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Perioperative uses of intravenous opioids in adults: General considerations

Perioperative uses of intravenous opioids in adults: General considerations
Elizabeth Casserly, PharmD, BCPS
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: Jul 19, 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.

Opioids selected for perioperative use bind primarily to mu receptors in the central nervous system to produce excellent analgesia, as well as respiratory depression, miosis, and euphoria. Opioid binding to mu receptors in the peripheral nervous system produces additional effects such as cough suppression (bronchial receptors) and opioid-induced constipation (intestinal receptors). (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Mechanism of action'.)

This topic will review perioperative uses, benefits, and adverse effects of IV opioid agents. Specific opioids used in the perioperative setting are reviewed in a separate topic. (See "Perioperative uses of intravenous opioids: Specific agents".)

Topics that review use of opioids in other settings (eg, critical care, palliative care, chronic pain management) are available elsewhere:

(See "Pain control in the critically ill adult patient", section on 'Opioid analgesics'.)

(See "Use of opioids in the management of chronic non-cancer pain".)

BENEFITS — The following effects of IV opioid agents make them useful during the perioperative period:

Effective analgesia. Opioids remain invaluable in the treatment of moderate to severe perioperative pain, and are sometimes necessary in multimodal analgesic regimens [1,2]. (See "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)", section on 'Management of pain' and "Pain control in the critically ill adult patient", section on 'Multimodal analgesia'.)

Additive or synergistic effects occur with coadministration of anesthetic or adjuvant agents from other pharmacologic classes (eg, sedative-hypnotics such as propofol, benzodiazepines, inhalation anesthetics), allowing dose reduction of these agents [3-14].

Attenuation of autonomic responses to noxious stimuli that would otherwise result in tachycardia and hypertension [13,15-19].

Suppression of the cough and gag reflex is a class effect of opioids that is useful during manipulation of the airway (eg, laryngoscopy, intubation, or fiberoptic bronchoscopy) [20-22]. However, although fentanyl causes dose-dependent cough suppression [20], fentanyl-induced cough is also a commonly observed phenomenon. This may be clinically relevant if increased intrathoracic, intracranial, or intraocular pressure during coughing could be clinically deleterious [23]. Fentanyl-induced cough can be ameliorated or prevented by very slow fentanyl administration over >30 seconds, or by co-administration of lidocaine, propofol, NMDA-receptor antagonists, alpha-2 agonists, or beta-2 agonists [24].

Reduction of pain caused by injection of IV sedative-hypnotics and other agents (eg, propofol, etomidate, rocuronium). Optimal pain reduction is achieved by coadministering IV opioid with an IV local anesthetic [25-28].

PREVENTION AND MANAGEMENT OF ADVERSE OPIOID EFFECTS — IV opioids have potential adverse side effects that can generally be prevented or treated:

Exacerbation of hypotensive effects of sedative-hypnotics (eg, propofol, inhalation agents) [10-12]. Although an opioid is often used to reduce the necessary dose of a sedative-hypnotic anesthetic agent with the goal of avoiding hypotension, administration of both classes of agent at standard or high doses may actually exacerbate hypotension, particularly in a hemodynamically unstable patient.

Respiratory depression and/or apnea [29]. Opioid-induced respiratory impairment occurs due to depression of the respiratory center in the brainstem, depression of consciousness, and depression of supraglottic airway muscle tone that may lead to upper airway obstruction [30]. During the intraoperative period, this may be a disadvantage in a spontaneously breathing patient or may delay time to tracheal extubation. Also, respiratory depression may lead to pulmonary complications in the postoperative period [31-36]. Thus, opioid doses are reduced if other agents that may cause respiratory depression are also administered. (See "Respiratory problems in the post-anesthesia care unit (PACU)", section on 'Opioids and anesthetic agents'.)

If significant hypoventilation occurs in a spontaneously breathing patient during monitored anesthesia care (MAC) or in the post-anesthesia care unit (PACU) after opioid administration, initial treatment is frequent stimulation to encourage adequate ventilation. Occasionally it is necessary to employ temporary positive pressure ventilation or to titrate low doses of IV naloxone (eg, initial dose 40 mcg, then titrated as necessary up to 400 mcg). Careful titration of these naloxone doses typically reverses opioid effects safely, while preserving some analgesia. Rarely, the sudden reversal of analgesia causes a sympathetic surge with resultant hypertension, tachycardia, myocardial ischemia, or flash pulmonary edema. (See "Acute opioid intoxication in adults", section on 'Management' and "Respiratory problems in the post-anesthesia care unit (PACU)", section on 'Pulmonary edema'.)

Postoperative respiratory depression occurs frequently in high-risk patients, including those of older age and/or those with obesity, obstructive sleep apnea, renal impairment, pre-existing cardiopulmonary disease (eg, chronic heart failure), male gender, or opioid naivety [37,38]. In one prospective observational trial in 1335 hospitalized patients, opioid-induced respiratory depression occurred in 46 percent [37].

Increased intracranial pressure if hypercarbia occurs due to hypoventilation. Thus, ventilation is carefully monitored when opioids are administered to a spontaneously breathing patient with a head injury [39].

Bradycardia, which may be severe with high doses of opioids [40-42]. Treatment with a beta-adrenergic agonist (eg, ephedrine 5 to 10 mg) or anticholinergic agent (eg, glycopyrrolate in 0.2 mg increments up to a total dose of 1 mg, or small incremental doses of atropine 0.2 mg) will typically restore adequate heart rate. (See "Arrhythmias during anesthesia", section on 'Other bradyarrhythmias'.)

Chest wall and skeletal muscle rigidity, which may make ventilation difficult. Dose and speed of opioid injection affect the likelihood and severity of rigidity. This problem is most common with lipophilic opioids, such as remifentanil, fentanyl, alfentanil, or sufentanil [43-51].

Rigidity is prevented or reversed by administration of a neuromuscular blocking agent (NMBA) as soon as the patient is unresponsive and mask ventilation has been successfully established. In spontaneously breathing patients, rigidity can be reversed with naloxone [43,44].

Delayed postoperative emergence or delirium. Management of these problems is described separately. (See "Delayed emergence and emergence delirium in adults", section on 'Opioids' and "Delayed emergence and emergence delirium in adults", section on 'Emergence delirium'.)

Postoperative nausea and vomiting, particularly with high doses of opioids administered for a prolonged duration [52]. (See "Postoperative nausea and vomiting", section on 'Anesthetic factors'.)

Postoperative pruritus [53]. This is uncommon if an IV synthetic opioid (eg, fentanyl or remifentanil) is administered only during the intraoperative period [54]. Treatment options include administration of an antihistamine; low doses of an opioid antagonist, such as naloxone administered in 4 mcg increments or 0.25 to 2 mcg/kg per hour to achieve the desired effect or until the patient experiences an increase in pain; or nalbuphine administered in 1 mg increments to a total of 5 mg [53,55,56].

Postoperative urinary retention. Management is discussed separately. (See "Overview of post-anesthetic care for adult patients", section on 'Inability to void'.)

Postoperative ileus and constipation. Management is discussed separately. (See "Postoperative ileus".)

Possible effects on cancer recurrence. The effects of opioids on cancer cell biology are variable and conflicting among various opioids, and in some cases have been shown to be protective. Further discussion is available in a separate topic. (See "Anesthesia and cancer recurrence", section on 'Opioids'.)

Potential for development of acute tolerance or opioid-induced hyperalgesia (OIH). Acute tolerance is a phenomenon whereby administration of opioids has a diminishing effect over a short period of time [57]. OIH is characterized by nociceptive sensitization, with greater sensitivity to painful stimuli [57-60]. These phenomena may increase postoperative pain and opioid dose requirements. Acute tolerance and OIH have been most thoroughly described with prolonged use (eg, outpatients with chronic pain, critically ill patients) and higher doses of remifentanil [61-65]. However, acute tolerance is possible with any opioid. Thus, use of multimodal, opioid-sparing techniques has become the standard of care to limit this issue and other opioid-related adverse effects [60]:

(See "Pain control in the critically ill adult patient", section on 'Multimodal analgesia'.)

(See "Pain control in the critically ill adult patient", section on 'Tolerance, withdrawal, and hyperalgesia'.)

(See "Pain control in the critically ill adult patient", section on 'Tolerance, withdrawal, and hyperalgesia'.)

Potential for diversion with abuse, misuse, and opioid-related death if perioperative use leads to postoperative outpatient opioid prescriptions [65-67]. Proposed solutions include software applications developed to track perioperative use of controlled substances, reduce discrepancies, and prevent diversion, as well as improved patient engagement in opioid management after hospital discharge [2,68].

Since opioid-related adverse events are dose-dependent, multimodal opioid-sparing strategies that reduce opioid requirements are desirable. For example, protocols for early recovery after surgery (ERAS) emphasize avoidance of nausea, constipation, and ileus by limiting opioid dosing [69-73] (see 'Dosing considerations' below and "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)"). Perioperative alternatives include use of regional analgesia; nonopioid analgesics, such as acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), or cyclooxygenase (COX)-2 specific inhibitors; and adjuvant agents with analgesic properties (eg, dexamethasone, ketamine) [74,75]. Although alpha-2 adrenergic receptor agonists such as dexmedetomidine or clonidine have been shown to reduce opioid requirements [76,77], their role in intraoperative period is limited by their significant adverse effects such as bradycardia and hypotension [78,79]. Similarly, beta-adrenergic receptor antagonists such as esmolol have been shown to reduce opioid requirements [80,81]. (See "Management of acute perioperative pain in adults", section on 'Therapeutic options' and "Pain control in the critically ill adult patient", section on 'Tolerance, withdrawal, and hyperalgesia'.)

DOSING CONSIDERATIONS — Doses of IV opioids are individualized to avoid overdosing. Initial dosing is based, in part, on ideal body weight. Then, doses are titrated during administration (eg, to produce the desired analgesic effect in an awake patient or to supplement other anesthetic agents during induction and/or maintenance of general anesthesia). Genetic variability accounts for considerable variation in an individual's response to the beneficial analgesic effects and the adverse effects of opioids [82].

Doses of opioids are often reduced for older patients and those with impaired renal, hepatic, or pulmonary function. Dosing may need to be increased in the setting of tolerance. Additionally, higher doses of opioids are sometimes used in conjunction with lower doses of sedative-hypnotic agents for induction of anesthesia in patients with depressed myocardial function (though this may impair early extubation efforts). (See "General anesthesia: Intravenous induction agents", section on 'Dosing considerations'.)

Also, for patients participating in enhanced recovery after surgery (ERAS), protocols, we employ intraoperative and postoperative multimodal pain prophylaxis and management strategies that minimize perioperative opioid use. (See "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)", section on 'Opioids' and "Anesthetic management for enhanced recovery after major noncardiac surgery (ERAS)", section on 'Management of pain'.)

In one large study, administration of high opioid doses during the intraoperative period (32 mg morphine equivalents [27 to 41 mg]) was associated with an increased risk of hospital readmission compared with low intraoperative doses (8 mg morphine equivalents [4 to 9 mg]; adjusted odds ratio [OR] 1.75, 95% CI 1.46-2.10; n = 40,000 ambulatory surgical patients), with a dose-response effect across opioid dosing quintiles [83]. Most readmissions occurred within 48 hours of ambulatory surgery. Administration of high opioid doses during the postoperative period has been associated with greater length of hospital stay, overall cost of care, and in-hospital cardiopulmonary complications including arrest [84-88].

Furthermore, a 2020 meta-analysis that included mostly noncardiac surgical studies noted that patients who received "high-dose" opioid administration during the intraoperative period may actually increase pain scores in the postoperative period compared with those receiving "low-dose" opioid administration [89]. Nevertheless, higher opioid doses are necessary to achieve the desired effect in some patients who have developed tolerance due to chronic opioid use, compared with those who are opioid naive. (See 'Chronic opioid use' below and "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Tolerance'.)

OPIOID-FREE AND OPIOID-SPARING ANESTHETIC TECHNIQUES — In light of the known adverse effects of opioids in both the intraoperative and post-acute postoperative phases of care, there have been concerted efforts to reduce opioid exposure [90]. Evidence supports the analgesic efficacy of such opioid-sparing anesthetic techniques [74,91], although they are underutilized in clinical practice [92].

Growing concern that higher doses of perioperative opioids may contribute to persistent postoperative opioid use and greater risk of dependence, addiction, and overdose has led some clinicians to advocate for "opioid-free" anesthesia [90,91], whereby multimodal nonopioid analgesic techniques including regional anesthetic techniques are used to reduce or completely eliminate intraoperative and postoperative opioid use [14,93-95]. A review of 1,104,324 surgical cases performed in 10 hospitals noted decreased intraoperative opioid use (from 152 to 129 mcg/kg parenteral morphine equivalent) from 2012 to 2016 [96]. However, the authors also noted substantial variability among institutions even after controlling for patient and surgical variables, which suggests that efforts to change intraoperative opioid use practices should be targeted at departmental or institutional levels. A 2019 systematic review of randomized trials investigating use of intraoperative opioid administration compared with other analgesic agents or placebo found that pain scores were equivalent in opioid-inclusive versus opioid-free groups, although the incidence of postoperative nausea and vomiting (PONV) was lower in the opioid-free group (risk ratio [RR] 0.78, 95% CI 0.61-0.97; 1304 patients, 23 trials) [97]. A subsequently published study noted similar results [98].

However, controversy exists regarding whether opioid-free anesthesia is necessary, or even feasible, in most surgical cases [99,100]. Aside from reducing PONV, there is a paucity of data to support use of opioid-free anesthetic techniques in attempts to alter short- or long-term postoperative outcomes [97]. Specifically, the use of opioid-free anesthetic techniques has not been shown to reduce postoperative opioid prescribing [65,73,100]. Furthermore, inadequate treatment of pain carries its own risks; thus, effective analgesia is a primary goal of the anesthesiologist [100,101]. Since all analgesic agents have potential adverse effects and risks as well as benefits, alternatives for each selected analgesic medication are considered for the individual patient’s planned analgesic regimen [100]. Studies of nonopioid agent administration to reduce opioid requirements include the following:

Dexmedetomidine – In one trial of opioid-free maintenance of general anesthesia in noncardiac surgical patients, a balanced technique using an inhaled volatile anesthetic (desflurane) combined with intravenous (IV) infusions of nonopioid analgesic agents that included ketamine, lidocaine, and dexmedetomidine was compared with use of desflurane combined with IV infusions of ketamine, lidocaine and remifentanil (plus a bolus dose of morphine administered at the end of surgery) [102]. The study was stopped prematurely, after enrollment of 156 patients in each group, because of five cases of severe bradycardia in patients receiving dexmedetomidine, as well as a higher incidence of postoperative hypoxemia in that group (relative risk 1.19. 95% CI 1.01-1.33). Although patients receiving intraoperative dexmedetomidine rather than remifentanil plus morphine had less postoperative nausea and vomiting (relative risk 0.64, 95% CI 0.45-0.90) and less morphine consumption (6 mg [0 to 17] versus 11 mg [5 to 21]), other outcomes including ileus, cognitive dysfunction, and measures of analgesia were similar in the two groups [102]. (See "Maintenance of general anesthesia: Overview", section on 'Dexmedetomidine'.)

Ketamine – In a systematic review of 130 studies that included 4588 patients receiving ketamine for a broad range of surgical procedures and 3753 controls, postoperative analgesic consumption and pain intensity were reduced by subanesthetic doses of ketamine without differences in adverse effects compared with controls [103]. A randomized trial of the effects of adding a low-dose ketamine infusion for postoperative pain control after spine surgery noted lower opioid requirements and lower pain scores for the first three postoperative days [104]. However, ketamine is generally avoided in patients with ischemic heart disease, systemic hypertension, or psychosis. (See "Maintenance of general anesthesia: Overview", section on 'Ketamine'.)

Gabapentinoids – Off-label administration of perioperative gabapentinoid has been included in perioperative opioid-sparing protocols [105]. Although some studies suggest that gabapentinoids may reduce perioperative pain and opioid consumption [106,107], other studies suggest no clinically significant analgesic effect, no effect on prevention of postoperative chronic pain, and a greater risk of adverse events (sedation, dizziness, and visual disturbances) [108]. Furthermore, a retrospective study that included nearly 14,000 patients undergoing a broad range of surgical procedures noted that preoperative gabapentinoid administration did not reduce risk for prolonged postoperative opioid use [109].

In general, we agree with consensus statements and expert opinion noting that data are not sufficient to recommend patient-specific or procedure-specific nonopioid agents and/or strategies such as regional anesthesia techniques for major invasive surgical procedures in order to completely avoid intraoperative opioid use, or to theoretically prevent persistent postoperative opioid use or undesirable opioid-related long-term outcomes [14,90,110,111]. The best practice is to utilize the lowest dose of opioid for the shortest period of time while providing adequate analgesia [14,92,94,99,100,112]. However, if opioids are minimized or avoided in an individual patient, it remains essential to ensure that intraoperative and postoperative analgesic alternatives are effective [99,100,112,113].

PERIOPERATIVE USES OF OPIOIDS — Opioids are commonly used in the perioperative period during general anesthesia or to supplement sedation and analgesia during regional anesthesia, as well as for treatment of acute pain in the postoperative period [114]. Specific uses, dosing, advantages, disadvantages, drug-drug interactions, and pharmacokinetics for opioids used during the perioperative period differ for each agent (eg, fentanyl, remifentanil, sufentanil, alfentanil, hydromorphone, morphine, methadone). (See "Perioperative uses of intravenous opioids: Specific agents".)

General anesthesia — IV opioids may be used during the induction, maintenance, or emergence phases of general anesthesia, during monitored anesthesia care (MAC), and to treat pain in the immediate postoperative period. Selection of opioid agents and dosing considerations depend on the specific use, desired speed of onset and offset, procedure-specific factors (eg, degree of analgesia required, planned duration of surgery), patient-specific factors (eg, age, comorbidities, tolerance to opioids), and whether other anesthetics or adjuvant agents are coadministered. (See "General anesthesia: Intravenous induction agents", section on 'Opioids' and "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)

Preinduction — An opioid (eg, IV fentanyl 25 to 50 mcg) may be employed as a sole or adjuvant preinduction agent for patients who complain of pain in the immediate preoperative period or for those undergoing a regional anesthetic procedure in the preinduction period.

Induction — Opioids are the most commonly used adjuvant agents during induction of general anesthesia.

Opioid use as an adjuvant agent — Typical doses of adjuvant opioid agents used during induction of anesthesia are noted in the table (table 1).

During laryngoscopy and endotracheal intubation, administration of an opioid is particularly useful for suppressing airway reflexes that result in coughing and/or bronchospasm [20-22], as well as blunting sympathetic nervous system responses that would otherwise result in tachycardia and hypertension [13,15-19]. Paradoxically, fentanyl may induce transient coughing. This can be ameliorated or prevented by very slow fentanyl administration over >30 seconds, or by co-administration of lidocaine, propofol, NMDA-receptor antagonists, alpha-2 agonists, or beta-2 agonists [24].

Opioid administration also reduces dose requirements for the selected sedative-hypnotic induction agent [6]. Furthermore, opioid coadministration with a local anesthetic during induction minimizes pain caused by injection of other agents (eg, propofol, etomidate, or neuromuscular blocking agents) [25-27,115,116].

High-dose opioid induction technique — In selected patients with poor myocardial function who will remain intubated with controlled ventilation for several postoperative hours after major surgery, some clinicians use a high-dose opioid technique for induction of general anesthesia (ie, "cardiac induction"). Typically, fentanyl 10 to 25 mcg/kg or sufentanil 1 to 3 mcg/kg is used for this technique. Administration of a large opioid dose to induce anesthesia results in minimal direct myocardial depression and only a small decrease in arterial blood pressure, while minimizing tachycardia and/or hypertension during laryngoscopy and endotracheal intubation. However, a large opioid dose delays extubation, and may cause bradycardia and chest wall rigidity if administered as a bolus. (See "Anesthesia for cardiac surgery: General principles", section on 'Higher-dose opioid technique' and 'Prevention and management of adverse opioid effects' above.)

Remifentanil intubation technique — Intubation techniques that include remifentanil, typically administration of propofol 2 to 2.5 mg/kg followed by remifentanil 3 to 5 mcg/kg, have been described for rapid sequence intubation (eg, when succinylcholine is contraindicated and the prolonged duration of a nondepolarizing neuromuscular blocking agent is undesirable). (See "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Remifentanil intubation'.)

For this intubation technique, a high dose of remifentanil (typically 3 to 5 mcg/kg) is administered as an IV bolus after administration of an induction dose of propofol. Ephedrine 10 mg IV is also administered to avoid bradycardia and hypotension that would otherwise result from a high dose of remifentanil combined with propofol (see 'Prevention and management of adverse opioid effects' above). This combination of agents typically provides good intubating conditions within 1 to 2.5 minutes while blunting the cough reflex and hemodynamic responses (eg, increased heart rate and blood pressure) [117-119]. A remifentanil intubation technique is also used by some clinicians for awake fiberoptic intubation [21,22]. Careful titration is employed in a spontaneously breathing patient to relieve pain and suppress airway reflexes, while maintaining the patient's ability to follow commands. However, this use is limited by the respiratory depressant effect of remifentanil. (See "Flexible scope intubation for anesthesia", section on 'Sedation'.)

Maintenance — During the maintenance phase of general anesthesia, an IV opioid is often employed as an adjuvant agent during an inhalation anesthetic technique. Opioids reduce the dose requirement for an inhalation anesthetic (ie, they reduce the minimum alveolar concentration [MAC] of an inhaled agent in the alveoli that is required to prevent movement in response to a surgical stimulus in 50 percent of patients). (See "Maintenance of general anesthesia: Overview", section on 'Dosing considerations'.)

An opioid is also commonly selected to provide the analgesic component of a total intravenous anesthesia (TIVA) technique, but none is sufficient to produce anesthesia if administered as a sole agent because opioids do not have a hypnotic effect. The addition of an opioid to a TIVA technique allows reduction of the required dose of the selected hypnotic agent, thereby hastening recovery at the end of the procedure. (See "Maintenance of general anesthesia: Overview", section on 'Analgesic component: Opioid agents'.)


Opioid use as an adjuvant agent — During emergence from general anesthesia, administration of a small dose of IV opioid (eg, fentanyl 25 to 50 mcg) is often employed to attenuate coughing and/or bronchospasm resulting from reflex airway responses to the endotracheal tube or laryngeal mask airway.

Remifentanil extubation technique — In selected cases, it is desirable to avoid all coughing or retching during extubation (eg, when there is patient risk with any increase in intracranial pressure or intraocular pressure). In such cases, an infusion of remifentanil ≥0.1 mcg/kg per minute may be briefly administered, with tracheal extubation as soon as the patient can follow commands, which typically occurs before spontaneous respiratory efforts or recovery of airway reflexes. (See "Extubation following anesthesia", section on 'Minimizing physiologic response to extubation' and "Anesthesia for emergency eye surgery", section on 'Emergence from anesthesia'.)

Monitored anesthesia care — Opioids are often administered during sedation with monitored anesthesia care (MAC) to provide analgesia during placement of a regional anesthetic block, alleviate discomfort due to uncomfortable positioning, or supplement a regional block during incision and subsequent surgical stimulation. Opioids with rapid onset and short duration of action (eg, fentanyl or remifentanil) are generally preferred. Oversedation with consequent respiratory depression is avoided [30]. Opioid choices and dosing for MAC procedures and patient- and procedure-specific indications are discussed separately. (See "Monitored anesthesia care in adults", section on 'Opioids'.)

Treatment of acute postoperative pain — IV opioids are widely used as a component of multimodal therapy to treat postoperative pain because of their ability to provide swift and potent analgesia. Opioid choices, dosing, indications, and cautions in the immediate postoperative period are discussed separately. (See "Management of acute perioperative pain in adults", section on 'Parenteral opioids'.)


Chronic opioid use — Patients who use opioids chronically may develop tolerance, withdrawal symptoms, and/or opioid-induced hyperalgesia with consequent use of higher opioid doses and/or alternative agents or techniques to provide analgesia in the perioperative period [65]. In a retrospective analysis of over 16 million patients undergoing major surgical procedures, almost 95,000 had a diagnosis of opioid dependence or abuse (0.6 percent) [120]. These patients had longer lengths of stay in the hospital and higher readmission rates than those without any history of opioid misuse. Attempts to mitigate these outcomes have led to efforts to reduce preoperative opioid use in chronic opioid users. One analysis of more than 57,000 chronic opioid users noted that changes (increases or decreases) to the preoperative opioid regimen were not associated with clinically significant differences for several postoperative outcomes including postoperative opioid use [121]. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Pain control in the critically ill adult patient", section on 'Tolerance, withdrawal, and hyperalgesia'.)

Tolerance – Patients who have received prolonged or high daily opioid doses typically develop tolerance, a phenomenon whereby administration of opioids has a diminishing effect over time. This can usually be overcome with higher doses of opioids, although the risk of opioid-related adverse effects is increased with this strategy [122-124]. Thus, perioperative use of multimodal, opioid-sparing techniques have become the standard of care. Options include use of continuous neuraxial or peripheral regional analgesia techniques, nonopioid analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase (COX)-2 specific inhibitors, gabapentinoids, and/or adjuvant inhalation or IV agents with analgesic properties (eg, nitrous oxide, ketamine, dexmedetomidine, clonidine). (See "Management of acute perioperative pain in adults", section on 'Strategy for perioperative pain control'.)

For tolerant patients who are chronically receiving methadone or buprenorphine, management of acute pain is discussed separately [65,122-125]. (See "Management of acute pain in the patient chronically using opioids for non-cancer pain".)

Withdrawal symptoms – Acute opioid withdrawal may occur when opioids are abruptly discontinued, particularly if high daily doses have been administered over a prolonged period. Classic symptoms due to rebound increases in neurotransmitter release may be exacerbated by inadequate relief of surgical pain. These include sweating, lacrimation, tachycardia, and hypertension (as well as anxiety, nausea, and vomiting in an awake patient) (table 2) [122,126]. (See "Opioid withdrawal in the emergency setting", section on 'Clinical features of opioid withdrawal'.)

Opioid withdrawal symptoms are assessed with validated scale such as the Clinical Opiate Withdrawal Scale (COWS) in the perioperative period (table 3) [127,128]. As with opioid-tolerant patients, multi-modal analgesia techniques are used whenever feasible to maximize analgesia and minimize opioid-related adverse effects. In addition, an alpha2 agonist, typically dexmedetomidine, may be administered to reduce the undesirable physiologic effects of opioid withdrawal [38,122,129]. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal", section on 'Withdrawal' and "Opioid withdrawal in the emergency setting", section on 'Management'.)

Opioid-induced hyperalgesia – Opioid-induced hyperalgesia (OIH) is a condition that may develop in patients chronically exposed to opioids. OIH is caused by nociceptive sensitization and is characterized by greater than expected sensitivity to painful stimuli and/or a paradoxical hyperalgesic response when an opioid is administered [58,60]. Thus, nonopioid techniques and agents are employed to provide adequate perioperative analgesia when possible, similar to management of opioid tolerance. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid-induced hyperalgesia'.)

Central sleep apnea – The pathophysiology of opioid-induced central sleep apnea in patients who use opioids chronically is based on dysfunction in respiratory rhythm generation and ventilatory chemoreflexes [130].

Acute opioid intoxication — Patients with acute opioid intoxication may require emergency surgery (eg, after trauma). These patients have increased risk for opioid adverse effects. For example, acutely intoxicated patients may develop respiratory depression if the opioid of abuse has not been eliminated from the patient's system, particularly if additional opioids are administered during the perioperative period. Thus, it is helpful to determine the opioid agent, likely dose, and time of most recent administration to estimate duration of effect, and to consider whether other intoxicant agents may have been ingested. (See "Anesthesia for patients with substance use disorder or acute intoxication", section on 'Opioids'.)

Since such patients may have used opioids chronically, the clinician should be aware of the potential for development of tolerance with associated challenges for later control of postoperative pain [122,123]. As noted above, perioperative analgesic management with nonopioid techniques and agents is employed when possible. (See 'Chronic opioid use' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opioid use disorder and withdrawal" and "Society guideline links: Acute pain management".)


Benefits – Benefits of perioperative use of intravenous (IV) opioids include effective analgesia, reduced requirements for other IV and inhalation anesthetic agents, attenuation of autonomic responses to noxious stimuli, and blunting of cough and gag reflexes during airway manipulation. (See 'Benefits' above.)

Adverse effects – Potential adverse effects of opioids include exacerbation of hypotensive effects of other anesthetic agents (eg, propofol, inhalation anesthetics), respiratory depression and/or apnea, increased intracranial pressure (if hypoventilation results in hypercarbia), bradycardia, chest wall and skeletal muscle rigidity, postoperative delayed emergence, nausea and vomiting, pruritus, urinary retention, and potential for acute tolerance and opioid-induced hyperalgesia. (See 'Prevention and management of adverse opioid effects' above.)

Perioperative uses of opioids (table 1) (See 'Perioperative uses of opioids' above.)

Provision of analgesia for general anesthesia We typically employ a short-acting opioid (eg, fentanyl) for bolus dosing during the preinduction, induction, maintenance, and/or emergence phases of general anesthesia. 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. (See 'General anesthesia' above.)

Provision of analgesia and supplemental sedation during monitored anesthesia care (MAC) We typically employ a short-acting opioid (eg, fentanyl) for bolus dosing during MAC. (See 'Monitored anesthesia care' above.)

Treatment of postoperative pain (table 1) 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. (See 'Treatment of acute postoperative pain' above.)

Dosing considerations – Doses of opioids are based on ideal body weight and are titrated to the desired analgesic effect (table 1). Doses are reduced with coadministration of anesthetic agents from other pharmacologic classes, older age or impaired renal or hepatic function, or hemodynamic abnormalities due to hypovolemia, vasodilation, or myocardial dysfunction. (See 'Dosing considerations' above.)

Perioperative alternatives to opioids – In general, we agree with consensus statements and expert opinion noting that data are not sufficient to recommend patient-specific or procedure-specific strategies to completely avoid intraoperative opioid use in order to theoretically prevent persistent postoperative opioid use or undesirable opioid-related long-term outcomes. We use the lowest dose of opioid for the shortest period of time while providing adequate analgesia. If opioids are minimized or avoided in an individual patient, it remains essential to ensure that intraoperative and postoperative analgesic alternatives are effective. (See 'Opioid-free and opioid-sparing anesthetic techniques' above.)

Special populations

Chronic opioid use – Patients who use opioids chronically may develop tolerance, withdrawal symptoms (table 2 and table 3), and/or opioid-induced hyperalgesia, which may necessitate use of higher opioid doses or alternative agents or techniques to provide analgesia in the perioperative period. (See 'Chronic opioid use' above.)

Acute opioid intoxication – Patients with acute opioid intoxication may have increased risk for opioid adverse effects and opioid tolerance, as well as difficulties with control of postoperative pain. Perioperative analgesic management with nonopioid techniques and agents is employed when possible. (See 'Acute opioid intoxication' above.)

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