What is the data on perioperative duloxetine (Cymbalta) during orthopedic surgery for pain reduction?

Comment by InpharmD Researcher

Perioperative Cymbalta® (duloxetine) for pain reduction has been extensively studied in randomized controlled trials and meta-analyses in the setting of orthopedic surgery. Based on available data, perioperative administration of duloxetine shows potential for reducing pain and postoperative opioid use in orthopedic surgery, especially in total knee arthroplasty. While duloxetine typically showed no pain reduction at 24 hours compared to control, it was found to consistently lower pain scores and decrease opioid consumption at 48 and 72 hours postoperatively and up to 6-8 weeks. However, its long-term effects on pain reduction appear to be limited, with no significant differences reported at later time points.
Background

A 2023 meta-analysis evaluated the efficacy of duloxetine in reducing pain and postoperative opioid use following lower extremity total joint arthroplasty (TJA). Among eight identified randomized controlled trials, six studies investigated duloxetine for total knee arthroplasty (TKA), one study investigated duloxetine for total hip arthroplasty (THA), and one study investigated both TKA and THA. Perioperative dosing regimens of duloxetine varied among trials, with a common regimen of 60 mg given 30 minutes to two hours preoperatively followed by 60 mg postoperatively for 14 days. While the quantitative analysis found no significant difference in opioid consumption at 24 hours between duloxetine- and placebo-recipients, use of duloxetine was associated with less opioid use at 48 (weighted mean difference [WMD] -11.98; 95% confidence interval [CI] -21.32 to -2.65; p= 0.012) and 72 (WMD -10.73; 95% CI -21.37 to -0.09; p= 0.048) hours. [1]

Patients receiving duloxetine experienced significantly lower visual analog scale (VAS) scores at rest at postoperative day 3 (POD 3; WMD -0.52; 95% CI: -0.83 to -0.22; p= 0.001), POD 7 (WMD -0.80; 95% CI -1.38 to -0.22; p= 0.007), and postoperative week 6 (WMD -2.01; 95% CI -2.41 to -1.61; p<0.001). For VAS with movement, significantly reduced pain was reported by duloxetine-treated patients at POD 1 (WMD -0.72; 95% CI -1.31 to -0.13; p= 0.016), POD 3 (WMD -0.56; 95% CI -0.99 to -0.12; p= 0.012), POD 7 (WMD -0.96; 95% CI -1.41 to -0.50; p<0.001), POD 14 (WMD -1.02; 95% CI -1.72 to -0.33; p= 0.004), postoperative week 6 (WMD -1.41; 95% CI -1.79 to -1.02; p<0.001), and postoperative month 3 (WMD -0.80; 95% CI -1.56 to -0.04; p= 0.038). While the preliminary data demonstrate duloxetine as a viable adjunctive agent in the setting of TJA procedures, variations in dosing regimens and inconsistent placebo use among evaluated trials may ameliorate the robustness of the overall conclusion. [1]

Another recent meta-analysis published in 2023 evaluated the efficacy and safety of duloxetine for postoperative recovery specifically after TKA. A total of 11 studies (N= 1,019) of patients undergoing TKA for primary knee osteoarthritis were included for analysis. Duloxetine had no statistically significant reduction in pain at rest compared with control at 24 hours (standard mean difference [SMD] -0.43; 95% CI -1.06 to 0.2; p= 0.18). However, compared with control, duloxetine showed a statistically significant reduction in pain at rest at 3 days (SMD -0.35; 95% CI -0.65 to -0.05; p= 0.02), 1 week (SMD -0.56; 95% CI -1.02 to -0.1; p= 0.02), 2 weeks (SMD -0.73; 95% CI -1.31 to -0.14; p= 0.02), and 6 weeks (SMD -0.78; 95% CI -1.36 to -0.21; p= 0.02). No significant differences were reported in pain at rest between duloxetine and control at 12 weeks, 6 months, and 12 months. [2]

For pain with movement, duloxetine again had no significant improvement compared with control at 24 hours (SMD -0.46; 95% CI -0.96 to 0.03; p= 0.07). However, duloxetine showed significant improvements compared to control for pain with movement at 5 days (SMD -0.65; 95% CI -1.21 to -0.09; p= 0.02), 1 week (SMD -0.74; 95% CI -1.12 to -0.36; p= 0.0001), 2 weeks (SMD -0.83; 95% CI -1.30 to -0.36; p= 0.0006), 4 weeks (SMD -0.98; 95% CI -1.33 to -0.62; p <0.00001), 6 weeks (SMD -0.99; 95% CI -1.84 to -0.13; p= 0.02), and 8 weeks (SMD -1.23; 95% CI -1.72 to -0.73; p<0.00001). Again, no significant differences for pain with movement were reported at 12 weeks, 6 months, and 12 months, indicating its long-term effects on pain may be limited. [2]

Duloxetine was found to significantly improve physical function compared with control at 1 week (SMD -1.79; 95% CI -2.56 to -1.01; p<0.00001), 2 weeks (SMD -1.44; 95% CI -1.89 to -0.99; p<0.00001), 4 weeks (SMD -1.54; 95% CI -2.62 to -0.46; p= 0.005), and 8 weeks (SMD -1.13; 95% CI -1.77 to -0.49; p= 0.0005). In terms of analgesic consumption, no significant differences between duloxetine and control were reported for consumption of patient-controlled analgesia with intravenous morphine or fentanyl. Cumulative opioid consumption at 24 hours, however, was significantly lower with duloxetine compared to the control group (MD -7.26; 95% CI -14.34 to -0.18; p= 0.04). At 7 days, no significant difference in cumulative opioid consumption occurred. [2]

Duloxetine showed significant improvements in range of motion of the knee at 6 weeks (MD 3.96; 95% CI 1.11 to 6.81; p= 0.006) compared to control, but not at 1 week or 12 weeks. Duloxetine also resulted in a lower score on the depression scale than in the control groups (MD -2.74; 95% CI -3.91 to -1.56; p<0.00001) and a better score on the SF-36 for mental health (MD 11.47; 95% CI 7.73 to 15.21; p <0.00001). Overall, no significant publication bias was noted within the analysis, and sensitivity analyses found the effect on pain on movement at 1 week to be similar when removing one study that was a significant source for heterogeneity. The rates of adverse events between duloxetine and control groups were similar within studies. [2]

A 2021 meta-analysis aimed to determine if duloxetine 60 mg given perioperatively is safe and effective at reducing postoperative opioid consumption and reported pain following elective orthopedic surgery. Five randomized controlled trials were included in the analysis (N= 314) for postoperative opioid consumption (24-hour period) and three studies for the 48-hour postoperative period. Duloxetine use was associated with statistically significant lower total opioid use at 24 hours (mean difference [MD] -31.9 MME [morphine milligram equivalents]; 95% confidence interval [CI] -54.22 to -9.6; p= 0.005) and overall (MD -31.68 MME; 95% CI -46.62 to -16.74; p<0.0001). In terms of adverse events, duloxetine use resulted in an increase in insomnia and decreased incidence of dizziness and somnolence in one study; other adverse events were similar between duloxetine and placebo groups in the included studies. The most notable adverse events reported were nausea and vomiting. The authors concluded that these results suggest adding preoperative administration of duloxetine 60 mg to a multimodal analgesia regimen within the orthopedic surgery setting significantly lowers total postoperative opioid consumption and reduces pain without significant adverse events. These results are limited by significant heterogeneity among the included studies, small sample sizes, and that various orthopedic surgeries were included; these factors limit the overall validity and generalizability of the meta-analysis. [3]

References:

[1] Jones IA, Talehakimi A, Murphy LS, et al. Duloxetine for Postoperative Pain Control Following Knee or Hip Replacement: A Systematic Review and Meta-Analysis. Arthroplast Today. 2023;20:101097. Published 2023 Feb 14. doi:10.1016/j.artd.2023.101097
[2] Yang JM, Wang Y, Li JY, et al. Duloxetine for rehabilitation after total knee arthroplasty: a systematic review and meta-analysis. Int J Surg. 2023;109(4):913-924. Published 2023 Apr 1. doi:10.1097/JS9.0000000000000230
[3] 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(2):394-403. doi:10.1007/s11096-020-01216-9
Literature Review

A search of the published medical literature revealed 9 studies investigating the researchable question:

What is the data on perioperative duloxetine (Cymbalta) during orthopedic surgery for pain reduction?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-9 for your response.

 

Effect of Duloxetine on Opioid Use and Pain After Total Knee Arthroplasty: A Triple-Blinded Randomized Controlled Trial

Design

Triple-blinded, randomized controlled trial

N= 160

Objective

To determine whether 60 mg of duloxetine daily provided analgesic benefits lasting up to 14 days for total knee arthroplasty (TKA) patients receiving a modern analgesic regimen of nerve blockade and oral multimodal analgesia, without patient-controlled analgesia (PCA)

Study Groups

Duloxetine (n= 80)

Placebo (n= 80)

Inclusion Criteria

Aged 25 to 75 years, scheduled to receive regional anesthesia for primary TKA, planning to be discharged home or to a participating rehabilitation facility

Exclusion Criteria

Opioid consumption for longer than 3 months; planned use of general anesthesia; prior major ipsilateral open knee surgery; allergy or intolerance to study medication; hepatic insufficiency; estimated creatine clearance < 50 mL/min; American Society of Anesthesiologists (ASA) physical status of IV; chronic gabapentin or pregabalin use (regular use for more than 3 months); using duloxetine or other serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, triptans, lithium, buspirone, or St. John's Wort

Methods

Patients were randomized (1:1) to take 15 oral doses of duloxetine 60 mg or placebo pills. The first dose was administered before transfer to the operating room (OR) and then once daily until the postoperative day (POD) 14. On the day of surgery, patients received preoperative study medication, 10 mg sustained-release oxycodone, and 15 mg meloxicam in addition to standard intraoperative and postoperative multimodal anesthetic protocol.

For postoperative pain management, patients were scheduled to receive study medication in addition to 4 doses of 1,000 mg intravenous (IV) acetaminophen every 6 hours followed by 1,000 mg oral acetaminophen every 8 hours; 4 doses of 15 mg IV ketorolac followed by 15 mg meloxicam every 24 hours; and 5-10 mg oral oxycodone given as needed for pain.

Duration

Interventions: 14 days postoperative

Enrollment: August 2017 to November 2020

Outcome Measures

Primary: Numeric Rating Scale (NRS) scores with movement on postoperative days 1, 2, and 14, and cumulative opioid consumption surgery through postoperative day 14

Secondary: pain at rest, satisfaction, side effects, Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS, JR)

Baseline Characteristics

  

Duloxetine (n= 80)

Placebo (n= 80)

      

Age, years

 63  64      

Female

50% 44%      

White

 89% 81%      

Preoperative medications

Acetaminophen

Nonsteroidal anti-inflammatory drugs (NSAIDs)


19%

42%


19%

41%

      

Opioids (not chronic)

1%

3.8%

      

Preoperative NRS

6.5

5.7

      

Preoperative KOOS, JR

47

50

      

Results

Dual primary outcomes

Duloxetine (n= 80)

Placebo (n= 80)

 Mean difference (95% CI) p-value for noninferiority p-value for superiority

Cumulative opioid consumption, mg oral morphine equivalent

 288 ± 226 432.5 ± 374 -126.5 (-221.5 to -31.4) < 0.00 0.0048

NRS pain with movement

POD 1

POD 2

POD 14



5.1 ± 2.6

6.2 ± 2.4

4.2 ± 2.0



5.0 ± 2.6

5.8 ± 2.3

4.8 ± 2.2



0.06 (-0.8 to 0.9)

-0.36 (-0.4 to 1.1)

-0.59 (-1.3 to 0.1)



< 0.001

< 0.001

0.0022

 N/A

Secondary outcomes

Duloxetine (n= 80)

Placebo (n= 80)

p-value

NRS pain at rest

POD 1

POD 2

POD 14


3.4 ± 2.3

4.0 ± 2.5

2.5 ± 2.0


2.7 ± 2.4

4.4 ± 2.8

3.0 ± 2.1


0.08

0.31

0.11

Median satisfaction with pain management (interquartile range [IQR])

10 (8 to 10)

8 (7 to 10)

0.046

Median length of stay, days (IQR)

2 (1.7 to 2.1)

2 (1.2 to 2.1)

0.35

KOOS, JR Score

6 weeks

3 months

 

71 ± 10

76 ± 12

 

68 ± 11

71 ± 12

 

0.05

0.02

Adverse Events

Common Adverse Events: 

Duloxetine: hallucinations, fall during physical therapy, inability to ejaculate, fever with rash at the surgical site, and increased pain

Placebo: hyponatremia, opioid overdose and influenza, oral Herpes simplex, surgical site blisters, 3rd cranial nerve palsy, kidney stone, fall on POD 90, hallucinations and confusion, diaphoresis, hypertension, diarrhea, decreased urine output and tooth pain, and acne

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: None

Study Author Conclusions

The 29% reduction in opioid use corresponds to 17 fewer pills of oxycodone, 5 mg, and was achieved without increasing pain scores. Considering the ongoing opioid epidemic, duloxetine can be used to reduce opioid usage after knee arthroplasty in selected patients that can be appropriately monitored for potential side effects of the medication.

InpharmD Researcher Critique

There was a high rate of patient exclusions. Additionally, the exclusion of patients taking concomitant antidepressants may limit the generalizability of the results.



References:

YaDeau JT, Mayman DJ, Jules-Elysee KM, et al. Effect of Duloxetine on Opioid Use and Pain After Total Knee Arthroplasty: A Triple-Blinded Randomized Controlled Trial. J Arthroplasty. 2022;37(6S):S147-S154. doi:10.1016/j.arth.2022.02.022

 

Effect of Preoperative Duloxetine Treatment on Postoperative Chronic Residual Pain after Total Hip or Knee Arthroplasty: A Randomised Controlled Trial

Design

Multicenter, pragmatic, prospective, randomized clinical trial

N= 111

Objective

To investigate the effects of preoperative treatment with duloxetine in sensitised knee and hip osteoarthritis (OA) patients on postoperative chronic residual pain up to 1 year after arthroplasty

Study Groups

Duloxetine (n= 57)

Control (n=54)

Inclusion Criteria

Patients who reported modified PainDETECT Questionnaire (m-PDQ) scores >12.0

Exclusion Criteria

Surgical hip or knee joint procedures in the past year; intra-articular hip/knee injection/ arthroscopy in the past 3 months; cognitive or neurological disorders that could strongly interfere with questionnaire surveys; a history of significant peripheral nerve injury; serious or unstable physical or mental medical conditions that could interfere with study participation; intended THA/TKA to another joint within the study period; previous exposure to duloxetine or a medical contraindication for the usage of duloxetine

Methods

Randomization occurred in a 1:1 allocation ratio. The preoperative treatment period was divided into three-time points. First time point, two weeks after baseline to assess safety and side effects, consisted of the treatment group receiving duloxetine 30mg/day in week one and 60 mg/day in week two. Second time point, eight weeks after baseline to assess effect of duloxetine on pain, was right after the seven week treatment with duloxetine 60 mg/day. Before surgery, the duloxetine dose tapered for two weeks to 30 mg/day. Duloxetine treatment was ended five to eight days before surgery for safety reasons related to platelet function. The third time point was one day before surgery. Patients in the care as usual group received the same set of questionaires at the same time points as the duloxetine group.

Duration

Recruited December 2014 to June 2018; follow up completed in 2019

Outcome Measures

Primary: pain at six months after arthroplasty assessed with the Pain Subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS) or the Hip disability and Osteoarthritis Outcome Score (HOOS) with a 0-100 scale. 

Secondary: change in general pain measured using the Visual Analogue Scale (VAS), amount of neuropathic-like pain measured using the m-PDQ 6 months post-operatively, time points 1,2, and 3 cover preoperative intervention period while time points 4,5,6, and 7 cover postoperative period (ranging from 48 hours to six weeks, six months, and 12 months)

Baseline Characteristics

  

Duloxetine

(n=57)

Care as usual

(n=54)

 p-value

Age, years

  61.5  64.0  

Female

38 31  

Knee

 31 30  

Duration of pain (months)

 48 36  

KOOS/HOOS Pain (0-100) 

 38.1 30.6  0.004*
mPDQ (-1-38)  15.6 16  
VAS- R  46.6  58.7  0.004*
VAS- M  68.1  71.1  

Abbreviations: VAS-R, Visual Analogue Scale for Pain in Rest; VAS-M, Visual Analogue Scale for Pain during Movement 

*The other baseline characteristics did not exhibit statistically significant differences between the two groups. 

Results

Endpoint

Duloxetine

(n=57)

Care as usual

(n=54)

p-value

Preoperatively: After 7 weeks targeted treatment

KOOS/HOOS-p

mPDQ

VAS-R

VAS-M

 

44

12.1

42.1

55.5 

 

35.7

15.1

55.2

68.8

 

0.021

0.018

0.002

0.002

Postoperatively: 6 weeks postarthroplasty

KOOS/HOOS-p

mPDQ

VAS-R

VAS-M

 

63.4

10.7

21.3

31.7 

 

67.6

9.1

21.8

25.9 

 

0.248

0.251

0.914

0.187 

Postoperatively: 6 months postarthroplasty

KOOS/HOOS-p

mPDQ

VAS-R

VAS-M

 

74.5

7.2

21.4

25.3 

 

76

7.1

15.5

21.3 

 

0.690

0.952

0.173

0.370 

Postoperatively: 12 months postarthroplasty

KOOS/HOOS-p

mPDQ

VAS-R

VAS-M

 

79.8

4.9

12.9

19.1 

 

81.6

4.9

15.7

18.7 

 

0.623

0.967

0.518

0.929 
Abbreviations: HOOS, Hip disability and Osteoarthritis Outcome Score; KOOS, Knee injury and Osteoarthritis Outcome Score; m-PDQ, modified PainDETECT Questionnaire; VAS-M, Visual Analogue Scale for pain during Movement; VAS-R, VAS for pain in Rest.

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Post-TKA infection (n=1), post-TKA aseptic loosening of the tibial component (n=1), serious adverse event not disclosed (n=1)

Percentage that Discontinued due to Adverse Events: 12 (21.1%)

Study Author Conclusions

Preoperative targeted treatment with duloxetine in end-stage hip and knee OA patients with sensitisation does not influence postoperative chronic residual pain after arthroplasty. Duloxetine does seem to have a treatment effect on pain in end-stage knee OA patients suffering from sensitisation, but clinically relevant thresholds were not met and applicability seems limited

InpharmD Researcher Critique

The study population involved both knee and hip arthroplasty patients which means the results are not generalizable to either of the populations. This study was not double-blinded meaning the patients may have believed to have or expected side effects to occur which could have led to discontinuation and skewing of the results.



References:

Rienstra W, Blikman T, Dijkstra B, et al. Effect of preoperative duloxetine treatment on postoperative chronic residual pain after total hip or knee arthroplasty: a randomised controlled trial. BMJ Open. 2021;11(11):e052944. Published 2021 Nov 3. doi:10.1136/bmjopen-2021-052944

 

Effect of Preoperative Duloxetine Treatment on Postoperative Chronic Residual Pain After Total Hip or Knee Arthroplasty: A Randomised Controlled Trial

Design

Multicenter, prospective, randomized controlled trial

N= 111

Objective

To investigate the effects of preoperative treatment with duloxetine in sensitized knee and hip osteoarthritis (OA) patients on postoperative chronic residual pain up to 1 year after arthroplasty

Study Groups

Duloxetine (n= 57)

Usual care (n= 54)

Inclusion Criteria

Patients with primary knee/hip OA planned for total hip arthroplasty (THA) or total knee arthroplasty (TKA), modified PainDETECT Questionnaire (m-PDQ) score > 12.0

Exclusion Criteria

Surgical hip or knee joint procedures in the past year; intra-articular hip/knee injection/arthroscopy in the past 3 months; cognitive or neurological disorders that could strongly interfere with questionnaire surveys; history of significant peripheral nerve injury; serious or unstable physical or mental medical conditions that could interfere with study participation; intended THA/TKA to another joint within the study period; previous exposure to duloxetine or a medical contraindication for usage of duloxetine

Methods

Participants were randomized (1:1) to receive duloxetine added to usual care for 10 weeks preoperatively or usual care. Patients in the duloxetine group were initiated on 30 mg/day during week 1 and increased to 60 mg/day in week 2. Before surgery, the dose of duloxetine was tapered for 2 weeks to 30 mg/day, to reduce discontinuation symptoms. Patients in the usual care group were allowed to continue with any pain medication they were already taking as well as any other ongoing treatment.

Duration

Recruitment: December 2014 to June 2018

Follow-up: completed in 2019

Outcome Measures

Primary: pain at 6 months after arthoplasty assessed with the pain subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS) or Hip disability and Osteoarthritis Outcome Score (HOOS)

Secondary: change in general pain at 6 months (assessed via Visual Analogue Scale [VAS]) and neuropathic-like pain (assessed via m-PDQ)

Baseline Characteristics

  

Duloxetine (n= 57)

Usual care (n= 54)

p-value

Age

 61.5  64.0  0.114

Female

66.7% 57.4% 0.334

Body mass index, kg/m2

 28.8 29.0 0.874

Knee

 54.4% 55.6% 0.999

Duration of pain, months

 48 36 0.312

Past surgery in index joint

 52.6% 53.7% 0.999

ASA score

I

II

III


33.9%

54.4%

12.5%


27.8%

68.5%

3.7%

 0.169

KOOS/HOOS

Pain

Symptoms

ADL

QOL


38

43.4

41.7

25.4 


30.6

41.1

38.6

21.4 


0.004

0.471

0.270

0.114

mPDQ

15.6

16

0.659

VAS-R

VAS-M


46.6

68.1


58.7

71.1


0.004

0.337

ADL, activities of daily living; QOL, quality of life, VAS-M, VAS for pain during movement; VAS-R, VAS for pain at rest

Results

Endpoint

 Duloxetine (n= 57)

Usual care (n= 54)

p-value 

Preoperative: After 7 weeks targeted treatment (95% confidence interval [CI])

KOOS/HOOS-p

mPDQ

VAS-R

VAS-M



44.0 (18.3–69.7)

12.1 (3.1–21.0)

42.1 (12.1–72.1)

55.5 (24.5–86.5) 



35.7 (10.1–61.4) 

15.1 (6.2–24.0)

55.2 (25.2–85.1)

68.8 (37.9–99.8)



0.021

0.018

0.002

0.002 

Postoperative: 6 months postarthroplasty (95% CI)

KOOS/HOOS-p

mPDQ

VAS-R

VAS-M

 

74.5 (48.8–100.2)

7.2 (–1.7–16.1)

21.4 (–8.6–51.4)

25.3 (–5.7–56.3)

 

 76.0 (50.3–101.7)

7.1 (–1.8–16.02) 

15.5 (–14.5–45.5)

21.3 (–9.7–52.2)

 

0.690

0.952

0.173

0.370 

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: 21.1% in the duloxetine group

Study Author Conclusions

Preoperative targeted treatment with duloxetine in end-stage knee and hip OA patients with sensitization does not influence postoperative chronic residual pain after TKA/THA.

InpharmD Researcher Critique

This study had a broad screening of all patients who were planned for total knee or hip arthroplasty, creating a representative study population. Due to the nature of the study and the outcomes evaluated, results can be subject to bias.



References:

Rienstra W, Blikman T, Dijkstra B, et al. Effect of preoperative duloxetine treatment on postoperative chronic residual pain after total hip or knee arthroplasty: a randomised controlled trial. BMJ Open. 2021;11(11):e052944. Published 2021 Nov 3. doi:10.1136/bmjopen-2021-052944

 

Analgesic Effect of Perioperative Duloxetine in Patients after Total Knee Arthroplasty: a Prospective, Randomized, Double-Blind, Placebo-Controlled Trial 
Design 

Prospective, randomized, double-blind, placebo-controlled trial study 

N= 100

Objective

To investigate the analgesic effect of perioperative use of duloxetine in patients who received total knee arthroplasty (TKA)

Study Groups

Duloxetine (n= 50)

Placebo (n= 50)

Inclusion Criteria

Patients diagnosed with knee osteoarthritis and scheduled to undergo primary unilateral TKA 

Exclusion Criteria

American Society of Anesthesiologists physical status IV, a known psychiatric disorder, Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) scores both < 7, intolerance or allergy to any of the study drugs, alcohol or opioid dependence, ongoing anticoagulant treatment, preoperative hepatic or renal dysfunction, serious cardiac and/or cerebrovascular comorbidities, concurrent use of duloxetine or other serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, tricyclic antidepressants, triptans, lithium, or buspirone.

Methods

Patients were either given a 60 mg duloxetine or a 60 mg placebo capsule every night before sleep two days preoperative till 14 days by a nurse who was not involved in this trial. The patients were followed up every day until 7 days after TKA, then 3 weeks and 3 months after TKA.

Duration

 June 8th 2020 to July 31st 2020

Outcome Measures

Primary: the visual analogue scale (VAS) score both at rest (rVAS) and at ambulation (aVAS) 

Secondary outcomes included: opioid consumption, range of motion (ROM), including both active (aROM) and passive (pROM)

Baseline Characteristics

  

Duloxetine (n= 50)

Placebo (n= 50)

  

Age, years 

 67.8 ± 10.12 66.2 ± 9.83  

Female

 30 (60%) 27 (54%)   

rVAS

 3.47 ± 1.77 3.62 ± 2.02  

aVAS

 6.31 ± 2.35 6.52 ± 2.60  

aROM

 100.37 ± 14.21 102.72 ± 13.52  

pROM

 104.12 ± 14.69 107.29 ± 14.37  

Results

Endpoint

Duloxetine (n= 50)

Placebo (n= 50)

p-value

rVAS Score 

          24 h postoperative

          7 days postoperative

 

4.7 ± 2.3

2.1 ± 1.6

 

5.9 ± 2.6 

2.8 ± 1.7

 

0.016

0.037

aVAS Score 

          24 h postoperative

          7 days postoperative

 

 

6.2 ± 2.1

3.3 ± 1.7

 

 

7.1 ± 2.2

4.1 ± 2.0

 

 

0.039 

0.034

 Opioid consumption, g

          24 h postoperative

          7 days postoperative

 

24.2 ± 10.1 

2.7 ± 2.5

 

28.5 ± 8.3 

4.1 ± 2.6

 

0.022

0.007

aROM after postoperative day 6, degree

 110.2 ± 9.9 107.5 ± 11.5 0.211

pROM after postoperative day 5, degree

 103.8 ± 12.1 99.5 ± 10.8 0.064

Adverse Events

Common Adverse Events (duloxetine vs. placebo): nausea/vomiting (10% vs. 30%), drowziness (40% vs. 20%), fatigue (46% vs. 52%), dryness of mouth (36% vs. 34%), constipation (6% vs. 22%)

constipation, fatigue, and dryness of mouth

Serious Adverse Events: None

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Several other RCTs have already mentioned the analgesic effect of duloxetine, but not in the immediate postoperative period. In this study, we found duloxetine could reduce acute postoperative pain in the immediate postoperative period and decrease the opioids consumption as well as accelerating postoperative recovery, without increasing the risk of adverse medication effects in patients undergoing TKA. Duloxetine could act as a good supplement in multimodal pain management protocol for patients undergoing TKA. 

InpharmD Researcher Critique

This study is limited by its small sample size and single-center nature. It also did not specify the ultimate duration for duloxetine to be given preoperatively for optimal postoperative pain management. 



References:

Yuan M, Tang T, Ding Z, Li H, Zhou Z. Analgesic effect of perioperative duloxetine in patients after total knee arthroplasty: a prospective, randomized, double-blind, placebo-controlled trial. BMC Musculoskelet Disord. 2022;23(1):242. Published 2022 Mar 12. doi:10.1186/s12891-022-05194-z

 

Duloxetine Reduces Pain After Total Hip Arthroplasty 

Design

Prospective, single-center, randomized, parallel-arm, double-blinded, placebo-controlled study

N= 96

Objective

To assess the efficacy of oral duloxetine in total hip arthroplasty (THA)

Study Groups

Duloxetine (n= 48)

Placebo (n=48)

Inclusion Criteria

Age > 18 years, American Society of Anesthesiologists (ASA) status I, II, or III, and scheduled to undergo primary THA for end-stage hip joint diseases with Hamilton Depression Scale (HAMD) and the Hamilton Anxiety Scale (HAMA) scores < 7

Exclusion Criteria

Known allergy to duloxetine, previous exposure to serotonin and norepinephrine reuptake inhibitors (SNRIs), known psychiatric disorders, alcohol or opioid abuse; acute infections of the hip joint; recent treatment for malignant diseases; major previous ipsilateral hip arthroplasty or open surgery; peripheral or central nerve impairment; cognitive dysfunction; history of peptic ulcers or bleeding tendency; impaired liver and/or renal function; and poor physical condition indicating the lack of ability to tolerate surgery

Methods

Patients were randomized 1:1 to receive duloxetine 60 mg or placebo, to be taken daily orally starting from 2 days pre-surgery to 14 days post-surgery. All operations were performed by the same surgeon. All participants accepted a multimodal and standardized analgesic strategy, including celecoxib for preemptive analgesia, as well as general and local anesthetics. After postoperative day 1, each patient was continued on celecoxib 200 mg orally twice daily for 2 weeks. Morphine was permitted as a rescue analgesic for unbearable acute pain. In perioperative period, only oral celecoxib and IV morphine were used for rescue analgesia before discharge.

Duration

Procedure: patients underwent operation between June 2020 to September 2020

Intervention: 2 days pre-operation to 14 days after surgery

Outcome Measures

Primary: pain severity upon movement measured by a visual analog scale (VAS)

Secondary: VAS scores for resting pain, morphine consumption, Harris Hip Score (HHS), patient satisfaction at discharge, length of postoperative hospital stay, adverse events

Baseline Characteristics

  

Duloxetine (n= 48)

Placebo (n= 48)

 p-Value

Age, years

 52.7 ± 12.0 50.2 ± 13.2 0.333

Male

22 (46%) 24 (50%) 0.683

Body mass index (BMI), kg/m2

 24.0 ± 2.9 23.9 ± 3.4 0.890

ASA status

I

II

III

 

8 (17%)

28 (58%)

12 (25%)

 

4 (8%)

32 (67%)

12 (25%)

 -

Surgical site (right/left)

 27/21 24/24 - 

Diagnosis

Osteonecrosis of femoral head 

Primary osteoarthritis 

Developmental dysplasia of hip 

Others 

 

16 (33%)

15 (31%)

9 (19%)

8 (17%)

 

17 (35%)

13 (27%)

10 (21%)

8 (17%) 

 -

Preoperative Brief Pain Inventory (BPI) pain severity score

Average

Worst

Least

Current

 

5.4 ± 1.3

7.6 ± 1.4

2.7 ± 1.2

5.4 ± 1.6

 

5.3 ± 1.1

7.2 ± 1.7

2.7 ± 1.1

5.1 ± 1.2

 

0.666

0.128

0.861

0.243 

Results

Endpoint

Duloxetine (n=48)

Placebo (n=48)

p-Value

Postoperative VAS score upon movement at:

3 hours

6 hours

12 hours

24 hours

48 hours

72 hours

1 week

3 weeks

3 months

 

6.0 ± 0.9

5.9 ± 0.8

5.4 ± 0.9

5.0 ± 1.0

4.4 ± 1.0

3.9 ± 0.9

2.8 ± 1.0

1.9 ± 1.0

1.6 ± 1.0 

 

6.5 ± 1.2

6.4 ± 1.0

5.9 ± 1.0

5.5 ± 1.2

4.8 ± 1.2

4.5 ± 1.1

3.5 ± 1.1

2.5 ± 1.1

1.8 ± 1.0 

 

0.029

0.016

0.010

0.033

0.041

0.004

< 0.001

0.007

0.469 

Postoperative VAS score for resting pain at:

3 hours

6 hours

12 hours

24 hours

48 hours

72 hours

1 week

3 weeks

3 months

 

4.1 ± 1.0

4.0 ± 1.0

3.3 ± 1.0

3.0 ± 1.1

2.3 ± 1.0

1.8 ± 0.9

1.0 ± 0.8

0.8 ± 0.7

0.6 ± 0.5 

 

4.5 ± 1.1

4.4 ± 1.0

3.8 ± 1.1

3.5 ± 1.1

2.8 ± 1.0

2.2 ± 1.0

1.3 ± 0.8

1.1 ± 0.7

0.7 ± 0.6

 

0.026

0.032

0.044

0.046

0.019

0.023

0.040

0.043

0.851 

Postoperative morphine consumption (mg) at:

24 hours

72 hours

1 week

 

11.0 ± 4.9

16.8 ± 6.1

18.7 ± 7.3

 

14.2 ± 5.9

20.4 ± 9.8

23.3 ± 13.6

 

0.006

0.032

0.039

Harris Hip Score, postoperatively at:

3 weeks

3 months

 

75.4 ± 5.5

87.2 ± 4.7

 

73.7 ± 6.1

87.8 ± 4.4

 

0.156

0.517

Patient satisfaction level

Extremely satisfied

Very satisfied

Somewhat satisfied

Neither satisfied nor dissatisfied

Somewhat dissatisfied

Very dissatisfied

Extremely dissatisfied

 

19 (40%)

21 (44%)

5 (10%)

2 (4%)

1 (2%)

0

0 

 

11 (23%)

17 (35%)

8 (17%)

6 (4%)

4 (8%)

2 (4%)

0

 - 

Length of postoperative hospital stay, hours

 63.4 ± 17.6 70.7 ± 23.7 0.089

Adverse events

Nausea and vomiting

Dry mouth

Insomnia

Somnolence

Constipation

Dizziness

Fatigue

 

8 (17%)

4 (8%)

5 (10%)

6 (13%)

7 (15%)

3 (6%)

5 (10%)

 

7 (15%)

2 (4%)

6 (13%)

3 (6%)

9 (19%)

4 (8%)

7 (15%)

 

0.779

0.677

0.749

0.486

0.584

1.000

0.537

Outcomes with statistically significant differences are bolded. While pain severity scores upon movement within the first 3 postoperative weeks were significantly lower in the duloxetine group compared to placebo, none of the between group differences met the threshold for minimum clinically important difference (MCID). 

Adverse Events

 See Results

Study Author Conclusions

Although it did not result in a clinically meaning reduction in pain after total hip arthroplasty, perioperative administration of 60 mg of duloxetine daily significantly alleviated pain in the postoperative 3 weeks and morphine requirements during the postoperative 48 h. Therefore, duloxetine still shows promise in optimizing the multimodal pain-management protocols in total hip arthroplasty

InpharmD Researcher Critique

The trial was performed at a single center (West China Hospital of Sichuan University), which may reduce generalizability due to varying procedural protocols in different hospitals/countries. Also, the limited sample size may not have been sufficient for determining significant difference for all relevant outcomes. 



References:

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(1):492. Published 2021 May 28. doi:10.1186/s12891-021-04377-4

 

Duloxetine and Subacute Pain after Knee Arthroplasty when Added to a Multimoodal Analgesic Regimen

Design

Single-center, triple-blinded, randomized, placebo-controlled trial

N= 106

Objective

To assess if administration of duloxetine, 60 mg daily for 15 days, starting on the day of surgery, would reduce pain severity with ambulation at 2 weeks after total knee arthroplasty (TKA)

Study Groups

Placebo (n= 53)

Duloxetine (n= 53)

Inclusion Criteria

 Age 25 to 75 years, patients with osteoarthritis scheduled for primary TKA, planned to have regional anesthesia and be discharged either to home or to participating rehabilitation center

Exclusion Criteria

Planned general anesthesia, allergy or intolerance to one of the study medications, major previous ipsilateral open knee surgery, American Society of Anesthesiologists physical status IV, hepatic failure, renal failure (estimated creatinine clearance less than 30ml/min), contraindication to using dexamethasone in the peripheral nerve block, difficult to manage diabetes mellitus (including insulin dependence), chronic gabapentin or pregabalin use (regular use for longer than 3 months), chronic opioid use (regular use for longer than 3 months), concurrent use of duloxetine or other serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, tricyclic antidepressants, triptans, lithium, buspirone, or St. John’s Wort.

Methods

Patients were randomized (1:1) to receive duloxetine (60 mg/day for 15 days) or placebo. 

Duration

November 2013 to May 2015

Outcome Measures

Primary: self-reported pain severity with ambulation (0 to 10 numerical rating scale [NRS] score) on post-operative day (POD) 14

Secondary: pain at rest, pain with knee flexion, opioid consumption 

Baseline Characteristics

  

Placebo (n= 53)

Duloxetine (n= 53)

  

Median Age, years

  63 67  

Female

 49.1% 52.8%  

White

 90.6% 90.6%  

Knee pain

Severity at rest

Severity with flexion

Severity with ambulation

 

2.9

5.5

5.2 

 

3.6

5.8

5.8 

 

 

Preoperative medications

Acetaminophen

NSAIDS

Opioids including tapentadol/tramadol

Bupropion

Escitalopram

Muscle relaxants

Gabapentinoids

 

20.8%

15.1%

7.5%

1.9%

1.0%

1.9%

0

 

24.5%

24.5%

9.4%

1.9%

0

1.9%

0

  

Results

Endpoint

Placebo (n= 53)

Duloxetine (n= 53)

p-value

NRS pain with ambulation on POD 14*

 3.8 ± 2.3   3.5 ± 2.1  0.386

*NRS pain scores with ambulation, flexion, and at rest did not differ between groups over the postoperative period (POD 1 through 6 weeks postoperatively) after adjustment for corresponding baseline pain severity (p= 0.293, 0.110, and 0.978, respectively)

Total opioid use was significantly reduced in the duloxetine group over the postoperative period (day of surgery through 3 months postoperatively (difference in means 8.7; 95% CI 3.3 to 14.1; p= 0.002)

Adverse Events

Common Adverse Events:

Placebo: atrial fibrillation (n=1); nausea, insomnia, and hypervigilance (n=1); headache (n=1)

Duloxetine: nausea, drowsiness, and fatigue (n=1); somnolence and dizziness (n=1); confusion and syndrome of innappropriate antidiuretic hormone secretion (n=1); nausea, drowsiness, and hypervigilance (n=1)

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: 16.9% vs. 9.4%

Study Author Conclusions

Administration of duloxetine for 2 weeks after TKA did not improve pain with ambulation, the study primary outcome. Duloxetine did not appear to cause major side effects.

InpharmD Researcher Critique

This study was done within a short time frame of two weeks. The majority of the patients were white and the study was conducted in a single setting which reduces generalizability.



References:

YaDeau JT, Brummett CM, Mayman DJ, et al. Duloxetine and Subacute Pain after Knee Arthroplasty when Added to a Multimodal Analgesic Regimen: A Randomized, Placebo-controlled, Triple-blinded Trial. Anesthesiology. 2016;125(3):561-572. doi:10.1097/ALN.0000000000001228

 

Significant Analgesic Benefits of Perioperative Duloxetine in Patients Who Have Depressive Symptoms Undergoing Total Hip Arthroplasty: A Randomized Controlled Trial

Design

Randomized, double-blinded, placebo-controlled trial

N= 67

Objective

To investigate the effect of perioperative short-term duloxetine on postoperative pain control in total hip arthroplasty (THA) patients with depressive symptoms

Study Groups

Duloxetine (n= 34)

Placebo (n= 33)

Inclusion Criteria

Ages 18-85, scheduled for primary unilateral THA, depression validated with the 17-item Hamilton Depression Scale (HAMD)

Exclusion Criteria

American Society of Anesthesiologists (ASA) status IV, allergy/intolerance to duloxetine, exposure to serotonin and norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), tricyclic anti-depressants (TCAs), or monoamine oxidase inhibitors (MAOIs) within 6 months prior to the surgery, impaired liver function, impaired renal function, a history of a hematopoietic or hemorrhagic disorder, peripheral or central nerve impairment, cognitive dysfunction, and opioid or alcohol dependence

Methods

Patients were randomized 1:1 to receive 60 mg duloxetine or placebo for 7 days starting on the day of surgery, 2 hours before surgery. Postoperative use of the visual analog scale (VAS) was used during walking, hip reaction, and resting to score and measure outcomes. 

Duration

December 21, 2021 to July 16, 2022 

Outcome Measures

Primary: pain while walking at postoperative week 1, as measured by VAS

Secondary: VAS score during walking, VAS score during hip flexion, and resting VAS score at 1, 2, and 3 days postoperatively and at 1, 2, 3, 6, and 12 weeks

Baseline Characteristics

  

Duloxetine (n= 34)

Placebo (n= 33)

Age, years (range)

 58 (28-79) 61 (38-78) 

Female (%)

 21 (61.8) 18 (54.5)  

Depressive symptoms

HAMD scores (range)

Prior diagnosis of depression (%)

History of antidepressants treatment (%)

History of psychotherapy treatment (%)

 

11.5 (9-13) 

4 (11.8)

2 (5.9)

3 (8.8 )

 

11 (9-14) 

2 (6.1)

1 (3.0)

1 (3.0)

VAS for knee

     With ambulation 

     With knee flexion 

     At rest

 

5.3 (3-8)

4.5 (2-8)

3.2 (1-5)

 

5.0 (3-8)

4.1 (1-7)

3.0 (1-6)

 

Endpoint

Duloxetine 

Placebo

p-Value

VAS pain score while walking (range)

1 d

2 d

3 d 

1 wk

2 wk

3 wk

6 wk

12 wk

 

6.4 (3-10)

5.3 (3-8)

4.0 (1-7) 

2.6 (1-7)

1.9 (0-5)

1.8 (0-5)

1.0 (0-3)

0.6 (0-3) 

 

6.6 (4-10)  

5.5 (3-8)

5.1 (2-9)

4.2 (1-7)

3.2 (1-6)

2.5 (1-6)

1.5 (0-3) 

1.0 (0-4)

 

NS

NS

0.003

< 0.001

0.001

0.031

NS

NS

VAS during hip flexion (range)

1 d

2 d

3 d 

1 wk

2 wk

3 wk

6 wk

12 wk

 

6.4 (3-9)

5.9 (3-8) 

4.1 (2-8) 

2.7 (1-6)

2.3 (0-5)

1.9 (0-5)

1.4 (0-4)

0.6 (0-2)

 

6.1 (3-9) 

5.6 (4-8)

5.2 (2-8)

3.9 (1-6)

3.3 (1-6) 

2.7 (1-6)

1.3 (0-4)

0.6 (0-2)

 

NS

NS

0.009

< 0.001

0.002

0.016

NS

NS

VAS while resting (range)

1 d

2 d

3 d 

1 wk

2 wk

3 wk

6 wk

12 wk

 

4.5 (2-8) 

4.0 (2-6)

2.4 (0-6)

1.8 (0-5)

1.4 (0-4)

1.0 (0-4)

0.7 (0-3) 

0.5 (0-2)

 

4.3 (2-7)

4.0 (2-7) 

3.4 (1-7)

2.5 (1-5)

2.1 (0-4) 

1.4 (0-3) 

0.8 (0-3) 

0.4 (0-2) 

 

NS

NS

0.004

0.002

0.003

NS

NS

NS

NS: not significant

Adverse Events

No significant adverse events were reported, potentially due to low clinical dosage utilized and short-term treatment duration

Study Author Conclusions

In conclusion, perioperative 7-day duloxetine administration decreased postoperative pain scores from day 3 to week 3, reduced morphine consumption, and improved hip function in patients who have depressive symptoms after THA. Incorporation of duloxetine into the current multimodal analgesic protocol in patients who have depressive symptoms may optimize postoperative pain control for this high-risk population. Further studies should focus on the optimal timing, dose, and duration of duloxetine administration. 

InpharmD Researcher Critique

The strict inclusion criteria make this study difficult to apply to real-world situations. Due to participants having baseline depression, it questions the validity of the results in patients that do not have depression. 



References:

Ding ZC, Li H, Huang C, et al. Significant Analgesic Benefits of Perioperative Duloxetine in Patients Who Have Depressive Symptoms Undergoing Total Hip Arthroplasty: A Randomized Controlled Trial. J Arthroplasty. 2023;38(3):519-524. doi:10.1016/j.arth.2022.10.007

 

Randomized Active-Controlled Study of a Single Preoperative Administration of Duloxetine to Treat Postoperative Pain and Numbness After Posterior Lumbar Interbody Fusion Surgery

Design

Single-center, prospective, randomized, double-blinded, active-controlled trial

N= 46

Objective

To assess whether a single preoperative administration of 40mg of duloxetine could decrease postoperative pain and numbness after posterior lumbar interbody fusion surgery (PLIF)

Study Groups

Duloxetine (n= 23)

Diazepam (n= 23)

Inclusion Criteria

Patients with an American Society of Anesthesiologists physical status I or II undergoing PLIF

Exclusion Criteria

Psychiatric disorders such as mania, bipolar disorder, depression, anxiety disorders, eating disorders, or a history of these disorders requiring medication within 1 year prior to enrollment; treatment with antidepressants such as amitriptyline or duloxetine that cannot be stopped for 2 weeks prior to surgery; treatment with opioids that cannot be stopped for 1 week prior to surgery; organic brain disorder, seizure disorder such as epilepsy, or history of these disorders; poorly controlled acute angle glaucoma; inability to understand the study protocol due to psychiatric disorders or dementia; serious cardiovascular (poorly controlled hypertension, history of myocardial infarction or angina, implanted pacemaker, moderate reduction of ejection fraction), hepatic (serum aspartate aminotransferase or alanine aminotransferase > 100 IU/L), renal (serum creatinine > 2mg/dL), respiratory (history of chronic obstructive pulmonary disease, poorly controlled asthma), or hematologic diseases (hemoglobin concentration < 9.5g/dL or platelet concentration < 75,000/ micro-L); excessive alcohol intake (average daily consumption > 60g of alcohol); history of hypersensitivity to duloxetine and diazepam; and treatment with MAO inhibitors and within 2 weeks of completion of treatment

Methods

Patients were randomly divided into two groups and received diazepam (4 mg, control) or duloxetine (40 mg) two hours before entering the operating room. 

Duration

N/A

Outcome Measures

Primary: postoperative pain at rest

Secondary: postoperative intravenous patient-controlled analgesia (PCA) fentanyl dose and request time; the administration rate of adjunctive analgesics; lower limb pain and numbness; and postoperative side effects according to the incidence of postoperative dizziness, nausea and vomiting, dry mouth, and confusion, compared with the control group

Baseline Characteristics

  

Diazepam (n= 18)

Duloxetine (n= 22)

  

Age, years

 67.2 61.8  

Female

44.4% 36.4%  

PLIF level (1/2)

 16/2 20/2   

Remifentanil, mg

 1.29 ± 0.44 1.51 ± 0.6  

Preoperative pain

Low back pain VAS

Low limb pain VAS

 

55.4

70

 

43

60

  

Abbreviations: VAS, Visual Analog Acale

Results

Endpoint

Diazepam (n= 18)

Duloxetine (n= 22)

p-value

Supplemental Drug Use

 44.4%  59.1%  0.638

The following data were presented as graph plots from which precise data was unretrievable:

  • The VAS score at rest in the lumbar region did not differ between the 2 groups (p= 0.192)
  • No significant difference was detected between the 2 groups for fentanyl use (p= 0.307, 0–48 hour)
  • No significant difference between the 2 groups for the request times for postoperative intravenous PCA fentanyl administration (p= 0.930, first request time, p= 0.831, second request time, P = 0.186, third request time)
  • The VAS score in the lower limbs at rest did not differ between the 2 groups (p= 0.139)
  • The numbness score in the lower limbs was significantly lower in the duloxetine group than in the diazepam group (p< 0.05 at 1, 3, 5, 18, and 51 hours after surgery)

Adverse Events

In the diazepam group, nausea was observed in 1 patient (5.6%, p= 0.450). There were no cases of confusion, dizziness, vomiting, or dry mouth.

Study Author Conclusions

In summary, a preoperative single administration of 40mg duloxetine did not improve postoperative PLIF pain and opioid use, but improved symptoms of lower limb numbness postoperatively. Duloxetine may reduce postoperative neuropathic pain-like symptoms after PLIF.

InpharmD Researcher Critique

The sample size was small which could have reduced the accuracy of the results. This study was done on posterior lumbar interbody fusion surgery so it is generalizable to only this patient population.



References:

Hiroki T, Fujita N, Suto T, et al. Randomized active-controlled study of a single preoperative administration of duloxetine to treat postoperative pain and numbness after posterior lumbar interbody fusion surgery. Medicine (Baltimore). 2022;101(50):e32306. doi:10.1097/MD.0000000000032306

 

Efficacy Of Duloxetine Compared With Opioid For Postoperative Pain Control Following Total Knee Arthroplasty

Design

Retrospective, single-center study

N= 290

Objective

To assess the efficacy of duloxetine as an alternative to opioid treatment for postoperative pain management following total knee arthroplasty (TKA)

Study Groups

Duloxetine (n= 118)

Opioid (n= 121)

Inclusion Criteria

Unilateral primary TKA with posterior-stabilized (PS) prosthesis, presence of moderate-to-severe pain at discharge (postoperative one week), no previous treatment with opioids or duloxetine

Exclusion Criteria

Diagnosis of osteonecrosis, inflammatory arthritis, traumatic osteoarthritis, flexion contracture greater than 20°, previous infection, or knee surgery on the operated knee

Methods

Patients received opioid (oxycodone/naloxone 10/5 mg) or duloxetine (30 mg daily) for pain control for 6 weeks when the pain Visual Analogue Scale (VAS) score was greater than 4 out of 10 at the time of discharge.

Duration

Surgery: January 2016 to June 2018

Outcome Measures

Primary: self-reported pain severity with ambulation (assessed using 10-point VAS score)

Secondary: pain at rest, pain at nighttime, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, patient-controlled analgesia (PCA) consumption, rate of further drug prescription (opioid or duloxetine), thirty-day readmission, and adverse events

Baseline Characteristics

 

Opioid (n= 121)

Duloxetine (n= 118)

p-value
Age, years

71.3 ± 7.2

70 ± 7

 0.181

Female

105 (86.8%)

98 (83.1%)

 0.472

Body mass index, kg/m2

26 ± 2.8

25.5 ± 3.4

0.2

ASA status

1

2

3

 

22 (18.2%)         

98 (81.0%)

1 (0.8%)

 

33 (28.0%)

82 (69.5%)

3 (2.5%)

0.101

Tourniquet time, minutes

44.8 ± 11.4

43.3 ± 10.8

 0.311

Results

Endpoint

Opioid (n= 121)

Duloxetine (n= 118)

p-Value

Pain on walking

Pre-operation

POD 6 weeks

POD 3 months

POD 6 months

POD 1 year

 

7.2 ± 1.0

3.5 ± 1.6

2.8 ± 1.4

2.2 ± 0.9

1.8 ± 1.2

 

7.1 ± 0.8

3.4 ± 1.5

2.7 ± 1.5

2.2 ± 0.8

1.9 ± 1.1

 

0.162

0.430

0.720

0.245

0.682

Pain during nighttime

Pre-operation

POD 6 weeks

POD 3 months

POD 6 months

POD 1 year


5.2 ± 1.6

3.5 ± 1.8

2.3 ± 1.6

1.5 ± 1.6

1.1 ± 1.1


5.3 ± 1.6

3.3 ± 1.6

2.3 ± 1.7

1.1 ± 1.4

0.9 ± 1.0


0.421

0.551

0.955

0.080

0.063

Pain at rest

Pre-operation

POD 6 weeks

POD 3 months

POD 6 months

POD 1 year


3.8 ± 1.7

1.8 ± 1.3

1.3 ± 1.3

1.1 ± 1.1

0.7 ± 0.8


3.6 ± 1.6

1.6 ± 1.2

1.3 ± 1.5

0.9 ± 0.9

0.6 ± 0.7


0.347

0.207

0.866

0.115

0.252

PCA consumption, mL

52.6

55.3

0.492

30-day readmission rate

1 (0.8%)

3 (2.5%)

> 0.05

WOMAC pain, stiffness, function, and total scores did not differ between groups (all p > 0.05).

Patients with hypertension or diabetes did not receive additional treatment or change treatment due to increased blood pressure or blood sugar by taking duloxetine.

POD, postoperative

Adverse Events

Common Adverse Events: nausea/vomiting (17.4% vs. 11.9%), constipation (13.2% vs. 11%), dizziness (17.4% vs. 16.1%), drowsiness (22.3% vs. 18.6%), headache (19% vs. 15.3%), dry mouth (22.3% vs. 21.2%)

Serious Adverse Events: Bleeding-related symptoms or hyponatremia after taking duloxetine were not observed.

Percentage that Discontinued due to Adverse Events: Two patients in the opioid group (nausea, vomiting, and drowsiness) vs. one patient in the duloxetine group (drowsiness)

Study Author Conclusions

Duloxetine and opioid did not show any difference in pain control, function, and side effects for up to one year after TKA. Although large-scale randomized controlled trials are still required to further confirm the side effects of duloxetine, it can be considered as an alternative to opioid for postoperative pain control following TKA.

InpharmD Researcher Critique

This study predominantly included a population of Korean female patients. Additionally, it was a retrospective study conducted in a single institution, making it difficult to control for confounding variables and selection bias, potentially limiting the internal and external validity of the study.

 

References:

Kim MS, Koh IJ, Choi KY, Yang SC, In Y. Efficacy of duloxetine compared with opioid for postoperative pain control following total knee arthroplasty. PLoS One. 2021;16(7):e0253641. Published 2021 Jul 2. doi:10.1371/journal.pone.0253641