August 2025
INTRODUCTION —
Intravenous (IV) opioids are commonly used to provide analgesia and supplement sedation during general anesthesia or monitored anesthesia care (MAC). This topic discusses specific intraoperative uses and dosing for individual opioid agents, as well as advantages and disadvantages, drug-drug interactions, and pharmacokinetics for each of these opioid agents.
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".)
Use of opioids in the treatment of acute postoperative pain is addressed separately. (See "Use of opioids for acute pain in hospitalized patients".)
Other topics review uses of opioids in other settings (eg, critical care, palliative care, chronic pain management). (See "Pain control in the critically ill adult patient", section on 'Opioid analgesics'.)
OVERVIEW —
Intraoperative uses and doses of intravenous opioid agentsand pharmacokinetics of specific agents are summarized in the tables (table 1 and table 2).
FENTANYL —
Fentanyl is a synthetic derivative of morphine in the phenylpiperidine family of opioid agents. It is a 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 (less than one minute onset; three to four minutes to peak effect), although the 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
●Preinduction – Fentanyl may be administered in 25 mcg increments in selected patients with 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", 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 technique – Fentanyl 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, and is avoided for surgical cases of short duration. (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 to avoid or treat hemodynamic responses to surgical stimuli. Timing the 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 — Use of fentanyl to treat acute pain in the postoperative period is discussed in a separate topic (table 3). (See "Use of opioids for acute pain in hospitalized patients", section on 'Choice of opioid'.)
Drug-drug interactions — Synergistic effects with coadministration of fentanyl and other anesthetic agents are discussed separately. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)
Other possible interactions specific to 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 the risk for serotonin syndrome (table 4). 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 [5,6]. Specific interactions may be determined using the drug interactions program. 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). The initial equilibration time is six minutes, with a slower redistribution to muscle and fat [7].
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 [8]. Remifentanil is highly lipophilic and has a rapid onset (less than one minute), similar to fentanyl, and an even more rapid penetration of the blood-brain barrier than fentanyl, sufentanil, or alfentanil. It also has a uniquely short duration of action (five to ten minutes after cessation of infusion) because metabolism occurs through esterases located in plasma, red blood cells, and interstitial tissues [2,9-11]. Remifentanil administration as an infusion is commonly employed for infusion during total intravenous anesthesia (TIVA).
However, its higher cost (compared with other opioids) has limited its use in many institutions [12]. Furthermore, if postoperative pain is anticipated, administration of an alternative analgesic agent or technique is necessary during emergence and/or the immediate postoperative period since the analgesic effect of remifentanil is terminated within minutes of discontinuing its infusion [11]. As an example, in an observational study of nearly 4000 adults undergoing spine surgery with neuromonitoring and a TIVA anesthetic technique, those receiving a remifentanil infusion had higher postoperative pain scores and opioid utilization, as well as longer postanesthesia care unit (PACU) stays, and greater risk of intensive care unit (ICU) admission compared to those receiving sufentanil infusions [13]. In addition, acute tolerance, and opioid-induced hyperalgesia (OIH) may occur after discontinuation of a remifentanil infusion [14,15]. However, 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 [16-18]. A 2024 systematic review of nine studies in 122 human volunteers noted that hyperalgesia after withdrawal of remifentanil infusion is mild and not clinically significant [19].
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 particularly suitable for a TIVA technique. Remifentanil has the fastest onset of action compared with all other opioids (<1 minute), which allows rapid attainment of steady state after a bolus dose (figure 3). Remifentanil also has a rapid offset due to a very short context-sensitive half-time after administration as an infusion (approximately three to five minutes), regardless of the duration of infusion (figure 1) [20]. Its rapid elimination makes it an ideal agent when early recovery and assessment of neurologic function are necessary [21]. During the maintenance phase of anesthesia, rapid titration to change anesthetic depth is possible when the intensity of surgical stimulation varies during the procedure. (See "Emergence from general anesthesia", section on 'Discontinue anesthetic agents'.)
Remifentanil is typically administered in combination with a propofol infusion during a TIVA technique since both agents have a short half-life and rapid elimination, facilitating a rapid recovery [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", 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 [22]. 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 [23,24].
●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'.)
Drug-drug interactions — Synergistic effects with coadministration of remifentanil and other anesthetic agents are discussed separately. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)
Otherwise, 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). The 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 to five minutes and a pharmacodynamic offset at approximately five minutes (figure 1) [20]. 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 [9,11,25]. 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 [2,3,26]. Like fentanyl, sufentanil is highly lipophilic with a 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) [27].
General anesthesia
●Induction – During induction of general anesthesia, sufentanil may be selected as the IV opioid adjuvant agent instead of fentanyl. A typical bolus dose of 0.05 to 0.1 mcg/kg is administered prior to the sedative-hypnotic induction agent. (See "General anesthesia: Intravenous induction agents", section on 'Opioids' and "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Opioid use as an adjuvant agent'.)
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 the context-sensitive half-time of sufentanil is shorter than equipotent doses of fentanyl, it is longer than that of remifentanil (figure 1), with a slower return of neurocognitive function [28]. However, unlike remifentanil, sufentanil has the advantage of providing an analgesic effect into the postoperative period. (See "Maintenance of general anesthesia", section on 'Analgesic component: Opioid agents'.)
Drug-drug interactions — Synergistic effects with coadministration of sufentanil and other anesthetic agents are discussed separately. (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 three to five 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 [9,27,29].
MORPHINE —
Morphine is the prototype opioid agent; it is approximately 100 to 200 times less potent than fentanyl [30]. It is a phenanthrene opioid that is less lipophilic than the synthetic opioids (eg, fentanyl, remifentanil, sufentanil, alfentanil), which results in a slower onset of action compared with other opioids (within five to ten minutes) due to poor penetration of the blood-brain barrier [31]. However, morphine has a long analgesic duration of three 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 – Administration of bolus doses of morphine is less common since shorter-acting IV opioids (eg, remifentanil, alfentanil, sufentanil) are available now. If selected, small IV bolus doses of morphine 1 to 2 mg are titrated as necessary [32]. (See "Maintenance of general anesthesia", 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 [33,34].
Treatment of acute postoperative pain — Use of morphine to treat acute pain in the postoperative period is discussed in a separate topic (table 3). (See "Use of opioids for acute pain in hospitalized patients", section on 'Choice of opioid'.)
Drug-drug interactions — Synergistic effects with coadministration of morphine and other anesthetic agents are discussed separately. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)
Pharmacokinetics — Pharmacokinetics for morphine are summarized in the table (table 2).
The onset of action after administration of an IV dose of morphine is five to ten minutes, with peak effect within 20 minutes [35]. Since morphine is primarily metabolized in the liver to glucuronide metabolites (morphine-6-glucuronide and morphine-3-glucuronide), the dose is reduced for patients with hepatic insufficiency. The morphine-6-glucuronide is renally excreted and produces ongoing opioid effects, including analgesia due to mu-receptor-stimulating properties [36]. Since morphine-6-glucuronide is potentially neurotoxic, morphine is unsuitable for patients with kidney function impairment (eg, creatinine clearance less than 30 mL/minute) due to potential accumulation of this metabolite [36,37].
The duration of action of IV morphine is three to five hours, with an elimination half-life of two to four hours, but up to seven hours are required for the elimination half-life of its morphine-6-glucuronide metabolite [38]. Renal elimination is typically complete within 24 hours.
HYDROMORPHONE —
Hydromorphone is a phenanthrene opioid that is a semi-synthetic morphine derivative. Compared with morphine, hydromorphone is approximately five times more potent, has slightly better analgesic efficacy, slightly more rapid onset (five minutes), with a peak effect within 10 to 20 minutes after IV administration [39], and a shorter half-life of two to three hours [39-41]. However, it has a long context-sensitive half-time (approximately two to three hours) (figure 1) [42,43].
Uses and dosing — Recommended doses of hydromorphone are presented in the table (table 1).
General anesthesia
●Maintenance – Hydromorphone 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 0.2mg are administered as necessary. (See "Maintenance of general anesthesia", section on 'Analgesic component: Opioid agents'.)
●Emergence – We often select small boluses of IV hydromorphone rather than morphine for administration near the end of surgery if a long-acting opioid will likely be needed to treat postoperative pain that may be severe or prolonged. Small boluses of hydromorphone (eg, 0.01 mg/kg bolus doses), typically up to a total dose of 0.2 to 1 mg, may be administered approximately 20 to 30 minutes before anticipated tracheal extubation. (See 'Uses and dosing' above.)
Treatment of acute postoperative pain — Use of hydromorphone to treat acute pain in the postoperative period is discussed in a separate topic (table 3). (See "Use of opioids for acute pain in hospitalized patients", section on 'Choice of opioid'.)
Drug-drug interactions — Synergistic effects with coadministration of hydromorphone and other anesthetic agents are discussed separately. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)
Coadministration with strong inducers of drug metabolism, such as rifampin, may reduce plasma concentrations of hydromorphone, thereby lessening its analgesic effect [44].
Pharmacokinetics — Pharmacokinetics for hydromorphone are summarized in the table (table 2).
Hydromorphone is primarily metabolized in the liver; thus, the 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 [45].
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 [30] (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 [46]. 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 [47].
Onset of analgesia is reported in six to eight minutes, but duration may extend to 24 to 36 hours when doses exceed the redistribution half-life (approximately 20 mg) [48].
Uses and dosing
General anesthesia — Most studies have used a single IV dose of methadone (typically 0.1 to 0.2 mg/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, with in an overall beneficial opioid-sparing effect [49,50]. One dose-finding study in short-stay surgical procedures concluded that 0.25 mg/kg was the optimal dose to balance the goals of maximal analgesia and minimal adverse effects [51].
Methadone use in the perioperative period has been proposed as a component of enhanced recovery after surgery (ERAS) protocols [52,53]. Randomized trials and meta-analyses in several surgical populations have noted perioperative opioid-sparing effects with such regimens as well as analgesia extending for up to three days [54-61]. One study in patients undergoing complex spine or cardiac surgical procedures noted continued analgesic benefits for up to three postoperative months [62]. 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 [63,64].
Disadvantages include the potential for postoperative respiratory depression that is similar to morphine, due to a long half-life [65,66] (see 'Pharmacokinetics' below). An observational study in 1478 patients who received intraoperative methadone 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) [65]. A retrospective study noted that 15/2437 (0.62 percent) patients who received intraoperative methadone needed naloxone within the first 24 hours after surgery, compared to 68/12,085 (0.56 percent) of those who received morphine [66]. Another retrospective study noted that 1/673 patients (0.1 percent) received naloxone after intraoperative methadone [67]. However, a review of 19 clinical investigations noted no overall increase in adverse respiratory events related to intraoperative methadone administration [49].
Drug-drug interactions — Synergistic effects with coadministration of sufentanil and other anesthetic agents are discussed separately. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Benefits'.)
Since methadone is metabolized in the liver mainly by CYPB6 and CYP3A4, medications inducing CYP2B6 and/or CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin, efavirenz) may increase metabolism of methadone, while medications inhibiting CYP2B6 and/or CYP3A4 (eg, fluconazole, voriconazole) may reduce metabolism and increase the likelihood of adverse effects (table 5) [49,68,69].
Methadone has the potential for prolonging the QTc interval on the electrocardiogram (ECG). Dose and chronicity of methadone use are associated with development of a prolonged QTc, particularly after long-term treatment of opioid use disorder [70]. Combined use of methadone with drugs that also prolong the QTc interval may further increase the risk for cardiotoxicity. 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, and those taking other agents that prolong the QTc.
Methadone interacts with selective serotonin reuptake inhibitors (SSRIs; (table 4)) and may increase serotonin levels and contribute to the development of serotonin syndrome [54,65]. Methadone is also relatively contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) due to a greater risk of serotonin toxicity [71]. (See "Serotonin syndrome (serotonin toxicity)".)
Pharmacokinetics — Pharmacokinetics for IV methadone are summarized in the table (table 2).
Methadone is metabolized in the liver mainly by CYPB6 and CYP3A4. 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 [48].
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].
Meperidine has a high risk of adverse effects , and relative lack of efficacy compared with other opioids [71,72,76-78]. This agent is generally avoided in pediatric patients [79], or for perioperative analgesia or labor pain in parturients [80].
Uses and dosing
Treatment for shivering — IV meperidine 12.5 to 25 mg is often used to treat perioperative shivering [81]. 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 [82-84].
Drug-drug interactions — Meperidine is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) due to a greater risk of serotonin toxicity [71], as well as other unpredictable, severe, and sometimes fatal reactions [78]. 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 [78].
Meperidine also causes serotonin and norepinephrine reuptake inhibition, which may contribute to the development of serotonin syndrome, particularly if patients are taking selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) (table 4). Management is discussed separately. (See "Serotonin syndrome (serotonin toxicity)".)
Pharmacokinetics — Pharmacokinetics for IV meperidine are summarized in the table (table 2).
Meperidine is primarily metabolized in the liver via the P450 cytochrome system, and its elimination half-life is greatly extended in patients with hepatic cirrhosis [85,86]. Its most clinically relevant metabolite, normeperidine is renally excreted and has a variable half-life up to 48 hours. Compared with meperidine, normeperidine has reduced analgesic properties but enhanced central nervous system (CNS) excitability, manifesting as anxiety, hyperreflexia, myoclonus, and seizures [87,88]. Kidney function impairment reduces excretion of meperidine and its metabolites, increasing risk of accumulation of normeperidine [77]. Significant accumulation of normeperidine can also occur with chronic or repeated use.
SUMMARY AND RECOMMENDATIONS
●Overview – Intraoperative uses and doses of intravenous opioid agents and pharmacokinetics of specific agents are summarized in the tables (table 1 and table 2). (See 'Overview' above.)
●Fentanyl – Fentanyl is commonly used intraoperatively, typically for bolus dosing during the preinduction, induction, or maintenance phases of general anesthesia (as the analgesic component of a total intravenous anesthesia [TIVA] technique or an adjunct agent during inhalation anesthesia). Fentanyl may also be used during monitored anesthesia care (MAC) and for the treatment of acute postoperative pain. (See 'Fentanyl' above.)
●Remifentanil – Remifentanil 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 (five to ten 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. Remifentanil may also be used as primary agent during intubation or extubation, or during a MAC technique. (See 'Remifentanil' above.)
●Sufentanil – Sufentanil 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.)
●Morphine – Morphine is the prototype opioid agent. It is less lipophilic than the synthetic opioids (eg, fentanyl, remifentanil, sufentanil), 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 for intraoperative administration to preemptively and/or urgently control postoperative pain. Disadvantages include potential for postoperative respiratory depression. (See 'Morphine' above.)
●Hydromorphone – Hydromorphone is a semi-synthetic morphine derivative that is approximately five times more potent than morphine with a slightly more rapid onset (peak effect within ten minutes after intravenous [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. Small boluses of hydromorphone may be administered near the end of surgery to control postoperative pain with greater analgesic efficacy and less respiratory depression compared with morphine. (See 'Hydromorphone' above.)
●Methadone – Methadone 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 (CNS). 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. Disadvantages include the potential for postoperative respiratory depression similar to morphine, due to a long half-life. (See 'Methadone' above.)
●Meperidine – Meperidine is used to treat perioperative shivering at doses of 12.5 to 25 mg. Use for analgesia is generally avoided due to its high risk for adverse effects (eg, CNS 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.)
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