Version May 2024
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 in hospitalized patients, 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 "Approach to the management of acute pain in adults" and "Use of opioids for postoperative pain control".)
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. (See "Approach to the management of acute pain in adults", section on 'Options for managing postoperative analgesia'.)
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).
●For all patients without contraindications, we suggest acetaminophen and nonsteroidal anti-inflammatory drugs.
●We suggest using gabapentinoids for most patients <75 years of age who undergo moderately or severely painful surgery, and who have no risk factors for respiratory depression (eg, older patients, patients with obstructive sleep apnea). (See 'Gabapentinoids' below.)
●We suggest 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).
●We suggest using ketamine for postoperative analgesia for patients who undergo moderately to severely painful surgery and who are at high risk for severe postoperative pain (eg, patients who are opioid tolerant or those with opioid use disorder). Ketamine can be considered for such patients who have moderate to severe nonsurgical pain as well.
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 for 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.
●Renal and hepatic impairment
•Patients with severe renal insufficiency (creatinine clearance ≤30 mL/min) may receive the usual doses, but not more often than once every six hours.
•Avoid use of acetaminophen in patients with alcoholic hepatitis, severe hepatic impairment, or severe active liver disease.
•Use acetaminophen cautiously in patients with mild to moderate hepatic impairment, (eg, limit to maximum 3g per day).
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 may be the most effective analgesics used as part of multimodal analgesia. (See 'Efficacy' below.)
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]. One observational study of patients with low back pain or temporomandibular disorder from the United Kingdom Biobank project found an association between the use of NSAIDs and the development of chronic pain, along with genetic analysis suggesting a protective effect of inflammation against the development of chronic pain [19]. Further study is required before recommending a change in practice with respect to the use of NSAIDs for acute pain. (See "Chronic postsurgical pain: Incidence, risk factors, and potential risk reduction", section on 'Analgesics and adjuncts'.)
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.
●Topical – Topical NSAIDs penetrate local tissues in the area of application but have limited systemic absorption and therefore fewer side effects and drug interactions. A topical NSAID may be appropriate for sprains or muscle strain in outpatients, particularly in patients who are at increased risk of side effects from systemic NSAIDs.
In the United States, the only available topical NSAID is diclofenac, which is available without a prescription. A topical product containing a combination of diclofenac and lidocaine is also available, only by prescription. Topical ibuprofen and ketoprofen may be available in other countries.
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 [20-23], 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 [24]. 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 [25]. (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 (table 1):
•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
•Preoperative − 600 to 800 mg orally or IV
•Postoperative − 600 to 800 mg orally or IV every 6 to 8 hours until discharge
•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 IV every 6 hours, lower doses for patients <50 kg or age ≥65 years, maximum 5 days
●Diclofenac (topical)
•Patch 1.3% - one patch applied once or twice daily
•Gel 1% - Up to 4 g to affected area up to four times daily, maximum dose per area 16 g per day, maximum total body dose 32 g per day
Efficacy — Systemic NSAIDs may be the most effective analgesic agents in multimodal perioperative protocols [20,26-28].
Examples of relevant studies of the use of systemic NSAIDs 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 [29].
●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 [30].
●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 [31].
●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 [32]. 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.
Randomized trials have found that topical NSAIDs are effective for sprains, strains, and overuse injury, particularly with the use of diclofenac gel. As an example, in a meta-analysis of 10 randomized trials (2050 patients) of patients with sprains, strains, or contusions, topical diclofenac increased the incidence of effective pain relief compared with placebo (74 versus 47 percent, risk ratio 1.6, 95% CI 1.5-1.7), without a difference in adverse effects [33]. There was substantial clinical and statistical heterogeneity in the included studies.
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 [34]. 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 [31].
●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 [25]. Most included studies evaluated ketorolac, diclofenac, ibuprofen, celecoxib, or ketoprofen.
Gabapentinoids — Pregabalin and gabapentin are the gabapentinoids used for perioperative analgesia. We suggest using gabapentinoids for most patients <75 years of age who undergo moderately or severely painful surgery, and who have no risk factors for respiratory depression (eg, older patients, patients with obstructive sleep apnea). However, 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 [35], but some more recent guidelines no longer recommend routine use [36]. (See 'Efficacy and adverse effects' below.)
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'.)
Gabapentin versus pregabalin — Gabapentin and pregabalin are probably similarly effective for perioperative analgesia, though there are some differences between the drugs. The author prefers to use pregabalin for its quicker onset of action. 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.
●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 [37].
●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. It is common practice to administer a preoperative loading dose that is greater than the maintenance dose, particularly for very painful surgery, although little evidence exists to support this. One meta-analysis of randomized trials of perioperative gabapentin did not find a consistent association between dose and clinical efficacy, while also noting that efficacy was similar with pre- and postoperative administration [38]. Practice regarding the use of a loading dose varies among UpToDate contributors.
•Preoperative − 75 to 150 mg orally
•Postoperative − 75 mg orally every 12 hours until hospital discharge
•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 [39]. 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) [40]. 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 trials 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) [41]. 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 [42]. 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 [43,44]. 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 [43]. Patients at higher risk of respiratory depression may require continuous respiratory monitoring if gabapentinoids are used along with opioids.
Intravenous lidocaine — We suggest IV lidocaine for patients who undergo thoracic or lumbar spine surgery or open abdominal surgery when continuous regional analgesia (eg, epidural or continuous peripheral nerve block) is not used (contraindicated, refused, or failed). The benefits of IV lidocaine may be relatively short-lived and optimal doses have not been established. However, IV lidocaine is generally well tolerated when administered as described here, and may slightly reduce pain and opioid consumption. (See 'Efficacy' below.)
Dosing and administration — The optimal dose and dose regimen for IV lidocaine for perioperative pain have not been established [45]. We use lidocaine doses that were effective in studies of lidocaine administration during spine surgery [46,47], and use ideal body weight (IBW) to minimize the risk of toxicity. Reported infusion doses range from 1 to 5 mg/kg/hour IV [48]. Because lidocaine is metabolized by the cytochrome P450 (CYP450) system [49], 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 [50]). 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 [51].
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 [45]:
●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 [46-48,52-55]. The mechanism of action of IV lidocaine when used for perioperative analgesia is unknown, but likely involves its anti-inflammatory properties [56].
●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 [48]. Compared with placebo, lidocaine resulted in a small, likely clinically unimportant reduction in pain scores in the first four hours after surgery (mean difference – 0.5/10). 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 [52], 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) [53].
●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 [54]. 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 [46,47].
Adverse effects — IV lidocaine is generally well tolerated. Toxicity relates to the total dose, speed and duration of infusion [45]. 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 [57,58]. 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 [48].
TOPICAL LIDOCAINE — Topical lidocaine may be used for superficial acute skin pain, and is widely available, low cost, and safe. Transdermal lidocaine may have modest benefits when used for superficial postoperative pain, primarily in outpatients. A systematic review of the literature on the use of topical lidocaine for perioperative pain found seven randomized trials including patients who had various types of surgery [59]. Transdermal lidocaine modestly reduced postoperative pain associated with laparoscopy trochar or cannula insertion sites, without improving patient function or reducing opioid consumption.
Topical lidocaine is available in a variety of preparations, including spray, solution, cream, gel, and patch. For postoperative pain a 3.5, 4, or 5% patch is most commonly used, applied at intervals that vary with the manufacturer.
Ketamine — We suggest using ketamine for postoperative analgesia for patients who undergo moderately to severely painful surgery and who are at high risk for severe postoperative pain (eg, patients who are opioid tolerant or those with opioid use disorder). Patients who have severe nonsurgical acute pain may also be good candidates for ketamine. Patients with obstructive sleep apnea may also benefit, since they are at higher risk for respiratory events with opioids.
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.
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 [60].
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 [61].
●Intraoperative − Ketamine 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) [62]. The benefit of an isolated intraoperative ketamine bolus without an infusion is likely low and therefore an infusion should be strongly considered [63].
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 or desired, there may still be benefit to intraoperative administration alone, or to small ketamine boluses (ie, 10 mg IV) in the PACU.
•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 [64].
•In a single institution observational study of the use of ketamine boluses in the post anesthesia care unit (PACU) for rescue analgesia for pain inadequately controlled by IV morphine, ketamine reduced pain scores by a mean of 2.7/10 at 30 minutes after administration [65]. Ketamine was administered as boluses of 10 mg IV, repeated as needed up to 0.25 mg/kg.
●Emergency department – Low dose ketamine (ie, 0.1 to 0.6 mg/kg IV) may be used for acute pain in the emergency department (ED), as an alternative or in addition to opioids [66-69]. Optimal doses have not been determined, however doses towards the lower end of this range may be sufficient for analgesia and may reduce side effects.
•In a single institution randomized trial of 98 patients who received IV ketamine for analgesia in the ED, analgesic effects and adverse effects were similar in patients who received 0.15 mg/kg versus 0.3 mg/kg IV [67]. The bolus of ketamine was administered over 15 minutes.
•In a multicenter retrospective study of approximately 380 patients who received ketamine in the ED for analgesia not as part of procedural sedation, analgesic efficacy and side effects were similar in patients who received < 0.3 mg/kg IV compared with those who received ≥ 0.3 mg/kg IV [70].
Use of ketamine for analgesia during procedural sedation in the ED is discussed separately. (See "Procedural sedation in adults in the emergency department: Medication selection, dosing, and discharge criteria", section on 'Ketamine'.)
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 Pain Medicine, AAPM, and ASA [60] 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 [60]. 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 [62,71-74]. 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 [64,75,76], others have shown no benefit [63,77,78].
●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 [61]. 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 [79].
●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 [63]. 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 [80], 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 [61,81]. (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, 8 to 10 mg for patients who undergo total joint arthroplasty or spinal fusion surgery, for both analgesia and anti-emetic effects. 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.)
Dexamethasone and methylprednisolone are the most commonly studied glucocorticoids [82]; dexamethasone is probably the most widely used.
Dosing — Higher doses of dexamethasone may be required for analgesia than for prevention of postoperative nausea and vomiting (PONV) [83]. 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 requirements [84,85].
Efficacy and adverse effects — Dexamethasone can improve postoperative pain and generally has few adverse effects. Studies have shown that the analgesic benefit is small [86].
●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) [87].
●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 [82].
●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 [84].
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 [88].
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 [89].
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 [88]. 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 [90], 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 [91].
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 [92], 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 [93]. 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 [89]. 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.
Skeletal muscle relaxants — The non-benzodiazepine muscle relaxants (cyclobenzaprine, baclofen, tizanidine) are a group of medications that may be used as analgesic adjuncts for patients with presumed muscle spasm contributing to their overall pain. In the perioperative period they may be administered for patients who undergo major spine, abdominal, pelvic and extremity surgery, and they are part of some enhanced recovery after surgery (ERAS) protocols for spine surgery.
●Doses – Optimal doses for use in acute pain states have not been determined. The following are based on efficacy for patients with acute back pain.
•Cyclobenzaprine – 5 to 10 mg orally every 8 hours as needed
•Baclofen – 5 to 10 mg orally every 8 hours as needed
•Tizanidine – 2 to 4 mg orally every 8 to 12 hours as needed; may titrate to as high as 8 mg orally per dose, maximum 24 mg per day
•Methocarbamol – 1.5 g orally every 6 to 8 hours as needed, or 1 g IV every 8 hours, both for up to 3 days
●Efficacy – There is limited literature on the efficacy of skeletal muscle relaxants for acute pain. Two randomized trials found reduction in postoperative pain and opioid consumption with the use of tizanidine [94,95]. Efficacy for acute back pain is discussed separately. (See "Treatment of acute low back pain", section on 'Second-line therapy'.)
●Adverse effects – The primary side effects of skeletal muscle relaxants are sedation and dizziness. Thus, these medications should be used with caution in patients who receive opioids or other sedating medications, and in older adults.
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 [96-99].
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 [100]. 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 and "Approach to the management of acute pain in adults", section on 'Creating a plan for analgesia'.)
●For all patients – We suggest acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) for all patients without contraindications who have postoperative pain or nonsurgical acute pain (Grade 2C).
•Acetaminophen – 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
-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.)
●Patients who have moderate or severe pain
•Gabapentinoids – We suggest using gabapentinoids for most patients <75 years of age who undergo moderately or severely painful surgery, and who have no risk factors for respiratory depression (eg, older patients, patients with obstructive sleep apnea) (Grade 2C).
-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).
-If used in older patients after weighing risks and benefits compared with alternatives, we reduce the doses.
-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 suggest IV lidocaine for patients who undergo thoracic or lumbar spine surgery or open abdominal surgery when continuous regional analgesia (eg, epidural or continuous peripheral nerve block) is not used (Grade 2C) (table 1). The beneficial effects of IV lidocaine have not been proven and the optimal dose and regimen have not been established. We usually 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 suggest using ketamine for postoperative analgesia for patients at high risk for severe postoperative pain (eg, patients who are opioid tolerant or those with opioid use disorder) and those who undergo surgery expected to be moderately to severely painful. Those who have severe nonsurgical acute pain may also be good candidates. Patients with obstructive sleep apnea may also benefit, since they are at higher risk for respiratory events with opioids.
-We rarely administer ketamine to older adult patients or patients with less severe pain, as adverse effects may outweigh the analgesic benefits.
-We rarely administer ketamine if regional anesthesia is being used for postoperative analgesia, unless the patient is opioid tolerant.
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.)
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