Pain, Agitation/Sedation, Delirium, Immobility, Sleep Disruption, and Neuromuscular Blockade
ii.
Dosage forms: Injectable (intravenous, subcutaneous) and oral; intravenous-to-oral conversion
is not a 1:1 mg ratio.
iii.
Adverse effects: CNS alterations (e.g., abnormal dreams, aggressive behavior, altered thinking),
respiratory depression, hypotension, constipation
Remifentanil (Ultiva)
Pharmacokinetics: Clearance by blood and tissue esterase; clearance not dependent on organ
function. Fast onset and short duration of action with little to no accumulation. High volume
of distribution, high protein binding.
ii.
Research primarily done in Europe; limited reported use in U.S. adult ICUs for ongoing
analgesic use.
iii.
Dosage form: Injectable only
iv.
Adverse effects: Respiratory depression, hypotension, bradycardia, constipation
Rebound pain: Quick offset (5–10 minutes) may lead to rebound pain and withdrawal symptoms,
and additional pain medication may be needed if remifentanil is interrupted or discontinued.
vi.
Benefit in adult ICUs: Decreased time on mechanical ventilation with short-term use (72 hours
or less)
Methadone
Pharmacokinetics: Phase I hepatic metabolism to inactive metabolites. Many drug
interactions: major substrate of CYP 2B6 and 3A4. Moderate inhibitor of CYP2D6, weak
inhibitor of CYP3A4. Longer-acting opiate with variable duration of action (12–48 hours); may
accumulate quickly in patients with hepatic failure or patients receiving hemodialysis. Animal
studies have found that the d-isomer of methadone works as both a partial mu-agonist and an
N-methyl-d-aspartate receptor antagonist (the l-isomer is a full mu-agonist). These properties
of the d-isomer are thought to decrease the tolerance effect to other opioids. Methadone is
currently marketed as the racemic mixture. On initiating oral methadone, steady state and
peak analgesic effect may not be reached for 3–5 days; oversedation and respiratory depression
may occur if titrated too quickly.
ii.
Dosage forms: Injectable (intravenous, intramuscular, subcutaneous) and oral. Intravenous-to-
oral conversion is not a 1:1.3 mg ratio.
iii.
Adverse effects: Dose-dependent QTc prolongation, altered mental status, respiratory
depression, confusion, dizziness, arrhythmias, constipation, risk of serotonin syndrome when
used with other serotonergic agents
Non-opioid adjunctive pain medications should be considered in combination with opioids to reduce
opioid requirements. Clinically stable patients may tolerate a conversion from opiates to non-opiate
medications.
Local and regional anesthetics such as bupivacaine. The PADIS guidelines do not recommend the
use of intravenous lidocaine as an adjunct to opioid therapy for pain management in critically ill
adults.
Acetaminophen (Tylenol, Ofirmev): The PADIS guidelines suggest using acetaminophen as an
adjunct to opioids to decrease pain intensity and opioid consumption.
Total daily acetaminophen doses should be considered from all acetaminophen combination
products, with a maximum total daily dose of 4 g. Decreased total daily dosing should be
considered in patients with significant liver disease or those older than 60 years of age.
ii.
Intravenous acetaminophen: Dose reduction recommended if the creatinine clearance
(CrCl) is 30 mL/minute/1.73 m2 or less or with continuous renal replacement therapy (every
8 hours); contraindicated in severe hepatic disease. The cost of the intravenous formulation
of acetaminophen is considerably higher than that of the oral or rectal formulations. The
intravenous formulation can also cause hypotension.