Pain Medicine 2015; 16: 1373–1385 Wiley Periodicals, Inc.
MUSCULOSKELETAL SECTION Original Research Article Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain: A Meta-Analysis of Randomized Controlled Trials
*Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China; †Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China; ‡Department of Pharmacy, Yue Bei People’s Hospital, Shantou University, Shaoguan, 512026, China; §Pharmaceutical Research & Development, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China Reprint request to: S. Y. Shi, Department of Pharmacy, Zhujiang Hospital, No.253, Industrial Road, Haizhu District, Guangzhou, Guangdong, China. Tel.: 18819312747; Fax: 186 20 61643010; E-mail: [email protected] or J. M. Lin, Pharmaceutical Research & Development, Zhujiang Hospital, No.253, Industrial Road, Haizhu District, Guangzhou, Guangdong, China. Tel.: 186 20 61643557; Fax: 186 20 61643010; E-mail: [email protected]. Conflict of interest: We have no conflicts of interest to declare. Authors Z. Y. Wang and S. Y. Shi contributed equally to this work. Author Contributions: Shengying Shi: data collection, data analysis/interpretation, drafting article, statistics; Zhaoyu Wang: concept, design, critical revision of article, approval of article; Jingming Lin: concept, design; F. Chen: critical revision of article, approval of
article; Shujie Li: data collection; H Chen and Haizhen Lin: assessed original text. Funding sources: Supported by Science and Technology Planning Project of Guangdong Province, China (2011B031700002, 2012A030100008), Supported by Natural Science Foundation of Guangdong Province, China (S2013010014796).
Abstract Objectives. The aim of this meta-analysis was to evaluate the efficacy and safety of duloxetine for management of osteoarthritis knee (OAK) pain. Methods. A systematic literature search of articles for management of OAK using duloxetine were performed in PubMed, EBSCO, EMBASE, ScienceDirect, MEDLINE, ClinicalTrials.gov, Google Scholar, and Cochrane Central Register of Controlled Trials from the available date of inception until the latest issue (October 2013). Potentially relevant randomized controlled trials (RCTs) regarding to comparison of efficacy and safety of duloxetine with placebo for managing OAK pain were included. Also, studies with specific data regarding to pain reductions and response rate, Patient Global Impression of Improvement (PGI-I), functional improvement, Western Ontario and McMaster Osteoarthritis Index (WOMAC), adverse events (AEs), treatment-emergent AEs (TEAEs), mortality were included and analyzed, and those with confounding conditions were excluded. Studies were assessed for quality using the Jadad five-point score for RCTs. Finally, a meta-analysis of all RCTs eligible for inclusion criteria was performed using Review Manager 5.1 meta-analysis software.
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Zhao Yu Wang,* Sheng Ying Shi,† Shu Jie Li,† Feng Chen,‡ Huang Chen,* Hai Zhen Lin,† and Jing Ming Lin§
Wang et al.
Conclusion. This analysis suggests duloxetine (60/ 120 mg quaque die (QD)), compared with placebo control, resulted in a greater reduction in pain, improved function and patient-rated impression of improvement, and acceptable adverse effects for the treatment of OAK pain after approximately 10 213 weeks of treatment. Key Words. Duloxetine; Osteoarthritis Knee Pain; Meta-Analysis; Randomized Controlled Trials
include weight loss, aerobic, and/or muscle strengthening exercises. Pharmacological management guidelines have recommended acetaminophen for first-line use, with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids as second and third lines of treatment [10–14]. However, reservations have been expressed concerning their long-term safety and efficacy, which are associated with potential use-limiting risks or side effects such as gastrointestinal bleeding, peptic ulcer disease, nephrotoxicity, and serious long term cardiovascular effects (NSAIDs) and risks of sedation, respiratory depression, overdose, misuse, or dependency (opioids) [15]. Duloxetine, a newly available treatment option in the United States, is a potent and selective inhibitor of 5-HT and NE reuptake (SNRI) in vitro and in vivo in the central nervous system (CNS). As the discovery of imbalance of serotonin and norepinephrine systems within central pain pathways have been implicated in the development and maintenance of central sensitization and associated chronic pain states [16,17] and chronic pain associated with osteoarthritis involves dysfunction of central pain pathways [18,19], duloxetine has been used to manage chronic pains such as OAK [20,21]. Several clinical trials comparing the efficacy and safety of duloxetine with placebo for OAK pain have been conducted and duloxetine has demonstrated efficacy in four distinct chronic pain conditions: diabetic peripheral neuropathic pain [22,23], fibromyalgia [24,25], chronic low back pain [26,27], and OAK pain [28–33]. While prior studies established the superiority of duloxetine relative to placebo in the aforementioned diseases, we conducted a systematic literature review followed by a meta-analysis to assess the efficacy and safety of duloxetine vs placebo as to address the clinical significance of those findings. To accomplish that, we applied the criteria of clinical significance in chronic pain trials, which include pain intensity, response, physical functioning, and patients’ ratings of overall improvement. Methods
Introduction Search Strategy Osteoarthritis of the knee (OAK) is the most common form of arthritis in older individuals and it is among the most prevalent and disabling chronic conditions worldwide [1]. OAK occurs when the protective cartilage on the ends of the bones wears down over time, and osteoarthritis often gradually worsens, which decreases overall quality of life [2], increases risk of depression and anxiety [3,4]. The lifetime risk of OAK is 44.7% among general population, but the prevalence increases with age, in females and obese population [5–7]. Also, pain is the chief complaints in OAK patients and brings patients to seek medical attention on most circumstances [8]. Therefore, in terms of clinical management, pain reduction and functional improvement are of paramount importance in the treatment of OKA [9]. To manage chronic pain, current guidelines recommend a combination of nonpharmacological and pharmacological therapies. Nonpharmacological managements of OAK 1374
We searched the following electronic databases for the identification of trials using the terms “duloxetine” or “Cymbalta” vs “osteoarthritis knee pain,” “osteoarthritis of the knee,” “knee pain due to osteoarthritis”: PubMed, EBSCO, EMBASE, ScienceDirect, MEDLINE, ClinicalTrials.gov, Google Scholar, and Cochrane Central Register of Controlled Trials. All databases were searched from the available date of inception until the latest issue (October 2013). Only English publications were included. In addition, the references of retrieved articles were examined to find additional articles relevant to the content of our meta-analysis. Selection Criteria Studies were selected for analysis if they met the following criteria: 1) Eligibility was limited to randomized
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Results. Three RCTs that enrolled 1,011 patients were included in our meta-analysis. There were statistically significant differences between patients taking duloxetine and those taking placebo with regard to the reductions in pain intensity (992 patients, mean difference [MD] 5 20.88, 95% confidence interval [CI] 21.11–20.65, P < 0.0001), a moderate improvement in pain intensity (>= 30% response rate; 989 patients, risk ratio [RR] 5 1.49, 95% CI 1.31–1.70, P < 0.0001), a substantial improvement in pain intensity (>=50% response rate; 989 patients, RR 5 1.69, 95% CI 1.27–2.25, P 5 0.0004). Statistically significant differences in PGI-I (976 patients, MD 5 20.47, 95% CI 20.63 to 20.30, P < 0.0001) and WOMAC—physical function subscale (977 patients, MD 5 24.25, 95% CI 25.82 to 22.68, P < 0.0001) were observed. Similarly, more AEs, TEAEs, and discontinuations for any reason were associated with the use of duloxetine than with placebo (1,011 patients, RR 5 2.15, 95% CI 1.48–3.11, P < 0.0001; 1,011 patients, RR 5 1.32, 95% CI 1.16–1.49, P < 0.0001; 1,011 patients, RR 5 1.43, 95% CI 1.14–1.78, P 5 0.002, respectively). However, differences in serious AEs were not significantly statistically different. Moreover, no deaths occurred during these three studies.
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
controlled trials (RCTs) of OAK; 2) Studies compared the efficacy and safety of duloxetine to placebo for the treatment of OAK pain; 3) Studies reported specific data regarding reductions in pain intensity, 30% response rate, 50% response rate, Patient Global Impression of Improvement (PGI-I), functional improvement, adverse events (AEs), TEAEs, mortality; 4) Only the placebo RCTs published in English could be included, both blinded and non-blinded trials were included. As the duration of the disease as well as the duration of the pain can influence the outcome of a trial, patients included in the trials should be in a chronic phase of their illness, but not necessarily in a treatment-refractory stage. Pain persisting at least 3 months is considered chronic [34]. In addition, patients included in the duloxetine trials should be at least 40 years-of-age and have OAK pains for a minimum of 14 days of each month for 3 months. Trials that involved patients with potentially confounding painful conditions and psychiatric illnesses, such as major depressive disorder, a previous diagnosis of psychosis, bipolar disorder, or schizoaffective disorder, were not included. RCTs without a clear description of OAK pain profiles, particularly those with insufficient data to allow calculation of pain intensity changes, PGI-I, functional
improvement and variances from baseline to the end of follow-up, were also excluded from our analysis. Data Extraction The two authors (S.Y. Shi and S.J. Li) independently extracted data (quality criteria, participant details, intervention details, outcome measures, baseline and postintervention results, and main conclusions), using a structured form. Any disagreements about extracted data between the two reviewers were resolved by consensus, or, if necessary, by a third reviewer. We selected the following indicators as outcomes: reductions in pain intensity, 30% response rate, 50% response rate, PGI-I, Western Ontario and McMaster Osteoarthritis Index (WOMAC), functional improvement. AEs were also pooled from the studies. Quality Assessment Study quality was independently assessed using the Jadad five-point score for RCTs [35]. The Jadad score included method of randomization (0–2 points), double blinding (0–2 points), and description of withdrawals or dropouts (0–1 point). If the specific method of randomization was described and it was appropriate, adding two points to the study; while the study was only 1375
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Figure 1 Flow chart of the process for selecting articles for the meta-analysis.
81(67.5) 7.1(7.2)
9.3(8.3) 6.2(1.3)
6.23(1.54)
70(63.1) 6.9(8.4)
9.0(8.7)
6.1(1.3)
6.16(1.58)
58(52.3) 59(49.2) 231 Duloxetine 30 mg/day at the first week, 60 mg/day at the next 6 weeks, 60 or 120 mg/day at the rest 6 weeks, allowed to have decreased or discontinued dose of NSAID during the study 13-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled
62.5(9.3) 100(83.3)
62.1(9.6) 94(84.7)
6.14(1.27)
6.1(1.3)
6.7(6.6)
107(83.6) 5.6(6.2)
61.9(9.2) 124(96.9)
Placebo (N 5 128)
13-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled
47(36.7) 53(41.4) 256 Duloxetine 30 mg/day at the first week, 60 mg/day at the next6 weeks, 60 or 120 mg/day at the rest 6 weeks, allowed to have decreased or discontinued dose of NSAID during the study
6.07(1.39)
6.0(1.2)
8.1(7.6)
89(69.5) 6.2(5.9)
63.2(8.8) 126(98.4)
SD: standard deviation; BPI 5 Brief Pain Inventory; NSAID: nonsteroidal anti-inflammatory drug.
Type of study
Age, mean (SD), years Ethnicity, n (%), Caucasian Female gender, n(%) Duration of osteoarthritis since diagnosis, mean (SD), years Mean duration of pain, mean (SD), years Weekly average pain severity score, mean (SD) BPI average pain, mean (SD) NSAID use, yes, n(%) Enrolled patients Dosage
Duloxetine (N 5 128)
Duloxetine (N 5 111)
Placebo (N 5 120)
Amy S. Chappell 2011
Amy S. Chappell 2009
Baseline patient characteristics
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Characteristics
Table 1
60.3(9.2) 206(79.5) 147(56.5) 9.2(8.9)
9.2(8.9) 6.36(1.41)
6.24(1.51)
61.6(9.2) 2218(82.6) 152(57.6) 9.8(8.9)
9.8(8.9) 6.27(1.41)
6.09(1.58)
10-week, randomized, double-blind, parallel-group, placebo-controlled
100 100 524 Duloxetine 30 mg/day at the first week, 60 mg/day at the next 2weeks, 60 or 120 mg/day at the rest 7 weeks, allowed to have optimized dose of NSAID during the study
Placebo (N 5 260)
Duloxetine (N 5 264)
E.P. Frakes 2011
Wang et al.
108 53(44.5) 108 35(29.4) 111 111 111 111
64(59.3) 51(47.2) 15(13.5) 1(0.9) 55(49.5) 34(30.6)
120 120 120 120
24(18.8) 3(2.3) 64(50.0) 35(27.3)
119 53(43.8)
119 79(65.3)
127 2.33(1.434)
128 22.46(1.770)
n
Duloxetine 60/120 mg/day (N 5 264)
E.P. Frakes 2011
Placebo (N 5 260)
254 2.93(1.434)
259 21.55(1.757)
n
254
255
n
128 128 128 128
7(5.5) 2(1.6) 41(32.0) 17(13.3)
121 41(32.3)
121 56(44.1)
128 128 128 128
40(15.2) 5(1.9) 167(63.3) 75(28.4)
127 92(35.5)
127 139(53.7)
264 264 264 264
23(8.8) 3(1.2) 129(49.6) 61(23.5)
259 41(16.1)
259 86(33.7)
260 260 260 260
255
255
118 210.75 (10.98) 126 215.09 (13.01) 258 210.25 (13.12) 256
123 3.09(1.08)
128 21.88(2.036)
n
Placebo (N 5 128)
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SD 5 standard deviation. PGI-I 5 Patient Global Impression of Improvement. WOMAC–Pf, WOMAC—physical function. AEs 5 adverse events. SAEs 5 serious adverse events. TEAEs 5 treatment emergent adverse events.
7(5.8) 2(1.7) 49(40.8) 24(20.0)
104 211.58 (12.39) 115 213.78 (10.78)
216.46 (14.65)
114 2.85(1.24)
104 2.91(1.281)
2.38(1.224)
119 22.72(2.263)
103 22.08(1.745)
N
22.92(1.725)
n
Duloxetine 60/120 mg/day (N 5 128)
Duloxetine 60/120 mg/day (N 5 111) Placebo (N 5 120)
Amy S. Chappell 2011
Amy S. Chappell 2009
Primary and secondary outcomes of the included RCTs
Reductions in pain intensity, mean (SD) Mean Values in PGI-I, mean (SD) Change from baseline to endpoint in WOMAC-Pf subscale, mean (SD) >=30% reduction in pain severity (%) >=50% reduction in pain severity (%) AEs (%) SAEs (%) TEAEs (%) Discontinuati-on (%)
Table 2
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
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Wang et al.
Table 3
Adverse events
Characteristics
Amy S. Chappell 2011
E.P. Frakes 2011
Duloxetine 60–120mg/day (N 5 111)
Placebo (N 5 120)
Duloxetine 60–120mg/day (N 5 128)
Placebo (N 5 128)
Duloxetine 60–120mg/day (N 5 264)
Placebo (N 5 260)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
7 7 4 1 5 4 5 3 2
2 (1.7) 1 (0.8) 0 1 (0.8) 1 (0.8) 2 (1.7) 3 (2.5) 1 (0.8) 2 (1.7)
13 (10.2) 2 (2.3) 10 (7.8) 7 (5.5) 5 (3.9) 6 (4.7) 6 (4.7) 6 (4.7) 6 (4.7)
3 (2.3) 1 (0.8) 2 (1.6) 0 3 (2.3) 2 (1.6) 3 (2.3) 3 (2.3) 1 (0.8)
41 (15.5) 18 (6.8) 23 (8.7) 10 (3.8) 14 (5.3) 17 (6.4) 18 (6.8) 13 (4.9) 25 (9.5)
12 4 8 1 7 7 10 3 7
(6.3) (6.3) (3.6) (0.9) (4.5) (3.6) (4.5) (2.7) (1.8)
P
(4.6) (1.5) (3.1) (0.4) (2.7) (2.7) (3.8) (1.2) (2.7)
0.10). Otherwise, if heterogeneity of P < 0.1 or I2 > 50% was found among the trials, a random-effects model was used. If heterogeneity of I2 > 70% was evident, the inferior quality study was eliminated from the meta-analysis. The overall effect was tested using a Z-
Table 4
score with significance set at P < 0.05. Publication bias was assessed by the funnel plot method [37]. Results Study Selection Process The process of study selection is depicted as the flow chart in Figure 1. Of the initial 685 articles identified, 35 articles were retrieved from a variety of databases based on the inclusion criteria. However, 28 of the studies were excluded by reviewing their abstracts and headlines, four of the seven remainder studies were eliminated based on the exclusion criteria. At last, three RCTs (28, 30, 32) for 1,011 patients (61.9 mean age, 646[63.9%] female/365[36.1%]male) met the selection criteria and were included in the meta-analysis. Study Characteristics All three included RCTs were randomized, double-blind, parallel-group, placebo-controlled trails. Patients in the duloxetine group received 60/120 mg QD duloxetine, whereas patients in the placebo group received a placebo treatment. Details of the three included RCTs are described in Table 1. The duration of pain ranged from 6.7 to 9.8 years across all three trials (Table 1),
Quality assessment of included RCTs
Study
Randomization
Double-Blinding
Withdrawals and Dropouts
Jadad Score
Amy.S. Chappell 2009 Amy.S. Chappell 2011 E.P. Frakes 2011
2 2 1
2 2 2
1 1 1
5 5 4
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Nausea Fatigue Constipation Hyperhidrosis Somnolence Dizziness Diarrhea Insomnia Dry mouth
Amy S. Chappell 2009
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
Figure 2 Meta-analysis: Change from baseline to endpoint in reductions in pain intensity of patients given either duloxetine or placebo for the treatment of OAK pain (Mean 6 Standard Deviation). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Specific data regarding the primary and secondary outcomes of the three included RCTs are shown in Table 2. The incidence of AEs occurring at a rate of >3% in the three OA trials is summarized in Table 3. Quality assessment of the included RCTs is presented in Table 4 and Jadad scores are depicted here as well. A funnel plot was used to estimate publication bias and a symmetric inverse funnel distribution was obtained.
Effect of Duloxetine on Pain Intensity Reductions in Pain Intensity These three included trials, as the majority of other RCTs, evaluated analgesic efficacy utilize reductions in pain intensity as their primary outcome, and the reductions in pain intensity of the effects of treatment on OAK pain are summarized in Figure 2. All three of the included RCTs provided specific relevant data for the comprehensive analysis of reductions in pain intensity. OA-1 [28] and OA-3 [32] measured changes in pain intensity by the weekly mean of the 24-hour average pain scores. This numerical rating scale is based on an 11-point Likert scale (an ordinal scale with 0 5 “no pain” and 10 5 “worst pain imaginable”). OA-2 [30] utilized the average pain score item from the Brief Pain Inventory (BPI) [44]. The Brief Pain Inventory Severity subscale allows the subject to rate their pain on a 0–10 Likert scale (with 0 5 no pain to 10 5 pain as bad as you can imagine). From a clinical stand point, these magnitudes of change on an ordinal scale of 0–10 may vary in meaning. IMMPACT recommends that a decrease of
Figure 3 Meta-analysis: Response to Treatment–The Number of Participants With a >= 30% Reduction of the primary outcome variable given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1379
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indicating that patients included in the duloxetine trials were well within the chronic phase of their illness [38]. Homogeneity of pain intensity at baseline is a very important variable. To minimize floor effects (patients with very little pain at baseline), the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [39] has recommended that only those patients who have a moderate pain severity of at least 4 on a 0–10 numeric rating scale can they be included in the RCTs. The pain severity ranged from 6.0/10 to 6.4/ 10 in three RCTs suggesting that patients across groups and trials were consistent at baseline in pain severity. Overall, patients participating in these three trials were fairly consistent within the same trial.
Wang et al.
Figure 4 Meta-analysis: Response to Treatment–The Number of Participants With a >= 50% Reduction of the primary outcome variable given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Improvements in Pain Severity Based on the IMMPACT recommendations, clinical meaningfulness is also based on the results of a responder analysis, specifically the proportion of patients experiencing a 30% or a 50% improvement in pain severity or a change from baseline to end point for the primary outcome variable. A 10–20% decrease in pain severity is considered to represent a minimal clinically important change, a 30% change represents a moderately important improvement and a 50% change represents a substantially important improvement. All included RCTs provided specific relevant data for the comprehensive analysis of a moderate improvement in pain severity. There were statistically significant differen-
ces in the 30% response rate between patients given duloxetine and those given placebo (989 patients, RR 5 1.49, 95% CI 1.31–1.70, P < 0.0001; Figure 3). Moreover, all included RCTs provided specific relevant data for the comprehensive analysis of a substantial improvement in pain severity. There were statistically significant differences in 50% response rates in the population between patients given duloxetine and those given placebo (989 patients, RR 5 1.69, 95% CI 1.27– 2.25, P 5 0.0004; Figure 4). A moderate and substantially important improvement in pain severity was observed in the duloxetine group from the metaanalysis, which suggests that the relative risk of experiencing a 30% and 50% improvement in pain severity statistically favored duloxetine. Patient Global Impression of Change Patient Global Impression of Improvement Other secondary measures including the PGI-I [45] were included in all three studies. The PGI-I is a one-item, seven-point scale which evaluates a patient’s impression of their overall change from randomization to the end of the trial. The scale ranges from 1 (very much better) to the midpoint of 4 (no change) to 7 (very much
Figure 5 Meta-analysis: Mean values in PGI-I of patients given either duloxetine or placebo for the treatment of OAK pain (Mean 6 Standard Deviation). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1380
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two points from baseline to end point is clinically meaningful for patients and represents an important decrease in chronic pain intensity [39]. Statistically significant differences were observed in reductions in pain intensity for patients given duloxetine compared with those given placebo (992 patients, MD 5 20.88, 95% CI 21.11 to 20.65, P < 0.0001; Figure 2), which suggested reductions in pain intensity favored the duloxetine group.
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
Figure 6 Meta-analysis: Change from Baseline to Endpoint in WOMAC–Physical Function Subscale of patients given either duloxetine or placebo for the treatment of OAK pain (Mean 6 Standard Deviation). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Effect of Duloxetine on Physical Functioning WOMAC-Physical Function All included RCTs provided specific relevant data for the comprehensive analysis of WOMAC of physical function. Therefore, WOMAC baseline and change from baseline total scores were extracted and standardized. Statistically, significant differences in WOMAC-physical function scores were observed in the duloxetine group (977 patients, MD 5 24.25, 95% CI 25.82 to 22.68, P < 0.0001; Figure 6). Moreover, duloxetine was found to statistically improve the WOMAC total score compared with placebo (P < 0.01). Safety No deaths occurred during the three studies. All included RCTs provided specific data for the comprehensive analysis of AEs, serious AEs, TEAEs, or discontinuations of the trial for any reason. Significantly more AEs, discontinuations, and TEAEs were associated with duloxetine (1,011 patients, RR 5 2.15, 95% CI 1.48–
3.11, P < 0.0001; 1,011 patients, RR 5 1.32, 95% CI 1.16–1.49, P < 0.0001; 1,011 patients, RR 5 1.43, 95% CI 1.14–1.78, P 5 0.002, respectively; Figures 7–9). However, there was no statistically significant difference in the occurrence of serious AEs between patients given duloxetine and those given placebo (1,011 patients, RR 5 1.30, 95% CI 0.48–3.47, P 5 0.61; Figure 10). Duloxetine patients had significantly more nausea, constipation, dry mouth, diarrhea, fatigue, dizziness, somnolence and insomnia (Table 4). Discussion The analgesic efficacy of duloxetine, an SNRI with CNS activity, is concerned with its effect on descending inhibitory pain pathways [46]. A number of recently completed pathway analysis have shown that reduction in pain was due to a direct analgesic effect and was independent of improvement in mood and anxiety [47–49]. The current study supports these findings which are consistent with the previously discussed role of serotonin and norepinephrine in the mediation of endogenous pain inhibitory pathways, the presumed mechanism of action of duloxetine’s analgesic effect. The efficacy of duloxetine as an analgesic for OAK pain was evaluated in three placebo-controlled RCTs which enrolled 1,011 patients. Subgroup analyses did not
Figure 7 Meta-analysis: Number of AEs of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1381
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worse; 2 5 much better and 3 5 a little better). Duloxetine showed significant improvement of PGI-I than the placebo (976 patients, MD 5 20.47, 95% CI 20.63 to 20.30, P < 0.0001; Figure 5).
Wang et al.
Figure 8 Meta-analysis: Number of TEAEs of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary. com.]
There were statistically significant differences between patients given duloxetine and those given placebo with regard to the reductions in pain intensity, 30% response rate, 50% response rate, PGI-I and Western Ontario MacMaster Universities Osteoarthritis Index (WOMAC)– physical function. In regard to its influence on reducing pain intensity, IMMPACT recommends that reducing two points from baseline to end point is clinically meaningful for patients and on behalf of a significant decrease. The results of the three trials reveal that duloxetine offers a clinically significant reduction in pain at about 4 weeks and that this is maintained for the rest of the trial periods [38]. Furthermore, 30% and 50%
responder analyses show that more duloxetine than placebo patients had moderate to substantial improvement in their pain intensity. An independent 16-week trial [41] evaluating duloxetine 60 mg/day and placebo in OAK pain in older patients over 65 as well as another pooled analysis [43] occurred the similar results. The three included studies investigated the chronic nature of OA by including only trials of 10 or more weeks (the recommended duration for confirmatory trials) and a more inclusive set of OA symptoms using WOMAC, which includes subscales for function and stiffness as well as pain. We also sought to confirm the influence of design and baseline factors observed in the meta-analysis. The authors report that the duloxetine group had a significantly greater reduction in pain and physical function (WOMAC function scores) relative to placebo. However, more AEs, TEAEs and discontinuations occurred in the duloxetine group. One reason for this could be that the greater severity of OAK pain and unstable patient condition when they begin duloxetine therapy leaves them more vulnerable to AEs. Among the patients in the three included RCTs, treatment with duloxetine was well tolerated, with the majority of AEs being of mild or moderate intensity, as in Table 3, for example, constipation, nausea, hyperhidrosis, cough,
Figure 9 Meta-analysis: Number of discontinuations for any reason of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1382
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show significant differences for patients with different durations and severities of osteoarthritic pain. Furthermore, no significant differences in treatment interaction by subgroups with regard to age, gender, and origin were found. A pooled analysis [42] about inspecting the differences between older over 65 and younger patients from 40–65 demonstrated that no statistically significant difference was observed between groups on OAK pain when treated with duloxetine. Both groups showed more statistically significant improvement over placebo. This finding suggests that duloxetine was equally efficacious regardless of age of the patients at baseline.
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
Figure 10 Meta-analysis: Number of serious AEs of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com].
There are several limitations of our meta-analysis that should be taken into account. First, the meta-analysis is based on a relatively small number of RCTs. Fortunately, the quality of the trials included in our meta-analysis was fairly high and each of the included trials included sufficient numbers of patients with OAK pain. Higgins’ group [50] evaluated 39 Cochrane reviews and found that 67% of them included
MUSCULOSKELETAL SECTION Original Research Article Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain: A Meta-Analysis of Randomized Controlled Trials
*Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China; †Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China; ‡Department of Pharmacy, Yue Bei People’s Hospital, Shantou University, Shaoguan, 512026, China; §Pharmaceutical Research & Development, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China Reprint request to: S. Y. Shi, Department of Pharmacy, Zhujiang Hospital, No.253, Industrial Road, Haizhu District, Guangzhou, Guangdong, China. Tel.: 18819312747; Fax: 186 20 61643010; E-mail: [email protected] or J. M. Lin, Pharmaceutical Research & Development, Zhujiang Hospital, No.253, Industrial Road, Haizhu District, Guangzhou, Guangdong, China. Tel.: 186 20 61643557; Fax: 186 20 61643010; E-mail: [email protected]. Conflict of interest: We have no conflicts of interest to declare. Authors Z. Y. Wang and S. Y. Shi contributed equally to this work. Author Contributions: Shengying Shi: data collection, data analysis/interpretation, drafting article, statistics; Zhaoyu Wang: concept, design, critical revision of article, approval of article; Jingming Lin: concept, design; F. Chen: critical revision of article, approval of
article; Shujie Li: data collection; H Chen and Haizhen Lin: assessed original text. Funding sources: Supported by Science and Technology Planning Project of Guangdong Province, China (2011B031700002, 2012A030100008), Supported by Natural Science Foundation of Guangdong Province, China (S2013010014796).
Abstract Objectives. The aim of this meta-analysis was to evaluate the efficacy and safety of duloxetine for management of osteoarthritis knee (OAK) pain. Methods. A systematic literature search of articles for management of OAK using duloxetine were performed in PubMed, EBSCO, EMBASE, ScienceDirect, MEDLINE, ClinicalTrials.gov, Google Scholar, and Cochrane Central Register of Controlled Trials from the available date of inception until the latest issue (October 2013). Potentially relevant randomized controlled trials (RCTs) regarding to comparison of efficacy and safety of duloxetine with placebo for managing OAK pain were included. Also, studies with specific data regarding to pain reductions and response rate, Patient Global Impression of Improvement (PGI-I), functional improvement, Western Ontario and McMaster Osteoarthritis Index (WOMAC), adverse events (AEs), treatment-emergent AEs (TEAEs), mortality were included and analyzed, and those with confounding conditions were excluded. Studies were assessed for quality using the Jadad five-point score for RCTs. Finally, a meta-analysis of all RCTs eligible for inclusion criteria was performed using Review Manager 5.1 meta-analysis software.
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Zhao Yu Wang,* Sheng Ying Shi,† Shu Jie Li,† Feng Chen,‡ Huang Chen,* Hai Zhen Lin,† and Jing Ming Lin§
Wang et al.
Conclusion. This analysis suggests duloxetine (60/ 120 mg quaque die (QD)), compared with placebo control, resulted in a greater reduction in pain, improved function and patient-rated impression of improvement, and acceptable adverse effects for the treatment of OAK pain after approximately 10 213 weeks of treatment. Key Words. Duloxetine; Osteoarthritis Knee Pain; Meta-Analysis; Randomized Controlled Trials
include weight loss, aerobic, and/or muscle strengthening exercises. Pharmacological management guidelines have recommended acetaminophen for first-line use, with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids as second and third lines of treatment [10–14]. However, reservations have been expressed concerning their long-term safety and efficacy, which are associated with potential use-limiting risks or side effects such as gastrointestinal bleeding, peptic ulcer disease, nephrotoxicity, and serious long term cardiovascular effects (NSAIDs) and risks of sedation, respiratory depression, overdose, misuse, or dependency (opioids) [15]. Duloxetine, a newly available treatment option in the United States, is a potent and selective inhibitor of 5-HT and NE reuptake (SNRI) in vitro and in vivo in the central nervous system (CNS). As the discovery of imbalance of serotonin and norepinephrine systems within central pain pathways have been implicated in the development and maintenance of central sensitization and associated chronic pain states [16,17] and chronic pain associated with osteoarthritis involves dysfunction of central pain pathways [18,19], duloxetine has been used to manage chronic pains such as OAK [20,21]. Several clinical trials comparing the efficacy and safety of duloxetine with placebo for OAK pain have been conducted and duloxetine has demonstrated efficacy in four distinct chronic pain conditions: diabetic peripheral neuropathic pain [22,23], fibromyalgia [24,25], chronic low back pain [26,27], and OAK pain [28–33]. While prior studies established the superiority of duloxetine relative to placebo in the aforementioned diseases, we conducted a systematic literature review followed by a meta-analysis to assess the efficacy and safety of duloxetine vs placebo as to address the clinical significance of those findings. To accomplish that, we applied the criteria of clinical significance in chronic pain trials, which include pain intensity, response, physical functioning, and patients’ ratings of overall improvement. Methods
Introduction Search Strategy Osteoarthritis of the knee (OAK) is the most common form of arthritis in older individuals and it is among the most prevalent and disabling chronic conditions worldwide [1]. OAK occurs when the protective cartilage on the ends of the bones wears down over time, and osteoarthritis often gradually worsens, which decreases overall quality of life [2], increases risk of depression and anxiety [3,4]. The lifetime risk of OAK is 44.7% among general population, but the prevalence increases with age, in females and obese population [5–7]. Also, pain is the chief complaints in OAK patients and brings patients to seek medical attention on most circumstances [8]. Therefore, in terms of clinical management, pain reduction and functional improvement are of paramount importance in the treatment of OKA [9]. To manage chronic pain, current guidelines recommend a combination of nonpharmacological and pharmacological therapies. Nonpharmacological managements of OAK 1374
We searched the following electronic databases for the identification of trials using the terms “duloxetine” or “Cymbalta” vs “osteoarthritis knee pain,” “osteoarthritis of the knee,” “knee pain due to osteoarthritis”: PubMed, EBSCO, EMBASE, ScienceDirect, MEDLINE, ClinicalTrials.gov, Google Scholar, and Cochrane Central Register of Controlled Trials. All databases were searched from the available date of inception until the latest issue (October 2013). Only English publications were included. In addition, the references of retrieved articles were examined to find additional articles relevant to the content of our meta-analysis. Selection Criteria Studies were selected for analysis if they met the following criteria: 1) Eligibility was limited to randomized
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Results. Three RCTs that enrolled 1,011 patients were included in our meta-analysis. There were statistically significant differences between patients taking duloxetine and those taking placebo with regard to the reductions in pain intensity (992 patients, mean difference [MD] 5 20.88, 95% confidence interval [CI] 21.11–20.65, P < 0.0001), a moderate improvement in pain intensity (>= 30% response rate; 989 patients, risk ratio [RR] 5 1.49, 95% CI 1.31–1.70, P < 0.0001), a substantial improvement in pain intensity (>=50% response rate; 989 patients, RR 5 1.69, 95% CI 1.27–2.25, P 5 0.0004). Statistically significant differences in PGI-I (976 patients, MD 5 20.47, 95% CI 20.63 to 20.30, P < 0.0001) and WOMAC—physical function subscale (977 patients, MD 5 24.25, 95% CI 25.82 to 22.68, P < 0.0001) were observed. Similarly, more AEs, TEAEs, and discontinuations for any reason were associated with the use of duloxetine than with placebo (1,011 patients, RR 5 2.15, 95% CI 1.48–3.11, P < 0.0001; 1,011 patients, RR 5 1.32, 95% CI 1.16–1.49, P < 0.0001; 1,011 patients, RR 5 1.43, 95% CI 1.14–1.78, P 5 0.002, respectively). However, differences in serious AEs were not significantly statistically different. Moreover, no deaths occurred during these three studies.
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
controlled trials (RCTs) of OAK; 2) Studies compared the efficacy and safety of duloxetine to placebo for the treatment of OAK pain; 3) Studies reported specific data regarding reductions in pain intensity, 30% response rate, 50% response rate, Patient Global Impression of Improvement (PGI-I), functional improvement, adverse events (AEs), TEAEs, mortality; 4) Only the placebo RCTs published in English could be included, both blinded and non-blinded trials were included. As the duration of the disease as well as the duration of the pain can influence the outcome of a trial, patients included in the trials should be in a chronic phase of their illness, but not necessarily in a treatment-refractory stage. Pain persisting at least 3 months is considered chronic [34]. In addition, patients included in the duloxetine trials should be at least 40 years-of-age and have OAK pains for a minimum of 14 days of each month for 3 months. Trials that involved patients with potentially confounding painful conditions and psychiatric illnesses, such as major depressive disorder, a previous diagnosis of psychosis, bipolar disorder, or schizoaffective disorder, were not included. RCTs without a clear description of OAK pain profiles, particularly those with insufficient data to allow calculation of pain intensity changes, PGI-I, functional
improvement and variances from baseline to the end of follow-up, were also excluded from our analysis. Data Extraction The two authors (S.Y. Shi and S.J. Li) independently extracted data (quality criteria, participant details, intervention details, outcome measures, baseline and postintervention results, and main conclusions), using a structured form. Any disagreements about extracted data between the two reviewers were resolved by consensus, or, if necessary, by a third reviewer. We selected the following indicators as outcomes: reductions in pain intensity, 30% response rate, 50% response rate, PGI-I, Western Ontario and McMaster Osteoarthritis Index (WOMAC), functional improvement. AEs were also pooled from the studies. Quality Assessment Study quality was independently assessed using the Jadad five-point score for RCTs [35]. The Jadad score included method of randomization (0–2 points), double blinding (0–2 points), and description of withdrawals or dropouts (0–1 point). If the specific method of randomization was described and it was appropriate, adding two points to the study; while the study was only 1375
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Figure 1 Flow chart of the process for selecting articles for the meta-analysis.
81(67.5) 7.1(7.2)
9.3(8.3) 6.2(1.3)
6.23(1.54)
70(63.1) 6.9(8.4)
9.0(8.7)
6.1(1.3)
6.16(1.58)
58(52.3) 59(49.2) 231 Duloxetine 30 mg/day at the first week, 60 mg/day at the next 6 weeks, 60 or 120 mg/day at the rest 6 weeks, allowed to have decreased or discontinued dose of NSAID during the study 13-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled
62.5(9.3) 100(83.3)
62.1(9.6) 94(84.7)
6.14(1.27)
6.1(1.3)
6.7(6.6)
107(83.6) 5.6(6.2)
61.9(9.2) 124(96.9)
Placebo (N 5 128)
13-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled
47(36.7) 53(41.4) 256 Duloxetine 30 mg/day at the first week, 60 mg/day at the next6 weeks, 60 or 120 mg/day at the rest 6 weeks, allowed to have decreased or discontinued dose of NSAID during the study
6.07(1.39)
6.0(1.2)
8.1(7.6)
89(69.5) 6.2(5.9)
63.2(8.8) 126(98.4)
SD: standard deviation; BPI 5 Brief Pain Inventory; NSAID: nonsteroidal anti-inflammatory drug.
Type of study
Age, mean (SD), years Ethnicity, n (%), Caucasian Female gender, n(%) Duration of osteoarthritis since diagnosis, mean (SD), years Mean duration of pain, mean (SD), years Weekly average pain severity score, mean (SD) BPI average pain, mean (SD) NSAID use, yes, n(%) Enrolled patients Dosage
Duloxetine (N 5 128)
Duloxetine (N 5 111)
Placebo (N 5 120)
Amy S. Chappell 2011
Amy S. Chappell 2009
Baseline patient characteristics
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Characteristics
Table 1
60.3(9.2) 206(79.5) 147(56.5) 9.2(8.9)
9.2(8.9) 6.36(1.41)
6.24(1.51)
61.6(9.2) 2218(82.6) 152(57.6) 9.8(8.9)
9.8(8.9) 6.27(1.41)
6.09(1.58)
10-week, randomized, double-blind, parallel-group, placebo-controlled
100 100 524 Duloxetine 30 mg/day at the first week, 60 mg/day at the next 2weeks, 60 or 120 mg/day at the rest 7 weeks, allowed to have optimized dose of NSAID during the study
Placebo (N 5 260)
Duloxetine (N 5 264)
E.P. Frakes 2011
Wang et al.
108 53(44.5) 108 35(29.4) 111 111 111 111
64(59.3) 51(47.2) 15(13.5) 1(0.9) 55(49.5) 34(30.6)
120 120 120 120
24(18.8) 3(2.3) 64(50.0) 35(27.3)
119 53(43.8)
119 79(65.3)
127 2.33(1.434)
128 22.46(1.770)
n
Duloxetine 60/120 mg/day (N 5 264)
E.P. Frakes 2011
Placebo (N 5 260)
254 2.93(1.434)
259 21.55(1.757)
n
254
255
n
128 128 128 128
7(5.5) 2(1.6) 41(32.0) 17(13.3)
121 41(32.3)
121 56(44.1)
128 128 128 128
40(15.2) 5(1.9) 167(63.3) 75(28.4)
127 92(35.5)
127 139(53.7)
264 264 264 264
23(8.8) 3(1.2) 129(49.6) 61(23.5)
259 41(16.1)
259 86(33.7)
260 260 260 260
255
255
118 210.75 (10.98) 126 215.09 (13.01) 258 210.25 (13.12) 256
123 3.09(1.08)
128 21.88(2.036)
n
Placebo (N 5 128)
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SD 5 standard deviation. PGI-I 5 Patient Global Impression of Improvement. WOMAC–Pf, WOMAC—physical function. AEs 5 adverse events. SAEs 5 serious adverse events. TEAEs 5 treatment emergent adverse events.
7(5.8) 2(1.7) 49(40.8) 24(20.0)
104 211.58 (12.39) 115 213.78 (10.78)
216.46 (14.65)
114 2.85(1.24)
104 2.91(1.281)
2.38(1.224)
119 22.72(2.263)
103 22.08(1.745)
N
22.92(1.725)
n
Duloxetine 60/120 mg/day (N 5 128)
Duloxetine 60/120 mg/day (N 5 111) Placebo (N 5 120)
Amy S. Chappell 2011
Amy S. Chappell 2009
Primary and secondary outcomes of the included RCTs
Reductions in pain intensity, mean (SD) Mean Values in PGI-I, mean (SD) Change from baseline to endpoint in WOMAC-Pf subscale, mean (SD) >=30% reduction in pain severity (%) >=50% reduction in pain severity (%) AEs (%) SAEs (%) TEAEs (%) Discontinuati-on (%)
Table 2
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
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Table 3
Adverse events
Characteristics
Amy S. Chappell 2011
E.P. Frakes 2011
Duloxetine 60–120mg/day (N 5 111)
Placebo (N 5 120)
Duloxetine 60–120mg/day (N 5 128)
Placebo (N 5 128)
Duloxetine 60–120mg/day (N 5 264)
Placebo (N 5 260)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
7 7 4 1 5 4 5 3 2
2 (1.7) 1 (0.8) 0 1 (0.8) 1 (0.8) 2 (1.7) 3 (2.5) 1 (0.8) 2 (1.7)
13 (10.2) 2 (2.3) 10 (7.8) 7 (5.5) 5 (3.9) 6 (4.7) 6 (4.7) 6 (4.7) 6 (4.7)
3 (2.3) 1 (0.8) 2 (1.6) 0 3 (2.3) 2 (1.6) 3 (2.3) 3 (2.3) 1 (0.8)
41 (15.5) 18 (6.8) 23 (8.7) 10 (3.8) 14 (5.3) 17 (6.4) 18 (6.8) 13 (4.9) 25 (9.5)
12 4 8 1 7 7 10 3 7
(6.3) (6.3) (3.6) (0.9) (4.5) (3.6) (4.5) (2.7) (1.8)
P
(4.6) (1.5) (3.1) (0.4) (2.7) (2.7) (3.8) (1.2) (2.7)
0.10). Otherwise, if heterogeneity of P < 0.1 or I2 > 50% was found among the trials, a random-effects model was used. If heterogeneity of I2 > 70% was evident, the inferior quality study was eliminated from the meta-analysis. The overall effect was tested using a Z-
Table 4
score with significance set at P < 0.05. Publication bias was assessed by the funnel plot method [37]. Results Study Selection Process The process of study selection is depicted as the flow chart in Figure 1. Of the initial 685 articles identified, 35 articles were retrieved from a variety of databases based on the inclusion criteria. However, 28 of the studies were excluded by reviewing their abstracts and headlines, four of the seven remainder studies were eliminated based on the exclusion criteria. At last, three RCTs (28, 30, 32) for 1,011 patients (61.9 mean age, 646[63.9%] female/365[36.1%]male) met the selection criteria and were included in the meta-analysis. Study Characteristics All three included RCTs were randomized, double-blind, parallel-group, placebo-controlled trails. Patients in the duloxetine group received 60/120 mg QD duloxetine, whereas patients in the placebo group received a placebo treatment. Details of the three included RCTs are described in Table 1. The duration of pain ranged from 6.7 to 9.8 years across all three trials (Table 1),
Quality assessment of included RCTs
Study
Randomization
Double-Blinding
Withdrawals and Dropouts
Jadad Score
Amy.S. Chappell 2009 Amy.S. Chappell 2011 E.P. Frakes 2011
2 2 1
2 2 2
1 1 1
5 5 4
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Nausea Fatigue Constipation Hyperhidrosis Somnolence Dizziness Diarrhea Insomnia Dry mouth
Amy S. Chappell 2009
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
Figure 2 Meta-analysis: Change from baseline to endpoint in reductions in pain intensity of patients given either duloxetine or placebo for the treatment of OAK pain (Mean 6 Standard Deviation). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Specific data regarding the primary and secondary outcomes of the three included RCTs are shown in Table 2. The incidence of AEs occurring at a rate of >3% in the three OA trials is summarized in Table 3. Quality assessment of the included RCTs is presented in Table 4 and Jadad scores are depicted here as well. A funnel plot was used to estimate publication bias and a symmetric inverse funnel distribution was obtained.
Effect of Duloxetine on Pain Intensity Reductions in Pain Intensity These three included trials, as the majority of other RCTs, evaluated analgesic efficacy utilize reductions in pain intensity as their primary outcome, and the reductions in pain intensity of the effects of treatment on OAK pain are summarized in Figure 2. All three of the included RCTs provided specific relevant data for the comprehensive analysis of reductions in pain intensity. OA-1 [28] and OA-3 [32] measured changes in pain intensity by the weekly mean of the 24-hour average pain scores. This numerical rating scale is based on an 11-point Likert scale (an ordinal scale with 0 5 “no pain” and 10 5 “worst pain imaginable”). OA-2 [30] utilized the average pain score item from the Brief Pain Inventory (BPI) [44]. The Brief Pain Inventory Severity subscale allows the subject to rate their pain on a 0–10 Likert scale (with 0 5 no pain to 10 5 pain as bad as you can imagine). From a clinical stand point, these magnitudes of change on an ordinal scale of 0–10 may vary in meaning. IMMPACT recommends that a decrease of
Figure 3 Meta-analysis: Response to Treatment–The Number of Participants With a >= 30% Reduction of the primary outcome variable given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1379
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indicating that patients included in the duloxetine trials were well within the chronic phase of their illness [38]. Homogeneity of pain intensity at baseline is a very important variable. To minimize floor effects (patients with very little pain at baseline), the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [39] has recommended that only those patients who have a moderate pain severity of at least 4 on a 0–10 numeric rating scale can they be included in the RCTs. The pain severity ranged from 6.0/10 to 6.4/ 10 in three RCTs suggesting that patients across groups and trials were consistent at baseline in pain severity. Overall, patients participating in these three trials were fairly consistent within the same trial.
Wang et al.
Figure 4 Meta-analysis: Response to Treatment–The Number of Participants With a >= 50% Reduction of the primary outcome variable given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Improvements in Pain Severity Based on the IMMPACT recommendations, clinical meaningfulness is also based on the results of a responder analysis, specifically the proportion of patients experiencing a 30% or a 50% improvement in pain severity or a change from baseline to end point for the primary outcome variable. A 10–20% decrease in pain severity is considered to represent a minimal clinically important change, a 30% change represents a moderately important improvement and a 50% change represents a substantially important improvement. All included RCTs provided specific relevant data for the comprehensive analysis of a moderate improvement in pain severity. There were statistically significant differen-
ces in the 30% response rate between patients given duloxetine and those given placebo (989 patients, RR 5 1.49, 95% CI 1.31–1.70, P < 0.0001; Figure 3). Moreover, all included RCTs provided specific relevant data for the comprehensive analysis of a substantial improvement in pain severity. There were statistically significant differences in 50% response rates in the population between patients given duloxetine and those given placebo (989 patients, RR 5 1.69, 95% CI 1.27– 2.25, P 5 0.0004; Figure 4). A moderate and substantially important improvement in pain severity was observed in the duloxetine group from the metaanalysis, which suggests that the relative risk of experiencing a 30% and 50% improvement in pain severity statistically favored duloxetine. Patient Global Impression of Change Patient Global Impression of Improvement Other secondary measures including the PGI-I [45] were included in all three studies. The PGI-I is a one-item, seven-point scale which evaluates a patient’s impression of their overall change from randomization to the end of the trial. The scale ranges from 1 (very much better) to the midpoint of 4 (no change) to 7 (very much
Figure 5 Meta-analysis: Mean values in PGI-I of patients given either duloxetine or placebo for the treatment of OAK pain (Mean 6 Standard Deviation). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1380
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two points from baseline to end point is clinically meaningful for patients and represents an important decrease in chronic pain intensity [39]. Statistically significant differences were observed in reductions in pain intensity for patients given duloxetine compared with those given placebo (992 patients, MD 5 20.88, 95% CI 21.11 to 20.65, P < 0.0001; Figure 2), which suggested reductions in pain intensity favored the duloxetine group.
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
Figure 6 Meta-analysis: Change from Baseline to Endpoint in WOMAC–Physical Function Subscale of patients given either duloxetine or placebo for the treatment of OAK pain (Mean 6 Standard Deviation). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Effect of Duloxetine on Physical Functioning WOMAC-Physical Function All included RCTs provided specific relevant data for the comprehensive analysis of WOMAC of physical function. Therefore, WOMAC baseline and change from baseline total scores were extracted and standardized. Statistically, significant differences in WOMAC-physical function scores were observed in the duloxetine group (977 patients, MD 5 24.25, 95% CI 25.82 to 22.68, P < 0.0001; Figure 6). Moreover, duloxetine was found to statistically improve the WOMAC total score compared with placebo (P < 0.01). Safety No deaths occurred during the three studies. All included RCTs provided specific data for the comprehensive analysis of AEs, serious AEs, TEAEs, or discontinuations of the trial for any reason. Significantly more AEs, discontinuations, and TEAEs were associated with duloxetine (1,011 patients, RR 5 2.15, 95% CI 1.48–
3.11, P < 0.0001; 1,011 patients, RR 5 1.32, 95% CI 1.16–1.49, P < 0.0001; 1,011 patients, RR 5 1.43, 95% CI 1.14–1.78, P 5 0.002, respectively; Figures 7–9). However, there was no statistically significant difference in the occurrence of serious AEs between patients given duloxetine and those given placebo (1,011 patients, RR 5 1.30, 95% CI 0.48–3.47, P 5 0.61; Figure 10). Duloxetine patients had significantly more nausea, constipation, dry mouth, diarrhea, fatigue, dizziness, somnolence and insomnia (Table 4). Discussion The analgesic efficacy of duloxetine, an SNRI with CNS activity, is concerned with its effect on descending inhibitory pain pathways [46]. A number of recently completed pathway analysis have shown that reduction in pain was due to a direct analgesic effect and was independent of improvement in mood and anxiety [47–49]. The current study supports these findings which are consistent with the previously discussed role of serotonin and norepinephrine in the mediation of endogenous pain inhibitory pathways, the presumed mechanism of action of duloxetine’s analgesic effect. The efficacy of duloxetine as an analgesic for OAK pain was evaluated in three placebo-controlled RCTs which enrolled 1,011 patients. Subgroup analyses did not
Figure 7 Meta-analysis: Number of AEs of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1381
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worse; 2 5 much better and 3 5 a little better). Duloxetine showed significant improvement of PGI-I than the placebo (976 patients, MD 5 20.47, 95% CI 20.63 to 20.30, P < 0.0001; Figure 5).
Wang et al.
Figure 8 Meta-analysis: Number of TEAEs of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary. com.]
There were statistically significant differences between patients given duloxetine and those given placebo with regard to the reductions in pain intensity, 30% response rate, 50% response rate, PGI-I and Western Ontario MacMaster Universities Osteoarthritis Index (WOMAC)– physical function. In regard to its influence on reducing pain intensity, IMMPACT recommends that reducing two points from baseline to end point is clinically meaningful for patients and on behalf of a significant decrease. The results of the three trials reveal that duloxetine offers a clinically significant reduction in pain at about 4 weeks and that this is maintained for the rest of the trial periods [38]. Furthermore, 30% and 50%
responder analyses show that more duloxetine than placebo patients had moderate to substantial improvement in their pain intensity. An independent 16-week trial [41] evaluating duloxetine 60 mg/day and placebo in OAK pain in older patients over 65 as well as another pooled analysis [43] occurred the similar results. The three included studies investigated the chronic nature of OA by including only trials of 10 or more weeks (the recommended duration for confirmatory trials) and a more inclusive set of OA symptoms using WOMAC, which includes subscales for function and stiffness as well as pain. We also sought to confirm the influence of design and baseline factors observed in the meta-analysis. The authors report that the duloxetine group had a significantly greater reduction in pain and physical function (WOMAC function scores) relative to placebo. However, more AEs, TEAEs and discontinuations occurred in the duloxetine group. One reason for this could be that the greater severity of OAK pain and unstable patient condition when they begin duloxetine therapy leaves them more vulnerable to AEs. Among the patients in the three included RCTs, treatment with duloxetine was well tolerated, with the majority of AEs being of mild or moderate intensity, as in Table 3, for example, constipation, nausea, hyperhidrosis, cough,
Figure 9 Meta-analysis: Number of discontinuations for any reason of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1382
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show significant differences for patients with different durations and severities of osteoarthritic pain. Furthermore, no significant differences in treatment interaction by subgroups with regard to age, gender, and origin were found. A pooled analysis [42] about inspecting the differences between older over 65 and younger patients from 40–65 demonstrated that no statistically significant difference was observed between groups on OAK pain when treated with duloxetine. Both groups showed more statistically significant improvement over placebo. This finding suggests that duloxetine was equally efficacious regardless of age of the patients at baseline.
Efficacy and Safety of Duloxetine on Osteoarthritis Knee Pain
Figure 10 Meta-analysis: Number of serious AEs of patients given either duloxetine or placebo for the treatment of OAK pain. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com].
There are several limitations of our meta-analysis that should be taken into account. First, the meta-analysis is based on a relatively small number of RCTs. Fortunately, the quality of the trials included in our meta-analysis was fairly high and each of the included trials included sufficient numbers of patients with OAK pain. Higgins’ group [50] evaluated 39 Cochrane reviews and found that 67% of them included
