Pain Medicine Section Editor: Spencer S. Liu

The Preoperative Use of Gabapentin, Dexamethasone, and Their Combination in Varicocele Surgery: A Randomized Controlled Trial Serhat Koc¸, MD* Dilek Memis, MD* Necdet Sut, PhD†

BACKGROUND: We investigated the effects of gabapentin and dexamethasone given together or separately 1 h before the start of surgery on laryngoscopy, tracheal intubation, intraoperative hemodynamics, opioid consumption, and postoperative pain in patients undergoing varicocele operations. METHODS: Patients were randomly divided into four double-blind groups: group C (control, n ⫽ 20) received placebo, group G (gabapentin, n ⫽ 20) received 800 mg gabapentin, group D (dexamethasone, n ⫽ 20) received 8 mg dexamethasone, group GD (gabapentin plus dexamethasone) received both 800 mg gabapentin and 8 mg dexamethasone IV 1 h before the start of surgery. Standard induction and maintenance of anesthesia were accomplished and continued by propofol and remifentanil infusion. Heart rate and arterial blood pressure were recorded before induction and after intubation. Intraoperative total remifentanil consumption was recorded. Hemodynamic variables and visual analog scale were recorded for 24 h. Side effects were noted. RESULTS: Hemodynamics at 1, 3, 5, and 10 min after tracheal intubation, total remifentanil consumption during surgery, postoperative visual analog scale scores at 30 min, 1, 2, 4, 6, and 12 h, and postoperative nausea and vomiting were found to be significantly lower in group GD than in group G and group D (P ⬍ 0.05 for both), and substantially lower when compared with group C (P ⬍ 0.001). All values in group C were also higher than in groups G and D (P ⬍ 0.05). CONCLUSION: Gabapentin and dexamethasone administered together an hour before varicocele surgery results in less laryngeal and tracheal intubation response, improves postoperative analgesia, and prevents postoperative nausea and vomiting better than individual administration of each drug. (Anesth Analg 2007;105:1137–42)

G

abapentin and dexamethasone are two well tolerated and mechanistically diverse drugs that have each shown promise in the management of postoperative pain. Gabapentin, a structural analog of ␥-aminobutyric acid, is used as an anticonvulsant drug. In addition, it has been shown to be effective in neuropathic pain (1), diabetic neuropathy (2), postherpetic neuralgia (3), and complex regional pain syndrome Type 1 (4). Studies have demonstrated that mechanical hyperalgesia surrounding the wound in postoperative patients, and experimentally, heat-induced, secondary hyperalgesia, share a common mechanism, and that central neuronal sensitization contributes to postoperative pain (5). Gabapentin has a selective effect on the nociceptive process involving central sensitization

From the Departments of *Anaesthesiology and Reanimation, and †Bioistatistic, Medical Faculty, Trakya University, Turkey. Accepted for publication June 13, 2007. Address correspondence and reprint requests to Dilek Memis, MD, Department of Anaesthesiology and Reanimation, Medical Faculty, Trakya University, 22030, Edirne, Turkey. Address e-mail to [email protected]. Copyright © 2007 International Anesthesia Research Society DOI: 10.1213/01.ane.0000278869.00918.b7

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(6 –10). Studies have shown synergism between gabapentin and morphine for analgesic effects in animals and in humans (11–13). Preoperative oral gabapentin reduces opioid consumption in patients undergoing surgery (14 –16). In a recent systematic review, perioperative oral gabapentin was a useful adjunct for the management of postoperative pain that provided analgesia through a different mechanism than opioids and other analgesic drugs and would make a reasonable addition to a multimodal analgesic treatment plan (17). Glucocorticoids are well-known for their analgesic, antiinflammatory, immune-modulating, and antiemetic effects, although the mechanisms by which glucocorticoids exert their action are far from clarified (18). Several randomized, clinical trials in many different major and minor surgical procedures have been conducted to examine the effects of a perioperative single-dose glucocorticoid administration on surgical outcome (19). The overall results on postoperative outcome have either been positive in favor of the glucocorticoid group or without differences between study groups, with postoperative nausea and vomiting and pain as outcome variables most significantly improved (17,19 –21). 1137

In our literature search, we could not find any study evaluation effect of gabapentin and dexamethasone on tracheal intubation and intraoperative hemodynamics and postoperative analgesia. For this reason, we investigated the effects of gabapentin and dexamethasone, given together or separately, 1 h before the start of the surgery, on the responses to laryngoscopy and intubation, intraoperative hemodynamics, opioid consumption, and postoperative pain in patients undergoing varicocele operations.

METHODS After obtaining the approval of the Institutional Ethics Committee (Trakya University, Edirne, Turkey) and written consent of the patients, 80 normotensive patients (ASA physical status I) undergoing elective varicocele surgery were randomly assigned to four groups of 20 patients each. Exclusion criteria were cardiac disease, contraindications to anesthetics, asthma, renal insufficiency, predicted difficulty in intubation or airway maintenance, and pregnancy. The study design was randomized and double-blind; patients were randomly allocated according to computer-generated randomization. The control group (n ⫽ 20) received oral placebo ⫹ IV 2 mL saline (group C), group G (n ⫽ 20) received oral 800 mg of gabapentin (Neurontin, 400-mg capsule, Pfizer, Goedecke GmbH, Germany) ⫹ IV 2 mL saline, group D (n ⫽ 20) received oral placebo ⫹ IV 8 mg dexamethasone (Dekort amp 4 mg/mL, Deva, Istanbul), and group GD (n ⫽ 20) received 800 mg of gabapentin ⫹ 8 mg of dexamethasone 1 h before surgery in the operating room. The study drugs were prepared by the pharmacy, and an appropriate code number was assigned. The occurrence of any side effects, such as nausea and vomiting, respiratory depression, dizziness, somnolence, peripheral edema, or headache, was recorded. After the patients had been taken to the operating room, crystalloid infusion was started through a 20-gauge IV cannula inserted in an appropriate antecubital vein, and the mean arterial blood pressure (MAP), heart rate (HR), and peripheral oxygen saturation (Spo2) were monitored. Oxygen was administered via an anesthetic breathing circuit and facemask. After 3 min of administration of oxygen, induction of anesthesia was achieved in all patients with a continuous infusion of remifentanil 0.5 ␮g 䡠 kg⫺1 䡠 min⫺1 followed by propofol 2 mg/kg. Then, 0.5 mg/kg atracurium was given to facilitate tracheal intubation and to maintain neuromuscular blockade, monitored by train-of-four stimulation with a peripheral nerve stimulator. Laryngoscopy and tracheal intubation were then performed 3 min after loss of verbal contact by the same experienced anesthesiologist using a Mcintosh three laryngoscope blade and 8.0 mm endotracheal tube. After tracheal intubation, the lungs were ventilated with 50% N2O in oxygen, and end-tidal CO2 was maintained at between 30 and 35 mm Hg. Remifentanil infusion was then reduced to 0.25 ␮g 䡠 kg⫺1 䡠 min⫺1 in all patients after propofol infusion (4 mg 䡠 kg⫺1 䡠 h⫺1) was started. 1138

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MAP, HR, and Spo2 were monitored through noninvasive continuous measurement. HR and MAP were recorded at baseline (before induction of anesthesia), which was the mean of the three resting measurements in the operating room before any instrumentation, 1, 3, 5, 10, 15, 30, 40, and 60 min after tracheal intubation. MAP and HR were maintained within 20% of baseline values using a predetermined decision algorithm for adjustment of the opioid and propofol. The remifentanil infusion rate was first decreased by 25% in case of hypotension or bradycardia; if this was insufficient to restore values to within 20% of baseline after two adjustments, the propofol infusion was also adjusted upward or downward by 25%. Five minutes were allowed between each adjustment. The total remifentanil and propofol consumption by each patient was determined and noted. Ephedrine (3 mg increments) was administered for hypotension (MAP ⬍80 mm Hg, or a decrease of ⬎30% from baseline values for ⬎60 s) and atropine, in 300 ␮g increments, for bradycardia (HR ⬍45 bpm/min). Immediately after the placement of the last skin suture, propofol, remifentanil, and N2O were discontinued. After patients were tracheally extubated, ventilation was assisted until the recovery of spontaneous breathing after the patients were extubated. After tracheal extubation, patients were transferred to the postanesthesia care unit. Assessment of postoperative pain was made with a visual analog scale score (VAS; 0 cm ⫽ no pain and 10 cm ⫽ worst pain imaginable). During the first 1 h in the postanesthesia care unit, then at 2, 4, 6, 12, and 24 h in the patient’s room, patients were evaluated for pain scores, HR, and MAP by an anesthesiology resident not otherwise involved in the study. Additional analgesic requirements for each group within 24 h were determined according to VAS; when VAS values were ⬎3, tenoxicam 20 mg IM was administered and noted. The occurrence of any side effects, such as nausea and vomiting, constipation, respiratory depression, dizziness, somnolence, peripheral edema, diarrhea, headache, and pruritis were recorded. On patient request, or if nausea and vomiting occurred, ondansetron 4 mg IV was given. Normality distribution of the variables was tested using the one sample Kolmogorov-Smirnov test. Demographic characteristics were compared using oneway ANOVA test, differences from baseline within groups were evaluated using repeated measures ANOVA test for normally distributed data, and the Freidman ANOVA test for nonnormal distributed data. Bonferroni post hoc tests were used to correct for multiple comparisons. Categorical variables were analyzed using the ␹2 test. Statistica 7.0 statistical software was used for statistical analysis. P ⬍ 0.05 was considered statistically significant.

RESULTS There were no significant differences among the four groups with respect to, age, weight, duration of ANESTHESIA & ANALGESIA

Table 1. Demographic Characteristics Variable

Group C (n ⫽ 20)

Group G (n ⫽ 20)

Group D (n ⫽ 20)

Group GD (n ⫽ 20)

Age (yr) Weight (kg) Duration of anesthesia (min) Duration of surgery (min) Intraoperative remifentanil consumption (mg)

41.10 ⫾ 20.85 72.65 ⫾ 12.28 78.2 ⫾ 25.92 67.35 ⫾ 22.85 745.7 ⫾ 119.7

39.45 ⫾ 19.27 74.55 ⫾ 10.02 90.75 ⫾ 37.60 79.25 ⫾ 36.50 408.5 ⫾ 139.7*

38.35 ⫾ 17.43 72.70 ⫾ 12.85 94.00 ⫾ 46.61 79.15 ⫾ 41.94 409.2 ⫾ 136.6*

35.25 ⫾ 18.01 76.25 ⫾ 11.29 86.05 ⫾ 28.14 73.55 ⫾ 27.47 249.1 ⫾ ⫺85.7†‡

Values *P ⬍ †P ⬍ ‡P ⬍

are shown as number (n) of patients or mean ⫾ SD. 0.05, when group C compared with group G and group D. 0.001, when group GD compared with group C. 0.05, when group gabapentin (G) and dexamethasone (D) compared with group gabapentin and group dexamethasone (GD).

Figure 1. Intraoperative mean arterial blood pressure data (mean ⫾ sd). The initial mean arterial blood pressure was similar in all groups. Mean arterial blood pressure values were statistically significantly lower in the gabapentin– dexamethasone group at 1, 3, 5, and 10 min after tracheal intubation than the dexamethasone group and gabapentin group (P ⬍ 0.05); when compared with the control group, these values were substantially lower (P ⬍ 0.001). The gabapentin group and dexamethasone group did not differ statistically (P ⬎ 0.05), whereas values were significantly lower in the gabapentin group and dexamethasone group compared with the control group (P ⬍ 0.05).

surgery (Table 1). We did not observe any side effects, such as nausea and vomiting, respiratory depression, dizziness, somnolence, peripheral edema, or headache during the 1-h period before surgery. Cardiovascular responses are shown in Figures 1 and 2. The initial hemodynamic variables were similar in all groups. HR and MAP values were significantly lower in group GD at 1, 3, 5, and 10 min after intubation than in group D and group G (P ⬍ 0.05) and in group C (P ⬍ 0.001). Hemodynamics was similar in group G and group D, but lower than group C (P ⬍ 0.05). One patient in group GD had transient hypotension (MAP ⬍80 mm Hg for ⬍1 min), which did not require ephedrine. There were no bradycardia, tachycardia, or arrhythmias, ST segment alterations, or other echocardiographic changes observed during the study. We did not use ephedrine or atropine. Intraoperative total remifentanil consumption was significantly lower in group GD (249.1 ⫾ 85.7 mg) than in group G (408.5 ⫾ 139.7 mg) and group D (409.2 ⫾ 136.6 mg) (P ⬍ 0.05 for both) and in group C (745.7 ⫾ 119.7 mg) (P ⬍ 0.001). Values in group C were higher than in group G and D (P ⬍ 0.05), whereas Vol. 105, No. 4, October 2007

group G and group D were similar (Table 1). The propofol infusion was kept constant. Postoperative MAP and HR variables were similar in the four groups at 30 min, 1, 2, 4, 6, 12, and 24 h after tracheal extubation (P ⬎ 0.05). VAS scores were found to be significantly lower in group GD at 30 min, 1, 2, 4, 6, and 12 h than in group G and group D (P ⬍ 0.05 for both) and in group C (P ⬍ 0.001). Values in group C were also higher in group G and D (P ⬍ 0.05). Group G and group D did not differ significantly from each other (Fig. 3). Total tenoxicam consumption during the first 24 h postoperatively was significantly lower in group GD (0 mg) than in group G (80 mg) and group D (80 mg) (P ⬍ 0.05 for both) and in group C (300 mg) (P ⬍ 0.001). Each of these values in group C was higher than group G and D (P ⬍ 0.05). Group G and group D did not differ significantly from each other. Postoperative nausea and vomiting occurred in 15 of 20 (75%) patients in group C, 8 of 20 (40%) patients in group G, 7 of 20 (35%) patients in group D, and 1 of 20 (5%) patients in group GD. The incidence of postoperative nausea and vomiting was less frequent in © 2007 International Anesthesia Research Society

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Figure 2. Intraoperative heart rate data

(mean ⫾ sd). The initial heart rate was similar in all groups. Heart rate values were statistically significantly lower in the gabapentin– dexamethasone group at 1, 3, 5, and 10 min after intubation than the dexamethasone group and gabapentin group (P ⬍ 0.05); when compared with the control group, these values were substantially lower (P ⬍ 0.001). The gabapentin group and dexamethasone group did not differ statistically (P ⬎ 0.05), whereas values were significantly lower in the gabapentin group and dexamethasone group compared with the control group (P ⬍ 0.05).

Figure 3. Postoperative visual analog score (VAS) changes. Postoperative visual analog scores were to be statistically significantly lower in the gabapentin–dexamethasone group at 30 min 1, 2, 4, 6, and 12 h than in the gabapentin group and dexamethasone group (P ⬍ 0.05), and substantially lower when compared with the control group (P ⬍ 0.001). These values were also each found lower in gabapentin group and dexamethasone group than in the control group (P ⬍ 0.05). The gabapentin group and dexamethasone group did not differ significantly.

Table 2. Adverse Effects Postoperative nausea–vomiting Treatment

Dry mouth

Vomiting

Nausea

Total

Headache

Pruritis

Control (n ⫽ 20) Gabapentin (n ⫽ 20) Dexamethasone (n ⫽ 20) Combination (n ⫽ 20)

4 (20) 3 (15) 3 (15) 1 (5)

14 (70) 7 (35) 7 (35) 1 (5)

1 (5) 1 (5) 0 (0) 0 (0)

15 (75) 8 (40)* 7 (35)* 1 (5)†‡

6 (30) 7 (35) 3 (15) 4 (20)

2 (10) 0 (0) 1 (5) 1 (5)

Values *P ⬍ †P ⬍ ‡P ⬍

inside parentheses indicate percentages. 0.05, when group C compared with group G and group D. 0.001, when group GD compared with group C. 0.05, when group gabapentin and dexamethasone compared with group gabapentin and group dexamethasone.

group GD compared with all other groups (P ⬍ 0.001). Nausea and vomiting in group G and group D were similar, but less than, in group C (P ⬍ 0.05). There were no differences among the groups in other side effects (Table 2).

DISCUSSION The above-mentioned results indicate that gabapentin and dexamethasone, administered together an hour before varicocele operation, result in less laryngeal and 1140

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tracheal intubation response, better postoperative analgesia, and less postoperative nausea and vomiting than the individual administration of each drug. In animal models of nociception, gabapentin reduces hypersensitivity associated with nerve injury, inflammation, and pain after surgery (22,23). Mechanical hyperalgesia surrounding the wound in postoperative patients and experimental, heat-induced secondary hyperalgesia share a common mechanism; namely, central neuronal sensitization that may contribute to some aspects of ANESTHESIA & ANALGESIA

postoperative pain. Antihyperalgesic drugs such as gabapentin may have a role in postoperative pain, and their combination with other antinociceptive drugs may produce synergistic analgesic effects (6). Gabapentin’s antihyperalgesic effects result from an action at the ␣2␦1 subunits of voltage-dependent Ca2⫹ channels (24), which are up-regulated in the dorsal root ganglia and spinal cord after peripheral injury (25). Gabapentin may also produce antihyperalgesia by decreasing glutaminergic transmission in the spinal cord (26). In addition, a study of gabapentin’s effect in rat hippocampus and neocortex suggested that it selectively inhibits Ca2⫹ influx by inhibiting voltage-operated Ca2⫹ channels in a subset of excitatory and inhibitory presynaptic terminals, thereby attenuating synaptic transmission (27). Although the molecular targets of gabapentin remain unknown, the inhibition of Ca2⫹ efflux from muscle cells, with a consequent inhibition of smooth muscle relaxation, might explain the effectiveness of gabapentin in the relaxation of laryngoscopy. The analgesic effects of glucocorticoids are provided through inhibition of the phospholipase enzyme and subsequent blockage of both the cyclooxygenase and the lipoxygenase pathways in the inflammatory chain reaction (18), as well as suppression of tissue levels of bradykinin (28) and release of neuropeptides from nerve endings (29). Both of these effects may enhance nociception in inflamed tissues and the surgical wound. In one review (19) regarding the effects of perioperative singledose glucocorticoid administration, randomized trials from several minor and major surgical procedures were analyzed. The authors concluded that glucocorticoid administration in major abdominal surgery probably has no or limited analgesic effects, except perhaps in minor surgical procedures such as hemorrhoidectomy, hallux valgus correction, thyroidectomy, and dental surgery (19), and now also in our model. Glucocorticoids suppress agonist-induced release of intracellular calcium in airway smooth muscle cells such as bradykinin (30). The suppressive effect of glucocorticoids on agonist-stimulated increases in intracellular calcium concentration may involve down regulation of adenosine receptors, reduced adenosine receptor affinities, or reduction in adenylate cyclase activity (31,32). This smooth muscle relaxation might also explain the effectiveness of dexamethasone in the suppression of laryngoscopy. Surgical procedures, endotracheal intubation, and anesthesia are stressful to the patient and may induce potentially harmful reactions, such as increases in HR and MAP (33). There is a clear relationship between surgical events producing intense sympathetic stimulation and perioperative myocardial ischemic episodes and postoperative myocardial infarction (34). Memis et al. (35) found that 800 mg gabapentin, given 1 h before surgery blunted the MAP and HR increase due to endotracheal intubation in the first 10 Vol. 105, No. 4, October 2007

min. Fassouloki et al. (36) demonstrated that 1600 mg gabapentin attenuated the pressor response, but not the tachycardia, associated with laryngoscopy and tracheal intubation. In our literature search, we failed to find any study evaluating the effect of dexamethasone or gabapentin– dexamethasone on intubation. The above results indicate that a gabapentin– dexamethasone combination provides significant decreases in MAP and HR values in the first 10 min after induction than the single drug gabapentin or dexamethasone. All three treatments attenuated the pressor response. This reduction was significantly greater with the combination than with either drug alone. Although observed changes in MAP and HR at intubation were statistically significant, they were modest and clinically acceptable. There were no incidences of bradycardia, tachycardia, arrhythmias, ST segment, or other echocardiographic changes observed during the study. Postoperative nausea and vomiting are a multifactorial problem, and several anesthetic and nonanesthetic factors must be controlled to obtain meaningful results. Gabapentin has been reported to be effective in the treatment of emesis in patients receiving cytotoxic drugs (37). The precise mechanism of gabapentin in the prevention of nausea and vomiting induced by cytotoxic drugs is not known, but mitigation of tachykinin neurotransmitter activity has been postulated to be useful (38). There is evidence that tachykinins activity is part of the pathogenesis of chemotherapyinduced emesis in ferrets, and that a selective tachykinins-receptor antagonist improves nausea and emesis (39,40). The mechanism by which glucocorticoids alleviate nausea and vomiting is not fully understood, but the effects are probably centrally mediated via inhibition of prostaglandin synthesis or inhibition of the release of endogenous opioids (20). In a metaanalysis of 17 randomized controlled trials, a single dose of dexamethasone in combination with 5-HT3 receptor antagonists significantly reduced postoperative nausea and vomiting when compared with placebo, but the optimal dose of this combination still needs to be identified (20). In our study, all three treatments reduced nausea and vomiting postoperative periods. This reduction was significantly greater with the combination than with either single drug. This study also demonstrated a decrease in the amount of remifentanil consumption in gabapentin– dexamethasone group more than in group gabapentin or dexamethasone. This reduction in nausea and vomiting may result from the lower opioid doses in group gabapentin– dexamethasone. This trial provides empirical evidence to support the clinical utility of a gabapentin– dexamethasone combination for postoperative pain. Future trials should further evaluate other analgesic combinations to enhance symptomatic improvement and functional recovery after surgery. © 2007 International Anesthesia Research Society

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