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The Journal of Neuroscience : the... Jan 2022Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it...
Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN. Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.
Topics: Analgesics; Animals; Antineoplastic Agents; Corticosterone; Duloxetine Hydrochloride; Female; Male; Oxaliplatin; Paclitaxel; Pain Management; Pain Threshold; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley
PubMed: 34880120
DOI: 10.1523/JNEUROSCI.1691-21.2021 -
ACS Chemical Neuroscience Apr 2023Antidepressants, such as duloxetine and amitriptyline, are effective for treating patients with chronic neuropathic pain. Inhibiting norepinephrine and serotonin...
Antidepressants, such as duloxetine and amitriptyline, are effective for treating patients with chronic neuropathic pain. Inhibiting norepinephrine and serotonin transporters at presynaptic terminals raises extracellular concentrations of norepinephrine. The α1- and α2-adrenergic receptor agonists inhibit glutamatergic input from primary afferent nerves to the spinal dorsal horn. However, the contribution of spinal α1- and α2-adrenergic receptors to the analgesic effect of antidepressants and associated synaptic plasticity remains uncertain. In this study, we showed that systemic administration of duloxetine or amitriptyline acutely reduced tactile allodynia and mechanical and thermal hyperalgesia caused by spinal nerve ligation in rats. In contrast, duloxetine or amitriptyline had no effect on nociception in sham rats. Blocking α1-adrenergic receptors with WB-4101 or α2-adrenergic receptors with yohimbine at the spinal level diminished the analgesic effect of systemically administered duloxetine and amitriptyline. Furthermore, intrathecal injection of duloxetine or amitriptyline similarly attenuated pain hypersensitivity in nerve-injured rats; the analgesic effect was abolished by intrathecal pretreatment with both WB-4101 and yohimbine. In addition, whole-cell patch-clamp recordings in spinal cord slices showed that duloxetine or amitriptyline rapidly inhibited dorsal root-evoked excitatory postsynaptic currents in dorsal horn neurons in nerve-injured rats but had no such effect in sham rats. The inhibitory effect of duloxetine and amitriptyline was abolished by the WB-4101 and yohimbine combination. Therefore, antidepressants attenuate neuropathic pain predominantly by inhibiting primary afferent input to the spinal cord via activating both α1- and α2-adrenergic receptors. This information helps the design of new strategies to improve the treatment of neuropathic pain.
Topics: Rats; Animals; Duloxetine Hydrochloride; Amitriptyline; Rats, Sprague-Dawley; Antidepressive Agents; Spinal Cord Dorsal Horn; Norepinephrine; Posterior Horn Cells; Hyperalgesia; Yohimbine; Neuralgia; Analgesics; Receptors, Adrenergic
PubMed: 36930958
DOI: 10.1021/acschemneuro.2c00780 -
Contrast Media & Molecular Imaging 2022Diabetic peripheral neuropathic pain (DPNP) is a common chronic pain condition affecting diabetic patients and has growing importance because of the increasing... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Diabetic peripheral neuropathic pain (DPNP) is a common chronic pain condition affecting diabetic patients and has growing importance because of the increasing prevalence of patients with type 2 diabetes mellitus. Pain is the most troublesome symptom of DPNP, increasingly recognized as an important and independent feature of DPNP. This meta-analysis aims to compare the efficacy and safety of duloxetine and gabapentin in the treatment of diabetic peripheral neuropathic pain (DPNP) and therefore to provide evidence-based medicine for clinical treatment.
METHODS
Relevant randomized controlled trials on duloxetine versus gabapentin for DPNP were searched from PubMed, Embase, Cochrane Library, Web of Science, CNKI, WanFang, VIP, and Chinese Biomedical Literature Database from database inception to October 2021. The data were analyzed by RevMan 5.3 software.
RESULTS
Seven studies were included. The results showed that, at the end of the study, duloxetine was significantly superior to gabapentin in terms of the incidence of adverse reactions (RR = 0.59, 95% CI: 0.45-0.79, < 0.01), sleep interference score (SMD = -0.35, 95% CI: -0.63 to -0.08, < 0.05), but no significant differences in VAS score (SMD = -0.14, 95% CI: -0.31-0.03, > 0.05), overall response rate (RR = 1.05, 95% CI: 0.92-1.20, > 0.05), and clinical global impression of change (SMD = 0.07, 95% CI: -0.20-0.35, > 0.05).
CONCLUSION
Compared with gabapentin, duloxetine has no obvious advantage in the treatment of diabetic peripheral neuralgia, but it has less side effects and significantly higher safety.
Topics: Analgesics; Chronic Disease; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Duloxetine Hydrochloride; Gabapentin; Humans; Neuralgia
PubMed: 35299589
DOI: 10.1155/2022/4084420 -
Scientific Reports Mar 2021We evaluated the duloxetine DNA damaging capacity utilizing the comet assay applied to mouse brain and liver cells, as well as its DNA, lipid, protein, and nitric oxide...
We evaluated the duloxetine DNA damaging capacity utilizing the comet assay applied to mouse brain and liver cells, as well as its DNA, lipid, protein, and nitric oxide oxidative potential in the same cells. A kinetic time/dose strategy showed the effect of 2, 20, and 200 mg/kg of the drug administered intraperitoneally once in comparison with a control and a methyl methanesulfonate group. Each parameter was evaluated at 3, 9, 15, and 21 h postadministration in five mice per group, except for the DNA oxidation that was examined only at 9 h postadministration. Results showed a significant DNA damage mainly at 9 h postexposure in both organs. In the brain, with 20 and 200 mg/kg we found 50 and 80% increase over the control group (p ≤ 0.05), in the liver, the increase of 2, 20, and 200 mg/kg of duloxetine was 50, 80, and 135% in comparison with the control level (p ≤ 0.05). DNA, lipid, protein and nitric oxide oxidation increase was also observed in both organs. Our data established the DNA damaging capacity of duloxetine even with a dose from the therapeutic range (2 mg/kg), and suggest that this effect can be related with its oxidative potential.
Topics: Animals; Brain; DNA Damage; Duloxetine Hydrochloride; Liver; Male; Mice; Oxidation-Reduction; Oxidative Stress; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 33767322
DOI: 10.1038/s41598-021-86366-0 -
International Journal of Molecular... Feb 2022While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million...
While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.
Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Duloxetine Hydrochloride; Hemostasis; Humans; Mice; Norepinephrine; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Serotonin; Serotonin Antagonists; Thrombosis
PubMed: 35269729
DOI: 10.3390/ijms23052587 -
Anais Da Academia Brasileira de Ciencias 2022This study aimed to evaluate the effect of duloxetine hydrochloride (DH) on Cryptococcus neoformans. DH minimum inhibitory concentration (MIC) and minimum fungicidal...
This study aimed to evaluate the effect of duloxetine hydrochloride (DH) on Cryptococcus neoformans. DH minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were 18.5 µg/mL, and the combination with fluconazole (FLZ) reduced the MIC value by 16-and 4-fold for DH and FLZ, respectively. The capsule size decreased by 67% and 16% when treated with DH and DH with FLZ, respectively. Therefore, this study showed that DH is active against C. neoformans alone and in combination with FLZ, leading to the reduction of the capsule size of this yeast.
Topics: Antifungal Agents; Cryptococcus neoformans; Duloxetine Hydrochloride; Fluconazole; Microbial Sensitivity Tests
PubMed: 35544847
DOI: 10.1590/0001-3765202220211021 -
American Journal of Otolaryngology 2020We investigated the frequency of tinnitus in fibromyalgia patients and the effect of drugs used for routine fibromyalgia on tinnitus.
OBJECTIVES
We investigated the frequency of tinnitus in fibromyalgia patients and the effect of drugs used for routine fibromyalgia on tinnitus.
METHODS
We included 101 diagnosed fibromyalgia patients. After detailed ear nose throat examination, audiometric tests and tinnitus handicap index (THI) were performed. After the tests, routine treatment for fibromyalgia was started by the physical therapy and rehabilitation department. Two months after the beginning of the treatment, THI were repeated again and the results were statistically evaluated.
RESULTS
All patients included in the study were women. 74.3% of the patients had tinnitus. Pregabalin and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant-treated patients were evaluated; In both groups, there was a statistically significant difference between pre- and post-treatment tinnitus levels (p < .001). However, there was no statistically significant difference between pregabalin group and diloxetine group according to treatment results.
CONCLUSIONS
The incidence of tinnitus is high in fibromyalgia patients. That pregabalin and duloxetine agents routinely used in fibromyalgia require further experimental and human studies in order to be able to use in tinnitus.
Topics: Adult; Aged; Antidepressive Agents; Duloxetine Hydrochloride; Female; Fibromyalgia; Humans; Middle Aged; Physical Therapy Modalities; Pregabalin; Selective Serotonin Reuptake Inhibitors; Tinnitus; Young Adult
PubMed: 31926598
DOI: 10.1016/j.amjoto.2020.102390 -
Dental Clinics of North America Oct 2023A patient with a past medical history significant for fibromyalgia presents for an incisional oral biopsy. The condition is being managed pharmacologically with... (Review)
Review
A patient with a past medical history significant for fibromyalgia presents for an incisional oral biopsy. The condition is being managed pharmacologically with duloxetine and ibuprofen. Given the patient's medical condition and medications, specific considerations were placed on chair positioning, muscle pain and tenderness, and achieving hemostasis through local measures. The patient was advised to follow up in 2 weeks for postoperative evaluation.
Topics: Humans; Fibromyalgia; Biopsy; Duloxetine Hydrochloride; Ibuprofen
PubMed: 37714615
DOI: 10.1016/j.cden.2023.06.002 -
Pain Jul 2020The dorsal root ganglia (DRG) are key structures in nociception and chronic pain disorders. Several gene expression studies of DRG in preclinical pain models have been...
The dorsal root ganglia (DRG) are key structures in nociception and chronic pain disorders. Several gene expression studies of DRG in preclinical pain models have been performed, but it is unclear if consistent gene changes are identifiable. We, therefore, compared several recent RNA-Seq data sets on the whole DRG in rodent models of nerve injury. Contrary to previous findings, we show hundreds of common differentially expressed genes and high positive correlation between studies, despite model and species differences. We also find, in contrast to previous studies, that 60% of the common rodent gene response after injury is likely to occur in nociceptors of the DRG. Substantial expression changes are observed at a 1-week time-point, with smaller changes in the same genes at a later 3- to 4-week time-point. However, a subset of genes shows a similar magnitude of changes at both early and late time-points, suggesting their potential involvement in the maintenance of chronic pain. These genes are centred around suppression of endogenous opioid signalling. Reversal of this suppression could allow endogenous and exogenous opioids to exert their analgesic functions and may be an important strategy for treating chronic pain disorders. Currently used drugs, such as amitriptyline and duloxetine, do not seem to appropriately modulate many of the critical pain genes and indeed may transcriptionally suppress endogenous opioid signalling further.
Topics: Duloxetine Hydrochloride; Ganglia, Spinal; Humans; Neuralgia; Nociceptors; Signal Transduction
PubMed: 32107361
DOI: 10.1097/j.pain.0000000000001847 -
Journal of Separation Science Aug 2022Two anionic β-cyclodextrins as chiral selectors were successfully applied in the enantioseparation of N-methyl duloxetine, duloxetine, and fluoxetine by countercurrent...
Two anionic β-cyclodextrins as chiral selectors were successfully applied in the enantioseparation of N-methyl duloxetine, duloxetine, and fluoxetine by countercurrent chromatography. Sulfobutyl ether-β-cyclodextrin and carboxymethyl-β-cyclodextrin showed opposite enantioselectivity for both duloxetine and N-methyl duloxetine enantiomers. Two biphasic solvent systems, n-hexane: 0.1 mol/L phosphate buffer pH 7.6 with 50 mmol/L of sulfobutyl ether-β-cyclodextrin (1:1, v/v) and n-hexane: 0.1 mol/L phosphate buffer pH 7.2 with 50 mmol/L of carboxymethyl-β-cyclodextrin (1:1, v/v), were selected for N-methyl duloxetine. Enantioseparation of duloxetine was achieved by recycling countercurrent chromatography using a solvent system composed of n-butyl acetate: 0.1 mol/L phosphate buffer pH 7.2 with 20 mmol/L of sulfobutyl ether-β-cyclodextrin or carboxymethyl-β-cyclodextrin (1:1, v/v). A solvent system composed of n-hexane: n-butyl acetate: 0.1 mol/L phosphate buffer pH 7.6 containing 20 mmol/L of sulfobutyl ether-β-cyclodextrin (6:4:10, v/v) was selected for enantioseparation of fluoxetine.
Topics: Anions; Countercurrent Distribution; Duloxetine Hydrochloride; Ethers; Fluoxetine; Phosphates; Solvents; Stereoisomerism; beta-Cyclodextrins
PubMed: 35598113
DOI: 10.1002/jssc.202200151