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Abstract

Background: Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) with clinical efficacy in chronic pain conditions. In this study, we aim to evaluate the analgesic effect and safety of duloxetine in total knee arthroplasty (TKA). Methods: A systematic search was completed on MEDLINE, PsycINFO, and Embase from inception to December 2022 to find relevant articles. We used Cochrane methodology to evaluate the bias of included studies. Investigated outcomes included postoperative pain, opioid consumption, adverse events (AEs), range of motion (ROM), emotional and physical function, patient satisfaction, patient-controlled analgesia (PCA), knee-specific outcomes, wound complications, skin temperature, inflammatory markers, length of stay, and incidence of manipulations. Results: Nine articles involving 942 participants were included in our systematic review. Out of nine papers, eight were randomized clinical trials and one was a retrospective study. The results of these studies indicated the analgesic effect of duloxetine on postoperative pain, which was measured using numeric rating scale and visual analogue scale. Deluxetine was also effective in reducing the morphine requirement and wound complications and enhancing patient satisfaction after surgery. However, the results on ROM, PCA, and knee-specific outcomes were contraventional. Deluxetine was generally safe without serious AEs. The most common AEs included headache, nausea, vomiting, dry mouth, and constipation. Conclusion: Duloxetine may be an effective treatment option for postoperative pain following TKA, but further rigorously designed and well-controlled randomized trials are required.

Keywords

total knee arthroplasty duloxetine systematic review postoperative pain safety

Introduction

Total knee arthroplasty (TKA) is a well-established and effective surgical treatment for severe osteoarthritis (OA) and rheumatoid arthritis (RA).¹ TKA is one of the most common orthopedic surgery procedures use to relieve pain, improve function, and patient quality of life.² The demand for TKA is estimated to increase by 673% to 3.48 million procedures annually by 2030.³ Postoperative pain is common following TKA, with 30% and 60% of patients experiencing moderate and severe pain after surgery, respectively.⁴ Moreover, up to 34% of patients suffer from chronic residual pain.⁵ Many patients may even postpone this procedure out of concern for the intense postoperative pain.⁶ Postoperative pain after TKA also impairs early ambulation and range of motion (ROM), increases the risk of thrombosis, and has an impact on rehabilitation process, patient quality of life and satisfaction, functioning, and overall results.^7,8

The high rate of pain following this procedure must therefore be considered a significant issue. As a result, there is growing interest in efficient approaches for management of postoperative pain to minimize opioid usage and side effects. Duloxetine (Cymbalta) is a norepinephrine reuptake inhibitor (SNRI) that has been widely used for major depressive disorder, anxiety disorders, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain.^9,10 Duloxetine inhibits serotonin and norepinephrine reuptake and modulates the descending inhibitory pain pathways in the central nervous system (CNS).¹¹ Duloxetine’s analgesic efficacy in individuals with centrally mediated musculoskeletal pain, particularly pain caused by chronic knee OA, has been extensively established.¹² A meta-analysis indicated that duloxetine has a statistically significant effect on pain, function, and quality of life in patients with knee OA.¹³ The analgesic effect of duloxetine is similar in both depressed and non-depressed individuals and is independent of its antidepressant effect.¹⁴

Duloxetine has shown effectiveness in four different chronic pain conditions including diabetic peripheral neuropathy pain, fibromyalgia, chronic low back pain, and OA pain. Several clinical trials have compared the efficacy and safety of duloxetine with placebo for TKA postoperative pain.^14–16 However, the use of duloxetine for postoperative pain relief remains controversial.^9,13,15,16 A systematic review is required to evaluate the efficacy of duloxetine in TKA since the current studies do not allow for the development of a definite conclusion. Additionally, there is not enough evidence to explain how duloxetine affects postoperative pain after TKA. In this paper, we aim to evaluate the efficacy of duloxetine on pain following TKA. We will also evaluate its effect on morphine consumption as a secondary outcome.

Method

Literature search and selection criteria

A systematic search was conducted on three databases, MEDLINE, PsycINFO, and Embase, through OVID from inception to December 2022. We followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for this systematic review.¹⁷ Relevant studies were identified by searching the following keywords: duloxetine, total knee arthroplasty, TKA, total knee replacement. We also examined the reference lists of all included articles and Google Scholar to avoid missing relevant articles. There were no restrictions on publication date and status. We applied the following inclusion criteria for the search and study selection: (1) Original studies that used duloxetine. (2) In patients that underwent TKA. (3) Assessed pain as primary outcome. (4) Full papers published in English. Systematic reviews, narrative reviews, meta-analysis, studies using the same dataset, letter to editor, commentaries, animal studies, case resort, case series, conference abstracts and guidelines were excluded.

Study selection

Two reviewers (EK, SM) independently evaluated title/abstract and full-text of articles collected from the electronic search according to inclusion and exclusion criteria in order to identify potentially eligible papers. Discussion was used to settle disagreements between the two reviewers. If the full text was not available, it was requested from the authors online.

Data extraction

Two reviewers (EK, SM) independently received the full-texts of eligible studies and extracted the following data from each article: name of first author, publication year, country, study design, intervention, treatment duration, limitations, participants, inclusion criteria, study results, protocol, primary outcome, adverse events (AE).

Outcome definition

The primary outcome of our review was the effect of duloxetine on postoperative pain which was assessed by validated scales and collected as mean change from baseline to study follow-ups. We also examined secondary outcomes of included studies such as ROM, emotional and physical function, patient satisfaction, patient-controlled analgesia (PCA), opioid consumption, knee-specific outcomes, wound complications, skin temperature, inflammatory markers, length of stay, AEs and incidence of manipulations. Participants who discontinued study medication or terminated participation in the trial due to an AE, regardless of its association with the study medication, were included in the discontinuations due to AEs. Treatment-emergent adverse events (TEAEs) were defined as any AE that occurred after the study medication was started; these events could or may not be related to the study medication. Serious adverse events (SAEs) were precisely defined as incidents that were officially categorized as “SAEs” by study personnel within the research’s term.

Quality assessment

Bias of randomized clinical trials (RCTs) was examined using the Cochrane Collaboration’s tool based on the following five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, bias in selection of the reported result, and other bias. This was completed in accordance with the guidelines in the Cochrane Handbook for Systematic Review of Interventions.¹⁸ If the specified protocols raised concerns about bias in more than one domain, the risk of bias was categorized as high. If a suitable methodology was defined for a certain area, it would be marked “low risk” (Table 1).

Table 1.

Risk of bias assessment for RCTs – Cochrane RoB results.

	Bias arising from the randomization process	Bias due to deviations from intended intervention	Bias due to missing outcome data	Bias in the measurement of the outcome	Bias in selection of the reported result
Kim et al. 2021	Some concerns	Low	Low	Low	Low
Rienstra et al. 2021	Low	Low	Low	Low	Low
YaDeau et al. 2022	Low	Low	Low	Low	Low
YaDeau et al. 2016	Low	Low	Low	Low	Some concerns
Ho et al. 2010	Low	Low	Low	Low	Some concerns
Yuan et al. 2022	Low	Low	Low	Low	Low
Wang et al. 2020	Some concerns	Low	Low	Low	Some concerns
Koh et al. 2019	Low	Low	Low	Low	Some concerns

Results

Search result

The systematic search resulted in 13 records. We also found 6 records through manual search of relevant studies. Out of 19 records, we excluded 8 records based on title/abstract screening. We reviewed the full texts of the remaining 11 papers in accordance with our inclusion criteria. After assessing the full texts, another two studies were excluded due to wrong outcome/population. Finally, nine articles including 942 individuals (470 in duloxetine group, 472 in control group) were included in this systematic review. Out of nine included studies, eight articles were RCTs and one was a retrospective study. The characteristics of the included studies are listed in Table 2. The study selection details are indicated in Figure 1.

Table 2.

Study demographics.

Author	Country	Study design	Treatment duration	Participants	Inclusion criteria	Intervention	Protocol	Primary outcome	Result	Limitations	Adverse events
Koh et al. 2019	Korea	RCT	6 weeks	Duloxetine group = 40 Control group = 40	Ages >18 years, TKA due to osteoarthritis, ASA class of I, II, or III	30 mg of oral duloxetine on the night before surgery and 30 mg daily	VAS scores were recorded on postoperative days 1, 3, and 5 and at postoperative weeks 1, 2, 6, and 12. BPI were assessed at postoperative weeks 1, 2, 6, and 12	VAS, BPI	Significantly better VAS and BPI score in follow up visits in the duloxetine group compared with the control group	Lack of placebo Small sample size	No significant difference between groups
Kim et al. 2021	Korea	Retrospective	6 weeks	Duloxetine group = 118 Opioid group = 121	VAS score more than 4 at discharger, no history of duloxetine or opioid use	Daily oxycodone/naloxone 10/5.0 mg or duloxetine 30 mg for 6 weeks at the time of discharge	VAS was assessed 6 weeks, 3 months, 6 months, and 1 year after	VAS	No significant difference in opioid and duloxetine groups	Most patients were women Retrospective comparative study based on the database of one institution	No significant difference between groups
Kim et al. 2021	Korea	RCT	10 weeks	Duloxetine group = 19 Placebo group = 20	TKA due to osteoarthritis, ASA class of I, II, or III	Duloxetine 30 mg or placebo from 2 weeks before surgery till 8 weeks after	VAS preoperatively; 1, 3, 5, and 7 days postoperative; and 2, 6, and 12 weeks postoperative BPI preoperatively and at 2, 6, and 12 weeks after surgery	VAS, BPI	Significantly better VAS and BPI score in follow up visits in the duloxetine group compared with the placebo group	Pain reduction immediately after surgery in terms of not having enough duloxetine administered before surgery	No significant difference between groups
Rienstra et al. 2021	Netherlands	RCT	10 weeks	Duloxetine group = 57 Control group = 54	TKA due to osteoarthritis, m-PDQ scores >12	Duloxetine 60 mg/day for 10 weeks	Measure was done 6 weeks, 6 and 12 months after arthroplasty	KOOS, HOOS	No significant difference in control and duloxetine groups	Placebo and nocebo effects Lack of blinding	12 patients from the intervention group (21%) discontinued duloxetine due to adverse effects
Yuan et al. 2022	China	RCT	17 days	Duloxetine group = 50 Placebo group = 50	TKA due to osteoarthritis	Duloxetine 60 mg or placebo daily from preoperative day 2 till postoperative day 14	VAS was measured 2, 4, 6, 24, 36, and 48 h, 2 to 7, 3 weeks and 3 months after surgery	VAS	VAS in the duloxetine group were significantly less than the placebo group throughout the postoperative period	Small sample size	Siginicalty higher incidence of drowsiness in duloxetine group
YaDeau et al. 2022	USA	RCT	14 days	Duloxetine group = 80 Placebo group = 80	Age 25–75 years	Duloxetine 60 mg or placebo daily from day of the surgery till day 14	NRS was measured 1, 2, 14 days after surgery	NRS	Duloxetine was noninferior to placebo for both primary outcomes (pain and opioid consumption) and was superior to placebo for opioid consumption	High rates of patient exclusions and refusal to enter the study	Siginicalty higher incidence of headache in duloxetine group
YaDeau et al. 2016	USA	RCT	15 days	Duloxetine group = 53 Placebo group = 53	Age 25–75 years	Duloxetine 60 mg or placebo daily for 15 days	NRS was measured 14 days after surgery	NRS	No significant difference in NRS scores	Reduced generalizability	No significant difference between groups
Ho et al. 2010	Singapore	RCT	2 days	Duloxetine group = 23 Placebo group = 24	Age 18–70 years, ASA class of I, II, or III	Duloxetine 60 mg or placebo 2 h before surgery and on the morning of the first postoperative day	Total morphine requirements at 24 h, 48 h after surgery	Morphine requirement	Morphine requirement was significantly lower in the duloxetine group	Both GA and RA anesthesia were included	No significant difference between groups
Wang et al. 2020	China	RCT	NR	Duloxetine group = 30 Celecoxib group = 30	Unilateral osteoarthritis who were eligible for initial total knee replacement surgery	Deluxetine 30 mg/bid or celecoxib 200 mg/bid	VAS scores on walking were recorded on postoperative day three and postoperatively at weeks one, two and four	VAS	VAS score on postoperative day three was not significantly different, but there were significant differences between the two groups at one, two and 4 weeks	Short follow-up	No significant difference between groups

ASA: American society of anesthesiologists; BPI: brief pain inventory; VAS: visual analogue scale; RCT: randomized controlled trial; KOOS: knee injury and osteoarthritis outcome score; HOOS: osteoarthritis outcome score; m-PDQ: modified pain detect questionnaire; NRS: numeric rating scale; GA: general anesthesia; RA: regional anesthesia.

Figure 1.

PRISMA flowchart of the literature search and selection of the articles.

Pain

Pain was evaluated in all included studies. Kim et al. (2021) conducted an RCT to evaluate the effect of duloxetine on postoperative pain following TKA. Patients were randomly assigned to the duloxetine (n = 19) or placebo groups (n = 20). Patients in the duloxetine group were given 30 mg of duloxetine daily from 2 weeks before to 8 weeks after surgery. The visual analog scale (VAS) was measured at rest, walking, and nighttime on 1, 3, 5, and 7 days, as well as at 2, 6, and 12 weeks postoperatively. Brief Pain Inventory (BPI) was evaluated 2, 6, and 12 weeks after surgery. The results of this study indicated that the duloxetine group had significantly lower rest, walking, nighttime, and average VAS pain scores than the placebo group at weeks 1, 2, and 6 after surgery (all p < 0.05). In terms of the emotional and activity subdimensions of BPI interference, the duloxetine group outperformed the placebo group 2, 6, and 12 weeks after surgery (all p < 0.05).¹⁹ In another RCT by Rienstra et al. (2021) the effect of duloxetine on chronic residual pain after TKA was evaluated. Patients were randomly assigned to receive 60 mg daily of duloxetine (n = 57) or placebo (n = 54) for a total of 10 weeks. Chronic residual pain was evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) or the Hip Disability and Osteoarthritis Outcome Score (HOOS), 6 weeks, 6 months, and 12 months after surgery. Secondary outcomes included neuropathic-like pain assessed using the PainDETECT-Questionnaire (m-PDQ) and VAS 6 months after surgery. The results of this study indicated no significant difference in HOOS/KOOS, VAS, and m-PDQ scores between placebo and duloxetine groups across all time points (all p > 0.05).²⁰

YaDeau et al. (2022) conducted a triple-blind RCT in which patients were randomly assigned to receive 60 mg of duloxetine daily (n = 80) or placebo (n = 80) for 14 days. The numeric rating scale (NRS) at rest and with movement was assessed on days 1, 2, and 14. Patients who received duloxetine had a significantly lower NRS score with movement on days 1, 2, and 14 in comparison with placebo (p < 0.01). However, the NRS score at rest on days 1, 2, and 14 was not significantly different (p > 0.05). Furthermore, neuropathic pain, which was defined as scores higher than 19 on painDETECT, was not significantly different between the groups (p = 0.23). On day 14, the median BPI summary interference scores were 2.3 (1.1, 4.7) versus 4.1 (2.3, 5.9) in duloxetine and placebo groups (p = 0.015). For all seven categories, statistical significance was achieved.²¹ In another RCT by YaDeau et al. (2016) patients were randomized to receive either duloxetine (60 mg orally daily for 15 days, n = 53) or placebo (n = 53). The primary outcome of this study was changes in NRS from day 1 till week 6. The results of this trial indicated that NRS pain scores with ambulation, flexion, and at rest did not significantly differ between groups over the postoperative period (Day 1 through 6 weeks postoperatively; p > 0.05). Furthermore, chronic pain, which was measured with painDETECT, was not significantly different between groups (p > 0.05).²²

Ho et al. (2010) evaluated the effect of two doses of oral duloxetine 60 mg on postoperative pain in patients who underwent TKA. Patients received two doses of duloxetine (n = 23) or placebo (n = 24) 2 hours before surgery and on the first day after surgery. NRS at rest and during movement were recorded 0.5, 1, 2, 6, 12, 24, and 48 hours after surgery. At all time points, there were no statistically significant differences in the pain scores between the placebo and duloxetine groups.²³ Furthermore, Yuan et al. (2022) conducted an RCT and assigned patients to 60 mg duloxetine (n = 50) or placebo (n = 50) groups for a total of 17 days. The primary outcome of this trial was VAS score at rest and upon ambulation, which was collected preoperatively and 2, 4, 6, 24, 36, and 48 hours after surgery. Throughout the postoperative period, the VAS score at rest in the duloxetine group was significantly lower than the placebo group (4.7 vs 5.9, p = 0.016, at 24 hours postoperative; 2.1 vs 2.8, p = 0.037, at 7 days postoperative). In terms of VAS upon ambulation, the duloxetine group continuously had a lower VAS score than the placebo group (6.2 vs 7.1, p = 0.039, at 24 hours postoperatively; 3.3 vs 4.1, p = 0.034, at 7 days postoperatively).²⁴

In an RCT by Koh et al. (2019) patients received duloxetine 30 mg daily (n = 40) or placebo (n = 40) for 6 weeks. The primary outcomes of this trial were VAS and BPI scores. VAS scores at walking, rest, and night were collected on days 1, 3, and 5 postoperatively and 1, 2, 6, and 12 weeks postoperatively. 6 and 12 weeks after surgery, BPI and VAS scores at walking, rest, and night were significantly lower in the duloxetine group (all p < 0.01).²⁵ Moreover, Kim et al. (2021) performed a retrospective study to compare the efficacy of duloxetine with opioids on postoperative pain following TKA. Patients who had moderate to severe pain (VAS score more than 4) were included and prescribed duloxetine or oxycodone/naloxone for 6 weeks after discharge. 118 patients received duloxetine 30 mg daily, and 121 patients received oxycodone/naloxone 10/5.0 mg. The primary outcome of this study was VAS score at rest, walking, and night 6 weeks, 3 months, and 6 months after surgery. Both groups had similar VAS scores at all follow-up timepoints (p > 0.05).²⁶

Finally, Wang et al. (2020) conducted an RCT to evaluate the efficacy of duloxetine in comparison with celecoxib on postoperative pain. Patients were randomized to duloxetine 30 mg/bid (n = 30) or celecoxib 200 mg/bid groups (n = 30). The primary outcome of this study was changes in VAS score during walking, which were measured preoperatively and day 3, weeks 1, 2, and 4 postoperatively. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score was also recorded 1 and 4 weeks after surgery. The results of this study indicated no significant differences in VAS score on day 3 postoperatively; however, 1, 2 and 4 weeks after surgery, the duloxetine group had significantly lower VAS scores (p < 0.05). In addition, the WOMAC score was lower in the duloxetine group at all follow-up time points (all p < 0.05).²⁷

Range of motion

The effect of duloxetine on ROM was evaluated in three studies. In an RCT by Kim et al. (2021) ROM was evaluated using a standard 60 cm goniometer 1, 2, 6, and 12 weeks after surgery. ROM was not significantly different between the duloxetine and placebo groups across all follow-up timepoints (all p > 0.0125).¹⁹ Furthermore, Yuan et al. (2022) recorded ROM 6, 24, 36, 48 hours, 2–7 days, 3 weeks, and 3 months after surgery. Active ROM was significantly better in the duloxetine group until 6 days after surgery and became insignificant after (p = 0.211). Moreover, patients in the deluxetine group had significantly better passive ROM until day 5, and then the difference became insignificant (p = 0.064).²⁴ In another study by Kim et al. (2021) ROM 6 weeks, 3 months, and 6 months after surgery was not significantly different between the opioid and duloxetine groups (all p > 0.05).²⁶

Emotional and physical function

Koh et al. (2019) measured emotional function by affective subdimension of the reactive dimension of the BPI, mental component summary (MCS) score of the Short Form-36 (SF36), knee version of the Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP) scale 28, and Hamilton Depression Scale. Physical function was measured by reactive dimension of the BPI and the physical component summary (PCS) score of the SF-36. Emotional and physical function were evaluated 6 and 12 weeks after surgery. Emotional and physical functions were significantly improved in the deluxetine group compared with the placebo group across all test scores (p < 0.01).²⁵

Patients satisfaction

Patients satisfaction was evaluated in one study. The results of this study indicated that duloxetine significantly improves patients satisfaction. Median [Q1, Q3] satisfaction with pain management was 10 vs 8 (duloxetine vs placebo; p = 0.046).²¹

Patient-controlled analgesia

In an RCT by Kim et al. (2021) PCA consumption was significantly lower in the duloxetine group (61.0 mL vs. 84.9 mL, p = 0.019).¹⁹ However, in Koh et al. (2019) (p = 0.557) and Kim et al. (2021) (52.6 ml in the opioid group and 55.3 ml in the duloxetine group, p = 0.492) studies, there were no significant differences.^25,26

Opioid consumption

Opioid consumption was evaluated in four studies. In a study by YaDeau et al. (2022) opioid consumption was significantly lower in the deluxetine group (288 ± 226 mg) compared to the placebo group (432.5 ± 374 mg) (p < 0.001).²¹ In another study by YaDeau et al. (2016) opioid consumption was significantly reduced in the duloxetine group over the postoperative period (day of surgery through 3 months postoperatively, p = 0.002).²² Moreover, the primary outcome of Ho et al. (2010) study was morphine requirements 48 hours after surgery. The morphine requirement after 24 hours of surgery was 12.9 mg in the duloxetine group and 19.8 mg in the placebo group (p = 0.039). Also, 48 hours after surgery, the duloxetine group’s total morphine requirement was significantly lower (19.5 mg) than that of the placebo group (30.3 mg) (p = 0.017).²³ Yuan et al. (2022) collected data on opioid consumption every day from the day of surgery to postoperative day 7. Opioid consumption per day was significantly lower in the duloxetine group than the placebo group (24.2 ± 10.1 g vs. 28.5 ± 8.3 g, p = 0.022, at 24 hours postoperatively; 2.7 ± 2.5 g vs. 4.1 ± 2.6 g, p = 0.007, at 7 days postoperatively).²⁴

Knee-specific outcomes

Knee-specific outcomes were evaluated in two studies by YaDeau et al. The outcomes of YaDeau et al. (2022), which included the KOOS Jr score and worst knee pain in the past week (0–10), were evaluated before and 3 weeks and 6 months after surgery. The outcomes were significantly different in patients that received duloxetine compared with placebo at 3 months follow-up time point (KOOS Jr score, duloxetine 76 ± 12 vs placebo 71 ± 12, p = 0.02, worst knee pain in past week, duloxetine 1.7 ± 1.5 vs placebo 2.7 ± 2.1, p = 0.02).²¹ Furthermore, YaDeau et al. (2016) evaluated the Knee Society Score 6 weeks after surgery, which was not significantly different between the placebo and duloxetine groups (p > 0.05).²²

Wound complications

Wound complications were evaluated in Kim et al. (2021) study and were defined as additional treatment or procedure during the first 12 weeks after surgery. Cosmetic surgical wound evaluation was also completed using the Vancouver Scar Scale (VSS) 12 weeks after surgery. The results of this study showed no significant difference in wound complications rate and VSS score between duloxetine and placebo groups (all p > 0.05). However, the duloxetine group had lower rates of wound complications.¹⁹

Skin temperature

Kim et al. (2021) evaluated skin temperature at the center of patella 2, 6, and 12 weeks postoperatively. Before surgery, there was no difference in wound temperature measured using a thermal imaging camera between the two groups (p > 0.05); however, 2, 6, and 12 weeks following surgery, the duloxetine group had significantly lower skin temperature than the control group (all p < 0.05).¹⁹

Inflammatory markers

C-reactive protein (CRP) levels CRP was evaluated in Kim et al. (2021) study preoperatively and 2 and 6 weeks after surgery. CRP levels were not significantly different between duloxetine and placebo groups across all follow-up follow-up time points (all p > 0.05).¹⁹

Length of stay

Two studies evaluated the effect of duloxetine on length of stay. Length of stay was not significantly different in patients that received duloxetine in comparison with placebo in both studies (p = 0.35, p = 0.46).^21,22

Adverse events

In Kim et al., (2021) YaDeau et al., (2016) Ho et al., (2010) Yuan et al., (2022) Koh et al., (2019) Kim et al., (2021) Wang et al. (2020) studies, there was no significant difference in AEs between the duloxetine and placebo group (p > 0.05). However, constipation, dry mouth, nausea and vomiting were more frequently reported in the duloxetine group.^19,22–27 In Rienstra et al. (2021) RCT, 12 patients in the deluxetine group discontinued the trial due to AEs. However, three of these patients’ AEs were not related to duloxetine, and nine patients were lost to follow-up.²⁰ Moreover, in the YaDeau et al. (2022) study, patients in the duloxetine group had a significantly higher incidence of headache in comparison with the placebo group (12 vs 4, p = 0.03).²¹ Serious AEs were not reported in any of these studies.

Incidence of manipulations

YaDeau et al. (2016) evaluated incidence of manipulations in duloxetine and placebo groups. The results of this study indicated no significant difference between duloxetine and placebo groups (4 vs 1, p = 0.363).²²

Discussion

We systematically identified, reviewed, and evaluated nine published studies which investigated the efficacy of duloxetine on postoperative pain following TKA. The analgesic effect of duloxetine was demonstrated in pain outcomes assessed by NRS, VRS, opioid consumption, PCA demand across included studies. We also found that duloxetine may have a positive impact on patients satisfaction, emotional and physical functions. Despite the potential benefits of duloxetine, reported incidences of headache, constipation, dry mouth, and nausea/vomiting were higher in participants who received the duloxetine versus placebo. The results of our review are consistent with previous meta-analyses and reviews that evaluated duloxetine’s efficacy on OA, chronic low back pain, and elective orthopedic surgeries.^13,28–30 Previous meta-analyses and reviews have reported statistically significant benefits of duloxetine on pain. Deluxetine has also been found to be effective in treating the painful symptoms of patients with depression, chemotherapy-induced painful peripheral neuropathy, and the primary pain symptoms of Parkinson’s disease.^31–34

Patients with OA or RA that may require TKA have significant changes in the structure of the joint and biochemical environment around peripheral joint nociceptors.³⁵ These changes can lead to peripheral nerve hyperexcitability and CNS sensitization, which can cause pain.³⁶ Further studies revealed that the dysfunction of the endogenous pain pathway, in which serotonin and noradrenaline play a crucial modulatory role, is linked to the enhanced reactivity of nociceptive neurons in the CNS.^37,38 Duloxetine activates opioid receptors and promotes the inhibitory activity of the endogenous pain pathway in the descending spinal cord by inhibiting serotonin and noradrenaline reuptake, which explains its direct analgesic action rather than mood modulation.^39,40 Besides, the antidepressant effect of duloxetine may upregulate patient pain threshold and emotional experience.³² It should be noted that all included studies excluded patients with a history of mood disorders, such as depression, to minimize the antidepressant effect of duloxetine.

Duloxetine’s safety has been well established in clinical studies involving over 32,000 participants across a variety of indications. Duloxetine has been used to treat over 530,000 individuals worldwide, suggesting that it is safe, well tolerated, and effective.⁴¹ A retrospective study of various ethnic groups, including Caucasians, Hispanics, Asians, and Blacks, revealed that duloxetine is safe in all ethnic groups.⁴² In terms of safety, we didn’t find a significant difference in rates of AEs between placebo and duloxetine in the included studies. The most commonly reported AEs were headache, nausea, vomiting, constipation, and dry mouth. These common AEs were mild to moderate in intensity, as indicated in these studies. The data also suggests that nausea, one of the most frequent AEs, would lessen when duloxetine was taken with meals or when it was started at a lower dose. These adverse effects also appeared early in the treatment period and subsequently gradually decreased in incidence. The results of our systematic review are consistent with previous reviews that demonstrated the safety profile of duloxetine.^13,28,29

Opioid consumption, which has a different function from VAS and NRS, is an indicator of postoperative pain. Opioids act as a remedial treatment and are administered when patients suffer from severe pain. In fact, patients fulminant pain is reflected in their opioid consumption. In our study, duloxetine significantly reduced opioid consumption across included studies. A reduced need for opioid analgesia is clinically significant for various reasons. Opioids are linked with postoperative complications such as hypoventilation, ileus, urine retention, nausea, and vomiting.⁴³ Other issues raised in the studies include a greatly increased risk of dependency, which can appear as early as 3 days post operation, and a significantly increased risk of mortality in the first 30 days after surgery.⁴⁴ Additionally, the use of opioids may prevent the body from producing its own opioids, which elongates and worsens postoperative pain.⁴⁵ Taken together, duloxetine is an effective way to relieve fulminant pain after TKA, and it acts quickly after application. Future RCTs should compare duloxetine to other oral drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), and determine duloxetine’s long-term safety and appropriate dose.

To our knowledge, the present study is one the most comprehensive reviews designed in a systematic manner to investigate the efficacy of duloxetine on postoperative pain following TKA. Notwithstanding, there are limitations that may affect the interpretation of our results. Firstly, the number of included studies and sample sizes were small. Also, pain and its understanding are subjective, vary from individual to individual, and are impacted by a person’s culture, experiences, age, gender, and ethnicity.⁴⁶ Variations in the type of surgery, anesthesia, and multimodal analgesia regimen are also important. In our review, the treatment strategy and baseline characteristics of patients were not similar across studies, which may influence the results. Finally, due to the heterogeneity of studies and insufficient data, a meta analysis was not possible.

In conclusion, duloxetine is a safe and effective analgesic method for controlling pain in patients that undergo TKA. Before starting treatment with duloxetine, physicians’ judgment and patient preferences must be taken into account.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Emad Kouhestani

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