Tricyclic Research Articles

Current Perspective of Carbazole Scaffolds in Cancer Therapy

Abstract: Cancer poses a significant threat to human life and well-being, resulting in numerous individuals suffering and succumbing to various forms of the disease each year. Considerable resources have been allocated to combat cancer, yet the limitations of existing anticancer agents, including their side effects and the development of drug resistance, have left substantial challenges in our quest to conquer cancer. Thus, there is an urgent necessity to discover and develop novel chemical compounds with the potential to inhibit cancer growth. In this review, we primarily focus on examining the effectiveness of two distinct classes of carbazole-based compounds: carboline derivatives and diazacarbazole derivatives. Diazacarbazole derivatives, a relatively unexplored area, hold promise for offering a fresh perspective and valuable opportunities to overcome the formidable obstacles in the ongoing battle against cancer. Additionally, we present several synthetic methods for creating the essential structural frameworks of carbazole-based tricyclic compounds.

Central Nervous System Medications: Pharmacokinetic and Pharmacodynamic Considerations for Older Adults.

Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10-40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.

A Photoinduced Radical Cascade Cyclization for the Synthesis of Angularly Fused Tricyclic Compounds.

A photoinduced electron transfer (PET)-triggered cascade reaction has been devised for the conversion of second-generation enol silyl ethers into angularly fused tricyclic scaffolds. Utilizing readily available and cost-effective DCA and phenanthrene as the catalytic systems, this cascade transformation is achieved with high efficiency. The reaction demonstrates a good substrate scope and excellent stereoselectivity, thereby enriching the realm of PET-induced cascade reactions. Additionally, the radical adducts generated through this process can serve as valuable subunits for the synthesis of complex molecules.

P.067 Pharmacological prophylaxis for chronic migraine: A systematic review and network meta-analysis of randomized controlled trials

Background: We performed a network meta-analysis of randomized controlled trials to assess the comparative effectiveness of available pharmacological prophylaxis for migraines. Methods: We searched MEDLINE, EMBASE, Web of Science, Scopus, PsycINFO and Cochrane CENTRAL up to October 2023 for trials that: (1) enrolled adults diagnosed with chronic migraine, and (2) randomized them to any prophylactic medication vs. another medication or placebo. We performed a random-effects frequentist network meta-analysis for patient-important outcomes. Results: We included 193 randomized trials. Compared to placebo, CGRP monoclonal antibodies (mean difference [MD] -1.7, 95%CI: -1.1 to -2.2), injection of botulinum toxin (MD -1.8, 95%CI: -0.7 to -2.9), calcium channel blockers (MD -1.8, 95%CI: -0.5 to -3.0), beta-blockers (MD -1.4, 95%CI: -0.2 to -2.6), and anticonvulsants (MD -1.1, 95%CI: -0.4 to -1.8) were among the most effective treatments in reducing average number of headache days per months. Anticonvulsants (Risk Ratio [RR] 2.3, 95%CI: 1.8 to 3.0), calcium channel blockers (RR 1.8, 95% CI: 1.1 to 3.1), and tricyclic antidepressants (RR 2.3, 95% CI: 1.3 to 3.8) showed the highest risk of discontinuation due to adverse events. Conclusions: Our findings suggest that CGRP inhibitors, botulinum toxin, and beta-blockers may provide the greatest benefit, and tolerability, for reducing the frequency of migraine headaches.

ANXIETY, DEPRESSION, AND PSYCHOTROPIC DRUGS USAGE BY UNIVERSITY STUDENTS OF MEDICAL GROUP IN BASRA, IRAQ

Background: Psychological disease is strongly prevalent among college and university students worldwide with negative impacts on students’ life. Specifically, medical group students have long time of study with suffer from competitive ambience and sleep privation, that lead to out of the way from perfect learning environment. When medical students are abused psychotropic drugs that lead to defect on performance, health, life style and interpose with their concentration. Aim: to investigate the prevalence rate of depression and anxiety in university students of medical group in Basra, and estimate the rate and type of psychotropic drugs consumption by them. Method: The study data was collected from 376 students of medical group at College of Medicine, College of Dentistry and College of Pharmacy of Basra University by questionnaire forma. Results: The prevalence rate of mental disorders was low about and many factors that affected on psychiatric state of them like gender, age, Family and friends Relation, missing one of parents etc. Among medical group students that used sedatives and hypnotics about (46%) than other psychotropic drugs like serotonin-norepinephrine reuptake inhibitor (SNRIs) (42.9%) tricyclic antidepressants (21.4%), and atypical antipsychotic (7.1%). Conclusions: Medical group students are more likely to consumption antipsychotic drugs by physician prescription or self-medications. Therefore, there are required more interesting and pursuits for college students especially medical college students for amelioration their college and social lives. Peer Review History: Received 6 February 2024; Revised 15 March 2024; Accepted 26 April; Available online 15 May 2024 Academic Editor: Dr. Asia Selman Abdullah, Pharmacy institute, University of Basrah, Iraq, asia_abdullah65@yahoo.com Average Peer review marks at initial stage: 6.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. A.A. Mgbahurike, University of Port Harcourt, Nigeria, amaka_mgbahurike@yahoo.com Prof. Hassan A.H. Al-Shamahy, Sana'a University, Yemen, shmahe@yemen.net.ye

Genetic diversity of cytochrome P450 in patients receiving psychiatric care in Greece: a step towards clinical implementation.

Aim: We herein inferred the genetic diversity of CYP450 isoenzymes to predict the percentage of patients who need dose adjustment in drugs used in psychiatry. Materials & methods: Data of 784 Greek patients receiving psychiatric care who were genotyped for CYP2D6, CYP2C19, CYP1A2, CYP3A5 and CYP2C9 isoenzymes were inferred to gene-drug pairs according to the US FDA, Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group annotations and published literature. Results: Atypical metabolism was found for 36.8% of patients in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9. Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.6% of haloperidoland 13.3% of risperidone treated patients. Conclusion: Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.

Prescribing patterns in patients with obsessive-compulsive disorder: Retrospective, single-center study.

Obsessive-compulsive disorder (OCD) is marked by a high rate of treatment resistance. Patients are often left trialing medications within multiple drug classes with little response, causing heterogeneity to emerge in prescribing patterns. This analysis seeks to investigate the selection and dosing of the pharmacotherapy utilized, to portray an overview of prescribing trends in the United States. This retrospective, single center, review of electronic medical records investigated the pharmacotherapy utilization of patients with a primary diagnosis of OCD. Two hundred and ninety-five patients who received OCD treatment at an urban, academic medical center were included in the study. Patients were included in the review if they were at least eighteen years of age and were assigned a diagnosis of OCD according to DSM-5 criteria. Psychotropic pharmacotherapy was integrated into the care of 93% of patients. Selective serotonin reuptake inhibitors were the most utilized medication class at 85% followed by benzodiazepines (47%) and second-generation antipsychotics (37%). Tricyclic antidepressants and first-generation antipsychotics were the two medication classes utilized the least at 13% and 2% respectively. Additionally, mood stabilizers and serotonin-norepinephrine reuptake inhibitors were utilized at rates of 8% and 16%, respectively. Evidence-based treatment guidelines are being followed with varying augmentation strategies widely prevalent, thus displaying the heterogeneity in treating OCD. A high rate of benzodiazepine utilization highlights a practice trend with potential ties to clinical factors, such as the latency to treatment effect of other first-line pharmacotherapies. Future prospective studies are required to determine the cultural, pharmacoeconomic and pharmacogenomic factors that contribute to the variation in prescribing practices and whether these variations influence treatment outcomes.

Assessing the prevalence of Beers medication utilization in the Medicare Part D population in 2020.

Medication utilization has been increasing in the U.S. year-over-year for several decades. As older adults take more medications, there is a higher risk of them being exposed to drug-drug or drug-disease interactions. The American Geriatrics Society in 2019 updated their Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults. The objective of this study was to assess the prevalence of utilization of medications included in the 2019 Beers Criteria. An analysis was conducted using the Medicare Part D Provider Utilization and Payment Data Public Use File for calendar-year 2020. Medications identified in the 2019 Beers Criteria were applied to the analysis. Two categories of medications were assessed: (1) "Avoid" and (2) "Use With Caution." In 2020, 56 million prescriptions were dispensed to Medicare patients 65 years and older that are recommended to be avoided without exception (4.7% of all prescriptions) totaling $957 million in medication costs. The most utilized medication classes in this category were benzodiazepines (25,949,994 prescriptions), "Z-drugs" (6,204,909 prescriptions), long-acting sulfonylureas (5,306,577 prescriptions), 1st-generation antihistamines (5,049,289 prescriptions), and tricyclic antidepressants (4,190,062 prescriptions). Additionally, 135 million prescriptions were dispensed to Medicare beneficiaries 65 years and older for medications which the Beers Criteria states to use caution (11.3% of all prescriptions) exceeding $2.85 billion in medication costs. The most utilized medications for this category were diuretics (74,599,126 prescriptions), selective serotonin reuptake inhibitors (30,033,121 prescriptions), serotonin and norepinephrine reuptake inhibitors (11,858,968 prescriptions), tramadol (11,450,878 prescriptions), and mirtazapine (5,737,304 prescriptions). Even with the existence of the AGS Beers Criteria for PIM Use in Older Adults and its continued updated versions, 16% of medications dispensed to Medicare Part D were potentially inappropriate. Future studies are needed to assess if this has led to worsened outcomes among older adults who utilized these PIM.

A Pain Physician’s Perspective on Recent Advances in Painful Diabetic Peripheral Neuropathy Management

Abstract Diabetic peripheral neuropathy (DPN) is a prevalent neurological complication linked to diabetes mellitus, exerting a substantial impact on the quality of life for those affected. This review article aims to discuss and review advances in the pain management of patients with DPN. We reviewed recent DPN management literature primarily from PubMed and SCOPUS using specific keywords, focusing on original research and recent advancements. The pathophysiology of DPN involves metabolic and vascular changes in nerve fibers, leading to direct damage and a decrease in their natural repair capacity. Effective glycemic control plays a central role in managing DPN, along with addressing other contributing factors such as comorbidities and lifestyle modifications. Nutraceuticals, including alpha-lipoic acid and Vitamin B12, have shown promising results in some studies. Antineuropathic agents such as calcium channel a2-δ ligands, serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants, and sodium channel blockers are commonly used in DPN pain management. Topical therapies, including capsaicin and lidocaine patches, have also demonstrated efficacy. Opioids are generally discouraged due to weak evidence and long-term deleterious side effects, along with the risk of addictive potential. Neuromodulation has emerged as a modality in resistant cases not responding to pharmacological management. Individualized treatment plans based on symptomatology, comorbidities, and side effect profiles should be developed for DPN patients. Comprehensive management of DPN involves a multidisciplinary approach, emphasizing patient education, regular assessment, and counseling to prevent further damage and complications.

Acupuncture versus tricyclic antidepressants in the prophylactic treatment of tension-type headaches: an indirect treatment comparison meta-analysis

BackgroundAcupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis.MethodsWe searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach.ResultsA total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23).ConclusionAcupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence.

Effectiveness of Vortioxetine in Patients with Major Depressive Disorder Associated with Chronic Pain: An Observational Study in a Spanish Population.

Chronic pain (CP) and depression/anxiety often coexist, worsening each other's symptoms. Treating this comorbidity is challenging. Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are the first-line treatment options for this comorbidity, although sometimes they are not effective and/or well tolerated by patients, and there is little clinical evidence that selective serotonin reuptake inhibitors are useful for controlling CP. The antidepressant vortioxetine, with a multimodal mechanism that may help reduce pain, has proven clinical efficacy in patients with major depressive disorder (MDD). This study investigated vortioxetine's effectiveness for MDD and CP in clinical practice. This was a 3-month, multicenter, prospective, open-label, non-interventional pharmacoepidemiologic study. Patients (n = 64) with MDD (9-item Patient Health Questionnaire [PHQ-9] score ≥ 15) and CP (visual analogue scale [VAS] score ≥ 4) were treated with vortioxetine for 3months (initiated with 10mg/day, with flexible dosing thereafter [5-20mg/day]). VAS, Clinical Global Impression (CGI), and Patient Global Impression (PGI) scales were used at baseline and at 1 and 3months. Brief Pain Inventory (BPI), PHQ-9 scale, and Satisfaction with Medicines Questionnaire (SATMED-Q) were used at baseline and at 3months. Adverse Events (AEs) were recorded. Descriptive statistics, chi-square tests, and Student's t-tests were used for paired data. MDD patients showed a statistically significant improvement in VAS from baseline (mean [standard deviation (SD)]: 7.42 [0.69]) to 1month (mean [SD]: 6.1 [0.81], P < 0.001) and 3months (mean [SD]: 5.09 [1.26], P < 0.0001). Similarly, BPI and PHQ-9 scores showed significant improvement from baseline (mean [SD]: 6.20 [0.80] and 16.63 [1.47], respectively) to 3months (mean [SD]: 4.73 [0.98] and 7.30 [2.60], P < 0.0001, respectively). Patients showed clinical improvement with CGI and PGI scales and reported being satisfied with the treatment in the SATMED-Q. A few mild EAs were registered. Vortioxetine can relieve depressive and pain symptoms, with a good safety profile, in patients with MDD and CP.

Novel Strategies for Acute Relief and Prevention of Migraine

Migraine is a debilitated disorder that is often under diagnosed in clinical practice. Early detection of migraine leads to outstanding improvements in patients’ quality of life. New researchers had developed the central sensitization and cutaneous allodina in chronic migraine which is helpful in early treatment approach with triptans and other agents in acute migraine episodes. Right now, five agents are accepted by US food and drug administration (FDA) for migraine prevention. They are namely Divalporex sodium, Propranolol, Timolol maleate, Topiramate and Methysergide. For so many years, other medications have been used to prevent migraine with not much more success rate. They are Tricyclic anti depressants, anti epileptic agents, Nonsteroidal anti-inflammatory drugs (NSAIDs), Selective serotonin reuptake inhibitors (SSRIS), Calcium channel blockers and muscle relaxants. Calcitonin gene related peptide antagonist, Ditans, Botulinum toxin type A, Orexin receptor antagonists etc were the recent novel agents in the treatment and management of migraine. These novel agents showed more affect than other medications in the acute and prophylactic management of migraines. They play a pivotal role in the standard care for migraine treatment that will improve the patient quality of life with better outcomes.

Risk factors for inadequate bowel preparation before colonoscopy: A meta-analysis.

This meta-analysis aimed to comprehensively explore the risk factors for inadequate bowel preparation (IBP). We searched the Embase, PubMed, Web of Science, and The Cochrane Library databases up to August 24, 2023, to identify observational studies and randomized controlled trials (RCTs) that examined risk factors for IBP. A random effects model was used to pool the adjusted odds ratios and 95% confidence intervals. A total of 125 studies (91 observational studies, 34 RCTs) were included. Meta-analyses of observational studies revealed that three preparation-related factors, namely, characteristics of last stool (solid or brown liquid), incomplete preparation intake, and incorrect diet restriction, were strong predictors of IBP. The other factors were moderately correlated with IBP incidence, including demographic variables (age, body mass index, male sex, Medicaid insurance, and current smoking), comorbidities (diabetes, liver cirrhosis, psychiatric disease, Parkinson's disease, previous IBP, poor mobility, inpatient, and Bristol stool form 1/2), medications (tricyclic antidepressants, opioids, antidepressants, narcotics, antipsychotics, and calcium channel blockers), and preparation-related factors (preparation-to-colonoscopy interval not within 3 to 5/6h, nonsplit preparation, and preparation instructions not followed). No colonoscopy indications were found to be related to IBP. Meta-analyses of RCTs showed that education, constipation, stroke/dementia, and discomfort during preparation were also moderately associated with IBP. Most of the other findings were consistent with the pooled results of observational studies. However, primarily due to imprecision and inconsistency, the certainty of evidence for most factors was very low to moderate. We summarized five categories of risk factors for IBP. Compared to demographic variables, comorbidities, medications, and colonoscopy indications, preparation-related elements were more strongly associated with IBP. These findings may help clinicians identify high-risk individuals and provide guidance for IBP prevention.

Neuropathic pain: Evidence based recommendations

Neuropathic pain continues to be a significant problem that lacks effective solutions for every single patient. In 2015, international guidelines (NeuPSIG) were published, while the French recommendations were updated in 2020. The purpose of this minireview is to provide an update on the process of developing evidence-based recommendations and explore potential changes to the current recommendations. Primary treatments for neuropathic pain include selective serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine, gabapentin, tricyclic antidepressants, as well as topical lidocaine and transcutaneous electrical nerve stimulation, which are specifically suggested for focal peripheral neuropathic pain. Pregabalin is a first line treatment according to international guidelines but second-line in the more recent French guidelines, due to lower efficacy seen in more recent studies and misuse risk. Additionally, tramadol, combination therapies, and psychotherapy as adjuncts are proposed second line; high-concentration capsaicin patches, and botulinum toxin A are proposed specifically for focal peripheral neuropathic pain. In cases where primary and secondary treatments prove insufficient, third-line options come into play. These include high-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the motor cortex, spinal cord stimulation, and the use of strong opioids when no alternative is available. To ensure optimal management of neuropathic pain in real-life situations, it is imperative to disseminate these recommendations widely and secure the acceptance of practitioners. By doing so, we can bridge the gap between theory and practice, and enhance the overall care and treatment of individuals suffering from neuropathic pain.

Tricyclic antidepressants: An update

Tricyclic antidepressants (TCAs) are a class of psychotropic medications primarily used in the treatment of major depressive disorders, although their indications extend to a variety of psychiatric and neurological conditions. This class of medications was one of the first to be developed for the treatment of depression, marking a revolution in the management of this condition in the mid-20th century. The aim of this study is to present a narrative review in the form of an update on the pharmacokinetic properties, pharmacodynamics, indications, and side effects of tricyclic antidepressants. For this purpose, a narrative review in the format of an update was carried out, which analyzed 42 manuscripts. TCAs have various pharmacological and therapeutic properties, low cost, but their major limitation is their side effects. Since the clinical trials for this class were conducted well before the launch of new antidepressants, new research is needed to allow comparison of these groups within the same methodology and with more up-to-date statistics.

Optimizing clozapine-loaded nanostructured lipid carriers through central composite design for enhance bioavailability in antipsychotic therapy

Clozapine (CLZ), a tricyclic dibenzodiazepine antipsychotic drug employed for the treatment of Schizophrenia. However, CLZ's significant first-pass effect, poor water solubility, and low oral bioavailability (27%) limit its potential for therapeutic use. The present investigation aimed to prepare CLZ-loaded nanostructured lipid carriers (NLCs) to improve its solubility, bioavailability, and therapeutic efficacy. The NLCs were prepared using an ultrasonic probe sonication technique using selected solid lipids (Gelucire 44/14), liquid lipids (Labrafil M 1944), and surfactants (Monoemul 80). A central composite design approach was adopted to optimize the NLCs. The optimized CLZ-loaded NLCs were evaluated in terms of particle size, zeta potential, surface morphology, crystallinity, drug loading, and in-vitro CLZ release studies. The optimized CLZ-loaded NLCs showed a particle size, zeta potential, and entrapment efficiency of 115.1 ± 2.48 nm, −17 mV and 96.74 ±1.82%, respectively. The morphology revealed the coarsely spherical shape of NLCs. Fourier transform infrared spectroscopy indicated the physical interaction between the CLZ and lipids rather than chemical interaction. The results of powder X-ray diffraction and differential scanning calorimetry showed the conversion of crystalline to amorphous form of CLZ and distributed molecular level in lipid matrix. In the in-vitro release study, pure CLZ showed 14±1.86% release, whereas CLZ-loaded NLC showed initial burst release (20.0±0.56%) followed by sustained release (69.0±1.03%) up to 24 hours. Collectively, results revealed that the developed novel CLZ-loaded NLCs could be a potential formulation to improve efficacy by increasing solubility and prolonging CLZ release and bioavailability with enhanced patient compliance and reduced side effects.

Central Neuromodulators in Irritable Bowel Syndrome: Why, How, and When.

Irritable bowel syndrome (IBS) is responsive to treatments using central neuromodulators. Central neuromodulators work by enhancing the synaptic transmission of 5-hydroxytryptamine, noradrenalin, and dopamine, achieving a slower regulation or desensitization of their postsynaptic receptors. Central neuromodulators act on receptors along the brain-gut axis, so they are useful in treating psychiatric comorbidities, modifying gut motility, improving central downregulation of visceral signals, and enhancing neurogenesis in patients with IBS. Choosing a central neuromodulator for treating IBS should be according to the pharmacological properties and predominant symptoms. The first-line treatment for pain management in IBS is using tricyclic antidepressants. An alternative for pain management is the serotonin and noradrenaline reuptake inhibitors. Selective serotonin reuptake inhibitors are useful when symptoms of anxiety and hypervigilance are dominant but are not helpful for treating abdominal pain. The predominant bowel habit is helpful when choosing a neuromodulator to treat IBS; selective serotonin reuptake inhibitors help constipation, not pain, but may cause diarrhea; tricyclic antidepressants help diarrhea but may cause constipation. A clinical response may occur in 6-8 weeks, but long-term treatment (usually 6-12 months) is required after the initial response to prevent relapse. Augmentation therapy may be beneficial when the therapeutic effect of the first agent is incomplete or associated with side effects. It is recommended to reduce the dose of the first agent and add a second complementary treatment. This may include an atypical antipsychotic or brain-gut behavioral treatment. When tapering central neuromodulators, the dose should be reduced slowly over 4 weeks but may take longer when discontinuation effects occur.

Brachioradial Pruritus Caused by Cervical Disc Herniation Precipitated by Trauma Treated with Anterior Cervical Discectomy and Fusion: Report of Two Cases and Review of the Literature

AbstractBrachioradial pruritis (BRP) is a rare form of dermatomal pruritis that appears to be caused both by cervical radiculopathy and exposure to ultraviolet-light, although the exact pathophysiology for the manifestation of these symptoms remains to be determined. A diagnosis of BRP is typically confirmed with the “ice-pack” test and evidence of cervical spine pathology using magnetic resonance imaging. Treatment options consist of application of ice, reduction in sun exposure, and topical capsaicin, antiepileptics, or tricyclic antidepressants. Patients with refractory symptoms and cervical spine pathology may be candidates for surgical decompression, particularly at the C5 and C6 levels. However, there are currently no established guidelines to treat BRP, or surgical procedures that have shown to be superior. Here, we report two cases of cervical disc herniations after traumatic events that presented as BRP. Both cases were successfully treated with anterior cervical discectomy and fusion with complete resolution of symptoms.

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

BackgroundMultisystem 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. MethodsThis 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. ConclusionThe 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 numberThe 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.

Decrypting the multifaceted peripheral neuropathy based on molecular pathology and therapeutics: a comprehensive review.

Peripheral neuropathy (PN) is a multifaceted complication characterized by nerve damage due to oxidative stress, inflammatory mediators, and dysregulated metabolic processes. Early PN manifests as sensory changes that develop progressively in a "stocking and glove" pattern. A thorough review of literature has been done to find the molecular pathology, clinical trials that have been conducted to screen the effects of different drugs, current treatments and novel approaches used in PN therapy. Diabetic neuropathy occurs due to altered protein kinase C activity, elevated polyol pathway activity in neurons, and Schwann cells-induced hyperglycemia. Other causes involve chemotherapy exposure, autoimmune ailments, and chronic ethanol intake. Symptomatic treatments for neuropathic pain include use of tricyclic antidepressants, anticonvulsants, and acetyl-L-carnitine. Patients will have new hope if clinicians focus on novel therapies including gene therapy, neuromodulation techniques, and cannabidiol as an alternative to traditional medications, as management is still not ideal.