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Evidence for the Efficacy of Systemic Opioid-Sparing Analgesics in Pediatric Surgical Populations: A Systematic Review

Zhu, Alyssa MD*; Benzon, Hubert A. MD, MPH; Anderson, T. Anthony MD, PhD*

doi: 10.1213/ANE.0000000000002434
Pediatric Anesthesiology: Systematic Review Article

While a large number of studies has examined the efficacy of opioid-sparing analgesics in adult surgical populations, fewer studies are available to guide postoperative pain treatment in pediatric patients. We systematically reviewed available publications on the use of systemic nonopioid agents for postoperative analgesia in pediatric surgical populations. A comprehensive literature search identified meta-analyses and randomized controlled trials (RCTs) assessing the effects of systemic, nonopioid agents on postoperative narcotic requirements or pain scores in pediatric surgical populations. If a meta-analysis was located, we summarized its results and any RCTs published after it. We located and reviewed 11 acetaminophen RCTs, 1 nonsteroidal anti-inflammatory drug (NSAID) meta-analysis, 2 NSAID RCTs, 1 dexamethasone meta-analysis, 3 dexamethasone RCTs, 2 ketamine meta-analyses, 5 ketamine RCTs, 2 gabapentin RCTs, 1 clonidine meta-analysis, 3 magnesium RCTs, 2 dexmedetomidine meta-analyses, and 1 dextromethorphan RCT. No meta-analyses or RCTs were found assessing the perioperative efficacy of intravenous lidocaine, amantadine, pregabalin, esmolol, or caffeine in pediatric surgical patients. The available evidence is limited, but suggests that perioperative acetaminophen, NSAIDs, dexamethasone, ketamine, clonidine, and dexmedetomidine may decrease postoperative pain and opioid consumption in some pediatric surgical populations. Not enough, or no, data exist from which to draw conclusions on the perioperative use of gabapentin, magnesium, dextromethorphan, lidocaine, amantadine, pregabalin, esmolol, and caffeine in pediatric surgical patients. Further pharmacokinetic and pharmacodynamics studies to establish both the clinical benefit and efficacy of nonopioid analgesia in pediatric populations are needed.

From the *Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Pediatric Anesthesiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

T. Anthony Anderson is currently affiliated with the Department of Anesthesiology, Perioperative and Pain Medicine, Lucile Packard Children's Hospital Stanford, Stanford University School of Medicine in Stanford, CA.

Accepted for publication July 24, 2017.

Funding: Support was provided solely from institutional and/or departmental sources of the Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, Boston, MA, and the Ann & Robert H. Lurie Children’s Hospital of Chicago Department of Pediatric Anesthesiology, Chicago, IL.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to T. Anthony Anderson, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Lucile Packard Children's Hospital Stanford, Stanford University School of Medicine, 300 Pasteur Dr, H3590A MC5640, Stanford, CA 94305. Address e-mail to tanders0@stanford.edu.

Perioperative analgesia commonly includes both opioid and nonopioid agents. Opioids have serious risks raising concern for their postoperative use in pediatric patients.1 In adults, early postoperative opioid prescription is associated with chronic opioid use.2 Up to 8.2% of opioid-naive patients may become chronic opioid users postsurgery.2–4 While no study has examined this risk in children, clinicians should reduce pediatric and adult patient exposure to opioids. The authors of one adult study conclude, “long-term postoperative analgesic use may best be addressed by preventing its initiation.”2 Numerous studies have examined opioid-sparing analgesic efficacy in adult surgical populations; fewer studies are available to guide pediatric postoperative pain treatment. We systematically reviewed the available literature for evidence of the impact of 14 systemic nonopioid agents on pediatric postoperative analgesia.

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METHODS

Literature Search

Figure. F

Figure. F

PubMed, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched using the following terms: “pediatric postoperative pain,” “acute pediatric pain,” “pediatric analgesics,” plus the drug of interest (acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDS], dexamethasone, ketamine, gabapentin, clonidine, magnesium, dexmedetomidine, dextromethorphan, lidocaine, amantadine, pregabalin, esmolol, and caffeine). There was no date limitation to the literature search. The last search was conducted on February 28, 2016. If a published meta-analysis was located assessing a study drug of interest, our literature search focused on articles published after the article’s last search date (Figure).

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Inclusion and Exclusion Criteria

Inclusion criteria were meta-analyses and prospective, randomized, controlled trials that evaluated pre- or intraoperative use of single, systemic, nonopioid medication in a pediatric surgical population (age ≤18 years) undergoing general anesthesia, used an opioid or placebo control, reported either primary outcome of interest, and published in English in a peer-reviewed journal. Primary outcomes of interest were postoperative analgesic requirements and pain scores. Secondary outcomes of interest included time to first analgesic use, postoperative nausea and vomiting (PONV), sedation, respiratory depression, emergence delirium, psychotomimetic effects, and hemodynamic changes. Excluded trials did not meet the inclusion criteria, compared a medication of interest to regional anesthesia or local anesthetic infiltration, or lacked a complete study description. Given the scarcity of evidence for the efficacy of many of these agents for postoperative pain in pediatric patients, we sought to be as inclusive as possible so that it might be possible to draw conclusions about the effectiveness of these medications. Thus, studies were included even if they included agents now discouraged from use in pediatric practice (codeine) or withdrawn from the market (rofecoxib).

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Appraisal and Validity Scoring

As suggested by the Cochrane Handbook for Systematic Reviews of Interventions,5 2 authors (A.Z. and T.A.) independently screened the literature, assessed study titles and abstracts for eligibility, and evaluated all studies using either the Consolidated Standards of Reporting Trials (CONSORT) checklist or A Measurement Tool to Assess Systematic Reviews (AMSTAR) instrument. Any differences were settled through discussion until consensus was reached. The methodological quality of included randomized, controlled studies was assessed using the evidence-based CONSORT Statement 25-item checklist, a set of minimum recommendations for randomized trial design and reporting.6 The methodological quality of included meta-analyses was assessed using the validated AMSTAR instrument.7,8 The AMSTAR instrument was developed to evaluate systematic review methodologic quality and consists of an 11-point checklist. The AMSTAR score relates to review quality.7

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Data Extraction

Table 1

Table 1

Table 2

Table 2

Data regarding primary and secondary outcomes of interest, study design, patient characteristics, procedures performed, type and dosages of opioid and nonopioid analgesic agents in the perioperative period, and method and time of agent delivery were recorded (Tables 1 and 2). Only quantitative data from primary end points were included.

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Analysis

A systematic review of the pediatric studies comparing opioid-sparing adjuncts to a control for postoperative pain and/or analgesic reduction was undertaken. Each study was evaluated for significant end point differences between experimental and control groups.

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RESULTS

Eight hundred fifty-six potentially relevant publications were retrieved and screened; 144 were reviewed in detail. One hundred sixteen were excluded, as they did not meet the inclusion criteria. Ultimately, 28 randomized controlled trials (RCTs) and 7 meta-analyses were included (Tables 1 and 2).

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Acetaminophen

Ninety-six studies were located from the initial literature search; 57 RCTs were potentially relevant. Eleven met inclusion criteria. 8 studies included more than one-half, and 3 studies less than half, of the 25 items of the CONSORT checklist.

Children undergoing outpatient surgery received rectal (per rectum [PR]) acetaminophen (20, 40, 60 mg·kg−1) or placebo after induction of general anesthesia.9 Fewer children who received 40 or 60 mg·kg−1 acetaminophen required postoperative morphine then children from the placebo or 20 mg·kg−1 groups (60 mg·kg−1 group: 23%, placebo group: 90%; P < .05). The average number of morphine doses was less in children who received 40 or 60 mg·kg−1 acetaminophen than children who received placebo or 20 mg·kg−1 (60 mg·kg−1 group: 0.2 doses per subject; placebo group: 1.2 doses per subject; P < .05). More subjects in the placebo group (80%) had pain at home than those in the 40 or 60 mg·kg−1 groups (17%–20%; P < .01).

Children undergoing adenotonsillectomy received oral acetaminophen (15 mg·kg−1) or acetaminophen (9.6 mg·kg−1) with codeine (1 mg·kg−1) for 10 days postoperatively.10 There was no difference in the amount of postoperative pain, pain medication use, PONV, or constipation between the groups over the study period.

Children undergoing cleft palate repair received rectal acetaminophen (10, 20, and 40 mg·kg−1) or placebo immediately postinduction.11 Acetaminophen had no effect on pain scores or opioid reduction in the early postoperative period; however, therapeutic plasma levels were not achieved. There were no reported adverse events including bradycardia, respiratory depression, or oxygen desaturation in the postanesthesia care unit (PACU) or emesis within the first 24 hours postoperatively.

Children undergoing tonsillectomy received intravenous (IV) acetaminophen (15 mg·kg−1) or intramuscular meperidine (1 mg·kg−1) intraoperatively.12 In the PACU, those who received acetaminophen had nonstatistically significant objective pain scores higher than those who received meperidine. More patients in the acetaminophen group required rescue morphine than those who received meperidine (7 vs 0 patients; P < .01). There was no significant difference in PONV between groups. Readiness for discharge was significantly shorter in the acetaminophen group. Patients who received meperidine were significantly more sedated on arrival to PACU.

Children undergoing lower abdominal surgery received oral (per os [PO]) ibuprofen (20 mg·kg−1), acetaminophen (35 mg·kg-1), or placebo 2 hours before surgery.13 Postoperative pain intensity did not differ between groups for up to 24 hours, nor analgesic consumption on the hospital floor. Patients in the acetaminophen and ibuprofen groups had significantly reduced agitation in the PACU.

Children undergoing ureteroneocystostomy received IV fentanyl (0.5 µg·kg−1 bolus, 0.25 µg·kg−1·hour−1 infusion, 0.25 µg·kg−1 boluses as needed) or acetaminophen-fentanyl (same fentanyl bolus, infusion, and as needed boluses plus acetaminophen 15 mg·kg−1 bolus, 1.5 mg·kg−1·hour−1 infusion, 1.5 mg·kg−1 boluses as needed) started during surgical closure.14 On postoperative days (POD) 1 and 2, the amount of fentanyl used (µg·kg−1) in the acetaminophen-fentanyl group was reduced compared to the fentanyl group (8.3 ± 3.7 vs 18.1 ± 4.6, P = .021; 7.0 ± 2.4 vs 16.6 ± 5.5; P = .042). Postoperative pain scores were comparable. The fentanyl group had a significantly greater number of patients with vomiting and sedation.14

Children undergoing either scoliosis or spondylolisthesis surgery received IV acetaminophen (30 mg·kg−1) or placebo at the end of surgery, and 2 additional doses at 8-hour intervals.15 On the hospital floor postoperatively, fewer patients had a visual analog scale (VAS) pain score ≥6 and number of hours with a VAS ≥6 in the acetaminophen group (39% and 9%, respectively) versus placebo (72% and 18%, both P < .05). There were no differences in oxycodone consumption, PONV, or adverse effects.

Children undergoing ophthalmic surgery received “high-dose” PR acetaminophen (40 mg·kg−1), “low-dose” PR acetaminophen (20 mg·kg−1), or “no drug” after induction of general anesthesia.16 A total of 63% of the no-drug group, 23% of the low-dose group (P = .0005), and 10% of the high-dose rectal acetaminophen group (P < .0001) required postoperative rescue analgesia during the first 24 hours postoperatively; there was no difference in time to first analgesic use. Observational pain scores were significantly lower (at postoperative hours 2, 5, 6, 8) and the number of patients with a recovery score of 4 was higher in the low- and high-drug groups compared to the no-drug group (P < .05). There were no differences in the need for rescue antiemetic between groups.

Neonates and infants undergoing major noncardiac surgery received IV acetaminophen (30 mg·kg−1·day−1) or morphine for up to 48 hours postoperatively.17 The cumulative postoperative morphine dose (µg·kg−1) in the acetaminophen group was lower than the morphine group (121 vs 357; P < .001). The number of morphine rescue doses, number of patients requiring rescue doses, postoperative pain scores, and the incidence of PONV, ileus, and other morphine-related adverse effects did not differ.

Children undergoing tonsillectomy received IV acetaminophen (15 mg·kg−1), dipyrone (15 mg·kg−1), or placebo after induction of general anesthesia and followed for 6 hours postoperatively.18 There was no difference in pain intensity between groups, but postoperatively the pain relief score was higher at 0.5 (P = .04) and 4 (P = .01) hours in the acetaminophen group and at 6 hours in the acetaminophen (P = .001) and dipyrone (P = .04) groups. At 6 hours, the acetaminophen and dipyrone groups had lower rescue analgesic (meperidine mg·kg−1) requirements than placebo (0.45 vs 0.67, P = .01; 0.48 vs 0.67, P = .03, respectively). There was no difference in PONV, PACU duration, or adverse events.

Children undergoing dental rehabilitation received rectal diclofenac (12.5–25 mg), acetaminophen (100–200 mg), or placebo before extubation.19 Acetaminophen and diclofenac resulted in lower mean Wong and Baker faces pain scores lower than placebo (3.4, 2.5, 7.4, respectively; P < .001). Postoperative opioid requirements were not reported.

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Nonsteroidal Anti-inflammatory Drugs

A meta-analysis on the perioperative use of NSAIDs in children, published in February 2012, with a last literature search of April 2011, was located. Seventy-four studies published after April 2011 were located from the initial literature search; 10 RCTs were potentially relevant. Two met inclusion criteria. Both studies included more than one-half of the 25 items of the CONSORT checklist. The meta-analysis received an AMSTAR score of 8.

In the meta-analysis, the effects of perioperative NSAIDs on postoperative pain parameters were assessed from 27 RCTs including children undergoing adenotonsillectomy, orthopedic, urological, thoracic, and general surgeries.20 NSAIDs in these studies included ketoprofen, ketorolac, rofecoxib, ibuprofen, naproxen, indomethacin, and diclofenac; the routes of administration included oral, rectal, IV, and intramuscular. NSAID use decreased PACU opioid consumption (standardized mean difference [SMD] −0.66), PACU pain intensity (SMD −0.85), and 24-hour opioid consumption (SMD −0.83). No difference was noted on pain intensity during the first POD. The use of NSAIDs significantly decreased PONV incidence during the first 24 hours postoperatively, but not PONV incidence in the PACU. There was no significant difference in the incidence of postoperative urinary retention or pruritus between groups.

Children undergoing adenotonsillectomy received a single dose of IV ibuprofen (10 µg·kg−1) or placebo on anesthesia induction.21 Ibuprofen reduced PACU rescue fentanyl (0.5 µg·kg−1) doses (1.6 vs 1.9; P = .021) and quantity of fentanyl (µg·kg−1) used (0.8 vs 0.9; P = .037). The percentage of patients who received more than 1 dose of fentanyl was lower in the ibuprofen group than placebo (42% vs 62%; P = .028). There was no statistically significant difference in pain scores, time to first rescue dose, or percentage of patients who required rescue analgesia, though there was a trend toward lower values in the ibuprofen group. There was no significant difference in adverse effects between groups.

Children undergoing adenotonsillectomy received PO celecoxib (6 mg·kg−1 preoperatively followed by 3 mg·kg−1 twice a day for 5 doses) or placebo.22 Celecoxib use resulted in a significant reduction in pain on POD 0–1 (≥10 mm on a VAS of 0–100 mm; P ≤ .01), a significantly lower acetaminophen consumption on POD 0–2 (78 vs 97 mg·kg−1; P = .03), and a nonsignificant trend toward lower morphine consumption (0.56 vs 0.70 mg·kg−1; P = .06). There was a similar incidence of PONV, diarrhea, dizziness, rash, headache, hospital visits for bleeding, and bleeding requiring surgery in both groups. Parent satisfaction did not differ and functional recovery at POD 7 was similar between groups.

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Dexamethasone

A meta-analysis on the perioperative use of dexamethasone in children, published in February 2006, with a last literature search of July 2005, was located. Seventy-two studies published after July 2005 were located from the initial literature search; 24 RCTs were potentially relevant. Three met inclusion criteria. Two studies included more than one-half, and 1 study less than half, of the 25 items of the CONSORT checklist. The meta-analysis received an AMSTAR score of 8.

In the meta-analysis, the effect of perioperative IV dexamethasone on postoperative pain scores was assessed from 8 RCTs including children undergoing tonsillectomy.23 The authors concluded that single dose of dexamethasone (0.4–1.0 mg·kg−1) resulted in a significant reduction in posttonsillectomy pain on POD 1 compared to placebo (SMD −0.97; P = .01). This study did not assess postoperative analgesic requirements.

Children undergoing adenotonsillectomy received preinduction IV dexamethasone (0.2 mg·kg−1), oral acetaminophen-codeine (20 mg·kg−1), or placebo.24 The study found that postoperative pain scores were not significantly different between the groups. Postoperative opioid requirements were not assessed. There was no significant difference between groups in anesthesia recovery times, PACU duration, or time to extubation. Emergence agitation was similar between subjects in the dexamethasone and acetaminophen-codeine groups but significantly less frequent than placebo.

Children undergoing elective tonsillectomy received IV dexamethasone 0.15 mg·kg−1, dexamethasone 0.5 mg·kg−1, or placebo on induction of general anesthesia.25 While early severe pain did not differ between the groups, the incidence of severe pain on POD 2 was significantly lower in the low-dose (20%) and high-dose (5%) dexamethasone groups compared to placebo (47%; P < .001). There was no difference in pain between the dexamethasone groups. Postoperative opioid requirements were not assessed. Both dexamethasone groups had significantly reduced early (POD ≤1) and late (POD 2) PONV compared to placebo.

Children undergoing tonsillectomy received IV dexamethasone (0.5 mg·kg−1), ketamine (0.5 mg·kg−1), both ketamine and dexamethasone, or placebo 15 minutes before general anesthesia induction.26 PACU observational pain scores were lower for all time points in the ketamine-dexamethasone group, some time points in the dexamethasone group, and no time points in the ketamine group compared to placebo (shown graphically, not quantitated in a table; P < .05). Observational pain scores for 24 hours postoperatively were lower only in the ketamine-dexamethasone group compared to placebo (P < .05). Postoperative analgesic requirements (mg PR acetaminophen) were lower in the ketamine-dexamethasone (0 ± 0), dexamethasone (128 ± 43), and ketamine (116 ± 49) groups compared to placebo (244 ± 51; P < .001). Antiemetic requirements and time to first oral intake were significantly less in all treatment groups compared to placebo. Early and late vomiting were significantly less in the ketamine-dexamethasone group compared to placebo. No complications related to dexamethasone administration occurred.

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Ketamine

Two meta-analyses on the perioperative use of ketamine in children were located. One was published in July 2011, with a last literature search February 2010 and the other was published in June 2014, with a last literature search of February 2013. Thirty-two studies published after February 2013 were located from the initial literature search; 9 RCTs were potentially relevant. Six met inclusion criteria. Five studies included more than one-half, and 1 study less than half, of the 25 items of the CONSORT checklist. One meta-analysis received an AMSTAR score of 7, and the other a score of 8.

In 1 meta-analysis, the effects of perioperative ketamine on postoperative analgesic consumption and pain intensity were assessed from 35 RCTs including children undergoing appendectomy, inguinal hernia repair, adenotonsillectomy, and ambulatory surgeries.27 Ketamine delivery included IV (bolus, intraoperative bolus and infusion, and infusion intraoperatively and postoperatively), topically/locally, and as an adjuvant during caudal analgesia. IV ketamine given either as a bolus or an infusion was associated with a decrease in PACU 2-hour pain scores (SMD −0.45; P = .0003) and analgesic requirements (both opioid and nonopioid; odds ratio 0.46; P = .0008) but not in the early postoperative period (6–24 hours). IV and local ketamine were not associated with PONV or psychotomimetic manifestations.

In another meta-analysis, the effects of perioperative IV and locally injected ketamine on postoperative analgesic consumption and pain were assessed from 24 RCTs including children undergoing tonsillectomy.28 Postoperative pain was decreased in the ketamine group compared to no treatment at 0 (SMD −1.71; P < .0001), 1 (SMD −0.87; P < .0001), and 4 hours (SMD −0.79, P < .0001), but not at 6, 12, and 24 hours. Postoperative analgesic requirements were lower in the ketamine group in the first 24 hours (SMD −1.34; P < .0001) compared to no treatment. There was no difference in postoperative pain or analgesic consumption in the ketamine compared to opioid groups. The incidence of PONV and amount of antiemetics required were both significantly lower in the ketamine group versus no treatment. There was no significant difference in psychotomimetic effects, incidence of sleep pattern changes, or hallucinations.

Children undergoing brief ophthalmic surgery received preoperative IV ketamine (1.0 mg·kg−1 before entering the operating room), intraoperative IV ketamine (0.5 mg·kg1 10 minutes before the end of surgery), or placebo (before entering the operating room).29 Both the 1.0 mg·kg1 (30%) and 0.5 mg·kg1 (20%) ketamine groups had a lower incidence of need for rescue fentanyl in the PACU compared to placebo (75%; P < .05). Both ketamine groups (4.00 ± 2.49 and 2.95 ± 2.43, respectively) had decreased Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) scores compared to control (7.90 ± 2.57; P < .05). There was no significant difference between time to PACU discharge or PONV.

Children undergoing strabismus surgery received IV dexmedetomidine (1 µg·kg1, then 1 µg·kg1·hour1), ketamine (1 mg·kg1, then 1 mg·kg1·hour1), or placebo after mask induction and peripheral IV catheter placement.30 While there were no significant differences in PACU pain scores between groups, CHEOPS scores were lower in the dexmedetomidine and ketamine groups “on the ward” compared to placebo (4; P < .017), with no difference between dexmedetomidine and ketamine groups. While acetaminophen was given as needed to subjects in each group, postoperative analgesic requirements were not reported. Sedation and time to PACU discharge were significantly longer, while emergence delirium was significantly reduced in the dexmedetomidine and ketamine groups compared to placebo. The incidence of postoperative emesis was decreased in the dexmedetomidine group compared to ketamine and placebo groups. No major respiratory events occurred although the incidence of oculocardiac reflex events was significantly higher with placebo than the dexmedetomidine and ketamine groups.

Children undergoing adenotonsillectomy received IV ketamine (0.25 mg·kg1) or placebo during anesthesia induction.31 Subjects who received ketamine had reduced postoperative pain compared to placebo (shown graphically, not quantitated in a table; P < .05). A smaller percentage of patients who received ketamine (36%) required postoperative acetaminophen compared to placebo (75%; P = .004). The incidence of emergence agitation was significantly lower in the ketamine group compared to placebo, while the incidence of PONV was not different between groups.

Children undergoing elective adenotonsillectomy received IV ketamine (0.5 mg·kg1), peritonsillar infiltration of tramadol (2 mg·kg1), both IV ketamine and tramadol infiltration, or placebo intraoperatively before tonsillectomy.32 Mean modified CHEOPS scores were significantly lower in the IV ketamine (4.1 ± 0.6, 1.6 ± 1.1) and combined arms (1.0 ± 2.6, 0.6 ± 1.2) at 60 minutes and 24 hours postoperatively compared to placebo (6.8 ± 1.4, 2.9 ± 1.8; P < .05). The combined ketamine/tramadol arm had the lowest pain scores while peritonsillar infiltration of tramadol had better pain scores than placebo for up to 4 hours postoperatively. The mean dosage of additional analgesic (rectal acetaminophen) was significantly lower in the combined arm (22 mg) compared with placebo (268 mg), IV ketamine (167 mg), or peritonsillar tramadol (246 mg). Patients who had received IV ketamine (with or without peritonsillar tramadol) were more sedated at the time of arrival to the PACU. Parent satisfaction was higher when both ketamine and tramadol (90%) were given compared with the other 3 groups (≤53%). There was no difference in the incidence of PONV and no reports of hallucination, dysphoria, diplopia, or psychological adverse effects.

Children undergoing tonsillectomy with or without adenoidectomy received IV ketamine (0.5 mg·kg1), fentanyl (1 µg·kg1), or placebo 10 minutes before the end of surgery.33 There was no difference in postoperative pain between groups. Those who received ketamine (0.19 ± 0.34) and fentanyl (0.18 ± 0.32) required less fentanyl (µg·kg1) in the PACU than those who received placebo (0.32 ± 0.43; P = .024); there was no significant difference between the fentanyl and ketamine groups. The incidence of emergence agitation was decreased in the ketamine and fentanyl groups compared to placebo with no difference between them. The incidence of PONV was increased in the fentanyl group. No complications occurred during the study period including somnolence, oxygen desaturation, respiratory depression, or psychotomimetic effects.

Children undergoing posterior spinal fusion for scoliosis received IV ketamine (0.5 mg·kg1, then 0.25 mg·kg1·hour1 intraoperatively, then 0.1 mg·kg1·hour1 postoperatively for 72 hours) or placebo beginning before skin incision.34 Although the trial was terminated early due to a smaller than expected effect size, pain scores at rest and when coughing, opioid consumption, and sedation were not different between groups for the first 96 hours after surgery. The incidence of PONV and pruritus was similar in both groups. No respiratory depression, cardiovascular events, or psychotomimetic effects occurred.

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Gabapentin

Forty-seven studies were located from the initial literature search. Ten RCTs were potentially relevant. Two met inclusion criteria. Both studies included more than one-half of the 25 items of the CONSORT checklist.

Children undergoing spinal fusion received PO gabapentin (15 mg·kg1 preoperatively, 5 mg·kg1 3 times per day × 5 days) or placebo.35 Total morphine consumption (mg·kg1·hour1) was lower in the gabapentin group on the day of surgery (0.044 ± 0.017 vs 0.064 ± 0.031; P = .003), POD 1 (0.046 ± 0.016 vs 0.055 ± 0.017; P = .051), and POD 2 (0.036 ± 0.016 vs 0.047 ± 0.019; P = .018) but not significantly different on POD 3–5. Pain scores were lower in the gabapentin group on arrival to the PACU (2.5 ± 2.8 vs 6.0 ± 2.4; P < .001) and the morning after surgery (3.2 ± 2.6 vs 5.0 ± 2.2; P < .05) but not significantly different on PODs 1–5. There were no significant differences in morphine-related side effects; the mean number of ondansetron, diphenhydramine, and diazepam doses was nonsignificantly lower in the gabapentin group.

Children undergoing scoliosis surgery received preoperative single-dose PO gabapentin (600 mg) or placebo. There was no difference in postoperative pain scores or analgesia requirements between groups.36 In addition, there was no difference in the number of side effects including PONV, sedation, and pruritus, or the number of ondansetron or diphenhydramine doses needed. Time to rescue analgesia was the same, as was the persistence of pain at 6 weeks.

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Clonidine

A meta-analysis on the efficacy of clonidine premedication for postoperative analgesia in children published January 2014, with a last literature search December 2012 was located. Fifteen studies published after December 2012 were located from the initial literature search; none was potentially relevant. The meta-analysis received an AMSTAR score of 11.

In the meta-analysis, the effects of perioperative clonidine on postoperative pain parameters were assessed from 11 RCTs in children undergoing adenotonsillectomy, ventriculoperitoneal shunt insertion, orthognathic, ophthalmologic, otologic, urologic, hernia repair, and other minor surgical procedures.37 In the included trials, high-dose (4 μg·kg1) or low-dose (2 μg·kg1) oral clonidine was compared to placebo or no treatment, to midazolam, and to fentanyl. While trial size and trial heterogeneity limit interpretation of clonidine’s effect on postoperative analgesic requirements and pain scores, data suggest that high-dose clonidine premedication, but not low dose, reduces the number of patients who require additional postoperative analgesics (risk ratio [RR] 0.24; P = .00022) and postoperative pain scores (SMD −1.11; P < .00001). The evidence suggests that clonidine may reduce the risk of PONV. Side effects, including significant hypotension, bradycardia, or substantial sedation, were not reported, although prophylactic atropine was used in some studies.

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Magnesium

Fifty-two studies were located from the initial literature search; 12 RCTs were potentially relevant. Three met inclusion criteria. All 3 studies included more than one-half of the 25 items of the CONSORT checklist.

Children with cerebral palsy undergoing orthopedic osteotomy received intraoperative IV magnesium (50 mg·kg1 bolus, 15 mg·kg1·hour1 infusion) or placebo.38 Patients in the magnesium group had decreased cumulative analgesic consumption (shown graphically, not quantitated in a table) at 24 hours (P = .017) and 48 hours (P = .001) postoperatively, but not at 30 minutes or 6 hours. Pain scores were decreased at 30 minutes, 6 hours, 24 hours, and 48 hours postoperatively (P < .05). There were no significant differences in the incidence of PONV or hemodynamic changes.

Children undergoing adenoidectomy and tonsillectomy received IV magnesium (30 mg·kg1 infused at a rate of 2 mL·minute1) or placebo before the end of the operation.39 There was no significant difference in Pain/Discomfort Scale scores up to 90 minutes postoperatively, time to PACU discharge, or side effects between groups. Postoperative analgesic use was not reported.

Children undergoing tonsillectomy received intraoperative IV magnesium (30 mg·kg1 bolus, 10 mg·kg1·hour1 infusion) or placebo.40 There was no statistically or clinically significant difference between the groups’ pain scores, morphine consumption, time to opioid use, pediatric anesthesia emergence delirium scores, parental satisfaction with anesthesia, or number of ibuprofen or acetaminophen-hydrocodone dosages in the first 24 hours postoperatively. No adverse events were observed in any study subjects.

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Dexmedetomidine

Two meta-analyses on the intraoperative use of dexmedetomidine in children were located. One was published in August of 2012 with last literature search July 2011, while the other was published online in February 2016, with a last literature search December 2015. Fifteen studies published after December 2015 were located from the initial literature search; none was potentially relevant. One meta-analysis received an AMSTAR score of 7, and the other a score of 8.

In 1 meta-analysis, the effects of perioperative IV dexmedetomidine on postoperative pain, rescue analgesia, and adverse effects were assessed from 11 RCTs including patients undergoing adenotonsillectomy, otolaryngology procedures, appendectomies, and other outpatient procedures.41 The bolus doses in the included studies ranged from 0.15 to 4.0 µg·kg1 and the continuous intraoperative doses ranged from 0.2 to 0.7 µg·kg1·hour1. Compared to placebo and fentanyl, there was decreased PACU pain (RR, 0.51; P = .004 and RR, 0.49; P = .03, respectively) and opioid consumption (RR, 0.4; P < .00001 and RR, 0.77; P = .05, respectively) in those who received dexmedetomidine intraoperatively. Children who received dexmedetomidine intraoperatively had significantly decreased emergence agitation compared to placebo; there was significantly decreased PONV compared to placebo or opioids. Adverse events were poorly reported.

In another meta-analysis, the effects of intraoperative IV dexmedetomidine on postoperative pain and analgesic consumption were assessed from 14 RCTs including patients undergoing adenotonsillectomy, various ophthalmologic procedures, and other outpatient surgeries.42 The bolus doses in the included studies ranged from 0.3 to 2.0 µg·kg1 and the continuous intraoperative doses ranged from 0.2 to 0.7 µg·kg1·hour1. Intraoperative dexmedetomidine administration either as bolus or continuous administration was associated with an opioid-sparing effect postoperatively (RR, 0.31; P < .0001). In addition, postoperative pain intensity was less in subjects who received dexmedetomidine intraoperatively (SMD −1.18; P < .0001). Subgroup analysis determined that bolus doses ≥0.5 µg·kg1, irrespective of the use of a continuous infusion, decreased postoperative opioid consumption and postoperative pain scores, except after adenotonsillectomy. PONV was not different between dexmedetomidine and placebo.

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Dextromethorphan

One hundred twelve studies were located from the initial literature search. Three were potentially relevant; 1 met inclusion criteria. The study included less than one-half of the 25 items of the CONSORT checklist.

In this study, children undergoing adenotonsillectomy received a single preoperative dose of PO dextromethorphan (1 mg·kg1) or placebo.43 Fewer patients in the dextromethorphan group required postoperative morphine compared to placebo (33% vs 68%; P = .03). The mean total postoperative dose of morphine was also reduced in the dextromethorphan group compared to placebo (0.35 vs 0.94 mg; P = .02). There was no difference in mean doses of oral acetaminophen-codeine used by either group in the PACU or for 24 hours postoperatively. There was no difference in the incidence of PONV or time to which an oral diet was tolerated between groups.

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IV Lidocaine

One hundred forty-nine studies were located from the initial literature search. Eight were potentially relevant; none met inclusion criteria.

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Amantadine

One hundred studies were located from the initial literature search. Four were potentially relevant; none met inclusion criteria.

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Pregabalin

Twenty-seven studies were located from the initial literature search. One was potentially relevant; none met inclusion criteria.

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Esmolol

Forty-five studies were located from the initial literature search. One was potentially relevant; none met inclusion criteria.

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Caffeine

Twenty studies were located from the initial literature search. Five were potentially relevant; none met inclusion criteria.

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DISCUSSION

Current literature supports acetaminophen,44,45 NSAIDS,46,47 dexamethasone,48 ketamine,49 clonidine,50 dexmedetomidine,51 gabapentin,52 magnesium,53 dextromethorphan,54 lidocaine,55,56 amantadine,57,58 pregabalin,59 esmolol,60 and caffeine61 use in adult surgical populations to decrease acute postoperative pain, opioid consumption, and/or opioid-related side effects including ileus, nausea, and vomiting. The evidence for the perioperative efficacy of these agents in children is more limited and was not previously summarized.

The data assembled here suggest the following: (1) Acetaminophen, even a single pre- or intraoperative dose, regardless of the route used, appears to be effective at decreasing postoperative pain and/or opioid consumption after a variety of pediatric surgeries as long as a therapeutic dose is used. (2) Perioperative NSAID use, regardless of type, decreases postoperative pain and/or opioid consumption in pediatric patients after a variety of pediatric surgeries. (3) A single, intraoperative dose of dexamethasone decreases pain measures after tonsillectomy in children. (4) Intraoperative ketamine decreases early postoperative pain and/or opioid consumption in pediatric patients after a variety of minor, outpatient surgeries. (5) Oral clonidine at a dose of 4 μg·kg1 decreases postoperative pain measures in children after a variety of minor surgeries. (6) Intraoperative dexmedetomidine, especially if at least 0.5 µg·kg1 is given, decreases postoperative pain measures in pediatric patients after a variety of ambulatory surgeries. The evidence here suggests that rectal acetaminophen may require a dose of at least 40 mg·kg1 to reach a therapeutic level. IV acetaminophen doses of 15–30 mg·kg1 appear efficacious.

Too few studies exist assessing the use of gabapentin, magnesium, and dextromethorphan for the reduction of postoperative pain and opioid consumption in pediatric patients from which to draw conclusions. Of the 2 published gabapentin studies, both in children undergoing spine surgery, only 1 found a reduction in postoperative pain measures when gabapentin was given perioperatively for 5 days; however, patients in the negative outcome study received a single preoperative dose. Two studies evaluated intraoperative magnesium and did not find it efficacious in decreasing pediatric pain measures after tonsillectomy. One magnesium study found a decrease in postoperative analgesic consumption when given during orthopedic surgery in pediatric patients with cerebral palsy. The 1 published dextromethorphan pediatric study showed that a single preoperative dose decreased postoperative pain measures.

Due to differences in bioavailabilities and clearances that change as children age, and given the significant side effects associated with opioid analgesic agents, pharmacokinetic and pharmacodynamic trials with opioid-sparing analgesics in the pediatric population are warranted. Pediatric medication doses are often extrapolated from adult doses. Empirical drug dosing increases the risk of subtherapeutic and toxic serum concentrations; the risk of an adverse drug event increases with off-label and unlicensed medication use.62–64 One review found off-label and unlicensed medicine prescribing in children from 3% to 56% of prescriptions in community practices and 36% to 100% in hospitals.65 Another review found significant off-label prescription use in neonatal (55%–80%) and pediatric (16%–62%) inpatients.66 A study of Australian prescription medication product information found many had inadequate pediatric dosing information, age: <1 month (81%), 1–3 months (79%), 3 months to 2 years (78%), 2–6 years (73%), and 6–12 years (72%).67

Children pose special difficulty to conduct randomized clinical trials in. The Food and Drug Administration has worked to address the problem of inadequate pediatric testing via voluntary and mandatory programs for pharmaceutical companies to test analgesics in children.68 The use of opioid sparing has been encouraged as a surrogate measure of analgesic efficacy in pediatric analgesic trials; such trials are of “tolerably low burden” and may be an effective way to assess for meaningful clinical outcomes.69

This review has limitations. Many agents examined have few pediatric trials, limiting our review to qualitative evaluation; firm conclusions cannot be drawn. Furthermore, the studies are heterogeneous, using different doses, timing, duration, and routes of administration.

Current evidence suggests that acetaminophen, NSAIDs, dexamethasone, ketamine, clonidine, and dexmedetomidine decrease postoperative pain and opioid consumption in some pediatric surgical populations. There are too limited data to draw conclusions on the use of gabapentin, magnesium, dextromethorphan, lidocaine, amantadine, pregabalin, esmolol, and caffeine in pediatric surgical patients. Further pharmacokinetic and pharmacodynamics studies to establish both the clinical benefit and efficacy of nonopioid analgesia in pediatric populations are needed.

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DISCLOSURES

Name: Alyssa Zhu, MD.

Contribution: This author helped write and revise the manuscript and approved the final manuscript.

Name: Hubert A. Benzon, MD, MPH.

Contribution: This author helped write and revise the manuscript and approved the final manuscript.

Name: T. Anthony Anderson, MD, PhD.

Contribution: This author helped write and revise the manuscript and approved the final manuscript.

This manuscript was handled by: James A. DiNardo, MD, FAAP.

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