PROCESS Trial: Effect of Duloxetine Premedication for Postherpetic Neuralgia Within 72 Hours of Herpes Zoster Reactivation-A Randomized Controlled Trial.

BACKGROUND: Postherpetic neuralgia (PHN) is the most common chronic complication of herpes zoster (HZ) and results in severe refractory neuropathic pain. This study aimed at evaluating the efficacy of premedication with duloxetine in the prevention of PHN. METHODS: The PROCESS trial is a multicenter, randomized, open-label, blinded-endpoint trial used a 1:1 duloxetine:control ratio. Adults 50 years or older with HZ who presented with vesicles within 72 hours were recruited. The primary outcome was the incidence of PHN at 12 weeks. PHN was defined as any pain intensity score other than 0 mm on the visual analog scale (VAS) at week 12 after the onset of the rash. The secondary outcomes were the number of participants with VAS >0 and VAS ≥3. The modified intention-to-treat (mITT) principle and per-protocol (PP) principle were used for the primary outcome analysis. RESULTS: A total of 375 participants were randomly assigned to the duloxetine group and 375 were assigned to the control group. There was no significant difference in the incidence of PHN in the duloxetine group compared with the control group in the mITT analysis (86 [22.9%] of 375 vs 108 [28.8%] of 375; P = .067). PP analysis produced similar results. However, there were significant differences between the 2 groups in the number of participants with VAS >0 and VAS ≥3 (P < .05 for all comparisons). CONCLUSIONS: Although absolute prevention of PHN does not occur, this trial found that premedication with duloxetine can reduce pain associated with HZ, and therefore can have clinically relevant benefits. Clinical Trials Registration. Clinicaltrials.gov, NCT04313335. Registered on 18 March 2020.

Duloxetine protected indomethacin-induced gastric mucosal injury by increasing serotonin-dependent RANTES expression and activating PI3K-AKT-VEGF pathway.

Antidepressant duloxetine has been shown protective effect on indomethacin-induced gastric ulcer, which was escorted by inflammation in the gastric mucosa. Cytokines are the principal mediators of inflammation. Thus, by screening the differential expression of cytokines in the gastric mucosa using cytokine array at 3 h after indomethacin exposure, when the gastric ulcer began to format, we found that indomethacin increased cytokines which promoted inflammation responses, whereas duloxetine decreased pro-inflammatory cytokines increased by indomethacin and increased RANTES expression. RANTES was consistently increased by pretreated with both 5 mg/kg and 20 mg/kg duloxetine at 3 h and 6 h after indomethacin exposure in male rats. Selective blockade of RANTES-CCR5 axis by a functional antagonist Met-RANTES or a CCR5 antagonist maraviroc suppressed the protection of duloxetine. Considering the pharmacologic action of duloxetine on reuptake of monoamine neurotransmitters, we examined the serotonin (5-HT), norepinephrine and dopamine contents in the blood and discovered 20 mg/kg duloxetine increased 5-HT levels in platelet-poor plasma, while treatment with 5-HT promoted expression of RANTES in the gastric mucosa and alleviated the indomethacin-induced gastric injury. Furthermore, duloxetine activated PI3K-AKT-VEGF signaling pathway, which was regulated by RANTES-CCR5, and selective inhibitor of VEGF receptor axitinib blocked the prophylactic effect of duloxetine. Furthermore, duloxetine also protected gastric mucosa from indomethacin in female rats, and RANTES was increased by duloxetine after 6 h after indomethacin exposure too. Together, our results identified the role of cytokines, particularly RANTES, and the underlying mechanisms in gastroprotective effect of duloxetine against indomethacin, which advanced our understanding in inflammatory modulation by monoamine-based antidepressants.

Amitriptyline and duloxetine attenuate activities of superficial dorsal horn neurons in a rat reserpine-induced fibromyalgia model.

Fibromyalgia (FM) is an intractable disease with a chief complaint of chronic widespread pain. Amitriptyline (AMI) and duloxetine (DLX), which are antidepressant drugs, have been reported to ameliorate pain in patients with FM and pain-related behaviors in several rodent models of FM. However, the mechanisms of action of AMI and DLX are not yet fully understood. Here, we examined the effects of these drugs on the responsiveness of superficial dorsal horn (SDH) neurons in the spinal cord, using a rat FM model developed by injecting a biogenic amine depleter (reserpine). Extracellular recordings of SDH neurons in vivo demonstrated that bath application of AMI and DLX at concentrations of 0.1-1.0 mM on the dorsal surface of the spinal cord markedly suppressed spontaneous discharge and von Frey filament-evoked mechanical firing in SDH neurons. The suppression induced by the drugs was noted in a concentration-dependent manner and the suppressive effects resolved after washing the spinal cord surface. These results show that SDH neurons are the site of action for AMI and DLX in a rat reserpine-induced FM model. Spinal mechanisms may underlie the therapeutic effects of these drugs in patients with FM.

Duloxetine to prevent neuropathy in breast cancer patients under paclitaxel chemotherapy (a double-blind randomized trial).

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major side effects and main reasons for affecting quality of life and dose reduction or even discontinuation of treatment in breast cancer patients. One of the most widely prescribed chemotherapies is the "taxanes." Considering that duloxetine has been used in treating neuropathies in recent years, this study aimed to investigate its effectiveness in preventing taxane-related neuropathy. MATERIAL AND METHODS: This is a randomized controlled trial on 47 patients: 24 received a placebo and 23 received duloxetine at 30 mg daily in the first week following the injection of paclitaxel and 60 mg during the second week in each chemotherapy cycle. Patients objective (nerve conduction velocity (NCV) values) and subjective symptoms (visual analog scale including; neuropathy, paresthesia, pain, cold sensitivity, and numbness), the grades of the patients' neuropathy (calculated according to Common Terminology Criteria for Adverse Events (CTCAE) v.5), and the presence of complications, before and after each chemotherapy cycle, were recorded. RESULTS: The placebo group experienced significantly higher occurrences of new neuropathy (8/23 in duloxetine vs 16/24 in placebo, P = 0.029) in NCV by tibial nerve latency (- 0.28% vs 19.87%, P = 0.006), tibial amplitude (4.40% vs - 10.88%, P = 0.049), and median nerve latency (8.72% vs 31.16%, P = 0.039); administration of duloxetine significantly reduced the scores of neuropathies (P < 0.001), pain (P = 0.027), during chemotherapy, and 6 weeks later; however, no significant effect was observed on paresthesia, numbness, cold sensitivity, and other NCV measurements. CONCLUSIONS: Paclitaxel can cause neuropathy, lasting for a long time. Our study showed duloxetine is potentially an effective medication that can prevent subjective and objective neuropathy.

Effect of duloxetine on changes in serum proinflammatory cytokine levels in patients with major depressive disorder.

OBJECTIVE: Accumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, exhibits anti-inflammatory effects both in vitro and in vivo. In this study, we investigated the impact of duloxetine on changes in serum proinflammatory cytokine levels among individuals diagnosed with MDD. METHODS: A cohort of 23 drug-naïve individuals diagnosed with MDD and 23 healthy controls were included in this study. The severity of depressive symptoms was evaluated using the 24-item Hamilton Depression Scale (HAMD-24). A panel of 7 proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were quantified using multiplex Luminex assays. The levels of serum cytokines in healthy controls and patients with MDD were compared at baseline. All patients received duloxetine at a dosage range of 40-60 mg/day for a duration of 4 weeks. The HAMD-24 scores and serum cytokine levels were compared before and after duloxetine treatment. RESULTS: Compared with healthy controls, patients with MDD had significantly greater levels of IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ (P < 0.05). Moreover, there was a significant decrease in HAMD-24 scores observed pre- and post-treatment (t = 13.161, P < 0.001). Furthermore, after 4 weeks of treatment, the serum levels of IL-8 (t = 3.605, P = 0.002), IL-12 (t = 2.559, P = 0.018), and IFN-γ (t = 3.567, P = 0.002) decreased significantly. However, there were no significant differences in other cytokines, including IL-1ß, IL-2, IL-6, and TNF-α, before and after treatment (P > 0.05). CONCLUSIONS: These findings present compelling evidence, potentially for the first time, indicating that duloxetine treatment may effectively reduce the serum concentrations of IL-8, IL-12, and IFN-γ in individuals diagnosed with MDD. However, the precise mechanisms underlying this effect remain unclear and warrant further investigation.

Suspected duloxetine-induced restless legs syndrome phenotypic variant: a case report.

BACKGROUND: Restless arms syndrome (RAS) is the most common variant of restless legs syndrome (RLS), which is easy to be ignored in clinical practice due to the lack of specific diagnostic criteria. When effective therapeutic agents induced RAS and symptoms persisted after briefly observation, clinicians will face the challenge of weighing efficacy against side effects. CASE PRESENTATION: A 67-year-old woman was admitted to a geriatric psychiatric ward with depression. Upon admission, the escitalopram dose was reduced from 15 mg to 10 mg per day, and the duloxetine dose was increased from 60 mg to 80 mg per day. The next night before bedtime, she developed itching and creeping sensations deep inside bilateral shoulders and arms, with the urge to move, worsening at rest, and alleviation after hammering. The symptoms persisted when escitalopram was discontinued. A history of RLS was confirmed. Treatment with 40 mg of duloxetine and 0.125 mg of pramipexole significantly improved depression, and the paresthesia disappeared, with no recurrence occurring 6 months after discharge. DISCUSSION AND CONCLUSIONS: This case suggests that psychiatrists should pay attention to RLS variants when increasing doses of duloxetine. Long-term improvement can be achieved through dosage reduction combined with dopaminergic drugs instead of immediate discontinuation.

Simultaneous identification and enantioseparation of ofloxacin and duloxetine without the single standard and computational calculation of their inclusion complexes.

Given the markedly different pharmacological activities between enantiomeric isomers, it is crucial to encourage the stereoselective determination of chiral drugs in the biological and pharmaceutical fields, and the combination of drugs makes this analysis more complicated and challenging. Herein, a capillary electrophoresis (CE) method for the enantioseparation of ofloxacin and duloxetine was established, enabling the simultaneous identification of four isomers in nonracemic mixtures with enantiomeric excess (ee%) values exceeding 5%. This was achieved through the integration of theoretical simulation and electron circular dichroism (ECD), all without reliance on individual standards. Molecular modeling explained and verified the migration time differences of these isomers in electrophoretic separation. Moreover, the correlation coefficients (R2 ) between the enantiomeric peak area differentials and ee% were both above 0.99. Recovery rates were quantified using bovine serum as the matrix, with results ranging from 93.32% to 101.03% (RSD = 0.030) and 92.69% to 100.52% (RSD = 0.028) for these two chiral drugs at an ee value of 23.1%, respectively.

Pharmacotherapy in Stress Urinary Incontinence; A Literature Review.

PURPOSE OF REVIEW: Stress urinary incontinence (SUI) is a commonly observed condition in females, as well as in males who have undergone prostatectomy. Despite the significant progress made in surgical techniques, pharmacotherapy has not yielded substantial outcomes within the clinical domain. This review aims to present a comprehensive overview of the existing pharmacotherapy options for stress urinary incontinence (SUI) and the emerging therapeutic targets in this field. RECENT FINDINGS: One meta-analysis demonstrated that α-adrenergic medications are more efficacious in improving rather than curing SUI symptoms. One trial showed reduced pad weight gain with PSD-503, a locally administered α-adrenergic receptor agonist. New data show that duloxetine's risk outweighs its benefits. One small-scale trial was found to support the use of locally administered estriol in improving subjective outcomes. Emerging targets include serotonin 5HT2C agonists, selective inhibitors of norepinephrine uptake, and myostatin inhibitors. Only one of the evaluated drugs, duloxetine, has been approved by some countries. Currently, trials are evaluating novel targets. Systemic adverse effects such as gastrointestinal upset with duloxetine and orthostatic hypotension with α-adrenoceptor agonists have hampered the efficacy of drugs used to treat SUI in women and men.

Diabetic Neuropathy: A Guide to Pain Management.

PURPOSE OF REVIEW: Diabetic neuropathy is a common complication of diabetes mellitus (DM) and can affect up to 50% of DM patients during their lifetime. Patients typically present with numbness, tingling, pain, and loss of sensation in the extremities. Since there is no treatment targeting the underlying mechanism of neuropathy, strategies focus on preventative care and pain management. RECENT FINDINGS: Up to 69% of patients with diabetic neuropathy receive pharmacological treatment for neuropathic pain. The United States Food and Drug Administration (FDA) confirmed four drugs for painful diabetic neuropathy (PDN): pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch. Nonpharmacological treatments such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) both show promise in reducing pain in DM patients. Despite the high burden associated with PDN, effective management remains challenging. This update covers the background and management of diabetic neuropathy, including its epidemiology, pathogenesis, preventative care, and current therapeutic strategies.

Environmentally benign first derivative synchronous spectrofluorimetry for the analysis of two binary mixtures containing duloxetine with avanafil or tadalafil in spiked plasma samples.

Antidepressants can cause sexual dysfunction side effects, necessitating the co-administration of phosphodiesterase type 5 inhibitors. The simultaneous determination of these drugs in biological fluids is critical for therapeutic drug monitoring. For the first time, two binary mixtures containing duloxetine with either avanafil or tadalafil were estimated utilizing simple green spectrofluorimetric methods without the need for a previous separation step. The study was based on first derivative synchronous spectrofluorimetry in ethanol using a change in wavelength difference (∆λ) of 20 and 25 nm for the first and second combinations, respectively. Duloxetine and avanafil were estimated at 297.7 and 331 nm in their binary mixture, while duloxetine and tadalafil were determined at 290.3 and 297.7 nm, respectively. The linearity was achieved over the ranges of 0.1-1.5 µg mL-1 for both duloxetine and avanafil and 0.01-0.40 µg mL-1 for tadalafil, with limits of detection of 0.013, 0.022, and 0.004 µg mL-1 for duloxetine, avanafil, and tadalafil, respectively. Successful application of the developed approaches was accomplished for the estimation of the two mixtures in dosage forms as well as human plasma with excellent percentage recoveries (96-103.75% in plasma), which supports their suitability for use in quality control laboratories and pharmacokinetic studies. Moreover, the adopted approaches' greenness was evidenced by applying three tools.

Duloxetine as an Analgesic in Patients Who Do Not Have Central Sensitivity Undergoing Single-Setting, Bilateral Total Knee Arthroplasty: A Prospective, Double-Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Pain control and patient satisfaction after total knee arthroplasty (TKA) have room for improvement. While studies have reported better analgesic outcomes with antidepressants like duloxetine in patients who do not have central sensitivity (CS), we undertook this trial to determine the short and midterm analgesic role of low-dose duloxetine in patients who do not have CS. METHODS: This prospective, double-blinded, randomized, placebo-controlled trial was conducted in 106 patients undergoing single-setting, bilateral TKA under spinal anesthesia. There were 2 matched groups, with one given 20 mg of duloxetine and the other given a placebo (similar in appearance and weight) from preoperative day 2 to postoperative day 28. Follow-ups were scheduled at 48-hours, 1-week, 2-weeks, 4-weeks, and 3-months. Pain was measured using a visual analogue scale at rest and visual analogue scale at mobilization (mVAS). Secondary measures included additional non-steroidal anti-inflammatory drug consumption, patient satisfaction, and safety profile. RESULTS: The visual analogue scale at rest in the duloxetine group was better in the first 48 hours (6.38 ± 1.32 versus 7.02 ± 0.99; P = .017), 1-week (4.76 ± 1.24 versus 5.89 ± 1.06; P < .001), and 2-weeks (3.34 ± 1.19 versus 4.26 ± 1.02; P < .001) follow-up. The mVAS remained significantly higher in the duloxetine group in the first 48 hours (7.23 ± 1.12 versus 8.21 ± 0.69; P < .001), 1-week (5.83 ± 1.11 versus 6.82 ± 0.92; P < .001), and 2 weeks (3.70 ± 0.89 versus 4.60 ± 1.03; P < .001) follow-up. Both outcomes became comparable from 4-week follow-up onward. Patient satisfaction (8.44 ± 1.68 versus 7.17 ± 1.04; P < .001) and additional non-steroidal anti-inflammatory drug consumption (2,770 ± 533.05 versus 3,566.04 ± 464.54; P < .001) were better in the duloxetine group, with a comparable safety profile. CONCLUSIONS: In patients who did not have CS, persistent pain after bilateral TKA can be managed safely and successfully by a daily dose of 20 mg Duloxetine, improving patient satisfaction and analgesic consumption in the acute postoperative phase.

Prediction of duloxetine efficacy in addition to self-management in painful temporomandibular disorders: A randomised, placebo-controlled clinical trial.

BACKGROUND: Conditioned pain modulation (CPM) is a potential predictor of treatment response that has not been studied in temporomandibular disorders (TMD). OBJECTIVES: We conducted a randomised, double-blind, placebo-controlled trial (RCT) of duloxetine in addition to self-management (SM) strategies to investigate its efficacy to reduce pain intensity in painful TMD patients. Moreover, we investigated whether baseline CPM would predict the duloxetine efficacy to reduce TMD pain intensity. METHODS: Eighty participants were randomised to duloxetine 60 mg or placebo for 12 weeks. The primary outcomes were the change in the pain intensity from baseline to week-12 and CPM-sequential paradigm at baseline. Safety, physical and emotional functioning outcomes were also evaluated. RESULTS: Of 80 participants randomised, 78 were included in intention-to-treat analysis. Pain intensity decreased for SM-duloxetine and SM-placebo but did not differ between groups (p = .82). A more efficient CPM was associated with a greater pain intensity reduction regardless of the treatment group (p = .035). Physical and emotional functioning did not differ between groups, but adverse events (p = .014), sleep impairment (p = .003) and catastrophizing symptoms (p = .001) were more prevalent in SM-duloxetine group. CONCLUSION: This study failed to provide evidence of a beneficial effect of adding duloxetine to SM strategies for treatment of painful TMD. Nonetheless, this RCT has shown the feasibility of applying pain modulation assessment to predict short-term treatment response in painful TMD patients, which confirms previous finds that CPM evaluation may serve a step forward in individualising pain treatment.

Does postoperative low-dose duloxetine provide analgesic effect and lower morphine consumption after primary total knee arthroplasty? A prospective, double-blind, randomized controlled trial.

INTRODUCTION: Duloxetine as an adjunct analgesic has shown effective results in trials of patients undergoing total knee arthroplasty (TKA). However, the regimen has not been standardized. We, therefore, evaluated the analgesic efficacy of low-dose duloxetine after TKA. MATERIALS AND METHODS: We conducted a double-blind, randomized controlled trial of patients undergoing unilateral primary TKA, comparing 30 mg/d of duloxetine for 6 weeks as an additive medication for pain control to modern multimodal analgesia after TKA. The primary outcome measure was a visual analogue scale (VAS) for pain at rest, during walking, and at night at 24 h, 72 h, 2 weeks, 6 weeks, and 12 weeks after the operation. Secondary outcomes were morphine consumption, adverse events, and functional outcomes: Oxford Knee Score, Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: Mean VAS for pain at rest, during walking, and at night at 24 h, 72 h, 2 weeks, 6 weeks, and 12 weeks showed no significant differences between the two groups, except a significantly lower mean VAS at night at 2 weeks in the duloxetine group. Mean total morphine consumption (0-72 h) was 33% less in the duloxetine group (6.8 ± 5.7 vs. 10.2 ± 7.3 mg, p = 0.04). There were no significant differences in adverse events and functional outcomes except better KOOS symptoms at 6 and 12 weeks in the duloxetine group. CONCLUSION: Low-dose duloxetine could reduce postoperative morphine consumption and improve KOOS symptoms at 6 and 12 weeks with good tolerability. However, it did not significantly reduce pain at rest or during walking. Low-dose duloxetine can be considered an addition to contemporary multimodal pain management after TKA. LEVEL OF EVIDENCE V: Therapeutic Level I.

Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting oncology patients' quality of life, chemotherapy-induced large-fiber (LF) neuropathy is amongst the least well understood components of CIPN, and one for which there is currently no established therapy. Preliminary clinical observations have led to the suggestion that Duloxetine, which is used for the treatment of pain associated with small-fiber CIPN (SF-CIPN), may be effective against LF-CIPN. In the present experiments we developed a model of LF-CIPN and studied the effect of Duloxetine on LF-CIPN induced by two neurotoxic chemotherapy agents: the proteasome inhibitor, Bortezomib, a first-line treatment of multiple myeloma; and, the anti-microtubule taxane, Paclitaxel, used in the treatment of solid tumors. Since there are currently no models for selective the study of LF-CIPN, our first aim was to establish a pre-clinical model in the rat. LF-CIPN was evaluated with the Current Perception Threshold (CPT) assay, which uses a high frequency (1000 Hz) electrical stimulus protocol that selectively activates large-fiber myelinated afferents. Our second aim was to use this model to test the hypothesis that Duloxetine can prevent LF-CIPN. We report that Bortezomib and Paclitaxel induce elevation of CPT, compatible with loss of large-fiber function, which are prevented by Duloxetine. Our findings support the clinical observation that Duloxetine may be an effective treatment for the large-fiber CIPN. We also suggest that CPT could be used as a biomarker for LF-CIPN in patients receiving neurotoxic chemotherapy.

Effect of duloxetine on opioid consumption and pain after total knee and hip arthroplasty: a systematic review and meta-analysis of randomized clinical trials.

OBJECTIVES: The purpose of this study was to investigate the analgesic effects of duloxetine, specifically on postoperative pain, opioid consumption, and related side effects following total hip or knee arthroplasty. METHODS: In this systematic review and meta-analysis, Medline, Cochrane, EMBASE, Scopus, and Web of Science were searched until November 2022 for studies which compared duloxetine with placebo when added to routine pain management protocols. Individual study risk of bias assessment was conducted based on Cochrane risk of bias tool 2. Random effect model meta-analysis was done on mean differences, to evaluate the outcomes. RESULTS: Nine randomized clinical trials (RCT) were included in the final analysis, totaling 806 patients. Duloxetine reduced opioid consumption (oral morphine milligram equivalents) on postoperative days (POD) 2 (mean difference (MD): -14.35, P = .02), POD 3 (MD: -13.6, P < .001), POD 7 (MD: -7.81, P < .001), and POD 14 (MD: -12.72, P < .001). Duloxetine decreased pain with activity on POD 1, 3, 7, 14, 90 (All P < .05), and pain at rest on POD 2, 3, 7, 14, and 90 (all P < .05). There was no significant difference in the prevalence of the side effects, except for increased risk of somnolence/drowsiness (risk ratio: 1.87, P = .007). CONCLUSION: Current evidence shows low to moderate opioid sparing effects of perioperative duloxetine and a statistically but not clinically significant reduction in pain scores. Patients treated with duloxetine had an increased risk for somnolence and drowsiness.

Efficacy of Duloxetine in Patients with Central Post-stroke Pain: A Randomized Double Blind Placebo Controlled Trial.

OBJECTIVE: Central post-stroke pain (CPSP) refers to neuropathic pain in areas of the body corresponding to stroke lesions. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is safe and effective against neuropathic pain. In this randomized double-blind placebo-controlled study, we studied the effect of duloxetine in CPSP patients. METHODS: Consecutive patients satisfying the inclusion criteria were enrolled in the study and were randomized in a simple 1:1 randomization to duloxetine and placebo groups. Baseline demographic, clinical and imaging data were obtained. Prespecified primary outcome was comparison of change in pain intensity from baseline to 4 weeks, as assessed on Numeric Rating Scale (NRS) in both groups. Prespecified secondary outcomes were comparison of change in average pain severity from baseline to 4 weeks as measured on Short-form McGill Pain Questionnaire-2 (SFMPQ-2) score and Pain Disability Index (PDI) score and comparison of Patient Global Impression of Change (PGIC) score at the end of 4 weeks of treatment in both groups. Duloxetine at doses of 30 mg and similarly appearing placebo tablets were given and the dose was doubled if there was no response at the end of 2 weeks. Response to treatment was defined as ≥2 points reduction of NRS pain score. RESULTS: In total, 82 patients were enrolled in the study, 41 in each group. There was a significant difference in reduction in NRS score between duloxetine and placebo group from baseline (6.51 ± 1.03 vs 6.37 ± 1.41) to 4 weeks (3.02 ± 1.70 vs 4.40 ± 1.77, P = .02 for difference in reduction between groups). SFMPQ-2 score (P = .032) and Pain Disability Index score (P = .005) also differ significantly from baseline to 4 weeks between the two groups. PGIC score at the end of 4 weeks was significantly different between the two groups (5.15 ± 1.54 vs 3.89 ± 1.51; P < .001). Responder rate (defined as % of patients with ≥ 2 points reduction on NRS pain score from baseline to end of 4 weeks), on post hoc analysis was found to be significantly higher in duloxetine group (80.5%) than placebo group (43.9%) (P = .042). CONCLUSIONS: Duloxetine can be an effective treatment option for patients with moderate to severe central post-stroke pain.

Upregulation by duloxetine of the transforming growth factor-α-induced migration of hepatocellular carcinoma cells via enhancement of the c-Jun N-terminal kinase activity.

Duloxetine, a selective reuptake inhibitor for serotonin and norepinephrine, is a medication widely used for major depression. Currently, duloxetine is also recommended for pain related to chemotherapy-induced peripheral neuropathy or cancer. Previously, we showed that transforming growth factor-α (TGF-α) induces the migration of human hepatocellular carcinoma (HCC)-derived HuH7 cells through the activation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and AKT. In the present study, we investigate whether duloxetine affects cell migration and its mechanism. Duloxetine significantly enhanced the TGF-α-induced migration of HuH7 cells. Fluvoxamine and sertraline, specific inhibitors of serotonin reuptake, also upregulated the TGF-α-induced cell migration. On the contrary, reboxetine, a specific norepinephrine reuptake inhibitor, failed to affect cell migration. Duloxetine significantly amplified the TGF-α-stimulated phosphorylation of JNK, but not p38 MAPK and AKT. In addition, fluvoxamine and sertraline, but not reboxetine, enhanced the phosphorylation of JNK. SP600125, a JNK inhibitor, suppressed the enhancement by duloxetine, fluvoxamine, or sertraline of TGF-α-induced migration of HuH7 cells. Taken together, our results strongly suggest that duloxetine strengthens the TGF-α-induced activation of JNK via inhibition of serotonin reuptake in HCC cells, leading to the enhancement of cell migration.

A randomized, double-blinded, placebo-controlled clinical trial of duloxetine hydrochloride enteric-coated tablets in the treatment of refractory chronic cough.

INTRODUCTION: Refractory cough, a chronic cough with an unclear diagnosis or poor treatment response. The symptoms are often stubborn and persistent, causing serious complications and lowering the patient's quality of life. Cough hypersensitivity syndrome (CHS) is proposed as a potential cause, and reducing sensory nerve hyperresponsiveness is suggested as an effective treatment. However, current drugs have low efficacy and benefit rates and numerous side effects. This trail proposes using duloxetine, a selective 5-HT and norepinephrine reuptake inhibitor, as a potential treatment for refractory cough, which has shown promise in treating pain and depression. Duloxetine may inhibit pain conduction and oxidative stress in peripheral nerves by inhibiting the activity of TRPV1 channels, which play an important role in the peripheral afferent pathway of refractory cough. Meanwhile, the antidepressant effects of duloxetine may also play a role in the treatment of refractory cough. METHODS AND ANALYSIS: This is a single-center, prospective, randomized, double-blind, and controlled trial. A total of 98 individuals will be randomized in a 1:1 ratio to duloxetine group and placebo control group (starting with 20 mg QD, increasing 20 mg daily until 20 mg TID). After a screening period, the second stage runs from baseline to the 42nd (last) day of treatment, with follow-up visits on the 3rd, 7th, 14th, 21st, 28th, 35th, 42nd and 49th days. The main end-stage observation indicators include objective cough frequency, cough visual analog scale (VAS), cough symptom score, Leicester Cough Questionnaire (LCQ), and cough evaluation test (CET); the secondary end-stage observation indicators include capsaicin cough sensitivity, Patient Health Questionnaire-9 (PHQ-9), Major Depression Inventory (MDI), the Generalized Anxiety Disorder-7 scale (GAD-7), Life Events Scale (LES-32), induced sputum supernatant. The safety measures will be AEs/SAEs, vital signs, liver and kidney function, fecal occult blood test. DISCUSSION: This study is the first randomized, double-blind, and controlled clinical trial investigating the use of duloxetine in the treatment of refractory coughs. The study aims to provide a high-quality basis for evaluating the efficacy and safety of duloxetine for this condition. TRIAL REGISTRATION: Our study was registered in the Chinese Clinical Trials Register ( www.chictr.org.cn/ ) (ChiCTR2000037429) in 28/08/2020.

Efficacy of perioperative duloxetine as a part of multimodal analgesia in laparoscopic colorectal cancer surgeries.

BACKGROUND: Although laparoscopic surgery provides earlier recovery, less morbidity and hospital stay, however, severe pain is still a problem after it. Duloxetine has been recently used in postoperative pain management. We tested perioperative duloxetine to evaluate its effect on patients undergoing laparoscopic colorectal cancer surgery. METHODS: Sixty patients were enrolled in this study divided into two equal groups; duloxetine group each patient received an oral duloxetine capsule (60 mg) 1st dose at night before surgery, the 2nd dose 1 h preoperative, and the 3rd dose 24 h postoperative. Placebo group received placebo capsules at the same times. The cumulative morphine consumption in 48 h, postoperative VAS score, quality of recovery (QoR-40 score), sedation, and adverse effects were evaluated. RESULTS: Duloxetine group had lower VAS scores compared to placebo group, (3 ± 0.69) VS. (4.17 ± 0.83), (2.5 ± 0.6) VS. (4.3 ± 0.9), (2.2 ± 0.7) VS. (3.9 ± 0.6), (1.6 ± 0.7) VS. (3.6 ± 0.8), (1.1 ± 0.8) VS. (3.7 ± 0.7), (0.7 ± 0.7) VS. (3.5 ± 0.8), (0.6 ± 0.7) VS. (3.5 ± 0.8) respectively, P ˂0.01. The cumulative morphine consumption was significantly reduced in the Duloxetine group compared to the placebo group (4.6 ± 2.9 vs. 11.3 ± 1.7 mg), P < 0.01. The total QoR-40 score for duloxetine group was (180.8 ± 4.5) vs. (156 ± 5.9) in placebo group (P < 0.01). Patients in Duloxetine group were more sedated in all the 48 h postoperatively in comparison to placebo group. CONCLUSIONS: Perioperative duloxetine had reduced postoperative pain, decreased opioid consumption, and improved the quality of recovery in patients undergoing laparoscopic colorectal surgery.

Evaluating the effects of duloxetine on prophylaxis of oxaliplatin-induced peripheral neuropathy in patients with gastrointestinal cancer: A randomized double-blind placebo controlled clinical trial.

BACKGROUND: Oxaliplatin is a key drug in treatment of gastrointestinal (GI) cancer. Peripheral neuropathy (PN) is a troublesome and dose-dependent adverse effect of oxaliplatin. It can occur in two distinct forms: acute and chronic. Its incidence is estimated about 65-98%, of which 22% of cases need to stop chemotherapy. In some cases, PN has a long-lasting effect on patient's quality of life (QOL). Therefore, this study was done to evaluate efficacy of duloxetine on prevention of oxaliplatin- induced peripheral neuropathy (OIPN) in patients with GI cancer. METHODOLOGY: In this randomized and double -blind clinical trial study conducted in a tertiary teaching hospital, eligible patients were divided into two groups. Treatment group received duloxetine the day before initiation of chemotherapy regimen at a dose of 30 mg/day for one week and then, the dose was titrated up to 60 mg/day until 12 weeks. For placebo group, one placebo capsule was prescribed daily for one week followed by 2 capsules daily until 12 weeks. In each of chemotherapy courses, PN was assessed using national cancer institute-common terminology criteria for adverse effects (NCI-CTCAE v4.03). Also, chemotherapy -related QOL at the baseline and 12 weeks was assessed by functional assessment of cancer treatment gynecologic oncology group - neurotoxicity (FACT/GOG-NTX). RESULTS: Forty patients were randomly assigned to treatment and placebo groups which were similar to each other in terms of chemotherapy regimen, type, and stage of cancer. Analysis of results obtained from the NCI-CTCAE (v4.03) showed that duloxetine could prevent worsening of paresthesia more than placebo (P = 0.025) and patients in duloxetine group experienced less peripheral sensory neuropathy (P = 0.001) than placebo group. Analysis of results obtained from the FACT/GOG-NTX demonstrated a significant worsening of tingling and discomfort in hands (P = 0.002, 0.001, respectively) and feet (P = 0.017, 0.019, respectively) in placebo group compared to duloxetine group. Also, patients experienced more cold temperature -induced pain in extremities (P = 0.001) in placebo group compared to duloxetine group. On the other hand, duloxetine could not improve QOL (P = 0.06) and had not significant effects on trouble feeling the shape of small objects in hand (P = 0.420) or trouble buttoning buttons (P = 0.086). The P-value < 0.05 was considered to be statistically significant.