Efficacy of patient education and duloxetine, alone and in combination, for patients with multisystem functional somatic disorder: Study protocol for the EDULOX trial.

BACKGROUND: Multisystem functional somatic disorder is characterized by specific patterns of persistent physical symptoms with a complex biopsychosocial etiology. The disorder can lead to disability and personal suffering. Current treatment options require specialized settings, therefore patients often wait a long time to receive specific treatment. Patient education is considered important in most treatment programs, but has only been investigated sparsely as a stand-alone treatment. Pharmacological treatment is limited to tricyclic antidepressants in low doses with no antidepressant properties. Duloxetine has been found effective in single organ functional disorders. As a treatment for multisystem functional somatic disorder, duloxetine could reduce symptoms and treat comorbid anxiety and depression. It may furthermore enhance the effect of patient education through a hypothesized effect on cognitive functioning. The purpose of the EDULOX trial is to study psycho-EDUcation and duLOXetine alone and in combination. METHODS: This is a nested study design. The parent trial "EDULOX1" (n = 424) will compare a patient education program with enhanced usual care in an open-labelled, randomized controlled trial. In addition to this, eligible participants will furthermore receive either duloxetine or active placebo in the nested, double-blinded, randomized controlled trial, "EDULOX2" (n = 212). Patient and clinician reported outcomes will be collected through questionnaires. CONCLUSION: The EDULOX trial may establish evidence for treatments applicable for the majority of patients with multisystem functional somatic disorder. If effective, duloxetine would be a more tolerable pharmacological treatment option that can target comorbid depression and anxiety, and potentially boost the effect of patient education. Trial registration number The study is registered at www. CLINICALTRIALS: gov (NCT06232473) and the internal list of research projects at the Region of Central Denmark (Case number 1-16-02-305-23). Approval from the Danish Medical Research Ethics Committees (Case number: 2212291) and the Danish Medicines Agency was obtained under EudraCT Number: 2022-002780-30 and Sponsor's Protocol Code Number: 9515.

Anticonvulsive activity of duloxetine: A new choice for the epileptic patients with depression.

The aim of this study was to investigate the antiepileptic effects of duloxetine in the maximal electroshock test and convulsions induced by four compounds: Pentylenetetrazole, 3-mercaptopropionic acid, thiosemicarbazide, and bicuculline. Duloxetine exhibited moderate anticonvulsive activity with an ED50 (median effective dose) of 48.21 mg/kg in the maximal electroshock test in mice. The anticonvulsive action of duloxetine was also confirmed in chemical-induced seizure tests, where this drug decreased tonic convulsions. Single administration of duloxetine (6.25-25 mg/kg) significantly increased the anticonvulsant effects of valproate, carbamazepine, and oxcarbazepine in the maximal electroshock test. Furthermore, pretreatment with thiosemicarbazide (an inhibitor of GABA synthesis enzyme) significantly increased the ED50 of duloxetine, suggesting the GABAergic system may contribute to the anticonvulsive action of duloxetine. These results support the use of duloxetine in the treatment of coexisting depression and epilepsy.

A three-pronged formulation approach to improve oral bioavailability and therapeutic efficacy of two lipophilic drugs with gastric lability.

The aim of present study was to co-administer curcumin (CRM) liquisolid pellets and coated duloxetine hydrochloride (DXH) pellets in rats to treat neuropathic pain (NP) associated with chronic constriction injury (CCI). To formulate liquisolid pellets of CRM, it was first dissolved in Tween-80 and then adsorbed on the porous surface of MCC PH102 and Syloid XDP that were used as carrier and coating materials, respectively. Central composite design was used to optimize the liquisolid formulation. The results of powder X-ray diffraction studies, differential scanning calorimetry, and scanning electron microscopy showed complete solubility of drug in Tween-80 followed by its complete adsorption on the porous surface of Syloid XDP and MCC PH102. Both DXH and liquisolid CRM powders were converted into pellets using extrusion-spheronization. DXH pellets were further coated with Eudragit S100 to bypass the gastric pH. About 32.31-fold increase in dissolution rate of CRM present in liquisolid formulation was observed as compared to its unprocessed form. Similarly, the dissolution profile in 0.1 N HCl for Eudragit S100-coated DXH showed complete protection of drug for 2 h and complete release after its introduction in buffer medium (0.2 M phosphate buffer pH 6.8). he pharmacokinetic studies carried out on rats revealed 7.3-fold increase in bioavailability of CRM present in liquisolid pellets and 4.1-fold increase in bioavailability of DXH present in coated pellets was observed as compared to their unprocessed pellets. This increase in bioavailability of drugs caused significant amelioration of CCI-induced pain in rats as compared to their unprocessed forms. The histological sections showed better improvement in regeneration of nerve fibers in rats.

Advances in the management of diabetic neuropathy.

The authors review current advances in the therapy of diabetic neuropathy. The role of glycemic control and management of cardiovascular risk factors in the prevention and treatment of neuropathic complications are discussed. As further options of pathogenetically oriented treatment, recent knowledge on benfotiamine and alpha-lipoic acid is comprehensively reviewed. Alpha-lipoic acid is a powerful antioxidant and clinical trials have proven its efficacy in ameliorating neuropathic signs and symptoms. Benfotiamine acts via the activation of transketolase and thereby inhibits alternative pathways triggered by uncontrolled glucose influx in the cells comprising polyol, hexosamine, protein-kinase-C pathways and formation of advanced glycation end products. Beyond additional forms of causal treatment, choices of symptomatic treatment will be summarized. The latter is mostly represented by the anticonvulsive agents pregabalin and gabapentin as well as duloxetine widely acknowledged as antidepressant. Finally, non-pharmacological therapeutic alternatives are summarized. The authors conclude that combination therapy should be more often suggested to our patients; especially the combination of pathogenetic and symptomatic agents.

Levetiracetam synergizes with gabapentin, pregabalin, duloxetine and selected antioxidants in a mouse diabetic painful neuropathy model.

RATIONALE: We have reported that levetiracetam, a novel anticonvulsant with analgesic properties, synergizes with ibuprofen/aspirin/paracetamol in a model of diabetic painful neuropathy (DPN). Most guidelines recommend gabapentin, pregabalin, and duloxetine as first- or second-line agents for DPN. OBJECTIVE: We examined the effects of combination treatment of first-/second-line analgesics with levetiracetam in a model of DPN. Additionally, the levetiracetam's combinations with antioxidants, low dose of aspirin, coenzyme Q10, or α-lipoic acid were evaluated. METHODS: Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin. The antinociceptive effects of orally administered levetiracetam, gabapentin, pregabalin, duloxetine (acute treatment) and aspirin, coenzyme Q10, and α-lipoic acid (preventive 7-day treatment), as well as combinations of levetiracetam with individual drugs were examined in the tail-flick test. In combination experiments, the drugs were coadministered in fixed-dose fractions of single-drug ED50; the type of interaction was determined by isobolographic analysis. RESULTS: About 60-, 32-, 30-, 26-, 18-, and 6-fold reductions of doses of both drugs in levetiracetam combinations with pregabalin, gabapentin, coenzyme Q10, aspirin, duloxetine, and α-lipoic acid, respectively, were detected. CONCLUSIONS: Combinations of levetiracetam with gabapentin/pregabalin/duloxetine that target different mechanisms/sites of action involved in DPN, as well as combinations of levetiracetam and low-dose aspirin/coenzyme Q10/α-lipoic acid that target underlying causes of DPN, produce marked synergistic interactions in reducing nociception in diabetic mice. This suggests that these combination treatments might be of great benefit for diabetic patients and should be explored further in clinical trials.

Effect of Duloxetine on Urethral Resting Pressure and on Sphincter Contractility in Response to Coughing and Magnetic Stimulation in Healthy Women.

OBJECTIVES: As a proof-of-mechanism (POM) study of drugs developed to treat stress urinary incontinence (SUI) has not been conducted, this urodynamic study in healthy women was performed to determine an appropriate method to confirm POM, and to evaluate the effect of duloxetine, a serotonin and noradrenaline reuptake inhibitor, on urethral resting pressure and on sphincter contractility in response to coughing and magnetic stimulation. METHODS: The urethral pressure profiles at rest, during coughing and during sacral root magnetic stimulation (SMS), and the motor threshold (MT) for urethral sphincter contraction in response to transcranial magnetic stimulation (TMS) were measured before and 6 h after the administration of 40 mg duloxetine in 10 healthy female subjects. RESULTS: Oral administration of duloxetine significantly increased the mean and maximal urethral closure pressures at rest over the proximal and middle third of the urethra. During coughing, duloxetine marginally significantly increased the mean distal urethral pressure and significantly reduced the mean delay in the distal urethral pressure peak relative to the vesical peak. Although duloxetine did not change amplitudes of pressure spikes in response to SMS, this drug significantly lowered the MT in response to TMS. CONCLUSION: The proposed method for measuring the urethral resistance in healthy women can be used in POM studies of new drugs developed to treat SUI. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000009096.

Complete Freund's adjuvant-induced reduction of exploratory activity in a novel environment as an objective nociceptive endpoint for sub-acute inflammatory pain model in rats.

BACKGROUND: Hind paw injection of complete Freund's adjuvant (CFA) is a commonly used sub-acute inflammatory pain model in rodents with typical subjective endpoint measurements of paw withdrawal to thermal or mechanical stimuli. METHODS: Here, we assessed CFA-induced reduction of exploratory activity in a novel environment (CRANE) as an objective nociceptive endpoint in rats. CFA (50%) was subcutaneously injected into the plantar aspect of the hind paw either unilaterally or bilaterally (150 µL/paw). Exploratory activity was recorded using an automated locomotor activity system. RESULTS: Bilateral CFA injection reduced exploratory activity 4-48 h following injection, compared to sham controls. Unilateral CFA injection produced less reduction of exploratory activity, compared to bilateral injection. Effects of orally dosed standard analgesics on CRANE were examined 48 h following bilateral CFA injection. Diclofenac treatment produced dose-related reversal of CRANE at 0.03-1.0 mg/kg with a plateau effect observed at higher doses (up to 30 mg/kg). Ibuprofen also produced dose-related reversal CRANE at 0.3-3.0 mg/kg with a plateau effect at higher doses (up to 60 mg/kg). Similarly, celecoxib produced dose-related reversal CRANE at 3-10 mg/kg, but not 30 mg/kg. Gabapentin (up to 100 mg/kg) and duloxetine (up to 30 mg/kg) produced no reversal of CRANE. CONCLUSIONS: The results presented here demonstrate that CRANE provides an objective assessment of pain behaviours for sub-acute inflammatory pain in rats. The pharmacological profile of standard analgesics supports that CRANE model may potentially be used to identify novel analgesic agents for the treatment of sub-acute inflammatory pain.

Maintained superiority of chronotherapeutics vs. exercise in a 20-week randomized follow-up trial in major depression.

OBJECTIVE: To investigate the long-term antidepressant effect of a chronotherapeutic intervention. METHOD: In this randomized controlled trial 75 patients with major depression were allocated to fixed duloxetine and either a chronotherapeutic intervention (wake group) with three initial wake therapies, daily bright light therapy, and sleep time stabilization or to a group using daily exercise. Patients were followed 29 weeks. We report the last 20 weeks, a follow-up phase, where medication could be altered. Patients were assessed every 4 weeks. Remission rates were primary outcome. RESULTS: Patients in the wake group had a statistically significant higher remission rate of 61.9% vs. 37.9% in the exercise group at week 29 (OR = 2.6, CL = 1.3-5.6, P = 0.01). This indicated continued improvement compared with the 9 weeks of treatment response (44.8% vs. 23.4%) with maintenance of the large difference between groups. HAM-D17 endpoint scores were statistically lower in the wake group with endpoint scores of 7.5 (SE = 0.9) vs. 10.1 (SE = 0.9) in the exercise group (difference 2.7, CL = 0.5-4.8, P = 0.02). CONCLUSION: In this clinical study patients continued to improve in the follow-up phase and obtained very high remission rates. This is the first study to show adjunct short-term wake therapy and long-term bright light therapy as an effective and feasible method to attain and maintain remission.