • It is commonly taught that there is no “maximal dose” of opioids. This is not entirely accurate. At high doses, opioids may rapidly cause opioid-induced hyperalgesia (a paradoxical process whereby excess opioid doses exacerbate pain). This seems to be most problematic with remifentanil and fentanyl, with one study showing that a single, large dose of fentanyl was capable of inducing hyperalgesia. (26655493) Whenever giving an opioid dose equivalent to >50 mg oral oxycodone daily, consider whether the dose is necessary and beneficial. Especially among medical patients, there's little rational explanation why such massive doses of opioids should be needed. A common error is to use high-dose opioids for their sedative properties (when such patients would be better served by receiving less opioid and more sedation).

gabapentinoids

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contraindications, drug interactions, side effects 👎

contraindications

  • Risks are compounded by renal dysfunction and other CNS-suppressive medications. However, mild sedation may have a beneficial effect on intubated patients.
  • ⚠️ Rapid discontinuation of gabapentinoids can cause withdrawal.
    • Patients on these medications before ICU admission should generally be continued on them (with dose adjustment as needed based on renal function).
    • Most dangerous for patients on gabapentin for the treatment of seizure disorder (withdrawal may provoke seizures).

drug-drug interactions

  • Gabapentin:
    • Antacids containing magnesium or aluminum hydroxide decrease bioavailability.
  • Pregabalin:
    • No pharmacokinetic interactions.

side effects

  • Limiting side effects include:
    • Somnolence, respiratory depression.
    • Hypoactive delirium
    • Myoclonus.
    • Dizziness, visual alteration, including diplopia. (32892818)
indications, advantages 👍

general indications for gabapentinoids

  • Gabapentinoid use is predominantly for neuropathic pain, for example:(Vincent 2023)
    • Guillain-Barre Syndrome.
    • Diabetic neuropathy.
    • Spinal cord injury.
    • Post-herpetic neuralgia.
    • Pain due to subarachnoid hemorrhage; post-stroke central pain.
  • Analgesia after cardiothoracic surgery:
    • Pregabalin (150 mg BID) for two weeks in combination with ketamine (0.1 mg/kg/hr for 48 hours) was shown in an RCT to reduce pain (including chronic pain), reduce opioid consumption, and improve long-term quality of life. (31149930; full study results are here) 75 mg BID has also shown efficacy in RCTs, including a reduction in chronic pain. (21474474)
    • Meta-analyses support the ability of pregabalin to reduce length of stay and decrease morphine consumption. (33763487)
    • Pregabalin may be preferable to gabapentin in terms of more rapid and consistent absorption and more predictable pharmacokinetics. The evidentiary support for pregabalin is much more robust than for gabapentin (which was found to delay extubation in some studies).
  • Partial seizures (with or without secondary generalization).
  • Anxiety.
  • Alcohol use disorder (gabapentin; treats both withdrawal and cravings).
  • Cannabis use disorder (gabapentin).
  • Restless leg syndrome (gabapentin).

selection of gabapentinoid

  • 🏆 Pregabalin is generally preferred due to superior pharmacokinetics. This is especially true in critical care, where we do not have time for gradual dose titration based on clinical effects.
dosing

gabapentin

  • Neuropathic pain: 300-1200 mg q8hr.
  • Focal seizures: ~900-3600 mg/day in divided doses. (Peck 2021; Scarth & Smith 2016)
  • Alcohol use disorder:
    • Start at 100-300 mg TID (for the treatment of acute withdrawal, it may be reasonable to start at moderate to high doses).
    • May up-titrate as high as 900 mg BID-TID. Doses >1800 mg/day (i.e., 900 mg BID) may be associated with more side effects (e.g., dizziness, somnolence, ataxia). (37526592)
  • Renal failure: Dose reduction required.

pregabalin:

  • General dosing: 75-150 mg q12hr.
  • Post-cardiothoracic surgery:
    • 150 mg PO BID may be a standard dose, although lower doses may be considered in the elderly. (32892818)
    • Dose reduction for renal failure:
      • GFR 30-60 ml/min: 75 mg BID.
      • GFR 15-30 ml/min: 75 mg daily.
  • Adjunctive antiseizure medication:
    • Loading dose of 150-600 mg (higher for intubated patients in status epilepticus).
    • Maintenance dose: up to 300 mg BID. (38117319)
  • Renal failure:
    • GFR >60 ml/min: no adjustment.
    • GFR 30-60 ml/min: Reduce dose by 50%.
    • GFR 15-30 ml/min: Reduce dose by 75%.
    • Hemodialysis for four hours will reduce plasma concentrations by ~50%. (Scarth & Smith 2016)
pharmacology

gabapentin

  • Absorption:
    • Dose-related absorption may be unpredictable.
    • As the dose increases, the bioavailability decreases (~80% at low doses; ~60% at 900 mg/day; 47% at 1200 mg/day; and 27% at 4800 mg/day). Absorption is mediated by the L-amino acid transport system in the small intestine, which is a saturable process.
  • Distribution:
    • Vd is ~60 L.
    • Protein binding is minimal (<3%).
  • Metabolism:
    • Gabapentin isn't metabolized.
  • Elimination:
    • Unchanged drug is excreted in the urine.
  • Half-life & duration of action:
    • Half-life: 5-7 hours with normal renal function (prolonged in renal dysfunction).
  • Mechanism of action:
    • Inhibits presynaptic voltage-gated calcium channels.
    • Some NMDA antagonist activity.
    • Reduce the release of monoamine neurotransmitters.
    • Stimulate glutamate decarboxylase (the enzyme that converts glutamate to GABA).
    • Increase the synaptic release of GABA. (Scarth & Smith, 2016)

pregabalin

  • Absorption:
    • Pregabalin is well absorbed with oral bioavailability of >90% (independent of dose).
    • Peak plasma levels are reached within ~1 hour under fasting conditions (food delays this to ~3 hours).
  • Distribution:
    • Vd is ~0.5 L/kg.
    • Protein binding is minimal.
    • Pregabalin penetrates the brain via the system L transporter.
  • Metabolism:
    • Not metabolized.
  • Elimination:
    • Unchanged drug is excreted in the urine.
  • Half-life & duration of action:
    • Half-life: 6-8 hours (prolonged in renal dysfunction).
  • Mechanism of action:
    • Pregabalin is structurally related to GABA, but doesn't actually interact with GABA receptors.
    • A primary mechanism of action may be binding to the alpha-2-delta subunit of voltage-gated calcium channels.

alpha-2 agonists in the ICU

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general comments

  • Alpha-2 agonists exert analgesic effects by affecting central alpha-2 receptors and imidazoline receptors. Depending on their activity upon different receptors, they have a spectrum of overlapping clinical effects.
  • The analgesic potency of alpha-2 agonists is mild. However, they may be beneficial within a multi-modal analgesic scheme, where they augment the efficacy of other agents (e.g., ketamine).
  • Central alpha-2 agonists cause varying degrees of sedation. The ability to provide sedation without respiratory suppression can be extremely useful.

tolerance and withdrawal to alpha-2 agonists

  • Perhaps the greatest drawback of alpha-2 agonists is the possibility of developing tolerance and withdrawal. Over time, patients may become tolerant to the medication, causing reduced clinical efficacy. If the medication is then stopped abruptly, this may cause a withdrawal syndrome (e.g., with tachycardia, hypertension, and anxiety).
  • These issues may be avoided as follows:
    • (1) Consider limiting the duration of dexmedetomidine infusions (e.g., to less than ~5 days). Dexmedetomidine is an excellent medication to facilitate extubation, but it may not be the optimal agent to serve as a maintenance analgosedative for indefinite periods of time.
    • (2) For patients who have been on oral alpha-2 agonists for several days, it may be preferable to taper off gradually (or taper abruptly with careful observation for withdrawal).
    • (3) It's essential to actively wean alpha-2 agonists as soon as possible (e.g., as patients are recovering and have decreasing needs for analgesia and sedation).
    • (4) Avoid very high doses of these medications.

combining alpha-2 agonists plus ketamine may be synergistically useful for several reasons:

  • Synergistic analgesia: The combination of ketamine plus an alpha-2 agonist provides more effective analgesia than either agent alone. (23711600, 20648205, 19095506)
  • Hemodynamic stability: Ketamine tends to increase blood pressure, whereas alpha-2 agonists tend to reduce blood pressure.
  • Avoidance of ketamine's psychotomimetic side effects: The major treatment limiting side effect of ketamine infusions is psychomimetic effects, which occur at higher doses (typically >0.2-0.3 mg/kg/hr). These side effects are generally minor and easily managed by pausing the infusion and then resuming at a lower rate. Alpha-2 agonists can exert a sedative effect which avoids ketamine induced psychomimetic effects, thereby widening the margin of safety when administering ketamine. (29870458, 19783371, 9507131, 27656531, 10773503) For example, one study found that clonidine dosed at 0.3 mg BID allowed patients to tolerate ketamine at 0.6 mg/kg/hr (a ketamine dose which should otherwise cause substantial psychomimetic effects). (26919405)
  • Avoidance of tolerance to alpha-2 agonists? Within 1-2 weeks, patients will develop tolerance to the sedative effects of alpha-2 agonists. Animal models suggest that ketamine may prevent this, thereby allowing alpha-2 agonists to maintain ongoing efficacy over time. (11465557)

dexmedetomidine

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contraindications, drug interactions, side effects 👎

contraindications/drawbacks

  • Hypotension & bradycardia (sympatholysis):
    • Dexmedetomidine may cause bradycardia and hypotension (especially when bolused).
    • Dexmedetomidine is contraindicated in patients with heart block, bradycardia, or severe hypotension. (However, this property can occasionally be useful in patients with tachycardia.)
    • In rare situations, dexmedetomidine may be a uniquely useful and necessary sedative. What should be done if dexmedetomidine is deemed to be mission-critical, but is causing bradycardia? A dexmedetomidine infusion may be combined with a simultaneous infusion of low-dose epinephrine or dobutamine (to offset the bradycardic effects).
  • Heart block, grade 2-3 (in the absence of a pacemaker as backup).
  • Prolonged uninterrupted use (>3-5 days) may cause tolerance and subsequent withdrawal after dexmedetomidine is discontinued. There is little evidence regarding long-term use of dexmedetomidine, so it is hard to know exactly how common this is. Using lower doses of dexmedetomidine (e.g., 0.8 mcg/kg/hr or less) might help avoid withdrawal. (32844730)
  • Targeting deep sedation: Dexmedetomidine is often unable to achieve very deep levels of sedation. Although deep sedation isn't usually preferred among ICU patients, it may be desirable in some situations (e.g., patients undergoing intubated prone ventilation).

drug-drug interactions

  • No clinically relevant CYP-mediated drug interactions.
  • QT prolongation may occur due to reduced heart rate, so caution should be used in patients with QT prolongation.

side effects

  • Hemodynamic:
    • Bradycardia.
    • Cardiogenic shock.
    • Hypotension.
  • Fever.
  • QT prolongation.
  • Atrial fibrillation.
  • Agitation.
indications, advantages 👍

  • Advantages:
    • Doesn't suppress respiration:
      • Can be used in patients who aren't intubated (e.g., on BiPAP).
      • Can be used to bridge patients through the entire extubation process (i.e., dexmedetomidine doesn't need to be stopped prior to extubation).
    • Titratable infusion, which can be discontinued easily.
    • Patients often remain arousable while on dexmedetomidine (so this may be used in situations requiring frequent neurologic examinations).
  • Use:
    • Sedation of patients who aren't intubated (e.g., BiPAP).
    • Management of nocturnal agitation (may promote physiological sleep and reduce delirium). (29498534)
    • Sedation of intubated patients who are close to extubation (e.g., within 2-4 days of extubation). Dexmedetomidine is especially useful for bridging patients through the extubation period, because it may be continued during this entire process (unlike propofol, which must be discontinued prior to extubation).
dosing
  • 🛑 Boluses of dexmedetomidine may cause bradycardia and hemodynamic collapse, so these should generally be avoided. Instead, the infusion may be started at a high rate (e.g., 1-1.4 mcg/kg/min) and down-titrated as the drug takes effect (within an hour).
  • Infusion rate at 0-1.4 mcg/kg/hr.
  • Ideally, try to down-titrate (or stop) dexmedetomidine during the day, with subsequent up-titration at night:
    • Decreasing dexmedetomidine during the day may help avoid tolerance and withdrawal.
    • Use of dexmedetomidine during the night may promote restorative sleep and help reset the circadian rhythm.
  • Patients on dexmedetomidine continuously for >3-5 days may be transitioned to oral clonidine or guanfacine to avoid withdrawal symptoms.
  • Cirrhosis: Consider dose reduction and monitor for clinical signs of toxicity (e.g., bradycardia).
  • Renal dysfunction: No adjustment (metabolites are inactive).
  • Morbid obesity: Dose based on lean body weight (calculator here). (29661414, Paw and Shulman 2025)
monitoring
  • Heart rate (may cause bradycardia).
  • Cardiac output (can promote shock).
pharmacology
  • Absorption:
    • IV administration. Infusion takes ~30-60 minutes to reach equilibrium levels.
  • Distribution:
    • Rapid distribution (distribution half-life of ~6 minutes).
    • Central volume of distribution: ~20 L.
    • Peripheral volume of distribution ~90 L.
    • The equilibrium Vd is ~120 liters.
    • Protein binding is ~94%.
    • LogP is 3.39 (32513237)
  • Metabolism:
    • Primary pathways:
      • ~33%: Glucuronidation by UGT2B10 and UGT1A4.
      • CYP2A6-mediated hydroxylation.
    • Minor pathways:  CYP1A2, CYP2E1, CYP2D6, and CYP2C19.
  • Elimination:
    • Renal elimination of metabolites (doesn't clinically accumulate in renal dysfunction).
  • Half-life & duration of action:
    • Terminal half-life of about 1.5-2 hours, although this is context-sensitive and may increase with ongoing infusions.
    • Clearance is extended in liver disease, with reduced cardiac output, or in older patients.

oral alpha-2 agonists (clonidine, guanfacine, tizanidine)

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contraindications, drug interactions, side effects 👎

contraindications

  • Class-wide contraindications to central alpha-2 agonists
    • Bradycardia.
    • Heart block.
    • Cardiogenic shock (or borderline cardiogenic shock).
    • Hypotension.
      • 0.3 mg PO clonidine may drop the MAP by an average of ~20 mm. (6424997)
    • ⚠️ Before initiation, review the medication list and consider discontinuing any beta-blockers or other antihypertensive agents.
  • Clonidine:
    • (See class-wide contraindications above & drug-drug interactions below.)
    • Renal failure: the half-life extends up to 41 hours in severe renal failure. This is a relative contraindication (discussed further in the section below on dosing).
  • Guanfacine:
    • (See class-wide contraindications above & drug-drug interactions below.)
  • Tizanidine:
    • (See class-wide contraindications above & drug-drug interactions below.)
    • Hepatic dysfunction. Normally, the majority of tizanidine is removed via first-pass metabolism in the liver, so hepatic dysfunction could lead to increased drug levels.

drug-drug interactions

  • Pharmacodynamic class-wide interactions:
    • Negative chronotropes (e.g., beta-blockers, diltiazem).
    • Antihypertensives.
  • Clonidine:
    • CYP2D6 inhibitors may increase exposure by over 5-fold.
  • Guanfacine:
    • CYP3A4 inducers or inhibitors.
    • Strong CYP3A4 inhibitors may require a 50% dose reduction.
  • Tizanidine:
    • Tizanidine is highly dependent on CYP1A2 for clearance.
    • Strong CYP1A2 inhibitors combined with tizanidine may cause severe overdose (e.g., ciprofloxacin).

side effects

  • Class side-effects:
    • Hypotension, bradycardia, heart block.
    • Sedation.
    • Dry mouth.
    • Rebound hypertension & anxiety upon cessation (more likely if high doses are used for several days).
  • Clonidine:
    • GI side-effects: Constipation, including colonic pseudo-obstruction; also anorexia, emesis.
  • Guanfacine:
    • Similar to clonidine.
  • Tizanidine:
    • Muscle weakness.
    • Liver injury.
    • More likely to cause hallucinations.
indications, selection of different alpha-2 agents, pharmacodynamics 👍

selection clonidine vs. guanfacine

  • Clonidine and guanfacine are both often utilized as oral sedatives. This raises a question of which choice is superior. In the absence of any high-quality head-to-head studies, the following considerations may be helpful: 
  • [#1] Is there a contraindication to one of the agents?
    • Clonidine contraindications:
      • Strong CYP2D6 inhibitor.
      • Severe renal failure may affect kinetics.
    • Guanfacine contraindications:
      • Strong CYP3A4 inhibitor or inducer.
  • [#2] How much hemodynamic reserve is there?
    • Guanfacine may produce a greater sedative effect with less antihypertensive effect.
    • If the patient can tolerate moderate to high doses of dexmedetomidine, this is probably not an issue.
    • The maximal drop in MAP due to high-dose clonidine is typically around 20 mmHg. If you have >20 mm of MAP to spare, then hypotension usually isn't a problem (e.g., patient with opioid withdrawal).
  • [#3] Is rapid onset important?
    • Clonidine takes effect within ~1-2 hours, whereas guanfacine takes effect more slowly (within ~2-4 hours).
    • If prompt onset is a priority, then oral clonidine may be preferable.
  • [#4] Are you trying to treat nocturnal agitation & delirium?
    • Guanfacine 2 mg QHS showed efficacy for delirium in one unpublished RCT. (NCT04578886) QHS guanfacine may promote normal circadian rhythmicity (with maximal sedation at night).  

tizanidine indications

  • Tizanidine is usually utilized primarily as an analgesic, with far less effect on hemodynamics. (18671474, 25849473, 26555871)  Tizanidine also has muscle-relaxant properties and mild sedative effects. Among the alpha-2 agonists, tizanidine may arguably be the most effective analgesic.
  • Tizanidine has traditionally been used for pain syndromes involving muscle spasm (e.g., back pain or myofascial pain). However, recent research shows efficacy in somatic pain as well (e.g., pain following cholecystectomy or hernia repair). (26555871, 26962521, 29468508)

alpha-2 agonist pharmacodynamics

  • Imidazoline receptors:
    • Causes hypotension and some analgesia.
    • Clonidine has a greater effect on imidazoline receptors. (15464067)
  • Alpha-1: Causes peripheral vasoconstriction & hypertension.
  • Alpha-2A:
    • ⍺-2A is the main therapeutic target, located in the prefrontal cortex and locus ceruleus of the brain.
    • Stimulation reduces sympathetic tone, with sedative/hypnotic effects and probably analgesic effects. (9813525, 19194166)
  • Alpha-2B:
    • Located peripherally.
    • Causes vasoconstriction and anti-shivering effects. (Guan 2023)
    • Stimulation of alpha-2B receptors may cause transient hypertension if a large bolus of dexmedetomidine is utilized.
  • Alpha-2C:
    • Located in the striatum and hippocampus.
    • Unclear clinical effects.
  • Selectivity of various agents: (38907529)
    • Dexmedetomidine: Alpha-2A = Alpha-2B = Alpha-2C
    • Clonidine: Alpha-2A >>> Alpha-2B >> Alpha-2C
    • Guanfacine: Alpha2A >>>> Alpha-2B = Alpha-2C

dosing

clonidine dosing

  • [1] Sedation and/or multimodal analgesia:
    • Clonidine may be used as a combination sedative plus adjunctive analgesic, similar to dexmedetomidine.
    • Among these agents, clonidine may cause the greatest degree of hypotension. This may be useful for patients with hypertension. However, for patients with tenuous hemodynamics, guanfacine may be a superior option.
    • Starting de novo: Start 0.2 mg q6hr, up-titrate to 0.5 mg q6hr if needed. (25809176, 25561923) 
    • Transition from dexmedetomidine: Start 0.2-0.3 mg q6hr, may up-titrate to 0.5 mg q6hr if needed. (25809176)
    • Although some studies have used q12hr dosing for analgesia, pharmacokinetic data suggest that the analgesic effect may only last for ~4-6 hours following a single dose. (2182959, 3281774)
    • The optimal clonidine concentration for sedation in the ICU has been estimated to be ~1.5-4 ug/mL.  A daily dose of 1.2 mg intravenously is estimated to achieve a level of >1.5 ug/mL in 95% of patients. (32150285) This implies that an oral regimen of 0.3 mg q6hr is likely providing a clinically meaningful degree of sedation. 
      • The peak concentration after a single 0.1 mg tablet in healthy subjects is ~0.45 ng/mL. (38275186)
      • The peak concentration after a single 0.3 mg tablet in healthy subjects is ~1.4 ng/mL. (38275186)
  • [2] Opioid withdrawal: Most studies have used up to ~0.6-1.2 mg/day in divided doses, titrated against symptoms. (27140827) However, with ICU-level monitoring, higher doses may be reasonable (e.g., up to a maximal dose of 2.4 mg/day in divided doses). (18709354)
    • 2.4 mg/day is generally considered the maximum clonidine dose. (Guan 2023)
  • [3] Hypertension:
    • Onset in ~1 hour, duration of action ~12 hours.
    • Start 0.2 mg q12 hours, maximal dose 1.2 mg q12 hours.
    • Oral accelerated dose titration: 0.2 mg PO followed by 0.1 mg q1hr PRN persistent hypertension, to a maximum of 0.6 mg total dose. This allows for rapid determination of an appropriate oral dose.
    • Clonidine has a U-shaped effect on blood pressure, with lower doses causing hypotension, but higher doses having a less pronounced impact on blood pressure. 🌊 (28833346) Clonidine levels >1 ng/mL generally cause no additional reduction in blood pressure.
  • [4] Restless leg syndrome: 0.1 – 0.3 mg, two hours before sleep.
  • 👅 If a patient is temporarily unable to take oral medication, clonidine may also be given sublingually (achieving similar pharmacokinetics compared to oral clonidine). (7986518)
  • Renal failure:
    • In severe renal failure, the half-life may extend up to 40 hours. This makes dose-titration essentially impossible and creates a risk of causing prolonged sedation or hypotension.
    • In mild to moderate renal failure, dose reduction may be reasonable (there is no clear guideline about exactly how to do this).
    • In severe renal failure, it's probably advisable to choose a different agent (e.g., guanfacine).

guanfacine dosing

  • Basic principles of clonidine dosing:
    • Dosing range: 0-5-4 mg/day. (33272699) The FDA recommends doses of up to 4 mg daily for attention-deficit/hyperactivity disorder. (36751225)
    • Renal failure: Guanfacine is less affected by renal failure than clonidine. Consider lower-end dosing for patients with severe renal failure.
  • Sedation:
    • Guanfacine functions primarily as an oral sedative. Guanfacine causes less hypotension than clonidine. (36349291) 
    • Dosing may start at 0.5 mg q8hr-q12hr and escalate as needed to a maximal dose of 1 mg q8hr. (36349291)
    • If transitioning from dexmedetomidine to guanfacine, patients on a higher dexmedetomidine dose will require higher doses of guanfacine. 
  • Delirium:
    • Observational reports and emerging RCT evidence support the use of guanfacine for the treatment of delirium. (29619866, 32591212, NCT04578886, 36751225, 33272699) This is further buttressed by the established efficacy of dexmedetomidine for delirium (based on a similar mechanism of action). 
    • Guanfacine may be given once daily before sleep (e.g., 2 mg QHS). (36751225)  This will maximize sedation at night while still providing some residual sedation during the day.
  • Adjunctive analgesia?
    • Guanfacine probably does provide analgesia, similar to clonidine. Clonidine is generally felt to exert most of its analgesic effects via inhibiting alpha-2A receptors, implying that guanfacine should function as an analgesic.
    • Various animal studies have found guanfacine to have analgesic properties.
    • In a retrospective case series describing the use of guanfacine to treat delirium, guanfacine seemed to reduce opioid requirements. (36751225) 
  • Antihypertensive efficacy ceiling: Guanfacine's antihypertensive effects appear to have a ceiling effect, wherein doses between 1-3 mg have similar effects. (16078088, 2668350, 6994778)
  • Renal failure: Guanfacine seems to be less affected by renal dysfunction than clonidine (hepatic metabolism accelerates as renal failure occurs, so that clearance is relatively stable). Even in severe renal failure, the half-life isn't dramatically prolonged. For mild to moderate renal dysfunction, usual doses can be utilized. In severe renal failure, conservative dosing and gradual up-titration may be reasonable.

tizanidine dosing

  • Dosing:
    • Start: 4 mg q6hr-q8hr (12-16 mg/day).
    • Max dose is 36 mg/day (12 mg q8).
    • Hold if SBP <100 mm or sedated.
  • Rebound hypertension may occur if doses >20 mg/day are used for extended periods. (30137790) This may be avoided by using tizanidine for short courses only and at lower doses.
pharmacology

clonidine pharmacology

  • Chemical properties:
    • Molecular weight: 230 mg
    • LogP: 1.6-2.2
  • Absorption:
    • Oral bioavailability is ~85%. However, this may decrease to ~65% with multiple dosing. (38275186)
    • Onset in ~1-2 hours for immediate-release formulations.  This may facilitate rapid oral up-titration.
  • Distribution:
    • Protein binding is relatively low (~30%).
    • Vd is 2 L/kg.
  • Metabolism:
    • ~50% is metabolized in the liver:
      • CYP2D6 (66% of hepatic metabolism).
      • CYP1A2 (10-20% of hepatic metabolism).
      • CYP3A4 (0-20% of hepatic metabolism).
    • The primary metabolite is 4-hydroxyclonidine. This is not lipophilic, so it doesn't contribute to the central effects of clonidine.
  • Elimination:
    • ~40-60% is excreted unchanged in the urine.
    • Renal clearance may exceed glomerular filtration, implying tubular secretion.
  • Half-life & duration of action:
    • Half-life of ~12-16 hours.
    • In renal dysfunction, the half-life of clonidine is extended up to 41 hours. (36349291, 38275186) Hepatic metabolism isn't altered in renal failure, so the clearance of clonidine may decrease by ~50%.  

guanfacine pharmacology

  • Chemical properties:
    • Molecular weight: 245 g/mol.
    • LogP: 2.1-2.7 (slightly higher than clonidine).
  • Absorption:
    • Oral bioavailability is ~80% with no evidence of substantial first-pass metabolism.
    • Onset is ~1-4 hours after administration of immediate-release formulations.
  • Distribution:
    • Protein binding is ~70%.
    • Vd is ~6 L/kg.
  • Metabolism:
    • ~50-70% undergoes hepatic metabolism via CYP3A4.
    • Strong CYP3A4 inhibitors or inducers may increase or decrease exposure by a factor of 3.
  • Elimination:
    • ~50% is cleared unchanged in the urine (including tubular secretion, possibly involving OCT1 and OCT2).
  • Half-life & duration of action:
    • The half-life averages ~17 hours, but ranges between 10-30 hours (longer than that of clonidine). (36751225)
    • Guanfacine levels don't seem to be strongly influenced by renal function.
    • A steady state may be reached after roughly four days (~5 half-lives). (36349291) If high doses are used (e.g., 3 mg/day), consider dose reduction after a few days if clinical efficacy is achieved (to prevent ongoing elevation in drug levels). 

tizanidine pharmacology

  • Chemical properties:
    • Molecular weight: 253 g/mol.
    • LogP: 2.1 (essentially the same as clonidine).
  • Absorption:
    • Oral bioavailability is 20-34% due to extensive first-pass hepatic metabolism. Bioavailability is somewhat variable (food may increase absorption of tizanidine tablets). (18199279)
    • Onset in ~1.5 hours.
  • Distribution:
    • Protein binding is 30%.
    • Vd is 2.4 L/kg.
  • Metabolism:
    • ~95% is metabolized, primarily by CYP1A2, into inactive metabolites.
    • Inhibition of CYP1A2 may increase levels of tizanidine by several fold.
  • Elimination:
    • Elimination occurs in the urine (60%) and feces (20%), primarily as inactive metabolites.
  • Half-life & duration of action:
    • Half-life of 2.5 hours (relatively short-acting). However, the duration of action may be longer (6-12 hours), due to receptor binding characteristics and tissue distribution.

melatonin

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contraindications, drug interactions, side effects 👎

contraindications

  • Severe hepatic dysfunction.
  • Pregnancy/breastfeeding.

drug-drug interactions

  • CYP1A2 inhibitors may increase melatonin levels.
  • Warfarin (potential interaction; may increase warfarin exposure).

side effects

  • Impaired glucose tolerance.
  • Sedation.
indications, advantages 👍
  • Typical role in ICU sedation: Adjunctive agent to prevent delirium and promote sleep.
  • SCCM suggests using melatonin based on its evidence-based review of 24 RCTs demonstrating:
    • Reduced prevalence of delirium (RR 0.7, CI 0.57-0.87).
    • Might decrease ICU LOS (Median -0.5 days; CI -0.89 to -0.1 days). (39982143)
  • Other possible benefits:
    • May preserve sleep and circadian rhythms.
    • May provide a very mild sedative effect (which reduces the required dose of other sedatives). (25969139)
  • Safe and inexpensive.
  • Note, however, that melatonin did not appear to prevent delirium in the largest and most robust multi-center RCT that evaluated 4 mg QHS (Pro-MEDIC trial). 📄
  • Caution: The quality control of some over-the-counter melatonin formulations is questionable. (However, the therapeutic window is very wide, so if the patient receives slightly more or less than the intended dose, it probably won't matter.)
dosing
  • 3 mg PO before sleep may be reasonable for most patients.
  • Up to 10 mg PO QHS has been studied in critically ill patients.
pharmacology for immediate-release melatonin tablets
  • Chemical properties:
    • Molecular weight: 232 g/mol.
    • LogP: 2
  • Absorption:
    • Oral bioavailability is low and variable (10-30%) due to first-pass metabolism.
    • Time to maximal concentration is ~30-60 minutes.
  • Distribution:
    • Protein binding is 60%.
    • Vd is large.
    • Melatonin readily crosses the blood-brain barrier and is also transported into mitochondria.
    • Distribution is facilitated by specific membrane transport proteins (GLUT1, PEPT1, PEPT2).
  • Metabolism:
    • Extensive hepatic metabolism, mostly by CYP enzymes (especially CYP1A2, also CYP1A1, CYP1B1, CYP2C19).
    • Factors influencing CYP1A2 alter melatonin levels.
  • Elimination:
    • Elimination is mainly renal, primarily with the excretion of metabolites (only 5% is excreted unchanged in the urine).
  • Half-life & duration of action:
    • The half-life is short (~30-60 minutes).
    • The half-life is extended in patients with hepatic dysfunction and the elderly.

benzodiazepines

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contraindications, drug interactions, side effects 👎

contraindications/disadvantages

  • Midazolam:
    • With repeated doses or a continuous infusion, it accumulates in fat tissue, thereby extending its half-life.
  • Lorazepam:
    • A slow onset time may be problematic, potentially leading to dose stacking.
    • Propylene glycol toxicity may result from high doses of IV lorazepam. Avoid using >1 mg/kg/day lorazepam. (18657015)
  • Diazepam:
    • Nordazepam (half-life 50-100 hours) and temazepam prolong sedation, especially in the context of hepatic or renal dysfunction. However, some accumulation is useful when treating alcohol withdrawal.
    • Extremely high doses can cause propylene glycol intoxication.
  • Oxazepam:
    • Only available PO.

drug-drug interactions

  • Midazolam:
    • CYP3A4 inhibitors or inducers.
  • Lorazepam:
    • No CYP interactions.
    • Glucuronidation can be inhibited by valproate and probenecid (should reduce the lorazepam dose by 50%).
  • Diazepam:
    • CYP3A4 inhibitors or inducers.
    • CYP2C19 inhibitors or inducers.
    • Diazepam may decrease the clearance of phenytoin.
  • Oxazepam:
    • No pharmacokinetic interactions.

side effects

  • Class-wide side effects:
    • Delirium – Benzodiazepines might be the most deliriogenic sedative agent, acting as a risk factor for the development of post-traumatic stress disorder (PTSD). (30672819) 
    • Paradoxical agitation.
    • Respiratory depression (generally mild in isolation, but may be additive with other CNS depressants).
    • Tolerance and withdrawal (after prolonged exposure).
  • Midazolam:
    • May accumulate over time in adipose tissue (particularly in patients with renal or hepatic dysfunction, or due to various drug-drug interactions).
  • Lorazepam:
    • Infusions often cause propylene glycol intoxication.
  • Diazepam:
    • Extraordinarily high doses can cause propylene glycol toxicity.
indications, advantages 👍

advantages of benzodiazepines

  • Class-wide benefits:
    • Hemodynamically stable.
    • Antiseizure activity.
    • Muscular relaxation.
    • Anteriograde amnesia.
    • Anxiolysis.
    • Sedation.
    • Hypnosis.
  • Midazolam advantages:
    • Useful in procedural sedation (rapid onset, short duration of action, reversal agent available).
    • Doesn't generate propylene glycol.
    • Best IM benzodiazepine (faster absorption than lorazepam).
  • Lorazepam advantages:
    • Front-line agent for status epilepticus.
    • Widely and immediately available in most locations.
  • Diazepam advantages:
    • IV diazepam takes effect very rapidly. This may allow for the immediate assessment of clinical response and avoid dose stacking. For example, these properties make diazepam the preferred benzodiazepine for the treatment of alcohol withdrawal.
    • Accumulation with a long half-life may be helpful in alcohol withdrawal therapy.
  • Oxazepam advantages:
    • It may be helpful in cirrhosis or elderly patients (metabolism is less affected by age and liver dysfunction than other benzodiazepines). Vd increases and clearance decreases in the very elderly, but these changes generally aren't significant for patients <80 years old.
    • Slower onset may decrease abuse potential (onset occurs over 3 hours, as opposed to 2 hours for lorazepam).

role of benzodiazepines in ICU sedation

  • Benzodiazepines are generally a sedative of last resort. The practice of bolusing patients with PRN lorazepam at night should be avoided like the plague. This will often work in the short term, but lorazepam will worsen delirium and agitation eventually. If a medication bolus is required to treat agitation, consider using haloperidol or up-titration of other medications (e.g., propofol).
  • Benzodiazepines do have roles in a few situations:
    • [1] Midazolam for procedural sedation.
    • [2] Sedative of choice for intoxication, especially sympathomimetic intoxication (due to muscle-relaxant and antiseizure properties).
    • [3] Patients with profound hypotension (who are too unstable to receive propofol or dexmedetomidine). However, ketamine may be more useful in this situation.
    • [4] Benzodiazepines may be used for alcohol withdrawal (although phenobarbital is generally better).
dosing

midazolam dosing

  • General:
    • Midazolam onset in 2-5 minutes.
    • Conversion: Lorazepam is roughly twice as potent as midazolam.
  • Cardioversion:
    • Load with midazolam 3-5 mg IV bolus (depending on age and weight).
    • Give 2 mg IV midazolam q2min PRN to target adequate sedation:
      • Eyes closed.
      • No response to gentle verbal/tactile stimuli.
      • Sluggish response to loud verbal commands or stronger tactile stimuli.
  • Status epilepticus:
    • Initial treatment:
      • 10 mg IV/IM.
      • Midazolam is the preferred IM medication for seizures (works faster than IM lorazepam).
    • Continuous infusion:
      • ⚠️ This should ideally be avoided for reasons discussed here. Additionally, the doses below are commonly quoted in textbooks and review articles, but they seem crazy high to me.  If these doses are utilized, they can accumulate, leading to prolonged coma.
      • Load: 0.2 mg/kg. May repeat this q5-10 up to 2 mg/kg total dose.
      • Infuse: 0.05-2 mg/kg/hr.
    • (More on status epilepticus therapy: 📖)
  • Sedation in an intubated patient:
    • Usual dosing: 2-5 mg IV q15-30 min PRN.
    • Infusion: 0.02-0.1 mg/kg/hr (avoid if possible; PRN dosing may be preferred to avoid over-sedation).
    • Morbid obesity: An increased volume of distribution with unchanged clearance may lead to an extended half-life.  To avoid accumulation, use an ideal body weight or adjusted body weight. (32513237)

lorazepam dosing

  • General:
    • Lorazepam is roughly twice as potent as midazolam.
    • IV has onset in 15-20 minutes.
    • PO:IV:IM has 1:1:1 conversion (despite differing lag time to Tmax).
  • Status epilepticus:
    • 0.1 mg/kg lorazepam IV is supported by the best evidence. (9738086, 33664203)
    • However, many guidelines recommend giving 4 mg IV initially, with a repeat dose if this isn't effective. That may also be reasonable. (More on status epilepticus therapy: 📖)
  • Sedation of an intubated patient:
    • 1-4 mg IV q30-60 min PRN.
    • 1-4 mg PO q6hr was validated in one RCT of oral sedation in the ICU. (23551983, 30616675)

diazepam dosing

  • Alcohol withdrawal:
    • Escalating IV doses as needed Q5-10 minutes (e.g., 10 mg, 10 mg, 20 mg, 20 mg, 20 mg, 40 mg, 40 mg, 40 mg). (Discussed further here: 📖)
  • Status epilepticus:
    • 10 mg IV.
    • May repeat q5-10 minutes to a maximum cumulative dose of 30 mg IV.
    • The rapid redistribution of diazepam from the brain into the peripheral tissues limits its duration of action, which may increase the risk of recurrent seizures as the diazepam wears off. (More on status epilepticus therapy: 📖)
  • Renal failure: No dose adjustment; titrate to effect.

oxazepam dosing

  • Usually dosed q6hr or q8hr.
  • Mild-moderate anxiety: 10-15 mg, 3-4 times daily.
  • Severe anxiety or anxiety with depression: 15-30 mg, 3-4 times daily.
  • Alcohol withdrawal: 15-30 mg, 3-4 times daily PRN.
  • Elderly patients: 10-15 mg three times daily.
  • Maximum recommended daily dose: 120 mg.
pharmacology

overview of benzodiazpines based on half-life

  • ~1.5-2.5 hours yet context-sensitive: Midazolam (VERSED™️)
  • ~2-5 hours: Triazolam (HALCION™️)
  • ~8 hours (range 6-12 hours): Oxazepam (SERAX™️)
  • ~8-20 hours: Temazepam (RESTORIL™️)
  • ~10-20 hours: Lorazepam (ATIVAN™️)
  • ~11 hours (range ~6-26 hours): Alprazolam (XANAX™️)
  • ~5-30 hours: Chlordiazepoxide (LIBRIUM™️)
  • ~30-40 hours: Clonazepam (KLONOPIN™️)
  • ~20-50 hours: Diazepam (VALIUM™️)
  • (Note: Half-life may vary depending on patient specifics, such as hepatic and renal function. Values quoted by different references vary substantially.)  

midazolam pharmacology

  • Absorption:
    • IV: 100%.
    • IM: Median time to maximal plasma concentration is ~30 minutes with 90% bioavailability.
    • Oral: Bioavailability ~30-50% due to extensive first-pass metabolism by intestinal and hepatic CYP3A4/5 enzymes. Slower onset of effect, typically within 20-30 minutes.
  • Distribution:
    • Vd of 1-3 L/kg (widely distributed, including in fat tissue). (32513237)
    • LogP of 3.33.
    • Protein binding is 97% (mostly to albumin).
  • Metabolism:
    • The liver almost completely metabolizes midazolam.
    • Primary pathway: CYP3A4 yielding 1-hydroxy-midazolam (aka alpha-1-hydroxymidazolam). This is subsequently glucuronidated to yield alpha-hydroxy midazolam glucuronide.  Alpha-1-hydroxy midazolam has ~10% of the activity of midazolam, and it may promote prolonged sedation (especially in the context of renal failure).
  • Elimination:
    • Metabolites are renally excreted.
    • In renal failure, alpha-hydroxy midazolam glucuronide may accumulate, causing sedation. (Paw and Shulman 2025)
  • Half-life & duration of action:
    • Following a single dose, arousal occurs when midazolam distributes out of the central circulation (similar to fentanyl).
    • Prolonged infusion may cause midazolam to accumulate in fat tissue, thereby extending its half-life in a context-dependent manner.
    • Renal dysfunction may lead to toxicity or prolonged efficacy due to the accumulation of the active metabolite. Consider dose reduction in renal or hepatic impairment. (33896531)

lorazepam pharmacology

  • Absorption:
    • IV: 100%.
    • IM: Rapid and complete absorption, Tmax in ~15-30 minutes.
    • Oral: 90% bioavailability with Tmax in ~2 hours (so IV: PO conversion is 1:1).
  • Distribution:
    • Vd of ~1 L/kg.
    • Protein binding is ~85% (mostly to albumin).
    • LogP ~2.4-3.5
  • Metabolism:
    • Lorazepam is hepatically metabolized via glucuronidation (UGT2B15) to inactive lorazepam glucuronide.
  • Elimination:
    • Inactive metabolites are renally excreted.
  • Half-life & duration of action:
    • Half-life of 10-20 hours.

diazepam pharmacology

  • Absorption:
    • IV: 100%.
    • PO: >90% bioavailability with peak plasma concentrations occurring in ~1-1.5 hours.
  • Distribution:
    • Vd of ~1 L/kg.
    • Protein binding is ~98%.
    • LogP is 2.8
    • Initial activity may wane due to redistribution out of the central compartment.
  • Metabolism:
    • Extensively metabolized in the liver with the generation of several active metabolites (N-desmethyldiazepam, temazepam, and oxazepam).
    • CYP3A4 & CYP2C19-mediated N-demethylation yields N-desmethyldiazepam (nordiazepam), which is metabolized into oxazepam.
    • CYP3A4 hydroxylation yields temazepam, which may be converted to oxazepam.  Both temazepam and oxazepam can be metabolized via glucuronidation.
    • CYP2C19 poor metabolizers have a 50% reduction in clearance.
  • Elimination:
    • Mainly excreted in the urine as glucuronide conjugates.
  • Half-life & duration of action:
    • Elimination half-life is prolonged and variable.
      • Diazepam has a half-life of up to 48 hours.
      • N-desmethyldiazepam has a half-life of up to 100 hours.
    • Clearance is reduced by ~50% in the elderly, cirrhosis, or CYP2C19 poor metabolizers.

oxazepam pharmacology

  • Absorption:
    • 90% oral bioavailability.
    • Slow onset of action, with Tmax after ~3 hours.
  • Distribution:
    • Vd of 0.6-2 L/kg.
    • Protein binding is 89% (mostly to albumin).
    • Minimal accumulation in adipose tissue.
    • LogP is 2-2.9
  • Metabolism:
    • Oxazepam is metabolized solely by glucuronidation to oxazepam glucuronide.
    • There are no active metabolites, nor involvement of the CYP system.
  • Elimination:
    • Inactive glucuronide metabolites are excreted in the urine.
  • Half-life & duration of action:
    • The half-life is 6-12 hours (shorter than lorazepam, which is ~10-20 hours).
    • Half-life is generally unchanged in patients with acute hepatitis or cirrhosis.

etomidate

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contraindications, drug interactions, side effects 👎

contraindications

  • ⚠️ Difficult airway or inability to bag-mask ventilate the patient.
  • ⚠️ Unable to tolerate adrenal suppression (e.g., septic shock, severe physiological stress).
  • ⚠️ Elderly or hepatic dysfunction: reduced protein binding and clearance increase the risk of prolonged sedation.

drug-drug interactions

  • Synergistic sedation with other CNS depressants.

side effects

  • Adrenal suppression (dose-dependent, after 0.3 mg/kg may last for ~6-8 hours).
  • Myoclonus.
  • Nausea and vomiting may occur during the recovery phase (but the risk is low at doses used for procedural sedation).
  • Injection site discomfort.
  • Respiratory:
    • Etomidate causes less respiratory suppression than propofol. After a 0.3 mg/kg bolus, a short period of hyperventilation usually occurs. Apnea may occur, but it is generally brief. (34060021)
    • Laryngospasm may rarely occur.
  • Allergic reactions (rare, but may be serious).
indications, advantages 👍
  • Procedural sedation (primarily useful for cardioversion).
  • Advantages:
    • Hemodynamic stability.
    • Relatively short duration of activity.
dosing
  • Induction of anesthesia: 0.2-0.6 mg/kg IV (usual dose of 0.3 mg/kg or ~20 mg).
  • Procedural sedation for cardioversion:
    • Initial dose 0.1 mg/kg.
    • Additional doses of 0.05 mg/kg every 2 minutes until adequate sedation is reached.
  • Dose-reduction in the elderly (due to reduced protein binding and reduced central compartment volume).
pharmacology
  • Absorption:
    • Intravenous only.
    • The onset of activity is rapid (within a minute).
    • Duration of action is brief (~5-10 minutes with 0.3 mg/kg). (34060021)
  • Distribution:
    • Rapid decline in serum levels over 30 minutes due to redistribution to peripheral tissues (with a distribution half-life of ~2-3 minutes).
    • Central compartment: 2-4.5 L/kg (reduced in the elderly).
    • Peripheral compartment: 75 L/kg (due to high lipid solubility).
    • Protein binding is ~75% (mostly to albumin).
  • Metabolism:
    • Hepatic and plasma esterases hydrolyze etomidate to an inactive metabolite (primarily etomidate carboxylic acid). EH is reported to range from 0.5-0.9 (34060021)
    • CYP enzymes aren't involved.
    • Cirrhosis may double the elimination half-life.
  • Elimination:
    • ~75% excreted in the urine (mainly as the carboxylic acid metabolite).
    • ~10% is excreted in the feces.
  • Half-life & duration of action:
    • Terminal elimination half-life is 3-5 hours.
  • Mechanism of action:
    • GABA-A agonist.
    • Hypnotic agent without analgesia.

flumazenil

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contraindications, drug interactions, side effects 👎

contraindications

  • Mixed intoxication (benzodiazepines often exert beneficial effects that protect against the effects of co-intoxicants such as tricyclic antidepressants or sympathomimetics).
  • Known seizure disorder.
  • Chronic benzodiazepine use.

drug-drug interactions

  • No pharmacokinetic drug-drug interactions.

side effects & risks

  • [1] Seizures (the most feared complication, not due to flumazenil itself).
  • [2] Resedation: The duration of flumazenil is only ~20-60 minutes (depending somewhat on the dose). For most benzodiazepines, this creates a risk of re-sedation when the flumazenil wears off.
  • [3] Nausea and vomiting.
  • [4] Anxiety, agitation, hypertension.
  • [5] Arrhythmias.
indications, advantages 👍
  • [1] The primary indication is after procedural sedation with a benzodiazepine in a previously benzodiazepine-naive patient. Specific indications could include:
    • Management of excessive sedation.
    • Management of paradoxical agitation.
    • Accelerate recovery after benzodiazepine administration.
  • [2] Benzodiazepine intoxication in a previously benzodiazepine-naive patient who solely overdosed on benzodiazepines.
    • In practice, this situation is rarely encountered (most patients who overdose on benzodiazepines also use them chronically).
  • [3] Flumazenil is effective for overdoses of zolpidem and zaleplon. (Goldfrank 10e)
dosing

procedural sedation reversal

  • Initial dose:
    • Dose: 0.2-0.5 mg (depending on severity). Repeat PRN to a maximal 1 mg cumulative dose.
    • Gradual administration (0.1 mg every minute) may allow patients to wake up more gradually and smoothly. (Goldfrank 10th ed.)  
    • Effects are typically observed within 1-2 minutes, with the peak effect occurring within 6-10 minutes.
    • The duration of antagonism is only ~20-60 minutes (depending on dose and plasma benzodiazepine levels). Administering a larger dose up-front will extend the duration of activity.
    • ⚠️ Beware of the risk of resedation.
  • Repeat doses:
    • Repeat doses may be required (max of ~3 mg in one hour).
    • A continuous infusion may occasionally be necessary.  Based on a half-life of ~60 minutes, the infusion rate may be estimated as equal to 0.7 times the loading dose per hour (e.g., if 1 mg was required to cause sedation reversal, an infusion of 0.7 mg/hr may be reasonable). 📖

benzodiazepine overdose reversal

  • Start with low doses as described above for sedation reversal.
  • Larger doses may be required (e.g., an initial cumulative dose of ~3 mg). Patients with a partial response to 3 mg may receive additional doses to a total dose of 5 mg. (Shoar 2024)

dosing in organ dysfunction

  • Renal dysfunction: No adjustment.
  • Hepatic dysfunction: Same initial loading dose, but metabolism is slowed down to subsequent doses may be reduced in size/frequency. (Wellington 3e)
pharmacology
  • Chemical characteristics:
    • Molecular weight is 303 g/mol.
    • LogP is 1.15
  • Absorption:
    • IV administration with 100% bioavailability.
  • Distribution:
    • Initial distribution half-life: ~5 minutes (correlating with entry into the brain and onset of activity).
    • Initial Vd is 0.5 L/kg.
    • Steady-state Vd is 1 L/kg.
    • Protein binding is 50% (mostly to albumin).
  • Metabolism:
    • Flumazenil is nearly completely metabolized in the liver via de-ethylation and glucuronidation to inactive metabolites.
  • Elimination:
    • Inactive metabolites are eliminated in the urine.
  • Half-life & duration of action:
    • Terminal half-life is 40-80 minutes.
    • In hepatic impairment, the half-life may be prolonged up to 2.4 hours.

concept of multi-modal therapy

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Multi-modal therapy is a useful principle which may be applied to a variety of topics (e.g., analgesia, sedation, hemodynamic support, antiemetics).

foundational concept #1 = low doses to optimize risk/benefit

  • Using lower medication doses can often allow substantial clinical benefit, with minimal toxicity (optimizing the risk/benefit ratio). This also creates a safety buffer; even if drug concentrations increase a bit, they will remain within a safe range.

foundational concept #2 = different agents function synergistically

  • Different agents frequently work in a synergistic fashion (i.e., 1+1 = 3).
  • Synergy allows moderate doses of several different agents to have a large combined impact.

putting it together: multi-modal therapy

  • A multi-modal strategy therefore involves using moderate doses of several different agents, in order to maximize efficacy while minimizing toxicity. This is in contrast, for example, to a traditional approach of treating pain with super-human doses of a single opioid.
  • For example:
    • Propofol monotherapy may require using a high dose of propofol. This may eventually may cause hypertriglyceridemia or propofol infusion syndrome.
    • Combining a low dose propofol infusion with an alpha-2 agonist may avoid the toxic effects of propofol, allowing the safe use of propofol for an extended duration.
  • Multi-modal therapy is more work, because it involves administration of more medications. This may be confusing to practitioners who aren't familiar with it (“why are we using four drugs when we could use one?”). However, the evidentiary basis for multi-modal therapy is reasonably robust (based largely on RCTs performed in operative and post-operative patients).

targeted treatment of pain, anxiety, and agitated delirium

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Ideally, an uncomfortable patient should be evaluated to determine the source of discomfort. This should be treated appropriately:

  • Pain should be treated with an analgesic agent.
  • Anxiety refers to fear or uneasiness in the absence of confusion. If medication is required, the optimal medication is a sedative (e.g., propofol or dexmedetomidine).
  • Agitated delirium refers to an acute confusional state marked by agitation. If medication is required, the optimal therapy is an antipsychotic.

Sorting out the cause of discomfort:

  • Among communicative patients, it's straightforward to ask about whether there is pain. Additional questioning may help sort out anxiety versus agitated delirium.
  • Among patients unable to communicate, behavioral pain scores may be used to assess pain. They provides a systematic approach to assess pain and titrate medication accordingly.

In practice, it may be impossible to differentiate precisely between pain, anxiety, or agitated delirium. The ultimate goal is to keep the patient comfortable and calm, while avoiding iatrogenic harm from medications. It may be necessary to empirically trial various medications, prior to selecting the medication(s) which work best for a specific patient.

daily sedation interruption?

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  • The basic concept here is to stop sedative and opioid infusions and re-titrate daily, to make sure that we're using the lowest possible dose.
  • Sedation interruption was extremely critical when we were using long-acting infusions (e.g., midazolam and fentanyl drips). The general concept remains useful today but should probably be applied in a modified fashion. Specifically, we should be continuously titrating drugs such as propofol or dexmedetomidine to achieve a target level of sedation – so stopping entirely doesn't make a lot of sense.
  • Key concepts:
    • 🔑 Re-assess the sedation regimen frequently (at least daily – but ideally more often).
    • 🔑 Always seek to use the lowest doses possible of all medications.
    • 🔑 Don't necessarily shut off everything in a robotic fashion. For example, if the patient is awake and comfortable (RASS = 0), then shutting off all the sedation could cause them to become agitated with no real benefit.

questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

Guide to emoji hyperlinks 🔗

  • 🧮 = Link to online calculator.
  • 💊 = Link to Medscape monograph about a drug.
  • 💉 = Link to IBCC section about a drug.
  • 📖 = Link to IBCC section covering that topic.
  • 🌊 = Link to FOAMed site with related information.
  • 🎥 = Link to supplemental media.

References

  • 07637157 Omote K, Satoh O, Sonoda H, Kumeta Y, Yamaya K, Namiki A. Masui. 1995;44(6):816-823. [PubMed]
  • 07986518 Cunningham FE, Baughman VL, Peters J, Laurito CE. Comparative pharmacokinetics of oral versus sublingual clonidine. J Clin Anesth. 1994;6(5):430-433. doi:10.1016/s0952-8180(05)80018-2 [PubMed]
  • 08124994 Riker RR, Fraser GL, Cox PM. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med. 1994 Mar;22(3):433-40. doi: 10.1097/00003246-199403000-00013 [PubMed]
  • 08874906 Park J, Forrest J, Kolesar R, Bhola D, Beattie S, Chu C. Oral clonidine reduces postoperative PCA morphine requirements. Can J Anaesth. 1996 Sep;43(9):900-6. doi: 10.1007/BF03011802 [PubMed]
  • 09507131 Jevtovic-Todorovic V, Wozniak DF, Powell S, Nardi A, Olney JW. Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects. Brain Res. 1998;781(1-2):202-211. doi:10.1016/s0006-8993(97)01247-x [PubMed]
  • 10773503 Handa F, Tanaka M, Nishikawa T, Toyooka H. Effects of oral clonidine premedication on side effects of intravenous ketamine anesthesia: a randomized, double-blind, placebo-controlled study. J Clin Anesth. 2000;12(1):19-24. doi:10.1016/s0952-8180(99)00131-2 [PubMed]
  • 11465557 Davies MF, Reid K, Guo TZ, Agashe GS, Amin YK, Maze M. Sedative but not analgesic alpha2 agonist tolerance is blocked by NMDA receptor and nitric oxide synthase inhibitors. Anesthesiology. 2001;95(1):184-191. doi:10.1097/00000542-200107000-00029 [PubMed]
  • 12933413 Guillou N, Tanguy M, Seguin P, Branger B, Campion JP, Mallédant Y. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003;97(3):843-847. doi:10.1213/01.ane.0000075837.67275.36 [PubMed]
  • 14581110 Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003;106(1-2):49-57. doi:10.1016/s0304-3959(03)00276-8 [PubMed]
  • 15235947 Ishihara H, Satoh Y, Kudo H, Yasuda T, Koh H, Matsuki A. No psychological emergence reactions in schizophrenic surgical patients immediately after propofol, fentanyl, and ketamine intravenous anesthesia. J Anesth. 1999;13(1):17-22. doi:10.1007/s005400050016 [PubMed]
  • 15592331 Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther. 2004;76(6):598-606. doi:10.1016/j.clpt.2004.08.018 [PubMed]
  • 15714324 Cigada M, Pezzi A, Di Mauro P, Marzorati S, Noto A, Valdambrini F, Zaniboni M, Astori M, Iapichino G. Sedation in the critically ill ventilated patient: possible role of enteral drugs. Intensive Care Med. 2005 Mar;31(3):482-6. doi: 10.1007/s00134-005-2559-7 [PubMed]
  • 15973913 Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005;33(3):311-322. doi:10.1177/0310057X0503300306 [PubMed]
  • 15983467 Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103(1):147-155. doi:10.1097/00000542-200507000-00022 [PubMed]
  • 16334492 Grass JA. Patient-controlled analgesia. Anesth Analg. 2005;101(5 Suppl):S44-S61. doi:10.1213/01.ane.0000177102.11682.20 [PubMed]
  • 16854557 Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006;60(7):341-348. doi:10.1016/j.biopha.2006.06.021 [PubMed]
  • 16894061 Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. doi:10.1001/archpsyc.63.8.856 [PubMed]
  • 18199279 Henney HR 3rd, Runyan JD. A clinically relevant review of tizanidine hydrochloride dose relationships to pharmacokinetics, drug safety and effectiveness in healthy subjects and patients. Int J Clin Pract. 2008;62(2):314-324. doi:10.1111/j.1742-1241.2007.01660.x [PubMed]
  • 18671474 Malanga G, Reiter RD, Garay E. Update on tizanidine for muscle spasticity and emerging indications. Expert Opin Pharmacother. 2008;9(12):2209-2215. doi:10.1517/14656566.9.12.2209 [PubMed]
  • 18709354 Liatsi D, Tsapas B, Pampori S, Tsagourias M, Pneumatikos I, Matamis D. Respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome. Intensive Care Med. 2009 Feb;35(2):275-81. doi: 10.1007/s00134-008-1251-0 [PubMed]
  • 19095506 Sollazzi L, Modesti C, Vitale F, et al. Preinductive use of clonidine and ketamine improves recovery and reduces postoperative pain after bariatric surgery. Surg Obes Relat Dis. 2009;5(1):67-71. doi:10.1016/j.soard.2008.09.018 [PubMed]
  • 19783371 Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147(1-3):107-115. doi:10.1016/j.pain.2009.08.015 [PubMed]
  • 20116842 Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010;375(9713):475-480. doi:10.1016/S0140-6736(09)62072-9 [PubMed]
  • 20189753 Memis D, Inal MT, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25(3):458-462. doi:10.1016/j.jcrc.2009.12.012 [PubMed]
  • 20648205 Nama S, Meenan DR, Fritz WT. The use of sub-anesthetic intravenous ketamine and adjuvant dexmedetomidine when treating acute pain from CRPS. Pain Physician. 2010;13(4):365-368. [PubMed]
  • 21074739 Palmer PP, Miller RD. Current and developing methods of patient-controlled analgesia. Anesthesiol Clin. 2010;28(4):587-599. doi:10.1016/j.anclin.2010.08.010 [PubMed]
  • 21676160 Forero M, Chan PS, Restrepo-Garces CE. Successful reversal of hyperalgesia/myoclonus complex with low-dose ketamine infusion. Pain Pract. 2012;12(2):154-158. doi:10.1111/j.1533-2500.2011.00475.x [PubMed]
  • 22420584 Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care. 2012;16(2):R49. Published 2012 Dec 12. doi:10.1186/cc11250 [PubMed]
  • 23269131 Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. doi:10.1097/CCM.0b013e3182783b72 [PubMed]
  • 23428794 Rasmussen KG, Lineberry TW, Galardy CW, et al. Serial infusions of low-dose ketamine for major depression. J Psychopharmacol. 2013;27(5):444-450. doi:10.1177/0269881113478283 [PubMed]
  • 23551983 Mistraletti G, Mantovani ES, Cadringher P, Cerri B, Corbella D, Umbrello M, Anania S, Andrighi E, Barello S, Di Carlo A, Martinetti F, Formenti P, Spanu P, Iapichino G; SedaEN investigators. Enteral vs. intravenous ICU sedation management: study protocol for a randomized controlled trial. Trials. 2013 Apr 3;14:92. doi: 10.1186/1745-6215-14-92 [PubMed]
  • 23711600 Nitta R, Goyagi T, Nishikawa T. Combination of oral clonidine and intravenous low-dose ketamine reduces the consumption of postoperative patient-controlled analgesia morphine after spine surgery. Acta Anaesthesiol Taiwan. 2013;51(1):14-17. doi:10.1016/j.aat.2013.03.003 [PubMed]
  • 25477978 Imani F, Motavaf M, Safari S, Alavian SM. The therapeutic use of analgesics in patients with liver cirrhosis: a literature review and evidence-based recommendations. Hepat Mon. 2014;14(10):e23539. Published 2014 Oct 11. doi:10.5812/hepatmon.23539 [PubMed]
  • 25530168 Jouguelet-Lacoste J, La Colla L, Schilling D, Chelly JE. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of the current literature. Pain Med. 2015;16(2):383-403. doi:10.1111/pme.12619 [PubMed]
  • 25561923 Farasatinasab M, Kouchek M, Sistanizad M, Goharani R, Miri M, Solouki M, Ghaeli P, Mokhtari M. A Randomized Placebo-controlled Trial of Clonidine Impact on Sedation of Mechanically Ventilated ICU Patients. Iran J Pharm Res. 2015 Winter;14(1):167-75 [PubMed]
  • 25809176 Gagnon DJ, Riker RR, Glisic EK, Kelner A, Perrey HM, Fraser GL. Transition from dexmedetomidine to enteral clonidine for ICU sedation: an observational pilot study. Pharmacotherapy. 2015 Mar;35(3):251-9. doi: 10.1002/phar.1559 [PubMed]
  • 25849473 Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31-39. doi:10.2344/0003-3006-62.1.31 [PubMed]
  • 25969139 Mistraletti G, Umbrello M, Sabbatini G, Miori S, Taverna M, Cerri B, Mantovani ES, Formenti P, Spanu P, D'Agostino A, Salini S, Morabito A, Fraschini F, Reiter RJ, Iapichino G. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol. 2015 Dec;81(12):1298-310 [PubMed]
  • 26025196 Moitra VK, Patel MK, Darrah D, Moitra A, Wunsch H. Low-Dose Ketamine in Chronic Critical Illness. J Intensive Care Med. 2016;31(3):216-220. doi:10.1177/0885066615587868 [PubMed]
  • 26650426 Terkawi AS, Tsang S, Kazemi A, et al. A Clinical Comparison of Intravenous and Epidural Local Anesthetic for Major Abdominal Surgery. Reg Anesth Pain Med. 2016;41(1):28-36. doi:10.1097/AAP.0000000000000332 [PubMed]
  • 26655493 Mauermann E, Filitz J, Dolder P, Rentsch KM, Bandschapp O, Ruppen W. Does Fentanyl Lead to Opioid-induced Hyperalgesia in Healthy Volunteers?: A Double-blind, Randomized, Crossover Trial. Anesthesiology. 2016;124(2):453-463. doi:10.1097/ALN.0000000000000976 [PubMed]
  • 26555871 Yazicioğlu D, Caparlar C, Akkaya T, Mercan U, Kulaçoğlu H. Tizanidine for the management of acute postoperative pain after inguinal hernia repair: A placebo-controlled double-blind trial. Eur J Anaesthesiol. 2016;33(3):215-222. doi:10.1097/EJA.0000000000000371 [PubMed]
  • 26919405 Lenze EJ, Farber NB, Kharasch E, Schweiger J, Yingling M, Olney J, Newcomer JW. Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial. World J Biol Psychiatry. 2016 Apr;17(3):230-8. doi: 10.3109/15622975.2016.1142607 [PubMed]
  • 26962521 Talakoub R, Abbasi S, Maghami E, Zavareh SM. The effect of oral tizanidine on postoperative pain relief after elective laparoscopic cholecystectomy. Adv Biomed Res. 2016;5:19. Published 2016 Feb 8. doi:10.4103/2277-9175.175905 [PubMed]
  • 27140827 Gowing L, Farrell M, Ali R, White JM. Alpha₂-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016 May 3;2016(5):CD002024. doi: 10.1002/14651858.CD002024.pub5 [PubMed]
  • 27426431 Fabritius ML, Geisler A, Petersen PL, et al. Gabapentin for post-operative pain management – a systematic review with meta-analyses and trial sequential analyses [published correction appears in Acta Anaesthesiol Scand. 2017 Mar;61(3):357-359]. Acta Anaesthesiol Scand. 2016;60(9):1188-1208. doi:10.1111/aas.12766 [PubMed]
  • 27656531 Trivedi S, Kumar R, Tripathi AK, Mehta RK. A Comparative Study of Dexmedetomidine and Midazolam in Reducing Delirium Caused by Ketamine. J Clin Diagn Res. 2016;10(8):UC01-UC4. doi:10.7860/JCDR/2016/18397.8225 [PubMed]
  • 27693975 Gagnon DJ, Fontaine GV, Smith KE, Riker RR, Miller RR 3rd, Lerwick PA, Lucas FL, Dziodzio JT, Sihler KC, Fraser GL. Valproate for agitation in critically ill patients: A retrospective study. J Crit Care. 2017 Feb;37:119-125. doi: 10.1016/j.jcrc.2016.09.006 [PubMed]
  • 27993418 Motov S, Yasavolian M, Likourezos A, et al. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2017;70(2):177-184. doi:10.1016/j.annemergmed.2016.10.014 [PubMed]
  • 28283340 Motov S, Mai M, Pushkar I, Likourezos A, Drapkin J, Yasavolian M, Brady J, Homel P, Fromm C. A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain in the ED. Am J Emerg Med. 2017 Aug;35(8):1095-1100. doi: 10.1016/j.ajem.2017.03.004 [PubMed]
  • 28468568 Buchheit JL, Yeh DD, Eikermann M, Lin H. Impact of Low-Dose Ketamine on the Usage of Continuous Opioid Infusion for the Treatment of Pain in Adult Mechanically Ventilated Patients in Surgical Intensive Care Units. J Intensive Care Med. 2019;34(8):646-651. doi:10.1177/0885066617706907 [PubMed]
  • 28833346 Gagnon DJ, Fontaine GV, Riker RR, Fraser GL. Repurposing Valproate, Enteral Clonidine, and Phenobarbital for Comfort in Adult ICU Patients: A Literature Review with Practical Considerations. Pharmacotherapy. 2017;37(10):1309-1321. doi:10.1002/phar.2017 [PubMed]
  • 29468508 Ahiskalioglu A, Yayik AM, Oral Ahiskalioglu E, et al. Ultrasound-guided bilateral superficial cervical block and preemptive single-dose oral tizanidine for post-thyroidectomy pain: a randomized-controlled double-blind study. J Anesth. 2018;32(2):219-226. doi:10.1007/s00540-018-2468-x [PubMed]
  • 29498534 Skrobik Y, Duprey MS, Hill NS, Devlin JW. Low-Dose Nocturnal Dexmedetomidine Prevents ICU Delirium. A Randomized, Placebo-controlled Trial. Am J Respir Crit Care Med. 2018 May 1;197(9):1147-1156. doi: 10.1164/rccm.201710-1995OC [PubMed]
  • 29619866 Srour H, Pandya K, Flannery A, Hatton K. Enteral Guanfacine to Treat Severe Anxiety and Agitation Complicating Critical Care After Cardiac Surgery. Semin Cardiothorac Vasc Anesth. 2018 Dec;22(4):403-406. doi: 10.1177/1089253218768537 [PubMed]
  • 29649890 Davis MP, McPherson ML, Mehta Z, Behm B, Fernandez C. What Parenteral Opioids to Use in Face of Shortages of Morphine, Hydromorphone, and Fentanyl. Am J Hosp Palliat Care. 2018 Aug;35(8):1118-1122. doi: 10.1177/1049909118771374 [PubMed]
  • 29733100 Davis MP, Fernandez C, Regel S, McPherson ML. Does nalbuphine have a niche in managing pain? J Opioid Manag. 2018 Mar/Apr;14(2):143-151. doi: 10.5055/jom.2018.0441 [PubMed]
  • 29870458 Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):521-546. doi:10.1097/AAP.0000000000000808 [PubMed]
  • 30113379 Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi:10.1097/CCM.0000000000003299 [PubMed]
  • 30137790 Ghanavatian S, Derian A. Tizanidine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. [PubMed]
  • 30268528 Perbet S, Verdonk F, Godet T, et al. Low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedated ICU patients: A randomised double-blind control trial. Anaesth Crit Care Pain Med. 2018;37(6):589-595. doi:10.1016/j.accpm.2018.09.006 [PubMed]
  • 30305124 Shi SB, Wang XB, Song JM, Guo SF, Chen ZX, Wang Y. Efficacy of intravenous acetaminophen in multimodal management for pain relief following total knee arthroplasty: a meta-analysis. J Orthop Surg Res. 2018;13(1):250. Published 2018 Oct 11. doi:10.1186/s13018-018-0950-7 [PubMed]
  • 30616675 Mistraletti G, Umbrello M, Salini S, Cadringher P, Formenti P, Chiumello D, Villa C, Russo R, Francesconi S, Valdambrini F, Bellani G, Palo A, Riccardi F, Ferretti E, Festa M, Gado AM, Taverna M, Pinna C, Barbiero A, Ferrari PA, Iapichino G; SedaEN investigators. Enteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial. Crit Care. 2019 Jan 7;23(1):3. doi: 10.1186/s13054-018-2280-x [PubMed]
  • 30638027 Erstad BL. Attempts to Limit Opioid Prescribing in Critically Ill Patients: Not So Easy, Not So Fast. Ann Pharmacother. 2019;53(7):716-725. doi:10.1177/1060028018824724 [PubMed]
  • 30672819 Opdenakker O, Vanstraelen A, De Sloovere V, Meyfroidt G. Sedatives in neurocritical care: an update on pharmacological agents and modes of sedation. Curr Opin Crit Care. 2019 Apr;25(2):97-104. doi: 10.1097/MCC.0000000000000592 [PubMed]
  • 30726545 Lee Y, Yu J, Doumouras AG, et al. Intravenous Acetaminophen Versus Placebo in Post-bariatric Surgery Multimodal Pain Management: a Meta-analysis of Randomized Controlled Trials. Obes Surg. 2019;29(4):1420-1428. doi:10.1007/s11695-019-03732-8 [PubMed]
  • 30778597 Subramaniam B, Shankar P, Shaefi S, et al. Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial [published correction appears in JAMA. 2019 Jul 16;322(3):276]. JAMA. 2019;321(7):686-696. doi:10.1001/jama.2019.0234 [PubMed]
  • 30845871 Wampole CR, Smith KE. Beyond Opioids for Pain Management in Adult Critically Ill Patients. J Pharm Pract. 2019;32(3):256-270. doi:10.1177/0897190019834479 [PubMed]
  • 31383385 Motov S, Masoudi A, Drapkin J, et al. Comparison of Oral Ibuprofen at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2019;74(4):530-537. doi:10.1016/j.annemergmed.2019.05.037 [PubMed]
  • 32068366 Olsen HT, Nedergaard HK, Strøm T, Oxlund J, Wian KA, Ytrebø LM, Kroken BA, Chew M, Korkmaz S, Lauridsen JT, Toft P. Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients. N Engl J Med. 2020 Mar 19;382(12):1103-1111. doi: 10.1056/NEJMoa1906759 [PubMed]
  • 32273047 Crowley KE, Urben L, Hacobian G, Geiger KL. Valproic Acid for the Management of Agitation and Delirium in the Intensive Care Setting: A Retrospective Analysis. Clin Ther. 2020 Apr;42(4):e65-e73. doi: 10.1016/j.clinthera.2020.02.007 [PubMed]
  • 32591212 Sher Y, Rabkin B, Maldonado JR, Mohabir P. COVID-19-Associated Hyperactive Intensive Care Unit Delirium With Proposed Pathophysiology and Treatment: A Case Report. Psychosomatics. 2020 Sep-Oct;61(5):544-550. doi: 10.1016/j.psym.2020.05.007 [PubMed]
  • 32844730 Ammar MA, Sacha GL, Welch SC, Bass SN, Kane-Gill SL, Duggal A, Ammar AA. Sedation, Analgesia, and Paralysis in COVID-19 Patients in the Setting of Drug Shortages. J Intensive Care Med. 2020 Aug 26:885066620951426. doi: 10.1177/0885066620951426 [PubMed]
  • 32912027 Subedi B, Louzon PR, Masood A, Recksieck S. Prolonged Refractory ICU Delirium Successfully Treated With Valproic Acid: Case Report and Literature Review. J Pharm Pract. 2020 Sep 10:897190020953017. doi: 10.1177/0897190020953017 [PubMed]
  • 33037818 George S, Johns M. Review of nonopioid multimodal analgesia for surgical and trauma patients. Am J Health Syst Pharm. 2020 Dec 4;77(24):2052-2063. doi: 10.1093/ajhp/zxaa301 [PubMed]
  • 33048904 Gandolfi JV, Di Bernardo APA, Chanes DAV, Martin DF, Joles VB, Amendola CP, Sanches LC, Ciorlia GL, Lobo SM. The Effects of Melatonin Supplementation on Sleep Quality and Assessment of the Serum Melatonin in ICU Patients: A Randomized Controlled Trial. Crit Care Med. 2020 Oct 13. doi: 10.1097/CCM.0000000000004690 [PubMed]
  • 33068459 Adams CD, Altshuler J, Barlow BL, Dixit D, Droege CA, Effendi MK, Heavner MS, Johnston JP, Kiskaddon AL, Lemieux D, Lemieux SM, Littlefield AJ, Owusu KA, Rouse GE, Thompson Bastin ML, Berger K. Analgesia and Sedation Strategies in Mechanically Ventilated Adults with COVID-19. Pharmacotherapy. 2020 Oct 17. doi: 10.1002/phar.2471 [PubMed]
  • 33105166 Harvin JA, Kao LS. Pain management in the surgical ICU patient. Curr Opin Crit Care. 2020 Dec;26(6):628-633. doi: 10.1097/MCC.0000000000000773 [PubMed]
  • 33272699 Jiang S, Czuma R, Cohen-Oram A, Hartney K, Stern TA. Guanfacine for Hyperactive Delirium: A Case Series. J Acad Consult Liaison Psychiatry. 2021 Jan-Feb;62(1):83-88. doi: 10.1016/j.psym.2020.10.003 [PubMed]
  • 33351427 Sibrack J, Patel P, Hammer R. Methocarbamol. 2024 Sep 10. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [PubMed]
  • 33935593 Page V, McKenzie C. Sedation in the Intensive Care Unit. Curr Anesthesiol Rep. 2021;11(2):92-100. doi: 10.1007/s40140-021-00446-5 [PubMed]
  • 34060021 Valk BI, Struys MMRF. Etomidate and its Analogs: A Review of Pharmacokinetics and Pharmacodynamics. Clin Pharmacokinet. 2021 Oct;60(10):1253-1269. doi: 10.1007/s40262-021-01038-6 [PubMed]
  • 35279975 Seo Y, Lee HJ, Ha EJ, Ha TS. 2021 KSCCM clinical practice guidelines for pain, agitation, delirium, immobility, and sleep disturbance in the intensive care unit. Acute Crit Care. 2022 Feb;37(1):1-25. doi: 10.4266/acc.2022.00094 [PubMed]
  • 35636044 Rech MA, Griggs C, Lovett S, Motov S. Acute pain management in the Emergency Department: Use of multimodal and non-opioid analgesic treatment strategies. Am J Emerg Med. 2022 Aug;58:57-65. doi: 10.1016/j.ajem.2022.05.022 [PubMed]
  • 26039709 Zeng Z, Lu J, Shu C, Chen Y, Guo T, Wu QP, Yao SL, Yin P. A comparision of nalbuphine with morphine for analgesic effects and safety: meta-analysis of randomized controlled trials. Sci Rep. 2015 Jun 3;5:10927. doi: 10.1038/srep10927 [PubMed]
  • 36349291 Fetters MB, Diep C, Ran R, Kloosterboer A. Effect of Enteral Guanfacine on Dexmedetomidine Use in the ICU. Crit Care Explor. 2022 Nov 1;4(11):e0785. doi: 10.1097/CCE.0000000000000785 [PubMed]
  • Guan, M., Fanelli, D., Verbeek, T., Warfield, D.J., Liu, H. (2023). Alpha-2 Adrenergic Agonists. In: Li, J., Jiang, W., Vadivelu, N. (eds) First Aid Perioperative Ultrasound. Springer, Cham. https://doi.org/10.1007/978-3-031-21291-8_12
  • 36751225 Jiang S, Hernandez M, Burke H, Spurling B, Czuma R, Varghese R, Cohen A, Hartney K, Sullivan G, Kozel FA, Maldonado JR. A Retrospective Analysis of Guanfacine for the Pharmacological Management of Delirium. Cureus. 2023 Jan 5;15(1):e33393. doi: 10.7759/cureus.33393 [PubMed]
  • 37260674 De Bels D, Bousbiat I, Perriens E, Blackman S, Honoré PM. Sedation for adult ICU patients: A narrative review including a retrospective study of our own data. Saudi J Anaesth. 2023 Apr-Jun;17(2):223-235. doi: 10.4103/sja.sja_905_22 [PubMed]
  • 37713724 Woolley B. Growing off-Label Neuro-Cognitive Uses for Guanfacine? An Informal Review of Publications from 2022 with Discussion about Two Clinical Trials Scheduled to Conclude in 2023-2024. Issues Ment Health Nurs. 2023 Sep;44(9):923-925. doi: 10.1080/01612840.2023.2242236 [PubMed]
  • 38275186 Amna S, Øhlenschlaeger T, Saedder EA, Sigaard JV, Bergmann TK. Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care. Basic Clin Pharmacol Toxicol. 2024 Apr;134(4):485-497. doi: 10.1111/bcpt.13979 [PubMed]
  • 38529017 Zhu LL, Wang YH, Zhou Q. Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations. J Pain Res. 2024 Mar 21;17:1257-1271. doi: 10.2147/JPR.S461032 [PubMed]
  • 38907529 Schuler A, Yoon CH, Caffarini E, Heine A, Meester A, Murray D, Harding A. Alpha2 Agonist Use in Critically Ill Adults: A Focus on Sedation and Withdrawal Prevention. J Pharm Pract. 2024 Jun 21:8971900241263171. doi: 10.1177/08971900241263171 [PubMed]
  • 39982143 Lewis K, Balas MC, Stollings JL, McNett M, Girard TD, Chanques G, Kho ME, Pandharipande PP, Weinhouse GL, Brummel NE, Chlan LL, Cordoza M, Duby JJ, Gélinas C, Hall-Melnychuk EL, Krupp A, Louzon PR, Tate JA, Young B, Jennings R, Hines A, Ross C, Carayannopoulos KL, Aldrich JM. A Focused Update to the Clinical Practice Guidelines for the Prevention and Management of Pain, Anxiety, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2025 Mar 1;53(3):e711-e727. doi: 10.1097/CCM.0000000000006574 [PubMed]

The Internet Book of Critical Care is an online textbook written by Josh Farkas (@PulmCrit), an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.


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