Diabetic Peripheral Neuropathy: Prevention and Treatment.

Diabetic peripheral neuropathy occurs in up to 50% of patients with diabetes mellitus and increases the risk of diabetic foot ulcers and infections. Consistent screening and clear communication are essential to decrease disparities in assessment of neuropathic symptoms and diagnosis. Physicians should address underlying risk factors such as poor glycemic control, vitamin B12 deficiency, elevated blood pressure, and obesity to reduce the likelihood of developing neuropathy. First-line drug therapy for painful diabetic peripheral neuropathy includes duloxetine, gabapentin, amitriptyline, and pregabalin; however, these medications do not restore sensation to affected extremities. Evidence for long-term benefit and safety of first-line treatment options is lacking. Second-line drug therapy includes nortriptyline, imipramine, venlafaxine, carbamazepine, oxcarbazepine, topical lidocaine, and topical capsaicin. Periodic, objective monitoring of medication response is critical because patients may not obtain desired pain reduction, adverse effects are common, and serious adverse effects can occur. Opioids should generally be avoided. Nondrug therapies with low- to moderate-quality evidence include exercise and neuromodulation with spinal cord stimulation or transcutaneous electrical nerve stimulation. Peripheral transcutaneous electrical nerve stimulation is well tolerated and inexpensive, but benefits are modest. Other treatments, such as acupuncture, alpha-lipoic acid, acetyl-L-carnitine, cannabidiol, and onabotulinumtoxinA need further study in patients with diabetic peripheral neuropathy.

Functional connectivity between the habenula and posterior default mode network contributes to the response of the duloxetine effect in major depressive disorder.

This study aims to investigate the functional connectivity (FC) changes of the habenula (Hb) among patients with major depressive disorder (MDD) after 12 weeks of duloxetine treatment (MDD12). Patients who were diagnosed with MDD for the first time and were drug-naïve were recruited at baseline as cases. Healthy controls (HCs) matched for sex, age, and education level were also recruited at the same time. At baseline, all participants underwent resting-state functional MRI. FC analyses were performed using the Hb seed region of interest, and three groups including HCs, MDD group and MDD12 group were compared using whole-brain voxel-wise comparisons. Compared to the HCs, the MDD group had decreased FC between the Hb and the right anterior cingulate cortex at baseline. Compared to the HCs, the FC between the Hb and the left medial superior frontal gyrus decreased in the MDD12 group. Additionally, the FC between the left precuneus, bilateral cuneus and Hb increased in the MDD12 group than that in the MDD group. No significant correlation was found between HDRS-17 and the FC between the Hb, bilateral cuneus, and the left precuneus in the MDD12 group. Our study suggests that the FC between the post-default mode network and Hb may be the treatment mechanism of duloxetine and the treatment mechanisms and the pathogenesis of depression may be independent of each other.

Antidepressants available in Japan for older people with major depressive disorder: A systematic review and meta-analysis.

AIM: To update the major depressive disorder (MDD) treatment guidelines of the Japanese Society of Mood Disorders, we conducted a systematic review and pairwise meta-analysis of double-blind, randomized, placebo-controlled trials of available antidepressants in Japan for older adults with MDD. METHODS: Outcome measures included response rate (primary), improvement in depressive symptom scale score, remission rate, all-cause discontinuation, discontinuation due to adverse events, and at least one adverse event. A random-effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI). RESULTS: Nine double-blind, randomized, placebo-controlled trials (n = 2145) were identified. No study has been conducted in Japan. Our meta-analysis included the following antidepressants: duloxetine, escitalopram, imipramine, sertraline, venlafaxine, and vortioxetine. Antidepressants have significantly higher response rates than placebo (RR [95% CI] = 1.38 [1.04, 1.83], p = 0.02). Antidepressants outperformed placebo in terms of improving depressive symptom scale score (SMD [95% CI] = -0.62 [-0.92, -0.33], p < 0.0001). However, antidepressants were associated with a higher discontinuation rate due to adverse events (RR [95% CI] = 1.94 [1.30, 2.88], p = 0.001) and a higher incidence of at least one adverse event (RR [95% CI] = 1.11 [1.02, 1.21], p = 0.02) compared to placebo. The groups did not differ significantly in terms of remission rate or all-cause discontinuation. CONCLUSIONS: Our meta-analysis concluded that treatment with antidepressants available in Japan is only weakly recommended for moderate to severe MDD in older adults.

Duloxetine improves chronic orofacial pain and comorbid depressive symptoms in association with reduction of serotonin transporter protein through upregulation of ubiquitinated serotonin transporter protein.

ABSTRACT: Chronic orofacial pain (COP) is relieved by duloxetine (DLX) and frequently causes depressive symptoms. The aim of this study was to confirm effects of DLX on pain and depressive symptoms, and to associate with their effectiveness in platelet serotonin transporter (SERT) expression, which is a target molecule of DLX and plasma serotonin concentration in COP patients with depressive symptoms. We assessed for the severity of pain and depressive symptoms using the Visual Analog Scale (VAS) and 17-item Hamilton Depression Rating Scale (HDRS), respectively. Chronic orofacial pain patients were classified into 2 groups based on their HDRS before DLX-treatment: COP patients with (COP-D) and without (COP-ND) depressive symptoms. We found that the VAS and HDRS scores of both groups were significantly decreased after DLX treatment compared with those before DLX treatment. Upregulation of total SERT and downregulation of ubiquitinated SERT were observed before DLX treatment in both groups compared with healthy controls. After DLX treatment, there were no differences in total SERT of both groups and in ubiquitinated SERT of COP-D patients compared with healthy controls; whereas, ubiquitinated SERT of COP-ND patients remained downregulated. There were positive correlations between changes of serotonin concentrations and of VAS or HDRS scores in only COP-D patients. Our findings indicate that DLX improves not only pain but also comorbid depressive symptoms of COP-D patients. Duloxetine also reduces platelet SERT through upregulation of ubiquitinated SERT. As the result, decrease of plasma serotonin concentrations may be related to the efficacy of DLX in relieving pain and depression in COP patients.

Co-treatment with Oral Duloxetine and Intraarticular Injection of Corticosteroid plus Hyaluronic Acid Reduces Pain in the Treatment of Knee Osteoarthritis.

BACKGROUND: Knee osteoarthritis (OA) is a common form of arthritis in elders which can lead to reduced daily activity and quality of life. It is important to administer a proper treatment with high efficacy and low side effects. In this study, we evaluated the efficacy of co-treatment with oral duloxetine and intraarticular (IA) injection of hyaluronic acid (HA) and corticosteroid (CS) in patients with knee OA. OBJECTIVES: This study aimed to test the hypothesis that an IA injection of CS+HA combined with duloxetine could achieve pain management superior to that of an IA injection of CS+HA alone in patients experiencing knee OA related pain. STUDY DESIGN: This study adopted a prospective, randomized, open-label blind endpoint study design. SETTING: The investigation was performed at Beijing Tiantan Hospital Affiliated with the Capital Medical University from October 2019 to December 2021. The study plan was approved by the Ethics Committee of Beijing Tiantan Hospital (KY 2019-086-02). METHODS: A total of 150 patients were randomly allocated to receive either duloxetine combined with an IA injection (n = 75) or a single IA injection alone (n = 75). All patients were followed for 24 weeks. The primary outcome was the change in the weekly 24 hours average mean pain scores, and the secondary outcomes included the proportion of patients with >= 30% or >= 50% pain reduction, Brief Pain Inventory (BPI) items, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, Patient Global Impression Improvement (PGI-I) ratings, hospital anxiety and depression scale (HADS) scores and adverse events (AEs).. RESULTS: Patients in the experimental group had significantly greater improvement in the change of weekly mean of the 24 hours average pain scores, BPI pain severity ratings (P < 0.001) and WOMAC scores (P < 0.001) at the study endpoint. A significantly greater percentage of patients in the experimental group rated PGI-I of <= 2 (P = 0.021) and >= 50% pain reduction (P = 0.029) at 24 weeks. There was no difference in the proportion of patients with <= 30% pain reduction, the HADS scores or frequency of AEs between the 2 groups. LIMITATIONS: The effectiveness and safety were examined only up to 24 weeks after treatment, and we did not perform a long-term follow-up as most previous studies have. Optimum dosage of duloxetine, as well as different molecular-weight HA, should be investigated in future studies. CONCLUSION: Patients receiving co-treatment with oral duloxetine and IA (HA+CS) injections experienced considerable improvement in pain and knee function compared to those who received an IA injection alone.

Assessing the efficacy of pelvic floor muscle training and duloxetine on urinary continence recovery following radical prostatectomy: A randomized clinical trial.

BACKGROUND: Urinary incontinence (UI) can negatively impact quality of life (QoL) after robot-assisted radical prostatectomy (RARP). Pelvic floor muscle training (PFMT) and duloxetine are used to manage post-RARP UI, but their efficacy remains uncertain. We aimed to investigate the efficacy of PFMT and duloxetine in promoting urinary continence recovery (UCR) after RARP. METHODS: A randomized controlled trial involving patients with urine leakage after RARP from May 2015 to February 2018. Patients were randomized into 1 of 4 arms: (1) PFMT-biofeedback, (2) duloxetine, (3) combined PFMT-biofeedback and duloxetine, (4) control arm. PFMT consisted of pelvic muscle exercises conducted with electromyographic feedback weekly, for 3 months. Oral duloxetine was administered at bedtime for 3 months. The primary outcome was prevalence of continence at 6 months, defined as using ≤1 security pad. Urinary symptoms and QoL were assessed by using a visual analogue scale, and validated questionnaires. RESULTS: From the 240 patients included in the trial, 89% of patients completed 1 year of follow-up. Treatment compliance was observed in 88% (92/105) of patients receiving duloxetine, and in 97% (104/107) of patients scheduled to PFMT-biofeedback sessions. In the control group 96% of patients had achieved continence at 6 months, compared with 90% (p = 0.3) in the PMFT-biofeedback, 73% (p = 0.008) in the duloxetine, and 69% (p = 0.003) in the combined treatment arm. At 6 months, QoL was classified as uncomfortable or worse in 17% of patients in the control group, compared with 44% (p = 0.01), 45% (p = 0.008), and 34% (p = 0.07), respectively. Complete preservation of neurovascular bundles (NVB) (OR: 2.95; p = 0.048) was the only perioperative intervention found to improve early UCR. CONCLUSIONS: PFMT-biofeedback and duloxetine demonstrated limited impact in improving UCR after RP. Diligent NVB preservation, along with preoperative patient and disease characteristics, are the primary determinants for early UCR.

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.

EEG abnormalities are not associated with poor antidepressant treatment outcome - A NeuroPharm study.

EEG brain abnormalities, such as slowing and isolated epileptiform discharges (IEDs), has previously been associated with non-response to antidepressant treatment with escitalopram and venlafaxine, suggesting a potential need for treatment with anticonvulsant property in some patients. The current study aims to replicate the reported association of EEG abnormality and treatment outcomes in an open-label trial of escitalopram for major depressive disorder (MDD) and explore its relationship to mood and cognition. Pretreatment, 6 min eyes-closed resting-state 256-channel EEG was recorded in 91 patients with MDD (age 18-57) who were treated with 10-20 mg escitalopram for 12 weeks; patients could switch to duloxetine after four weeks. A certified clinical neurophysiologist rated the EEGs. IED and EEG slowing was seen in 13.2%, and in 6.6% there were findings with unclear significance (i.e., Wicket spikes and theta activity). We saw no group-difference in remission or response rates after 8 and 12 weeks of treatment or switching to duloxetine. Patients with EEG abnormalities had higher pretreatment mood disturbances driven by greater anger (p=.039) and poorer verbal memory (p=.012). However, EEG abnormality was not associated with improved mood or verbal memory after treatment. Our findings should be interpreted in light of the rarity of EEG abnormalities and the sample size. While we cannot confirm that EEG abnormalities are associated with non-response to treatment, including escitalopram, abnormal EEG activity is associated with poor mood and verbal memory. The clinical utility of EEG abnormality in antidepressant treatment selection needs careful evaluation before deciding if useful for clinical implementation.

Antidepressant duloxetine hydrochloride protects against ovariectomy-induced bone loss in mice by inhibiting osteoclast differentiation.

BACKGROUND: Several studies have reported the association between osteoporosis and major depressive disorder (MDD) as well as the use of antidepressants. However, it remains to be elucidated whether these associations are related to exposure to antidepressants, a consequence of a disease process, or a combination of both. METHODS: This study investigates the independent effect of the antidepressant duloxetine hydrochloride (DH) on ovariectomy-induced bone loss in mice. One week after ovariectomy, the treated mice received DH. To explore the mechanism underlying the rescue of bone loss, bone marrow cells were isolated from mouse femurs and tibias, and macrophages extracted from them were induced to become osteoclasts in vitro while being treated with DH. Subsequently, the osteoclasts underwent Bulk RNA-Seq to reveal the involved signaling pathways. The results of the bioinformatic analysis were then validated through in vitro experiments. RESULTS: The in vivo experiments demonstrated that DH treatment compromised ovariectomy-induced bone loss after 7 weeks. The in vitro experiments suggested that DH treatment attenuated osteoclast differentiation via the MAPKs/NFATc1 signaling pathway. CONCLUSION: The findings from this study suggest that DH, instead of causing bone mass loss, may assist in alleviating postmenopausal osteoporosis. These results can serve as a reference for the clinical treatment of patients with perimenopausal or postmenopausal depression using antidepressants.

Treatment-induced neuropathy of diabetes: challenges in diagnosing neuropathic pain, value of sudomotor function testing.

A patient in his 60s was admitted for an extensive neurological work-up due to progressive asymmetrical, distally pronounced pain in both feet and legs. Conventional pain relievers did not help in pain reduction. A Sudoscan revealed small fibre damage in all extremities indicating an underlying neuropathy. The patient had started insulin treatment around 6 months prior to hospitalisation because of a newly diagnosed late-onset diabetes. Due to a rapid drop in glycated haemoglobin (from over 14% to 6% in 4 months), treatment-induced neuropathy of diabetes (TIND) was hypothesised. On increasing the dose of pregabalin and adding duloxetine, the patient reported improvement of symptoms, which further underlined the suspected diagnosis. Hence, in patients with severe hyperglycaemia, changes in glycaemic control should be stepwise and not rapid; however, to date, no guidelines exist how to avoid TIND.

Chronic Pain Syndromes: Fibromyalgia.

Fibromyalgia is a chronic pain syndrome that is considered a pain processing disorder; its pathophysiology is not completely understood. The estimated prevalence in the general population varies from 0.5% to 12%, depending on the population studied and diagnostic criteria used. It is more common in females than males. There is no diagnostic laboratory test. The two currently used diagnostic methods are scoring criteria from the American College of Rheumatology (ACR) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION)-American Pain Society (APS). These diagnostic criteria include chronic widespread pain of at least 3 months' duration plus poor sleep and/or fatigue and other somatic symptoms. Other pain syndromes also should be considered in the differential diagnosis. A multimodal, targeted symptom management approach that emphasizes self-management is recommended. Nonpharmacotherapies include patient education, exercise, and cognitive behavior therapy. Pharmacotherapy should be based on predominant symptoms. Amitriptyline and pregabalin are effective for management of pain, fatigue, and sleep issues. Milnacipran (Savella) is effective for pain and fatigue. Duloxetine is effective for management of pain and depression. There is no evidence of benefit of analgesics. Common comorbidities, such as regional pain conditions and mental disorders, should be addressed.

A Comparative Assessment of the Inflammatory Markers in Patients with Fibromyalgia under Duloxetine Treatment.

BACKGROUND: This study was carried out to compare the levels of inflammatory markers in the complete blood count before and after they began receiving duloxetine in patients with fibromyalgia syndrome (FMS). METHODS: The patient and control groups were composed of 40 patients diagnosed with FMS in accordance with the 2016 American College of Rheumatology (ACR) criteria and 40 healthy volunteers, respectively. The data collection tools comprised the sociodemographic information form, the fibromyalgia impact questionnaire (FIQ), and the sleep hygiene index (SHI), which were used to assess patients' sociodemographic characteristics, FMS disease activity, and sleep quality, respectively. The inflammatory markers of the patient group were assessed by complete blood count before and after the duloxetine treatment and compared with those of the control group. RESULTS: The white blood cell (WBC), neutrophil, and lymphocyte counts were significantly higher in the patient group than in the control group (p < 0.001, p = 0.036 and p = 0.004, respectively). Moreover, platelet distribution width (PDW) was significantly lower, whereas mean platelet volume (MPV) was significantly higher in the patient group than in the control group (p < 0.001 for both cases). In addition to patients' platelet-to-lymphocyte ratio (PLR) values, C-reactive protein (CRP) levels, and white blood cell (WBC) counts decreasing but not significantly (p = 0.083, p = 0.068, and p = 0.065, respectively), their neutrophil-to-lymphocyte ratio (NLR), hemoglobin (Hgb), and hematocrit (Hct) values declined substantially after commencing duloxetine treatment (p = 0.001, p = 0.008, and p = 0.001, respectively). CONCLUSIONS: The significant reduction in NLR, Hgb, and Hct levels following duloxetine treatment may indicate that these parameters can be utilized as biomarkers in determining the efficacy of treatment and in the follow-up of the treatment in FMS patients.

Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. The lifetime prevalence of DPN is thought to be >50%, and 15%-25% of patients with diabetes experience neuropathic pain, referred to as "painful DPN." Appropriate treatment of painful DPN is important because this pain contributes to a poor quality of life by causing sleep disturbance, anxiety, and depression. The basic principle for the management of painful DPN is to control hyperglycemia and other modifiable risk factors, but these may be insufficient for preventing or improving DPN. Because there is no promising diseasemodifying medication for DPN, the pain itself needs to be managed when treating painful DPN. Drugs for neuropathic pain, such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, alpha-lipoic acid, sodium channel blockers, and topical capsaicin, are used for the management of painful DPN. The U.S. Food and Drug Administration (FDA) has approved pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch as drugs for the treatment of painful DPN. Recently, spinal cord stimulation using electrical stimulation is approved by the FDA for the treatment for painful DPN. This review describes the currently available pharmacological and nonpharmacological treatments for painful DPN.

The Impact of the CYP2D6 and CYP1A2 Gene Polymorphisms on Response to Duloxetine in Patients with Major Depression.

Depression is a global mental health concern, and personalized treatment approaches are needed to optimize its management. This study aimed to investigate the influence of the CYP2D6 and CYP1A2 gene polymorphisms on the efficacy of duloxetine in reducing depressive and anxiety symptoms. A sample of 100 outpatients with major depression, who initiated monotherapy with duloxetine, were followed up. Polymorphisms in the CYP2D6 and CYP1A2 genes were assessed. The severity of depressive and anxiety symptoms was recorded using standardized scales. Adverse drug reactions (ADRs) were analyzed. Statistical analyses, including linear regression, were conducted to examine the relationships between genetic polymorphisms, clinical variables, and treatment outcomes. Patients with higher values of the duloxetine metabolic index (DMI) for CYP2D6, indicating a faster metabolism, achieved a greater reduction in anxiety symptoms. The occurrence of ADRs was associated with a lower reduction in anxiety symptoms. However, no significant associations were found between studied gene polymorphisms and reduction in depressive symptoms. No significant effects of the DMI for CYP1A2 were found. Patients with a slower metabolism may experience less benefit from duloxetine therapy in terms of anxiety symptom reduction. Personalizing treatment based on the CYP2D6 and CYP1A2 gene polymorphisms can enhance the effectiveness of antidepressant therapy and improve patient outcomes.

The antidepressant drugs vortioxetine and duloxetine differentially and sex-dependently affect animal well-being, cognitive performance, cardiac redox status and histology in a model of osteoarthritis.

Osteoarthritis represents a leading cause of disability with limited treatment options. Furthermore, it is frequently accompanied by cardiovascular and cognitive disorders, which can be exacerbated by osteoarthritis or drugs used for its treatment. Here, we examined the behavioral and cardiac effects of the novel antidepressant vortioxetine in an osteoarthritis model, and compared them to duloxetine (an established osteoarthritis treatment). Osteoarthritis was induced in male and female rats with an intraarticular sodium-monoiodoacetate injection. Antidepressants were orally administered for 28 days following induction. During this period the acetone, burrowing and novel-object-recognition tests (NORT) were used to assess the effects of antidepressants on pain hypersensitivity (cold allodynia), animal well-being and cognitive performance, respectively. Following behavioral experiments, heart muscles were collected for assessment of redox status/histology. Antidepressant treatment dose-dependently reduced cold allodynia in rats with osteoarthritis. Duloxetine (but not vortioxetine) depressed burrowing behavior in osteoarthritic rats in a dose-related manner. Osteoarthritis induction reduced cognitive performance in NORT, which was dose-dependently alleviated by vortioxetine (duloxetine improved performance only in female rats). Furthermore, duloxetine (but not vortioxetine) increased oxidative stress parameters in the heart muscles of female (but not male) rats and induced histological changes in cardiomyocytes indicative of oxidative damage. Vortioxetine displayed comparable efficacy to duloxetine in reducing pain hypersensitivity. Furthermore, vortioxetine (unlike duloxetine) dose-dependently improved cognitive performance and had no adverse effect on burrowing behavior (animal surrogate of well-being) and cardiac redox status/histology. Our results indicate that vortioxetine could be a potential osteoarthritis treatment (with better characteristics compared to duloxetine).

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.

Duloxetine HCl Alleviates Asthma Symptoms by Regulating PI3K/AKT/mTOR and Nrf2/HO-1 Signaling Pathways.

Asthma is an inflammatory disease characterized by airway hyperresponsiveness, airway remodeling, and airway inflammation. In recent years, the prevalence of asthma has been increasing steadily and the pathogenesis of asthma varies from person to person. Due to poor compliance or resistance, existing drugs cannot achieve the desired therapeutic effect. Therefore, developing or screening asthma therapeutic drugs with high curative effects, low toxicity, and strong specificity is very urgent. Duloxetine HCl (DUX) is a selective serotonin and norepinephrine reuptake inhibitor, and it was mainly used to treat depression, osteoarthritis, and neuropathic pain. It was also reported that DUX has potential anti-infection, anti-inflammation, analgesic, antioxidative, and other pharmacological effects. However, whether DUX has some effects on asthma remains unknown. In order to investigate it, a series of ex vivo and in vivo experiments, including biological tension tests, patch clamp, histopathological analysis, lung function detection, oxidative stress enzyme activity detection, and molecular biology experiments, were designed in this study. We found that DUX can not only relax high potassium or ACh precontracted tracheal smooth muscle by regulating L-type voltage-dependent Ca2+ channel (L-VDCC) and nonselective cation channel (NSCC) ion channels but also alleviate asthma symptoms through anti-inflammatory and antioxidative response regulated by PI3K/AKT/mTOR and Nrf2/HO-1 signaling pathways. Our data suggests that DUX is expected to become a potential new drug for relieving or treating asthma.

Pelvic floor muscle exercise with or without duloxetine for postprostatectomy urinary incontinence: A retrospective single-center study.

This study aimed to evaluate the effectiveness of combined pelvic floor muscle exercise (PFME) and duloxetine treatment in the recovery from postprostatectomy urinary incontinence (PPUI). Participants were patients who underwent radical prostatectomy (RP) between 2018 and 2021 and who were able to attend follow-up appointments every 3 months for at least 12 months. Continence was defined as the use of ≤1 pad per day. PPUI was compared at each follow-up period by dividing the participants into the PFME group (PFME only after RP) and the PFME + DUL group (PFME and 30 mg duloxetine daily after RP). A total of 197 patients were included. No significant differences were observed in the baseline characteristics between the 2 groups. In the PFME group (n = 127), the PPUI was 77.17%, 27.56%, 17.32%, 12.60%, and 9.45% at 2 weeks, 3 months, 6 months, 9 months, and 12 months, respectively. In the PFME + DUL group (n = 70), the PPUI was 62.50%, 17.86%, 12.50%, 8.93%, and 5.36%, respectively, at the same follow-up period. At 2 weeks, the PFME + DUL group demonstrated a better incontinence rate than the PFME group (P = .019). However, no significant differences were found in the incontinence rates between the 2 groups at each follow-up period after 3 months. Compared to PFME monotherapy, the combination therapy of PFME and duloxetine has short-term effectiveness in improving PPUI, but it does not have a significant long-term impact. Therefore, for early recovery from PPUI, duloxetine should be administered for a short period during PFME.

Duloxetine for fibromyalgia syndrome: a systematic review and meta-analysis.

INTRODUCTION: The optimal dose of duloxetine in the management of fibromyalgia remains still controversial. Therefore, a systematic review and meta-analysis to investigate efficacy and safety of duloxetine was conducted. The outcomes of interests were to assess changes in Fibromyalgia Impact Questionnaire (FIQ), Brief Pain Inventory (BPI), and Clinical Global Impression (CGI). The rate of of adverse events and those leading to therapy discontinuation were also investigated. MATERIAL AND METHODS: This study followed the 2020 PRISMA guidelines. The literature search started in December 2022 accessing PubMed, Google scholar, Embase, and Scopus databases. All the RCTs investigating the efficacy and safety of daily administration of duloxetine for fibromyalgia were accessed. Studies reporting quantitative data under the outcomes of interest, and including a minimum of 10 patients who completed a minimum of 4 weeks follow-up, were included. Studies on combined pharmacological and non-pharmacological managements for fibromyalgia were not considered. RESULTS: Data from 3432 patients (11 RCTs) were included. The mean age of the patients was 46.4 ± 10.7 years old, and the mean BMI 25.3 ± 3.2 kg/m2. 90% (3089 of 3432 patients) were women. The 60 mg/daily cohort reported the higher FIQ, followed by the 30, 30-60, 120 mg/daily, and placebo groups, while the 60-120 mg /daily group performed the worst results. Concerning the CGI severity scale, placebo resulted in the lowest improvement, and no differences were found in the other groups. Concerning the BPI interference and severity pain scores, the 30-60 mg/daily group reported the worst result, along with the placebo group. The rate of adverse events leading to study discontinuation were lower in the 60-120 group, followed by the 30-60 and 30 mag/daily groups. Duloxetine was superior in all the comparisons to placebo, irrespective of the doses, in all endpoints analysed. CONCLUSIONS: Duloxetine could help in improving symptoms of fibromyalgia. The dose of duloxetine should be customised according to individual patients. Irrespective of the doses, duloxetine was more effective than placebo in the management of fibromyalgia. The dose of duloxetine must be customised according to individual patients. Level of evidence I Meta-analysis of double-blind RCTs.