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Perioperative uses of intravenous opioids: Specific agents

Perioperative uses of intravenous opioids: Specific agents
Author:
John C Alexander, MD, MBA
Section Editor:
Girish P Joshi, MB, BS, MD, FFARCSI
Deputy Editor:
Nancy A Nussmeier, MD, FAHA
Literature review current through: Nov 2022. | This topic last updated: May 23, 2022.

INTRODUCTION — Intravenous (IV) opioids are commonly used to provide analgesia and supplement sedation during general anesthesia or monitored anesthesia care (MAC), and are the most widely used agents for treatment of acute pain in the immediate postoperative period.

This topic discusses specific perioperative uses for individual opioid agents, as well as the advantages, disadvantages, drug-drug interactions, dosing, and pharmacokinetics for each of these opioid agents. The occasional use of meperidine to treat postoperative shivering is noted elsewhere. (See "Perioperative temperature management", section on 'Shivering'.)

A separate topic reviews typical uses for opioids in the perioperative setting as well as general considerations for opioid dosing and benefits and adverse effects associated with opioid administration in this setting. (See "Perioperative uses of intravenous opioids in adults: General considerations".)

Other topics review uses of opioids in other settings (eg, critical care, palliative care, chronic pain management). (See "Use of opioids in the management of chronic non-cancer pain" and "Pain control in the critically ill adult patient", section on 'Opioid analgesics'.)

OVERVIEW OF DOSING AND USES OF OPIOIDS — Perioperative uses of opioids are discussed in detail in a separate topic. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Perioperative uses of opioids'.)

Dosing – Recommended doses of IV opioids for various uses in the perioperative setting and pharmacokinetic considerations for these agents are summarized in the tables (table 1 and table 2).

General anesthesia and monitored anesthesia care – We typically employ a short-acting opioid (eg, fentanyl) for bolus dosing during general anesthesia or monitored anesthesia care (MAC). Remifentanil is most suitable for continuous infusion during a total intravenous anesthesia (TIVA) technique, particularly when the intensity of surgical stimulation will vary during the procedure.

Postoperative analgesia – For postoperative analgesia, we typically administer a long-acting opioid (eg, morphine or hydromorphone) approximately 20 to 30 minutes before anticipated tracheal extubation, with dose reduction if non-opioid analgesic agents or techniques are coadministered.

FENTANYL — Fentanyl is a synthetic derivative of morphine in the phenylpiperidine family of opioid agents. It is the most commonly used intraoperative opioid agent for bolus dosing during general anesthesia or monitored anesthesia care (MAC). Fentanyl is 50 to 100 times more potent than morphine. Fentanyl is highly lipophilic, which allows rapid penetration of the blood-brain barrier and rapid onset of action (four to six minutes), although maximal analgesic and respiratory depressant effects of fentanyl may not be evident for several minutes. Fentanyl has the longest duration of action of the agents in the phenylpiperidine family.

Uses and dosing — Recommended doses of IV fentanyl are presented in the table (table 1).

General anesthesia

PreinductionFentanyl may be administered in 25 mcg increments in selected patients complaining of pain or requiring a regional anesthetic procedure during the preinduction period; the total preinduction dose is typically ≤100 mcg.

Induction – During induction of general anesthesia, fentanyl is often selected as the IV opioid adjuvant agent (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Induction'). A typical dose is 25 to 100 mcg (or 0.5 to 1 mcg/kg), administered as a bolus or in divided doses three to five minutes before injection of the sedative-hypnotic induction agent [1]. (See "General anesthesia: Intravenous induction agents", section on 'Opioids'.)

In selected patients with poor myocardial function, a high dose of fentanyl (eg, 10 to 25 mcg/kg) may be employed to induce general anesthesia if the patient will remain intubated with controlled ventilation for several postoperative hours (eg, after a cardiac surgical procedure). (See "Anesthesia for cardiac surgery: General principles", section on 'Higher-dose opioid technique'.)

Maintenance – (See "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)

Supplemental agent for inhalation technique Fentanyl is often selected to provide supplemental analgesia during maintenance of general anesthesia with an inhalation technique. Typical adult bolus doses are 25 to 50 mcg, administered as needed to provide analgesia and to avoid or treat hemodynamic responses to surgical stimuli (eg, tachycardia, hypertension) [2].

Analgesic component for a TIVA techniqueFentanyl may be selected to provide the analgesic component of a total intravenous anesthesia (TIVA) technique, but has a prolonged context-sensitive half-time (the time in minutes required for a 50 percent decrease in effect-site concentration after the infusion is discontinued); this leads to delayed recovery (figure 1) [2-4]. Therefore, a fentanyl infusion is not as ideal for TIVA as some other opioid agents (eg, remifentanil, sufentanil) if extubation is planned at the end of the surgical procedure. (See 'Remifentanil' below and 'Sufentanil' below.)

Occasionally fentanyl may be selected for infusion during a TIVA technique (eg, when a period of controlled postoperative ventilation is planned). A typical dose is 1 to 2 mcg/kg per hour, with adjustments as needed to deepen analgesia in order to avoid or treat hemodynamic responses to surgical stimuli. Timing discontinuation of the fentanyl infusion is challenging when delayed emergence and respiratory depression are undesirable at the end of the surgical procedure (see 'Pharmacokinetics' below). Alternatively, fentanyl can be administered in incremental boluses as part of a TIVA technique to deepen analgesia or treat hemodynamic responses to surgical stimuli.

Monitored anesthesia care — Fentanyl is typically used in small, intermittent IV bolus doses of 25 to 50 mcg during MAC. (See "Monitored anesthesia care in adults", section on 'Opioids'.)

Treatment of acute postoperative pain — Fentanyl may be administered in the post-anesthesia care unit (PACU) in doses of 25 to 50 mcg every five minutes for moderate acute pain or in doses of 50 to 100 mcg every two to five minutes for severe acute pain, until the pain is relieved or unwanted adverse effects become evident (eg, respiratory depression, sedation, oxygen saturation <95 percent, hypotension). After initial pain control, the clinician should reassess the postoperative analgesic regimen to determine the best options for further management. (See "Management of acute perioperative pain in adults", section on 'Fentanyl'.)

Advantages — In addition to the benefits of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), fentanyl has the following specific advantages:

Rapid onset (three to five minutes).

High potency (100 times compared with morphine).

Effective analgesia for surgical trauma causing severe pain during the intraoperative or immediate postoperative period, due to a prolonged duration of action.

Minimal effect on myocardial or hemodynamic function.

Absence of histamine-releasing properties; thus, fentanyl is appropriate for patients with bronchospasm.

Generally lower cost compared with sufentanil, alfentanil, and remifentanil.

Disadvantages — In addition to the potential adverse effects of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'), fentanyl has the following specific disadvantages:

Prolonged context-sensitive half-time when administered as an infusion (figure 1). For example, after infusion of fentanyl for 200 minutes, approximately 200 more minutes are necessary to achieve a 50 percent decrease in its effect-site concentration. Thus, emergence from general anesthesia may be delayed after a fentanyl infusion. For this reason, we usually avoid a fentanyl infusion for surgical cases of short or intermediate duration.

Brief self-limiting coughing that occasionally occurs after bolus dosing [5,6].

Drug-drug interactions — In addition to synergistic effects with coadministration of fentanyl and other anesthetic agents (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), possible interactions specific for fentanyl include:

Serotonergic agents – Coadministration of fentanyl with serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) may increase risk for serotonin syndrome (table 3). Management is discussed separately. (See "Serotonin syndrome (serotonin toxicity)".)

CYP3A4 inhibitors – Administration of CYP3A4 inhibitors such as diltiazem, ritonavir, or voriconazole may increase plasma levels of fentanyl since it is metabolized through cytochrome 3A4 [7,8]. Specific interactions may be determined using the Lexicomp drug interactions tool. Reduction of the fentanyl dose may be necessary when such agents have been administered to avoid adverse opioid effects such as respiratory depression.

Pharmacokinetics — Pharmacokinetics for fentanyl are summarized in the table (table 2).

Fentanyl is highly lipophilic, with rapid distribution to highly perfused tissues (eg, brain, heart, kidney, and gastrointestinal tract). Initial equilibration time is six minutes, with a slower redistribution to muscle and fat [9].

Fentanyl has a short duration of action when administered as a bolus dose (30 to 45 minutes) due to its high lipid solubility and redistribution to fatty tissue (figure 2). However, fentanyl has a prolonged context-sensitive half-time when administered as an infusion, which increases with duration of infusion (figure 1). Also, stores in muscle and fat are mobilized after discontinuation of an infusion, potentially contributing to prolonged sedation.

Fentanyl has a high hepatic extraction ratio of 0.8 to 1.0 such that hepatic blood flow determines the rate of its metabolism. In the liver, fentanyl is metabolized by cytochrome CYP3A4 to norfentanyl, an inactive metabolite that is excreted in the urine. Neither renal nor hepatic insufficiency affects fentanyl pharmacokinetics. The elimination half-life is three to six hours.

REMIFENTANIL — Remifentanil is an ultrashort-acting fentanyl derivative in the phenylpiperidine family of opioid agents, with a potency that is one to two times that of fentanyl [10]. Remifentanil is highly lipophilic and has an even more rapid penetration of the blood-brain barrier and more rapid onset of action (one to two minutes) than fentanyl, sufentanil, or alfentanil. It also has a uniquely short duration of action (5 to 10 minutes after cessation of infusion) because metabolism occurs through esterases located in plasma, red blood cells, and interstitial tissues [2,11-13]. Remifentanil administration as an infusion is the most commonly employed agent for infusion during total intravenous anesthesia (TIVA).

Uses and dosing — Recommended doses of remifentanil are presented in the table (table 1).

General anesthesia

Remifentanil intubation technique – (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Remifentanil intubation technique'.)

Maintenance

Analgesic component for a TIVA technique – Among the IV opioids, a remifentanil infusion is the most suitable agent for a TIVA technique, particularly when the intensity of surgical stimulation varies during the procedure. Remifentanil is typically administered in combination with a propofol infusion since both agents have a short half-life and rapid elimination. Thus, recovery is rapid [4]. For procedures of short to intermediate duration with moderate to intense surgical stimulation, this combination of remifentanil and propofol infusions usually provides satisfactory anesthesia and absence of patient movement. Since the analgesic effect of remifentanil is rapidly terminated after stopping the infusion, its use is most ideal in procedures that incur little or no postoperative pain. (See "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)

Remifentanil is infused at 0.05 to 0.3 mcg/kg per minute beginning during or shortly after induction to maintain anesthesia for a TIVA technique [14]. We do not usually employ a loading dose since the pharmacokinetics of remifentanil allow attainment of a steady state without loading. Some clinicians do elect to administer a loading dose, typically 0.5 to 1 mcg/kg over 60 to 90 seconds before starting the continuous infusion.

Supplemental agent for inhalation technique Remifentanil may be employed as an adjuvant agent during an inhalation anesthetic technique. Remifentanil infusion at 0.05 to 0.3 mcg/kg per minute improves tolerance to intensely painful surgical stimuli and decreases the required dose of the potent volatile agent [15,16].

Remifentanil extubation technique – (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Remifentanil extubation technique'.)

Monitored anesthesia care — Remifentanil may be administered as an infusion during monitored anesthesia care (MAC), with or without initial or intermittent bolus doses. Details regarding this use are discussed separately. (See "Monitored anesthesia care in adults", section on 'Opioids'.)

Advantages — In addition to the benefits of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), remifentanil has the following specific advantages:

Fastest onset of action compared with all other opioids (one to two minutes).

Rapid attainment of steady state after a bolus dose (figure 3).

Rapid offset due to a very short context-sensitive half-time after administration as an infusion (approximately three minutes), regardless of the duration of infusion (figure 1) [17]. This allows rapid titration to change anesthetic depth during maintenance, as well as a quick recovery during emergence. (See "Emergence from general anesthesia", section on 'Discontinue anesthetic agents'.)

Ideal when early recovery and assessment of neurologic function are necessary, due to its rapid elimination [18]. (See "Anesthesia for craniotomy", section on 'Our anesthesia strategy'.)

Unaffected by hepatic or renal insufficiency because it is metabolized by ester hydrolysis in the blood and tissues.

Possible lower incidence of postoperative nausea and vomiting, allowing more rapid discharge from the post-anesthesia care unit (PACU), compared with fentanyl [19].

Disadvantages — In addition to the potential adverse effects of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'), remifentanil has the following specific disadvantages:

Generally higher cost than other opioids, particularly if used for long surgical cases.

Possible muscle and chest wall rigidity with rapid administration and/or high doses.

Higher incidence of hypotension compared with other opioids [20]. In some cases, this may be due to the greater potency of remifentanil compared with fentanyl since remifentanil is often used as if it is equipotent [10].

Possible tachyphylaxis during administration [21].

Need for administration of an alternative analgesic agent or technique during emergence and/or the immediate postoperative period if postoperative pain is anticipated, because the analgesic effect of remifentanil is terminated within minutes of discontinuing its infusion [13].

Possible acute tolerance and opioid-induced hyperalgesia (OIH) after discontinuation of a remifentanil infusion [22,23]. These adverse effects are dose-dependent and more likely with high doses >0.3 mcg/kg per minute or a cumulative dose >50 mcg/kg [21,24,25]. However, data are inconsistent [26].

Higher incidence of postoperative shivering compared with other opioids [27]. Treatment of postoperative shivering is discussed separately. (See "Perioperative temperature management", section on 'Shivering'.)

Drug-drug interactions — Except for the synergistic effects with coadministration of other anesthetic agents (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), remifentanil has minimal drug interactions due to its rapid metabolism.

Pharmacokinetics — Pharmacokinetics for remifentanil are summarized in the table (table 2).

Remifentanil is highly lipophilic, with extremely rapid distribution to highly perfused tissues (eg, brain, heart, kidney, and gastrointestinal tract). Initial equilibration time is one to two minutes.

Remifentanil has a very short duration of action, with a context-sensitive half-time of approximately three minutes and a pharmacodynamic offset at approximately five minutes (figure 1) [17]. It is metabolized by nonspecific plasma esterases in the plasma, red blood cells, and interstitial tissue to an inactive metabolite (remifentanil acid), which is subsequently excreted unchanged in the urine. Elimination half-life for remifentanil is 10 to 20 minutes [11,13,28]. There is no evidence of accumulation in patients with renal and/or hepatic dysfunction.

SUFENTANIL — Sufentanil is a phenylpiperidine opioid that is approximately 10 times more potent than fentanyl and is used in similar settings [2,3,29]. Like fentanyl, sufentanil is highly lipophilic with rapid onset (three to five minutes) and low cost compared with newer synthetic opioids such as remifentanil.

Uses and dosing — Recommended doses of sufentanil are presented in the table (table 1) [30].

General anesthesia

Induction – During induction of general anesthesia, sufentanil is often selected as the IV opioid adjuvant agent (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Induction'). A typical dose is 0.1 to 0.2 mcg/kg, administered in divided doses three to five minutes prior to the sedative-hypnotic induction agent. (See "General anesthesia: Intravenous induction agents", section on 'Opioids'.)

In selected patients with poor myocardial function, a high dose of sufentanil (eg, 1 to 3 mcg/kg) may be employed to induce general anesthesia if the patient will remain intubated with controlled ventilation for several postoperative hours (eg, after a cardiac surgical procedure). (See "Anesthesia for cardiac surgery: General principles", section on 'Higher-dose opioid technique'.)

Maintenance

Supplemental agent for inhalation technique – During maintenance of general anesthesia with an inhalation technique, sufentanil is often the selected adjuvant opioid agent. Typically, 5 to 10 mcg bolus doses are administered as necessary to provide supplemental analgesia or to treat hemodynamic responses to surgical stimulation (eg, tachycardia, hypertension) [2].

Analgesic component for a TIVA technique Sufentanil may be selected to provide the analgesic component of general anesthesia with a total intravenous anesthesia (TIVA) technique, particularly in cases with a prolonged duration (eg, cardiac and neurologic surgery) when rapid emergence is not needed. Typically, 5 to 10 mcg bolus doses or a continuous infusion at 0.05 to 0.15 mcg/kg per hour (or 0.0008 to 0.0025 mcg/kg per minute) is administered. Although sufentanil has a shorter context-sensitive half time than fentanyl, it is longer than that of remifentanil (figure 1), with a slower return of neurocognitive function. However, unlike remifentanil, sufentanil has the advantage of providing an analgesic effect into the postoperative period. (See "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)

Advantages — In addition to the benefits of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), sufentanil has the following specific advantages:

Rapid onset (three to five minutes for peak effect).

High potency (5 to 10 times more potent than fentanyl).

Shorter context-sensitive half time compared with fentanyl (figure 1). Thus, recovery is more rapid after infusions lasting several hours, compared with equipotent doses of fentanyl [31].

Low cost compared with remifentanil.

Ideal for longer procedures when continuous opioid administration and a postoperative analgesic effect are desirable.

Disadvantages — Potential adverse effects of sufentanil are similar to those of other lipophilic opioids [32-34]. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'.)

Drug-drug interactions — Synergistic effects occur with coadministration of sufentanil and other anesthetic agents. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)

Pharmacokinetics — Pharmacokinetics for sufentanil are summarized in the table (table 2).

Sufentanil is rapidly distributed to highly perfused tissues with an initial equilibration time of six minutes. The context-sensitive half time is shorter than that for fentanyl, but longer than for remifentanil (figure 1). For example, after continuous infusion of sufentanil for 200 minutes, a 50 percent decrease in its effect-site concentration occurs in 30 to 45 minutes, compared with approximately 200 minutes for fentanyl or four minutes for remifentanil.

Sufentanil is metabolized in both the small intestine and liver, and is excreted in the urine. Its elimination half-life is two to four hours [11,30,35].

ALFENTANIL — Alfentanil is a phenylpiperidine opioid that is approximately three times less potent than fentanyl and is used in similar settings [2,3,29]. It is highly lipophilic, allowing very rapid penetration of the blood-brain barrier and rapid onset of action (one to three minutes). The cost for alfentanil is intermediate between that of remifentanil and sufentanil.

Uses and dosing — Recommended doses of alfentanil are presented in the table (table 1).

General anesthesia

Induction – During induction of general anesthesia, alfentanil is occasionally selected as the IV opioid adjuvant agent (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Induction'). A typical adult dose is 500 mcg administered as a bolus (which may be repeated until the desired effect is achieved), or 50 to 100 mcg/kg administered in divided doses.

Maintenance – During maintenance of general anesthesia with an inhalation technique, alfentanil is occasionally selected to provide supplemental analgesia. Typically, small IV doses of 500 mcg are titrated as necessary to provide analgesia and to avoid or treat hemodynamic responses to surgical stimuli (eg, tachycardia, hypertension) [2]. Alfentanil has a context-sensitive half time similar to that for sufentanil (figure 1), and is suitable for cases lasting longer than six hours when a rapid decrease in opioid effect is desirable [36]. The dose range for continuous infusion of alfentanil is 0.5 to 1.5 mcg/kg per minute. (See "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)

Advantages — In addition to the benefits of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), alfentanil has the following specific advantages:

Very rapid onset of action (one to three minutes) which is faster than fentanyl but slightly less rapid than remifentanil.

Rapid attainment of steady state after a bolus dose.

Shorter context-sensitive half time compared with fentanyl (similar to that for sufentanil) (figure 1).

Disadvantages — In addition to the potential adverse effects of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'), a major disadvantage for alfentanil is focal activation of the cerebral cortex in susceptible patients, which produces seizure-like electrical activity that can be identified with electroencephalogram monitoring. Thus, alfentanil is avoided in patients with risk factors for seizures.

Drug-drug interactions — Synergistic effects occur with coadministration of alfentanil and other anesthetic agents (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'). Similar to fentanyl, interactions with CYP3A4 inhibitors such as voriconazole may increase plasma levels of alfentanil since it is metabolized through cytochrome 3A4 [37]. Specific interactions may be determined using the Lexicomp drug interactions tool.

Pharmacokinetics — Pharmacokinetics for alfentanil are summarized in the table (table 2).

Alfentanil is rapidly distributed to highly perfused tissues with an initial equilibration time of one to three minutes [36]. Its context-sensitive half time is comparable to that of sufentanil (ie, 30 to 45 minutes).

Hepatic metabolism of alfentanil is less predictable than for fentanyl and sufentanil due to significant inter-individual variability in activity of hepatic CYP3A4 (the enzyme primarily responsible for biotransformation of alfentanil). Elimination half-life is typically 1.5 to 2 hours.

MORPHINE — Morphine is the prototype opioid agent; it is approximately 100 to 200 times less potent than fentanyl [38]. It is a phenanthrene opioid that is less lipophilic than the synthetic opioids (eg, fentanyl, remifentanil, sufentanil, alfentanil), which results in slower onset of action compared with other opioids (within 20 minutes) due to poor penetration of the blood-brain barrier [39]. However, morphine has a long analgesic duration of four to five hours. For this reason, it is often selected to preemptively and/or urgently control postoperative pain.

Uses and dosing — Recommended doses of IV morphine are presented in the table (table 1).

General anesthesia

Maintenance – Bolus dosing of morphine during the maintenance phase of anesthesia is less common since the development of shorter-acting IV opioids (eg, remifentanil, alfentanil, sufentanil). If selected, small IV bolus doses of morphine 1 to 2 mg are titrated as necessary [40]. (See "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)

Emergence – For patients undergoing a major surgical procedure who have received a non-opioid analgesic agent (eg, acetaminophen, nonsteroidal anti-inflammatory drug [NSAID]) and/or technique (eg, a regional anesthetic), small doses of IV morphine may be administered in 1 to 2 mg increments (up to 0.05 to 0.1 mg/kg ideal body weight) beginning approximately 15 to 20 minutes prior to tracheal extubation. Patients who did not receive a non-opioid analgesic agent or technique may require a larger upper range for morphine dosing in this setting (ie, 0.1 to 0.2 mg/kg ideal body weight) to provide adequate analgesia. Doses are decreased for older patients >65 years of age and those with comorbidities (eg, hepatic insufficiency) due to the higher risk of adverse effects in such patients [41,42].

Treatment of acute postoperative pain — As noted above, for postoperative analgesia, one can administer a long-acting opioid such as IV morphine approximately 20 to 30 minutes before anticipated tracheal extubation. In the post-anesthesia care unit (PACU), dosing for acute pain is 1 to 3 mg every five minutes until pain is relieved or unwanted adverse effects become evident (eg, respiratory depression, sedation, oxygen saturation <95 percent, hypotension) [43]. After initial pain control, 2 to 4 mg IV every three hours is typically needed. (See "Management of acute perioperative pain in adults", section on 'Morphine'.)

Advantages — In addition to the benefits of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), morphine has the following specific advantages:

Low cost and wide availability.

Prolonged duration of action (four to six hours). This is an advantage if severe postoperative pain is anticipated.

Disadvantages — In addition to the potential adverse effects of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'), morphine has the following specific disadvantages:

Slower onset of analgesia (within 20 minutes) and slower time to peak analgesic effect compared with the synthetic opioids (eg, fentanyl, remifentanil, sufentanil, alfentanil), due to lower lipid solubility and a longer lag time for penetration of the blood-brain barrier.

Long context-sensitive half time (approximately 4.5 hours) (figure 1). Use of morphine as a continuous infusion is generally avoided since it is difficult to titrate when rapid changes in anesthetic depth are necessary.

Higher incidence of most opioid-related adverse side effects (eg, pruritus, urinary retention, constipation, and nausea), compared with other opioids.

Association with histamine release that may result in facial flushing, pruritus, diaphoresis, and hypotension.

Increased tone or spasm of the sphincter of Oddi and the common bile duct, which diminishes biliary and pancreatic secretions and may lead to biliary colic.

Unsuitable for patients with hemodynamic instability due to possible exacerbation of hypotension by histamine release, as well as persistence of its effects due to a long context-sensitive half time and the mu-receptor-stimulating properties of its morphine-6-glucuronide metabolite. (See 'Pharmacokinetics' below.)

Unsuitable for patients with renal insufficiency (creatinine clearance less than 30 mL/minute) due to likely accumulation of its renally-excreted, potentially neurotoxic morphine-6-glucuronide metabolite. This metabolite also has mu-receptor-stimulating properties which may prolong the effects of morphine [44,45].

Cautious use in patients with a history of seizures if renal insufficiency is present, due to neuroexcitation caused by the morphine-6-glucuronide metabolite, with possible occurrence of myoclonus or exacerbation of seizure activity.

Drug-drug interactions — Morphine has synergistic effects with coadministration of other anesthetic agents. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)

Pharmacokinetics — Pharmacokinetics for morphine are summarized in the table (table 2).

Onset of action after administration of an IV dose of morphine is within 10 minutes, with a peak effect after 15 to 30 minutes [43]. Morphine is primarily metabolized in the liver to glucuronide metabolites, morphine-6-glucuronide and morphine-3-glucuronide; thus, dose is reduced for patients with hepatic insufficiency. Morphine-6-glucuronide produces ongoing analgesia due to mu-receptor-stimulating properties [45].

The elimination half-life for morphine is two to three hours, but up to seven hours are required for the elimination half-life of its morphine-6-glucuronide metabolite [36]. Renal elimination is typically complete within 24 hours.

HYDROMORPHONE — Hydromorphone is a phenanthrene opioid that is a semi-synthetic morphine derivative. It is approximately five times more potent than morphine, has a slightly more rapid onset (with a peak effect within 10 minutes after IV administration [46]), and a shorter half-life of 2.4 hours [47].

Uses and dosing — Recommended doses of hydromorphone are presented in the table (table 1).

General anesthesia

MaintenanceHydromorphone may be the selected opioid to provide supplemental analgesia with either an inhalation anesthetic or a total intravenous anesthesia (TIVA) technique. Typically, small IV bolus doses of hydromorphone 0.25 to 0.5 mg are administered as necessary. (See "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)

Emergence – Similar to morphine, small boluses of hydromorphone may be administered near the end of surgery to control postoperative pain, typically to a total dose of 0.25 to 1 mg. (See 'Uses and dosing' above.)

Treatment of acute postoperative pain — For postoperative analgesia, we typically administer a long-acting opioid such as IV hydromorphone 0.01 mg/kg approximately 20 to 30 minutes before anticipated tracheal extubation. In the post-anesthesia care unit (PACU), dosing for acute pain is 0.2 to 0.5 mg IV every five minutes until pain is relieved or unwanted adverse effects become evident (eg, respiratory depression, sedation, oxygen saturation <95 percent, hypotension). After initial pain control, 0.2 to 0.5 mg IV every three to four hours is typically needed. (See "Management of acute perioperative pain in adults", section on 'Hydromorphone'.)

Advantages — In addition to the benefits of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'), hydromorphone has the following specific advantages:

Low cost and wide availability.

Prolonged duration of action (four to six hours), similar to morphine. This is an advantage if severe postoperative pain is anticipated.

Analgesic efficacy that is slightly better than morphine [47].

Disadvantages — In addition to the potential adverse effects of most opioids (see "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'), hydromorphone has the following specific disadvantages:

Slower onset of analgesia (5 to 10 minutes) and slower time to peak analgesic effect compared with the synthetic agents (eg, fentanyl, remifentanil, sufentanil, alfentanil), due to lower lipid solubility and a longer lag time for penetration of the blood-brain barrier.

Long context-sensitive half time (approximately two to three hours) (figure 1) [48,49]. Hydromorphone is not typically used as a continuous infusion since it is difficult to titrate when rapid changes in anesthetic depth are necessary.

Caution with use in patients with renal insufficiency (creatinine clearance less than 30 mL/minute) due to likely accumulation of its renally-excreted potentially neurotoxic hydromorphone-3-glucuronide metabolite.

Cautious use in patients with seizures due to neuroexcitation caused by its hydromorphone-3-glucuronide metabolite, with possible occurrence of myoclonus or exacerbation of seizure activity.

Drug-drug interactions — Synergistic effects occur with coadministration of hydromorphone and other anesthetic agents. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)

Co-administration with strong inducers of drug metabolism such as rifampin may reduce plasma concentrations of hydromorphone, thereby lessening its analgesic effect [50].

Pharmacokinetics — Pharmacokinetics for hydromorphone are summarized in the table (table 2).

Hydromorphone is primarily metabolized in the liver; thus, dose is reduced in patients with hepatic insufficiency. Its hydromorphone-3-glucuronide metabolite is renally excreted. Although this metabolite is effectively removed during hemodialysis, it may accumulate and cause neuroexcitation between dialysis treatments [51]. (See 'Disadvantages' above.)

METHADONE — Methadone is a synthetic opioid that is unique because of its effects at multiple sites integral to the transmission and modulation of nociceptive signaling. The potency of intravenous methadone is roughly equivalent to that of morphine [38] (see 'Morphine' above). Its mechanism of action is via agonism of the mu-opioid receptor as well as antagonist effects at N-methyl-D-aspartate (NMDA) receptors and inhibition of serotonin and norepinephrine reuptake in the central nervous system [52]. The analgesic effect is greater with methadone plus ketamine compared with methadone alone, providing evidence that the primary analgesic effect of methadone is via mu-opioid agonism rather than NMDA antagonism [53].

Onset of analgesia is reported in as little as eight minutes, but duration may extend to 24 to 36 hours when doses exceed the redistribution half-life (approximately 20 mg) [54].

Uses and dosing

General anesthesia — Most studies have used a single IV dose of methadone (typically 0.1 to 0.2mg/kg ideal body weight up to 20 mg total) administered during induction of anesthesia to provide analgesia through the intraoperative and postoperative phases of care [55]. Randomized trials and meta-analyses in several surgical populations and have noted perioperative opioid-sparing effects with such regimens as well as analgesia extending for up to three days [56-63]. In one study of patients undergoing complex spine or cardiac surgical procedures, continued analgesic benefits were noted for up to three postoperative months [64].

Acute postoperative pain — Due to the extended half-life at higher doses, close observation and monitoring are necessary in the postoperative period if methadone is administered to treat acute postoperative pain, particularly if methadone is administered after induction of general anesthesia (ie, during the intraoperative or early postoperative period). Since peak respiratory depressant effects of a single IV dose of methadone occur within 45 minutes of administration in most patients, administration at induction usually ensures that the patient will remain intubated until after these peak effects have occurred [54]. Although titration of methadone can be done safely in the post-anesthesia care unit (PACU), careful monitoring of sedation status and respiratory rate must be ensured to avoid overdose [55].

Advantages — Administration of a single dose of methadone during induction of general anesthesia can provide analgesia throughout the intraoperative and postoperative periods, resulting in an overall beneficial opioid-sparing effect [65]. Theoretically, the NMDA antagonist and serotonin/norepinephrine effects each contribute to a duration of analgesia that exceeds the elimination half-life, although this hypothesis has not been demonstrated [66,67].

Disadvantages

Potential for postoperative respiratory depression due to a long half-life (see 'Pharmacokinetics' below). An observational study noted a 37 percent incidence of respiratory depression (defined as respiratory rate <8 breaths/minute, or need for >2 L per minute of supplemental oxygen to maintain peripheral arterial oxygen saturation [SpO2] >96 percent [68]. However, a review of clinical investigations noted no overall increase in adverse respiratory events related to intraoperative methadone administration [55].

Potential for prolonged QTc. Dose and chronicity of methadone use are associated with development of a prolonged QTc, particularly after long-term treatment of opioid use disorder [69]. Although the effect of a single perioperative dose of methadone on QTc has not been specifically studied, it is prudent to avoid administration of methadone in patients who already have prolonged QTc on their electrocardiogram.

Drug-drug interactions — Methadone is metabolized in the liver by CYP2D6 [70,71]. Medications inducing CYP2D6 (eg, phenobarbital, phenytoin) may increase metabolism of methadone, while CYP2D6 inhibitors such as fluoxetine, sertraline, and ticlopidine may reduce metabolism and increase the likelihood of adverse effects [55]. Methadone also interacts with selective serotonin reuptake inhibitors (SSRIs), and may increase serotonin levels.

Pharmacokinetics — Pharmacokinetics for intravenous (IV) methadone are summarized in the table (table 2). The redistribution half-life of methadone is six minutes, but once dosing exceeds redistribution capacity the elimination half-life (approximately 30 hours) predominately determines the duration of action [54].

MEPERIDINE — Meperidine is a synthetic opioid with analgesic effects due to mu-opioid agonism [72]. Meperidine also inhibits reuptake of serotonin and norepinephrine [73], and has local anesthetic effects [74]. It is approximately 10 times less potent than morphine [75].

Uses and dosing

Treatment for shivering Meperidine 12.5 to 25 mg IV is often used to treat perioperative shivering [76]. Some experts note that other agents and routes of administration (eg, IV tramadol, IV ketamine, IV or intrathecal dexmedetomidine, or intrathecal fentanyl or sufentanil) have similar efficacy with fewer side effects [77-79].  

Perioperative/peripartum analgesiaMeperidine is uncommonly administered in doses of 25 to 50 mg IV (or 50 to 150 mg orally or 25 to 100 mg subcutaneously or intramuscularly), that may be repeated every three to four hours [80]. The maximum recommend dose for adults is <600 mg/day for no more than 48 hours [81].

Advantages

Rapid onset (<10 minutes) [82]

Generally lower cost compared with sufentanil, alfentanil, and remifentanil

Disadvantages — Due to high risk of adverse effects and relative lack of efficacy compared with other opioids, meperidine is generally avoided in pediatric patients [83], or for perioperative analgesia or labor pain in parturients [80].

Central nervous system (CNS) excitatory effects manifesting as anxiety, hyperreflexia, myoclonus, and seizures due to the active metabolite normeperidine [84]. Use of meperidine for infusions or patient-controlled analgesia is not recommended due to risk of metabolite accumulation and toxicity. Furthermore, risk of normeperidine toxicity is increased in renal insufficiency due to reduced excretion [85].

Contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) due to unpredictable, severe, and sometimes fatal reactions. The mechanism of such reactions is unknown, but may be related to preexisting hyperphenylalaninemia. Clinical presentation of these reactions may be similar to serotonin syndrome or acute opioid overdose, with symptoms that include hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension [86]

Serotonin and norepinephrine reuptake inhibition, which may contribute to development of serotonin syndrome, particularly if patients are taking selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) (table 3). Management is discussed separately. (See 'Drug-drug interactions' below and "Serotonin syndrome (serotonin toxicity)".)

Anticholinergic effects causing agitation, confusion, disorientation, visual hallucinations, and memory deficits [72]. (see "Anticholinergic poisoning")

Possible contribution to negative mood [84].

High abuse potential leading to frequent addiction and diversion [72].

Drug-drug interactions — Interactions specific for meperidine include severe reactions in patients taking MAOIs, and possible serotonin syndrome in patients taking SSRIs or SNRIs (table 3), as noted above. (See 'Disadvantages' above.)

Pharmacokinetics — Pharmacokinetics for IV meperidine are summarized in the table (table 2).

Since meperidine is primarily metabolized in the liver via the P450 cytochrome system, its elimination half-life life is greatly extended in patients with hepatic cirrhosis [87,88]. Normeperidine is the most clinically relevant metabolite, with a variable half-life up to 48 hours; thus, significant accumulation can occur with chronic or repeated use [82,85]. Renal insufficiency reduces excretion of meperidine and its metabolites, leading to accumulation of normeperidine [85]. Compared with meperidine, normeperidine has reduced analgesic properties but enhanced CNS excitability [89,90].

Intramuscular meperidine has an average half-life of three to four hours, though there is high variability for this route of administration due to interpatient variability in absorption and metabolism [72].

NALBUPHINE — Nalbuphine is a phenanthrene synthetic opioid with agonist-antagonist actions commercially available only in an injectable formulation [91]. It is a weak mu-opioid receptor antagonist and kappa-opioid receptor agonist [92]. At sub-analgesic doses, the mu-opioid receptor antagonism is clinically useful for reversing opioid-related adverse effects. At higher doses, the kappa-opioid receptor agonist effects predominate resulting in analgesia, and is and is equianalgesic to morphine.

Uses and dosing

Perioperative analgesiaNalbuphine is used to provide postoperative analgesia due to its kappa-opioid receptor agonist action. Usual dosage is 10 mg IV every three to six hours up to 160 mg/day [91,93].

Treatment of opioid adverse effects – Sub-analgesic dosing of nalbuphine is used to treat opioid-related adverse effects (eg, pruritus, urinary retention, respiratory depression) without compromising analgesia [94-96]. Doses in the 2.5 to 5 mg range are especially effective in treating opioid-induced pruritus, although this is an off-label use [97].

Advantages

Rapid onset of analgesia

Reversal of opioid-related adverse effects without compromising analgesia [94-96]

Disadvantages

May precipitate opioid withdrawal in opioid tolerant patients taking mu-opioid receptor agonists [92,98].

May cause respiratory depression similar to morphine, but exhibits a ceiling effect such that doses >30 mg do not induce further respiratory depression [91].

Drug-drug interactions — Nalbuphine has few interactions with other anesthetic agents since it is metabolized by UGT2B7 rather than via the P450 cytochrome system [92,99]. However, as noted above, administration of nalbuphine to patients taking mu-opioid receptor agonists can precipitate opioid withdrawal. (See 'Disadvantages' above.)

Pharmacokinetics — Pharmacokinetics for IV nalbuphine are also summarized in the table (table 2).

Onset is rapid (two to three minutes) after IV administration (<15 minutes after subcutaneous or intramuscular administration). Duration of action is three to six hours with an elimination half-life of five hours [91]. Nalbuphine is metabolized in the liver via UGT2B7 with inactive metabolites, with renal clearance [91]. Although dose reduction is recommended in renal insufficiency [91], one study showed little accumulation of an orally administered formulation in dialysis patients [100].

SUMMARY AND RECOMMENDATIONS

General considerations (See 'Overview of dosing and uses of opioids' above.)

Dosing – Recommended doses of intravenous (IV) opioids used in the perioperative setting and pharmacokinetics of these agents are summarized in the tables (table 1 and table 2).

General anesthesia and monitored anesthesia care – We typically employ a short-acting opioid (eg, fentanyl) for bolus dosing during general anesthesia or monitored anesthesia care (MAC). Remifentanil is most suitable for continuous infusion during a total intravenous anesthesia (TIVA) technique, particularly when the intensity of surgical stimulation will vary during the procedure.

Postoperative analgesia – For postoperative analgesia, we typically administer a long-acting opioid (eg, morphine or hydromorphone) approximately 20 to 30 minutes before anticipated tracheal extubation, with dose reduction if non-opioid analgesic agents or techniques are coadministered.

FentanylFentanyl is the most commonly used intraoperative opioid, typically for bolus dosing during the preinduction, induction, or maintenance phases of general anesthesia (as the analgesic component of a TIVA technique or an adjunct agent during inhalation anesthesia). Fentanyl may also be used during MAC, or for treatment of acute postoperative pain. (See 'Nalbuphine' above.)

RemifentanilRemifentanil is an ultra-short-acting fentanyl derivative that is one to two times more potent than fentanyl, with a more rapid onset of action (one to two minutes) and attainment of steady state (figure 3), as well as a uniquely short duration of action (5 to 10 minutes after cessation of infusion) because metabolism occurs through esterases located in plasma, red blood cells, and interstitial tissues. A remifentanil infusion is often selected as the analgesic component of a TIVA technique, or is employed during inhalation general anesthesia, or as during a MAC technique. Remifentanil is also used as primary agent during remifentanil intubation or extubation. (See 'Remifentanil' above.)

SufentanilSufentanil is approximately ten times more potent than fentanyl and is used in similar settings. Sufentanil has a low cost compared with remifentanil and a shorter context-sensitive half time compared with fentanyl allowing for more rapid recovery after infusions lasting several hours (figure 1). Thus, sufentanil is ideal for longer procedures when continuous opioid administration and a postoperative analgesic effect are desirable. (See 'Sufentanil' above.)

AlfentanilAlfentanil is approximately three times less potent than fentanyl, and is used in similar settings. It is highly lipophilic, allowing very rapid penetration of the blood-brain barrier and rapid onset of action (one to three minutes). Its cost is intermediate between that of remifentanil and sufentanil. (See 'Alfentanil' above.)

MorphineMorphine is the prototype opioid agent. It is less lipophilic than the synthetic opioids (eg, fentanyl, remifentanil, sufentanil, alfentanil), which results in slower onset of action (within 20 minutes) due to poor penetration of the blood-brain barrier. Because of its long analgesic duration of four to five hours, morphine is often selected to preemptively and/or urgently control postoperative pain. (See 'Morphine' above.)

HydromorphoneHydromorphone is a semi-synthetic morphine derivative that is approximately five times more potent than morphine and has a slightly more rapid onset (peak effect within 10 minutes after IV administration), and a shorter half-life of 2.4 hours. Hydromorphone is sometimes selected to provide supplemental analgesia with either an inhalation anesthetic or a TIVA technique. Similar to morphine, small boluses of hydromorphone may be administered near the end of surgery and/or during the postoperative period to control postoperative pain. (See 'Hydromorphone' above.)

MethadoneMethadone has a unique mechanism of action via agonism of the mu-opioid receptor as well as antagonism at N-methyl-D-aspartate (NMDA) receptors and inhibition of serotonin and norepinephrine reuptake in the central nervous system. Onset of analgesia may occur within eight minutes, but duration may extend to 24 to 36 hours when doses exceed the redistribution half-life (approximately 20 mg). Thus, methadone may be administered as a single IV dose during induction of anesthesia to provide analgesia through the intraoperative and postoperative periods. If methadone is administered to treat acute postoperative pain, close monitoring is necessary due to its extended half-life. (See 'Methadone' above.)

MeperidineMeperidine is most commonly used to treat perioperative shivering at doses of 12.5 to 25 mg. Use for perioperative analgesia is generally avoided due to its high risk for adverse effects (eg, central nervous system excitatory effects [anxiety, hyperreflexia, myoclonus, seizures] due to its active metabolite normeperidine; serotonin and norepinephrine reuptake inhibition; anticholinergic effects; severe reactions in patients taking monoamine oxidase inhibitors [MAOIs]; high abuse potential), as well as its relative lack of efficacy compared with other opioids. (See 'Meperidine' above.)

NalbuphineNalbuphine is a phenanthrene synthetic opioid with agonist-antagonist actions. It is used to provide perioperative analgesia with a potency equivalent to morphine because of its kappa-opioid receptor agonist action. Sub-analgesic dosing is used to treat opioid-related adverse effects (eg, pruritus, urinary retention, respiratory depression) without compromising analgesia. Nalbuphine may precipitate opioid withdrawal in opioid tolerant patients taking mu-opioid receptor agonists. (See 'Nalbuphine' above.)

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