Abstract
Study objective
Gabapentin is an inhibitory neurotransmitter of the central nervous system. This prospective randomized double-blind study was conducted to evaluate the effects of gabapentin on intraoperative propofol requirements, hemodynamic variables, and postoperative pain relief in breast cancer patients.
Materials and methods
Forty adult females of the American Society of Anesthesiologists (ASA) Grade I-II physical status, undergoing total mastectomy for breast cancer were included. Patients were randomly allocated into two groups. Two hours prior to surgery the gabapentin group received gabapentin 600 mg and the control group received placebo. Anesthesia was induced with intravenous fentanyl, propofol, and vecuronium, and maintained with propofol infusion titrated according to the bispectral index. Postoperative analgesia was provided with intramuscular diclofenac sodium and intravenous morphine on demand.
Results
The intraoperative propofol consumption was significantly less in the gabapentin group as compared with the control group (p = 0.009), whereas there was no difference in fentanyl and vecuronium requirements. Patients in the gabapentin group had lower pain scores at 30 minutes, 1 hour, and 2 hours postoperatively (p < 0.001). The postoperative morphine consumption was also less in the gabapentin group compared with the control group (p = 0.006). No significant adverse effects were noticeable.
Conclusion
Preoperative administration of gabapentin reduced intraoperative propofol requirements and postoperative analgesic consumption in breast cancer patients undergoing total mastectomy.
Keywords
anticonvulsants; gabapentin; general anesthesia; mastectomy; propofol;
1. Introduction
Second-generation anticonvulsant drugs such as gabapentin have been used as adjuvants in the treatment of chronic neuropathic pain as well as acute postoperative pain. The possible mechanisms of action of gabapentin are modulation of voltage gated calcium channels1 and blocking of excitatory neurotransmission via N-methyl D-aspartate (NMDA) and α-amino methyl propionic acid receptors.2, 3 Drugs having inhibitory action on NMDA receptors have been found to reduce intraoperative propofol requirements. Induction of anesthesia with a combination of ketamine and propofol reduces the subsequent maintenance dose of propofol, compared with induction with propofol alone.4 Magnesium sulfate, which also has NMDA antagonistic effects, has been found to reduce the propofol requirement during maintenance of anesthesia.5, 6 Even though the role of gabapentin in reducing postoperative pain and analgesic consumption has been demonstrated in previous studies,7, 8, 9 there have been no clinical trials evaluating the interaction of gabapentin with anesthetic agents.
The primary aim of this double-blind, randomized, placebo-controlled study was to compare the effects of gabapentin pretreatment on intraoperative propofol requirements in patients undergoing breast cancer surgery. The complementary goals of this study were to evaluate whether the use of gabapentin would affect the consumption of intraoperative fentanyl and vecuronium, hemodynamic variables, early recovery profile, postoperative pain, and morphine requirement.
2. Materials and methods
After obtaining approval from the Hospital Ethics Review Committee and written informed consent from the patients, 40 adults aged 30–60 years, of the American Society of Anesthesiologists (ASA) Grade I–II physical status, undergoing total mastectomy with axillary node dissection for carcinoma breast in the period from October 2008 to November 2009 were enrolled in the study. Patients already on gabapentin or other anticonvulsants, having hepatic or renal dysfunction, morbid obesity, pregnancy, or known allergy to any of the drugs used were excluded. They were randomly allocated into two groups by using a computer-generated random number table. Gabapentin group patients received 600 mg of gabapentin and control group patients were given identical placebo capsules 2 hours prior to the anticipated start of surgery. The care providers and the investigators involved in the further patient management and data collection were blinded to the group assignment.
The patients were fasted 8 hours prior to surgery. Preoperative anxiety was assessed prior to induction, using a 100-mm horizontal visual analog scale (VAS), with “no anxiety” anchored at one end and “worst imaginable anxiety” on the other.10 All patients were monitored for electrocardiogram, pulse oximetry, noninvasive blood pressure, capnography, bispectral index (BIS), and neuromuscular transmission during intraoperative period. Anesthesia was induced with intravenous fentanyl 2 μg/kg and propofol in 20 mg increments every 5 seconds until the BIS value had reached 60. Muscle relaxation was achieved with vecuronium bromide 0.1 mg/kg and tracheal intubation was performed when the train-of-four (TOF) count had reached 0. Anesthesia was maintained with continuous propofol infusion and 65% nitrous oxide in oxygen. Propofol infusion was started at the rate of 200 μg/kg/minute and then titrated to maintain the BIS value at 45–55. The infusion rate was adjusted in increment of 20 μg/kg/minute when the BIS value lay outside the target range for >10 seconds. Muscle relaxation was maintained with vecuronium bromide bolus (0.02 mg/kg) when more than two responses were detected in TOF stimulation. The lungs were ventilated mechanically to maintain end-tidal carbon dioxide between 35 mmHg and 40 mmHg. The heart rate and blood pressure were recorded at preinduction, postinduction, postintubation, and then every 5 minutes until the end of surgery. If the BIS value was within the targeted range and the mean arterial pressure (MAP) or heart rate exceeded more than 20% of the baseline, 0.5 μg/kg bolus of intravenous fentanyl was administered. Hypotension (MAP 20% below the baseline or <60 mmHg) was treated with infusion of normal saline, and if required mephentermine 6 mg bolus. Normothermia was maintained during the procedure. All patients were given a continuous infusion of normal saline at a rate of 6–8 ml/kg/hour and blood loss was replaced by adequate volume of crystalloid or colloid administration. Propofol infusion was discontinued at skin closure. Residual neuromuscular blockade was reversed with neostigmine and atropine. The endotracheal tube was removed when the TOF ratio was >90% and BIS >80, with the patient being conscious and breathing adequately. The time from start of induction to BIS60 (induction time), and the time from cessation of propofol infusion to BIS80 (recovery time) were recorded. The duration of surgery, propofol requirement during induction and maintenance of anesthesia (primary outcome), and the total consumption of fentanyl and vecuronium were noted.
Patients were observed for 6 hours in the postanesthesia care unit and followed-up for 24 hours by one of the investigators blinded to the group assignment. The heart rate, blood pressure, and oxygen saturation were recorded at 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours postextubation. The postoperative pain was assessed at same intervals by using a 10-cm VAS, comprising 0 with “no pain” and 10 with “worst imaginable pain”. Postoperative analgesia was provided with intramuscular diclofenac sodium 1.5 mg/kg every 8 hours and intravenous morphine 3 mg bolus on demand or whenever the VAS pain score reached 4 or higher. The cumulative morphine consumption at 2 hours, 6 hours, and 24 hours was recorded. Patients were observed for nausea/vomiting, giddiness, headache, visual disturbances, and light-headedness for 24 hours postoperatively. Ondansetron 4 mg was administered intravenously if the patient had severe nausea and/or vomiting.
Sample size was calculated on the basis of pilot study with mean ± standard deviation propofol consumption of 87.54 ± 14.4 μg/kg/minute. To detect 15% reduction in propofol consumption during maintenance, taking a power of 80% and a type I error of 0.05 we required a sample size of at least 18 patients in each group. The statistical analysis was carried out using SPSS (version 17.0 for Windows; SPSS Inc., Chicago, IL, USA). Normally distributed data (duration of surgery, intraoperative anesthetic agent consumption, and induction and recovery times) were compared using Student t test. For skewed data, the Mann–Whitney test was applied. Qualitative or categorical variables were compared using Chi-square test (rescue analgesia) or Fisher's exact test (postoperative adverse effects). Repeated measures analysis of variance with post hoc analysis was used to compare measures over time (hemodynamic variables, VAS score, morphine consumption). All statistical tests were two-sided and were performed at a significance level of α = 0.05.
3. Results
A total of 46 patients with breast carcinoma undergoing total mastectomy with axillary dissection was assessed, of whom six were excluded, four due to not meeting the inclusion criteria (uncontrolled hypertension/coronary heart disease in 3, morbid obesity in 1) and two who refused to participate in the study. The remaining 40 patients were randomly allocated into two groups. The demographic variables were evenly distributed between the groups. The duration of surgery was also comparable among groups. Patients in the gabapentin group were found to have lower preoperative anxiety scores than those in the control group (Table 1).
The propofol requirement for induction and maintenance of anesthesia was significantly lower in the gabapentin group as compared with the control group. None of the patients in the gabapentin group required additional fentanyl and two patients in the control group required fentanyl boluses during the intraoperative period, but the consumption did not differ statistically. The vecuronium consumption was also comparable between groups. The induction and recovery times were similar in both groups (Table 2).
Patients in the gabapentin group showed lower heart rate and mean arterial pressure at base line (preinduction) and postintubation in comparison with the control group (Table 2). In the control group, there was a significant increase in MAP after intubation compared with baseline value (p = 0.03). In the gabapentin group, MAP decreased after induction and reached the baseline value after intubation. None of the patients had bradycardia or required mephentermine.
Patients in the gabapentin group had lower pain scores at 30 minutes, 1 hour, and 2 hours postoperatively (p < 0.001). More patients in the control group required rescue analgesia than the gabapentin group (p = 0.03). The cumulative morphine consumption in the gabapentin group was significantly less as compared with the control group (Table 3). The postoperative heart rate, blood pressure, and respiratory rate were similar in both groups. None of the patients sustained hypoxia or hypoventilation. Vomiting occurred in six (30%) patients in the gabapentin group and nine (45%) patients in the control group (p = 0.51). Three patients in the gabapentin group complained of mild giddiness. No other side effects were reported.
4. Discussion
This study demonstrated that administration of 600 mg gabapentin prior to surgery reduced propofol requirements for induction and maintenance of anesthesia as well. However, the consumption of additional fentanyl and vecuronium did not differ between two groups. Gabapentin also reduced preoperative anxiety, pressure response to laryngoscopy, and postoperative morphine requirement.
To our knowledge this is the first clinical trial evaluating the effects of gabapentin on intraoperative propofol requirements. However, a recent study on the effect of gabapentin on postcraniotomy pain reported that reduced propofol consumption was achieved in patients receiving 1200 mg gabapentin.11 The decreased propofol requirement in patients receiving gabapentin may either due to the direct potentiation of the anesthetic effect of propofol or due to the enhancement of NMDA antagonism of propofol by gabapentin. Another mechanism could involve the reduction of catecholamine release or decrease of stress response to surgery.12
We did not find any difference in intraoperative fentanyl consumption between the two groups as revealed differently by previous studies.11, 13 This may because we used 2 μg/kg fentanyl bolus at induction and 65% nitrous oxide in oxygen during maintenance of anesthesia. Therefore, the requirement of additional fentanyl was low in both the groups. Previous studies, which found reduced intraoperative opioid requirement, had used either continuous infusion of remifentanil11 or lesser dose of fentanyl (1 μg/kg).13 The higher dose of gabapentin (1200 mg) was used in these studies. We used 600 mg gabapentin based on a previous study, which demonstrated that this could be an optimal pre-emptive dose for postoperative pain relief.14 However, in a later study, van Elstraete et al reported that 21.7 mg/kg is the median effective dose of pre-emptive gabapentin for pain relief after posterior lumbar spinal fusion.15
Gabapentin has been administered as a single dose of 300–1200 mg 1–2 hours prior to surgery for postoperative analgesia in various procedures.11, 14, 16 Clinical trials investigating the analgesic efficacy of gabapentin have shown that patients receiving gabapentin pretreatment experience less pain after surgery and require less rescue analgesia as compared with the control group.9, 17, 18 In our study, the patients receiving 600 mg gabapentin 2 hours prior to surgery had lower pain scores and reduced morphine requirement during the postoperative period.
In the present study, the preinduction heart rate and blood pressure were lower in the gabapentin group as compared with the control group. This may be due to the anxiolytic effect of gabapentin.18 The patients receiving gabapentin were found to have significantly lower anxiety scores in this study. We observed a significant increase in MAP after intubation in the control group but not in the gabapentin group. These results are consistent with previous studies in which gabapentin was found to attenuate the hemodynamic response to laryngoscopy and intubation.19, 20
In a single 600 mg dose, gabapentin did not produce any significant side effect except mild giddiness in a few patients. No other adverse effects such as headache, tremor, ataxia, nystagmus, excessive sedation, or respiratory depression were recorded. The limitation of our study is that we studied only a single dose of gabapentin. As gabapentin produces dose-dependent inhibition of NMDA receptors, a dose-response relationship of gabapentin with its effect on intraoperative anesthetic and analgesic requirement needs further evaluation.
In conclusion, preoperative administration of gabapentin reduces intraoperative propofol requirements, suppresses hemodynamic response to intubation, and reduces postoperative morphine consumption. However, further studies are needed to assess the effect of different doses of gabapentin on the requirement of various anesthetic agents.
Funding source
No financial support or funding has been received from any organization.