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Objectives: Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus (DM) with symptoms like intense pain and impaired quality of life. This condition has no treatment; instead, the pain is managed with various antidepressants, including duloxetine. The aim of this study is to analyze the evidence on the efficacy of duloxetine in the management of DPN. Methods: A systematic search in different databases was conducted using the keywords "diabetic neuropathy", "duloxetine therapy", "neuropathic pain", and "Diabetes Mellitus". Finally, eight studies were included in this meta-analysis. Results: All articles comparing duloxetine at different doses vs. a placebo reported significant differences in favor of duloxetine on pain scales like 24 h Average Pain Severity (standardized mean difference [SMD] = -1.06, confidence interval [CI] = -1.09 to -1.03, and p < 0.00001) and BPI Severity (SMD = -0.70, CI = -0.72 to -0.68, and p < 0.00001), among others. A total of 75% of the meta-analyses of studies comparing duloxetine at different doses showed a tendency in favor of the 120 mg/d dose. There were significant differences in favor of duloxetine when compared to routine care on the Euro Quality of Life (SMD = -0.04, CI = -0.04 to -0.03, and p < 0.00001) and SF-36 Survey (SMD = -5.86, CI = -6.28 to -5.44, and p < 0.00001) scales. There were no significant differences on the visual analog scale (VAS) when comparing duloxetine and gabapentin. Conclusions: Duloxetine appears to be effective in the management of DPN in different pain, symptom improvement, and quality of life scales.

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Cryptococcosis is an invasive mycosis caused mainly by Cryptococcus gattii and C. neoformans and is treated with amphotericin B (AMB), fluconazole and 5-fluorocytosine. However, antifungal resistance, limited and toxic antifungal arsenal stimulate the search for therapeutic strategies such as drug repurposing. Among the repurposed drugs studied, the selective serotonin reuptake inhibitors (SSRIs) have shown activity against Cryptococcus spp. However, little is known about the antifungal effect of duloxetine hydrochloride (DH), a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), against C. neoformans and C. gattii. In this study, DH inhibited the growth of several C. neoformans and C. gattii strains at concentrations ranging from 15.62 to 62.50 µg/mL. In addition, DH exhibited fungicidal activity ranging from 15.62 to 250 µg/mL. In biofilm, DH treatment reduced Cryptococcus spp. biomass at a level comparable to AMB, with a significant reduction (85%) for C. neoformans biofilms. The metabolic activity of C. neoformans and C. gattii biofilms decreased significantly (99%) after treatment with DH. Scanning electron micrographs confirmed the anti-biofilm activity of DH, as isolated cells could be observed after treatment. In conclusion, DH showed promising antifungal activity against planktonic cells and biofilms of C. neoformans and C. gattii, opening perspectives for further studies with DH in vivo.

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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.

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Abstract Aim To identify the phenotypic characteristics of individuals with temporomandibular disorders (TMD) who may benefit from adding duloxetine to self-management (SM) strategies. Methodology This was a post hoc exploratory analysis of a randomized, placebo-controlled clinical trial with SM-duloxetine (duloxetine 60 mg/day plus SM strategies for 12 weeks) in adult participants with painful TMD. The primary outcome was the proportion of responders to treatment (individuals with ≥ 30% reduction in pain intensity) in SM-duloxetine and SM-placebo group at week 12. For responder analysis, five phenotyping domains recommended by Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials were assessed: pain, psychological, sleep, quantitative sensory testing, and conditioned pain modulation. Relative risk (RR), 95% confidence intervals (CI), and absolute risk reduction were calculated. Results Among participants treated with SM-duloxetine, severe pain intensity (RR 1.33, 95% CI: 0.56, 3.17), pain disability (RR 1.30, 95% CI: 0.63, 2.67), ≥ 1 painful comorbidity (RR 1.48, 95% CI: 0.57, 3.79), and anxiety symptoms (RR 1.80, 95% CI: 0.75, 4.34) were associated with greater likelihood of response to treatment. Among individuals treated with SM-placebo, only temporal summation of pain was associated with greater likelihood of response to treatment. Conclusion Personalized medicine may be implemented in painful TMD management, and phenotype characteristics related to pain and psychological domains may predict which individuals with painful TMD are more likely to respond to the addition of serotonin and norepinephrine reuptake inhibitors to SM strategies to clinically and significantly reduce pain intensity.

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Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED30, von Frey testing) and thermal hyperalgesia (ED50, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED30 and ED50 for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.

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BACKGROUND: To evaluate the effect of duloxetine when added to a multimodal analgesia regimen on posthemorrhoidectomy pain, opioid consumption, and side effects. METHODS: Prospective, randomized, double-blind placebo-controlled trial. This study included 62 patients who underwent hemorrhoidectomy. The patients were randomly assigned to receive oral duloxetine 60 mg or placebo 2 h before and 24 h after surgery. The primary outcomes were pain intensity - measured on an 11-point visual analog pain scale - and cumulative morphine consumption at 12, 24, and 48 postoperative hours. RESULTS: Fifty-two patients completed the study (25 in the duloxetine group and 27 in the placebo group). Pain scores did not differ between duloxetine and placebo: 4.5; 3.0 - 7.0 vs. 5.0; 3.5 - 7.0, p = 0.68 at 12 h, 3.0; 2.0 - 5.0 vs. 3.0; 2.0 - 5.0, p = 0.56 at 24 h, and 2.5; 1.75 - 3.75 vs. 1.5; 0.5 - 3, p = 0.08 at 48 h. Further, cumulative morphine consumption did not differ between the duloxetine and placebo groups: 4; 1.25 - 10.75 mg vs. 7; 1.0 - 12.0 mg, p = 0.68 at 12 h, 9.5; 2.0 - 17.5 mg vs. 8.0; 4.0 - 18.0 mg; p = 0.80 at 24 h, and 11.0; 2.0 - 27.0 mg vs. 10; 4.0 - 24.0 mg, p = 0.78 at 48 h. Side effects did not differ between the groups. CONCLUSIONS: Compared with placebo, duloxetine did not decrease pain intensity or morphine consumption during the first 48 h postoperatively. TRIAL REGISTRATION: The study was retrospectively registered on the Brazilian Clinical Trials Registry (identifier: RBR-9pdgms, registration date: 08/10/2020).

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ABSTRACT BACKGROUND AND OBJECTIVES: The association of the use of some drugs with hyperprolactinemia and galactorrhea has been reported in the literature, but information on the role of duloxetine in these alterations is scarce. Therefore, the aim of this study was to highlight this adverse effect and discuss the pathophysiological causes of galactorrhea associated with the use of duloxetine in a patient undergoing treatment for chronic pain. CASE REPORT: Female patient, 70 years old, with herpetic neuropathy diagnosis. She developed refractory pain after drug treatment and was referred to the pain clinic. Duloxetine (60mg) taken once a day was maintained and associated with blocks with local anesthetic in regions of herpetic pain. The patient complained of galactorrhea and changes in weight and showed an increase in serum prolactin. Then, the possibility of hyperprolactinemia due to duloxetine was raised. Duloxetine was suspended, and after one month, a significant reduction in serum prolactin levels and end of galactorrhea were observed. CONCLUSION: The treatment of patients with neuropathic pain is extremely challenging and the detailed understanding, especially of the pharmacological strategy and its possible adverse effects, is fundamental for the better management of patients and their well-being. Therefore, it is concluded that duloxetine, although rarely, can cause an increase in serum prolactin and galactorrhea in users.

RESUMO JUSTIFICATIVA E OBJETIVOS: A associação do uso de alguns fármacos com hiperprolactinemia e galactorreia tem sido relatada na literatura, mas são escassas as informações sobre o papel da duloxetina nestas alterações. Portanto, o objetivo deste estudo foi destacar este efeito adverso e discutir as causas fisiopatológicas da galactorreia associada ao uso de duloxetina no tratamento da dor crônica. RELATO DO CASO: Paciente do sexo feminino, 70 anos, com diagnóstico de neuropatia herpética. Evoluiu com refratariedade álgica após tratamento farmacológico, sendo encaminhada à clínica de dor. Optou-se por manter a duloxetina (60 mg) uma vez ao dia e associar bloqueios com anestésico local em regiões de dor herpética. A paciente queixou-se de galactorreia e alteração de peso e apresentou elevação da prolactina sérica. Foi aventada, então, a possibilidade de hiperprolactinemia pela duloxetina. Foi, então, realizada a suspensão da duloxetina e, após um mês, foi observada redução expressiva dos níveis séricos da prolactina e cessação da galactorreia. CONCLUSÃO: O tratamento de pacientes com dor neuropática é extremamente desafiador e a compreensão detalhada do processo, em destaque para a estratégia farmacológica e seus possíveis efeitos adversos é fundamental para o melhor manejo dos pacientes e manutenção do bem-estar. Diante disso, concluiu-se que a duloxetina, apesar de acontecer raramente, pode causar aumento da prolactina sérica e galactorreia em usuários.

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SUMMARY OBJECTIVES: This study aimed to investigate the effects of duloxetine and pregabalin primarily on pain and functional status in patients with knee osteoarthritis and secondarily on quality of life, depression, anxiety, and sleep disturbance. METHODS: A total of 66 patients with knee osteoarthritis were randomized to use duloxetine or pregabalin. Patients were evaluated by Visual Analog Scale, Neuropathic Pain Diagnostic Questionnaire, Western Ontario and McMaster University Osteoarthritis Index, Short Form-36, Beck Depression Inventory, Beck Anxiety Inventory, and Pittsburg Sleep Quality Index before the treatment and after 4 and 12 weeks of treatment. RESULTS: Improvements occurred in Visual Analog Scale, Neuropathic Pain Diagnostic Questionnaire, Western Ontario and McMaster University Osteoarthritis Index, Short Form-36 (with an exception of the mental health subgroup scores in duloxetine-treated group), Beck Depression Inventory, and Beck Anxiety Inventory scores in both groups from 4 weeks after baseline. Pittsburg Sleep Quality Index total scores and SF-36 mental health subgroup scores started to improve on the 4th and 12th weeks in pregabalin- and duloxetine-treated groups, respectively. CONCLUSION: Osteoarthritis pain, a complex outcome with nociceptive and neuropathic components, leads to central sensitization in a chronic phase. Using centrally acting drugs in the control of pain and associated symptoms would increase the probability of treatment success.

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BACKGROUND: Amitriptyline, duloxetine, and pregabalin are among the most pharmacotherapeutic, effective treatments for neuropathic pain control. However, the evaluation of synergism by combining these treatments is still poorly investigated. OBJECTIVES: To evaluate the pharmacokinetics of the combination of pregabalin plus duloxetine and pregabalin plus amitriptyline, as well as the effect of these on neuropathic pain on rodent model. STUDY DESIGN: The experimental study. SETTING: The research took place in the research laboratories at the Federal University of Alfenas after ethics committee approval. METHODS: This study used male Wistar rats weighing between 220 and 250 g. The animals were randomly divided into the following groups: monotherapy (pregabalin, amitriptyline, duloxetine), combined therapy (pregabalin + amitriptyline, pregabalin + duloxetine), and vehicle (ultrapure water). Pharmacokinetic analysis of pregabalin or combination (pregabalin + amitriptyline or pregabalin + duloxetine) in the plasma were performed by ultraperformance liquid chromatography tandem mass spectrometry. Neuropathic pain was induced by sciatic nerve constriction (chronic constriction injury [CCI]) model, and nociceptive threshold was measured by von Frey filaments test. In addition, to evaluate the influence of the treatments on the motor coordination, the rotarod test was used. RESULTS: The pharmacokinetic disposition of pregabalin was changed in the association with amitriptyline, presenting a clearance reduction and consequently an increase in bioavailability. Furthermore, after the 14th day of CCI, pregabalin was administered orally and induced antiallodynic effect after 1, 2:15, 4, and 8 hours of its administration and showed the greatest antiallodynic effect after 4 hours of its administration. Moreover, this effect was prolonged (up to 8 hours) by combination with amitriptyline. Additionally, pregabalin and pregabalin + duloxetine showed a hypoalgesic effect in sham rats. In addition, the rotarod test results showed that drugs did not influence the motor coordination of the rats. LIMITATIONS: Potential competition mechanisms during the excretion of pregabalin, when pregabalin was combined with amitriptyline, were not investigated in this study. CONCLUSIONS: The data demonstrated that combined therapy of pregabalin plus amitriptyline improved the bioavailability of pregabalin and potentiated the efficacy of the antiallodynic effect of pregabalin alone, proving to be advantageous for the treatment of sciatic neuropathic pain.

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ABSTRACT Ejaculation is controlled by both the sympathetic and parasympathetic system and consists of an emission and expulsion phase. Ejaculation latency time is regulated by the sympathetic system. Hypothetically, by reducing ejaculatory latency time, spontaneous ejaculation can occur. Extending the duration of ejaculation is a well-known side effect of antidepressants, especially selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and noradrenergic reuptake inhibitors. Adrenergic drugs are sometimes used as treatment for delayed ejaculation. A spontaneous ejaculation due to the use of these drugs has rarely been reported. Although most reports of spontaneous ejaculations are related to the use of venlafaxine and reboxetine, this study is based on a case of the side effect of duloxetine.

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