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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e31826ac3b9
Obstetric Anesthesiology

A Single Preoperative Dose of Gabapentin Does Not Improve Postcesarean Delivery Pain Management: A Randomized, Double-Blind, Placebo-Controlled Dose-Finding Trial

Short, Jonathan MB, BS, FRCA*; Downey, Kristi MSc*; Bernstein, Paul MD, FRCPC; Shah, Vibhuti MD, MSc, FRCPC; Carvalho, Jose C. A. MD, PhD, FANZCA, FRCPC*†

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From the *Department of Anesthesia and Pain Management, Department of Obstetrics and Gynecology, and Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Accepted for publication June 28, 2012.

Published ahead of print September 25, 2012

Jonathan Short is now with the Department of Anaesthesia, King’s College Hospital, London, United Kingdom.

Funding: Departmental resources.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the 2011 Annual Meeting of the Society for Obstetric Anesthesia and Perinatology.

Reprints will not be available from the authors.

Address correspondence to Jose C. A. Carvalho, MD, PhD, Department of Anesthesia and Pain Management, Mount Sinai Hospital, 600 University Avenue, Room 781, Toronto, ON, Canada. Address e-mail to jose.carvalho@uhn.ca.

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Abstract

BACKGROUND: A single preoperative dose of 600 mg gabapentin, combined with multimodal analgesia, has previously been shown to reduce postcesarean pain and improve maternal satisfaction but was associated with increased maternal sedation. We hypothesized that a lower dose of gabapentin may be effective with less sedation.

METHODS: We conducted a doubleblind, randomized, placebo-controlled study. Women undergoing elective cesarean delivery were randomized into 3 groups to receive 300 or 600 mg oral gabapentin, or placebo, 1 hour before surgery. Temporal summation (TS) testing was performed at the time of study drug administration, and a visual analog scale (0 to 100 mm) difference ≥10 mm between the 1st and 10th stimuli was considered TS+. Spinal anesthesia and postoperative analgesia were instituted, including intrathecal fentanyl and morphine, oral diclofenac and acetaminophen, and systemic morphine as required. Pain assessments at rest and on movement (visual analog scale 0 to 100 mm) were conducted at 6, 12, 24, and 48 hours after surgical incision. The primary outcome was pain on movement at 24 hours. Secondary outcomes included satisfaction with analgesia, supplemental opioid consumption, lactation difficulties, neonatal outcomes, maternal sedation, and other adverse effects. Three months after delivery, patients were contacted for assessment of chronic pain.

RESULTS: One hundred thirty-two women were randomized and 6 were excluded. The difference in mean pain scores at 24 hours (95% confidence intervals [CI]) were as follows: 600 mg versus 300 mg mean difference: 5 mm (95% adjusted CI, −7 to 17); 600 mg versus placebo: 3 mm (−9 to 15); 300 mg versus placebo: −2 mm [−14 to 10]; overall P value = 0.61. There was no apparent benefit of gabapentin in TS+ women, although overall pain scores were significantly higher in these women irrespective of the study group.

CONCLUSION: Given the wide confidence intervals of the differences in mean pain scores, the current study did not allow us to determine whether a single preoperative dose of gabapentin (300 mg and 600 mg) improved postcesarean analgesia compared to placebo in the context of a multimodal analgesic regimen. A larger study is required.

Pain after cesarean delivery is the greatest concern for parturients, and the most common acute postoperative complaint.1,2 Furthermore, acute severe pain after cesarean delivery may be a significant risk factor for the development of chronic pain and postpartum depression.3–5

Optimization of postoperative analgesia can improve maternal satisfaction, reduce the risk of postoperative complications, and reduce the incidence of chronic pain and postpartum depression after cesarean delivery. However, effective optimization of postoperative pain management requires the identification of women at higher risk for pain and further individualization of care, as pain perception is a very individual experience. Several preoperative predictive tests for postcesarean pain have been developed.6,7 Although most lack the practicality for use in the clinical setting, mechanical temporal summation (TS) has shown to be a simple predictive test for the severity of postoperative pain on movement8 and could be useful in the obstetric population.

Current regimens of postcesarean pain management are good but usually generic, not designed for specific individuals. Despite great advances in this area, pain relief and maternal satisfaction remain inadequate in some patients.1,9 Further improvements in postcesarean pain management are therefore warranted.

Gabapentin has been shown to reduce acute postoperative pain and opioid consumption after various surgical procedures, including total abdominal hysterectomy.10,11 A systematic review investigating the postoperative effects of gabapentin included studies that administered a single dose of gabapentin given before surgery.12 An overall effect in favor of gabapentin was seen, even in studies that used a single preoperative dose of 300 mg.

In a recent study, our group showed that women given 600 mg oral gabapentin before cesarean delivery showed a significant reduction in pain scores on movement and an increase in maternal satisfaction up to 48 hours after surgery. However, this was associated with an increase in maternal sedation.13 It is possible that a lower dose of gabapentin may still be beneficial while producing less sedation.

This study was conducted to assess the efficacy of different doses of gabapentin to reduce postcesarean pain, as part of a multimodal analgesic regimen, and to address the potential adverse event of maternal sedation caused by this medication. We hypothesized that a single preoperative dose of 300 mg gabapentin given to women before undergoing elective cesarean delivery under spinal anesthesia would result in an intermediate decrease in postoperative pain scores relative to placebo and a 600 mg dose. Furthermore we hypothesized that a 300 mg dose would result in less sedation than the 600 mg dose.

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METHODS

This randomized, double-blind, placebo-controlled clinical trial received Institutional Research Ethics Board approval, and a No Objection Letter from Health Canada. This trial was registered with the United States National Institute of Health at www.clinicaltrials.gov under number NCT01094925.

Eligible participants were ASA physical status I or II women with singleton term pregnancies who were admitted for elective cesarean delivery and who were enrolled after written informed consent. Exclusion criteria were contraindications to neuraxial anesthesia or to any of the medications used in the study, a history of epilepsy, central nervous system or mental disorders, chronic pain, drug abuse, or use of neuropathic analgesic or antiepileptic drugs. Women carrying a fetus with known congenital abnormalities were also excluded.

Participants were allocated into 3 groups: 600 mg gabapentin, 300 mg gabapentin, or placebo. Hospital pharmacists, who were not otherwise involved in the study, placed doses of 300 mg gabapentin or lactose placebo in identical blue capsule covers. Two capsules were placed in sequentially numbered envelopes, according to a computer-generated randomization table. The randomization was done in blocks of 6. After written informed consent was obtained, each woman was assigned an ascending sequential study number, and given the study medication by mouth with a sip of water 1 hour before the anticipated time of the surgical incision. The medication was administered by the study personnel, who also performed the subsequent assessments. Study personnel were blinded to group assignment until all women had been recruited and assessments were completed. Study personnel performing the postoperative assessments were not blinded to the TS results (see below) for individual subjects.

Mechanical TS assessment was performed at the time of study drug administration. It was evoked with a 180 g von Frey filament (North Coast Medical, San Jose, CA) applied to the skin of the volar aspect of the nondominant forearm. Women were exposed to a single stimulus and asked to rate the perceived pain intensity on an unmarked visual analog scale (VAS) from 0 to 100 mm, where 0 mm was no pain and 100 mm was the most severe pain imaginable. Subsequently, 10 repetitive stimuli at 1-second intervals were applied within an area of 1 cm2 on the skin at the same site as the initial stimulus. Women were then again asked to rate the perceived pain according to the VAS. The difference in the VAS between the 1st and the 10th stimuli was defined as the magnitude of the TS. Women presenting with a ≥10 mm increase in their VAS were arbitrarily defined as TS positive (TS+), in contrast to those exhibiting an increase in VAS <10 mm, defined as TS negative (TS−).

All women received a preload of 10 mL/kg Ringer’s lactate solution before induction of spinal anesthesia, along with antibiotic prophylaxis. Spinal anesthesia consisted of 13.5 mg 0.75% hyperbaric bupivacaine, 10 μg fentanyl, and 100 μg preservative-free morphine. Exteriorization of the uterus for repair and tubal ligation was recorded. Intraoperative pain was treated with IV fentanyl at the discretion of the anesthesiologist. An oxytocin infusion, 20 IU over 8 hours, was initiated and administered after umbilical cord clamping. At the end of the operation, 30 mg IV ketorolac and 1300 mg PR acetaminophen were administered. Women were subsequently transferred to the post-anesthesia care unit (PACU) where they were observed for approximately 2 hours. In the PACU, pain was treated with 2 mg IV morphine at 5-minute intervals on patient request. Postoperatively, women received 50 mg oral diclofenac every 8 hours and 1 g acetaminophen every 6 hours for 72 hours. Breakthrough pain in the first 24 postoperative hours was treated with 2 mg subcutaneous morphine on request. Subsequently patients received 10 mg oral morphine as required for breakthrough pain. Nausea was treated with 50 mg IM dimenhydrinate every 6 hours as required, and pruritus was treated with 5 mg subcutaneous nalbuphine every 4 hours as required.

A respiratory therapist was present at all deliveries and was responsible for the initial assessment and resuscitation of the neonate, including assigning Apgar scores. After the initial assessment, the baby was wrapped and given to the parents. Breast-Feeding was initiated in the PACU with the aid of a trained nurse. On the ward, the mother had access to lactation consultants and breast-feeding education sessions. All the babies were assessed by a pediatrician within 48 hours of birth.

Maternal demographics (age, height, weight, body mass index), ASA physical status, parity, and the indication for cesarean delivery were recorded. Postoperative pain intensity was assessed at 6, 12, 24, and 48 hous after surgical incision using an unmarked VAS of 0 to 100 mm, with 0 mm indicating no pain and 100 mm being the worst possible pain. Women rated their pain at rest, and when moving from lying flat to sitting. Satisfaction with pain management was also assessed using a VAS of 0 to 100 mm, with 0 mm being not satisfied and 100 mm being completely satisfied. Nausea, vomiting, sedation, and pruritus were reported by the patient on a 4-point scale (0 = absent, 1 = mild, 2 = moderate, or 3 = severe). The use of supplemental morphine and medication for treatment of nausea and pruritus, difficulties with breast-feeding, and consultations with the lactation nurses were recorded.

Women were contacted by telephone 3 months after surgery, and asked if they had pain or abnormal sensations at the incision site, the pain intensity using a verbal numerical scale of 0 (no pain) to 10 (worst pain imaginable), if the pain limited their activities of daily living, and if they were still requiring analgesics to treat the pain.

Gestational age, birth weight, and gender were recorded, along with Apgar scores at 1 and 5 minutes, umbilical cord blood gases, and the requirement for neonatal intensive care unit (NICU) admission, and respiratory support.

The primary endpoint was the VAS score (100 mm scale) for maternal pain on movement at 24 hours after surgical incision.

Our sample size calculation was based on a previous study in a similar population, in which 21 women received 600 mg gabapentin and 23 women received placebo.13 At 24 hours after surgery, the gabapentin group had a reduction in pain on movement of 20 mm, from 41 mm to 20 mm when compared to the placebo group. We assumed a linear correlation, so that 300 mg gabapentin would produce a VAS score of 31 mm. Various scenarios on either side of this linear relationship were also calculated. To detect an overall difference in pain scores across gabapentin doses represented by minimal clinically significant differences of 10 mm between doses (e.g., a score of 21 mm for 600 mg and a score of 41 mm for placebo),14 41 women would need to be randomized to each of 3 treatment groups, for a total sample of 123 patients. This calculation was based on the power formulae by Muller and Peterson15 to achieve 90% power to detect differences among the means versus the alternative of equal means using an F test with a 0.05 significance level. The common SD within a group was assumed to be 25. Finally, based on findings from our previous study, we increased the sample size by 6% to account for protocol violation and dropouts.

Descriptive statistical methods were used to describe the study population. Maternal demographics and mechanical TS scores were summarized and compared across the 3 treatment groups using means and standard deviations for continuous factors, and frequencies and proportions for categorical factors.

To assess the primary hypothesis of differences in VAS pain scores on movement at 24 hours across the treatment groups, a mixed-effects model, repeated-measures analysis of variance (RM-ANOVA) approach with the treatment group as the between-subjects factor, time as the within-subject factor, and the individual as a random factor was used. Mean differences and pairwise 95% confidence intervals (CI) using a Bonferroni adjustment (pairwise α = 0.05/3 comparisons = 0.016) for multiple comparisons were used to evaluate the differences in pain scores across the 3 treatment groups at 24 hours. The autoregressive covariance structure was used in the models and verified against other structures using Akaike’s Information Criterion. Secondary hypotheses evaluating differences in neonatal outcomes across the treatment groups were evaluated using Fisher’s exact tests for categorical factors due to small numbers of events (e.g., NICU admission, lactation consultation). Secondary hypotheses of differences in continuous factors were compared across treatment groups using analysis of variance (F tests) where assumptions of normality of residuals (as determined by the Shapiro-Wilk test for normality) and homogeneity of variances (as determined by the Levene’s test for homogeneity of variances) were met (e.g., umbilical pH, PCO2, pHCO3, PO2), and using nonparametric Kruskal-Wallis tests where parametric assumptions were violated (e.g., 1- and 5-minute Apgar scores). For continuous outcomes, Bonferroni corrections were applied where pairwise comparisons across the 3 treatment groups were indicated. The Bonferroni correction resulted in a 0.008 (i.e., 0.05/3 comparisons × 2 timepoints) α level for each individual comparison. The incidence of maternal adverse reactions was also compared across the treatment groups using Fisher’s exact test.

We examined whether there was an effect of TS on the response to gabapentin by comparing the VAS scores and satisfaction scores between TS+ and TS− women, and comparing the VAS score among the three groups using RM-ANOVA with TS as the covariate. As a subanalysis, the efficacy of gabapentin in TS+ and TS− women were also examined using the RM-ANOVA. For all analyses, a P value of ≤0.05 was considered statistically significant. SAST (version 9.2; SAS Institute Inc., Cary, NC) and R version 2.10.1 were used in the data analysis; sample size was determined using the SAS procedure GLMPOWER.

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RESULTS

The study was conducted from April to November 2010. Two hundred and thirty-four women were approached, and 132 participated in the study (Fig. 1). Six women were excluded from analysis after randomization had taken place. A further block of 6 women was randomized at the end of the initial recruitment period to replace those excluded. This was done using computer-generated block randomization, and it is coincidental that the numbers in each group are equal.

Figure 1
Figure 1
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Table 1 outlines the distribution of demographic and clinical variables. Three women in the placebo group, 2 in the 300 mg gabapentin group, and 1 in the 600 mg gabapentin group required supplemental intraoperative analgesia.

Table 1
Table 1
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The VAS scores for pain on movement and at rest are reported in Figure 2, 2A and 2B, respectively. The difference in mean pain scores at 24 hours (95% CI) were as follows: 600 mg versus 300 mg mean difference: 5 mm (95% adjusted CI, −7 to 17); 600 mg versus placebo: 3 mm (−9 to 15); 300 mg versus placebo: −2 mm (−14 to 10); overall P value = 0.61.

Figure 2
Figure 2
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The results of the secondary maternal outcomes are reported in Tables 2 and 3 and Figures 3, 34, and 5.

Table 3
Table 3
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Table 2
Table 2
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Figure 3
Figure 3
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Twenty-nine (23%) women were TS+, 11 in the placebo group, 9 in the gabapentin 300 mg group, and 9 in the 600 mg gabapentin group. There was an increase in pain on movement at 48 hours in those who were TS+, irrespective of their group allocation (mean difference 14 mm, 95% CI, 6 to 23) (Fig. 4). There was also higher maternal satisfaction scores in TS− women at 48 hours, compared with TS+ women (mean difference for satisfaction: 9 mm, 95% CI, 1 to 17).

Figure 4
Figure 4
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Neonatal outcomes are reported in Table 4. There were 5 NICU admissions (2 in the placebo, 2 in the 300 mg, and 1 in the 600 mg group) during the first 48 hours after delivery. Four neonates were active upon delivery, but subsequently required admission for respiratory support; the fifth was an unexpected Trisomy 21 neonate, in the 300 mg gabapentin group, born with poor Apgar scores.

Table 4
Table 4
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Five women reported breast-feeding difficulties (3 in the placebo, 1 in the 300 mg, 1 in the 600 mg group), and required assistance from the lactation nurses. In 1 subject in the placebo group the difficulty was attributed to neonatal sedation. The 5 babies who were admitted to the NICU were fed by expressed breast milk.

One hundred twelve women were contacted by telephone 3 months after cesarean delivery; 14 women were lost to follow-up. Ten women reported persistent pain at 3 months. There were no significant differences in the rate of women reporting persistent pain at 3 months among the groups.

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DISCUSSION

This study did not replicate the positive results from a previous study from our own group evaluating the analgesic benefits of gabapentin 600 mg given orally preoperatively to women undergoing elective cesarean delivery.13 We did not observe an improvement in pain scores with either 300 or 600 mg gabapentin. However, although the mean pain scores were not statistically different among the studied groups, the CI were wide and included clinically significant differences. Therefore, no definitive conclusions can be drawn from our results.

It was surprising that the 2 studies should produce such different results. To confirm that the results of our current study were genuine, we analyzed a batch of the study drug and of the placebo by gas chromatography-mass spectrometry. The results of this chemical analysis were reassuring, and we can be confident that the results of this study have not been distorted by any pharmacy error.

Women defined as TS+, irrespective of their group allocation, exhibited higher pain scores and less maternal satisfaction when compared to TS− women after delivery, but only at 48 hours. These results do not support any definitive conclusions, and further studies are warranted to clarify the role of TS as a useful tool to identify women at higher risk for postoperative pain. Gabapentin has been previously demonstrated to significantly inhibit TS of cutaneous pain,16 so we wanted to investigate whether women who exhibited TS would respond differently to gabapentin. However, in our study, TS+ women did not exhibit a superior response to gabapentin.

The current study was in part motivated by the increased sedation observed with gabapentin 600 mg in our previous study. Sedation is a common side effect of gabapentin, particularly in individuals who have not previously been exposed to the drug. In our earlier study, 19% of women who received 600 mg gabapentin experienced severe sedation. Consequently, we hypothesized that a lower dose of 300 mg may still produce analgesic benefits but with less sedation. Our current study however did not show any increase in sedation in women who received gabapentin, irrespective of the dose. It is possible that investigator bias may have contributed to the increase in sedation observed in the previous study.13 We attempted to eliminate this from our results by using a standardized preprinted questionnaire when assessing side effects of gabapentin and avoiding any deviation from this questionnaire when approaching the patients during data collection in the postoperative period.

Particular care was taken to observe any potential effects of gabapentin on the neonate. We did not observe any deleterious neonatal effects that could be attributed to maternal pretreatment with gabapentin. Apgar scores, umbilical artery pH, and breast-feeding difficulties were similar among groups. Although this study was not powered to examine neonatal outcomes, our results are nevertheless reassuring, and are consistent with the neonatal outcomes observed in the previous study.

Overall, 8.9% of the women continued to complain of discomfort around the scar after 3 months. This rate of persistent pain is comparable to previous studies that have examined the rate and impact of chronic pain after cesarean delivery.3,4 It should be noted that our study was not powered to detect differences for this outcome across the study groups.

The most important limitation of our study is that it appears to be underpowered for our purpose. It should be noted that our original sample size calculation was based on an optimistic scenario in which a linear 20 mm difference between the lowest and highest dose (i.e., placebo and 600 mg) was assumed. Therefore this study was not sufficiently powered for discriminating between the observed differences nor for comparisons between the dose groups. Although we used data from a previous study conducted at our own institution, and both the patient population and clinical practice have remained essentially the same, our results exhibited more variability than we predicted. There are no statistical differences in mean pain scores among the groups, but the wide 95% CI include clinically significant differences. Therefore we are unable to draw any definitive conclusions.

In conclusion, this study did not replicate the favorable results of our previous study. A single preoperative dose of 300 mg or 600 mg gabapentin did not improve postcesarean pain management and maternal satisfaction in the context of a multimodal analgesic regimen inclusive of intrathecal morphine. The study was however underpowered to allow any definitive conclusion. It was reassuring that we did not observe any significant maternal sedation or neonatal side effects with these doses of gabapentin. The results of this study should prove useful for the planning of future studies addressing the role of gabapentin in the postoperative management of patients undergoing cesarean delivery. E

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DISCLOSURES

Name: Jonathan Short, MB, BS, FRCA.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Jonathan Short has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Kristi Downey, BSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Kristi Downey has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Paul Bernstein, MD, FRCPC.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Paul Bernstein has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Vibhuti Shah, MD, FRCPC, MSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Vibhuti Shah has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jose C. A. Carvalho, MD, PhD, FANZCA, FRCPC.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Jose Carvalho has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Cynthia A. Wong, MD.

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ACKNOWLEDGMENTS

Statisticians: Ye, Xiang Y, MSc, Maternal-Infant Care Research Center, Mount Sinai Hospital, Toronto, ON, Canada; J. Charles Victor, MSc, PStat, Director, Research Practice, Institute for Clinical Evaluative Sciences, Toronto, ON; Chemist: Johannes Zeidler, PhD, DABCC, Toxicology Laboratory, St. Joseph’s Healthcare, Hamilton, ON, Canada.

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REFERENCES

Figure 5
Figure 5
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6. Pan PH, Coghill R, Houle TT, Seid MH, Lindel WM, Parker RL, Washburn SA, Harris L, Eisenach JC. Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement Anesthesiology. 2006;104:417–25

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8. Weissman-Fogel I, Granovsky Y, Crispel Y, Ben-Nun A, Best LA, Yarnitsky D, Granot M. Enhanced presurgical pain temporal summation response predicts post-thoracotomy pain intensity during the acute postoperative phase J Pain. 2009;10:628–6

9. Lavand’homme P. Postcesarean analgesia: effective strategies and association with chronic pain Curr Opin Anaesthesiol. 2006;19:244–8

10. Dierking G, Duedahl TH, Rasmussen ML, Fomsgaard JS, Møiniche S, Rømsing J, Dahl JB. Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: A randomized double-blind trial Acta Anaesthesiol Scand. 2004;48:322–7

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