Opioids commonly used for postoperative pain

Drug	Sample initial dose for opioid naïve adults*	Onset of analgesia	Elimination half life	Duration of analgesic effect^¶	Metabolism and clearance	Comments
Parenteral
Fentanyl	25 to 50 mcg IV for moderate pain or 50 to 100 mcg for more severe pain; repeat every 2 to 5 minutes as needed until adequate pain relief or side effects occur; then reassess pain control regimen	<1 minute; peak effect within several minutes	2 to 4 hours for bolus	30 to 60 minutes	Metabolized by CYP3A4 to inactive metabolite Metabolite excreted by kidney Short duration of initial dose(s) due to redistribution	Less histamine release relative to other opioids; may therefore be preferred in the presence of hemodynamic instability or bronchospasm Rapid redistribution results in an initial short duration of analgesic effect relative to the elimination half life Frequent repeated doses and infusions can significantly prolong the duration of analgesic effect Drug interactions with CYP450 3A4 inducers or inhibitors^Δ
Morphine	1 to 3 mg IV; repeat every 5 to 10 minutes as needed until adequate pain relief; then 1 to 3 mg IV every 1 to 4 hours as needed	5 to 10 minutes; peak effect within 20 minutes	2 to 4 hours	3 to 5 hours	Metabolized by non-CYP enzymes to morphine-6-glucuronide (active analgesic) and morphine-3-glucuronide (potential neurotoxin) Metabolites excreted by kidney	Reduce dose and increase dosing interval in patients with mild to moderate kidney or liver impairment due to decreased clearance of metabolites that may contribute to neuroexcitation Avoid use in patients with severe kidney dysfunction (CrCl <30 mL/minute) Histamine release and vagally mediated venodilation, hypotension, and bradycardia may be intolerable in some patient May interact with drugs that alter P-gp- mediated efflux
Hydromorphone	0.2 to 0.5 mg IV; repeat every 5 minutes as needed until adequate pain relief, then 0.2 to 0.5 mg IV every 3 to 4 hours as needed	5 minutes; peak effect 10 to 20 minutes	2 to 3 hours	3 to 4 hours	Metabolized by glucuronidation (ie, non-CYP enzymes) to inactive hydromorphone-3-glucuronide (potentially neuroexcitatory) Metabolites excreted by kidney	Reduce dose in patients with hepatic dysfunction Reduce dose and increase dosing interval in patients with kidney dysfunction
Oliceridine	Initial dose 1.5 mg IV; subsequent doses of 0.75 mg IV no more frequently than hourly^◊; maximum total cumulative daily dose 27 mg IV	2 to 5 minutes	1.3 to 3 hours; increased in patients with hepatic dysfunction	1 to 3 hours	Metabolized by CYP3A4 and 2D6 enzymes to inactive metabolites Metabolites excreted by kidney (70%) and fecally (30%)	IV formulation only Drug interactions with CYP450 3A4 and 2D6 inducers or inhibitors^Δ CYP2D6 poor metabolizers have ~2-fold greater drug exposure (AUC_0-24) relative to others^Δ Not studied for >48 hours of use Maximum daily dose of 27 mg due to risk for prolonged QT interval
Oral
Oxycodone (immediate release)	5 to 10 mg orally every 3 to 4 hours as needed	10 to 15 minutes; peak effect 0.5 to 1 hour	3 to 4 hours; increased in kidney or hepatic dysfunction	3 to 6 hours	Hepatic metabolism by CYP3A4 and CYP2D6 (minor) to active metabolites noroxycodone and oxymorphone, and inactive metabolites noroxymorphone, alpha- and beta-noroxycodol, and alpha- and beta-oxymorphol Metabolites excreted by kidney	Reduce dose in patients with hepatic dysfunction Reduce dose and increase dosing interval in patients with kidney dysfunction Drug interactions with CYP450 3A4 and 2D6 inducers or inhibitors^Δ Also available in combinations with acetaminophen, aspirin, or ibuprofen; nonopioid component dose limits apply to combinations
Hydromorphone (immediate release)	2 to 4 mg orally every 3 to 4 hours as needed	15 to 30 minutes; peak effect 30 to 60 minutes	2 to 3 hours	3 to 4 hours	Metabolized by glucuronidation (ie, non-CYP enzymes) to inactive hydromorphone-3-glucuronide (potentially neuroexcitatory) Metabolites excreted by kidney	Reduce dose in patients with hepatic dysfunction Reduce dose and increase dosing interval in patients with kidney dysfunction
Hydrocodone (immediate release)	5 to 10 mg orally every 4 to 6 hours as needed	10 to 30 minutes; peak effect 60 minutes	~4 hours	4 to 8 hours	Hepatic metabolism via CYP3A4 and CYP2D6 (minor) to active metabolites hydromorphone and norhydrocodone	In the United States immediate-release hydrocodone is available only in combination with ibuprofen or acetaminophen Not recommended for first-line use as part of multimodal analgesia^§ Drug interactions with CYP450 3A4 and 2D6 inducers or inhibitors^Δ
Morphine (immediate release)	10 to 15 mg orally every 3 to 4 hours as needed	~30 minutes	2 to 4 hours	3 to 5 hours	Metabolized by non-CYP enzymes to morphine-6-glucuronide (active analgesic) and morphine-3-glucuronide (potential neurotoxin) Metabolites excreted by kidney	Reduce dose and increase dosing interval in patients with mild to moderate kidney or liver impairment due to decreased clearance of metabolites that may contribute to neuroexcitation Avoid use in patients with severe kidney dysfunction (CrCl <30 mL/minute) May interact with drugs that alter P-gp-mediated efflux Lowest dose available tablet is 15 mg; Oral solution available
Tramadol (immediate release)	50 to 100 mg orally every 4 to 6 hours as needed (maximum 400 mg per day)	Within 1 hour; peak effect 2 to 3 hours	6 to 9 hours (including active metabolite); increased in kidney or hepatic dysfunction	4 to 6 hours	Hepatic metabolism via CYP3A4 and CYP2D6 (minor) to active metabolite O-desmethy tramadol Metabolites excreted by kidney	In addition to mu opioid receptor binding, inhibits reuptake of serotonin and norepinephrine Reduce dose in patients with severe hepatic dysfunction Reduce dose and increase dosing interval in patients with kidney dysfunction Drug interactions with CYP450 3A4 and 2D6 inducers or inhibitors; variable effects of CYP450 polymorphisms^Δ Risk for serotonin syndrome and seizure in patients using other serotoninergic drugs (eg, MAO-I, SSRI, SNRI, and TCA medications) Serotoninergic effects not reversed by naloxone Available in combinations with acetaminophen; dose limits apply
Tapentadol (immediate release)	50 to 100 mg orally every 4 to 6 hours as needed; maximum dose: First day: 700 mg per day Day 2 and subsequent days: 600 mg per day	Within 1 hour; peak effect 1.25 hours	4 hours; increased in kidney or hepatic dysfunction	4 to 6 hours	Hepatic metabolism primarily via glucuronidation (non-CYP) to inactive metabolites tapentadol-O-glucuronide Metabolites excreted by kidney (70%)	In addition to binding to mu opioid receptors, inhibits norepinephrine reuptake Reduce dose in patients with moderate liver dysfunction, avoid in patients with severe hepatic dysfunction Avoid in patients with severe kidney dysfunction (CrCl <30 mL/minute) Risk of serotoninergic drug interactions (refer to tramadol) High cost and limited availability on hospital formularies limit use as a first-line drug for acute postsurgical pain
Codeine (immediate release)	15 to 60 mg orally every 4 to 6 hours as needed	0.5 to 1 hour; peak effect 1 to 1.5 hours (variable; refer to comment)	~3 hours	4 to 6 hours	Hepatic metabolism via CYP2D6 to morphine (active) and via CYP3A4 to norcodeine (inactive) Metabolites excreted by kidney (90%)	Analgesic efficacy requires conversion via CYP2D6 enzymes to active metabolite (morphine) Due to genetic variation in CYP2D6 activity, onset and potency can vary widely between individuals^Δ Drug interactions with CYP450 3A4 and 2D6 inducers or inhibitors Not recommended for first-line use as part of multimodal analgesia
Methadone	2.5 to 5 mg orally every 8 to 12 hours	0.5 to 1 hour	8 to ≥59 hours	4 to 8 hours for single dose, increases to 8 to 12 hours with repeated doses	Hepatic metabolism via CYP3A4, 2D6, and other CYP enzymes to inactive metabolites Complex pharmacokinetics resulting in widely variable effects with single compared with repeated doses Significant risk of accumulation with repeated doses and when titrating	In addition to binding mu opioid receptors, antagonizes NMDA receptors and inhibits serotonin and norepinephrine, which may contribute to analgesic efficacy Risk of prolonged respiratory depression warrants close monitoring in postoperative use Should only be used by clinicians familiar with use and typically only when it is not possible to use other opioids May prolong QT interval Extensive drug interactions with CYP P450 inducers or inhibitors and by other mechanisms^Δ

IV: intravenous; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin-norepinephrine reuptake inhibitor; TCA: tricyclic antidepressants; CrCl: creatinine clearance; AUC_0-24: area under plasma concentration versus time at 0-24 hours after dose; NMDA: N-methyl-D-aspartate; MAO-I: monoamine oxidase inhibitor; P-gp: P-glycoprotein.

* Lower doses may be effective for patients who simultaneously receive nonopioid analgesics. A dose reduction of approximately 50% and a reduced frequency is warranted for older or debilitated adults or patients with impaired liver or kidney functioning, low cardiac output, or respiratory compromise.

¶ The duration of action is highly variable among individuals and is influenced by the dose, variations in metabolism, subjective patient experience, and combination with other therapies. As such, the expected duration of action for each type of opioid is only a rough estimate.

Δ Opioids metabolized by CYP pathways or substrates of P-gp-mediated efflux may be subject to interaction with drugs that either inhibit or accelerate CYP metabolism or P-gp-mediated efflux. Lists of drugs that alter CYP3A4, 2D6, and P-gp-mediated efflux are available as separate tables in UpToDate. In addition, patients may have polymorphisms of cytochrome P450 (CYP) genes that affect drug metabolism. Polymorphisms may contribute to either diminished or absent metabolic enzymes or excessive metabolism, either of which can change the clinical effect of a given dose of opioid. Poor, intermediate, extensive, and ultrarapid CYP2D6 function types have been well characterized. Significant drug interactions may be identified by use of the Lexicomp drug interaction program available through UpToDate.

◊ After initial two doses, oliceridine dose may be titrated, if needed, based on tolerability and response up to a maximum of 3 mg per dose, at intervals of one hour or more; maximum cumulative dose is 27 mg per day.

§ Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are usually administered on a regular basis as part of multimodal therapy. Avoiding combination preparations (ie, opioid plus nonopioid) allows fixed schedule administration of the nonopioid medication regardless of the patient's opioid utilization, without limitation by the maximum daily dose of the nonopioid.

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Opioids commonly used for postoperative pain