THERAPY UPDATE  Nonopioid agents

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Perioperative nonopioid agents for pain control in spinal surgery Anna Rivkin and Mark A. Rivkin

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ptimal postoperative pain management presents a challenge for healthcare providers across all surgical specialties. Immediate postsurgical pain affects four out of five patients, with 18% reporting extreme pain. 1-3 Inadequate pain control occurs in up to half of patients and predisposes them to dissatisfaction and failure to ambulate, theoretically resulting in a longer hospitalization. 4,5 On the other hand, excessive administration of commonly prescribed perioperative pain regimens, namely opioids,6 may also facilitate suboptimal patient outcomes and adverse events in up to 23% of patients.1,7 Studies have found that the inflammatory cascade that causes postoperative discomfort originates before the patient awakens from surgery and that preemptive analgesia may lead to reduced postprocedural pain.8-10 Moreover, agents with diverse mechanisms of action are reportedly more effective in providing pain relief compared with standard therapies.7,11 Preemptive multimodal pain therapy has been successfully implemented for numerous surgical procedures,

Purpose. Commonly used nonopioid analgesic agents that are incorporated into multimodal perioperative pain management protocols in spinal surgery are reviewed. Summary. Spinal procedures constitute perhaps some of most painful surgical interventions, as they often encompass extensive muscle dissection, tissue retraction, and surgical implants, as well as prolonged operative duration. Perioperative nonopioid analgesics frequently used in multimodal protocols include gabapentin, pregabalin, acetaminophen, dexamethasone, ketamine, and nonsteroidal antiinflammatory drugs (NSAIDs). There is evidence to suggest that gabapentin is safe and effective in reducing opioid consumption and pain scores at optimal doses of 600–900 mg orally administered preoperatively. Pregabalin 150–300 mg orally perioperatively has been shown to reduce both pain and narcotic consumption. Most reports concur that a single 1-g i.v. perioperative dose is safe in adults and that this dose has

often resulting in decreased narcotic consumption and a shorter hospital stay.12-14 Preemptive therapy is pharmacologic intervention initiated before a painful stimulus in order to inhibit nociceptive mechanisms

Anna Rivkin, Pharm.D., BCPS, is Assistant Professor of Pharmacy Practice, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, and Clinical Pharmacist, Critical Care, Mercy Fitzgerald Hospital, Darby, PA. Mark A. Rivkin, D.O., M.Sc., is Chief Resident, Neurosurgery, Philadelphia College of Osteopathic Medicine, Bala Cynwyd, PA. Address correspondence to Dr. Anna Rivkin (arivkin@mercy health.org).

been shown to reduce pain and attenuate narcotic requirements. Dexamethasone’s influence on postoperative pain has primarily been investigated for minor spinal procedures, with limited evidence for spinal fusions. Ketamine added to a patientcontrolled analgesia regimen appears to be efficacious for 24 hours postoperatively when implemented for microdiskectomy and laminectomy procedures at doses of 1 mg/mL in a 1:1 mixture with morphine. For patients undergoing laminectomy or diskectomy, NSAIDs appear to be safe and effective in reducing pain scores and decreasing opioid consumption. Conclusion. Preemptive analgesic therapy combining nonopioid agents with opioids may reduce narcotic consumption and improve patient satisfaction after spinal surgery. Such therapy should be considered for patients undergoing various spinal procedures in which postoperative pain control has been historically difficult to achieve. Am J Health-Syst Pharm. 2014; 71:184557

before they are triggered. However, the utility of this approach remains poorly characterized in spine literature. Preliminary results are promising, as a comprehensive multimodal protocol has been shown to sig-

The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/1101-1845. DOI 10.2146/ajhp130688

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nificantly attenuate opioid demand in patients undergoing multilevel spinal surgery.15 Spinal procedures constitute perhaps some of the most painful surgical interventions, as they often encompass extensive muscle dissection, tissue retraction, and surgical implants, as well as prolonged operative duration. Pain management in this population is further complicated by the number of patients with chronic pain as well as the paucity of patients who have never received treatment with an opioid.16 Inadequate postoperative analgesia or excessive pharmacotherapy may lead to diminished functional capacity and prolonged hospitalization. This article reviews frequently used nonopioid analgesic agents that are incorporated into multimodal perioperative pain management protocols, addressing each agent’s mechanism of action and analgesic properties, applications to surgical patients, and effectiveness in perioperative analgesia, specifically after spinal surgery. Gabapentin Mechanism of action and analgesic properties. Gabapentin is structurally related to the neurotransmitter g-aminobutyric acid (GABA). However, gabapentin and its metabolites do not bind to GABAA or GABAB receptors or influence the degradation or uptake of GABA.17 Gabapentin binds the a-2-d subunits of voltage-dependent calcium ion channels and blocks the development of hyperalgesia (pain-related behavior in response to a normally innocuous stimulus) and central sensitization.18 It produces antinociception by inhibiting calcium influx via these channels, subsequently inhibiting the release of excitatory neurotransmitters (e.g., substance P, calcitonin gene-related peptide) from the primary afferent nerve fibers in the pain pathway. Gabapentin has antihyperalgesic (exaggerated response to painful stimuli) properties with only a minor effect on normal nocicep1846

tion. It reduces the hyperexcitability of dorsal horn neurons induced by tissue injury. Central sensitization of these neurons plays a role in chronic neuropathic pain but also occurs after trauma and surgery. Reduction in central sensitization by an antihyperalgesic drug like gabapentin may reduce acute postoperative pain.19 Gabapentin is able to activate heterodimeric GABAB receptors, which consist of GABAB1a and GABAB2 subunits, and cause enhancement of the N-methyl-d-aspartate (NMDA) current at GABA-ergic interneurons. It can also block a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor-mediated transmission in the spinal cord. Gabapentin has been shown to inhibit the release of glutamate, aspartate, substance P, and calcitonin gene-related peptide from the spinal cord in animal models. The descending noradrenergic system, spinal a-adrenergic receptors, and an intact spino-bulbo-spinal circuit are crucial elements influencing the analgesic effects of gabapentin in addition to a-2-d interaction.20 Role in spinal surgery. Perioperative gabapentin dosing has been reported in various types of surgical procedures including abdominal hysterectomy; vaginal hysterectomy; radical mastectomy; oncological breast surgery; major orthopedic surgery; nephrectomy; laparoscopic cholecystectomy; ear, nose, and throat (ENT) surgery; and spinal surgery.18,21 Great variability exists among dosage protocols, with some patients receiving a single preoperative dose while others are continued on the drug until postoperative day 2. Likewise, the dose itself and frequency of administration vary. Ho et al.18 conducted a literature review of randomized controlled trials using gabapentin as a perioperative adjunct. The authors concluded that across all surgical procedures, a single dose of ≤1200 mg before surgery attenuated postoperative narcotic requirements, provided improvement in pain

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scores, and prolonged the duration until breakthrough analgesia was required. Multiple postoperative doses, however, were not associated with improved analgesia. In a later review, Clivatti et al.22 confirmed these findings and reported a decrease of >80% in opioid use subsequent to a single preoperative gabapentin dose. Contrary to this, two prospective randomized trials failed to demonstrate the utility of a single dose of gabapentin before cesarean delivery23 or total hip arthroplasty.24 Few clinical trials have evaluated the administration of perioperative gabapentin in spinal surgery. Turan et al.25 prospectively used a single 1200-mg dose of preoperative gabapentin versus placebo and recorded postoperative pain scores in patients undergoing elective lumbar surgery. The authors found a significant gabapentin-associated reduction in pain up to 4 hours after the procedure (p < 0.01). The mean 1, 2, and 4-hour visual analog scale (VAS) scores were 2, 0, and 0 in the gabapentin group compared with 3, 2, and 2 for the control group, respectively (with lower scores indicating less pain). Mean ± S.D. morphine consumption was less in the treatment group at every time point up to 24 hours as well as the 24-hour total (16.3 ± 8.9 mg versus 42.8 ± 10.9 mg). Moreover, postoperative vomiting and urinary retention were also lower in the treatment group, reaching statistical significance (p < 0.05). Dizziness and nausea were the most frequent adverse events, occurring with similar frequency in both groups. Van Elstraete and colleagues 26 used a variable dose of preoperative gabapentin and assessed pain requirements in patients scheduled to undergo lumbar fusion procedures. The dose effective at reducing narcotic consumption was determined to be more than 21 mg/kg in this population. Drowsiness, dizziness, and nausea were the most common

THERAPY UPDATE  Nonopioid agents

adverse effects reported in the study. The authors concluded that, in light of the large gabapentin doses used, further trials are necessary. Contrary to this, Radhakrishnan et al.27 investigated a single 800-mg dose of gabapentin in patients undergoing lumbar laminectomy and microdiskectomy. Only short-term outcomes, up to 8 hours postoperatively, were measured and did not demonstrate a difference in patient discomfort or morphine demands between treatment and placebo groups. These results may be due to the lower doses of gabapentin used as well as the reporting of 8-hour data as opposed to data for 24 hours or longer. Pandey et al.28 reported the results of a prospective, randomized controlled trial aimed to determine the optimal dose of preoperative gabapentin after single-level lumbar microdiskectomy. Postoperative pain scores and narcotic consumption decreased in all treatment groups (doses of 300, 600, 900, and 1200 mg) compared with placebo. The authors determined the 600-mg dose to be optimal, as there were no differences between this group and those receiving higher doses in terms of postoperative pain or fentanyl requirements. VAS scores at 24 hours for the 600-mg and placebo groups were 2.3 and 4.5, respectively. The mean ± S.D. total of fentanyl consumed in the 600-mg group was 702.5 ± 117.4 mg versus 1217.5 ± 182.0 mg in the placebo group. Again, nausea and vomiting were the most common adverse events encountered in the study overall, while doses of 900 mg or more were associated with lightheadedness. The narcoticsparing effect seen with lower gabapentin doses in this study could be attributed to enhanced statistical power conferred by a larger number of participants (n = 100) as well as the use of the more potent fentanyl instead of morphine. Most recently, Khan and colleagues29 conducted the largest ran-

domized controlled trial that was similar to that of Pandey et al.’s, including 175 patients undergoing a lumbar laminectomy. The authors administered varying doses of gabapentin before or after the incision and evaluated pain scores as well as total narcotic consumption. Gabapentin doses of at least 900 mg, given either before or immediately after the operation, appeared to equally reduce pain scores and mean ± S.D. total morphine demands (31.5 ± 9.6 mg versus 19.2 ± 2.7 mg), as well as the mean ± S.D. time to first dose of morphine for breakthrough pain (69.6 ± 33.7 minutes versus 156.0 ± 59.4 minutes). Again, large patient number and data points up to 24 hours postoperatively may account for beneficial results at lower doses. While nausea, vomiting, and dizziness were once again the most common adverse effects, there were no significant differences among groups receiving variable doses. Pregabalin Mechanism of action and analgesic properties. Tissue injury leads to an inflammatory response, releasing potassium ions, substance P, bradykinin, and prostaglandins (PGs). The inflammatory response induces gene expression in the dorsal root ganglion, resulting in an increased synthesis of peripheral receptors, which contributes to the increased sensitivity of the nociceptor. Peripheral sensitization results in an increased nociceptive input to the spinal cord. Prolonged afferent nociceptive input may induce a reversible increase in the excitability of central sensory neurons, mostly via activation of the NMDA receptor.30 Pregabalin (3-isobutyl GABA) is a GABA analog that is mechanistically and structurally similar to gab­ apentin. It does not, however, bind directly to GABAA, GABAB, or benzodiazepine receptors; does not augment GABAA responses in cultured neurons; does not alter rat brain

GABA concentrations; and does not have acute effects on GABA uptake or degradation. In cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity.31-33 Like gabapentin, pregabalin has antiepileptic, analgesic, and anxiolytic activities. There are, however, differences between pregabalin and gabapentin that may explain the differences in pain management. Pregabalin binds with higher affinity than gabapentin to the a-2-d site, an auxiliary subunit of voltage-gated calcium ion channels in central nervous system (CNS) tissues.31-33 Evidence from animal models of nerve damage and persistent pain suggests that the antinociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotoninergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.34 By binding to the a-2-d subunits of voltage-gated calcium ion channels and decreasing calcium influx at nerve terminals, pregabalin reduces the release of several excitatory neurotransmitters that are involved in pain mechanisms, such as noradrenalin, glutamate, and substance P. Pregabalin can reduce the hypersensitivity induced by inflammation or nerve injury.34 Role in spinal surgery. Pregabalin has also been used in acute postoperative pain management. Reports of its administration in dental procedures, gynecological surgery, laparoscopic cholecystectomy and hysterectomy, total joint arthroplasty, endoscopic thyroidectomy, mammoplasty, and spinal surgery have been published.35,36 Similar to gabapentin, the dose and frequency of administration are highly variable, ranging from a single preoperative dose to up

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to two weeks postoperatively.36 In a meta-analysis, Zhang et al.35 reported that pregabalin doses of over 300 mg seem to more effectively decrease opioid consumption at 24 hours. Postoperative nausea and vomiting appeared to be reduced in patients receiving pregabalin rather than placebo. However, two trials reported an increase in visual problems with pregabalin doses of 100–600 mg,37,38 while others encountered dizziness and increased sedation.35 Another group confirmed these results and found that preoperative pregabalin doses of at least 300 mg were sufficient to reduce postoperative analgesia requirements as well as nausea and vomiting.36 Again, dizziness and visual problems appeared to increase at these doses. Four publications have addressed the role of perioperative pregabalin in spinal surgery. In the only longterm study, Burke and Shorten 39 investigated the utility of the drug when given to patients undergoing lumbar diskectomy. Patients received 300 mg before surgery as well as 150 mg for two postoperative doses 12 hours apart versus placebo at equal time points. The pregabalin group faired favorably compared with the placebo group in terms of discomfort (VAS of 25.3 versus 37.6) and functional outcome (36-item short-form health survey [SF-36] total score of 516.2 versus 435.1, with higher scores indicating better functional outcome) at three months postoperatively. Two prospective, randomized, placebo-controlled studies evaluated the short-term impact of pregabalin on patients undergoing lumbar microdiskectomy. Spreng et al.40 administered 150 mg of pregabalin in a single preoperative dose and found that patients had a decreased narcotic demand, compared with placebo, at 4 hours but not at 24 hours postoperatively. Pain scores and frequency of complications were equal in both groups on postoperative day 7. Nausea and vomiting were the most 1848

common adverse effects reported but did not significantly differ between the treatment and placebo groups. Ozgencil and colleagues41 evaluated a 150-mg dose given twice (before and after surgery at 12-hour intervals). The mean ± S.D. opioid requirements at 24 hours in morphine equivalents were lower (0.36 ± 0.13 mg/kg versus 0.51 ± 0.14 mg/kg) while patient satisfaction was higher in the pregabalin group compared with those receiving placebo (“good” satisfaction in 10 of 30 patients versus 3 of 30 patients). Nausea, shivering, and pruritus were common in the placebo group, while dizziness, somnolence, and nausea were common in the pregabalin group. Pruritus was the only adverse effect for which the difference between groups was significant (lower in the treatment group, reported as p < 0.05 versus placebo). Possible factors influencing differing outcomes between these two trials are the primary endpoints and the methods of data reporting. Spreng et al.40 investigated a single time point, 2-hour outcomes, and reported total narcotic consumption, while Ozgencil et al.41 recorded data for 24 hours and reported narcotic utilization per unit of weight. Kumar et al.42 further confirmed pregabalin efficacy in patients undergoing lumbar laminectomy. A single 150-mg preoperative dose reduced patient anxiety (1.8 versus 3.3 on a 5-point scale), reduced mean ± S.D. narcotic requirements (24.8 ± 22.0 mg of fentanyl versus 31.2 ± 27.73 mg of fentanyl), and was associated with less nausea and vomiting compared with the control group. Acetaminophen Mechanism of action and analgesic properties. The mechanism of action of acetaminophen in reducing pain is not fully understood but may be due to the inhibition of central PG synthesis and an elevation of the pain threshold.43,44 Other proposed mechanisms for analgesia include indirect

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activation of cannabinoid (CB 1) receptors, modulation of serotoninergic and opioid pathways, inhibition of nitric oxide production, and hyperalgesia induced by substance P. PGs are lipid mediators derived from arachidonic acid that play central roles in the pathogenesis of inflammation, fever, and pain.43-45 Acetaminophen inhibits a specific site on the PGH2 synthase (PGHS) molecule, the two isoforms (PGHS1 and PGHS2) of which are also referred to as cyclooxygenase 1 and 2 (COX-1 and COX-2). PGHS has two active sites: the cyclooxygenase (COX) site and the peroxidase site. Acetaminophen acts as a reducing cosubstrate at the peroxidase site. The cellular selectivity of acetaminophen is derived from sensitivity to the ambient peroxide levels of various cell types. The central analgesic and antipyretic effects of acetaminophen may be exerted through PGHS inhibition (inhibition of PGE2) within vascular endothelial cells and neurons, where peroxide concentrations are low. In activated leukocytes and platelets, however, where peroxide concentrations are high, acetaminophen is prevented from affecting inflammation and platelet thrombosis.43,45 Cannabinoids produce analgesia in both acute and chronic pain. Endogenous cannabinoids (anandamide and 2-arachidonylglycerol) control the basal nociceptive threshold.46,47 Cannabinoids produce antinociceptive effects by descending spinal inhibition, and cannabinoid CB 1 receptors are involved. The cannabinoid-induced antinociception seems to depend to some extent on the release of opioid peptides onto brain m-receptors and spinal k-receptors. The local transformation of acetaminophen into AM404, an inhibitor of endocannabinoid transport, could lead to increased tissue levels of endocannabinoids such as anandamide and 2-arachidonoyl glycerol and therefore explain the antinociceptive effects of acetaminophen.

THERAPY UPDATE  Nonopioid agents

Serotoninergic pathways are part of the descending pain system.48 In the dorsal horn of the spinal cord, serotonin 5-HT3 receptors are concentrated in the superficial layers (lamina I) and on interneurons innervated by descending serotoninergic pathways. Descending pathways originate in brain stem nuclei, the hypothalamus, and the cortex and interact with afferent fibers and interneurons, projecting neurons in the dorsal horn of the spinal cord. Action at these sites either suppresses or enhances nociceptive information to cerebral structures. The serotoninergic system is present in the analgesic mechanism of action of acetaminophen. Thus, acetaminophen can reinforce descending inhibitory pathways. Role in spinal surgery. Acetaminophen is an established adjunct to perioperative pain management during thoracic, orthopedic, obstetric, gynecological, and general surgery procedures.49-52 It has been well-known for its pain-reducing and fever-controlling properties for over 100 years, and the i.v. form gained approval from the Food and Drug Administration for pain management for individuals age two years and older.53 A review of i.v. acetaminophen use in major surgery demonstrated a significant decrease in morphine requirements at 24 hours postoperatively (mean difference, –6.34 mg; 95% confidence interval, –9.02 to –3.65 mg) but little effect on nausea or vomiting.54 However, the difference in opioid requirements was small and did not warrant routine administration of the drug in the immediate postsurgical setting. In contrast, Sinatra et al.53 reviewed the use of i.v. acetaminophen for patients undergoing orthopedic procedures and found a significant decrease in postoperative pain scores at 24 hours for patients receiving the drug compared with placebo and a 33% decrease in the use of medication for breakthrough pain. Reports of perioperative acetaminophen for spinal surgery are

scarce. An early randomized controlled trial by Hernández-Palazón et al.55 using propacetamol, an i.v. prodrug version of acetaminophen, during spinal fusion surgery yielded promising results. Patients were treated with 2 g of acetaminophen or placebo every 6 hours for three postoperative days. Patients who received the acetaminophen regimen achieved a significant decrease in analgesia as well as a decreased mean ± S.D. opioid consumption at 72 hours postoperatively (60.3 ± 20.5 mg of morphine versus 112.2 ± 39.1 mg of morphine). Grundmann et al.56 compared a single 1-g i.v. dose of acetaminophen preoperatively for patients undergoing lumbar microdiskectomy with other nonopioid adjuncts as well as placebo. There was no significant difference in immediate postoperative pain with acetaminophen compared with placebo on arrival at the recovery room. The trials of HernándezPalazón et al.55 and Grundmann et al.56 differed by the amount of drug administered, number of doses administered, and time points of data collection, accounting for contradictory results. A recent randomized placebocontrolled trial evaluated acetaminophen during spinal surgery for scoliosis in children.57 An experimental group received 30 mg/kg i.v. on completion of surgery and two subsequent postoperative doses 8 hours apart. Although the treatment group demonstrated lower pain scores over the first 24 hours after surgery (39% of patients with a VAS of >6 versus 72%), its oxycodone consumption did not differ from that of the placebo group. Cakan et al.58 reported similar findings in a randomized controlled trial involving adults undergoing lumbar diskectomy or laminectomy. The authors administered 1 g of i.v. acetaminophen intraoperatively followed by every 6 hours over the first postoperative day. Postopera-

tive analgesia was significantly better at 24 hours in the treatment group compared with patients receiving placebo while nausea was decreased. However, the study did not find a significant decrease in narcotic requirements between groups. Dexamethasone Mechanism of action and analgesic properties. The occurrence of inflammatory and neuropathic pain may depend on the action of various cytokines and other molecules, including eicosanoids, endorphins, calcitonin-gene-related peptide, free radicals, and transcription factors.59 Antiinflammatory effects of glucocorticoids result from their ability to inhibit the expression of collagenase (the key enzyme involved in tissue degeneration during inflammatory mechanisms) and proinflammatory cytokines or to stimulate the synthesis of lipocortin, which blocks the production of eicosanoids. Dexamethasone is a long-acting synthetic glucocorticoid devoid of mineralocorticoid effects. Glucocorticoids decrease inflammation by stabilizing the lysosomes in neutrophils, which prevent degranulation and the resulting inflammatory response.60 Glucocorticoids also induce the antiinflammatory protein lipocortin. This protein inhibits the enzyme phospholipase A2, which inhibits synthesis of PGs and lipoxygenase products. Glucocorticoids also decrease the stability of selected messenger RNA molecules that alter gene transcription. Genes affected by this action include those involved in synthesis of collagenase, elastase, plasminogen activator, nitric oxide synthase, COX-2, cytokines, and chemokines. Glucocorticoids reduce pain through multiple mechanisms. They inhibit PG synthesis and the associated inflammation, and they reduce tissue edema by decreasing vascular permeability. Steroid receptors, which are found in the central and peripheral nervous systems, are

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involved in neuronal growth, differentiation, and plasticity. Glucocorticoids reduce neuropathic pain by inhibiting spontaneous discharges in injured nerves.61 Dexamethasone’s analgesic activity can attenuate inflammation, edema, and nerve depolarization. Glucocorticoids inhibit PG synthesis and are therefore beneficial in pain syndromes that involve PG release, such as bone pain. Corticosteroids reduce capillary permeability, making them useful in situations where edema facilitates noxious stimuli, such as back pain due to spinal cord compression. Corticosteroids have been shown to reduce spontaneous discharge in injured nerves and are therefore beneficial for the treatment of neuropathic pain.62 Role in spinal surgery. Dexamethasone is commonly used perioperatively to reduce postoperative nausea and vomiting.63,64 Its role as an adjunct to analgesia has been reported for ENT surgery, hysterectomy, cholecystectomy, thyroidectomy, anorectal surgery, mastectomy, and spinal surgery. De Oliveira et al.64 performed a literature review to elucidate the efficacy and optimal dose of dexamethasone for postoperative pain across all surgical procedures. Narcotic requirements were decreased for intermediatedose (0.11–0.2 mg/kg) and high-dose (≥0.21 mg/kg) dexamethasone phosphate groups at 24 hours, along with pain scores, pain during movement, and nausea and vomiting, without a noticeable increase in complications. Waldron et al. 65 investigated the utility of a single preoperative dose for patients undergoing general anesthesia. Their review concluded that one dose before surgery attenuated narcotic requirements at 24 hours, decreased pain scores, lessened the need for breakthrough-pain medication, and had no impact on wound healing. Dexamethasone has been extensively studied in the spine literature both in preoperative and perioperative settings. It has been administered 1850

intravenously, intramuscularly, and directly into the wound and has been described in the literature for lumbar disk surgery dating back to 1977.66-69 During the past decade, few groups investigated preoperative or intraoperative dosing on postoperative parameters. Karst et al.70 conducted a randomized controlled trial initially designed to evaluate the efficacy of celecoxib on postoperative pain in patients undergoing lumbar disk surgery. However, during surgery, 14 patients were noted to have significant compressive pathology on neural elements, which warranted intraoperative i.v. administration of dexamethasone phosphate 20–80 mg. Interestingly, the authors found that while celecoxib alone did not reduce analgesia requirements or pain scores at 24 hours, patients receiving dexamethasone, compared with those not treated with dexamethasone, had a significant decrease in analgesia consumption and improved pain (VAS on movement of 2.44 versus 4.94) over the same time period (p = 0.003). The only reported complications were nausea and vomiting, whose occurrence did not significantly differ between groups. Aminmansour et al.71 evaluated dexamethasone phosphate 40 mg versus 80 mg i.v. intraoperatively compared with placebo in a randomized controlled trial involving patients undergoing lumbar diskectomy. Both treatment groups showed improvement over placebo in mean ± S.D. pain scores on postoperative day 1 (1 ± 1.24, 1 ± 1.14, and 1.5 ± 2.67 for the 40-mg, 80-mg, and placebo groups, respectively), but the 40mg group demonstrated decreased opioid consumption compared with the placebo group (5.6 mg of morphine versus 9 mg) during the same time interval. It is worth mentioning that while the differences in both VAS scores and morphine consumption reached statistical significance (p = 0.006 and p = 0.012, respectively),

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the clinical importance of these differences is unlikely to be significant. There were no corticosteroid-related complications noted two months after surgery, specifically gastrointestinal bleeding or diskitis, with a single wound complication occurring in the placebo group. Ketamine Mechanism of action and analgesic properties. The NMDA receptor, a member of the glutamate receptor family, is an example of an ion channel-coupled receptor with excitatory properties that has been implicated in the mechanism of general anesthesia, analgesia, and neurotoxicity.72 Ketamine is a noncompetitive, use-dependent, NMDA channel blocker that prevents the induction of synaptic potentiation.73 It interacts with opiate receptors at central and spinal sites as well as with norepinephrine, serotonin, muscarinic cholinergic receptors, and voltage-sensitive calcium ion channels. Moreover, it inhibits interleukin-6 and catecholamine uptake. 72,74,75 NMDA receptors play a central role in the processes of induction and maintenance of pain sensitization, accounting for the analgesic efficacy of ketamine.73 NMDA antagonists can provide specific treatment of central hypersensitivity, given the involvement of the NMDA receptor in the generation of neuronal hyperexcitability.30 Preemptive administration of ketamine might prevent the development of pain (both acute and chronic) by preventing the sensitization of neuronal circuits. Acute analgesic effects of ketamine can outlast the expected half-life of the drug, suggesting that there may be some suppression of neural sensitization in pain circuits.73 Ketamine has been reported to interact with m-, d-, and k-opioid receptors. In vivo data have shown that S-ketamine is two to three times more potent than Rketamine as an analgesic.72

THERAPY UPDATE  Nonopioid agents

Role in spinal surgery. Ketamine was initially introduced as an anesthetic in 1970 but quickly fell out of favor secondary to reported adverse psychiatric effects.76 In the past two decades, there has been a resurgence of ketamine in the perioperative setting due to its supposed contribution to the control of acute postoperative pain. Bell et al.77 investigated this claim in a Cochrane database review of 55 randomized controlled trials of adults undergoing surgery. Study results were mixed, with much variability in the ketamine dose administered, route of administration, and dosing frequency. In these trials, ketamine was used in the perioperative setting for hysterectomy, gastrectomy, major abdominal surgery, rectal cancer, joint replacement, nephrectomy, elective outpatient procedures, thoracotomy, and spinal surgery. Ketamine, administered intravenously or intramuscularly before surgery, resulted in reduced postoperative opioid demands in 8 of 13 such trials, with 24-hour postoperative pain scores decreasing in patients in 7 of the 13 trials. A bolus dose of ketamine given intraoperatively had a similar narcotic-sparing effect in 3 of 7 trials.77 Studies examining continuous i.v. infusion of ketamine demonstrated decreased opioid demands in 9 of 13 trials, with patients in 2 trials maintaining reduced pain scores for 48 hours postoperatively. In a similar publication, Subramaniam et al.78 reported on the utility of ketamine as an opioid adjunct in surgical patients for four methods of administration: one-time i.v. dose, continuous infusion, patient-controlled analgesia (PCA), and epidural preparations. Ketamine in addition to opioid PCA failed to demonstrate a decrease in postoperative pain. However, continuous infusion as well as a single-dose regimen successfully attenuated narcotic consumption in 6 of 11 trials and 7 of 11 trials, respectively.

The first report of ketamine in spinal surgery, by Javery et al.,79 examined the utility of adding the drug to opioid PCA in patients undergoing lumbar microdiskectomy. The investigators prospectively evaluated morphine consumption and pain scores at 24 hours postoperatively. Using ketamine 1-mg/mL PCA doses, the authors showed a significant improvement in mean ± S.D. pain scores (2.3 ± 1.67 versus 4.5 ± 1.54) and adverse effects such as nausea and urinary retention compared with the group receiving morphine alone. Similarly, Aveline et al.80 demonstrated the effectiveness of adding ketamine to a PCA regimen in a randomized controlled trial using a 0.15-mg/kg dose. Lumbar microdiskectomy patients faired better after receiving both ketamine and morphine, compared with morphine alone, with an overall 57% decrease in narcotic needs at 24 hours after surgery and diminished pain scores both at rest and with activity. In addition, postoperative nausea and vomiting complications were significantly reduced in the treatment group (p = 0.001). The data with respect to major spinal surgery are conflicting. Loftus et al.81 evaluated the effect of intraoperative ketamine infusion for patients undergoing lumbar fusion procedures. The protocol doses of 0.5 mg/kg i.v. at the start of the procedure followed by an infusion of 10 mg/kg/min for the remainder of the case were implemented. The authors found that mean pain scores (4.1 versus 5.6) and mean ± S.D. total opioid requirements (142 ± 82 mg versus 202 ± 176 mg of morphine equivalent) were lower postoperatively compared with patients receiving an equal volume of 0.9% sodium chloride injection, and these effects persisted for up to six weeks (0.8 ± 1.1 mg versus 2.8 ± 6.9 mg of morphine equivalent). The findings were further amplified by the lack of opioid-naive patients in this study. Nausea, vomiting, hallucinations,

and urinary retention were the major adverse effects reported but did not differ between treatment and control groups either at 48 hours or six weeks postoperatively. On the contrary, Subramaniam et al.82 failed to demonstrate a decrease in opioid consumption or pain scores for patients undergoing lumbar or thoracolumbar fusion. The treatment group received 0.15 mg/kg of ketamine at the start of anesthesia and was maintained on a 2-mg/kg/ min continuous infusion for 24 hours after surgery; the comparator group received 0.9% sodium chloride injection. This protocol resulted in no statistically significant difference in either narcotic requirements or pain scores at any time point up to 48 hours postoperatively. Adverse CNS events (headache, hallucinations, anxiety, confusion, insomnia), occurred in 9 of 15 patients in the control group while the ketamine group had 5 of 15 patients affected; the difference was not significant. Differing outcomes may be secondary to the number of participants and bolus doses used. Loftus et al.81 randomized 102 patients while Subramaniam et al. 82 evaluated just 30. Moreover, Loftus et al. implemented a higher preoperative ketamine bolus dose, which may explain the favorable results. COX-2 NSAIDs Mechanism of action and analgesic properties. Nonsteroidal antiinflammatory drugs (NSAIDs) exert their antiinflammatory effect through inhibition of PG G/H synthase, or COX, which is the enzyme that catalyzes the transformation of arachidonic acid to PGs and thromboxanes.83 COX includes both COX-1 and COX-2. Selective inhibition of COX-2 leads to decreased adverse gastrointestinal effects. Activation of endothelial cells and expression of cell adhesion molecules play a role in targeting circulating cells to inflammatory sites. NSAIDs have a more

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significant effect on pain resulting from the increased peripheral sensitization that occurs during inflammation and leads nociceptors to respond to stimuli that are normally painless. It is believed that inflammation leads to a lowering of the response threshold of polymodal nociceptors.83 In the descending pain control system, the nerve impulses flow from the forebrain to the spinal cord and other relay structures.84 An important structure of the descending pain control system is the gray substance located around the aqueduct of Sylvius in the midbrain, known as the periaqueductal gray matter (PAG). Dorsal-dorsolateral portions of the PAG are involved in stress-induced analgesia, which is independent of opioids but dependent on endocannabinoids. The lateral-ventrolateral portions of the PAG are involved in both opioid analgesia and analgesia induced by NSAIDs. The PAG funnels impulses onto the nucleus raphe magnus and neighboring structures of the rostral ventromedial medulla (RVM). In the RVM there are two classes of neuron that project to the spinal cord: the “on-cells,” which facilitate transmission of pain signals, and the “off-cells,” which inhibit this transmission. Analgesia by NSAIDs along the descending pain control system also requires an activation of the CB1 endocannabinoid receptor. Opioids, NSAIDs, and cannabinoids in PAG and RVM cooperate to decrease GABAergic inhibition and thus enhance the descending flow of impulses that inhibit pain. Role in spinal surgery. NSAIDs are well-established nonopioid agents with proven analgesic properties in the perioperative setting.8-10,85,86 Their use in ENT, orthopedic, general, gynecological, and spinal surgeries has been reported in the literature.87 However, NSAID use in spinal surgery is a highly contentious issue secondary to potential bleeding complications reported during other types of major surgery88,89 as well as inter1852

ference with spinal fusion.90-95 COX inhibition has been demonstrated to attenuate the initial stage of bone healing—the inflammatory stage—if NSAIDs are administered within the first seven days after surgery.96,97 Several investigators evaluated NSAID safety and efficacy in spinal fusion surgery. Riew et al.91 examined the resumption of indomethacin after spinal fusion in rabbits. The treatment group received the drug at two weeks postoperatively and had statistically significant decreases in fusion rates (p < 0.002). These animal findings were confirmed by other investigators.92 Li et al.94 showed similar results in humans in a meta-analysis of spinal fusion literature where normal doses of NSAIDs for 14 days or fewer did not seem to affect fusion, regardless of the agent used. In a retrospective review, Reuben et al.93 reported on a lumbar fusion surgery cohort receiving oral celecoxib (200–600 mg/day), rofecoxib (50 mg/day), or ketorolac tromethamine (20–240 mg/day) during the first 5 days after surgery and assessed nonunion rates at one year. The authors discovered that rofecoxib and celecoxib did not appear to influence fusion, while only high ketorolac dosages of >120–240 mg/ day were associated with higher nonunion rates. Deguchi et al.98 conducted a retrospective review evaluating the effects of 25 variables on spinal fusion rates in patients treated for spondylolisthesis. Twenty-seven patients were continuously consuming NSAIDs for the initial three months after surgery and subsequently demonstrated staggering fusion rates in patients not consuming NSAIDs (97%), compared with 44% in patients taking NSAIDs at one year. Similarly, Lumawig et al.99 retrospectively assessed the effects of dose escalation of diclofenac sodium on lumbar fusion rates. The high-dose group received over 300 mg orally daily for 14 days after surgery and experienced

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more pseudarthrosis and delayed fusion compared with the lower-dose (≤300-mg) and control groups. Several conclusions can be drawn from the available literature regarding the safety of NSAIDs after spinal fusion surgery. It appears that lowdose NSAID administration for the first several postoperative days is safe and does not result in decreased fusion rates. Most studies suggest that only immediate postoperative high dosing may be associated with pseudarthrosis. In addition, NSAIDs administered beyond 14 days from surgery may attenuate spinal fusion in a more significant manner. In contrast, decompressive spinal procedures do not rely on bone fusion. The utility of NSAIDs in these procedures has been evaluated by several groups. Cassinelli et al.100 reported the results from a randomized controlled trial for patients undergoing lumbar laminectomy, with the treatment group receiving three perioperative ketorolac doses. Both mean ± S.D. opioid consumption (8.0 ± 7.5 mg of morphine versus 22.1 ± 18.0 mg) and pain scores (3.3 ± 2.4 versus 5.7 ± 2.5) were diminished in the treatment group, compared with the placebo group, at every time point up to 24 and 16 hours, respectively. No renal or hepatic complications were reported in the study, and 1 patient developed an epidural hematoma necessitating an additional operation. That single patient was found to be randomized to the placebo group. Le Roux and Samudrala101 shared similar results in a randomized controlled trial evaluating pain and narcotic consumption after lumbar diskectomy. The treatment group was given ketorolac tromethamine 30 mg intramuscularly postoperatively for up to 36 hours, compared with the placebo group, and demonstrated a decreased mean ± S.D. narcotic demand (20.8 ± 5.3 mg of morphine versus 98.3 ± 9.8 mg) and patient discomfort (average VAS score of 2.9 versus 6.7). Interestingly, six week

THERAPY UPDATE  Nonopioid agents

after surgery, all patients in the treatment group were free from back pain compared with 19.2% of the placebo group who still had back pain (p = 0.03). However, another randomized controlled trial examining the administration of a single ketorolac dose failed to demonstrate improvement in pain or morphine requirements in a postsurgical lumbar diskectomy population.102 Karst et al.70 prospectively investigated this issue using celecoxib 200 mg twice daily orally for three days, with the first dose given the night before lumbar diskectomy. The authors reported no analgesic or opioid-sparing effects of celecoxib. A major drawback, however, is that some patients also received dexamethasone at the time of surgery, making it difficult to evaluate the effects of celecoxib in this 34-patient trial. Despite the fusion controversy, Munro et al.103 reported on a posterior lumbar fusion population who was randomized to receive doses of placebo or up to 15 mg of ketorolac tromethamine orally for 36 hours after surgery. Mean ± S.D. opioid consumption (0.7 ± 0.4 mg/ kg/day versus 1 ± 0.5 mg/kg/day of morphine) and pain scores were lower on postoperative day 2 in the treatment group. No differences between groups were reported with respect to nausea, vomiting, pruritus, or bleeding complications. In a similar randomized controlled trial, Aubrun et al.104 evaluated the effect of ketoprofen on postoperative values after spinal fusion. Compared with placebo, ketoprofen 100 mg orally starting at the conclusion of surgery and continued every 8 hours successfully attenuated mean ± S.D. opioid requirements (25 ± 17 mg versus 38 ± 20 mg of morphine) and resulted in lower pain scores 24 hours postoperatively. Building a multimodal protocol Numerous conflicting reports make it difficult for the treating prac-

titioner to design a useful protocol. Lack of consistency in dosing, number and timing of administrations, and single-agent versus multiagent therapies, as well as types of surgical procedures studied further compound this issue. However, after careful analysis of the studies discussed in the current report, certain recommendations can be made regarding the use of the previously mentioned agents. Gabapentin. There is evidence to suggest that gabapentin is safe and effective in reducing opioid consumption and pain scores at optimal doses of 600–900 mg orally administered preoperatively. Higher doses may predispose patients to a greater likelihood of adverse CNS effects while providing decreased benefit in terms of pain control. Lower doses, however, were associated with less nausea and vomiting in some reports. There is insufficient evidence to recommend multiple gabapentin doses in addition to a single preoperative dose. Moreover, this agent appears to be efficacious for a wide variety of spinal procedures, including microdiskectomies, laminectomies, and lumbar fusions. Pregabalin. Pregabalin 150–300 mg orally perioperatively has been shown to reduce both pain and narcotic consumption. Several trials using doses of >300 mg reported an increase in dizziness and visual problems. However, doses of ≤150 mg were associated with diminished pain control compared with placebo at 24 hours postoperatively. Little evidence exists to recommend single or multiple administrations in the perioperative period as long as the desirable dose of the agent is reached no later than on postoperative day 1. Furthermore, data are lacking regarding pregabalin efficacy in lumbar fusion surgery, as most investigations focused on less-extensive procedures. Acetaminophen. Evidence of acet­ aminophen use in spinal surgery is limited. Most reports concur that a

single 1-g i.v. perioperative dose is safe in adults and that this dose has been shown to reduce pain and attenuate narcotic requirements. There are weak data to suggest that repeated oral or i.v. postoperative doses of the agent may play a larger role in reducing pain scores than in reducing opioid consumption. Acetaminophen has been studied in major and minor spinal procedures and has demonstrated promise in both settings. The safety of scheduled administration of the drug up to postoperative day 3 has been reported.55 Acetaminophen is primarily metabolized in the liver and involves three main pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation via the cytochrome P-450 isoenzyme pathway.43 It should be used with caution in patients with hepatic impairment due to the risk of hepatotoxicity. In patients with mildto-moderate hepatic impairment (Child-Pugh class A or B), limiting the total daily dose of acetaminophen to 2 g daily may be warranted.105,106 In patients with severe hepatic impairment (Child-Pugh class C), use of acetaminophen is contraindicated.43 Dexamethasone. Dexamethasone has been extensively studied in the spine literature and recently received attention as a postoperative pain management adjunct. However, there is no consensus on optimal dosing for dexamethasone phosphate, as the doses studied in trials reporting a beneficial effect on postoperative pain and narcotic utilization ranged from greater than 0.1 mg/kg to 80 mg. Weak evidence suggests that a single perioperative dose is sufficient to demonstrate clinical effect for up to 24 hours after the procedure. Dexamethasone’s influence on postoperative pain has primarily been investigated for minor spinal procedures, with limited evidence for spinal fusions. The adverse-effect profile of this agent appears to be favorable. Nausea and vomiting have been shown to be reduced while

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reports of gastrointestinal bleeding and infections are exceedingly rare. Although this agent is commonly associated with hyperglycemia, especially in diabetic patients, no trial has specifically evaluated or reported significant complications resulting from blood glucose elevations. Therefore, it is not unreasonable to assume that hyperglycemia secondary to a single dexamethasone dose is transient and self-limiting in this setting. Ketamine. The utility of ketamine has been examined in the setting of spinal surgery as an adjunct to opioid PCA as well as a continuous infusion, showing promise in reducing both postoperative pain and narcotic consumption. Ketamine added to a PCA regimen appears to be efficacious for 24 hours postoperatively when implemented for microdiskectomy and laminectomy procedures at doses of 1 mg/mL in a 1:1 mixture with morphine.79 However, trials investigating more extensive procedures, such as lumbar fusions, implemented a perioperative infusion with a weightbased bolus dose followed by a dose of 0.12–0.6 mg/kg/hr. Evidence of a beneficial ketamine effect for major spinal procedures is mixed, making it difficult to formulate a recommendation for or against the agent in this setting. Nonetheless, the adverseeffect profile appears to be favorable for ketamine use across all surgery subtypes and doses. Nausea, vomiting, and urinary retention improved in the treatment groups of several trials, while no trial demonstrated an increase in hallucinations or other adverse CNS effects. NSAIDs. NSAIDs are perhaps the best known of the nonopioid analgesics for their analgesic properties. Numerous agents from this class have been evaluated in spinal surgery. As previously discussed, the safety of NSAIDs in spinal surgery depends on whether a fusion is performed. For patients undergoing laminectomy or diskectomy, these agents appear to be safe and effective in reducing 1854

pain scores and decreasing opioid consumption. Multiple perioperative doses for up to 24–36 hours appear to have a greater effect than a single preoperative dose. Little evidence points to an increase in adverse drug reactions, specifically bleeding risks or renal problems. In the setting of spinal fusions, NSAIDs can still be a useful adjunct to opioid therapies. However, smaller doses appear to exhibit a limited effect on pseudarthrosis, especially if NSAIDs are administered only in the first few days after spinal fusion surgery. Consumption of these agents beyond 14 days and doses of ketorolac tromethamine in excess of 120 mg/day orally were associated with significant nonunion rates. Combination therapy. Our review identified only a few reports examining these agents in combination as part of a preemptive multimodal pain protocol. Rajpal et al.6 evaluated the pain scores and opioid consumption of 100 consecutive patients undergoing any spinal surgery. These patients received preoperative and postoperative scheduled extendedrelease oxycodone, gabapentin, and acetaminophen; intraoperative dolasetron, and as-needed postoperative short-acting oral oxycodone. The authors compared the data to 100 historical controls receiving standard PCA therapy and found a reduction in mean ± S.D. morphine consumption in favor of the multimodal group (49.97 ± 38.20 mg versus 31.20 ± 22.14 mg) at 24 hours postoperatively. No drugrelated complications were noted in this trial, while the multimodal treatment group had less nausea and drowsiness, as these adverse effects may have been attenuated by the other agents used. In a more recent trial, 41 patients undergoing extensive lumbar fusions received acetaminophen, NSAIDs, gabapentin, S-ketamine, dexamethasone, ondansetron, and epidural local anesthetic infusion or PCA with

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morphine.15 Again, data for narcotic use were compared with 44 patients from historical controls (receiving a nonstandardized opioid regimen). On average, the intervention group had decreased opioid requirements (110 mg versus 15 mg of morphine on postoperative day 1, and 100 mg versus 30 mg of morphine on postoperative day 2) at the 48-hour time point. The authors reported no complications related to any of the agents in the multimodal protocol. Most recently, Garcia et al.107 conducted a randomized controlled trial with only 22 patients undergoing multilevel lumbar surgery. The patients received morphine alone or the combination of celecoxib, pregabalin, and extended-release oxycodone for postoperative pain control. The multimodal group consumed significantly less morphine at 24 hours (mean ± S.D., 53.3 ± 28.9 mg versus 22.2 ± 11.7 mg) compared with the morphine-only group and reported much lower pain scores over the same time period (mean ± S.D. VAS, 1.6 ± 2.1 for the multimodal group versus 6.3 ± 2.0 for the morphineonly group). The authors reported no major complications and no differences in the number of complications among the two groups. Other concerns with multimodal regimens. Several concerns still remain regarding multimodal pain regimens. Although early available trials indicate that it is safe to combine these agents, these conclusions rely largely on data from historical controls or a small number of patients. Another important issue is that of incremental benefit to combining multiple agents. There is insufficient evidence in the literature to comment on this point. In part, the current literature is lacking data investigating multiagent protocols versus protocols using a single agent. Moreover, we believe that to fully evaluate comparative effectiveness of multiagent protocols, future studies need to examine length of stay and

THERAPY UPDATE  Nonopioid agents

overall cost data for this treatment approach. Conclusion Preemptive analgesic therapy combining nonopioid agents with opioids may reduce narcotic consumption and improve patient satisfaction after spinal surgery. Such therapy should be considered for patients undergoing various spinal procedures in which postoperative pain control has been historically difficult to achieve. References 1. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003; 97:534-40. 2. Warfield CA, Kahn CH. Acute pain management programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology. 1995; 83:1090-4. 3. Patak LS, Tait AR, Mirafzali L et al. Patient perspectives of patient-controlled analgesia (PCA) and methods for improving pain control and patient satisfaction. Reg Anesth Pain Med. 2013; 38:326-33. 4. Gurbet A, Bekar A, Bilgin H et al. Preemptive infiltration of levobupivacaine is superior to at-closure administration in lumbar laminectomy patients. Eur Spine J. 2008; 17:1237-41. 5. Kim JC, Choi YS, Kim KN et al. Effective dose of peri-operative oral pregabalin as an adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery. Spine. 2011; 36:428-33. 6. Rajpal S, Gordon DB, Pellino TA et al. Comparison of perioperative oral multimodal analgesia versus iv PCA for spine surgery. J Spinal Disord Tech. 2010; 23:139-45. 7. Grass JA, Sakima NT, Valley M et al. Assessment of ketorolac as an adjuvant to fentanyl patient-controlled epidural analgesia after radical retropubic prostatectomy. Anesthesiology. 1993; 78:642-8. 8. Beilin B, Bessler H, Mayburd E et al. Effects of preemptive analgesia on pain and cytokine production in the postoperative period. Anesthesiology. 2003; 98:151-5. 9. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001; 63:1979-84. 10. Dirks J, Møiniche S, Hilsted KL, Dahl JB. Mechanisms of postoperative pain: clinical indications for a contribution of central neuronal sensitization. Anesthesiology. 2002; 97:1591-6.

11. Kehlet H, Rung GW, Callesen T. Postoperative opioid analgesia: time for a reconsideration? J Clin Anesth. 1996; 8:441-5. 12. Lee BH, Park JO, Suk KS et al. Preemptive and multi-modal perioperative pain management may improve quality of life in patients undergoing spinal surgery. Pain Physician. 2013; 16:E217-26. 13. Blanco JS, Perlman SL, Cha HS, Delpizzo K. Multimodal pain management after spinal surgery for adolescent idiopathic scoliosis. Orthopedics. 2013; 36(suppl):33-5. 14. Duellman TJ, Gaffigan C, Milbrandt JC, Allan DG. Multi-modal, pre-emptive analgesia decreases the length of hospital stay following total joint arthroplasty. Orthopedics. 2009; 32:167. 15. Mathiesen O, Dahl B, Thomsen BA et al. A comprehensive multimodal pain treatment reduces opioid consumption after multilevel spine surgery. Eur Spine J. 2013; 22:2089-96. 16. Ivanova JI, Birnbaum HG, Schiller M et al. Real-world practice patterns, healthcare utilization, and costs in patients with low back pain: the long road to guideline-concordant care. Spine J. 2011; 11:622-32. 17. Gabapentin [monograph]. In: Micromedex Drugdex [online database]. Greenwood Village, CO: Truven Health Analytics (accessed 2013 Aug 2). 18. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain—a systematic review of randomized controlled trials. Pain. 2006; 126:91-101. 19. Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg. 2007; 104:1545-56. 20. Kong V, Irwin M. Gabapentin: a multimodal perioperative drug? Br J Anaesth. 2007; 99:775-86. 21. Hurley RW, Cohen SP, Williams KA et al. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med. 2006; 31:237-47. 22. Clivatti J, Sakata RK, Issy AM. Review of the use of gabapentin in the control of postoperative pain. Rev Bras Anestesiol. 2009; 59:87-98. 23. Short J, Downey K, Bernstein P et al. A single preoperative dose of gabapentin does not improve postcesarean delivery pain management: a randomized, double-blind, placebo-controlled dose-finding trial. Anesth Analg. 2012; 115:1336-42. 24. Clarke H, Pereira S, Kennedy D et al. Adding gabapentin to a multimodal regimen does not reduce acute pain, opioid consumption or chronic pain after total hip arthroplasty. Acta Anaesthesiol Scand. 2009; 53:1073-83. 25. Turan A, Karamanlioğlu B, Memiş D et al. Analgesic effects of gabapentin after spinal surgery. Anesthesiology. 2004; 100:935-8.

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40. Spreng UJ, Dahl V, Raeder J. Effect of a single dose of pregabalin on postoperative pain and pre-operative anxiety in patients undergoing discectomy. Acta Anaesthesiol Scand. 2011; 55:571-6. 41. Ozgencil E, Yalcin S, Tuna H et al. Perioperative administration of gabapentin 1,200 mg day-1 and pregabalin 300 mg day-1 for pain following lumbar laminectomy and discectomy: a randomised, double-blinded, placebocontrolled study. Singapore Med J. 2011; 52:883-9. 42. Kumar KP, Kulkarni DK, Gurajala I, Gopinath R. Pregabalin versus tramadol for postoperative pain management in patients undergoing lumbar laminectomy: a randomized, double-blinded, placebo-controlled study. J Pain Res. 2013; 6:471-8. 43. Tylenol (acetaminophen) product information. Skillman, NJ: McNeil Consumer Healthcare; 2013. 44. Acetaminophen [monograph]. In: Micromedex Drugdex [online database]. Greenwood Village, CO: Truven Health (accessed 2013 Jul 20). 45. Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther. 2006; 79:9-19. 46. Ottani A, Leone S, Sandrini M et al. The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. Eur J Pharmacol. 2006; 531:280-1. 47. Dani M, Guindon J, Lambert C, Beaulieu P. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol. 2007; 573:214-5. 48. Pickering G, Esteve V, Loriot MA et al. Acetaminophen reinforces descending inhibitory pain pathways. Clin Pharmacol Ther. 2008; 84:47-51. 49. Cornesse D, Senard M, Hans GA et al. Comparison between two intraoperative intravenous loading doses of paracetamol on pain after minor hand surgery: two grams versus one gram. Acta Chir Belg. 2010; 110:529-32. 50. Peduto VA, Ballabio M, Stefanini S. Efficacy of propacetamol in the treatment of postoperative pain. Morphine-sparing effect in orthopedic surgery. Acta Anaesthesiol Scand. 1998; 42:293-8. 51. Sinatra RS, Jahr JS, Reynolds LW et al. The efficacy and safety of single and repeated administration of intravenous acetaminophen injection (paracetamol) 1 g for pain management following major orthopedic surgery. Anesthesiology. 2005; 102:822-31. 52. Maund E, McDaid C, Rice S et al. Paracetamol and selective and nonselective non-steroidal anti-inflammatory drugs for the reduction in morphinerelated side-effects after major surgery: a systematic review. Br J Anaesth. 2011; 106:292-7.

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THERAPY UPDATE  Nonopioid agents

83. Dugowson CE, Gnanashanmugam P. Nonsteroidal anti-inflammatory drugs. Phys Med Rehabil Clin North Am. 2006; 17:347-54. 84. Vanegas H, Vazquez E, Tortorici V. NSAIDs, opioids, cannabinoids and the control of pain by the central nervous system. Pharmaceuticals. 2010; 3:133547. 85. Svensson CI, Yaksh TL. The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing. Annu Rev Pharmacol Toxicol. 2002; 42:553-83. 86. Southworth S, Peters J, Rock A, Pavliv L. A multicenter, randomized, doubleblind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain. Clin Ther. 2009; 31:1922-35. 87. De Oliveira GS Jr, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a metaanalysis of randomized trials. Anesth Analg. 2012; 114:424-33. 88. Slappendel R, Weber EW, Benraad B et al. Does ibuprofen increase perioperative blood loss during hip arthroplasty? Eur J Anaesthesiol. 2002; 19:829-31. 89. Li W, Lian YY, Yue WJ et al. Experimental study of COX-2 selective and traditional non-steroidal anti-inflammatory drugs in total hip replacement. J Int Med Res. 2009; 37:472-8. 90. Dahners LE, Mullis BH. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J Am Acad Orthop Surg. 2004; 12:139-43. 91. Riew KD, Long J, Rhee J et al. Timedependent inhibitory effects of indo-

methacin on spinal fusion. J Bone Joint Surg Am. 2003; 85:632-4. 92. Martin GJ Jr, Boden SD, Titus L. Recombinant human bone morphogenetic protein-2 overcomes the inhibitory effect of ketorolac, a nonsteroidal antiinflammatory drug (NSAID), on posterolateral lumbar intertransverse process spine fusion. Spine. 1999; 24:2188-94. 93. Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth. 2005; 52:506-12. 94. Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spinal fusion: a metaanalysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine. 2011; 36:E461-8. 95. Glassman SD, Rose SM, Dimar JR et al. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine. 1998; 23:834-8. 96. Simon AM, Manigrasso MB, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002; 17:963-76. 97. Kalfas IH. Principles of bone healing. Neurosurg Focus. 2001; 10:E1. 98. Deguchi M, Rapoff AJ, Zdeblick TA. Posterolateral fusion for isthmic spondylolisthesis in adults: analysis of fusion rate and clinical results. J Spinal Disord. 1998; 11:459-64. 99. Lumawig JM, Yamazaki A, Watanabe K. Dose-dependent inhibition of diclo­ fenac sodium on posterior lumbar interbody fusion rates. Spine J. 2009; 9:343-9. 100. Cassinelli EH, Dean CL, Garcia RM et al. Ketorolac use for postoperative

pain management following lumbar decompression surgery: a prospective, randomized, double-blinded, placebocontrolled trial. Spine. 2008; 33:1313-7. 101. Le Roux PD, Samudrala S. Postoperative pain after lumbar disc surgery: a comparison between parenteral ketorolac and narcotics. Acta Neurochir. 1999; 141:261-7. 102. Mack PF, Hass D, Lavyne MH et al. Postoperative narcotic requirement after microscopic lumbar discectomy is not affected by intraoperative ketorolac or bupivacaine. Spine. 2001; 26:658-61. 103. Munro HM, Walton SR, Malviya S et al. Low-dose ketorolac improves analgesia and reduces morphine requirements following posterior spinal fusion in adolescents. Can J Anaesth. 2002; 49:461-6. 104. Aubrun F, Langeron O, Heitz D et al. Randomised, placebo-controlled study of the postoperative analgesic effects of ketoprofen after spinal fusion surgery. Acta Anaesthesiol Scand. 2000; 44:934-9. 105. Periáñez-Párraga L, Martínez-López I, Ventayol-Bosch P et al. Drug dosage recommendations in patients with chronic liver disease. Rev Esp Enferm Dig. 2012; 104:165-84. 106. Amarapurkar DN. Prescribing medications in patients with decompensated liver cirrhosis. Int J Hepatol. 2011; 2011:519-26. 107. Garcia RM, Cassinelli EH, Messerschmitt PJ et al. A multimodal approach for postoperative pain management after lumbar decompression surgery: a prospective, randomized study. J Spinal Disord Tech. 2013; 26:291-7.

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