The Efficacy of Preemptive Analgesia for Postoperative Pain Control: A Systematic Review of the Literature BARBARA PENPRASE, PhD, RN, CNE, ANEF; ELISA BRUNETTO, MSN, CRNA; EMAN DAHMANI, MSN, CRNA; JOLA JANAQI FORTHOFFER, MSN, BSN, CRNA; SAMANTHA KAPOOR, MSN, RN, CRNA

ABSTRACT The purpose of preemptive analgesia is to reduce postoperative pain, contributing to a more comfortable recovery period and reducing the need for narcotic pain control. The efficacy of preemptive analgesia remains controversial. This systematic review of the literature evaluated the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, and gabapentin as preemptive oral analgesics for surgical patients. Included articles were limited to studies of adult patients that compared the difference in postoperative pain between control and treatment groups. Of 40 studies reviewed, 14 met the inclusion criteria, including two on NSAIDs, four on COX-2 inhibitors, and eight on gabapentin. Research was predominantly conducted outside the United States. Gabapentin and COX-2 inhibitors were found to be the most effective preemptive analgesics for postoperative pain control. As part of a collaborative team, perioperative nurses and certified RN anesthetists are responsible for ongoing pain assessment and management for preemptive analgesic interventions. AORN J 101 (January 2015) 94-105. Ó AORN, Inc, 2015. http://dx.doi.org/10.1016/j.aorn.2014.01.030 Key words: preemptive analgesia, postoperative pain control, nonsteroidal anti-inflammatory drugs, NSAIDs, cyclooxygenase-2 inhibitors, COX-2 inhibitors, gabapentin.

R

ecent studies have shown that acute postoperative pain continues to be undermanaged even as surgery and anesthesia become safer.1 Effective postoperative pain management increases patient satisfaction, improves patient outcomes, and reduces the cost of care.2 Therefore, there has been an increasing emphasis

on improving postoperative pain control. As focus is increasingly directed toward controlling pain and reducing narcotic use, preemptive analgesia may become more prevalent. A number of clinical trials have suggested that preemptive analgesia leads to a decrease in postoperative pain, less total analgesic consumption, and improved patient comfort.3 It is http://dx.doi.org/10.1016/j.aorn.2014.01.030

94 j AORN Journal  January 2015 Vol 101 No 1

Ó AORN, Inc, 2015

EFFICACY OF PREEMPTIVE ANALGESIA important that perioperative nurses understand the use of preemptive analgesia so they can evaluate outcomes of treatment, especially as related to postoperative pain control. According to the International Association for the Study of Pain, pain is an unpleasant sensation associated with sensory and emotional experiences that can cause potential or actual tissue damage.4 Acute postoperative pain typically is caused by mechanical, chemical, and thermal nociceptive stimuli (ie, painful, sometimes detrimental or injurious, stimuli). Acute nociceptive signals associated with tissue damage initiate alterations in the peripheral and central pain pathways. Primary afferent neurons detect noxious stimuli from the periphery and through transduction conduct pain signals to the dorsal horn of the central nervous system (CNS). An inflammatory response occurs with tissue damage and leads to the release of chemical mediators such as substance P, histamine, bradykinin, and prostaglandin. This leads to peripheral sensitization caused by increased conduction of nociceptive stimuli to the CNS. Central sensitization occurs as a result of amplification of nociceptive neurons in the dorsal horn of the CNS.5 In addition, severe acute pain is a risk factor for the development of chronic pain. Preemptive analgesia is an antinociceptive treatment applied before tissue injury to prevent peripheral and central sensitization.6 By decreasing sensitization, preemptive analgesia is thought to decrease the incidence of postoperative hyperalgesia and allodynia.3 Decreasing sensitization is thought to reduce the magnitude and duration of postoperative pain. The concept of preemptive analgesia for postoperative pain control was pioneered in 1913 by George W. Crile, MD, who based his assumptions on clinical observations that suggested that analgesic interventions were more effective when they were administered before a surgical procedure.7 Subsequent experimental evidence suggested that it may be possible to decrease or prevent the neurophysiological and biochemical effects of noxious input to the CNSdsuch as

www.aornjournal.org

surgerydrather than initiating treatment after a noxious event occurs.5 The efficacy of preemptive analgesia remains controversial in the United States because the majority of studies have been conducted in other countries and multiple medications and modes of delivery have been used; in addition, results from trials in humans have been inconsistent. Preemptive analgesia has been researched widely in oral surgical procedures, especially in countries other than the United States, and is becoming popular in a variety of surgical procedures, including laparoscopic cholecystectomy, coronary artery bypass surgery, thyroidectomy, lumbar discectomy, and joint replacements.8-11 If the research shows that preemptive analgesia is used successfully to relieve postoperative pain in other countries, it would be important for health care practitioners in the United States to consider its use. Although animal studies have shown positive benefits from preemptive analgesia, clinical trials in humans remain inconsistent regarding efficacy, as well as medication use.3 This inconsistency may be caused by many factors, such as a lack of uniformity in defining preemptive analgesia, variation in methodology used for clinical trials, timing of the prestimulus versus poststimulus dose, and lack of an objective standard for pain measurement.2 Researchers are just beginning to study what types of medications are most beneficial for use; thus, the optimal medication treatment choices have not been clearly established by the literature. Preemptive analgesia began to be used more frequently at our hospital when new anesthesiologists joined the staff. This practice resulted in controversy between anesthesia providers regarding whether preemptive analgesia is effective. Thus, we conducted a systematic review of the literature, focusing specifically on the preemptive analgesia being used at our clinical site. Clinical trials on preemptive analgesia have evaluated different analgesics using a variety of administration routes. The majority of clinical studies and reviews for preemptive analgesia focus on an individual AORN Journal j 95

January 2015 Vol 101 No 1

PENPRASE ET AL

between 2003 and 2013. We used a broad free-text medication or a combination of medications with search of full-text articles with the following terms: IV, intramuscular, and neuraxial modes of adminpre-emptive analgesia, postoperative analgesia, and istration. Research has indicated minimal efficacy preincisional analgesia. The retrieved results were with preemptive analgesic opioids and N-methylthen limited to studies involving oral NSAIDs, COXD-aspartate antagonists.12,13 We examined key 2 inhibitors, and gabapentin because these were the research findings regarding the use of oral nonmost widely researched oral medications related to steroidal anti-inflammatory drugs (NSAIDs), preemptive analgesia. We also limited our review to cyclooxygenase-2 (COX-2) inhibitors, and gabastudies involving adult patients. Many of the studies pentin in preemptive analgesia for postoperative that we retrieved were conducted outside the United pain control. Because the bioavailability of these States, but results for all studies were similar. medications can vary, we elected to review studies We sought studies of quantitative design that in which oral medications that share similar pharwere randomized blinded studies so that biases macokinetic profiles were used. were lessened, increasing the rigor of the research Perioperative nurses and certified registered findings. We initially identified 100 articles (Figure 1). nurse anesthetists (CRNAs) are part of a collaboOf these, 60 were not specific to our search criteria. rative team with physicians and anesthesiologists We screened the rewho are responsible maining 40 articles, of for patients’ ongoing which 14 met inclusion pain assessment and Perioperative nurses and certified registered criteria for this review. management. When nurse anesthetists are part of a collaborative We excluded 26 studies use of preemptive an- team with physicians and anesthesiologists who are responsible for patients’ ongoing for various reasons: algesia is planned, it pain assessment and management. two were not available is vital that CRNAs in English, two did not initiate preoperative explain the type of analgesic orders, presurgery conducted, one was very similar to another operative nurses ensure that preemptive analgesics study by the same authors, and the rest used different are administered in a timely manner, and postopmedications (ie, multimodal treatments) in different erative nurses evaluate the outcomes of preemptive experimental groups preoperatively. We identified analgesia. The purpose of preemptive analgesia is six studies that met our research criteria for oral to reduce postoperative pain for surgical patients, NSAIDs for preemptive analgesia; however, four of allowing a more comfortable recovery period and these were excluded because of coadministration of reducing the need for narcotic pain control. The puroral NSAIDs with local anesthetic. Of the 14 studies pose of this systematic review of the literature was that were included in the review, two discussed to present current research regarding best practices NSAIDs,14,15 four discussed COX-2 inhibitors,16-19 related to preemptive analgesia. We completed this review to help guide future practices for health care and eight discussed gabapentin8-10,20-24 for preproviders at our facility regarding the potential beneemptive analgesia in surgical patients. A summary fits and risks of using preemptive analgesia for of the literature included in this systematic review our patients. is presented in Supplementary Table 1. METHODS We conducted electronic literature searches using CINAHLÒ, PubMedÒ, and OVIDÒ databases with restrictions to papers published in English 96 j AORN Journal

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Nonsteroidal anti-inflammatory drugs are among the most popular medications used to relieve pain,

EFFICACY OF PREEMPTIVE ANALGESIA

www.aornjournal.org

Figure 1. Of 100 articles identified in the initial search, 40 articles were screened. Of these, 14 met inclusion criteria for the systematic review of the literature.

fever, and inflammation. In the United States, more than 70 million NSAID prescriptions are written annually, and over-the-counter purchases reach a consumption of 30 billion doses.25 Nonsteroidal anti-inflammatory drugs are of particular interest to the practice of anesthesia because, unlike opioids, they do not cause respiratory depression, nausea, sedation, or urinary retention. The significance of using NSAIDs for preemptive analgesia lies in their peripheral and central mechanism of action; these

medications inhibit the enzymes called cyclooxygenases and lead to decreased production of prostaglandins. Prostaglandins are primary chemicals produced by the body that carry out a variety of important chemical and biological body functions. By inhibiting the action of COX-1 and COX-2 and preventing the production of prostaglandins, NSAIDs decrease inflammation, vasodilatation, capillary permeability, pain, and fever.26 AORN Journal j 97

January 2015 Vol 101 No 1

The two studies on the use of NSAIDs as preemptive analgesia that met criteria for this systematic review were randomized double-blind clinical studies that assessed postoperative pain control in oral surgery. The medications used for the studies were ibuprofen and ketoprofen. Both studies were performed outside the United States. The effectiveness of ketoprofen as a preemptive analgesic was studied in Poland by Kaczmarzyk et al14 in patients undergoing third molar surgery. A total of 96 patients were randomly divided into three groups: pretreatment, posttreatment, and no treatment (ie, placebo). Patients in the pretreatment group (n ¼ 34) received ketoprofen 60 minutes before surgery and a placebo 60 minutes after surgery, patients in the posttreatment group (n ¼ 30) received a placebo 60 minutes before surgery and ketoprofen 60 minutes after surgery, and patients in the placebo group (n ¼ 32) received a placebo 60 minutes before surgery and 60 minutes after surgery. Researchers found that pre- and postoperative administration of ketoprofen resulted in delayed pain development compared to placebo; however, postoperative ketoprofen administration was more effective in providing pain control than preoperative administration. The second study, by Jung et al,15 was conducted in Korea to determine whether ibuprofen provided postoperative pain relief when started preoperatively. Eighty patients undergoing surgical removal of the mandibular third molar were divided into a pretreatment (n ¼ 25), a posttreatment (n ¼ 26), or a no-treatment group (n ¼ 29). The posttreatment group demonstrated the greatest pain relief compared with the other two groups. The researchers’ findings indicated that NSAIDs would not be beneficial for preemptive analgesia. However, they found that postoperative administration provided significant pain relief. Both studies focused on patients undergoing oral surgery, so the generalizability of the results to other types of surgery is questionable. The findings revealed that NSAIDs when administered postoperatively provided significant pain relief and 98 j AORN Journal

PENPRASE ET AL decreased the intensity of pain. Outside of oral surgical procedures, we found that NSAIDs were not used widely for preemptive analgesia. It appears from the research published on preemptive analgesia that more effective oral medications have replaced NSAIDs during the past 10 years. CYCLOOXIGENASE-2 INHIBITORS Activation of COX-2 by surgical trauma produces hyperalgesia, which increases the sensitivity of peripheral nociceptors.27 Nonsteroidal anti-inflammatory drugs inhibit both the COX-1 and COX-2 enzymes, which, along with the desired effects of providing pain relief and inflammation reduction, may lead to the inhibition of normal platelet function and gastrointestinal toxicity.16 The selectivity of COX-2 inhibitors causes the lack of gastrointestinal and platelet function effects; thus, COX-2 inhibition seems to be an excellent choice for postoperative pain management. The COX-2 inhibitors that are commonly used for preemptive analgesia include celecoxib, rofecoxib, valdecoxib, etoricoxib, and lumiracoxib.28 Research indicates that the use of COX-2 inhibitors for preemptive analgesia reduces postoperative pain and decreases the overall use of opioids postoperatively.17 In this review, we found that clinical studies supported the efficacy of using COX-2 inhibitors as a preemptive analgesic for various surgical procedures, including thoracotomies, arthroscopic knee surgeries, and laparoscopic cholecystectomies. Of the four research studies we reviewed, one study was a randomized controlled trial,16 two studies were double-blinded randomized controlled trials,17,18 and one study was a retrospective chart review.19 The surgical procedures were more complex than oral surgical procedures and thus potentially resulted in greater postoperative pain. The different surgical procedures were valuable to compare and evaluate the efficacy of preemptive analgesia for postoperative pain. Two studies were conducted in the United States; the others were conducted in Thailand and Turkey. In a study by Horattas et al18 from the United States, 116 patients undergoing laparoscopic

EFFICACY OF PREEMPTIVE ANALGESIA

www.aornjournal.org

group that was given a preemptive selective COX-2 cholecystectomies received 50 mg of rofecoxib or inhibitor. Thus, COX-2 inhibitors administered as placebo before surgery. This study showed a sigpreemptive analgesia decreased the length of stay nificant decrease in postoperative narcotic use and and overall need for narcotic pain control. an increase in postoperative activity level in the A study by Boonriong et al16 showed mixed treatment group. The study was limited to laparoscopic cholecystectomies. However, the three other results for a sample of 102 patients in Thailand studies involving surgical procedures supported undergoing anterior cruciate ligament reconstructhat COX-2 inhibitors significantly decreased pain tion. Patients were divided into three groups; the levels postoperatively in these patients. first group received 120 mg of etoricoxib before 19 Research by Duellman et al focused on comsurgery (n ¼ 35), the second group received 400 mg of celecoxib before surgery (n ¼ 35), and the paring the effect of preemptive analgesia with third group received placebo (n ¼ 32). Although patient-controlled analgesia (PCA). The research patients in the etoricoxib group had significantly was conducted in the United States on patients lower postoperative pain intensity, patients in the undergoing total joint arthroplasties and was celecoxib group showed no significant difference prompted by the adverse effects caused by postcompared with paoperative PCA adtients in the placebo ministration, such as group. These findings nausea, decreased Research indicates that the use of distinguished between rehabilitation particicyclooxygenase-2 inhibitors for preemptive analgesia reduces postoperative pain and dethe effectiveness of pation, and increased creases the overall use of opioids postoperatively. etoricoxib and celelength of stay. The coxib; etoricoxib sigresearchers’ focus was nificantly decreased to identify an alternapostoperative pain whereas no significance was tive pain relief modality for patients undergoing noted postoperatively with celecoxib. total joint arthroplasty. Fifty-eight patients received In a double-blind placebo-controlled prospective 200 mg of celecoxib every 12 hours preoperatively study conducted in Turkey involving 60 patients while they were in the hospital waiting for surgery; undergoing thoracotomy,17 half the patients were postoperatively, patients received another 200 mg of celecoxib every 12 hours with an oral narcotic given 50 mg of rofecoxib preoperatively and the (ie, oxycodone) during the rest of the hospital stay. other half received placebo. The researchers found The postoperative medication regimen began when that patients who received rofecoxib before surgery the patient asked for pain medication, so the reghad a significant decrease in opioid requirements imen varied according to patients’ needs. For compared with patients in the placebo group. Albreakthrough pain, patients received IV narcotics though each group had only 30 patients, the results as needed during the postoperative period. In the were promising regarding the effectiveness of control group, 69 patients received no preoperative COX-2 inhibitors in decreasing postoperative pain. celecoxib and were treated postoperatively with an Clearly results showed that regardless of the IV narcotic via the PCA pump for 48 hours and surgical procedure, COX-2 inhibitors adminiswith an oral narcotic until discharge. The patients tered preoperatively had positive effects on postin the PCA group required significantly more operative pain scores, opioid use, and length of morphine (average dose, 17.7 vs 7.2 mg), had hospital stay. Additional research using COX-2 a longer average hospital stay (3.7 vs 2.7 days), inhibitors for preemptive analgesia should be and had a significant decrease in participation in conducted, especially in the United States, for postoperative rehabilitation compared with the surgical procedures that can result in significant AORN Journal j 99

January 2015 Vol 101 No 1

PENPRASE ET AL

although pathological pain is reduced, other protective nociceptive mechanisms remain intact with the use of gabapentin.10 Research results also have demonstrated that the combination of gabapentin GABAPENTIN with other antinociceptive medications produces a Historically, the mainstay for postoperative pain synergistic action.22 management has been opioids, although adverse Although the exact mechanism of action of effects (eg, nausea, vomiting, pruritus, respiratory gabapentin is not clearly understood, it appears depression) may limit their use. In addition, as there may be multiple mechanisms. Gabapentin mentioned, NSAIDs are used commonly as addoes not act via opioid mechanisms; rather, it binds juncts to reduce pain after minor surgery, but their to alpha-2-delta subunits of voltage-gated calcium use may be limited in patients with bleeding channels located presynaptically in the dorsal root diathesis or renal or gastrointestinal problems,20 ganglia.8 This effect reduces the release from and research does not support the use of NSAIDs sensory neurons of for preemptive anal14,15 excitatory neurotransgesia. An alternamitters involved in tive approach to pain Gabapentin has demonstrated an inhibitory control, gabapentin is effect on preexisting allodynia and hyperalgesia, pain pathways, inbut it has shown no effect on pain transmission cluding glutamate, a structural analogue in normal skin. noradrenaline, and of gamma aminobusubstance P.8,20 Addityric acid and is an tional proposed mechantiepileptic drug for anisms of pain reduction from gabapentin include partial seizures; its role in pain management has an increase in the concentration and rate of synbeen limited to neuropathic pain, diabetic neuthesis of gabapentin in the brain, modulation of ropathy, postherpetic neuralgia, and reflex 21 glutamate receptors, inhibition of voltage-activated sympathetic dystrophy. An increasing number sodium channels, and an increase in serotonin of studies have suggested that gabapentin used as concentrations.8,9 Therefore, it is believed that a preemptive analgesic has a beneficial effect on preoperative dosing of gabapentin exerts its analboth pain scores and postoperative opioid con8-10,20-24 gesic effects by preemptively decreasing the spinal sumption. There has been limited research cord excitation caused by surgical trauma.23 conducted in the United States related to the use To determine whether preoperative gabapentin of gabapentin as a preemptive analgesic, which was effective in reducing postoperative pain and is surprising because gabapentin has been studwhether the research findings demonstrated eviied extensively in other countries. dence of opioid-sparing effects, we identified 16 In clinical studies, gabapentin has been shown to articles according to our research criteria for reduce hypersensitivity induced by inflammation gabapentin. We eliminated eight because they and injury. In addition, gabapentin has demoneither compared gabapentin to pregabalin, melastrated an inhibitory effect on preexisting allodynia tonin, or other oral medications; compared its efand hyperalgesia, as well as the development of ficacy to regional anesthesia; or tried to find the secondary allodynia and hyperalgesia resulting from effective dose for preemptive analgesia. central sensitization, but it has shown no effect on 10 Eight studies met our criteria for postoperative pain transmission in normal skin. Compared with pain between control and treatment groups when results found with remifentanil (ie, a synthetic opipreemptive analgesic measures were initiated. Each oid analgesic), these results are of considerable study reviewed a different type of surgery, as well importance to postoperative pain relief because postoperative pain, such as abdominal or thoracic surgeries.

100 j AORN Journal

EFFICACY OF PREEMPTIVE ANALGESIA

www.aornjournal.org

KEY TAKEAWAYS FOR CLINICAL PRACTICE Preemptive Analgesia Can Improve Postoperative Pain Control Why Did We Do This Research? n Preemptive analgesia is used to decrease postoperative pain worldwide, but is not a fully accepted practice in the United States. We performed a literature review to investigate whether nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, and gabapentin are effective for reducing postoperative pain.

What Did We Find? n Based on our findings, preemptive administration of gabapentin and COX-2 inhibitors is effective for postoperative pain control, but using NSAIDs for preemptive analgesia does not improve postoperative pain control.

How Can Clinicians Use These Results? n Clinicians: Clinicians need to be aware that gabapentin has become the medication of choice for preemptive analgesia and that research does not support the use of NSAIDs as a preemptive analgesic for postoperative pain relief. n Managers: Managers should be aware that the practice of preemptive analgesia is increasing in the United States, which will affect preoperative preparation. n Educators: Educators also should be aware of the increase in the use of preemptive analgesia in the United States, especially gabapentin, and that perioperative nursing teams need to be educated on the uses and adverse effects of this form of treatment for postoperative pain control.

Penprase B, Brunetto E, Dahmani E, Forthoffer JJ, Kapoor S. The efficacy of preemptive analgesia for postoperative pain control: a systematic review of the literature. AORN J. 2015;101(1):94-105. Copyright Ó AORN, Inc, 2015.

as multiple gabapentin dosages and administration times. The surgeries included in this review were thyroidectomy, tongue reconstruction with anterolateral thigh flap, coronary artery bypass graft, lower-extremity orthopedic surgery, caesarean delivery, lumbar discectomy, abdominal surgery, and minilaparoscopic open cholecystectomy. Of the eight studies we reviewed, seven were randomized placebo-controlled trials8-10,21-24 and one was a nonrandomized retrospective cohort study.20 In all the studies, patients in the gabapentin groups received a single preoperative dose of gabapentin ranging between 300 and 1,200 mg. To facilitate analysis of the researchers’ results, we created three subgroups based on preoperative doses: 300 mg, 600 mg, and 1,200 mg. Each study included an analysis of pain intensity using pain scores, analgesic consumption, and breakthrough pain control. All the researchers also recorded and analyzed the occurrence of adverse effects related to gabapentin administration in addition to postoperative pain scores and opioid consumption. The most commonly reported adverse effects were nausea, vomiting, sedation, dizziness, respiratory depression, and pruritus. Sample sizes ranged from

50 to 120, and because all studies had a control group, treatment groups were uniform. We included two studies9,10 that used a preoperative dose of 300 mg of gabapentin in our analysis. In both studies, patients in the treatment group had significantly lower pain scores at all intervals measured in the first 24 hours after surgery. Although the two studies involved different opioids for postoperative pain control, fentanyl9 and morphine,10 patients in both treatment groups required less medication in the first 24 hours after surgery compared with the control groups. In the study conducted by Montazeri et al9 in Iran, the researchers reported the total 24-hour morphine consumption to be, on average, 15.43 mg for patients in the gabapentin group versus 17.94 mg for patients in the control group who underwent lower-extremity orthopedic surgery. The results also demonstrated a significant difference between the two groups in the first time a patient requested morphine administration after surgery (31.57 minutes in the gabapentin group versus 26.71 minutes in the placebo group), but no difference in recovery duration. Similarly, a study by Pandey et al10 in India showed that total fentanyl consumption in AORN Journal j 101

January 2015 Vol 101 No 1

PENPRASE ET AL

24-hour period after surgery compared with the the first 24 hours after undergoing lumbar discontrol group. coidectomy surgery was significantly less in the We included two studies involving a preopgabapentin group (233.5 mg) than in the control erative dose of 1,200 mg of gabapentin in our group (359.6 mg). Groups were small in both review.20,24 One study was performed in Kuwait,24 studies, with only 28 or 35 participants, but it is noteworthy that similar results were identified in and the other, in Hong Kong20; surgeries included two different locations. patients undergoing either thyroidectomy or tongue We included four studies using a preoperative construction. Both studies showed that postoperative 8,21-23 dose of 600 mg of gabapentin in our analysis. pain assessment scores were significantly lower 21,22 inthe gabapentin group compared with the control Two studies were conducted in India, one was 23 group in the first 24 conducted in Canada, hours after surgery. and one was conducted 8 in Turkey. All four Advanced practice nurses, certified registered For postoperative analgesia, both studies used studies concluded nurse anesthetists, anesthesiologists, and morphine; morphine that pain scores in surgeons should collaboratively establish preoperative protocols and practice guidelines consumption was the treatment groups were significantly lower for the implementation of preemptive analgesia. significantly lower in the gabapentin groups than pain scores for the compared with the control groups for the control groups. Although sample sizes were different first 24 hours after surgery both at rest and with (7224 and 5020 participants), the studies were permovement or coughing. In the study by Srivastava et al,22 two groups consisted of 60 patients each. formed in different countries, and they involved patients undergoing different surgical procedures, The researchers assessed pain scores at 24 hours both studies indicated significant reductions in after surgery and found that pain scores were postoperative pain with 1,200 mg of gabapentin significantly lower for the group that received administered preoperatively. gabapentin. At 48 hours, they found pain levels All the studies using gabapentin were conducted to be comparable in both the treatment and outside the United States; therefore, there is a gap control groups. in this research related to the value of using gabaMedications used for postoperative pain control 8,23 21 pentin for preemptive analgesia in the United in the studies included morphine, diclofenac, States. However, results of these studies show evand tramadol.22 Gabapentin was used as the preidence of the efficacy of gabapentin (300 mg, 600 mg, emptive analgesia before the surgical procedure. In or 1,200 mg) for preemptive analgesia. Administhree of the studies, total medication consumption tration of preoperative gabapentin was effective for postoperative pain and need for breakthrough for controlling acute postoperative pain and is the pain control were lower in the gabapentin groups.8,21,22 8 medication of choice currently being used for preMenda et al found that total morphine consumpemptive analgesia throughout the world.8-10,20-24 tion in the first 24 hours after surgery was 57% lower in the gabapentin group versus the control group. However, a study by Moore et al23 in CanDISCUSSION AND IMPLICATIONS ada showed no difference in postoperative opioid Through this review of the literature, we learned consumption when gabapentin was administered that how preemptive analgesia is delivered varies preoperatively. The research findings revealed that across the globe. Based on this review, we consider patients’ pain was decreased and satisfaction scores preemptive analgesia with oral COX-2 inhibitors were higher in the gabapentin group in the first and gabapentin to be beneficial; the research 102 j AORN Journal

EFFICACY OF PREEMPTIVE ANALGESIA reviewed supports their administration for select surgical procedures to benefit patients. Based on our review of NSAIDs, there appears to be no clinical benefit for their use as preemptive analgesia. Evidence supports that health care providers should advocate for the use of preemptive COX-2 inhibitors and gabapentin to reduce postoperative pain. Advanced practice nurses, CRNAs, anesthesiologists, and surgeons should collaboratively establish preoperative protocols and practice guidelines for the implementation of preemptive analgesia. Specific barriers must be considered when implementing preemptive analgesia in perioperative practice. For example, patients may refuse to take the preemptive analgesic medication as prescribed, and some surgeons and anesthesiologists may be concerned about the use of preemptive analgesic medication because of potential adverse effects. The adverse effects of gabapentin include but are not limited to nausea, vomiting, sedation, pruritus, constipation, urinary retention, and dizziness.22 Potential prothrombotic effects of COX-2 inhibition and delayed wound healing must be considered.18 Fortunately, as demonstrated by this review, recent studies have shown favorable results regarding the safe use for both medications. However, concerns about adverse effects when administering these medications must be considered for all patients, along with potential drug-to-drug interactions when given with other medications. Preemptive analgesia is widely used in many countries. Of studies conducted in the United States, preemptive analgesia has been used in a variety of surgical procedures: oral surgery, laparoscopic cholecystectomy, and total joint arthroplasty. The results of these studies are similar to results in other countries. Evidence supports the use of COX-2 inhibitors and gabapentin as treatment options to reduce postoperative pain and significantly decrease the need for narcotics.29 Perioperative nurses need to remain aware of how to care for patients who are being treated with preemptive analgesia. For example, nurses need to be aware that the medications must be given on time for

www.aornjournal.org

the first 24 to 48 hours to maintain an optimal threshold, close observation for any adverse reactions from the medications is necessary, and there still may be a need for narcotics for postoperative pain control. The primary role of the postoperative nurse has not changed. Nurses must ensure that good postoperative pain control is established and maintained based on the assessment of the patient’s pain. The preoperative use of gabapentin and COX-2 inhibitors was found to be the most effective method for reducing postoperative pain in diverse types of surgeries. Additional studies should be conducted to continue evaluating their efficacy in reducing postoperative pain. Future research should focus on the best times to administer the medication(s), what schedule works the best to maintain optimal pain control and long-term pain reduction, and cost-effectiveness. In addition, future studies should focus attention on the effectiveness of coadministration of these medications as preemptive analgesics for specific surgeries. SUPPLEMENTARY DATA The supplementary table associated with this article can be found in the online version at http://dx.doi .org/10.1016/j.aorn.2014.01.030. Editor’s notes: CINAHL, Cumulative Index to Nursing and Allied Health Literature, is a registered trademark of EBSCO Industries, Birmingham, AL. PubMed is a registered trademark of the US National Library of Medicine, Bethesda, MD. Ovid is a registered trademark of CDP Technologies, Inc, New York, NY. References 1. Peng PW, Wijeysundera DN, Li CC. Use of gabapentin for perioperative pain controlda meta-analysis. Pain Res Manag. 2007;12(2):85-92. 2. Heck U, Mitchell VD. Preemptive analgesia: physiology and clinical studies. In: Benzon HT, Raja SN, Malloy RE, Liu SS, Fishman SM, eds. Essentials of Pain Medicine and Regional Anesthesia. 2nd ed. Philadelphia, PA: Elsevier-Churchill Livingstone; 2005:229-234. 3. Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain

AORN Journal j 103

January 2015 Vol 101 No 1

4.

5. 6.

7. 8.

9.

10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

management: a meta-analysis. Anesth Analg. 2005; 100(3):757-773. International Association for the Study of Pain. IASP Taxonomy. http://www.iasp-pain.org/Education/Content .aspx?ItemNumber¼1698. Accessed August 13, 2014. Dahl JB, Møiniche S. Pre-emptive analgesia. Br Med Bull. 2004;71:13-27. Kelly DJ, Ahmed M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth. 2001;48(10):1000-1010. Crile GW. The kinetic theory of shock and its prevention through anoci-association. Lancet. 1913;185:7-16. Menda F, K€oner O, Sayın M, Ergenoglu M, K€uc‚€ukaksu S, Aykac‚ B. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24(5): 808-813. Montazeri K, Kashefi P, Honarmand A. Pre-emptive gabapentin significantly reduces postoperative pain and morphine demand following lower extremity orthopedic surgery. Singapore Med J. 2007;48(8):748-751. Pandey CK, Sahay S, Gupta D, et al. Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy. Can J Anaesth. 2004;51(10):986-989. Sandhu T, Paiboonworachat S, Ko-iam W. Effects of preemptive analgesia in laparoscopic cholecystectomy: a double-blind randomized controlled trial. Surg Endosc. 2011;25(1):23-27. Møiniche S, Kehlet H, Dahl BD. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology. 2002;96(3):725-741. Kissin I. Preemptive analgesia. Anesthesiology. 2000; 93(4):1138-1143. Kaczmarzyk T, Wichlinski J, Stypulkowska J, Zaleska M, Woron J. Preemptive effect of ketoprofen on postoperative pain following third molar surgery. A prospective, randomized, double-blinded clinical trial. Int J Oral Maxillofac Surg. 2010;39(7):647-652. Jung YS, Kim MK, Um YJ, Park HS, Lee EW, Kang JW. The effects on postoperative oral surgery pain by varying NSAID administration times: comparison on effect of preemptive analgesia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;100(5):559-563. Boonriong T, Tangtrakulwanich B, Glabglay P, Nimmaanrat S. Comparing etoricoxib and celecoxib for preemptive analgesia for acute postoperative pain in patients undergoing arthroscopic anterior cruciate ligament reconstruction: a randomized controlled trial. BMC Musculoskelet Disord. 2010;11:246. Celik JB, Gormus N, Gormus ZI, Okesli S, Solak H. Preoperative analgesia management with rofecoxib in thoracotomy patients. J Cardiothorac Vasc Anesth. 2005; 19(1):67-70. Horattas MC, Evans S, Sloan-Stakleff KD, Lee C, Snoke JW. Does preoperative rofecoxib (Vioxx) decrease postoperative pain with laparoscopic cholecystecomy. Am J Surg. 2004;188(3):271-276. 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(3):167.

104 j AORN Journal

PENPRASE ET AL 20. Chiu TW, Leung CC, Lau EY, Burd A. Analgesic effects of preoperative gabapentin after tongue reconstruction with the anterolateral thigh flap. Hong Kong Med J. 2012; 18(1):30-34. 21. Parikh HG, Dash SK, Upasani CB. Study of the effect of oral gabapentin used as preemptive analgesia to attenuate post-operative pain in patients undergoing abdominal surgery under general anesthesia. Saudi J Anaesth. 2010; 4(3):137-141. 22. Srivastava U, Kumar A, Saxena S, Mishra AR, Saraswat N, Mishra S. Effect of preoperative gabapentin on postoperative pain and tramadol consumption after minilap open cholecystectomy: a randomized double-blind, placebocontrolled trial. Eur J Anaesthesiol. 2010;27(4):331-335. 23. Moore A, Costello J, Wieczorek P, Shah V, Taddio A, Carvalho J. Gabapentin improves postcesarean delivery pain management: a randomized, placebo-controlled trial. Anesth Analg. 2011;112(1):167-173. 24. Al-Mujadi H, A-Refai AR, Katzarov MG, Dehrab NA, Batra YK, Al-Qattan AR. Preemptive gabapentin reduces postoperative pain and opioid demand following thyroid surgery. Can J Anaesth. 2006;53(3):268-273. 25. Wiegand TJ, Tarabar A. Nonsteroidal anti-inflammatory agent toxicity. Medscape. http://emedicine.medscape .com/article/816117-overview. Updated March 3, 2014. Accessed August 13, 2014. 26. Sundy JS. Nonsteroidal anti-inflammatory drugs. In: Koopman WJ, Moreland LW, eds. Arthritis and Allied Conditions: A Textbook of Rheumatology. 15th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:680-704. 27. Reuben SS, Bhopatkar S, Maciolek H, Joshi W, Sklar J. The preemptive analgesic effect of rofecoxib after ambulatory arthroscopic knee surgery. Anesth Analg. 2002;94(1):55-59. 28. Kaye AD, Baluch A, Kaye AJ, Gebhard R, Lubarsky D. Pharmacology of cyclooxygenase-2 inhibitors and preemptive analgesia in acute pain management. Curr Opin Anaesthesiol. 2008;21(4):439-445. 29. Kodali BS, Oberoi JS. Management of postoperative pain. http://www.uptodate.com/contents/management-of -postoperative-pain. Accessed August 13, 2014.

Barbara Penprase, PhD, RN, CNE, ANEF, is a professor at the School of Nursing, Oakland University, Rochester, MI. Dr Penprase has no declared affiliation that could be perceived as posing a potential conflict of interest in the publication of this article. Elisa Brunetto, MSN, CRNA, is a certified registered nurse anesthetist at Promedica, Toledo, OH. Ms Brunettto has no declared affiliation that could be perceived as posing a potential conflict of interest in the publication of this article.

EFFICACY OF PREEMPTIVE ANALGESIA

Eman Dahmani, MSN, CRNA, is a certified registered nurse anesthetist at McLaren Medical Center, Flint, MI. Ms Dahmani has no declared affiliation that could be perceived as posing a potential conflict of interest in the publication of this article. Jola Janaqi Forthoffer, MSN, BSN, CRNA, is a certified registered nurse anesthetist at St John Hospital Medical Center, Detroit, MI. Ms Forthoffer has no declared affiliation that

www.aornjournal.org

could be perceived as posing a potential conflict of interest in the publication of this article. Samantha Kapoor, MSN, BSN, RN, CRNA, is a certified registered nurse anesthetist at McLaren Hospital, Flint, MI. Ms Kapoor has no declared affiliation that could be perceived as posing a potential conflict of interest in the publication of this article.

AORN Journal j 105

Topic NSAIDs

NSAIDs

Author/year Jung et al (2005)1

Kaczmarzyk et al (2010)2

Country Korea

Poland

Purpose

Design

Sample

To determine the best administration time for ibuprofen in providing postoperative pain relief

Randomized, 80 participants undergoing double-blind, parallel-group, removal of a single-center, mandibular third molar active-controlled test design

To determine the effect of preemptive analgesia (ie, ketoprofen) on postoperative pain

Prospective, randomized, double-blind, clinical trial

96 patients undergoing third molar surgery

Measurement n

n

n

n

Limitations

Participants in the posttreatment group demonstrated the greatest pain relief Ibuprofen administered preoperatively was not beneficial

Convenience sample

Preoperative and postoperative administration of ketoprofen resulted in delayed pain development when compared with placebo Postoperative ketoprofen administration was more

Convenience sample

PENPRASE ET AL

Participants were randomly divided into 3 groups: n Pretreatment (n ¼ 25): NSAID administered 1 hr before surgery n Posttreatment (n ¼ 26): NSAID administered 1 hr after surgery n No treatment (n ¼ 29): no NSAID administered Participants were randomly divided into 3 groups: n Pretreatment (n ¼ 34): ketoprofen 60 minutes before surgery and placebo 60 minutes after surgery n Posttreatment (n ¼ 30): placebo 60

Findings

January 2015 Vol 101 No 1

105.e1 j AORN Journal

SUPPLEMENTARY TABLE 1. Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

Topic

COX-2 inhibitors

Boonriong et al (2010)3

Celik et al (2005)4

Country

Thailand

Turkey

Purpose

To compare analgesic efficacy of a single preoperative administration of etoricoxib v celecoxib for postoperative pain

To determine the efficacy of preoperative analgesia with rofecoxib for

Design

Randomized controlled trial

Prospective, randomized, double-blind, placebocontrolled trial

Sample

102 patients undergoing anterior cruciate ligament reconstruction

60 patients undergoing a thoracotomy

Measurement minutes before surgery and ketoprofen 60 minutes after surgery n No treatment (n ¼ 32): placebo 60 minutes before and 60 minutes after surgery Patients were divided into 3 groups: n 120 mg of etoricoxib before surgery (n ¼ 35) n 400 mg of celecoxib before surgery (n ¼ 35) n Placebo (n ¼ 32)

Patients were divided into 2 groups: n 50 mg of rofecoxib before

Findings

Limitations

effective in providing pain control than preoperative administration

n

n

n

Participants in the etoricoxib group had significantly lower postoperative pain intensity than the other groups Participants in the celecoxib group showed no significant difference compared with the placebo group Patients who received rofecoxib before surgery had a significant

Convenience sample

Convenience sample

(table continued)

www.aornjournal.org

AORN Journal j 105.e2

COX-2 inhibitors

Author/year

EFFICACY OF PREEMPTIVE ANALGESIA

SUPPLEMENTARY TABLE 1. (continued) Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

Topic

Author/year

Country

Purpose

Design

postoperative pain management in surgical patients

Sample

Measurement

n

Duellman et al (2009)5

Retrospective United States To compare the chart review effect of multimodal preemptive analgesia v patient-controlled analgesia on postoperative nausea, rehabilitation participation, and length of stay

COX-2 inhibitors

Horattas et al (2004)6

United States To determine the effects of preemptive analgesia with rofecoxib on postoperative pain

Prospective, randomized, double-blind clinical trial

127 patients who 2 groups of paunderwent total tients were joint arthroplasty reviewed: n Postoperative patientcontrolled analgesia n Preemptive analgesia with 200 mg of celecoxib and postoperative pain control with oral oxycodone and celecoxib Patients were 116 patients undergoing divided into elective laparo2 groups: scopic cholen 50 mg of rofecystectomy coxib before surgery (n ¼ 58) n Placebo before surgery (n ¼ 58)

Limitations

decrease in opioid requirements compared with patients in the placebo group Patients who Convenience received presample emptive analgesia n Required significantly less pain medication n Had shorter lengths of hospital stay n Had increased participation in postoperative rehabilitation n

Patients who received the COX-2 inhibitor exhibited a significant decrease in postoperative narcotic use and an increase in

PENPRASE ET AL

COX-2 inhibitors

surgery (n ¼ 30) Placebo (n ¼ 30)

Findings

January 2015 Vol 101 No 1

105.e3 j AORN Journal

SUPPLEMENTARY TABLE 1. (continued ) Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

Topic

Author/year

Country

Purpose

Design

Sample

Gabapentin Al-Mujadi et al (2006)7

Kuwait

To determine whether preemptive gabapentin reduces postoperative pain and opioid demand after thyroid surgery

Prospective, 72 patients randomized, undergoing double-blind trial thyroidectomy

Gabapentin Chiu et al (2012)8

Hong Kong

To investigate the effectiveness of gabapentin in reducing postoperative pain

Nonrandomized open-label trial

50 patients undergoing tongue construction

Measurement

Findings

Convenience sample

Convenience sample

(table continued)

www.aornjournal.org

AORN Journal j 105.e4

postoperative activity level n Rofecoxib was effective in decreasing postoperative pain Patients were n Pain scores divided into were signifi2 groups: cantly lower in patients who n 1,200 mg of received gabapentin gabapentin before surgery (n ¼ 37) n Postoperative opioid conn Placebo before sumption was surgery (n ¼ 35) significantly lower for patients who received gabapentin Patients were Patients who divided into received gaba2 groups: pentin before n 1,200 mg of surgery had gabapentin n Significantly before surgery reduced post(n ¼ 25) operative pain scores n No gabapentin (n ¼ 25) n Significantly less narcotic use after surgery

Limitations

EFFICACY OF PREEMPTIVE ANALGESIA

SUPPLEMENTARY TABLE 1. (continued ) Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

Topic

Author/year

Country

Purpose

Design

Turkey

Randomized, To determine the double blind, effects of singleplacebodose gabapentin controlled trial on postoperative pain and morphine consumption after cardiac surgery

Gabapentin Montazeri et al (2007)10

Iran

To determine whether preemptive gabapentin significantly reduced postoperative pain and morphine demand after lower-extremity orthopedic surgery

Randomized double-blind study

Gabapentin Moore et al (2011)11

Canada

To determine whether gabapentin reduced pain after

Randomized placebocontrolled trial

60 patients undergoing coronary artery bypass graft surgery

Measurement

Findings

Limitations

Patients were Patients who Convenience randomly received gabasample assigned to 1 pentin exhibited of 2 groups: a significant n 600 mg of n Decrease in gabapentin pain scores before surgery compared with (n ¼ 30) patients in the placebo group n Placebo before surgery (n ¼ 30) n Difference in postoperative narcotic use compared with patients in the placebo group 70 patients Patients were n Patients in the Convenience undergoing randomly gabapentin sample lower-extremity assigned to 1 group had orthopedic of 2 groups: significantly surgery less pain n 300 mg of postoperatively gabapentin before surgery n Patients in the (n ¼ 35) gabapentin group required n Placebo before significantly surgery (n ¼ 35) less narcotic pain control after surgery 46 women under- Patients were n At 24 hr, the Convenience going scheduled randomly sample mean pain cesarean assigned to 1 of score was delivery 2 groups: significantly

PENPRASE ET AL

Gabapentin Menda et al (2010)9

Sample

January 2015 Vol 101 No 1

105.e5 j AORN Journal

SUPPLEMENTARY TABLE 1. (continued ) Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

Topic

Author/year

Country

Purpose

Design

Sample

Measurement n

cesarean delivery

n

Findings

600 mg of gabapentin before surgery (n ¼ 21) Placebo before surgery (n ¼ 25) n

India

To determine whether preemptive analgesia using gabapentin decreases postoperative pain after lumbar discoidectomy

Randomized, blinded, placebocontrolled trial

Gabapentin Parikh et al (2010)13

India

To determine the effect of oral gabapentin used as preemptive analgesia to lessen postoperative pain in patients undergoing

Randomized double-blind study

56 patients undergoing singledisc lumbar discoidectomy

Patients were randomly assigned to 1 of 2 groups: n 300 mg of gabapentin 2 hr before surgery (n ¼ 28) n Placebo 2 hr before surgery (n ¼ 28). 60 patients under- Patients were going abdominal randomly surgery assigned to 1 of 2 groups: n 600 mg of gabapentin before surgery (n ¼ 30)

n

n

There was a significant difference in pain scores reported among patients in the gabapentin group after surgery

Convenience sample

Convenience sample

(table continued)

www.aornjournal.org

AORN Journal j 105.e6

Gabapentin Pandey et al (2004)12

lower in patients in the gabapentin group compared with patients in the placebo group There was no difference in opioid consumption noted between the 2 groups Patients who received gabapentin before surgery had less pain and used less opioids postoperatively

Limitations

EFFICACY OF PREEMPTIVE ANALGESIA

SUPPLEMENTARY TABLE 1. (continued ) Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

Topic

Author/year

Country

Purpose

Design

abdominal surgery under general anesthesia

Sample

Measurement n

Findings

Placebo before surgery (n ¼ 30) n

Gabapentin Srivastava et al (2010)14

India

Randomized, To determine the double-blind, effect of preoperative gabaplacebopentin on controlled trial postoperative pain and tramadol consumption after minilaparoscopic open cholecystectomy

120 patients unPatients were dergoing minirandomly laparoscopic assigned to 1 open of 2 groups: cholecystectomy n 600 mg of gabapentin before surgery (n ¼ 60) n Placebo before surgery (N ¼ 60)

n

compared with patients in the placebo group Patients in the gabapentin group required significantly less narcotics after surgery compared with patients in the placebo group Postoperative pain scores were significantly lower in patients in the gabapentin group at all points during postoperative day 1; however, at 48 hr, pain scores were comparable between the groups

Limitations

January 2015 Vol 101 No 1

105.e7 j AORN Journal

SUPPLEMENTARY TABLE 1. (continued ) Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

Convenience sample

PENPRASE ET AL

Topic

Author/year

Country

Purpose

Design

Sample

Measurement

Findings n

Limitations

Total 24-hr tramadol consumption was lower in patients who received gabapentin compared with those who received placebo, but consumption was similar on day 2

EFFICACY OF PREEMPTIVE ANALGESIA

SUPPLEMENTARY TABLE 1. (continued ) Summary of Literature Discussing Preemptive Analgesia for Surgical Patients

COX-2 ¼ cyclooxygenase-2; NSAIDs ¼ nonsteroidal anti-inflammatory drugs.

www.aornjournal.org

AORN Journal j 105.e8

1. Jung YS, Kim MK, Um YJ, Park HS, Lee EW, Kang JW. The effects on postoperative oral surgery pain by varying NSAID administration times: comparison on effect of preemptive analgesia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;100(5):559-563. 2. Kaczmarzyk T, Wichlinski J, Stypulkowska J, Zaleska M, Woron J. Preemptive effect of ketoprofen on postoperative pain following third molar surgery. A prospective, randomized, double-blinded clinical trial. Int J Oral Maxillofac Surg. 2010;39(7):647-652. 3. Boonriong T, Tangtrakulwanich B, Glabglay P, Nimmaanrat S. Comparing etoricoxib and celecoxib for preemptive analgesia for acute postoperative pain in patients undergoing arthroscopic anterior cruciate ligament reconstruction: a randomized controlled trial. BMC Musculoskelet Disord. 2010;11:246. 4. Celik JB, Gormus N, Gormus ZI, Okesli S, Solak H. Preoperative analgesia management with rofecoxib in thoracotomy patients. J Cardiothorac Vasc Anesth. 2005;19(1):67-70. 5. 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(3):167. 6. Horattas MC, Evans S, Sloan-Stakleff KD, Lee C, Snoke JW. Does preoperative rofecoxib (Vioxx) decrease postoperative pain with laparoscopic cholecystecomy. Am J Surg. 2004;188(3):271-276. 7. Al-Mujadi H, A-Refai AR, Katzarov MG, Dehrab NA, Batra YK, Al-Qattan AR. Preemptive gabapentin reduces postoperative pain and opioid demand following thyroid surgery. Can J Anaesth. 2006;53(3):268-273. 8. Chiu TW, Leung CC, Lau EY, Burd A. Analgesic effects of preoperative gabapentin after tongue reconstruction with the anterolateral thigh flap. Hong Kong Med J. 2012;18(1):30-34. €ner O, Sayın M, Ergenog lu M, Ku €c¸u €kaksu S, Aykac¸ B. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 9. Menda F, Ko 2010;24(5):808-813. 10. Montazeri K, Kashefi P, Honarmand A. Pre-emptive gabapentin significantly reduces postoperative pain and morphine demand following lower extremity orthopedic surgery. Singapore Med J. 2007;48(8): 748-751. 11. Moore A, Costello J, Wieczorek P, Shah V, Taddio A, Carvalho J. Gabapentin improves postcesarean delivery pain management: a randomized, placebo-controlled trial. Anesth Analg. 2011;112(1):167-173. 12. Pandey CK, Sahay S, Gupta D, et al. Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy. Can J Anaesth. 2004;51(10):986-989. 13. Parikh HG, Dash SK, Upasani CB. Study of the effect of oral gabapentin used as preemptive analgesia to attenuate post-operative pain in patients undergoing abdominal surgery under general anesthesia. Saudi J Anaesth. 2010;4(3):137-141. 14. Srivastava U, Kumar A, Saxena S, Mishra AR, Saraswat N, Mishra S. Effect of preoperative gabapentin on postoperative pain and tramadol consumption after minilap open cholecystectomy: a randomized double-blind, placebo-controlled trial. Eur J Anaesthesiol. 2010;27(4):331-335.