The effect of pregabalin and gabapentin on preoperative anxiety and sedation: a double blind study

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1 ORIGINAL ARTICLE The effect of pregabalin and gabapentin on preoperative anxiety and sedation: a double blind study Anju Ghai, MD*, Monika Gupta, MD**, Neha Rana, MD***, Raman Wadhera, MS**** *Professor, ** Senior Resident, ***Assistant Professor Department of Anaesthesiology ****Professor, Department of ENT Pt B.D.Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana (India) Correspondence: Dr Anju Ghai, 19/9J, Medical Campus, PGIMS, Rohtak, Haryana (India); Phone: ; dr.wadhera@yahoo.com; kadyann@ymail.com ABSTRACT Background: Pregabalin and gabapentin are compounds, which have been alleged to possess anxiolytic, analgesic, and anticonvulsant properties. Both are amino acid derivatives of gamma amino butyric acid. Pregabalin has a similar pharmacological profile to that of gabapentin. It has an amino acid substitution at third position which allows better lipid solubility and diffusion across blood brain barrier, better pharmacokinetic properties and fewer drug interactions due to absence of hepatic metabolism. We hypothesized that premedication with oral pregabalin and gabapentin would produce dose-related reductions in acute (state) anxiety and increase in sedation (sleepiness) before induction of general anaesthesia. Methodology: 90 women were randomly assigned to receive 300 mg pregabalin and 900 mg gabapentin and placebo 60 minutes prior to surgery. Anxiety and sedation was assessed before administration of drug and 1 hour later. A uniform anaesthetic technique was used in all groups. Parameters including sedation scores and various side effects were assessed. Results: Demographic variables were comparable. The preinduction anxiety scores were statistically significant from the baseline values in group 1 and 11. The sedation scores were statistically significant 1 hour after the drug. There was statistically significant difference between group I and II (p=), I and III (p=) and II and III(p=0.015). Analysis of sedation scores after surgery were comparable at all time intervals between group I and II. However statistically significant difference was noted between group I and III (p=) and group II and III (p=). A higher percentage of patients in the pregabalin group complained of dizziness and somnolence than the gabapentin and control group. Conclusion: Preoperative pregabalin (300mg) and gabapentin (900mg) administration 1 hour before surgery led to significant reduction in preoperative anxiety and improves sedation without producing significant side effects. Keywords: Gabapentin, pregabalin, sedation, anxiety Citation: Ghai A, Gupta M, Rana N, Wadhera R. The effect of pregabalin and gabapentin on preoperative anxiety and sedation: a double blind study. Anaesth Pain & Intensive Care 2012;16(3): INTRODUCTION Preoperative anxiety remains a problem for many patients during the perioperative period. High anxiety level make the control of postoperative pain more difficult. 1 Although benzodiazepines are effective in reducing perioperative anxiety, but the anxiolytic effect is frequently accompanied by undesirable sedation. GABA analogues are structural analogues ANAESTH, PAIN & INTENSIVE CARE; VOL 16(3) SEP-DEC

2 the effect of pregabalin and gabapentin of the inhibitory neurotransmitter gamma amino butyric acid(gaba) and bind in a state dependent manner to the alpha-2 delta subunit of voltage gated Ca channels in over excited presynaptic neurons reducing release of excitatory neurotransmitters, leading to a reduction in levels of anxiety and pain. 2 Pregabalin has an amino acid substitution at third position which allows better lipid solubility and diffusion across blood brain barrier, better pharmacokinetic properties and fewer drug interactions. A study in patients with generalized anxiety disorders found that chronic use of pregabalin and gabapentin was significantly more effective than benzodiazepine in improving somatic anxiety symptoms, but its role in acute anxiety needs to be yet evaluated. 3,4 Premedication with gabapentin 1200 mg improved preoperative anxiolysis in patients undergoing lumbar discectomy and arthroscopic anterior cruciate ligament repair, where it exerted anxiolysis without exerting anamnesis effects, 5,6 though administration of gabapentin 600 mg did not have this effect in patients undergoing total hip arthroplasty. 7 Preoperative pregabalin administration ( mg po) increased perioperative sedation in a dose-related fashion, but failed to reduce preoperative anxiety after minor elective procedures. 8 The studies have not reached any conclusion due to conflicting results. There has been no study in literature comparing the effect of these two drugs on preoperative anxiety and sedation. Hence, we planned to compare the effect of pregabalin and gabapentin on preoperative anxiety and sedation. The primary objective of this study was a decrease in the level of acute state anxiety before induction of general anaesthesia. The secondary objective was to determine its effect on postoperative sedation and the side effect. METHODOLOGY With approval of the ethics committee and written informed consent, 90 women belonging to ASA status I-II, aged 35 to 65 years, scheduled for elective abdominal hysterectomy undergoing general anaesthesia were included in the study. Although the wide age range, may affect the level of anxiety in patients, but it was chosen to include all the subjects in that period as the study was time bound. Patients with history of central nervous system disorders, chronic pain, use of regular analgesics, known hypersensitivity to gabapentin or pregabalin, impaired renal function and those with body weight >20% of ideal body weight were excluded from the study. All patients were visited on the day before surgery. The general physical examination was carried out. Routine investigations were noted. A linear 0-10cm visual analogue scale (VAS) for anxiety (where 0 denoted no anxiety and 10 was for worst imaginable anxiety) was explained to each patient. The computer generated block randomization schedule was prepared using random number generator to create a list of random numbers by our statistician and was handed over to the hospital pharmacist. To ensure the equal number of patients in each group, block randomization was done. Stat Trek (stattrek.com) program was used to derive the randomization list. The patients were assigned to one of the following groups. I (n=30) received pregabalin capsules 300mg II (n=30) received gabapentin capsules 900mg III (n=30) received placebo capsules Sample size was decided in consultation with our statistician. The primary end point for this study was a reduction in the patient s preoperative level of anxiety as assessed using the VAS. Based on a predicted 20% reduction from the patient s pretreatment (baseline) VAS anxiety score (mean value of 5 and SD of 3), a minimum of 25 subjects were required in each of the three study groups under the assumptions of an α level of 0.05 and power of 80%. The study medication was prepared by the hospital pharmacy in identical appearing capsules and was put in 90 numbered envelopes containing 3 capsules each to maintain blinding. The capsules were kept with the pharmacy only and were taken from them when required. The patients, clinical investigators, attending anesthesiologists and nurses in the recovery room who were involved in the patients care were all blinded to the content of the study medication. The patients received the study medication 60 minutes before induction of general anaesthesia. No sedative premedication other than the gabapentinoid was given. Anxiety and sedation levels were assessed before administration of drug and 60 minutes later. Sedation was observed and scored as follows: 0=Alert, conversant, 1=Awake but drowsy, 2=Asleep but arousable, 3=Asleep and not arousable. On arrival in the operating room, intravenous line was secured with intravenous cannula of appropriate size. Monitoring of non invasive blood pressure (NIBP), heart rate, electrocardiogram and arterial oxygen saturation (SpO 2 ) was carried out and the basal readings were noted. A uniform anaesthetic technique was used in all groups. After preoxygenation for 3 minutes, anaesthesia was induced with propofol 2 mg/kg and intubation of trachea was facilitated with vecuronium bromide 0.1 mg/kg. Haemodynamic parameters were recorded just before injecting propofol, just before tracheal intubation, immediately after tracheal intubation and after 1, 3, 5 and 10 minutes of intubation. 258 ANAESTH, PAIN & INTENSIVE CARE; VOL 16(3) SEP-DEC 2012

3 original article Anaesthesia was maintained with 67% N 2 O in 33% O 2, halothane 0.5% and intermittent doses of vecuronium bromide. Analgesia was provided with 1mg/kg of inj. tramadol at the commencement of surgery. Blood pressure, heart rate, ECG and SpO 2 were monitored throughout the intraoperative period. At the end of surgery, residual neuromuscular blockade was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg intravenously. After extubation, all patients were transferred to post anaesthesia care unit for observation. After surgery, an anaesthesiologist who was not a part of anaesthesia team assessed various parameters like sedation scores and various side effects at 1, 2, 6 and 12 hours. At the end of study, the data was compiled and analyzed using one way ANOVA, method of Least Significant Difference (LSD) and Chi-square statistical tests. RESULTS 100 patients were screened for eligibility to participate in this study and 90 were subsequently enrolled. There was no significant difference with respect to age, weight, ASA physical status, and duration of surgery. (Table 1) Table 2: Preoperative anxiety score on visual analogue score (Mean+SD)* Preoperative anxiety score Just before drug 1hour after drug I * II * III F P *p value <.05 Table 3: Sedation scores (Mean+SD) (p value <.05) Sedation scores Just before drug 1 hour after drug I * II III ** F P.000 * I and II, I and III (p=) ** II and III (p value <.05) Table 1: Distribution of mean weight, age and duration of surgery (Mean+SD) Weight (kg) Age (in years) Duration of surgery(min) III The anxiety scores one hour after the drug administration were statistically significant from the baseline values in I and II, but were comparable in III (Table 2). Preoperative sedation scores were comparable in all of the groups and were statistically significant (p<0.05) 1 hour after the drug in I and II but not in III using ANOVA. On applying method of LSD, there was statistically significant difference between I and II (p=), I and III (p=) and II and III (p=0.015) (Table 3). On analyzing postoperative sedation scores statistically, I and II were comparable at all time intervals. However statistically significant difference was noted between I and III (p=) and II and III (p=) (Table 4). A higher percentage of patients in the pregabalin group complained of dizziness and somnolence than the gabapentin group. (Table 5) Table 4: Post operative sedation score at different time intervals (Mean + SD) Postoperative sedation score 1 hour 2 hour 6 hour 12 hour I II III * * * * F P LSD 1 & II 1& III II & III p value <0.05 Table 5: Comparison of side effects (n=30) Side effects 1 II III Dizziness Somnolence Blurred vision Headache Peripheral edema ANAESTH, PAIN & INTENSIVE CARE; VOL 16(3) SEP-DEC

4 the effect of pregabalin and gabapentin DISCUSSION Patients routinely receive sedatives for reduction of anxiety before surgery at most of the centres. A previous study concluded that benzodiazepines administered before surgery have minimal beneficial effects on the postoperative clinical course of women undergoing abdominal hysterectomy. 9 Gabapentin has been reported as an anxiolytic drug in previous studies. 3,10,11 For example, it was effective in treating anxiety associated with panic disorders. 3,11,12 Recently, de-paris et al. demonstrated that gabapentin attenuated anxiety associated with simulated public speaking in volunteers. 12 This disorder may be related to the preoperative anxiety state. The interest in using gabapentin preoperatively to decrease preoperative anxiety is a result of its limited side effects. Moreover, gabapentin seems anxiolytic without exerting amnesic effects. 13 Reducing preoperative anxiety with gabapentin may have contributed to the improved postoperative pain and to the reduced morphine use because there is a possible association between preoperative anxiety and postoperative pain. 14,15 The efficacy of 300 mg pregabalin has been well proven in previous trials and it has proven efficacious at doses 2-4 fold lower than that of gabapentin. 16 Hence, an equipotent dose of gabapentin 900 mg (3 fold higher) was chosen. Our study suggests that a single dose of gabapentin 900 mg and pregabalin 300 mg administered 60 minutes prior to surgery was effective in reducing acute preoperative (state) anxiety and increased levels of sedation before and after surgery. Pregabalin 300 mg is a better anxiolytic and sedative than gabapentin which could be explained due to better alpha 2-delta ligand binding property. 17 Postoperative sedation was comparable with both GABA analogues which can be due to short half life of pregabalin (5-6 hours). 18 Dose of 1200 mg of gabapentin given 1-2 hours before surgery has been found to decrease anxiety and postoperative pain after knee surgery. 6 But preoperative sedation scores were not assessed in that study. Our results with gabapentin are similar to this study, but at lower dose. The anxiety findings observed with pregabalin in our study is in contrast while sedation scores are comparable to the findings by White et al, where they studied 75, 150, 300 mg of pregabalin and compared it with placebo. Anxiety levels remained unchanged in their study during the preoperative evaluation period and did not differ among all the groups, though sedation scores were higher with pregabalin 300 mg group at the preinduction assessment and 90 and 120 minutes after surgery compared with 75 mg, 150 mg and placebo. 8 Nutt et al evaluated acute onset of anxiolytic activity using a dental anxiety model in 89 patients using 150 mg pregabalin, alprazolam 0.5 mg and a placebo 4 hours before dental procedure and found significant improvement in anxiety and sedation with pregabalin and alprazolam compared with placebo. They suggested that onset of anxiolytic effect after single dose pregabalin occurs within first 3-4 hours. 19 CONCLUSION In summary, our results indicate that premedication with 900 mg oral gabapentin and 300 mg pregabalin decreases preoperative anxiety, and improves sedation without producing significant side effects. 260 ANAESTH, PAIN & INTENSIVE CARE; VOL 16(3) SEP-DEC 2012

5 original article References 1. Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized placebo-controlled study. J Pain Jan;10(1): [Medline] 2. Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57: [Medline] 3. Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry Jul;155(7): [Medline] 4. Baldwin DS, Ajel K. Role of pregabalin in the treatment of generalized anxiety disorder. Neuropsychiatr Dis Treat Apr;3(2): [Medline] 5. Kiskira O, Kolotoura A, Tsitsopoulos P; karmiri, E; Emexidis Th.; Pouliou, A. The effect of Gabapentin on preoperative anxiety in patients undergoing lumbar discectomy: A-557 European Journal of Anaesthesiology. 2006;23: Ménigaux C, Adam F, Guignard B, Sessler DI, Chauvin M. Preoperative Gabapentin decreases anxiety and improves early functional recovery from knee surgery. Anesth Analg May;100(5): [Medline] 7. Clarke H, Kay J, Orser BA, Gollish J, Mitsakakis N, Katz J. Gabapentin does not reduce preoperative anxiety when given prior to total hip arthroplasty. Pain Med Jun;11(6): doi: / j x. [Medline] 8. White PF, Tufanogullari B, Taylor J, Klein K. The effect of Pregabalin on preoperative anxiety and sedation levels: A dose ranging study. Anesth Analg Apr;108(4): doi: /ane.0b013e31818d40ce [Medline] 9. Kain ZN, Sevarino FB, Rinder C, Pincus S, Alexander GM, Ivy M, Heninger G. Preoperative anxiolysis and postoperative recovery in women undergoing abdominal hysterectomy. Anesthesiology Mar;94(3): [Medline] 10. Chouinard G, Beauclair L, Belanger MC. Gabapentin: long-term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders. Can J Psychiatry Apr;43(3):305. [Medline] 11. Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, et al. Placebocontrolled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol Aug;20(4): [Medline] 12. de-paris F, Sant Anna MK, Vianna MR, Barichello T, Busnello JV, Kapczinski F, et al. Effects of gabapentin on anxiety induced by simulated public speaking. J Psychopharmacol Jun;17(2): [Medline] 13. de-paris F, Busnello JV, Vianna MR, Salgueiro JB, Quevedo J, Izquierdo I, et al. The anticonvulsant compound gabapentin possesses anxiolytic but not amnesic effects in rats. Behav Pharmacol Apr;11(2): [Medline] 14. Lynch EP, Lazor MA, Gellis JE, Orav J, Goldman L, Marcantonio ER. Patient experience of pain after elective noncardiac surgery. Anesth Analg Jul;85(1): [Medline] 15. Kalkman CJ, Visser K, Moen J, Bonsel GJ, Grobbee DE, Moons KG. Preoperative prediction of severe postoperative pain. Pain Oct;105(3): [Medline] 16. Laurea-Horner BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs Apr;12(4): [Medline] 17. Jones D, Sorkin L. Systemic gabapentin and S(+)-3-isobutyl gamma- aminobutyuric acid on the secondary hyperalgesia. Brain Res Nov 9;810(1-2):93-9. [Medline] 18. Kavoussi R. Pregabalin: from molecule to medicine. Eur Neuropsychopharmacol Jul;16 Suppl 2:S [Medline] 19. Nutt D, Mandel F, Baldinetti F. Early onset anxiolytic efficacy after a single dose of pregabalin: double-blind, placebo- and active-comparator controlled evaluation using a dental anxiety model. J Psychopharmacol Nov;23(8): doi: / [Medline] Pearls Prayer is not a spare wheel that you pull out when in trouble, but it is a steering wheel that directs the right path throughout the journey. So why is a Car s WINDSHIELD so large & the Rear View Mirror so small? Because our PAST is not as important as our FUTURE. So, Look Ahead and Move on. Friendship is like a BOOK. It takes a few minutes to burn, but it takes years to write. All things in life are temporary. If going well, enjoy it, they will not last forever. If going wrong, don t worry, they can t last long either. Old Friends are Gold! New Friends are Diamond! If you get a Diamond, don t forget the Gold! Because to hold a Diamond, you always need a Base of Gold! Often when we lose hope and think this is the end, GOD smiles from above and says, Relax, sweetheart, it s just a bend, not the end! When GOD solves your problems, you have faith in HIS abilities; when GOD doesn t solve your problems HE has faith in your abilities. A blind person asked St. Anthony: Can there be anything worse than losing eye sight? He replied: Yes, losing your vision! When you pray for others, God listens to you and blesses them, and sometimes, when you are safe and happy, remember that someone has prayed for you. WORRYING does not take away tomorrow s TROUBLES, it takes away today s PEACE. Live simply. Love generously. Care deeply. Speak kindly. Leave the rest to God. ANAESTH, PAIN & INTENSIVE CARE; VOL 16(3) SEP-DEC