at SciVerse ScienceDirect

Acta Anaesthesiologica Taiwanica 51 (2013) 10e13

Contents lists available

Acta Anaesthesiologica Taiwanica

journal homepage: www.e-aat .com

Original Article

Effect of gabapentin pretreatment on propofol consumption, hemodynamicvariables, and postoperative pain relief in breast cancer surgeryq

Neerja Bharti*, Indu Bala, Vidhya Narayan, Gurpreet SinghDepartment of Anesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Chandigarh, India

a r t i c l e i n f o

Article history:Received 9 April 2012Received in revised form15 October 2012Accepted 18 October 2012

Key words:anticonvulsants;gabapentin;general anesthesia;mastectomy;propofol

q The work was presented at the 16th Internationaciation of Palliative Care (IAPC).* Corresponding author. Department of Anesthes

Graduate Institute of Medical Education and ResearchE-mail address: bhartineerja@yahoo.com (N. Bhar

1875-4597/$ e see front matter Copyright � 2013, Tahttp://dx.doi.org/10.1016/j.aat.2013.03.009

a b s t r a c t

Study objective: Gabapentin is an inhibitory neurotransmitter of the central nervous system. This pro-spective randomized double-blind study was conducted to evaluate the effects of gabapentin on intra-operative propofol requirements, hemodynamic variables, and postoperative pain relief in breast cancerpatients.Materials and methods: Forty adult females of the American Society of Anesthesiologists (ASA) Grade I-IIphysical status, undergoing total mastectomy for breast cancer were included. Patients were randomlyallocated into two groups. Two hours prior to surgery the gabapentin group received gabapentin 600 mgand the control group received placebo. Anesthesia was induced with intravenous fentanyl, propofol, andvecuronium, and maintained with propofol infusion titrated according to the bispectral index. Post-operative analgesia was provided with intramuscular diclofenac sodium and intravenous morphine ondemand.Results: The intraoperative propofol consumption was significantly less in the gabapentin group ascompared with the control group (p ¼ 0.009), whereas there was no difference in fentanyl andvecuronium 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 thegabapentin group compared with the control group (p ¼ 0.006). No significant adverse effects werenoticeable.Conclusion: Preoperative administration of gabapentin reduced intraoperative propofol requirements andpostoperative analgesic consumption in breast cancer patients undergoing total mastectomy.

Copyright � 2013, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rightsreserved.

1. Introduction

Second-generation anticonvulsant drugs such as gabapentinhave been used as adjuvants in the treatment of chronic neuropathicpain as well as acute postoperative pain. The possible mechanismsof action of gabapentin are modulation of voltage gated calciumchannels1 and blocking of excitatory neurotransmission via N-methyl D-aspartate (NMDA) and a-amino methyl propionic acidreceptors.2,3 Drugs having inhibitory action on NMDA receptorshave been found to reduce intraoperative propofol requirements.Induction of anesthesia with a combination of ketamine and pro-pofol reduces the subsequent maintenance dose of propofol,compared with induction with propofol alone.4 Magnesium sulfate,

l Conference of Indian Asso-

ia and Intensive Care, Post, Chandigarh 160012, India.ti).

iwan Society of Anesthesiologists.

which also has NMDA antagonistic effects, has been found to reducethe propofol requirement duringmaintenance of anesthesia.5,6 Eventhough the role of gabapentin in reducing postoperative pain andanalgesic consumption has been demonstrated in previousstudies,7e9 there have been no clinical trials evaluating the inter-action of gabapentin with anesthetic agents.

The primary aim of this double-blind, randomized, placebo-controlled study was to compare the effects of gabapentin pre-treatment on intraoperative propofol requirements in patientsundergoing breast cancer surgery. The complementary goals of thisstudy were to evaluate whether the use of gabapentin would affectthe consumption of intraoperative fentanyl and vecuronium, he-modynamic variables, early recovery profile, postoperative pain,and morphine requirement.

2. Materials and methods

After obtaining approval from the Hospital Ethics ReviewCommittee and written informed consent from the patients, 40

Published by Elsevier Taiwan LLC. All rights reserved.

Table 1Patient demographics, anxiety scores, and duration of surgery.

Variables Gabapentin group Control group

Age (y) 45.3 � 8.9 47.8 � 8.5Weight (kg) 59.4 � 13.2 59.2 � 12.7ASA grade (I:II) 14:6 17:3Anxiety scores, median (IQR) 20 (10e29) 30 (25e50)*Duration of surgery (min), 106 � 30.6 97.9 � 26.3

Data are presented as number of patients or mean � SD.*p ¼ 0.002.IQR ¼ interquartile range; SD ¼ standard deviation.

Gabapentin reduces propofol consumption 11

adults aged 30e60 years, of the American Society of Anesthesiol-ogists (ASA) Grade IeII physical status, undergoing total mastec-tomy with axillary node dissection for carcinoma breast in theperiod from October 2008 to November 2009 were enrolled in thestudy. Patients already on gabapentin or other anticonvulsants,having hepatic or renal dysfunction, morbid obesity, pregnancy, orknown allergy to any of the drugs used were excluded. They wererandomly allocated into two groups by using a computer-generatedrandom number table. Gabapentin group patients received 600 mgof gabapentin and control group patients were given identicalplacebo capsules 2 hours prior to the anticipated start of surgery.The care providers and the investigators involved in the furtherpatient management and data collection were blinded to the groupassignment.

The patients were fasted 8 hours prior to surgery. Preoperativeanxiety was assessed prior to induction, using a 100-mmhorizontalvisual analog scale (VAS), with “no anxiety” anchored at one endand “worst imaginable anxiety” on the other.10 All patients weremonitored for electrocardiogram, pulse oximetry, noninvasiveblood pressure, capnography, bispectral index (BIS), and neuro-muscular transmission during intraoperative period. Anesthesiawas induced with intravenous fentanyl 2 mg/kg and propofol in20 mg increments every 5 seconds until the BIS value had reached60. Muscle relaxation was achieved with vecuronium bromide0.1 mg/kg and tracheal intubation was performed when the train-of-four (TOF) count had reached 0. Anesthesia was maintainedwith continuous propofol infusion and 65% nitrous oxide in oxygen.Propofol infusion was started at the rate of 200 mg/kg/minute andthen titrated to maintain the BIS value at 45e55. The infusion ratewas adjusted in increment of 20 mg/kg/minute when the BIS valuelay outside the target range for>10 seconds. Muscle relaxationwasmaintained with vecuronium bromide bolus (0.02 mg/kg) whenmore than two responses were detected in TOF stimulation. Thelungs were ventilated mechanically to maintain end-tidal carbondioxide between 35mmHg and 40mmHg. The heart rate and bloodpressure were recorded at preinduction, postinduction, post-intubation, and then every 5 minutes until the end of surgery. If theBIS value was within the targeted range and the mean arterialpressure (MAP) or heart rate exceeded more than 20% of thebaseline, 0.5 mg/kg bolus of intravenous fentanyl was administered.Hypotension (MAP 20% below the baseline or <60 mmHg) wastreated with infusion of normal saline, and if required meph-entermine 6 mg bolus. Normothermia was maintained during theprocedure. All patients were given a continuous infusion of normalsaline at a rate of 6e8 ml/kg/hour and blood loss was replaced byadequate volume of crystalloid or colloid administration. Propofolinfusion was discontinued at skin closure. Residual neuromuscularblockade was reversed with neostigmine and atropine. The endo-tracheal 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 thetime from cessation of propofol infusion to BIS80 (recovery time)were recorded. The duration of surgery, propofol requirementduring induction and maintenance of anesthesia (primaryoutcome), and the total consumption of fentanyl and vecuroniumwere noted.

Patients were observed for 6 hours in the postanesthesia careunit and followed-up for 24 hours by one of the investigatorsblinded to the group assignment. The heart rate, blood pressure,and oxygen saturation were recorded at 30 minutes, 1 hour, 2hours, 4 hours, 6 hours, and 24 hours postextubation. The post-operative pain was assessed at same intervals by using a 10-cmVAS, comprising 0 with “no pain” and 10 with “worst imaginablepain”. Postoperative analgesia was provided with intramusculardiclofenac sodium 1.5 mg/kg every 8 hours and intravenous

morphine 3 mg bolus on demand or whenever the VAS pain scorereached 4 or higher. The cumulative morphine consumption at 2hours, 6 hours, and 24 hours was recorded. Patients were observedfor nausea/vomiting, giddiness, headache, visual disturbances, andlight-headedness for 24 hours postoperatively. Ondansetron 4 mgwas administered intravenously if the patient had severe nauseaand/or vomiting.

Sample size was calculated on the basis of pilot study withmean � standard deviation propofol consumption of87.54 � 14.4 mg/kg/minute. To detect 15% reduction in propofolconsumption duringmaintenance, taking a power of 80% and a typeI error of 0.05 we required a sample size of at least 18 patients ineach group. The statistical analysis was carried out using SPSS(version 17.0 for Windows; SPSS Inc., Chicago, IL, USA). Normallydistributed data (duration of surgery, intraoperative anestheticagent consumption, and induction and recovery times) werecompared using Student t test. For skewed data, the ManneWhit-ney test was applied. Qualitative or categorical variables werecompared using Chi-square test (rescue analgesia) or Fisher’s exacttest (postoperative adverse effects). Repeated measures analysis ofvariance with post hoc analysis was used to compare measures overtime (hemodynamic variables, VAS score, morphine consumption).All statistical tests were two-sided and were performed at a sig-nificance level of a ¼ 0.05.

3. Results

A total of 46 patients with breast carcinoma undergoing totalmastectomy with axillary dissection was assessed, of whom sixwere excluded, four due to not meeting the inclusion criteria (un-controlled hypertension/coronary heart disease in 3, morbidobesity in 1) and two who refused to participate in the study. Theremaining 40 patients were randomly allocated into two groups.The demographic variables were evenly distributed between thegroups. The duration of surgery was also comparable amonggroups. Patients in the gabapentin group were found to have lowerpreoperative anxiety scores than those in the control group(Table 1).

The propofol requirement for induction and maintenance ofanesthesia was significantly lower in the gabapentin group ascompared with the control group. None of the patients in thegabapentin group required additional fentanyl and two patients inthe control group required fentanyl boluses during the intra-operative period, but the consumption did not differ statistically.The vecuronium consumption was also comparable betweengroups. The induction and recovery times were similar in bothgroups (Table 2).

Patients in the gabapentin group showed lower heart rate andmean arterial pressure at base line (preinduction) and post-intubation in comparison with the control group (Table 2). In thecontrol group, there was a significant increase in MAP after intu-bation compared with baseline value (p ¼ 0.03). In the gabapentingroup, MAP decreased after induction and reached the baseline

Table 2Intraoperative anesthetic requirement, induction, and recovery times.

Gabapentingroup

Control group p

Induction dose of propofol (mg/kg) 1.44 � 0.25 1.66 � 0.34 0.024Maintenance dose of propofol

(mg/kg/ min)73.50 � 13.08 93.85 � 30.11 0.009

Total dose of fentanyl (mg/kg) 2.0 � 0.4 2.08 � 0.32 0.682Total dose of vecuronium (mg/kg) 0.12 � 0.02 0.13 � 0.04 0.283Induction time, s 88.7 � 21 103.5 � 27.6 0.07Recovery time, min 10.8 � 4.6 10.3 � 3.5 0.64Base line heart rate (beats/min) 78.2 � 12.1 88.3 � 14.4 0.021Heart rate after induction 70.4 � 12.5 78.3 � 13.2 0.084Heart rate after intubation 80.5 � 12.7 91.4 � 14.5 0.013Heart rate 5 min postintubation 73.6 � 11.6 81.5 � 13.6 0.057Base line MAP 95.8 � 7.9 103.8 � 9.5 0.006MAP after induction 72.7 � 10.2* 80.1 � 12.6* 0.043MAP after intubation 94.9 � 10.9 116.8 � 19.2* 0.000MAP 5 min postintubation 89.9 � 8.1 95.5 � 15.5 0.188

Data are presented as number of patients or mean � SD.*p < 0.05 as compared to base line.MAP ¼ mean arterial pressure.

N. Bharti et al.12

value after intubation. None of the patients had bradycardia orrequired mephentermine.

Patients in the gabapentin group had lower pain scores at 30minutes, 1 hour, and 2 hours postoperatively (p < 0.001). Morepatients in the control group required rescue analgesia than thegabapentin group (p ¼ 0.03). The cumulative morphine consump-tion in the gabapentin group was significantly less as comparedwith 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. Vom-iting occurred in six (30%) patients in the gabapentin group andnine (45%) patients in the control group (p¼ 0.51). Three patients inthe gabapentin group complained of mild giddiness. No other sideeffects were reported.

4. Discussion

This study demonstrated that administration of 600 mg gaba-pentin prior to surgery reduced propofol requirements for induc-tion and maintenance of anesthesia as well. However, theconsumption of additional fentanyl and vecuronium did not differbetween two groups. Gabapentin also reduced preoperative anxi-ety, pressure response to laryngoscopy, and postoperativemorphine requirement.

To our knowledge this is the first clinical trial evaluating theeffects of gabapentin on intraoperative propofol requirements.However, a recent study on the effect of gabapentin on post-craniotomy pain reported that reduced propofol consumption wasachieved inpatients receiving 1200mg gabapentin.11 The decreasedpropofol requirement in patients receiving gabapentin may eitherdue to the direct potentiation of the anesthetic effect of propofol ordue to the enhancement of NMDA antagonism of propofol bygabapentin. Another mechanism could involve the reduction ofcatecholamine release or decrease of stress response to surgery.12

Table 3Postoperative morphine requirement.

Variables Gabapentin group Control group p

Requirement of rescueanalgesic, no.

11/20 18/20 0.034

Cumulative morphine consumption, mg (mean � standard deviation)2 h 0.3 � 0.9 2.7 � 2.5 0.0016 h 1.2 � 1.5 3.4 � 2.6 0.00424 h 2.1 � 2.2 4.9 � 3.4 0.006

No. ¼ number of patients.

We did not find any difference in intraoperative fentanyl con-sumption between the two groups as revealed differently by pre-vious studies.11,13 This may because we used 2 mg/kg fentanyl bolusat induction and 65% nitrous oxide in oxygen during maintenanceof anesthesia. Therefore, the requirement of additional fentanyl waslow in both the groups. Previous studies, which found reducedintraoperative opioid requirement, had used either continuousinfusion of remifentanil11 or lesser dose of fentanyl (1 mg/kg).13 Thehigher dose of gabapentin (1200 mg) was used in these studies. Weused 600 mg gabapentin based on a previous study, whichdemonstrated that this could be an optimal pre-emptive dose forpostoperative pain relief.14 However, in a later study, van Elstraeteet al reported that 21.7 mg/kg is the median effective dose of pre-emptive gabapentin for pain relief after posterior lumbar spinalfusion.15

Gabapentin has been administered as a single dose of 300e1200 mg 1e2 hours prior to surgery for postoperative analgesia invarious procedures.11,14,16 Clinical trials investigating the analgesicefficacy of gabapentin have shown that patients receiving gaba-pentin pretreatment experience less pain after surgery and requireless rescue analgesia as compared with the control group.9,17,18 Inour study, the patients receiving 600 mg gabapentin 2 hours priorto surgery had lower pain scores and reduced morphine require-ment during the postoperative period.

In the present study, the preinduction heart rate and bloodpressure were lower in the gabapentin group as compared with thecontrol group. This may be due to the anxiolytic effect of gaba-pentin.18 The patients receiving gabapentin were found to havesignificantly lower anxiety scores in this study. We observed asignificant increase inMAP after intubation in the control group butnot in the gabapentin group. These results are consistent withprevious studies in which gabapentin was found to attenuate thehemodynamic response to laryngoscopy and intubation.19,20

In a single 600 mg dose, gabapentin did not produce any sig-nificant side effect except mild giddiness in a few patients. No otheradverse effects such as headache, tremor, ataxia, nystagmus,excessive sedation, or respiratory depression were recorded. Thelimitation of our study is that we studied only a single dose ofgabapentin. As gabapentin produces dose-dependent inhibition ofNMDA receptors, a dose-response relationship of gabapentin withits effect on intraoperative anesthetic and analgesic requirementneeds further evaluation.

In conclusion, preoperative administration of gabapentin re-duces intraoperative propofol requirements, suppresses hemody-namic response to intubation, and reduces postoperative morphineconsumption. However, further studies are needed to assess theeffect of different doses of gabapentin on the requirement ofvarious anesthetic agents.

Funding source

No financial support or funding has been received from anyorganization.

References

1. Hahm TS, Ahn HJ, Bae CD, Kim HS, Lim SW, Cho HS, et al. Protective effects ofgabapentin on allodynia and alpha 2 delta 1-subunit of voltage-dependentcalcium channel in spinal nerve-ligated rats. J Korean Med Sci 2009;24:146e51.

2. Hara K, Sata T. Inhibitory effect of gabapentin on N-methyl-D-aspartate re-ceptors expressed in Xenopus oocytes. Acta Anaesthesiol Scand 2007;51:122e8.

3. Shimoyama M, Shimoyama N, Hori Y. Gabapentin affects glutamatergic excit-atory neurotransmission in the rat dorsal horn. Pain 2000;85:405e14.

4. Aouad MT, Moussa AR, Dagher CM, Muwakkit SA, Jabbour-Khoury SI,Zbeidy RA, et al. Addition of ketamine to propofol for initiation of proceduralanesthesia in children reduces propofol consumption and preserves hemody-namic stability. Acta Anaesthesiol Scand 2008;52:561e5.

Gabapentin reduces propofol consumption 13

5. Choi JC, Yoon KB, Um DJ, Kim C, Kim JS, Lee SG. Intravenous magnesium sulfateadministration reduces propofol infusion requirements during maintenance ofpropofoleN2O anesthesia. Anesthesiology 2002;97:1137e41.

6. Seyhan TO, Tugrul M, Sungur MO, Kayacan S, Telci L, Pembeci K, et al. Effects ofthree different dose regimens of magnesium on propofol requirements, he-modynamic variables and postoperative pain relief in gynaecological surgery.Br J Anaesth 2006;96:247e52.

7. Dahl JB, Mathiesen O, Møiniche S. ’Protective premedication’: an option withgabapentin and related drugs? A review of gabapentin and pregabalin in thetreatment of post-operative pain. Acta Anaesthesiol Scand 2004;48:1130e6.

8. Koç S, Memis D, Sut N. The preoperative use of gabapentin, dexamethasone,and their combination in varicocoele surgery: a randomized controlled trial.Anesth Analg 2007;105:1137e42.

9. Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB.A randomized study of the effects of single dose gabapentin versus placebo onpostoperative pain and morphine consumption after mastectomy. Anesthesi-ology 2002;97:560e4.

10. Kindler CH, Harms C, Amsler F, Ihde-Scholl T, Scheidegger D. The visual analogscale allows effective measurement of preoperative anxiety and detection ofpatients’ anesthetic concerns. Anesth Analg 2000;90:706e12.

11. Türe H, Sayin M, Karlikaya G, Bingol CA, Aykac B, Türe U. The analgesic effect ofgabapentin as a prophylactic anticonvulsant drug on postcraniotomy pain: aprospective randomized study. Anesth Analg 2009;109:1625e31.

12. Todd RD, McDavid SM, Brindley RL, Jewell ML, Currie KP. Gabapentin inhibitscatecholamine release from adrenal chromaffin cells. Anesthesiology 2012;116:1013e24.

13. Turan A, Memis D, Karamanlio�glu B, Ya�giz R, Pamukçu Z, Yavuz E. The analgesiceffects of gabapentin in monitored anesthesia care for ear-nose-throat surgery.Anesth Analg 2004;99:375e8.

14. Pandey CK, Navkar DV, Giri PJ, Raza M, Behari S, Singh RB, et al. Evaluation ofthe optimal preemptive dose of gabapentin for postoperative pain relief afterlumbar diskectomy. J Neurosurg Anesthesiol 2005;17:65e8.

15. Van Elstraete AC, Tirault M, Lebrun T, Sandefo I, Bernard JC, Polin B, et al.The median effective dose of preemptive gabapentin on postoperativemorphine consumption after posterior lumbar spinal fusion. Anesth Analg2008;106:305e8.

16. Montazeri K, Kashefi P, Honarmand A. Pre-emptive gabapentin significantlyreduces postoperative pain and morphine demand following lower extremityorthopaedic surgery. Singapore Med J 2007;48:748e51.

17. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia withgabapentin and local anesthetics prevents acute and chronic pain after breastsurgery for cancer. Anesth Analg 2005;101:1427e32.

18. Ménigaux C, Adam F, Guignard B, Sessler DI, Chauvin M. Preoperative gaba-pentin decreases anxiety and improves early functional recovery from kneesurgery. Anesth Analg 2005;100:1394e9.

19. Memis D, Turan A, Karamangioglu B, Seker S, Ture M. Gabapentin reducescardiovascular responses to laryngoscopy and tracheal intubation. Eur JAnaesthesiol 2006;23:686e90.

20. Kaya FN, Yavascaoglu B, Baykara M, Altun GT, Gülhan N, Ata F. Effect oforal gabapentin on the intraocular pressure and haemodynamic re-sponses induced by tracheal intubation. Acta Anaesthesiol Scand 2008;52:1076e80.