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Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 3  |  Page : 316-320  

Effect of preoperative duloxetine hydrochloride on reducing postoperative morphine requirement after open radical cholecystectomy in cancer patients: A randomized controlled study


Department of Anaesthesiology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Submission25-Apr-2022
Date of Decision16-Aug-2022
Date of Acceptance17-Aug-2022
Date of Web Publication09-Dec-2022

Correspondence Address:
Dr. Aparna Shukla
Department of Anaesthesiology, King George's Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aer.aer_75_22

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   Abstract 

Background: Recently, opoids are linked with cancer recurrence. Duloxetine hydrochloride (DH), an anxiolytic may reduce total opoid requirement after cancer surgery. Aims: We assessed the efficacy of a single dose of DH in reducing the total morphine requirement after open radical cholecystectomy. We also calculated the Visual Analog Scale (VAS) score, patient satisfaction score (PSS), and time taken to the use of the first rescue analgesic. Setting and Designes: This is a prospective, randomized, double blind, controlled study conducted in the patients aged 20–70 years (American Society of Anaesthesiologists classes I–III) undergoing open radical cholecystectomy under general anesthesia for carcinoma gall bladder. Materials and Methods: The patients were divided into two groups of 32 patients each by computer-generated randomization. Group A received oral DH (60 mg); Group B received identical placebo capsules 2 h before surgery with a sip of water. Postoperatively, intravenous morphine was given using a patient-controlled analgesia pump. After 24 h, total morphine consumption, the VAS score, time to the first rescue analgesia, and PSS were recorded. Statistical Analysis: Statistical Package for the Social Sciences software (SPSS version 22.0, IBM Corp., Chicago, IL, USA 2013). P value < 0.05 or 0.001 was considered statistically significant. Results: The total morphine consumption and VAS score were significantly lower in Group A. No significant effects was observed on PSS. Conclusion: A single 60 mg dose of DH administered 2 h before open radical cholecystectomy reduced total morphine consumption and improved VAS score postoperatively with no effect on PSS.

Keywords: Duloxetine hydrochloride, gallbladder neoplasms, morphine, pain, postoperative


How to cite this article:
Haider N, Shukla A, Chaurasia MK, Verma R, Hemlata, Singh GP. Effect of preoperative duloxetine hydrochloride on reducing postoperative morphine requirement after open radical cholecystectomy in cancer patients: A randomized controlled study. Anesth Essays Res 2022;16:316-20

How to cite this URL:
Haider N, Shukla A, Chaurasia MK, Verma R, Hemlata, Singh GP. Effect of preoperative duloxetine hydrochloride on reducing postoperative morphine requirement after open radical cholecystectomy in cancer patients: A randomized controlled study. Anesth Essays Res [serial online] 2022 [cited 2023 Feb 3];16:316-20. Available from: https://www.aeronline.org/text.asp?2022/16/3/316/363137


   Key Points Top





   Introduction Top


Gallbladder cancer is a treatable malignancy. Many modalities have been used to improve outcome and reduce pain, anxiety and cancer recurrence postoperatively.[1],[2] Duloxetine hydrochloride (DH), effectively treats persistent and chronic pain, including chronic musculoskeletal pain.[3]

Our primary objective was to study the efficacy of preoperative single dose (60 mg) DH in reducing total morphine requirement 24 h postoperatively. The secondary objectives was to assess the time required for the first rescue analgesic; measurement of Visual Analog Scale (VAS) score at 30 min and 1, 6, 12 and 24 h; and assessment of patient satisfaction score (PSS) postoperatively at 24 h.


   Materials and Methods Top


The study was approved by the Institutional Ethics Committee ECR/262/Inst/UP/2013/RR-19 and Registered under the Clinical Trial Registry CTRI/2021/102/031033, REF/2021/01/040400. The duration of the study was 1 year from September 2020 to September 2021. This was a double-blind, prospective, randomized, controlled study. The sample size was calculated based on the average morphine consumption in a retrospective sample of 25 patients who underwent surgery for gallbladder malignancy at our institution. Approximately 22 patients in each group were required for a power of 0.80 at an α level of 0.05 to detect a 5% difference in morphine consumption between groups 24 h postsurgery. Ten more patients were included in both the groups to account for data loss.

Patients with American Society of Anesthesiologists (ASA) PS classes I–III, aged 20–70 years who gave written informed consent were included in the study. Patients who did not provide consent, pregnant and nursing mothers, patients with allergies to DH or morphine, or patients with preexisting pain syndrome were not included in the study. The included patients had undergone open radical cholecystectomy under general anesthesia for gallbladder cancer and were divided into two groups of 32 patients each. The computer-generated randomization using IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. (Armonk, NY: IBM Corp.) was used for the study so that all the participants had the equal chance for allocation in either group [Table 1]. The concept of VAS score and PSS was explained to the patients during preanesthetic evaluation. On the morning of surgery, patients did not receive any premedication. Patients in Group A received oral DH (60 mg). Group B patients received identical placebo capsules 2 h before the surgery with a sip of water. The patient and the investigator NH who recorded the study parameters were unaware about the drug given preoperatively. To conceal the allocation, the study medications were marked with consecutive numbers by investigator AS according to a computer-generated table of random numbers and medications were given by investigator MC. Standard operating theater monitoring included electrocardiography, noninvasive arterial pressure measurement, pulse oximetry, and capnography. Induction of anesthesia was performed with intravenous fentanyl (2 μg.kg−1) and intravenous propofol (2 mg.kg−1). This was followed by intravenous vecuronium (0.1 mg.kg−1) to facilitate endotracheal intubation. Intraoperatively, inhalation of a mixture of oxygen, sevoflurane, and an intermittent dose of intravenous vecuronium were used for maintainence. General anesthesia was standardized for all patients. Intraoperatively, acetaminophen (1 g) infusion was also administered.
Table 1: Comparison of demographic profiles of patients in Group A and Group B

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Systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate were measured every 15 min. After the surgery, pain treatment consisted of patient-controlled analgesia (PCA) using morphine delivered by PCA pump. The pump was set to a 2-mg bolus with a maximum hourly limit of 8 mg. The lockout time was 5 min. No other analgesics were administered, and patients requiring other forms of analgesia were excluded. When the patient pressed the button for the first time, a bolus of morphine was administered as the first rescue analgesic. A blinded observer who was not part of the anesthesia team or the study team followed the patients. The primary outcome measure was the total morphine requirement 24 h after surgery. The secondary outcome measures were VAS score and PSS, and the presence or absence of adverse effects such as nausea, headache, vomiting, dizziness, and drowsiness. VAS scores were recorded at 0.5, 1, 6, 12, and 24 h after surgery on a 10-point numeric rating scale (VAS score) in which 0 indicates no pain and 10 indicates the worst possible pain. PSS at 24 h was also recorded on a numerical score of 1 to 4 (1, poor; 2, fair; 3, good; 4, excellent).

Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Sciences software (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). When required, continuous variables were evaluated by mean (standard deviation) or range values. Dichotomous variables were presented in number/frequency and analyzed using the Chi-square or Fisher's exact test. Student's t-test with a 95% confidence interval was used to compare the means between the two groups. A P value of <0.05 or 0.001 was considered statistically significant.


   Results Top


Patients were comparable in both the groups in terms of age, sex, body mass index, and ASA status. During the intraoperative period, SBP, DBP, and pulse rate were higher at 15, 30, 45, and 60 min in the placebo group than in the DH group. However, the mean difference was not statistically significant [Table 2]. The pulse rate also remained lower in the study group, but the difference was not statistically significant [Figure 1].
Figure 1: Graphical comparsion of pulse rate of Group A and Group B

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Table 2: Comparison of systolic and diastolic blood pressure of patients in Group A and Group B

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The mean morphine consumption (mg) of patients in Group A and Group B was 14.68 ± 4.88 mg for Group A and 20.84 ± 3.93 mg for Group B at 12 h and 22.78 ± 4.72 mg for Group A and 31.53 ± 6.42 mg for Group B at 24 h. The mean difference was statistically significant [P < 0.0001, [Table 3]].
Table 3: Comparison of postoperative analgesic requirement, total morphine consumption, patient satisfaction, and Visual Analog Scale score in Group A and Group B

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The mean first rescue analgesic requirement time (h) of patients in Group A (n = 32) and Group B (n = 32) was 1.48 ± 0.81 and 1.17 ± 0.58, respectively. The mean difference was not statistically significant (P = 0.0833).

The mean VAS score of patients in Group A remained significantly low (P = 0.0213, P = 0.0061, P < 0.0001, P < 0.0001, P < 0.0001 at 0.5, 1, 6, 12, and 24 h, respectively) indicating good pain relief [Table 3].

Major adverse events noticed in patients from Group A were nausea, vomiting, and dizziness. These were observed in four patients. In comparison, eight patients in Group B had vomiting, followed by constipation in five patients and insomnia in four patients. The mean difference was not statistically significant [P = 0.7209, [Figure 2]].
Figure 2: Graphical comparsion of adverse event of patients of Group A and Group B

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   Discussion Top


DH is a selective serotonin reuptake inhibitor used to treat depression and anxiety disorders. DH has demonstrated efficacy in chronic pain conditions, such as painful diabetic neuropathy and postherpetic neuralgia.

In our study, the two groups were comparable in terms of demographic profiles and mean duration of surgery. Group A patients had lower SBP, DBP, and heart rate during the intraoperative period than those in Group B. However, this difference was not statistically significant.

The mean morphine consumption (mg) of patients in Group A and Group B was 14.68 ± 4.88 mg for Group A and 20.84 ± 3.93 mg for Group B at 12 h and 22.78 ± 4.72 mg for Group A and 31.53 ± 6.42 mg for Group B at 24 h. The mean difference was statistically significant at both time intervals. We found a statistically significant difference in the mean VAS scores of Group A and Group B patients at 0.5, 1, 6, 12, and 24 h. Most patients in Group A had good PSS, followed by excellent and fair satisfaction scores. At the same time, most patients in Group B had fair PSS, followed by excellent and poor PSS. Although nausea and vomiting were the most common adverse effects in all groups in our study, the differences were not statistically significant.

Li et al.[4] also found that a daily preoperative dose of DH (60 mg) considerably reduced postoperative pain in patients who underwent total hip arthroplasty while moving and resting during the first 3 postoperative weeks compared to those who received a placebo. They also reported a significant decrease in morphine consumption in the DH Group 48 h after surgery.

Similar benefits were reported by Bedin et al.,[5] who observed that the patients who took DH required significantly less fentanyl postoperatively for 48 h after spine surgery.

Castro-Alves et al. documented that preoperative administration of DH considerably reduced the need for morphine in the postoperative period and it also improved postoperative recovery following abdominal hysterectomy.[6]

Another author observed that in the DH group, the time to first rescue analgesia was longer in patients who underwent mastectomy.[7]

Hetta et al. opined that DH given preoperatively in the patients undergoing modified radical mastectomy reduces opoid consumption and decreases sevearity of pain in the postoperative period. They further said that 60 mg is the optimal dose because it is associated with maximum benefits with minimal side effects.[8]

In contrast to our study, Takmaz et al. studied 80 women who underwent laparoscopic hysterectomy. The study found that DH did not affect need for narcotic analgesia and length of hospital stay.[9]

Attia and Mansour[10] determined the effect of perioperative DH combined with etoricoxib on postoperative pain and opioid needs in lumbar laminectomies. They discovered that, neither DH nor etoricoxib had an impact on pain with movement on their own. However, their combination resulted in a significant reduction in pain levels throughout the postoperative period at rest and during an action.

Similarly, Bastanhagh et al. evaluated the efficacy of preoperative DH for postoperative pain. The authors suggested that DH was ineffective in controlling pain following abdominal hysterectomy.[11]

A meta-analysis done by Branton et al. to determine if DH 60 mg given perioperatively to the patients undergoing elective orthopaedic surgeries, is safe and effective at reducing postoperative opioid consumption and reported pain. They found that addition of perioperative DH 60 mg to a multimodal analgesia regimen significantly lowers total postoperative opioid consumption and reduces pain without significant adverse effects.[12]

Another meta-analysis was conducted to assess the effects of DH on total analgesic consumption, postoperative pain, and side effects in the adult patients undergoing any type of elective surgery. The total 13 studies were included. They found that DH significantly reduces postoperative pain and opioid consumption during the first 48 h postoperative. However, there was low effect sizes, high risk-of-bias and inter-study heterogeneity and therefore they did not recommend DH for acute postoperative pain.[13]

The analgesic effect of DH may be attributed to its dual central and peripheral actions. It may also have an influence on descending inhibitory pain pathways in the brain and spinal cord, and thereby, cause the activation of certain cerebral prefrontal areas. DH was used in our study because of its antidepressant and anxiolytic effects, which are particularly important in carcinoma patients.

The limitations of this study include its single-center design and limited sample size. Limiting the study to a specific type of surgery may impair its generalizability. As a result, the authors recommend more multicenter investigations and large meta-analysis on different surgical procedures with a large sample size to increase reliability and generalizability.


   Conclusion Top


Postoperative pain is mediated by distinct mechanisms at different brain locations. Thus, analgesics with many modes of action can alleviate postoperative pain. It can be concluded from this study that a single dose of DH (60 mg), administered 2 h preoperatively, had an insignificant effect on the hemodynamic profile of patients, but it significantly reduced total morphine consumption postoperatively. In addition, it improved the VAS score with no increase in adverse effects. However, PSS did not improve significantly.

Financial support and sponsorship

Patient controlled analgesia pump which was used in the study was taken from the Department of Anesthesiology King George's Medical University, Lucknow.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Sharma SK, Thakur K, Mudgal SK, Payal YS. Acute postoperative pain experiences and satisfaction with its management among patients with elective surgery: An observational study. Indian J Anaesth 2020;64:403-8.  Back to cited text no. 1
  [Full text]  
2.
Pal AR, Mitra S, Aich S, Goswami J. Existing practice of perioperative management of colorectal surgeries in a regional cancer institute and compliance with ERAS guidelines. Indian J Anaesth 2019;63:26-30.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Smith HS, Smith EJ, Smith BR. Duloxetine in the management of chronic musculoskeletal pain. Ther Clin Risk Manag 2012;8:267-77.  Back to cited text no. 3
    
4.
Li H, Zeng WN, Ding ZC, Yuan MC, Cai YR, Zhou ZK. Duloxetine reduces pain after Total hip arthroplasty: A prospective, randomized controlled study. BMC Musculoskelet Disord 2021;22:492.  Back to cited text no. 4
    
5.
Bedin A, Caldart Bedin RA, Vieira JE, Ashmawi HA. Duloxetine as an analgesic reduces opioid consumption after spine surgery: A randomized, double-blind, controlled study. Clin J Pain 2017;33:865-9.  Back to cited text no. 5
    
6.
Castro-Alves LJ, Oliveira de Medeiros AC, Neves SP, Carneiro de Albuquerque CL, Modolo NS, De Azevedo VL, et al. Perioperative Duloxetine to improve postoperative recovery after abdominal hysterectomy: A prospective, randomized, double-blinded, placebo-controlled study. Anesth Analg 2016;122:98-104.  Back to cited text no. 6
    
7.
Nasr DA. Efficacy of perioperative Duloxetine hydrochloride on acute and chronic postmastectomy pain. Ain Shams J Anaesthesiol 2014;7:129-33.  Back to cited text no. 7
    
8.
Hetta DF, Elgalaly NA, Hetta HF, Fattah Mohammad MA. Preoperative Duloxetine to improve acute pain and quality of recovery in patients undergoing modified radical mastectomy: A dose-ranging randomized controlled trial. J Clin Anesth 2020;67:110007.  Back to cited text no. 8
    
9.
Takmaz O, Bastu E, Ozbasli E, Gundogan S, Karabuk E, Kocyigit M, et al. Perioperative Duloxetine for pain management after laparoscopic hysterectomy: A randomized placebo-controlled trial. J Minim Invasive Gynecol 2020;27:665-72.  Back to cited text no. 9
    
10.
Attia JZ, Mansour HS. Perioperative Duloxetine and Etoricoxibto improve postoperative pain after lumbar Laminectomy: A randomized, double-blind, controlled study. BMC Anesthesiol 2017;17:162.  Back to cited text no. 10
    
11.
Bastanhagh E, Zamiri F, Samimi Sadeh S, Adabi K, Pourfakhr P. Effect of preoperative Duloxetine on opioid consumption in women undergoing abdominal hysterectomy: A randomized, double-blinded, placebo-controlled trial. Anesth Pain Med 2020;10:e103729.  Back to cited text no. 11
    
12.
Branton MW, Hopkins TJ, Nemec EC. Duloxetine for the reduction of opioid use in elective orthopedic surgery: A systematic review and meta-analysis. Int J Clin Pharm 2021;43:394-403.  Back to cited text no. 12
    
13.
de Oliveira Filho GR, Kammer RS, Dos Santos HC. Duloxetine for the treatment acute postoperative pain in adult patients: A systematic review with meta-analysis. J Clin Anesth 2020;63:109785.  Back to cited text no. 13
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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