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Psychotherapy and Psychosomatics 2018Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim... (Review)
Review
BACKGROUND
Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation.
METHODS
PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: "duloxetine" OR "venlafaxine" OR "desvenlafaxine" OR "milnacipran" OR "levomilnacipran" OR "SNRI" OR "second generation antidepressant" OR "serotonin norepinephrine reuptake inhibitor" AND "discontinuation" OR "withdrawal" OR "rebound." Only published trials in the English language were included.
RESULTS
Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well.
CONCLUSIONS
Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.
Topics: Adrenergic Uptake Inhibitors; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Humans; Mood Disorders; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome; Venlafaxine Hydrochloride
PubMed: 30016772
DOI: 10.1159/000491524 -
Handbook of Experimental Pharmacology 2019This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE...
This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Unlike the selective serotonin (5-HT) reuptake inhibitors (SSRIs), most of these antidepressants have an ascending rather than a flat dose-response curve. The chapter provides a brief review of the chemistry, pharmacology, metabolism, safety and adverse effects, clinical use, and therapeutic indications of each antidepressant. Venlafaxine, a phenylethylamine, is a relatively weak 5-HT and weaker NE uptake inhibitor with a 30-fold difference in binding of the two transporters. Therefore, the drug has a clear dose progression, with low doses predominantly binding to the 5-HT transporter and more binding of the NE transporter as the dose ascends. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine (ODV; desvenlafaxine) by CYP2D6, and it therefore is subject to significant inter-individual variation in blood levels and response dependent on variations in CYP2D6 metabolism. The half-life of venlafaxine is short at about 5 h, with the ODV metabolite being 12 h. Both parent compound and metabolite have low protein binding and neither inhibit CYP enzymes. Therefore, both venlafaxine and desvenlafaxine are potential options if drug-drug interactions are a concern, although venlafaxine may be subject to drug-drug interactions with CYP2D6 inhibitors. At low doses, the adverse effect profile is similar to an SSRI with nausea, diarrhea, fatigue or somnolence, and sexual side effects, while venlafaxine at higher doses can produce mild increases in blood pressure, diaphoresis, tachycardia, tremors, and anxiety. A disadvantage of venlafaxine relative to the SSRIs is the potential for dose-dependent blood pressure elevation, most likely due to the NE reuptake inhibition caused by higher doses; however, this adverse effect is infrequently observed at doses below 225 mg per day. Venlafaxine also has a number of potential advantages over the SSRIs, including an ascending dose-antidepressant response curve, with possibly greater overall efficacy at higher doses. Venlafaxine is approved for MDD as well as generalized anxiety disorder, social anxiety disorder, and panic disorder. Desvenlafaxine is the primary metabolite of venlafaxine, and it is also a relatively low-potency 5-HT and NE uptake inhibitor. Like venlafaxine it has a favorable drug-drug interaction profile. It is subject to CYP3A4 metabolism, and it is therefore vulnerable to enzyme inhibition or induction. However, the primary metabolic pathway is direct conjugation. It is approved in the narrow dose range of 50-100 mg per day. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. Milnacipran is marketed as an antidepressant in some countries, but not in the USA. It is approved in the USA and some other countries as a treatment for fibromyalgia. It has few pharmacokinetic and pharmacodynamic interactions with other drugs. Milnacipran has a half-life of about 10 h and therefore needs to be administered twice per day. It is metabolized by CYP3A4, but the major pathway for clearance is direct conjugation and renal elimination. As with other drugs in this class, dysuria is a common, troublesome, and dose-dependent adverse effect (occurring in up to 7% of patients). High-dose milnacipran has been reported to cause blood pressure and pulse elevations. Levomilnacipran is the levorotary enantiomer of milnacipran, and it is pharmacologically very similar to the racemic compound, although the side effects may be milder within the approved dosing range. As with other NE uptake inhibitors, it may increase blood pressure and pulse, although it appears to do so less than some other medications. All medications in the class can cause serotonin syndrome when combined with MAOIs.
Topics: Antidepressive Agents; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Humans; Serotonin; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 30838456
DOI: 10.1007/164_2018_164 -
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 -
Nature Sep 2021Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has...
Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.
Topics: Animals; Antidepressive Agents; Bacteria; Bioaccumulation; Caenorhabditis elegans; Cells; Click Chemistry; Duloxetine Hydrochloride; Gastrointestinal Microbiome; Humans; Metabolomics; Models, Animal; Proteomics; Reproducibility of Results
PubMed: 34497420
DOI: 10.1038/s41586-021-03891-8 -
The Primary Care Companion For CNS... May 2022
Topics: Duloxetine Hydrochloride; Erythema Multiforme; Humans
PubMed: 35522835
DOI: 10.4088/PCC.21cr02983 -
Wiener Klinische Wochenschrift Sep 2015In this case report, we describe a case in which the clinical pharmacy team was asked to provide recommendations on possible continued use of combination antidepressants... (Review)
Review
OBJECTIVE
In this case report, we describe a case in which the clinical pharmacy team was asked to provide recommendations on possible continued use of combination antidepressants in a 62-year-old Slovenian female patient with major depressive disorder following agomelatine and duloxetine hydrochloride-induced excessive sweating. When agomelatine was administered as an additional treatment, drug-induced excessive sweating was observed after a daily intake of 90 mg of duloxetine hydrochloride and 25 mg of agomelatine. After thorough discussion, it was decided not to rechallenge with agomelatine because of the serious adverse effect. After agomelatine discontinuation and switching to trazodone, symptoms immediately improved.
DISCUSSION
Duloxetine hydrochloride-induced sweating has been reported frequently, but excessive sweating induced by agomelatine and duloxetine hydrochloride has not been reported in the literature. The adverse effect was determined by a clinical pharmacist using the Naranjo probability scale and was probably associated with agomelatine use (6 points) and possibly associated with duloxetine hydrochloride use (4 points). The exact mechanism for this adverse effect in this patient is not known, but we believe that a pharmacodynamic drug-drug interaction between agomelatine and duloxetine hydrochloride had occurred.
CONCLUSION
Such a case has not yet been described in literature; however, an adverse effect associated with drug-drug interaction can occur, as this report clearly demonstrates. The benefits of this antidepressant combination need to be carefully balanced with the risks associated with its use. This case report also highlights the increased potential for adverse reactions when prescribing antidepressant combinations and importance of clinical pharmacists' involvement in the psychiatric patients' pharmacotherapy.
Topics: Acetamides; Antidepressive Agents; Drug Combinations; Drug Interactions; Duloxetine Hydrochloride; Female; Humans; Hyperhidrosis; Middle Aged
PubMed: 25576334
DOI: 10.1007/s00508-014-0688-0 -
Inflammation Dec 2023Asthma is an inflammatory disease characterized by airway hyperresponsiveness, airway remodeling, and airway inflammation. In recent years, the prevalence of asthma has...
Asthma is an inflammatory disease characterized by airway hyperresponsiveness, airway remodeling, and airway inflammation. In recent years, the prevalence of asthma has been increasing steadily and the pathogenesis of asthma varies from person to person. Due to poor compliance or resistance, existing drugs cannot achieve the desired therapeutic effect. Therefore, developing or screening asthma therapeutic drugs with high curative effects, low toxicity, and strong specificity is very urgent. Duloxetine HCl (DUX) is a selective serotonin and norepinephrine reuptake inhibitor, and it was mainly used to treat depression, osteoarthritis, and neuropathic pain. It was also reported that DUX has potential anti-infection, anti-inflammation, analgesic, antioxidative, and other pharmacological effects. However, whether DUX has some effects on asthma remains unknown. In order to investigate it, a series of ex vivo and in vivo experiments, including biological tension tests, patch clamp, histopathological analysis, lung function detection, oxidative stress enzyme activity detection, and molecular biology experiments, were designed in this study. We found that DUX can not only relax high potassium or ACh precontracted tracheal smooth muscle by regulating L-type voltage-dependent Ca channel (L-VDCC) and nonselective cation channel (NSCC) ion channels but also alleviate asthma symptoms through anti-inflammatory and antioxidative response regulated by PI3K/AKT/mTOR and Nrf2/HO-1 signaling pathways. Our data suggests that DUX is expected to become a potential new drug for relieving or treating asthma.
Topics: Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Duloxetine Hydrochloride; NF-E2-Related Factor 2; Asthma; Signal Transduction; TOR Serine-Threonine Kinases; Anti-Inflammatory Agents
PubMed: 37644164
DOI: 10.1007/s10753-023-01892-5 -
The Clinical Journal of Pain Nov 2016To systematically review the evidence for duloxetine in the management of painful diabetic neuropathy (PDN). (Review)
Review
OBJECTIVE
To systematically review the evidence for duloxetine in the management of painful diabetic neuropathy (PDN).
METHODS
Electronic searches of Medline and PubMed were performed from 2005 till October 2015 using medical subject headings and free-text words. Two independent reviewers extracted the data and assessed the methodological quality of the selected studies.
RESULTS
Twenty-three studies met our inclusion criteria and 8 were considered of high quality and were included to this review. Because of heterogeneity of the studies included in this review, statistical pooling of the data was not possible. We found good evidence for use of duloxetine in PDN over placebo and pregabalin but there was no benefit of duloxetine over amitriptyline.
CONCLUSIONS
Duloxetine has a beneficial effect over placebo. Nevertheless, the evidence of superiority of duloxetine over pregabalin and amitriptyline should be explored further as there was only 1 trial for each category. Provided majority of the PDN patients share cardiovascular complications, use of duloxetine will be a good option for treating pain associated with PDN over amitriptyline. Future randomized controlled trials should be designed keeping this in mind.
Topics: Analgesics; Diabetic Neuropathies; Duloxetine Hydrochloride; Humans; Neuralgia; Randomized Controlled Trials as Topic
PubMed: 26710221
DOI: 10.1097/AJP.0000000000000343 -
BMC Pulmonary Medicine Aug 2023Refractory cough, a chronic cough with an unclear diagnosis or poor treatment response. The symptoms are often stubborn and persistent, causing serious complications and... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Refractory cough, a chronic cough with an unclear diagnosis or poor treatment response. The symptoms are often stubborn and persistent, causing serious complications and lowering the patient's quality of life. Cough hypersensitivity syndrome (CHS) is proposed as a potential cause, and reducing sensory nerve hyperresponsiveness is suggested as an effective treatment. However, current drugs have low efficacy and benefit rates and numerous side effects. This trail proposes using duloxetine, a selective 5-HT and norepinephrine reuptake inhibitor, as a potential treatment for refractory cough, which has shown promise in treating pain and depression. Duloxetine may inhibit pain conduction and oxidative stress in peripheral nerves by inhibiting the activity of TRPV1 channels, which play an important role in the peripheral afferent pathway of refractory cough. Meanwhile, the antidepressant effects of duloxetine may also play a role in the treatment of refractory cough.
METHODS AND ANALYSIS
This is a single-center, prospective, randomized, double-blind, and controlled trial. A total of 98 individuals will be randomized in a 1:1 ratio to duloxetine group and placebo control group (starting with 20 mg QD, increasing 20 mg daily until 20 mg TID). After a screening period, the second stage runs from baseline to the 42nd (last) day of treatment, with follow-up visits on the 3rd, 7th, 14th, 21st, 28th, 35th, 42nd and 49th days. The main end-stage observation indicators include objective cough frequency, cough visual analog scale (VAS), cough symptom score, Leicester Cough Questionnaire (LCQ), and cough evaluation test (CET); the secondary end-stage observation indicators include capsaicin cough sensitivity, Patient Health Questionnaire-9 (PHQ-9), Major Depression Inventory (MDI), the Generalized Anxiety Disorder-7 scale (GAD-7), Life Events Scale (LES-32), induced sputum supernatant. The safety measures will be AEs/SAEs, vital signs, liver and kidney function, fecal occult blood test.
DISCUSSION
This study is the first randomized, double-blind, and controlled clinical trial investigating the use of duloxetine in the treatment of refractory coughs. The study aims to provide a high-quality basis for evaluating the efficacy and safety of duloxetine for this condition.
TRIAL REGISTRATION
Our study was registered in the Chinese Clinical Trials Register ( www.chictr.org.cn/ ) (ChiCTR2000037429) in 28/08/2020.
Topics: Humans; Duloxetine Hydrochloride; Cough; Tablets, Enteric-Coated; Quality of Life; Prospective Studies; Pain; Double-Blind Method; Treatment Outcome
PubMed: 37533019
DOI: 10.1186/s12890-023-02575-5 -
Medwave Oct 2017Many osteoarthritis patients continue to present symptoms despite nonsurgical treatment. Duloxetine might be a viable alternative for such cases, but real clinical... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Many osteoarthritis patients continue to present symptoms despite nonsurgical treatment. Duloxetine might be a viable alternative for such cases, but real clinical relevance remains unclear.
METHODS
A literature review was conducted in Epistemonikos, the largest database for systematic reviews in health that compiles multiple sources, including MEDLINE, EMBASE, and Cochrane, among others. Relevant data were extracted, and information from the primary studies was reanalyzed. A subsequent meta-analysis was conducted, and summary of findings tables were constructed using the GRADE methodology.
RESULTS AND CONCLUSIONS
Four systematic reviews including four randomized trials, were identified. In conclusion, while duloxetine slightly improves pain and functionality in osteoarthritis patients, its use is associated with frequent adverse side effects. Therefore, the benefit/risk balance appears unfavorable.
Topics: Analgesics; Duloxetine Hydrochloride; Humans; Osteoarthritis; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 29053665
DOI: 10.5867/medwave.2017.08.7063