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Scientific Reports Sep 2022Traumatic brain injury (TBI) is a significant public health concern, with the majority of injuries being mild. Many TBI victims experience chronic pain. Unfortunately,...
Traumatic brain injury (TBI) is a significant public health concern, with the majority of injuries being mild. Many TBI victims experience chronic pain. Unfortunately, the mechanisms underlying pain after TBI are poorly understood. Here we examined the contribution of spinal monoamine signaling to dysfunctional descending pain modulation after TBI. For these studies we used a well-characterized concussive model of mild TBI. Measurements included mechanical allodynia, the efficacy of diffuse noxious inhibitory control (DNIC) endogenous pain control pathways and lumber norepinephrine and serotonin levels. We observed that DNIC is strongly reduced in both male and female mice after mild TBI for at least 12 weeks. In naïve mice, DNIC was mediated through α2 adrenoceptors, but sensitivity to α2 adrenoceptor agonists was reduced after TBI, and reboxetine failed to restore DNIC in these mice. The intrathecal injection of ondansetron showed that loss of DNIC was not due to excess serotonergic signaling through 5-HT receptors. On the other hand, the serotonin-norepinephrine reuptake inhibitor, duloxetine and the serotonin selective reuptake inhibitor escitalopram both effectively restored DNIC after TBI in both male and female mice. Therefore, enhancing serotonergic signaling as opposed to noradrenergic signaling alone may be an effective pain treatment strategy after TBI.
Topics: Amines; Animals; Brain Concussion; Brain Injuries, Traumatic; Chronic Pain; Duloxetine Hydrochloride; Female; Male; Mice; Norepinephrine; Ondansetron; Reboxetine; Receptors, Adrenergic; Serotonin; Selective Serotonin Reuptake Inhibitors
PubMed: 36175479
DOI: 10.1038/s41598-022-20292-7 -
The Journal of International Medical... Sep 2022Painful post-traumatic trigeminal neuropathy (PPTTN) can result from iatrogenic injury to one or more branches of the trigeminal nerve during oral surgical procedures...
Painful post-traumatic trigeminal neuropathy (PPTTN) can result from iatrogenic injury to one or more branches of the trigeminal nerve during oral surgical procedures such as tooth extractions. Like other chronic neuropathic pain conditions, PPTTN can significantly alter the patient's quality of life, especially when pharmacological treatment is ineffective or not tolerated. As such, new treatment options have been investigated, including local injections of botulinum toxin type A (BTX-A). A 29-year-old woman presented to our tertiary orofacial pain clinic for evaluation of chronic electric shock-like pain attacks and severe allodynia in the territory of the right inferior alveolar nerve and buccal nerve following right mandibular third molar extraction 3 years prior. Following several failed attempts at classic pharmacological management (including carbamazepine, venlafaxine, duloxetine, pregabalin, clonazepam, and amitriptyline), BTX-A injections were administered in the vicinity of the right mental nerve. This treatment provided significant improvement in the patient's condition and overall quality of life with no significant adverse effects. Because both neuropathies were significantly improved by remote BTX-A injections, this case report provides preliminary clinical evidence supporting spinopetal transport of BTX-A, as shown in animal models, as an underlying pathophysiological mechanism of BTX-A-mediated analgesia.
Topics: Amitriptyline; Animals; Botulinum Toxins, Type A; Carbamazepine; Clonazepam; Duloxetine Hydrochloride; Humans; Mandibular Nerve; Neuralgia; Pregabalin; Quality of Life; Venlafaxine Hydrochloride
PubMed: 36172992
DOI: 10.1177/03000605211047704 -
Biomedicine & Pharmacotherapy =... Sep 2022Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in...
Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B in relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in mice with streptozotocin-induced PDN. We examined metformin's efficacy following oral (acute and prolonged 7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a single oral dose, whereas vitamin B was intraperitoneally administered for 7 days. In combination experiments, metformin (prolonged treatment) and analgesics/vitamin B were co-administered in fixed-dose fractions of their ED values and the type of interaction was determined using isobolographic analysis. Metformin produced dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B also dose-dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises with analgesics/vitamin B, with a 6-7 fold dose reduction of both drugs in the examined combinations. In conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and peripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B in reducing hyperalgesia. Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer) analgesic doses for treating PDN. Combined metformin-vitamin B use may provide more effective pain relief and mitigate metformin-induced vitamin B deficiency.
Topics: Analgesics; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Duloxetine Hydrochloride; Hyperalgesia; Hypoglycemic Agents; Metformin; Mice; Oxycodone; Pain; Vitamin B 12; Vitamins
PubMed: 36076556
DOI: 10.1016/j.biopha.2022.113441 -
Revista Brasileira de Ginecologia E... Sep 2022To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women.
OBJECTIVE
To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women.
DATA SOURCES
Searches were carried out in the PubMed, Cochrane Central, Embase, Lilacs, OpenGrey, and Clinical Trials databases.
SELECTION OF STUDIES
The searches were carried out by two of the authors, not delimiting publication date or original language. The following descriptors were used: OR , associated with MESH/ENTREE/DeCS: , , , , , , , , , , , , , , , , and , with the Boolean operator . Case reports and systematic reviews were excluded.
DATA COLLECTION
The following data were extracted: author, year of publication, setting, type of study, sample size, intervention details, follow-up time, and results.
DATA SYNTHESIS
A total of 218 articles were found, with 79 being excluded because they were repeated, leaving 139 articles for analysis: 90 were excluded in the analysis of the titles, 37 after reading the abstract, and 4 after reading the articles in full, and 1 could not be found, therefore, leaving 7 articles that were included in the review.
CONCLUSION
Most of the studies analyzed have shown pain improvement with the help of neuromodulators for chronic pain. However, no improvement was found in the study with the highest statistical power. There is still not enough evidence that neuromodulatory drugs reduce the intensity of pain in women with CPP.
Topics: Amitriptyline; Anticonvulsants; Antidepressive Agents; Antidepressive Agents, Tricyclic; Chronic Pain; Citalopram; Duloxetine Hydrochloride; Female; Gabapentin; Humans; Imipramine; Norepinephrine; Nortriptyline; Pelvic Pain; Pregabalin; Serotonin; Sertraline; Venlafaxine Hydrochloride
PubMed: 36044916
DOI: 10.1055/s-0042-1755459 -
Evidence-based Complementary and... 2022The effect of Chaihu Shugan pills (CHSG) on the pharmacokinetics of duloxetine and its metabolite 4-hydroxyduloxetine in beagle dogs was investigated by establishing an...
The effect of Chaihu Shugan pills (CHSG) on the pharmacokinetics of duloxetine and its metabolite 4-hydroxyduloxetine in beagle dogs was investigated by establishing an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to simultaneously measure the concentrations of duloxetine and 4-hydroxyduloxetine in beagle dog plasma. Duloxetine and 4-hydroxyduloxetine were separated on the UPLC-C18 column after acetonitrile precipitation and detected by mass spectrometry with multireaction detection mode (MRM). Six adult healthy beagle dogs (weighing 7-9 kg, male and female) were randomly selected and examined for a single-dose administration of duloxetine hydrochloride (2 mg/kg, control group) and oral administration of CHSG (0.3 g/kg) twice daily for 15 consecutive days followed by a single-dose administration of duloxetine hydrochloride (2 mg/kg, experimental group) using the self-control method. All plasma samples were treated in the same way, and then the concentrations of duloxetine and 4-hydroxyduloxetine were determined using the established UPLC-MS/MS method. The obtained data were subjected to DAS 2.0 software to calculate the pharmacokinetic parameters, and SPSS 20.0 software was used to compare the differences between the two groups. Duloxetine and 4-hydroxyduloxetine had a good linear relationship in the ranges of 1-1000 ng/ml and 0.1-100 ng/ml, and the lower limits of quantification (LLOQ) were 1 ng/mL and 0.1 ng/ml, respectively. The precision, accuracy, extraction recovery, matrix effect, and stability meet the requirements of the guiding principles. After combination with CHSG, and AUC of duloxetine decreased by 49.33% and 13.08%, respectively, and was shortened to 10.17 h; and AUC of 4-hydroxyduloxetine decreased by 71.47% and 48.78%, respectively, and was shortened to 7.97 h. The UPLC-MS/MS method was fully developed to simultaneously measure the plasma concentration of duloxetine and its metabolite 4-hydroxyduloxetine in beagle dogs. CHSG could slow down the absorption of duloxetine, induce the metabolism of duloxetine and 4-hydroxyduloxetine in beagle dogs, and reduce plasma exposure.
PubMed: 36034951
DOI: 10.1155/2022/2350560 -
Physiological Reports Aug 2022Previous trials have demonstrated that the combination of noradrenergic reuptake inhibitors with an antimuscarinic can substantially reduce the apnoea-hypopnoea index... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous trials have demonstrated that the combination of noradrenergic reuptake inhibitors with an antimuscarinic can substantially reduce the apnoea-hypopnoea index (AHI) and improve airway collapsibility in patients with obstructive sleep apnoea (OSA). However, some studies have shown that when administered individually, neither noradrenergic or serotonergic agents have been effective at alleviating OSA. This raises the possibility that serotonergic agents (like noradrenergic agents) may also need to be delivered in combination to be efficacious. Therefore, we investigated the effect of an antimuscarinic (oxybutynin) on OSA severity when administered with either duloxetine or milnacipran, two dual noradrenergic/serotonergic reuptake inhibiters. A randomized, double-blind, 4 way cross-over, placebo-controlled trial in ten OSA patients was performed. Patients received each drug condition separately across four overnight in-lab polysomnography (PSG) studies ~1-week apart. The primary outcome measure was the AHI. In addition, the four key OSA endotypes (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non-invasively from the PSGs using validated techniques. There was no significant effect of either drug combinations on reducing the total AHI or improving any of the key OSA endotypes. However, duloxetine+oxybutynin did significantly increase the fraction of hypopnoeas to apnoeas (F ) compared to placebo (p = 0.02; d = 0.54). In addition, duloxetine+oxybutynin reduced time in REM sleep (p = 0.009; d = 1.03) which was positively associated with a reduction in the total AHI (R = 0.62; p = 0.02). Neither drug combination significantly improved OSA severity or modified the key OSA endotypes when administered as a single dose to unselected OSA patients.
Topics: Arousal; Drug Combinations; Duloxetine Hydrochloride; Humans; Muscarinic Antagonists; Polysomnography; Sleep Apnea, Obstructive
PubMed: 36029192
DOI: 10.14814/phy2.15440 -
Lancet (London, England) Aug 2022Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.
BACKGROUND
Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP.
METHODS
OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443.
FINDINGS
Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway.
INTERPRETATION
To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy.
FUNDING
National Institute for Health Research (NIHR) Health Technology Assessment programme.
Topics: Amitriptyline; Analgesics; Cross-Over Studies; Diabetes Mellitus; Diabetic Neuropathies; Double-Blind Method; Duloxetine Hydrochloride; Humans; Neuralgia; Pregabalin; Treatment Outcome; gamma-Aminobutyric Acid
PubMed: 36007534
DOI: 10.1016/S0140-6736(22)01472-6 -
Cell Death & Disease Aug 2022Duloxetine (DLX) has been approved for the successful treatment of psychiatric diseases, including major depressive disorder, diabetic neuropathy, fibromyalgia and...
Duloxetine (DLX) has been approved for the successful treatment of psychiatric diseases, including major depressive disorder, diabetic neuropathy, fibromyalgia and generalized anxiety disorder. However, since the usage of DLX carries a manufacturer warning of hepatotoxicity given its implication in numerous cases of drug-induced liver injuries (DILI), it is not recommended for patients with chronic liver diseases. In our previous study, we developed an enhanced human-simulated hepatic spheroid (EHS) imaging model system for performing drug hepatotoxicity evaluation using the human hepatoma cell line HepaRG and the support of a pulverized liver biomatrix scaffold, which demonstrated much improved hepatic-specific functions. In the current study, we were able to use this robust model to demonstrate that the DLX-DILI is a human CYP450 specific, metabolism-dependent, oxidative stress triggered complex hepatic injury. High-content imaging analysis (HCA) of organoids exposed to DLX showed that the potential toxicophore, naphthyl ring in DLX initiated oxidative stress which ultimately led to mitochondrial dysfunction in the hepatic organoids, and vice versa. Furthermore, DLX-induced hepatic steatosis and cholestasis was also detected in the exposed EHSs. We also discovered that a novel compound S-071031B, which replaced DLX's naphthyl ring with benzodioxole, showed dramatically lower hepatotoxicities through reducing oxidative stress. Thus, we conclusively present the human-relevant EHS model as an ideal, highly competent system for evaluating DLX induced hepatotoxicity and exploring related mechanisms in vitro. Moreover, HCA use on functional hepatic organoids has promising application prospects for guiding compound structural modifications and optimization in order to improve drug development by reducing hepatotoxicity.
Topics: Chemical and Drug Induced Liver Injury; Depressive Disorder, Major; Duloxetine Hydrochloride; Fatty Liver; Humans
PubMed: 35915074
DOI: 10.1038/s41419-022-05042-x -
Brain and Behavior Aug 2022Migraine is common in primary headaches, and with the development of social economy and the increase in living pressure, the prevalence of migraine has an upward trend.
BACKGROUND
Migraine is common in primary headaches, and with the development of social economy and the increase in living pressure, the prevalence of migraine has an upward trend.
OBJECTIVE
To observe the clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine with comorbid depression and anxiety disorders and to provide a reference for clinical treatment.
METHODS
A total of 118 patients with chronic migraine complicated with depression and anxiety disorder admitted to our hospital from June 2018 to August 2020 were selected and divided into two groups according to treatment methods, 59 cases in each group. The control group was treated with flunarizine combined with loxoprofen sodium, and the observation group was treated with flunarizine combined with duloxetine. The changes of electroneurophysiological indexes, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high sensitivity-C reactive protein (hs-CRP), Hamilton depression scale (HAMD) score, and Hamilton anxiety scale (HAMA) score before and after treatment in the two groups were recorded, and the total effective rate of clinical treatment in the two groups was counted.
RESULTS
After treatment, TNF-α, IL-6, and hs-CRP in the two groups decreased gradually (p < .05). Further comparison between groups showed that TNF-α, IL-6, and hs-CRP in the observation group were lower than those in the control group (p < .05). After treatment, the HAMD score and the HAMA score of the two groups decreased gradually (p < .05). Further comparison between the two groups showed that HAMD score and HAMA score of the observation group were lower than those of the control group (p < .05).
CONCLUSION
Flunarizine combined with duloxetine in the treatment of chronic migraine with depression and anxiety disorder can effectively improve neuroelectrophysiological indexes, reduce inflammation, and reduce depression and anxiety.
Topics: Anxiety; Anxiety Disorders; C-Reactive Protein; Comorbidity; Depression; Duloxetine Hydrochloride; Flunarizine; Humans; Interleukin-6; Migraine Disorders; Tumor Necrosis Factor-alpha
PubMed: 35791513
DOI: 10.1002/brb3.2689 -
Journal of Analytical Toxicology Oct 2022Duloxetine, known by its brand name, CymbaltaTM, is a selective serotonin and norepinephrine reuptake inhibitor used to treat major depressive disorders. Determination...
Duloxetine, known by its brand name, CymbaltaTM, is a selective serotonin and norepinephrine reuptake inhibitor used to treat major depressive disorders. Determination of patient compliance for duloxetine is typically determined through medication possession ratio (MPR) or plasma concentrations. The purpose of this paper was to characterize normal urinary duloxetine concentrations in patients prescribed duloxetine to monitor patient adherence. Patient data collected from routine screens for duloxetine concentrations in urine were included in this study. Inclusion criteria consisted of patients who were prescribed duloxetine and (i) tested positive for duloxetine, (ii) tested negative for illicit substances and (iii) included creatinine, age and duloxetine dose administered. Of the 5,592 patient urines screened, 2,004 of the results fit into the inclusion criteria. Positive urine concentrations of duloxetine ranged from 50 to 2,722 ng/mL. Duloxetine urine concentrations were normalized to creatinine and dose further characterized by sex, age, body mass index (BMI) and dose in milligrams. Sample distribution included urines collected from 1,487 females and 517 males. The age range of the specimen donors was between 15 and 90 years old with an average age of 52. BMI levels ranged from 13.9 (underweight) to 88.1 (obese), with the average BMI being 33.5. The most common dose of duloxetine prescribed was a daily, oral dose of 60 mg. Analysis of the normalized, transformed creatinine concentrations showed that there was a significant statistical difference (P < 0.05) in the urinary duloxetine concentrations by sex and by dose (mg). Female patients further showed a statistical difference in urinary duloxetine concentration in age groups 18-64 and 64 and older. By characterizing urinary duloxetine concentrations in patients prescribed the medication, normalized distributions of data ranges have been established. These data ranges for urinary duloxetine concentrations can be used to determine patient compliance with duloxetine in routine, clinical samples.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Creatinine; Depressive Disorder, Major; Duloxetine Hydrochloride; Female; Humans; Male; Middle Aged; Norepinephrine; Patient Compliance; Serotonin; Selective Serotonin Reuptake Inhibitors; Thiophenes; Young Adult
PubMed: 35748596
DOI: 10.1093/jat/bkac043