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Nonopioid pharmacotherapy for acute pain in adults

Nonopioid pharmacotherapy for acute pain in adults
Author:
Eric S Schwenk, MD, FASA
Section Editor:
Robert Maniker, MD
Deputy Editor:
Marianna Crowley, MD
Literature review current through: Nov 2022. | This topic last updated: Nov 08, 2022.

INTRODUCTION — The use of multimodal opioid-sparing analgesia is a key concept and a guiding principle for acute pain management, including perioperative pain. Multimodal analgesia may include nonpharmacologic strategies, local and regional anesthesia techniques, nonopioid analgesics, and opioids only when necessary. This topic will discuss the various options for nonopioid analgesic medications, including appropriate use, doses, efficacy, and adverse effects. The focus will be on perioperative pain, though this information is applicable to other types of acute pain.

An overall approach to management of acute pain in hospitalized patients and use of opioids for postoperative pain are discussed separately. (See "Management of acute perioperative pain in adults".)

Management of acute perioperative pain in children is also discussed separately. (See "Approach to the management of acute perioperative pain in infants and children" and "Pharmacologic management of acute perioperative pain in infants and children".)

Use of regional anesthesia techniques for perioperative pain control is discussed in multiple topics on those various techniques.

MULTIMODAL ANALGESIA — Nonopioid medications are an integral part of multimodal analgesia. The use of multimodal analgesia is a key concept and a guiding principle for perioperative pain management [1]. This strategy involves a combination of analgesic techniques and medications with differing mechanisms of action, with the goal of improving analgesia, reducing side effects, and minimizing reliance on opioids.

Multimodal perioperative analgesia may include nonpharmacologic therapy (eg, patient education, psychological preparation, immobilization, compression, elevation, or cryotherapy of a body part), local or regional anesthesia techniques, nonopioid medications, and opioids if necessary.

STRATEGY FOR MULTIMODAL NONOPIOID PHARMACOTHERAPY — We suggest a stepwise approach to the use of multimodal nonopioid analgesics, starting with a basic strategy for all patients, and addition of further options for patients with moderate and severe pain. The potential analgesic benefit must be weighed against possible side effects and complications, tailored to the specific patient and expected degree of pain. The literature supporting some of the options for postoperative analgesia is not strong. However, even small reductions in opioid consumption may be beneficial. A general strategy for postoperative pain management is shown in an algorithm (algorithm 1).

Doses, evidence of efficacy, and adverse effects for nonopioid options are discussed below. (See 'Options for nonopioid pharmacotherapy' below.)

OPTIONS FOR NONOPIOID PHARMACOTHERAPY — Dosing and administration nonopioid analgesics that are commonly used for acute perioperative pain are shown in a table (table 1).

Acetaminophen — We suggest administering acetaminophen as part of multimodal analgesia for all patients with acute pain and without contraindications. Intravenous (IV) acetaminophen is contraindicated for patients with severe hepatic insufficiency or severe active liver disease. Acetaminophen is effective for many types of acute pain and is associated with few side effects when administered within recommended doses for relatively brief periods. In addition, acetaminophen does not affect platelet function, an advantage for perioperative administration.

A 2022 multisociety consensus statement on the guiding principles of acute perioperative pain management recommended routine use of acetaminophen in patients without contraindications [1].    

Dosing and administration — Acetaminophen is available in oral, IV, and rectal formulations; rectal administration is only rarely used.

For most surgical patients we administer a preoperative oral dose (1 g for patients who weigh ≥50 kg), or if that dose is missed, an IV dose intraoperatively.

We administer acetaminophen on a scheduled basis rather than “as needed” in the early postoperative period and for acute nonsurgical pain. Scheduled administration (also referred to as around-the-clock or time-contingent) is routinely used and endorsed by many organizations and guidelines, with the rationale that pain control may be more even and may reduce delays in medication administration. However, the benefits of scheduled administration remain unproven, as there is very little literature comparing scheduled versus as needed administration of acetaminophen or other nonopioid analgesics [2]. .

The usual doses of acetaminophen are as follows:

Oral or rectal – 325 to 1000 mg orally or rectally, every four to six hours, to a maximum dose of 4 g/day  

IV

Patients ≥50 kg − 650 mg every four hours or 1000 mg every six hours, not to exceed 4 g per day.

Patients <50 kg or with chronic alcoholism, malnutrition, or dehydration − 12.5 mg/kg every four hours or 15 mg/kg every six hours, maximum 750 mg/dose, maximum 3.75 g/day.

IV acetaminophen is contraindicated in patients with severe hepatic insufficiency or severe active liver disease.

Patients with severe renal insufficiency (creatinine clearance ≤30 mL/min) may receive the usual dose, but not more often than once every six hours.

Efficacy — Acetaminophen may be effective for mild postoperative pain, and for some procedures, it may be beneficial in combination with nonsteroidal anti-inflammatory drugs (NSAIDs). Acetaminophen and NSAIDs form the foundation of most multimodal analgesia protocols and are recommended together when not contraindicated in the 2022 multisociety consensus statement on perioperative pain management [1]. The degree to which acetaminophen reduces pain scores and opioid consumption after major surgery is unclear, and literature is conflicting. Examples of studies include the following:

A 2010 meta-analysis of randomized trials found that the addition of acetaminophen (IV or oral) to morphine patient controlled analgesia following major surgery resulted in a modest decrease in morphine use in the first 24 hours postoperatively (mean difference 6.3 mg, 95% CI 3.7-9.0) [3].

In a 2017 meta-analysis of four studies (three randomized, one observational) including patients who underwent total joint arthroplasty, IV acetaminophen was associated with reduced postoperative morphine consumption at 24 hours (weighted mean difference 4.0 mg, 95% CI 3.9-5.0 mg), without a clinically significant difference in pain scores [4].

In contrast, in a single institution randomized trial of approximately 150 patients who underwent major abdominal surgery, the addition of IV acetaminophen to a multimodal analgesic protocol did not reduce pain scores or opioid consumption in the first 48 hours after surgery [5].

The benefits of combining acetaminophen and NSAIDs, versus NSAID alone, may be procedure specific.

A systematic review (14 randomized trials, 1129 patients) comparing the use of NSAIDs alone or in combination with acetaminophen for postoperative pain after various surgeries found that the combination was more effective than NSAIDs alone in 64 percent of the studies [6]. Improved analgesia was found in more studies of ear nose and throat surgery than in orthopedic or gynecologic surgery, though this was based on small numbers of studies. A meta-analysis was not possible.

In a randomized trial of 559 patients who underwent total hip arthroplasty, regularly scheduled acetaminophen and ibuprofen reduced 24-hour postoperative opioid consumption compared with either medication alone, with a modest reduction compared with ibuprofen alone (median difference 6 morphine mg equivalents, 99.6% CI -2 to 16 mg) [7].

IV versus oral — In most patients IV acetaminophen has a more rapid and predictable onset of effect (5 to 10 minutes) and time to peak concentration (15 minutes) compared with rectal or oral administration (onset 10 to 60 minutes or more). However, in most studies of perioperative pain, efficacy is similar with IV or oral acetaminophen [8-16], and duration of action is similar. For patients who are able to take oral medication, there is likely little to no analgesic benefit of using IV rather than oral acetaminophen, and the IV formulation is more expensive.

We use IV acetaminophen for patients who are unable to take oral medication (eg, patients with nausea, or after gastrointestinal surgery). We also use IV acetaminophen for rapid onset of analgesia in the early postoperative period in patients for whom maximal opioid avoidance is desired (eg, patients with obstructive sleep apnea or taking buprenorphine).

In a trial of 120 patients who underwent hip or knee arthroplasty and who were randomly assigned to receive oral versus IV acetaminophen preoperatively and every six hours for 24 hours in addition to multimodal analgesia, visual analog pain scores were lower in the first four hours for patients who received IV acetaminophen (3.0 versus 3.4 on a scale from 0 to 10), but similar thereafter [17]. Opioid consumption in the first 24 hours was similar in the two groups.  

Adverse effects — Acetaminophen has relatively few adverse effects when used for a brief period of time perioperatively. However, adverse events, including cardiac events, gastrointestinal bleeding, and renal dysfunction, have been occasionally associated with analgesic doses of acetaminophen [18].

In the studies on efficacy described above, clinically significant adverse effects were similar in patients who received acetaminophen, compared with those who received placebo [3-5].

Nonsteroidal anti-inflammatory drugs — We suggest administering NSAIDs as part of multimodal analgesia for all patients with acute pain and without contraindications. NSAIDs are contraindicated in the setting of coronary artery bypass surgery due to risk of thrombosis. They are usually avoided after intracranial surgery because of bleeding concerns. They should be used with caution in patients with kidney dysfunction or peptic ulcer disease. We reduce the doses of NSAIDs for adults ≥75 years of age and avoid NSAIDs for older adults with kidney dysfunction.

A 2022 multisociety consensus statement on the guiding principles of acute perioperative pain management recommended routine use of NSAIDs in patients without contraindications [1].    

Choice of NSAID — NSAIDs act on the cyclooxygenase enzyme, which exists in two isoforms (COX-1 and COX-2). COX-2 inhibitors are NSAIDs that act selectively on the COX-2 isoform.

Oral – Oral NSAIDs commonly used for postoperative pain include nonselective NSAIDs ibuprofen, diclofenac, naproxen, and ketoprofen, and the COX-2 inhibitor celecoxib. Celecoxib is the only COX-2 inhibitor available in the United States.  

IV – Commonly used IV NSAIDs include nonselective NSAIDs ketorolac and ibuprofen. Outside the US, IV preparations of diclofenac (nonselective) and parecoxib (COX-2 inhibitor) are also available.  

Meloxicam is a semi-selective NSAID available in both oral and IV formulations.

Nonselective NSAIDs versus COX-2 inhibitors — COX-2 selective and nonselective NSAIDs have similar overall analgesic [19-22], anti-inflammatory, and antipyretic effects in the doses used clinically. In a meta-analysis of trials including surgical patients randomly assigned to receive NSAIDs versus placebo, there were no differences in pain scores or opioid consumption in patients who received nonselective NSAIDs versus COX-2 inhibitors [23]. Conclusions from this meta-analysis are limited by the overall low quality of the data and lack of reporting of clinically significant adverse effects.  

At the author’s institution, most preoperative multimodal analgesia protocols include celecoxib rather than nonselective NSAIDs because of reduced risk of gastrointestinal toxicity.

COX-2 selective NSAIDs have little to no effect on platelet function and therefore do not increase the risk of bleeding, which may be an advantage for surgical patients. However, existing evidence does not show an increased surgical bleeding risk with either nonselective NSAIDs or COX-2 inhibitors [24]. (See 'Adverse effects' below.)

Like nonselective NSAIDs, COX-2 inhibitors are associated with cardiovascular and renal toxicities. (See "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.)

COX-2 inhibitors may have reduced gastrointestinal toxicity compared with nonselective NSAIDs. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity", section on 'Pathogenesis of gastroduodenal toxicity'.)

We usually avoid celecoxib in patients with a sulfonamide allergy and instead use a nonselective NSAID if there are no contraindications, since celecoxib contains a sulfonamide moiety. Whereas existing studies suggest that cross-reactivity in patients with sulfonamide allergy is unlikely, celecoxib is associated with occurrence of Stevens-Johnson syndrome in susceptible patients. Thus avoiding celecoxib may be particularly important in patients with a prior history of fever with sulfonamides or a blistering reaction to any medication. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Celecoxib'.)

Meloxicam is a semiselective NSAID that preferentially inhibits COX-2 at low doses. However, at the doses recommended for acute pain, there is greater effect on COX-1, and when used clinically, meloxicam has effects and toxicities similar to other nonselective NSAIDs.

Dosing and administration — Similar to acetaminophen, NSAIDs are usually administered on a scheduled basis rather than as needed. We use scheduled dosing to ensure consistent administration and avoid missed doses in favor of opioids. However, the benefits of scheduled administration remain unproven, as there is very little literature comparing scheduled versus as needed administration of NSAIDs or other nonopioid analgesics [2].

Usual doses for the most commonly used NSAIDs are as follows, with doses for other NSAIDs shown in a table:

Celecoxib

Preoperative − 200 to 400 mg orally; 200 mg orally for adults ≥75 years of age

Postoperative − 200 mg orally once or twice daily, scheduled, until discharge; once daily for adults ≥75 years of age

Ibuprofen

Preoperative − 600 to 800 mg orally or IV

Postoperative − 600 to 800 mg orally or IV every 6 to 8 hours until discharge

Naproxen

Preoperative − 500 mg orally

Postoperative − 500 mg orally every 12 hours

Ketorolac – We avoid ketorolac in patients with renal dysfunction.

Intraoperative − 15 to 30 mg IV intraoperatively after discussion with the surgeon to confirm adequate hemostasis

Postoperative − For patients unable to take oral medications, 15 to 30 mg every 6 hours, lower doses for patients <50 kg or age ≥65 years, maximum 5 days (table 1)  

Efficacy — NSAIDs may be the most effective analgesic agents in multimodal perioperative protocols [19,25-27]. Examples of relevant studies include the following:

In a database study of over 1,300,000 patients who received multimodal analgesia for total hip or knee arthroplasty, increasing number of multimodal interventions were associated with decreasing postoperative opioid use, opioid prescriptions, and some opioid-related side effects; the strongest association was with the use of nonselective NSAIDs and COX-2 inhibitors [28].

In one systematic review of studies that assessed the efficacy of various postoperative nonopioid analgesics, NSAIDs were associated with a reduction in 24 hour morphine consumption of 10 mg [29].

In a meta-analysis of eight randomized trials that compared diclofenac with placebo or other NSAIDs for postoperative pain found that diclofenac was superior to placebo and similar to other NSAIDs. Conclusions from this meta-analysis are limited by the low quality of data, with high clinical and statistical heterogeneity [30].

In a meta-analysis of 8 randomized trials (1177 patients) that compared ketoprofen with placebo for postoperative pain, 60 percent of patients who received ketoprofen 50 mg achieved 50 percent reduction in pain, compared with 20 percent after placebo [31]. Ketoprofen also reduced the number of patients who needed additional analgesics within 6 hours (50 percent versus 80 percent). The quality of evidence of included studies ranged from very low to moderate.

Adverse effects — All NSAIDs have US Food and Drug Administration warnings for serious cardiovascular thrombotic events (myocardial infarction, stroke) and gastrointestinal (bleeding, ulceration, perforation) adverse events, which can occur early in therapy. Thus the labels recommend using the lowest effective dose for the shortest duration possible.

However, available data is insufficient to determine whether NSAIDs increase these or other adverse events when used for perioperative analgesia. Risks of adverse events in older patients have not been determined, as most studies have excluded older patients.

A meta-analysis of studies that assessed efficacy and adverse effects of a single dose of ketorolac compared with opioids or other NSAIDs found that overall adverse events may occur at a slightly higher rate with ketorolac than with other NSAIDs, and a rate similar to opioids [32]. However, there were insufficient high-quality data to determine whether rates of bleeding, renal dysfunction, or cardiovascular events were different with ketorolac, compared with other NSAIDs. Similar results were found in another meta-analysis that evaluated a single dose of IV diclofenac for perioperative pain [30].

In a meta-analysis of 68 randomized or cohort studies that assessed surgical bleeding after administration of various NSAIDs in patients who underwent a variety of procedures, NSAIDs were not associated with increased risk of clinical bleeding, whether the NSAID was administered in the preoperative, intraoperative, or postoperative period [24]. Most included studies evaluated ketorolac, diclofenac, ibuprofen, celecoxib, or ketoprofen.

Gabapentinoids — Pregabalin and gabapentin are the gabapentinoids used for perioperative analgesia. The author administers pregabalin for most patients <75 years old who undergo moderately or severely painful surgery. For patients who report “allergic” or idiosyncratic reactions to one preparation, the author has successfully used the other. An exception would be anaphylactic reactions, which are rare but would warrant avoidance of both drugs.

We usually avoid gabapentinoids for patients ≥75 years old because of concerns about sedation or delirium. If used in older patients after weighing risks and benefits compared with alternatives, we suggest reducing the doses. (See "Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies", section on 'Intravenous agents associated with higher risk'.)  

The use of gabapentinoids for perioperative analgesia is controversial, and practice varies. Some experts have stopped routinely using gabapentinoids due to concerns about side effects and safety, particularly when combined with opioids and in older patients. Older guidelines suggested use of gabapentinoids for analgesia after most types of surgery [33], but some more recent guidelines no longer recommend routine use [34]. (See 'Efficacy and adverse effects' below.)

Gabapentin versus pregabalin — Gabapentin and pregabalin are probably similarly effective for perioperative analgesia, though there are some differences between the drugs.

Pregabalin is more rapidly and predictably absorbed than gabapentin; peak blood concentration occurs within an hour of ingestion of pregabalin, versus approximately three hours for gabapentin [35].

Pregabalin is more potent than gabapentin. (See 'Dosing and administration' below.)

Gabapentin is less expensive than pregabalin, which may be an issue for patients who pay for the drug out of pocket after discharge.

Dosing and administration — The optimal doses of gabapentinoids have not been established, and it is not clear whether higher doses are more effective. We use the following doses, with the goal of balancing efficacy against the risk of adverse effects at higher doses.

These drugs are administered orally. We administer only a preoperative dose for patients who have ambulatory surgery and for inpatients expected to have mild postoperative pain (ie, no postoperative doses). For patients expected to have moderate to severe postoperative pain, we continue gabapentin postoperatively for duration of hospital admission, at doses shown below.

Pregabalin

Preoperative − 75 to 150 mg orally

Postoperative − 75 mg orally every 12 hours until hospital discharge

Gabapentin

Preoperative − 300 to 800 mg orally

Postoperative − 300 to 600 mg orally every 8 hours until hospital discharge

Efficacy and adverse effects — Gabapentinoids were developed as antiseizure agents and act as inhibitors of voltage-gated calcium channels [36]. Because of their ability to suppress neuronal excitability, they have been also used for pain; they are first-line therapies for chronic neuropathic pain. However, adverse effects are increasingly recognized, and the analgesic benefits when added to multimodal protocols are unclear. For many procedures, gabapentinoids may modestly reduce postoperative opioid consumption, but may also increase side effects, including dizziness, sedation, visual disturbance, and/or respiratory depression. The risk/benefit ratio may be most favorable for patients having very painful surgery, particularly those with opioid dependence or opioid use disorder. In contrast, gabapentinoids should be used cautiously if at all for patients at high risk of respiratory depression (eg, older patients, patients with obstructive sleep apnea).

Examples of relevant meta-analyses are discussed here; they include patients who have had all types of surgery.

In a 2020 meta-analysis of 281 trials (24,682 patients) of adult surgical patients, gabapentinoids reduced postoperative pain scores by statistically significant but clinically unimportant amounts at 6 to 48 hours (-3 to 10 percent), and at 4 to 12 weeks postoperatively (-6 percent) [37]. Gabapentinoids reduced 24-hour opioid use by approximately 8 mg (25.3 versus 32.6 mg). Gabapentinoids reduced postoperative nausea and vomiting and increased the incidence of dizziness and visual disturbance. The quality of evidence was judged as low for postoperative pain outcomes and very low for postoperative opioid consumption.  

A 2016 meta-analysis of 13 randomized trails that compared perioperative gabapentin with placebo found that gabapentin reduced 24-hour opioid consumption by 3.1 mg morphine equivalents (MME; 95% CI 0.5–5.6 mg) [38]. In studies that assessed the addition of gabapentin to a multimodal analgesic regimen, there was no effect on 24-hour opioid consumption. Gabapentin did not increase adverse effects.

In a 2017 meta-analysis of randomized trials that evaluated perioperative pregabalin in adults, pregabalin reduced 24-hour opioid consumption by 5.8 MME (95% CI 3.2–8.5), based on 11 trials [39]. When added to a multimodal analgesic regimen, pregabalin reduced 24-hour opioid consumption by 3.7 MME (95% CI 1.5–6.0). Pregabalin increased serious adverse events, dizziness, vomiting, and visual disturbance.

The risk of respiratory depression associated with the perioperative combination of gabapentinoids and opioids is increasingly recognized. Large database studies have found that the risk of adverse events is very low, but adding gabapentinoids to opioids may increase the risk of opioid overdose and the need for administration of naloxone [40,41]. In a United States database study of over five million adults who underwent major surgery, opioid overdose occurred in 1.4 per 10,000 patients who received gabapentin plus opioids, compared with 0.4 per 10,000 patients who received opioids alone [40]. Patients at higher risk of respiratory depression may require continuous respiratory monitoring if gabapentinoids are used along with opioids.

Intravenous lidocaine — We administer IV lidocaine for patients who undergo thoracic or lumbar spine surgery or open abdominal surgery when epidural analgesia is not used (contraindicated, refused, or failed).

Dosing and administration — The optimal dose and dose regimen for IV lidocaine for perioperative pain have not been established [42]. We use lidocaine doses that were effective in studies of lidocaine administration during spine surgery [43,44], and use ideal body weight (IBW) to minimize the risk of toxicity. Reported infusion doses range from 1 to 5 mg/kg/hour IV [45]. Because lidocaine is metabolized by the cytochrome P450 (CYP450) system [46], caution should be exercised when using it in patients with liver disease. We usually reduce the dose of lidocaine in patients with liver disease and consult a pharmacist for patients who are taking medications that interact with the CYP450 system.

Intraoperative − We administer lidocaine 1 to 1.5 mg/kg IBW IV as a bolus near the time of induction of anesthesia, and follow with an infusion at 1.5 to 2 mg/kg/hour (1 mg/kg/hour in older adults [47]). For most patients we stop the infusion at the time of skin closure.

Postoperative − For patients with expected difficulty with pain control (eg, opioid tolerant) or who need maximal opioid avoidance (eg, patients with obstructive sleep apnea), we may continue lidocaine infusion into the postoperative period. However, existing evidence does not support continuing lidocaine infusions postoperatively beyond 60 minutes [48].

At the author’s institution, most patients receive postoperative lidocaine infusions on general medical floors at a fixed rate and titration is not permitted. Patients receiving lidocaine infusions titrated by nurses (based on pain scores and adverse effects) under the order of a clinician must be in a monitored setting (eg, post anesthesia care unit [PACU] or intensive care unit).

An international consensus statement on the intraoperative use of IV lidocaine made several recommendations, including the following, while recognizing that the optimal doses for lidocaine have not been established and the recommended dose limits are not evidence based [42]:

Dosing for IV lidocaine should be based on IBW.

Initial bolus should be ≤1.5 mg/kg IV, followed by continuous infusion at ≤1.5 mg/kg/hour IV.

The infusion may be initiated intraoperatively and may be continued postoperatively in a monitored setting for up to 24 hours, depending on local protocol.

Administration of IV lidocaine should be delayed for at least four hours after the patient has received a regional anesthetic or local anesthetic infiltration.

A regional anesthesia procedure should be delayed at least four hours after discontinuing an IV lidocaine infusion.

Efficacy — Although there has been a long history of using IV lidocaine in acute and chronic pain settings, the literature on the beneficial effects of perioperative IV lidocaine is inconclusive, both overall and for specific types of surgery [43-45,49-52]. The mechanism of action of IV lidocaine when used for perioperative analgesia is unknown, but likely involves its anti-inflammatory properties [53].

A 2018 meta-analysis of 68 randomized trials that compared IV lidocaine with either placebo or epidural analgesia after various surgical procedures found unclear evidence of beneficial effects of lidocaine on gastrointestinal recovery, postoperative nausea, opioid consumption, or postoperative pain [45]. The overall quality of the evidence for most outcomes was very low. In contrast with a previous meta-analysis by the same group of authors [49], there were no differences in outcomes for particular types of surgery.

Some small single institution randomized trials have reported opioid-sparing benefits and improved pain scores after IV lidocaine for specific types of surgery (eg, laparoscopic inguinal hernia repair) [50].

A 2020 meta-analysis of 10 randomized trials (508 patients) of patients who underwent colorectal surgery, IV lidocaine resulted in statistically significant but clinically unimportant reductions in pain scores, time to defecation, and length of stay [51]. Postoperative morphine consumption was similar between groups.

Two randomized trials of patients who underwent lumbar spine surgery found that IV lidocaine reduced postoperative opioid consumption, with a statistically significant but clinically unimportant reduction in postoperative pain scores [43,44].

Adverse effects — IV lidocaine is generally well tolerated. Toxicity relates to the total dose, speed and duration of infusion [42]. The most common adverse effect is central nervous system toxicity (drowsiness, light headedness, perioral numbness, tinnitus). Cardiac side effects (eg, sinus slowing, asystole, hypotension, shock) are uncommon even among patients with significant underlying heart disease [54,55]. These effects are discussed separately. (See "Major side effects of class I antiarrhythmic drugs", section on 'Lidocaine (intravenous)' and "Local anesthetic systemic toxicity".)

In patients who have received IV lidocaine for perioperative analgesia, serious adverse events are very rare. In the previously mentioned meta-analysis of 68 trials, no side effects were reported in approximately half of the trials, with only minor events reported in the remaining trials [45].

Ketamine — We administer ketamine primarily for opioid-tolerant patients and those with opioid use disorder who undergo surgery expected to be moderately to severely painful, or who have severe nonsurgical acute pain. Patients with obstructive sleep apnea may also benefit, since they are at higher risk for respiratory events with opioids. These recommendations are consistent with 2018 guidelines from American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Academy of Pain Medicine (AAPM), and the American Society of Anesthesiologists (ASA) for the use of ketamine for acute pain [56]. We rarely administer ketamine to older adult patients or patients undergoing surgery that is not expected to be very painful, in whom adverse effects may outweigh the analgesic benefits. We do not usually administer ketamine if regional anesthesia is being used for postoperative analgesia, unless the patient is opioid tolerant.

Dosing and administration — Ketamine can be used to induce and maintain general anesthesia. It is used at subanesthetic doses for perioperative analgesia, though the dose considered subanesthetic has not been well defined. Optimal doses of ketamine for acute pain and perioperative analgesia have not been well studied, and comparative dose studies are lacking. One meta-analysis of 47 randomized trials found a reduction in postoperative opioid consumption in patients who received perioperative ketamine; the timing of administration (pre- or postincision), use of bolus alone, infusion alone, or combination, and the dose of ketamine (≤0.5 mg/kg to >1 mg/kg IV) did not affect analgesic efficacy [57].

IntraoperativeKetamine is commonly initiated intraoperatively with a bolus dose of 0.25 to 0.5 mg/kg IV followed by an infusion of 0.1 to 0.5 mg/kg/hour (2 to 8 mcg/kg/minute) [58]. The benefit of an isolated intraoperative ketamine bolus without an infusion is likely low and therefore an infusion should be strongly considered [59].

We usually reduce the infusion (or stop it if postoperative infusion is not planned) 45 to 60 minutes prior to the end of surgery, to avoid prolonging emergence.

Postoperative − While continuing ketamine infusions into the postoperative period is ideal, it may not always be possible because of local institutional policies and ketamine's status as an anesthetic drug. When postoperative infusion is not possible, there may still be benefit to intraoperative administration alone. In a randomized trial of 100 opioid-dependent patients who underwent spine surgery, intraoperative ketamine (bolus plus infusion) without postoperative infusion reduced postoperative opioid consumption at 24 and 48 hours and six weeks after surgery, and reduced pain scores in the PACU and at six weeks, compared with placebo [60].

Because ketamine is an anesthetic agent with potential for both psychomimetic adverse effects and unconsciousness, its use is restricted in many hospitals to anesthesiologists and emergency medicine clinicians in monitored settings. The guidelines mentioned above from ASRA, AAPM, and ASA [56] recommend that ketamine administration should be supervised by clinicians experienced with ketamine pharmacology and with at least moderate sedation and advanced cardiac life support training [56]. The guidelines also recommend a monitored setting for patients who receive infusion at rates beyond 1 mg/kg/hour.

Efficacy — Ketamine is an N-methyl-D-aspartate receptor antagonist but also interacts with mu-opioid, cholinergic, nicotinic, and voltage-gated calcium channels [58,61-64]. Although the science that supports the potential benefits of ketamine is compelling, the evidence for the best use of ketamine, alone or in combination, is evolving but inconclusive.

While some studies have shown favorable results using ketamine in a multimodal regimen for the reduction of postoperative pain [60,65,66], others have shown no benefit [59,67,68].

In a 2011 meta-analysis of 47 trials of perioperative IV ketamine, there was a reduction in total opioid consumption and an increase in the time to first analgesic [57]. Patients having the most painful surgical procedures, including thoracic, upper abdominal, and major orthopedic operations, had improvement in pain scores despite a decrease in opioid consumption. Ketamine was not effective for patients having surgery associated with mild pain, such as tonsillectomy, dental, or head and neck surgery.

In another meta-analysis of randomized trials including patients who underwent spine surgery, supplemental ketamine reduced morphine consumption and pain scores during the first 24 postoperative hours, without an increase in adverse events [69].

In a multicenter randomized trial including 672 patients >60 years of age who underwent major surgery, administration of a single intraoperative subanesthetic bolus dose of ketamine did not reduce postoperative pain scores or opioid consumption [59]. There were more postoperative hallucinations and nightmares in patients who received ketamine compared with placebo, but no differences in other adverse outcomes.

IV ketamine may be effective at preventing chronic postsurgical pain as suggested by one meta-analysis, but further studies are needed to define the optimal dose and timing [70], patient factors and the type of surgery for which ketamine may be beneficial.  

Adverse effects and contraindications — Ketamine at anesthetic doses can cause hypertension and tachycardia, psychotomimetic effects after emergence from anesthesia (eg, hallucinations, nightmares, and vivid dreams), and increased intracranial pressure. However, most of these adverse effects are likely rare at subanesthetic doses, however the reported comparative incidence of adverse effects varies [57,71]. (See "General anesthesia: Intravenous induction agents", section on 'Disadvantages and adverse effects'.)

The decision to use ketamine for perioperative analgesia should be individualized based on patient factors and the proposed surgery. We agree with the joint 2018 guidelines that ketamine should usually be avoided in patients with poorly controlled cardiac disease, pregnancy, active psychosis, severe liver disease, elevated intracranial pressure, and elevated intraocular pressure.  

Glucocorticoids — We administer a single intraoperative dose of IV dexamethasone, 4 to 8 mg for patients who undergo total joint arthroplasty or spinal fusion surgery, for both analgesia and anti-emetic effects. Dexamethasone and methylprednisolone are the most commonly studied glucocorticoids [72]; dexamethasone is probably the most widely used.

We generally avoid dexamethasone in patients with poorly controlled diabetes, (eg, HgA1C >7 percent, preoperative blood glucose >200 mg/dL), because of the risk of severe hyperglycemia. (See 'Efficacy and adverse effects' below.)

Dosing — Higher doses of dexamethasone may be required for analgesia than for prevention of postoperative nausea and vomiting (PONV) [73]. The recommended dose range for PONV prophylaxis is 4 to 8 mg IV in adults, whereas a dose at the higher end of this range may be required for analgesia. Two meta-analyses of studies comparing lower-dose (<0.1 mg/kg IV) dexamethasone with higher doses (>0.1 mg/kg) found that higher doses were required for reduced opioid requirement [74,75].

Efficacy and adverse effects — Dexamethasone can improve postoperative pain and generally has few adverse effects. Studies have shown that the analgesic benefit is small.

In a 2019 meta-analysis of six studies of patients who underwent various types of surgery (eg, abdominal, pelvic, lower extremity) under spinal anesthesia, perioperative dexamethasone reduced 24-hour morphine consumption by a significant but possibly clinically unimportant amount (4 mg, 95% CI 3-5 mg) [76].

A 2013 meta-analysis of 45 trials including approximately 5800 surgical patients, dexamethasone 1.25 to 20 mg IV resulted in statistically significant but clinically nonsignificant decreases in pain scores, postoperative opioid consumption, and time to first dose of analgesic [72].

In a 2011 meta-analysis of 24 randomized trials including approximately 2750 patients and multiple surgical procedures, dexamethasone >0.1 mg/kg IV, but not lower doses, resulted in a small reduction in postoperative pain and opioid consumption [74].

IV dexamethasone may also reduce postoperative sore throat pain, and may extend the duration of peripheral nerve blocks. (See "Overview of peripheral nerve blocks", section on 'Adjuvants' and "Complications of airway management in adults", section on 'Strategies to reduce sore throat'.)

Data on the safety of prophylactic dexamethasone are inconclusive, and the use of dexamethasone should be individualized. Risks of perioperative glucocorticoids may include impaired healing, hyperglycemia, and immunocompromise. These issues are discussed separately. (See "Postoperative nausea and vomiting", section on 'Glucocorticoids' and "Anesthesia for tonsillectomy with or without adenoidectomy in children", section on 'Dexamethasone'.)

Alpha-2 receptor agonists — The two commonly used alpha-2 receptor agonists in perioperative medicine are clonidine and dexmedetomidine.

We use clonidine as an adjunct to mitigate ketamine-related adverse effects, rather than as a standalone agent, mostly when ketamine infusions are planned for two days or more or high doses are anticipated. It may be particularly beneficial in patients with hypertension or tachycardia who are at risk for, or are experiencing, poorly controlled pain.

We administer dexmedetomidine for patients expected to have severe postoperative pain and who have risk factors for emergence delirium, such as a history of emergence delirium or alcohol abuse.

Doses — Optimal doses of these agents for perioperative administration have not been established.

Clonidine – Clonidine can be given via oral, intramuscular, transdermal, or IV routes. The most commonly used doses are 200 or 300 mcg orally or 1 to 4 mcg/kg IV, either prior to induction of anesthesia or postoperatively for awake patients [77].

We use a 0.2 mg transdermal patch for patients receiving ketamine infusions for multiple days.

Dexmedetomidine – We typically start the infusion intraoperatively at a rate of 0.3 to 0.7 mcg/kg/h and continue it into the PACU. Dexmedetomidine is sometimes administered with a loading dose, though this may be unnecessary when it is used as part of multimodal analgesia (as opposed to sedation). If a bolus is administered, it should be limited to ≤0.5 mg/kg to avoid hypotension and bradycardia [78].

Efficacy

Clonidine – The role of clonidine in multimodal analgesia still remains unclear. A meta-analysis of 57 trials including approximately 14,800 surgical patients found that clonidine reduced analgesic consumption, PONV and postoperative shivering, and improved hemodynamic stability [77]. Conclusions are limited by high heterogeneity among the included studies.

Dexmedetomidine – Dexmedetomidine has an alpha-2/alpha-1 selectivity ratio of 1620, which is 5 to 10 times greater than that of clonidine [79], indicating that it may be more likely to produce sedation as well as analgesia. The literature on the use of dexmedetomidine for postoperative analgesia is limited.  

In one small randomized controlled trial of 34 patients undergoing open living donor hepatectomy, the addition of dexmedetomidine to standard anesthetic care reduced the amount of intraoperative anesthetic medication and bleeding and reduced the postoperative pain and opioid use up to 24 hours [80].

Existing literature does not support the routine use of IV dexmedetomidine for analgesia after cesarean delivery. (See "Post-cesarean delivery analgesia", section on 'Adjuvant analgesics'.)

Dexmedetomidine may suppress the surgical stress response and accompanying inflammation [81], which can be advantageous for patients with compromised or decreased immune function, such as those with cancer, autoimmune disorders, and organ transplantation taking immunosuppressants.

Dexmedetomidine may also reduce emergence delirium in both adults and children. A meta-analysis found that dexmedetomidine is effective at reducing postoperative delirium in adult patients [82]. The effects of dexmedetomidine on emergence delirium are discussed in detail separately. (See "Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies", section on 'Intravenous agents associated with lower risk' and "Emergence delirium and agitation in children", section on 'Prevention'.)

Adverse effects — All alpha-2 receptor agonists have the potential to cause hypotension, bradycardia, and sedation. A meta-analysis of 56 studies that evaluated cardiovascular effects of perioperative clonidine and dexmedetomidine found that both drugs can cause hypotension and bradycardia, though only dexmedetomidine bolus doses of greater than 0.5 mcg/kg caused bradycardia [78]. These adverse effects were noted to occur even after cessation of treatment, so patients may need monitoring for additional time beyond the last dose, especially for dexmedetomidine. Monitoring for an additional hour is typically sufficient. At many institutions, including the author’s, dexmedetomidine may not be administered outside of critical care areas, which limits its use. For most postoperative patients, it will be stopped during the PACU recovery period.

Combinations of multimodal analgesics — Most multimodal analgesia protocols include more than one nonopioid agent. Multiple institutional multimodal analgesia protocols have been published and an exhaustive list is out of the scope of this review. One common protocol includes pre- and postoperative acetaminophen, celecoxib, and pregabalin, with or without opioids [83-86].

Combinations of agents should be tailored to the individual patient and planned surgery. As examples, we often avoid gabapentinoids in the older adults, NSAIDs for those with renal dysfunction or a history of gastrointestinal bleeding, and ketamine in ambulatory patients undergoing mildly painful surgery, to minimize the risk of adverse effects (table 1).  

Many studies of the efficacy of multimodal analgesia protocols are unable to separate out effects of one component versus others. Nevertheless, some studies have attempted to do this.

In a trial of 556 patients who underwent total hip arthroplasty, patients were randomly assigned to the combination of ibuprofen and paracetamol, ibuprofen alone, or paracetamol alone [7]. Pain relief was similar in patients who received the combination of agents versus ibuprofen alone, and both of those groups had better pain relief than paracetamol alone, implying that ibuprofen was the more effective drug of the two [7].

In a small trial including 42 patients who underwent total hip arthroplasty, patients were randomly assigned to receive gabapentin, dexamethasone, and ketamine in addition to paracetamol and ketorolac, versus paracetamol and ketorolac alone; postoperative pain scores were modestly reduced (16 to 7 mm, at rest, 16 to 11 mm with movement, on a 100 mm scale) with the additional drugs [87]. There was a trend towards reduced 24-hour morphine consumption in the combination group, but it did not reach statistical significance (13±12 mg versus 22±18 mg).

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: Acute pain management".)

SUMMARY AND RECOMMENDATIONS

Strategy for nonopioid pharmacotherapy We use nonopioid analgesics as part of a multimodal opioid-sparing strategy for perioperative pain control, based on the expected degree of postoperative pain and patient factors (algorithm 1). (See 'Strategy for multimodal nonopioid pharmacotherapy' above.)

Acetaminophen We suggest acetaminophen for all patients without contraindications who have postoperative pain. Acetaminophen is effective for many types of pain and has few side effects when used for perioperative pain. We administer acetaminophen preoperatively and intraoperatively, and postoperatively on a regularly scheduled basis (table 1). (See 'Acetaminophen' above.)

NSAIDs

We suggest NSAIDs for all patients without contraindications who have postoperative pain (table 1). NSAIDS may be the most effective of the nonopioid analgesics. (See 'Efficacy' above.)

We administer NSAIDs preoperatively and intraoperatively if the surgeon agrees, and postoperatively on a regularly scheduled basis. (See 'Dosing and administration' above.)

COX-2 selective and nonselective NSAIDs have similar analgesic effects. (See 'Nonselective NSAIDs versus COX-2 inhibitors' above.)

NSAIDs are contraindicated in patients who undergo coronary bypass surgery and should be used cautiously in patients with renal dysfunction, peptic ulcer disease, or high bleeding risk. (See 'Adverse effects' above.)

Gabapentinoids The use of gabapentin or pregabalin for perioperative analgesia is controversial. The author uses pregabalin for most patients <75 years of age who have moderately or severely painful surgery. The potential for modestly reduced postoperative opioid consumption must be balanced against side effects including dizziness, sedation, visual disturbance, and respiratory depression (especially when combined with opioids). Gabapentinoids should be used cautiously if at all in patients at high risk of respiratory depression (eg, older patients, patients with obstructive sleep apnea) (table 1). (See 'Gabapentinoids' above.)

Intravenous lidocaine We administer intravenous (IV) lidocaine for patients who undergo thoracic or lumbar spine surgery or open abdominal surgery when epidural analgesia is not used (table 1). The beneficial effects of IV lidocaine have not been proven and the optimal dose and regimen have not been established. For most patients we administer an intraoperative bolus and infusion and stop the infusion at the end of surgery. For select patients the infusion can be continued postoperatively for up to 24 hours with appropriate cardiovascular monitoring. (See 'Intravenous lidocaine' above.)

Ketamine We administer subanesthetic ketamine primarily for opioid-tolerant patients and those with opioid use disorder who undergo surgery expected to be moderately to severely painful. Optimal doses have not been established; we use an intraoperative bolus followed by infusion, and continue postoperatively in a monitored setting when necessary (table 1). (See 'Ketamine' above.)

Others

Dexamethasone – We administer dexamethasone for patients who undergo total joint arthroplasty or spinal fusion, for both analgesia and prophylaxis for postoperative nausea and vomiting (table 1). (See 'Glucocorticoids' above.)

Alpha-2 receptor agonists – The role of these agents in perioperative analgesia is unclear. We administer clonidine to mitigate the side effects for patients who receive ketamine, and dexmedetomidine for patients who are at risk for emergence delirium (eg, past history of emergence delirium or alcohol abuse) (table 1). (See 'Alpha-2 receptor agonists' above.)

  1. Mariano ER, Dickerson DM, Szokol JW, et al. A multisociety organizational consensus process to define guiding principles for acute perioperative pain management. Reg Anesth Pain Med 2022; 47:118.
  2. Pillai Riddell RR, Craig KD. Time-contingent schedules for postoperative analgesia: a review of the literature. J Pain 2003; 4:169.
  3. McDaid C, Maund E, Rice S, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess 2010; 14:1.
  4. Liang L, Cai Y, Li A, Ma C. The efficiency of intravenous acetaminophen for pain control following total knee and hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e8586.
  5. Subramaniam K, Esper SA, Mallikarjun K, et al. The Effect of Scheduled Intravenous Acetaminophen in an Enhanced Recovery Protocol Pathway in Patients Undergoing Major Abdominal Procedures: A Prospective, Randomized, and Placebo-Controlled Clinical Trial. Pain Med 2022; 23:10.
  6. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg 2010; 110:1170.
  7. Thybo KH, Hägi-Pedersen D, Dahl JB, et al. Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty: The PANSAID Randomized Clinical Trial. JAMA 2019; 321:562.
  8. Jibril F, Sharaby S, Mohamed A, Wilby KJ. Intravenous versus Oral Acetaminophen for Pain: Systematic Review of Current Evidence to Support Clinical Decision-Making. Can J Hosp Pharm 2015; 68:238.
  9. Fenlon S, Collyer J, Giles J, et al. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior? Br J Anaesth 2013; 110:432.
  10. Plunkett A, Haley C, McCoart A, et al. A Preliminary Examination of the Comparative Efficacy of Intravenous vs Oral Acetaminophen in the Treatment of Perioperative Pain. Pain Med 2017; 18:2466.
  11. Hickman SR, Mathieson KM, Bradford LM, et al. Randomized trial of oral versus intravenous acetaminophen for postoperative pain control. Am J Health Syst Pharm 2018; 75:367.
  12. Wasserman I, Poeran J, Zubizarreta N, et al. Impact of Intravenous Acetaminophen on Perioperative Opioid Utilization and Outcomes in Open Colectomies: A Claims Database Analysis. Anesthesiology 2018; 129:77.
  13. Wilson SH, Wolf BJ, Robinson SM, et al. Intravenous vs Oral Acetaminophen for Analgesia After Cesarean Delivery: A Randomized Trial. Pain Med 2019; 20:1584.
  14. Westrich GH, Birch GA, Muskat AR, et al. Intravenous vs Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: A Randomized, Blinded Trial. J Arthroplasty 2019; 34:S215.
  15. Patel A, Pai B H P, Diskina D, et al. Comparison of clinical outcomes of acetaminophen IV vs PO in the peri-operative setting for laparoscopic inguinal hernia repair surgeries: A triple-blinded, randomized controlled trial. J Clin Anesth 2020; 61:109628.
  16. Mallama M, Valencia A, Rijs K, et al. A systematic review and trial sequential analysis of intravenous vs. oral peri-operative paracetamol. Anaesthesia 2021; 76:270.
  17. Politi JR, Davis RL 2nd, Matrka AK. Randomized Prospective Trial Comparing the Use of Intravenous versus Oral Acetaminophen in Total Joint Arthroplasty. J Arthroplasty 2017; 32:1125.
  18. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis 2016; 75:552.
  19. Bikhazi GB, Snabes MC, Bajwa ZH, et al. A clinical trial demonstrates the analgesic activity of intravenous parecoxib sodium compared with ketorolac or morphine after gynecologic surgery with laparotomy. Am J Obstet Gynecol 2004; 191:1183.
  20. Ng A, Temple A, Smith G, Emembolu J. Early analgesic effects of parecoxib versus ketorolac following laparoscopic sterilization: a randomized controlled trial. Br J Anaesth 2004; 92:846.
  21. Barton SF, Langeland FF, Snabes MC, et al. Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparotomy surgery. Anesthesiology 2002; 97:306.
  22. Malan TP Jr, Gordon S, Hubbard R, Snabes M. The cyclooxygenase-2-specific inhibitor parecoxib sodium is as effective as 12 mg of morphine administered intramuscularly for treating pain after gynecologic laparotomy surgery. Anesth Analg 2005; 100:454.
  23. Doleman B, Leonardi-Bee J, Heinink TP, et al. Pre-emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery. Cochrane Database Syst Rev 2021; 6:CD012978.
  24. Bongiovanni T, Lancaster E, Ledesma Y, et al. Systematic Review and Meta-Analysis of the Association Between Non-Steroidal Anti-Inflammatory Drugs and Operative Bleeding in the Perioperative Period. J Am Coll Surg 2021; 232:765.
  25. Varrassi G, Marinangeli F, Agrò F, et al. A double-blinded evaluation of propacetamol versus ketorolac in combination with patient-controlled analgesia morphine: analgesic efficacy and tolerability after gynecologic surgery. Anesth Analg 1999; 88:611.
  26. O'Hanlon JJ, Beers H, Huss BK, Milligan KR. A comparison of the effect of intramuscular diclofenac, ketorolac or piroxicam on post-operative pain following laparoscopy. Eur J Anaesthesiol 1996; 13:404.
  27. Mixter CG 3rd, Meeker LD, Gavin TJ. Preemptive pain control in patients having laparoscopic hernia repair: a comparison of ketorolac and ibuprofen. Arch Surg 1998; 133:432.
  28. Memtsoudis SG, Poeran J, Zubizarreta N, et al. Association of Multimodal Pain Management Strategies with Perioperative Outcomes and Resource Utilization: A Population-based Study. Anesthesiology 2018; 128:891.
  29. Dahl JB, Nielsen RV, Wetterslev J, et al. Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review. Acta Anaesthesiol Scand 2014; 58:1165.
  30. McNicol ED, Ferguson MC, Schumann R. Single-dose intravenous diclofenac for acute postoperative pain in adults. Cochrane Database Syst Rev 2018; 8:CD012498.
  31. Gaskell H, Derry S, Wiffen PJ, Moore RA. Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults. Cochrane Database Syst Rev 2017; 5:CD007355.
  32. McNicol ED, Ferguson MC, Schumann R. Single-dose intravenous ketorolac for acute postoperative pain in adults. Cochrane Database Syst Rev 2021; 5:CD013263.
  33. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain 2016; 17:131.
  34. Guidelines published by Scientific Societies covering regional anesthesia and pain therapy. The European Society of Regional Anaesthesia & Pain Therapy. Available at: https://esraeurope.org/guidelines/?tab=2 (Accessed on September 02, 2022).
  35. Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 2010; 49:661.
  36. Alles SRA, Cain SM, Snutch TP. Pregabalin as a Pain Therapeutic: Beyond Calcium Channels. Front Cell Neurosci 2020; 14:83.
  37. Verret M, Lauzier F, Zarychanski R, et al. Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. Anesthesiology 2020; 133:265.
  38. Fabritius ML, Geisler A, Petersen PL, et al. Gabapentin for post-operative pain management - a systematic review with meta-analyses and trial sequential analyses. Acta Anaesthesiol Scand 2016; 60:1188.
  39. Fabritius ML, Strøm C, Koyuncu S, et al. Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses. Br J Anaesth 2017; 119:775.
  40. Bykov K, Bateman BT, Franklin JM, et al. Association of Gabapentinoids With the Risk of Opioid-Related Adverse Events in Surgical Patients in the United States. JAMA Netw Open 2020; 3:e2031647.
  41. Cozowicz C, Bekeris J, Poeran J, et al. Multimodal Pain Management and Postoperative Outcomes in Lumbar Spine Fusion Surgery: A Population-based Cohort Study. Spine (Phila Pa 1976) 2020; 45:580.
  42. Foo I, Macfarlane AJR, Srivastava D, et al. The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety. Anaesthesia 2021; 76:238.
  43. Kim KT, Cho DC, Sung JK, et al. Intraoperative systemic infusion of lidocaine reduces postoperative pain after lumbar surgery: a double-blinded, randomized, placebo-controlled clinical trial. Spine J 2014; 14:1559.
  44. Farag E, Ghobrial M, Sessler DI, et al. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery. Anesthesiology 2013; 119:932.
  45. Weibel S, Jelting Y, Pace NL, et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database Syst Rev 2018; 6:CD009642.
  46. Olkkola KT, Isohanni MH, Hamunen K, Neuvonen PJ. The effect of erythromycin and fluvoxamine on the pharmacokinetics of intravenous lidocaine. Anesth Analg 2005; 100:1352.
  47. Daykin H. The efficacy and safety of intravenous lidocaine for analgesia in the older adult: a literature review. Br J Pain 2017; 11:23.
  48. Khan JS, Yousuf M, Victor JC, et al. An estimation for an appropriate end time for an intraoperative intravenous lidocaine infusion in bowel surgery: a comparative meta-analysis. J Clin Anesth 2016; 28:95.
  49. Weibel S, Jokinen J, Pace NL, et al. Efficacy and safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic review with trial sequential analysis. Br J Anaesth 2016; 116:770.
  50. Ghimire A, Subedi A, Bhattarai B, Sah BP. The effect of intraoperative lidocaine infusion on opioid consumption and pain after totally extraperitoneal laparoscopic inguinal hernioplasty: a randomized controlled trial. BMC Anesthesiol 2020; 20:137.
  51. Rollins KE, Javanmard-Emamghissi H, Scott MJ, Lobo DN. The impact of peri-operative intravenous lidocaine on postoperative outcome after elective colorectal surgery: A meta-analysis of randomised controlled trials. Eur J Anaesthesiol 2020; 37:659.
  52. Wallon G, Erbacher J, Omar E, et al. Effect of intravenous lidocaine on pain after head and neck cancer surgery (ELICO trial): A randomised controlled trial. Eur J Anaesthesiol 2022; 39:735.
  53. Ortiz MP, Godoy MC, Schlosser RS, et al. Effect of endovenous lidocaine on analgesia and serum cytokines: double-blinded and randomized trial. J Clin Anesth 2016; 35:70.
  54. Roos JC, Dunning AJ. Effects of lidocaine on impulse formation and conduction defects in man. Am Heart J 1975; 89:686.
  55. Kunkel F, Rowland M, Scheinman MM. The electrophysiologic effects of lidocaine in patients with intraventricular conduction defects. Circulation 1974; 49:894.
  56. Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med 2018; 43:456.
  57. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth 2011; 58:911.
  58. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med 2018; 43:521.
  59. Avidan MS, Maybrier HR, Abdallah AB, et al. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet 2017; 390:267.
  60. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology 2010; 113:639.
  61. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol 1983; 79:565.
  62. Smith DJ, Perrotti JM, Mansell AL, Monroe PJ. Ketamine analgesia is not related to an opiate action in the periaqueductal gray region of the rat brain. Pain 1985; 21:253.
  63. Seeman P, Ko F, Tallerico T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry 2005; 10:877.
  64. Ketamine – More mechanisms of action than just NMDA blockade. Trends in Anaesthesia and Critical Care 2014; 4:76.
  65. Murphy GS, Avram MJ, Greenberg SB, et al. Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients: A Randomized, Double-blind, Placebo-controlled Trial. Anesthesiology 2021; 134:697.
  66. Mathiesen O, Dahl B, Thomsen BA, et al. A comprehensive multimodal pain treatment reduces opioid consumption after multilevel spine surgery. Eur Spine J 2013; 22:2089.
  67. Maheshwari K, Avitsian R, Sessler DI, et al. Multimodal Analgesic Regimen for Spine Surgery: A Randomized Placebo-controlled Trial. Anesthesiology 2020; 132:992.
  68. Bauchat JR, Higgins N, Wojciechowski KG, et al. Low-dose ketamine with multimodal postcesarean delivery analgesia: a randomized controlled trial. Int J Obstet Anesth 2011; 20:3.
  69. Pendi A, Field R, Farhan SD, et al. Perioperative Ketamine for Analgesia in Spine Surgery: A Meta-analysis of Randomized Controlled Trials. Spine (Phila Pa 1976) 2018; 43:E299.
  70. McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain. Acta Anaesthesiol Scand 2014; 58:1199.
  71. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev 2006; :CD004603.
  72. Waldron NH, Jones CA, Gan TJ, et al. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth 2013; 110:191.
  73. Liang S, Xing M, Jiang S, Zou W. Effect of Intravenous Dexamethasone on Postoperative Pain in Patients Undergoing Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. Pain Physician 2022; 25:E169.
  74. De Oliveira GS Jr, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology 2011; 115:575.
  75. Lunn TH, Kehlet H. Perioperative glucocorticoids in hip and knee surgery - benefit vs. harm? A review of randomized clinical trials. Acta Anaesthesiol Scand 2013; 57:823.
  76. Heesen M, Rijs K, Hilber N, et al. Effect of intravenous dexamethasone on postoperative pain after spinal anaesthesia - a systematic review with meta-analysis and trial sequential analysis. Anaesthesia 2019; 74:1047.
  77. Sanchez Munoz MC, De Kock M, Forget P. What is the place of clonidine in anesthesia? Systematic review and meta-analyses of randomized controlled trials. J Clin Anesth 2017; 38:140.
  78. Demiri M, Antunes T, Fletcher D, Martinez V. Perioperative adverse events attributed to α2-adrenoceptor agonists in patients not at risk of cardiovascular events: systematic review and meta-analysis. Br J Anaesth 2019; 123:795.
  79. Virtanen R, Savola JM, Saano V, Nyman L. Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist. Eur J Pharmacol 1988; 150:9.
  80. Tseng WC, Lin WL, Lai HC, et al. Adjunctive dexmedetomidine infusion in open living donor hepatectomy: A way to enhance postoperative analgesia and recovery. Int J Clin Pract 2021; 75:e14002.
  81. Wang K, Wu M, Xu J, et al. Effects of dexmedetomidine on perioperative stress, inflammation, and immune function: systematic review and meta-analysis. Br J Anaesth 2019; 123:777.
  82. Duan X, Coburn M, Rossaint R, et al. Efficacy of perioperative dexmedetomidine on postoperative delirium: systematic review and meta-analysis with trial sequential analysis of randomised controlled trials. Br J Anaesth 2018; 121:384.
  83. Karam JA, Schwenk ES, Parvizi J. An Update on Multimodal Pain Management After Total Joint Arthroplasty. J Bone Joint Surg Am 2021; 103:1652.
  84. Trabulsi EJ, Patel J, Viscusi ER, et al. Preemptive multimodal pain regimen reduces opioid analgesia for patients undergoing robotic-assisted laparoscopic radical prostatectomy. Urology 2010; 76:1122.
  85. Kim SI, Ha KY, Oh IS. Preemptive multimodal analgesia for postoperative pain management after lumbar fusion surgery: a randomized controlled trial. Eur Spine J 2016; 25:1614.
  86. Harvin JA, Albarado R, Truong VTT, et al. Multi-Modal Analgesic Strategy for Trauma: A Pragmatic Randomized Clinical Trial. J Am Coll Surg 2021; 232:241.
  87. Rasmussen ML, Mathiesen O, Dierking G, et al. Multimodal analgesia with gabapentin, ketamine and dexamethasone in combination with paracetamol and ketorolac after hip arthroplasty: a preliminary study. Eur J Anaesthesiol 2010; 27:324.
Topic 133187 Version 7.0

References