Effect of Single Preoperative Dose of Duloxetine on Postoperative Analgesia in Patients Undergoing Total Abdominal Hysterectomy under Spinal Anesthesia.

BACKGROUND: Women undergoing hysterectomy present a unique set of challenges to the anesthesiologist in terms of postoperative pain management. This study was conducted to see the effect of single-dose perioperative duloxetine 60 mg on postoperative analgesia following abdominal hysterectomy under spinal anesthesia.
MATERIALS AND METHODS: This prospective randomized placebo-controlled study was conducted on 64 patients scheduled to undergo elective abdominal hysterectomy under spinal anesthesia. The patients were divided into two groups of 32 in each, Group D received duloxetine 60 mg 2 h preoperatively and Group P received placebo 2 h preoperatively. Postoperatively, the patients were evaluated by an independent observer for pain on rest and during cough at 0 (arrival at postanesthesia care unit), 2, 4, 6, 12, and 24 h. In addition, the postoperative analgesic requirements and adverse effects were noted. STATISTICAL ANALYSIS USED: Independent t-test/Mann-Whitney U-test was used to compare the pain score between two groups.
RESULTS: The demographic data were comparable between both the groups. The mean Visual Analogue Scale scores assessed postoperatively at rest and during cough which were not statistically significant between the two groups. The rescue analgesic consumption in Group D (0.97 ± 0.86) and Group P (1.25 ± 0.76) was comparable and statistically not significant. The total analgesic requirement between duloxetine (4.94 ± 0.84) and placebo (1.25 ± 0.76) group was comparable and statistically not significant. The incidence of nausea vomiting and somnolence was higher in Group D.
CONCLUSION: We conclude that patients receiving a single dose of 60 mg duloxetine as premedication before hysterectomy under spinal anesthesia are no better than placebo on postoperative pain during the first 24 h. Copyright:

INTRODUCTION

Inadequate control of postoperative pain is associated with increased length of hospital stay, increased hospital cost, sleep disturbance, depression, and functional impairment and impedes the quality of life.[123] Abdominal hysterectomy is one of the commonly performed gynecological procedures. Female gender is a known risk factor for increased postoperative pain, poor quality of recovery, and increased length of hospital stay.[345] Preemptive analgesia is the analgesic treatment initiated before the surgical procedure to prevent central sensitization from the noxious stimuli. Drugs such as gabapentin, pregabalin, serotonin–norepinephrine reuptake inhibitors, dexamethasone, and cyclooxygenase-2 inhibitors have been used for preemptive analgesia.[67]

Serotonin–norepinephrine reuptake inhibitors modulate the descending inhibitory pain pathways by increasing the availability of serotonin and norepinephrine.[8] It can be used as an adjunct with other modalities to control postoperative pain. Duloxetine is a potent serotonin–norepinephrine reuptake inhibitor commonly used for treating chronic pain.[9] It allays anxiety and depression in patients experiencing pain.[1] The analgesic property of duloxetine is independent of its antidepressant action, with a similar reduction in pain in both depressed and nondepressed patients.[10] There are many studies that have shown preoperative use and continued postoperative use of duloxetine for a few days to weeks has a significant effect on reducing postoperative pain and on reducing analgesic requirements in various surgical patients.[89101112] There is no literature available on the effect of single preoperative dose of duloxetine on postoperative pain following spinal anesthesia. In the present study, we hypothesized that a single dose of 60 mg duloxetine may reduce postoperative pain in patients undergoing abdominal hysterectomy under spinal anesthesia. The primary objective was to assess the postoperative pain scores with preoperative administration of 60 mg duloxetine in comparison to placebo. The secondary objective was to assess the postoperative analgesic consumption in the first 24 h postoperatively.

MATERIALS AND METHODS

After obtaining Institutional Ethical Committee approval and informed consent, female patients aged 30–60 years belonging to the American Society of Anesthesiologists Classes I and II body mass index – 18–35 kg.m−2 who were scheduled to undergo elective abdominal hysterectomy were included in the study. Patients with contraindications to neuraxial anesthesia, renal or liver disease, on long-term opioids or antidepressants, and hypersensitivity to duloxetine were excluded from the study. Those satisfying inclusion criteria were randomly allocated into two groups by a computer-generated random number table. Patients in Group D received oral duloxetine 60 mg 2 h prior to surgery with a sip of water and patients in Group P received oral placebo capsule resembling duloxetine 2 h before the scheduled surgery.

On arrival in the operation room after instituting minimal mandatory monitoring, all patients received subarachnoid block with 3 mL of 0.5% bupivacaine heavy and 90 μg of buprenorphine. All patients received oxygen via face mask at 5 L.min−1 throughout the intraoperative period and vital parameters were monitored. In the postoperative period, pain at rest and on coughing was noted on Visual Analog Scale (VAS) at 1 h, 6 h, 12 h, and 24 h. All patients received paracetamol 1 g intravenous infusion on arrival in the postanesthesia care unit and thereafter every 8 h. If the patient's VAS score was more than 4 or the patient requested for analgesia, tramadol 50 mg was given as infusion over 15 min as rescue analgesia. If a patient still continued to complain of pain or VAS score remained more than 4 after 30 min following the first rescue analgesic, diclofenac 75 mg was given as an infusion over 15 min.

Statistical analysis

Sample size estimation

In a study by Castro-Alves et al.,[9] the median pain score at rest was 3 (0–4) in the duloxetine group and 5 (1.5–7) in the placebo group during the first 24 h postoperatively. In the present study, expecting similar results with 80% power, 95% confidence level, and a minimum detectable difference of 1.5 points between the two groups, the study requires a minimum of 32 subjects in each group.

Demographic data were summarized in terms of mean with standard deviation and analyzed using an unpaired t-test. Descriptive statistics of pain score and doses of rescue analgesia were analyzed and summarized in terms of mean with standard deviation. Independent t-test/Mann–Whitney test was used to compare the pain score between the two groups. Repeated ANOVA/Friedman test was used to compare pain score between different time points within the group. Statistical analysis was done using Statistical analysis was done using SPSS© (Statistical Package for the Social Sciences) version 18 (IBM Corp., Armonk, NY, USA). Microsoft Word and Excel have been used to generate graphs and tables.

RESULTS

In the present study, 64 patients were recruited and were randomized to receive either 60 mg of duloxetine or placebo. Completed data were obtained from all the participants and were included for the data analysis. The demographic profile between the two groups was comparable [Table 1]. Pain at rest and on coughing as assessed by VAS at various time points during the first 24 h postoperatively was found to be similar between the two groups [Table 2]. The requirement of rescue analgesia doses was also found to be similar between the two groups [Table 3]. Ten patients in Group D had nausea and vomiting as compared to two patients in Group P. Seven patients in Group D were somnolent in Group D compared to none in Group P. The incidence of headache and dizziness was similar between the two groups [Table 4].

Table 1

Demographic profile

Variable	Group D	Group P	P
Age (years)†	44.53±6.33	46.94±6.85	0.150
Weight (kg)†	63.09±11.26	67.11±10.95	0.153
Height (cm)†	151.50±4.86	152.59±3.66	0.313
BMI (kg.m−2)†	27.31±4.47	28.66±4.61	0.238
ASA grade (1/2)‡	12/20	11/21	0.794
Duration of surgery (min)†	114.25±15.21	117.66±14.16	0.357

Data presented as †Mean±SD, ‡Number (n). SD=Standard deviation, BMI=Body mass index, ASA=American Society of Anesthesiologists

Table 2

Pain scores (Visual Analog Scale) at different time points

Time points (h)	Mean VAS score at rest†			Mean VAS score on coughing†
	Group D	Group P	P	Group D	Group P	P
0	0.00±0.00	0.00±0.00	-	0.00±0.00	0.00±0.00	-
1	0.03±0.18	0.00±0.00	0.321	0.81±1.40	0.56±1.13	0.436
6	4.34±1.10	4.22±1.04	0.641	5.38±1.13	5.28±0.99	0.725
12	4.78±1.13	5.13±1.56	0.317	5.75±1.22	6.13±1.56	0.288
24	3.94±0.67	3.88±0.98	0.766	5.00±0.72	4.88±0.98	0.562

Data presented as †Mean±SD. SD=Standard deviation, VAS=Visual Analog Scale

Table 3

Doses of analgesic consumption in the first 24 h postoperatively

Analgesic (number of doses)	Group D	Group P	P
Tramadol (0/1/2)	11/20/1	5/25/2	0.245
Diclofenac (0/1)	23/9	21/11	0.590

Table 4

Adverse effects

	Group D, n (%)	Group P, n (%)	P
Nausea and vomiting	10 (31.3)	2 (6.3)	0.010*
Headache	5 (15.6)	3 (9.4)	0.450
Somnolence	7 (21.9)	0	0.011*
Dizziness	1 (3.1)	0	1.000
Pruritus	0	0	-

*P<0.05

DISCUSSION

In the present study, a single dose of 60 mg of duloxetine given orally 2 h before surgery did not significantly reduce pain scores at rest and on coughing during the first 24 h postoperatively following abdominal hysterectomy under spinal anesthesia when compared to a placebo. In addition, there was no significant difference in the analgesic requirement postoperatively with duloxetine compared to placebo.

The results of the studies employing duloxetine to decrease postoperative pain has been equivocal. Ho et al.[8] did not find any significant difference in pain scores postoperatively when two doses of duloxetine 60 mg were used when compared to placebo in patients undergoing knee replacement surgery. These results are similar to the results of the present study. However, Castro-Alves et al.[9] found a significant reduction in the pain scores following the administration of a similar dose of duloxetine in patients undergoing abdominal hysterectomy under spinal anesthesia. Nasr[11] administered duloxetine 60 mg from 2 days prior to surgery till 2 weeks postoperatively in patients undergoing mastectomy and found that it not only reduced pain postoperatively but also a reduction in chronic pain at 3 months and 6 months postoperatively. Govil et al. found total morphine consumption up to 24 h was significantly decreased in the duloxetine group when used for a total duration of 7 days perioperatively.[12] But in the current study, we have used only a single dose of 60 mg duloxetine preoperatively, duloxetine has a mean plasma half-life of 12 h thus might not have had a significant effect on postoperative pain. Duloxetine, when used alone as single dose preoperatively, did not have a significant effect on reducing postoperative pain but when combined with dexamethasone had a significant reduction in requirements for rescue analgesia.[13]

In our study, a single dose of duloxetine used preoperatively did not have any significant reduction in postoperative analgesic consumption. This is in line with other studies where there were equivocal results with some studies finding a significant reduction in analgesic consumption,[9] while others finding no such difference.[8] In our study, patients receiving duloxetine had a higher incidence of postoperative nausea, vomiting, and somnolence unlike other studies wherein there were no significant adverse effects.[8910]

The present study had certain limitations. The effect of duloxetine on perioperative anxiety, quality of recovery, and chronic postsurgical pain was not assessed. Our results cannot be extrapolated to other surgeries done under general anesthesia. We assessed the effect of a single dose of preoperative duloxetine on postoperative analgesia and analgesic consumption, unlike other studies where duloxetine was not only used preoperatively also for a few days/weeks postoperatively. In addition, we have not studied the effects of combining duloxetine with other adjuvants/analgesics to reduce postoperative pain.

We conclude that a single dose of 60 mg duloxetine preoperatively did not significantly reduce pain scores and analgesic consumption in patients undergoing abdominal hysterectomy under spinal anesthesia. In addition, duloxetine had a higher incidence of nausea, vomiting, and somnolence during the first 24 h postoperatively.

CONCLUSION

We conclude that a single dose of 60 mg duloxetine preoperatively did not significantly reduce pain scores and analgesic consumption in patients undergoing abdominal hysterectomy under spinal anesthesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.