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.