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Volume:4 Issue:7 Number:4 ISSN#:2563-559X
OE Original

Duloxetine for Acute Postoperative Pain Management in Patients Undergoing Orthopedic Surgery: A Meta-analysis of Randomized Controlled Trials

Authored By: OrthoEvidence

July 26, 2021

How to Cite

OrthoEvidence. Duloxetine for Acute Postoperative Pain Management in Patients Undergoing Orthopedic Surgery: A Meta-analysis of Randomized Controlled Trials. OE Original. 2021;4(7):4. Available from: https://myorthoevidence.com/Blog/Show/140

Highlights


  • - Nine randomized controlled trials (RCTs), investigating the use of duloxetine for postoperative pain management in patients undergoing orthopedic surgery, were eligible and included.

  • - Eight of the included RCTs were published in or after 2016. Five of them explored the use of duloxetine in patients undergoing knee or hip arthroplasty, while 4 RCTs centered on patients who received lumbar spinal surgical operations.

  • - Among several time points post surgery (i.e., 0.5, 1, 2, 4, 6, 12, 24, 48, 72 hours), use of duloxetine in the analgesic protocol resulted in significant reductions in acute postoperative pain on a 0-100 normalized scale in patients undergoing orthopedic surgery at 24 hours [mean difference (MD): -7.48; 95% confidence interval (CI): -14.49 to -0.47; Low quality of evidence], 48 hours (MD: -10.83; 95% CI: -18.04 to -3.63; Low quality of evidence), and 72 hours (MD: -0.43; 95% CI: -0.74 to -0.13; Moderate quality of evidence) after surgery, compared to the pain management protocol not including duloxetine.

  • - Involving duloxetine in the analgesic protocol significantly reduced the consumption of opioids (e.g., morphine and fentanyl, mg) in patients undergoing orthopedic surgery at 24 hours (MD: -8.95; 95% CI: -14.38 to -3.52; Low quality of evidence) and 48 hours (MD: -12.59; 95% CI: -18.82 to -6.36; Low quality of evidence), but not at 72 hours (Very low quality of evidence) post surgery.

  • - Use of duloxetine in the analgesic protocol in patients undergoing orthopedic surgery seems to be safe as the evidence showed no statistical differences in the incidences of nausea/vomiting, dizziness, headache, and somnolence between patients receiving duloxetine and those who did not (Moderate to low quality of evidence).


With the aim to explore the potential of reducing opioid consumption which has been found to be associated with a number of negative consequences (e.g., acute side effects, risk of tolerance and dependence), we reviewed evidence from RCTs with respect to using tapentadol, a new class of analgesics differing from classic opioids, for the postoperative pain management among patients undergoing knee/hip arthroplasty in a recently published OE Original:



Use of Tapentadol for Postoperative Pain Management in Patients after Knee/Hip Arthroplasty: A Scoping Review



In addition to tapentadol, there has been an increasing interest in using duloxetine, as a part of multimodal analgesic protocol, for postoperative pain management in patients receiving elective orthopedic surgery. 


Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), approved by the United States Food and Drug Administration (US FDA) for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain such as osteoarthritis, chronic back pain, etc.


In this OE Original, we conduct a systematic review and meta-analysis to examine the RCT evidence regarding the safety and efficacy of duloxetine in terms of controlling acute postoperative pain and reducing opioid consumption in patients undergoing elective orthopedic surgery. Moreover, we also hypothesized that the efficacy of duloxetine might vary according to different characteristics, which were surgical sites (or type of orthopedic surgery) and different analgesic protocol. We aimed to conduct subgroup analyses based on data availability.




Methods


We searched OrthoEvidence, Ovid MEDLINE, Ovid EMBASE, and Cochrane Controlled Register of Trials (CENTRAL) from inception to July 12, 2021 with both indexed terms and free text terms with regard to duloxetine and postoperative pain adult orthopedic surgical patients.


We also searched for existing systematic reviews to identify additional eligible studies (i.e., Branton et al., 2021; de Oliveira Filho et al., 2020; Zorrilla-Vaca et al., 2019).


We included only RCTs with full texts published in English. For eligible studies, duloxetine treatment refers to short-term perioperative duloxetine administration, defined by de Oliveira Filho et al. (2020) as “30 or 60 mg doses administered by the oral route for no more than three days before surgery and continued for at least 24 or 48 h after surgery but no more than six weeks postoperatively.” Outcomes measured within 72 hours after surgery were synthesized.


We adopted the Cochrane risk-of-bias tool and the GRADE approach to determine the risk of bias (RoB) and the quality of evidence for included RCTs, respectively. Two reviewers independently worked on the study screening and selection processes.




Results


1. Characteristics of included studies


In total, we retrieved 276 records, among which 9 RCTs were eligible and included (Altiparmak et al., 2018; Attia et al., 2017; Bedin et al., 2017; El-Behairy et al., 2019; Govil et al., 2020; Ho et al., 2010; Koh et al., 2019; Li et al., 2021; YaDeau et al., 2016).


Reasons for excluding RCTs investigating the use of duloxetine in pain management after orthopedic surgery included the duration of duloxetine administration not meeting the criteria (Hyer et al., 2015; Kim et al., 2021), abstract only (YaDeau, 2016), no access to the study (Saoud et al., 2014). 


The characteristics of the 9 included RCTs are presented in Table 1. All of the studies were published in 2016 and after except one in 2010 (Ho et al., 2010).


Most studies involved 2 treatment arms while Altiparmak et al. (2018) and Attia et al. (2017) compared 3 and 4 treatments, respectively. The sample sizes were relatively small in each study range from 50 to 120.


Seven studies were conducted in Asia (Altiparmak et al., 2018; Attia et al., 2017; El-Behairy et al., 2019; Govil et al., 2020; Ho et al., 2010; Koh et al., 2019; Li et al., 2021), 1 in North America (YaDeau et al., 2016), and 1 in South America (Bedin et al., 2017).


Five studies investigated the use of duloxetine for postoperative pain management in patients undergoing knee or hip arthroplasty (El-Behairy et al., 2019; Ho et al., 2010; Koh et al., 2019; Li et al., 2021; YaDeau et al., 2016), while 4 RCTs focused on patients who received lumbar spinal surgical operations (Altiparmak et al., 2018; Attia et al., 2017; Bedin et al., 2017; Govil et al., 2020).


Table 1: Characteristics of included RCTs

Study ID

Country

Sample Size

Condition

Age (years)

Altiparmak et al. (2018)

Turkey

99

Elective repair of lumbar disc herniation

Duloxetine: mean (SD): 53 (11);

Pregabalin: 54 (11);

Placebo: 54 (11)

Attia et al. (2017)

Egypt

120

Single level lumbar spinal disc prolapse surgery.

Duloxetine: 48.36 (9.8);

Etoricoxib: 45.26 (7.5);

Duloxetine + etoricoxib: 47.5 (10.14);

Placebo: 46.5 (8.74)

Bedin et al. (2017)

Brazil

60

Lumbar spinal fusion of 1 segment under open surgery

Duloxetine: 48 (12);

Placebo: 48 (14)

El-Behairy et al. (2019)

Egypt

60

Hip surgery

Duloxetine: 45.7 (8);

Placebo: 43 (8.5)

Govil et al. (2020)

India

96

Lumbar canal stenosis surgery

Duloxetine: 41.4 (14.6);

Placebo: 43 (15.1)

Ho et al. (2010)

Singapore

50

Elective knee replacement surgery

Duloxetine: 65.2 (range: 50 to 80);

Placebo: 65.7 (51 to 79)

Koh et al. (2019)

South Korea

80

Centrally sensitized patients undergoing total knee arthroplasty

Duloxetine: 69.1 (5.8);

Placebo: 68.6 (9.5)

Li et al. (2021)

China

96

Total hip arthroplasty

Duloxetine: 52.7 (12);

Placebo: 50.2 (13.2)

YaDeau et al. (2016)

United States

106

Knee arthroplasty

Duloxetine: 67 (range: 61 to 71);

Placebo: 63 (57 to 67)




Information on the analgesic protocols in the RCTs, including background analgesia and rescue analgesia are shown in Table 2.

We found a high variation in the analgesic strategies across included RCTs.




Table 2: Analgesic protocols in the included RCTs




Study ID

Intervention

Control

Background Analgesia

Rescue Analgesia

Altiparmak et al. (2018)

Duloxetine 60 mg orally 1 hour before surgery, placebo 12 hours postoperatively, duloxetine 60 mg orally 24 hours after surgery

1. Pregabalin 75 mg orally 1 hour before surgery, 12 and 24 hours after surgery.

2. Placebo

Intravenous 1000 mg acetaminophen every 8 hours until the end of the first postoperative day

Intramuscular 75 mg diclofenac sodium

Attia et al. (2017)

Duloxetine capsule 60 mg + two placebo tablet given 1 hour before and 24 hours after surgery

1. Etoricoxib: placebo capsule + two etoricoxib tablets 60 mg.

2. Duloxetine + etoricoxib: duloxetine 60 mg capsules + two etoricoxib tablets 90 mg.

3. Placebo: placebo capsule + two placebo tablet

Intravenous 1000 mg acetaminophen every 6 hours until 48 hours after surgery

Morphine (2 mg bolus at 10 min intervals)

Bedin et al. (2017)

Duloxetine 60 mg orally 1 hour before surgery and 24 hours after surgery

Placebo

Intravenous ketorolac every 6 hours for 48 hours after discharge from the post anesthesia care unit

Intravenous fentanyl (a bolus of 0.2 mg/kg and a 10-minute lockout time, with a maximum of 4.5 mg/kg over 4 hours)

El-Behairy et al. (2019)

Duloxetine 60 mg on two divided doses 30 mg every 12h for three days before the operation, 2h pre-operative and 12h after the surgery

Placebo

No Information

Morphine (2 mg bolus at 10 min interval)

Govil et al. (2020)

Oral duloxetine 30 mg daily for 2 days before surgery. The dose was incremented to 60 mg from the day of surgery to the second postoperative day, again tapered to 30 mg for the next 2 days until 5 days post surgery (total duration 7 days)

Placebo

Oral acetaminophen 325 mg and tramadol 37.5 mg twice a day for pain until day 7 after surgery

Intravenous morphine 0.05 mg/kg

Ho et al. (2010)

Oral duloxetine 60 mg 2 hours before surgery and on the morning of the first postoperative day.

Placebo

Acetaminophen 1 g 6 hourly, etoricoxib 120 mg daily and tramadol 50 mg 8 hourly for 2 weeks

Morphine for 48 h after operation

Koh et al. (2019)

Oral duloxetine 30 mg on the night before surgery and 30 mg per day for 6 weeks after surgery

No duloxetine

1 mg of oxycodone every 12 hours for 7 days and 200 mg of celecoxib, 37.5 mg of tramadol, and 650 mg of acetaminophen every 12 hours for 6 weeks after the operation

Intravenous patient-controlled anesthesia pump that administered 1 mL of a 100-mL mixture containing 2000 mg of fentanyl on demand

Li et al. (2021)

Oral duloxetine 60 mg per day starting from 2 days pre-surgery to 14 days post-surgery

Placebo

Oral administration of celecoxib (200 mg twice a day) since day 1 until 2 weeks after surgery

Morphine (5 mg intravenously)

YaDeau et al. (2016)

Oral duloxetine 60 mg per day starting from 30 min pre-surgery to 14 days post-surgery

Placebo

Intravenous ketorolac 30 mg followed by meloxicam 15 mg/day

PCEA (bupivacaine / hydromorphone until 5 pm on day 1 after surgery); oxycodone 5 mg / paracetamol 325 mg 1 to 2 orally every 4 hours as situation demands




In terms of RoB assessment (Figure 1), all the included RCTs blinded participants by involving oral placebo in the control groups except one study (Koh et al., 2019). There lacked adequate information in a number of included studies to determine whether the outcome assessors were blinded (Bedin et al., 2017; El-Behairy et al., 2019; Koh et al., 2019; Li et al., 2021) or whether the results were selectively reported (Altiparmak et al., 2018; El-Behairy et al., 2019; Govil et al., 2020; Ho et al., 2010) (Figure 1).





2. Meta-analysis results

2.1 Pain on a normalized scale


All 9 included RCTs reported pain-related outcomes, including visual analogue scale (VAS) pain and numeric rating scale (NRS) pain. We incorporated these pain outcomes to a normalized scale ranging from 0 to 100. A higher score indicates worse pain.


Among patients who underwent orthopedic surgery, no significant differences were found between the duloxetine and control groups in pain reduction at 0.5, 1, 2, 4, 6, and 12 hours post surgery (Figure 2).


However, postoperative pain management involving duloxetine resulted in significant acute postoperative pain relief in patients undergoing orthopedic surgery at 24 hours [mean difference (MD): -7.48; 95% confidence interval (CI): -14.49 to -0.47], 48 hours (MD: -10.83; 95% CI: -18.04 to -3.63), and 72 hours (MD: -0.43; 95% CI: -0.74 to -0.13) after surgical operation, compared to the treatment involving placebo or no duloxetine (Figure 2).



2.2 Opioid consumption


Eight included RCTs reported opioid consumption, including morphine and fentanyl use in milligram (mg) (Attia et al., 2017; Bedin et al., 2017; El-Behairy et al., 2019; Govil et al., 2020; Ho et al., 2010; Koh et al., 2019; Li et al., 2021; YaDeau et al., 2016).





As shown in Figure 3, adding duloxetine to the analgesic protocol significantly reduced the postoperative consumption of opioids in patients at 24 hours (MD: -8.95; 95% CI: -14.38 to -3.52) and 48 hours (MD: -12.59; 95% CI: -18.82 to -6.36) after orthopedic surgery. However, no significant differences were found between the duloxetine and control groups in opioid consumption reduction at 72 hours post surgery (Figure 3).




2.3 Adverse events


We summarized the incidence of several adverse events, such as nausea/vomiting, dizziness, headache, and somnolence.



We did not identify any significant differences in the occurrence of nausea/vomiting, dizziness, headache, and somnolence between analgesic protocols involving duloxetine and not involving duloxetine among patients receiving orthopedic surgery.





2.5 Subgroup analysis


For subgroup analysis, we were able to conduct subgroup analyses based on surgical sites: spine surgery (Altiparmak et al., 2018; Attia et al., 2017; Bedin et al., 2017; El-Behairy et al., 2019; Govil et al., 2020) vs. knee/hip joint arthroplasty (Ho et al., 2010; Koh et al., 2019; Li et al., 2021; YaDeau et al., 2016).


We selected the pain or opioid consumption outcomes that involved as many included studies as possible (i.e., pain at 6, 12, 24, and 48 hours after surgery, opioid consumption at 24 and 48 hours post surgical operation) for the subgroup analyses.


No subgroup effects were identified for pain at 6, 12, 24, and 48 hours after surgery as well as for opioid consumption at 24 and 48 hours post surgery (Figure 5).







Summary and Interpretation


In this OE Original, we conducted a systematic review and meta-analysis to examine RCT evidence with respect to the efficacy and safety of using duloxetine in postoperative pain management among patients undergoing orthopedic surgery. Nine eligible studies, among which eight were published in and after 2016 and one in 2010, were identified. The summary of meta-analysis results and assessment of quality of evidence are presented in Table 3.


First of all, adding duloxetine to analgesic protocol in patients undergoing orthopedic surgery seems to be safe as we found moderate to low quality of evidence showing no statistical differences in the incidences of nausea/vomiting, dizziness, headache, and somnolence between patients receiving duloxetine and those who did not (Figure 4 and Table 1).


The included RCTs reported various pain outcomes, using either VAS or NRS to measure the severity of pain at rest or on movement. As Jacobs et al. (2016) pointed out, “For mechanical conditions such as joint pain, reducing pain during ambulation is more important than reducing pain at rest…” Accordingly, we selected pain on movement over pain at rest in our meta-analysis when both of them were available in one study. Duloxetine might be effective in postoperative management at some points in time as the quantitative synthesis found that involving duloxetine in the analgesic protocol resulted in significant reductions in acute postoperative pain in patients undergoing orthopedic surgery at 24 hours (MD: -7.48; 95% CI: -14.49 to -0.47; Low quality of evidence), 48 hours (MD: -10.83; 95% CI: -18.04 to -3.63; Low quality of evidence), and 72 hours (MD: -0.43; 95% CI: -0.74 to -0.13; Moderate quality of evidence) after surgery, compared to the pain management protocol not including duloxetine (Figure 2 and Table 3). However, the differences in pain reduction at 0.5, 1, 2, 4, 6, and 12 hours post surgery remain insignificant (Low to Very low quality of evidence) (Figure 2 and Table 3).


We also examined and synthesized the evidence regarding the efficacy of duloxetine in reducing opioid use for postoperative pain management in patients receiving orthopedic surgery. In addition to pain outcomes in analgesic clinical trials, researchers have argued that outcomes measuring opioid consumption is also an essential component (Berde et al., 2012). Our meta-analysis suggests that adding duloxetine in analgesic protocol significantly reduced the consumption of opioids, such as morphine and fentanyl, in patients undergoing orthopedic surgery at 24 hours (MD: -8.95; 95% CI: -14.38 to -3.52; Low quality of evidence) and 48 hours (MD: -12.59; 95% CI: -18.82 to -6.36; Low quality of evidence), but not at 72 hours (Very low quality of evidence) post operation (Figure 3 and Table 3).


Majority of outcomes on pain and opioid consumption were of low to very low quality of evidence, indicating that our confidence that these outcomes reflected the true effects were low to very low. One of the major concerns is the high heterogeneity determined by the magnitude of heterogeneity (I2). The source of heterogeneity may have derived from the variation across analgesic protocols and different surgical sites (or types of surgery) in these RCTs. Our subgroup analyses based on surgical sites found no subgroup differences. Variations in analgesic protocols were too high across included studies to classify into subgroups.


Table 3. Summary of meta-analysis and assessment of quality of evidence

Outcome

Point Estimate Favors

Statistical Significance

Quality of Evidence

Pain (0.5 hours post surgery)

Duloxetine

No Significance

Low

Pain (1 hour post surgery)

Duloxetine

No Significance

Very Low

Pain (2 hours post surgery)

Duloxetine

No Significance

Low

Pain (4 hours post surgery)

Duloxetine

No Significance

Low

Pain (6 hours post surgery)

Duloxetine

No Significance

Low

Pain (12 hours post surgery)

Duloxetine

No Significance

Low

Pain (24 hours post surgery)

Duloxetine

Yes,

MD: -7.48; 95% CI: -14.49 to -0.47

Low

Pain (48 hours post surgery)

Duloxetine

Yes,

MD: -10.83; 95% CI: -18.04 to -3.63

Low

Pain (72 hours post surgery)

Duloxetine

Yes,

MD: -0.43; 95% CI: -0.74 to -0.13

Moderate

Opioid consumption (mg, 24 hours post surgery)

Duloxetine

Yes,

MD: -8.95; 95% CI: -14.38 to -3.52

Low

Opioid consumption (mg, 48 hours post surgery)

Duloxetine

Yes,

MD: -12.59; 95% CI: -18.82 to -6.36

Low

Opioid consumption (mg, 72 hours post surgery)

Duloxetine

No Significance

Very Low

Adverse events - Nausea/vomiting

Duloxetine

No Significance

Moderate

Adverse events - Dizziness

Control

No Significance

Moderate

Adverse events - Headache

Duloxetine

No Significance

Low

Adverse events - Somnolence

Control

No Significance

Moderate



Bottom Line


Involving duloxetine in the analgesic protocol for pain management patients who have undergone orthopedic surgery seems to be safe and beneficial in terms of markedly relieving acute pain at 24, 48, and 72 hours post surgery and significantly decreasing opioid consumption at 24 and 48 hours after surgical operation. 




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