Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 7  |  Issue : 2  |  Page : 129-133

Efficacy of perioperative duloxetine on acute and chronic postmastectomy pain


Anesthesia and Intensive Care Medicine, Ain Shams University, Cairo, Egypt

Date of Submission03-Dec-2013
Date of Acceptance27-Dec-2013
Date of Web Publication31-May-2014

Correspondence Address:
Dalia A Nasr
Anesthesia and Intensive Care Medicine, Ain Shams University, 6-Tawfikia Buildings, Mostafa El-Nahas St, 8th District, Nasr City, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.133345

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  Abstract 

Objectives
Acute postoperative pain following radical mastectomy has been shown to increase the risk for chronic postmastectomy pain, a type of neuropathic pain. Preemptive analgesia has been shown to be effective in reducing the incidence of some types of neuropathic pain. We investigated the analgesic efficacy of duloxetine on acute and chronic pain in patients undergoing breast surgery.
Materials and methods
Fifty patients scheduled for radical mastectomy with axillary dissection were randomized in a double-blinded manner to receive either duloxetine 60 mg (group D) starting 2 days before operation for 2 weeks followed by 30 mg until the end of study or placebo capsules (group P) for the same course. Total morphine consumption over the first 48 h, time to first rescue analgesic, and pain scores were recorded [visual analog scale (VAS)] at 2, 4, 12, and 24 h postoperatively, daily until the fourth day, then 3 and 6 months later.
Results
In the duloxetine group compared with the placebo group, total morphine consumption was less (at 24 h, 14 ± 2.3 vs. 24 ± 1.7 and at 48 h, 11.5 ± 2.5 vs. 20 ± 1.4, P < 0.001, respectively), time to first rescue analgesic was longer (4.6 ± 0.7 h vs. 2.5 ± 0.5 h, P < 0.001, respectively), with significant decrease in VAS scores of pain at all time points (P < 0.001), and the incidence of pain was less at 3- and 6-month follow-up.
Conclusion
Duloxetine significantly reduced postoperative analgesic requirements, VAS, and incidence of chronic pain at 3- and 6-month follow-up in women undergoing breast surgery.

Keywords: Chronic pain, duloxetine, postmastectomy pain


How to cite this article:
Nasr DA. Efficacy of perioperative duloxetine on acute and chronic postmastectomy pain. Ain-Shams J Anaesthesiol 2014;7:129-33

How to cite this URL:
Nasr DA. Efficacy of perioperative duloxetine on acute and chronic postmastectomy pain. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Oct 27];7:129-33. Available from: http://www.asja.eg.net/text.asp?2014/7/2/129/133345


  Introduction Top


Acute postoperative pain following modified radical mastectomy particularly after axillary lymph nodes dissection has been shown to increase the risk of development of chronic postmastectomy pain, which is considered as a type of neuropathic pain [1].

Tissue trauma resulting from surgery can sensitize peripheral nociceptors leading to central neuronal sensitization. Preemptive analgesia has been shown to be effective in reducing the incidence of some types of neuropathic pain [2]. Serotonin and norepinephrine are involved in the modulation of descending inhibitory pain pathways in the central nervous system [3]. They may increase inhibition of nociceptive input and improve pain relief, reducing opioid use and its associated adverse effects. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated efficacy in chronic pain conditions such as painful diabetic neuropathy [4],[5]. We aimed to investigate the analgesic efficacy of duloxetine on acute and chronic pain in patients undergoing breast surgery.


  Materials and methods Top


After approval from the local ethics committee and obtaining informed written patient's consent, 50 female patients, ASA physical status I-II, 40-55 years of age scheduled for unilateral modified radical mastectomy and axillary dissection were enrolled in this randomized, double-blind placebo-controlled study. The study was conducted at Ain shams University Surgery Hospital from May 2012 to April 2013.

The exclusion criteria included known allergy to duloxetine or morphine, abnormal renal and liver function tests, uncontrolled narrow-angle glaucoma, patients taking opioid-containing medications on a long-term basis, history of chronic pain, and regular medication with SNRI or analgesics (excluding acetaminophen and nonsteroidal anti-inflammatory drugs).

Two days before surgery, patients visited the outpatient clinic for assessment and to be explained about the study protocols, including analgesic administration on request and the visual analog scale (VAS) score of pain. Laboratory investigations were performed and patients were informed that they can stop participation in the study at any time.

On the morning of the operation, patients were admitted to the hospital. Using computer-generated random numbers with closed-sealed envelope, eligible patients were randomly assigned into one of the two groups. Group D (25 patients) received oral duloxetine 60 mg (Cymbalta; Eli Lilly & Company, Indiana, USA) 2 days before surgery to be continued for the first 2 weeks and then tapered to 30 mg (delayed-release capsule) until the end of the study. Patients of the other group (group P, 25 patients) received identical matching placebo capsules on the same dosage schedule. Patients were instructed to take the medication at the same time each day with food, as this may help to reduce nausea that may occur at the start of treatment in case of duloxetine [6]. The study drugs were prepared by the hospital pharmacy and given to the patients. Randomization and allocation were only revealed for data analysis after the study was completed.

On arrival in the operating room, electrocardiogram, pulse oximetry, and noninvasive arterial blood pressure were applied. Baseline vital signs were obtained and subsequent values were recorded every 5 min throughout the surgical procedure. Anesthesia was induced with fentanyl 1.5 μg/kg and propofol 1.5-2 mg/kg until loss of eyelash reflex. Tracheal intubation was facilitated with atracurium 0.5 mg/kg. Anesthesia was maintained with isoflurane (1-2%) in 40% oxygen, and intermittent doses of muscle relaxant was given to maintain adequate muscle relaxation throughout the procedure. The respiratory tidal volume was adjusted to keep end-tidal CO 2 at 4.8-5.2%. The isoflurane concentration was adjusted to keep the heart rate and blood pressure within 20% of preinduction values throughout the anesthesia period. All surgical procedures were completed by the same surgeon. At the end of surgery, the surgeon injected 10 ml bupivacaine 2.5 mg/ml subcutaneously into the surgical field; atropine 0.02 mg/kg and neostigmine 0.05 mg/kg were given intravenously for antagonism of neuromuscular blockade. After tracheal extubation, patients were transferred to the postanesthesia care unit.

During the first 48 h postoperative, paracetamol 1 g intravenously (perfalgan; Bristol-Myers Squibb, New York, USA) was given every 8 h to both groups; the first dose was given about 6 h after the surgery was completed. If patients complained of pain (VAS was ≥ 40), they received titrated dose of morphine (2 mg bolus at 10 min interval), and then morphine 20-30 mcg/kg until the VAS was less than 40.

Pain scores (VAS of '0' being 'no pain' and '100' being the 'worst possible pain') were recorded at 2, 6, 12, and 24 h postoperatively then daily until discharge from hospital on the fourth day, weekly for 2 weeks, and at 3 and 6 months after surgery. The nursing staff who were blinded to the patients' group assignment assessed time to first rescue analgesic and total morphine consumption over the first 48 h.

Postoperative side effects (nausea, vomiting, dizziness, headache, somnolence, and pruritus) were recorded and treated. Nausea was treated by 10 mg metoclopramide intravenously, vomiting was treated by 4 mg ondansetron intravenously, and itching was treated by pheniramine maleate (45 mg/2 ml).

Before discharge from the hospital, all patients were prescribed with acetaminophen 500 mg/codeine 30 mg tablets/6 h (Feminax-Bayer). They were instructed to note the amount of pain they had at home and their analgesic needs. They were evaluated by phone for the first 2 weeks. Patients were invited to a pain evaluation (by an anesthetist blinded to their treatment group), then 3 and 6 months later to assess pain at rest and during movement (abduction of the arm on the operated side by 90°). We defined chronic pain as the presence of pain 3 and 6 months after surgery, independent of its intensity or analgesic requirements.

The primary aim of our study was to investigate the efficacy of duloxetine in reducing acute postoperative pain, measured by total morphine consumption 48 h after surgery. Secondary aims include time to first rescue analgesic, postoperative pain scores, adverse effects of the studied drug, and the incidence of chronic pain at 3 and 6 months postoperative in patients undergoing unilateral modified radical mastectomy and axillary dissection.

Sample size calculation was based on morphine consumption in data from patients who undergo modified radical mastectomy; 22 patients in each group were required to detect 50% difference in morphine consumption between groups at 48 h postsurgery with a power of 0.8 at an α level of 0.05. The statistical analysis was performed using a standard SPSS software package (SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean values ± SD, numbers (n), and median (range). Differences in VAS scores were analyzed using the Mann-Whitney U-test. Student's t-test was used to analyze the parametric data, and discrete (categorical) variables were analyzed using the c2 -test, with P values less than 0.05 considered statistically significant.


  Results Top


Twenty-four patients in the duloxetine group and 23 patients in the placebo group completed the study. Flow chart of patients is presented in [Figure 1]. The demographic data showed no significant differences in the patient's characteristics with respect to age, ASA physical status, weight, duration of operation, and number of patients receiving radiotherapy or chemotherapy [Table 1].
Figure 1:

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Table 1: Patients characteristics

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Total morphine consumption was less in group D compared with group P (at 24 h, 14 ± 2.3 vs. 24 ± 1.7, P < 0.001 and at 48 h, 11.5 ± 2.5 vs. 20 ± 1.4, P < 0.001, respectively) and time to first rescue analgesic was significantly longer in group D compared with group P (4.6 ± 0.7 h vs. 2.5 ± 0.5 h, P < 0.001, respectively) [Table 2].
Table 2: Time to first rescue analgesic and total morphine consumption

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There was a statistically significant decrease in VAS scores of pain at all time points between group D and group P (P < 0.001) [Figure 2] and [Figure 3].
Figure 2:

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Figure 3:

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At 3- and 6-month follow-up, the incidence of pain was less in group D compared with group P (at 3 months at rest, three vs. nine patients, P = 0.04, and during movement, six vs. 14 patients, P = 0.03, respectively; at 6 months at rest, three vs. nine patients, P = 0.04, and during movement four vs. 12 patients, P = 0.01, respectively) [Table 3].
Table 3: Pain characteristics at rest and on movement 3 and 6 months postoperatively

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There were no significant differences in the incidence of nausea and vomiting, dizziness, somnolence, headache, and pruritus between the two groups [Table 4].
Table 4: Adverse effects

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  Discussion Top


This study showed that, in patients undergoing unilateral modified radical mastectomy and axillary dissection, duloxetine 60 mg administered 2 days before and for 2 weeks after surgery followed by 30 mg for 6 months had resulted in reduction in morphine requirements at 24 and 48 h after surgery, with significant decrease in pain scores throughout the study with less number of patients experiencing pain at rest and on movement 3 and 6 months postoperative with no differences in adverse effects compared with patients who received placebo. Neuroplastic changes resulting from surgical tissue injury can manifest as hyperalgesia or allodynia in patients after surgery [7]. Perioperative administration of gabapentin 300 mg/day as 'antihyperalgesic' and venlafaxine 37.5 mg/day extended release has equipotent effects in reducing opioid requirements and pain scores (acute and chronic) after mastectomy [8].

Duloxetine is a selective SNRI that is efficacious in chronic pain conditions such as painful diabetic neuropathy and fibromyalgia [9]; a capsule 60 mg once daily demonstrated efficacy in painful physical symptoms associated with depression [10].

The dose of duloxetine was based on previous study conducted by Hoi et al. [11] administering perioperative duloxetine 60 mg in knee replacement surgery, which is the same dose used for chronic neuropathic pain [9].

Total morphine consumption was less in group D compared with group P and the time to first rescue analgesic was longer; this was consistent with the study conducted by Hoi et al. [11] who found that perioperative duloxetine 60 mg was efficacious in reducing morphine requirements 48 h after knee replacement surgery. The possible mechanism of action of duloxetine in our study could be explained by the central pain inhibitory action secondary to the potentiation of serotonergic and noradrenergic activities in the central nervous system.

In our study, the VAS pain scores were lower in group D compared with group P throughout the entire study period. In contrast to our results regarding acute pain, Hoi et al. [11] found that pain scores were slightly higher in the first few hours after surgery in the duloxetine group compared with the placebo group; this difference may be related to the time of administration of duloxetine. In Hoi study, the first dose was given just 2 h before surgery, whereas our first dose was given 2 days before surgery. As recommended by the manufacturer of duloxetine, the drug starts to work in chronic pain conditions within the first week [12], and Hoi explained that the peak plasma concentration of duloxetine was only achieved about 6 h after oral administration [11]. We chose the time of starting the drug 2 days before as this was the time the patients attend the hospital for anesthetic evaluation and laboratory investigations.

The number of patients experiencing chronic pain at 3 and 6 months was significantly less in group D. A common psychopharmacology between pain and depression suggests that compounds inhibiting the reuptake of serotonin and/or noradrenaline are likely to produce relief from chronic pain [13], and as pain is a common symptom of depression and depression is frequent in chronic pain patients, this supports the hypothesis that pain and depression share some common biochemical mechanisms [14].

The most common adverse effects of duloxetine, which may lead to discontinuation of the drug, are nausea, dizziness, and somnolence [15]. Our study showed that the incidence of adverse effects was similar between group D and group P placebo; the similarity of adverse effects may be related to the low dose of duloxetine.

There are some limitations in our study. First, during the first 2 weeks, patients were evaluated by phone. Second, patients could not remember the exact doses of analgesia needed at home, and hence we depend on the interview conducted 3 and 6 months after surgery for the detection of chronic pain.

In conclusion, our study showed that perioperative administration of duloxetine 60 mg was efficacious in reducing morphine requirements in 48 h postmastectomy with less pain at rest and on movement 3 and 6 months postoperatively.


  Acknowledgements Top


Conflicts of interest

None declared.

 
  References Top

1.Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006; 367:1618-1625.  Back to cited text no. 1
    
2. Woolf CJ, Chong MS. Preemptive analgesia-preventing postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77:362-367.  Back to cited text no. 2
    
3. Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984; 7:309-338.  Back to cited text no. 3
[PUBMED]    
4. Arnold LM, Rosen A, Pritchett YL, D′Souza DN, Goldstein DJ, Iyengar S, Wernicke JF. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 2005; 119:5-15.  Back to cited text no. 4
    
5. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 2005; 116:109-118.  Back to cited text no. 5
    
6. Perahia DGS, Pritchett YL, Kajdasz DK, Bauer M, Jain R, Russell JM, et al. A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder. J Psychiatr Res 2007; 42:22-34.  Back to cited text no. 6
    
7. Wilder-Smith OH, Arendt-Nielsen L. Postoperative hyperalgesia: its clinical importance and relevance. Anesthesiology 2006; 104:601-607.  Back to cited text no. 7
    
8. Amr YMYoussef AA. Evaluation of efficacy of the perioperative administration of venlafaxine or gabapentin on acute and chronic postmastectomy pain. Clin J Pain 2010; 26:381-385.  Back to cited text no. 8
    
9. Lunn MP, Hughes RA, Wiffen P. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev 2009; 7:CD007115.  Back to cited text no. 9
    
10.1Brannan SK, Mallinckrodt CH, Brown EB, Wohlreich MM, Watkin JG, Schatzberg AF. Duloxetine 60 mg once daily in the treatment of painful physical symptoms in patients with major depressive disorder. J Psychiatr Res 2005; 39:43-53.  Back to cited text no. 10
    
11.1Hoi K, Tay W, Yeo M, Liu H, Yeo SJ, Chia SL, Lo NN. Duloxetine reduces morphine requirements after knee replacement surgery. Br J Anaesth 2010; 3:371-376.  Back to cited text no. 11
    
12.1Cymbalta. Package Insert. Indianapolis, Indiana, USA: Eli Lilly and Company; 2011.  Back to cited text no. 12
    
13.1Briley M. New hope in the treatment of painful symptoms in depression. Curr Opin Investig Drug 2003; 4:42-45.  Back to cited text no. 13
    
14.1Juan A, Denis A, Esther B, Alain E. Antidepressants and pain. Trends Pharmacol Sci 2006; 27:348-354.  Back to cited text no. 14
    
15.1Allgulander C, Nutt D, Detke M, Erickson J, Spann N, Walker D, et al. A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder. J Psychopharmacol 2008; 22:417-425.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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