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Bleeding gums: Duloxetine may be the cause
Abstract
Duloxetine is a newly introduced drug. It is being prescribed for the management of diabetic neuropathic pain and major depressive disorder. The most frequently observed adverse events with duloxetine are nausea, dry mouth and somnolence, constipation, diarrhea, decreased appetite, weight loss, feeling of fatigue, dizziness, somnolence, hypohidrosis, decreased libido and erectile dysfunction. One of the patients being prescribed the drug developed bleeding gums on being started with the drug which resolved on stopping it. We hereby report this case.
... • Paroxetine 25 mg/day [111] Mania due to antidepressant withdrawal • Imipramine 150 mg/day [112] Upper Gastrointestinal Bleeding • Sertraline 100 mg/day [113] Bleeding gums • Duloxetine 40 mg/day [114] Safety in overdose • Paroxetine 560 mg/day [115] Serotonin syndrome • Sertraline, trazodone and tramadol [116] • Lithium carbonate, amlodipine, phenytoin, sertraline, trazodone and escitalopram [117] Facial Paresthesia/facial numbness and dysmorphic symptoms • Sertraline [118] • Fluoxetine 20 mg/day [119] Behavioral activiation and Suicidality • Escitalopram [120] of trichotillomania with trichobezoar, [72] Atypical bulimia Nervosa, [73] Skin Picking, [74] Persistent developmental stuttering, [75] primary hypersomnia, [76] cognitive functioning in depression, [77] proctalgia fugax with dysthymia, [78] palmar-plantar hyperhidrosis, [79] severe resistant depression [80] etc. One open label study also evaluated the usefulness of sertraline in chronic tension type headache and showed that sertraline leads to significant reduction in mean analgesic intake per week, but there is no difference in reduction of headache index and frequency of headache. ...
... [81] Tolerability of Antidepressants As is evident from Tables 1 to 6, tricyclic antidepressants are poorly tolerated compared to the newer antidepressants. Additionally, there are multiple case reports implicating various antidepressants for induction of hypomania/mania, [87][88][89][90][91][92][93][94][95][96] hyponatremia/Syndrome of inappropriate antidiuretic hormone secretion (SIADH), [97][98][99] extrapyramidal symptoms, [100] acute colonic (pseudo) obstruction (Ogilvie syndrome), [101,102] psychosis, [103] hypertension, [104] vascular headache, [105] torsades de pointes, [106] alopecia, [107] cardiogenic shock, [108] seizures, [109,110] galactorrhoea, [111] mania on withdrawal of antidepressants, [112] upper gastrointestinal bleeding, [113] bleeding gums, [114] serotonin syndrome [116,117] etc [ Table 9]. ...
Data suggests that antidepressants are useful in the management of depressive disorders, anxiety disorders, sexual dysfunction, eating disorders, impulse control disorders, enuresis, aggression and some personality disorders. Research focusing on the usefulness of antidepressants in India has more or less followed the trends seen in the West. Most of the studies conducted in India have evaluated various antidepressants in depression. In this article, we review studies conducted in India on various antidepressants. The data suggests that antidepressants have been evaluated mainly in the acute phase treatment and rare studies have evaluated the efficacy in continuation phase treatment.
... For the sake of simplicity, we will only refer to SSRIs, though it is reasonable on the basis of available data to assume that the following discussion can be extended to the use of the SNRIs and the tertiary tricyclic antidepressants (imipramine, amitriptyline, and clomipramine) that also block serotonin reuptake (2,3). This effect results in an increase in bleeding time, and there are many clinical case reports that associate SSRI use with manifestations of abnormal bleeding such as ecchymosis, menorrhagia, and hemoptysis (4)(5)(6)(7)(8). ...
Objective:
This study aimed to review the data on the effect of selective serotonin reuptake inhibitors (SSRIs) on bleeding during or after operative procedures and to offer guidelines for clinical management.
Data sources:
Search of PubMed and MEDLINE for all articles in English from 1990-2016 with key words depression, antidepressants, bleeding, platelets, and operation.
Study selection:
Studies were included if they reported information on bleeding complications during operative or childbirth procedures in patients taking antidepressants.
Data extraction:
Because of the limited number and heterogeneity of studies with respect to the range of operative procedures and definition of bleeding complications, a qualitative approach was taken to summarize results rather than abstracting and aggregating data.
Results:
The weight of the evidence is that SSRI use increases the risk of bleeding complications during and immediately after surgery. However, given the limited data, we cannot estimate the risk for a given patient having a given procedure.
Conclusions:
Clinicians must consider the risk-to-benefit ratio of discontinuing an SSRI before an elective operative procedure. Discontinuing SSRI medications may result in discontinuation syndrome, symptom recrudescence, or relapse of depression, whereas continuing an SSRI during surgery exposes patients to significant bleeding risks. Antidepressant prescribers must be cognizant of and take responsibility for discussing this potential problem and considering different options. This issue must also be the responsibility of the doctor performing the procedure, but, frequently, it will be the prescribing physician who alerts the surgeon to the potential bleeding risk associated with SSRIs.
... Considering pharmacological inhibition of serotonin uptake in platelets as the allegedly most important mechanism in SSRIassociated haemorrhages [19], not only SSRIs but also other antidepressive agents exhibiting non-selective serotonin reuptake inhibition may affect haemostasis and thus may increase the risk of haemorrhages related to antidepressive psychopharmacotherapy [19]. Indeed, the literature provides some evidence for bleeding events (not due to pharmacokinetic drugdrug interactions) related to amitriptyline [39,40], duloxetine [41][42][43] (notably, duloxetine did not significantly influence the pharmacodynamics and-kinetics of warfarin at steady state [44]), imipramine [45], maprotiline [46], St. John's wort/hypericum [47], trazodone [39], and venlafaxine [48][49][50][51][52][53]. Though several hypotheses that apply to SSRI-associated bleedings appear plausible also in the context of non-selective serotonin reuptake inhibiting antidepressants (NSRI) (such as amitriptyline, clomipramine, trazodone, or venlafaxine) [19], data (especially based on systematic approaches) regarding bleeding events related to NSRIs are sparse. ...
Introduction:
There is increasing evidence for an association between treatment with selective serotonin reuptake inhibitors (SSRI) and an increased risk of bleeding events. The most important underlying mechanism appears to be inhibition of serotonin uptake in platelets, an effect that is also present in antidepressants with non-selective serotonin-reuptake inhibition (NSRI). Accordingly, also NSRI may be associated with an increased risk of bleeding. However, there is little data in this regard.
Methods:
Based on data (spontaneous reports of adverse drug reactions) from 2 pharmacovigilance databases (WHO-database/Vigibase™; BfArM/AkdÄ-database in Germany) we used a case/non-case approach and calculated reporting odds ratios (ROR) as measures for disproportionality regarding the association of treatment with an agent of the group SSRI/NSRI and haemorrhages.
Results:
Whereas both positive control agents (ASS and diclofenac) were statistically associated with haemorrhages in both databases (ASS: BfArM/AkdÄ, ROR 13.62 [95% CI 12.76-14.53]/WHO, ROR 12.96 [95% CI 12.75-13.16]; diclofenac: BfArM/AkdÄ, ROR 3.01 [95% CI 2.71-3.21]/WHO, ROR 2.11 [95% CI 2.05-2.16]), none of the agents of the group SSRI (ROR<1) was associated with haemorrhages. In group NSRI, only St. John's wort/hypericum was associated with haemorrhages (WHO-database, ROR 1.31 [95% CI 1.06-1.63]).
Discussion:
Signal detectioning in 2 pharmacovigilance databases suggest that serotonin reuptake inhibition is not associated with an increased risk of bleeding. However, underreporting may have accounted for the evaluated absent associations, particularly concerning SSRI. Regarding the detected increased risk of bleeding associated with hypericum, pharmacokinetic drug-drug interactions may be relevant independent of serotonin reuptake inhibition.
... Potentially serious AEs such as bleeding, hepatoxicity, and suicidality have been associated with the use of duloxetine or drugs in its class, and precautions or warnings for these AEs are found in the Food and Drug Administration package insert. The use of duloxetine in adult patients is not known to be associated with risk to a degree likely to produce economically relevant consequences, and quantifying the potential impact of additional AEs was not feasible from the limited description of these events in the published literature [19,[100][101][102][103][104]. ...
Objective: To assess the cost-effectiveness of duloxetine in the treatment of chronic low back pain (CLBP) from a US private payer perspective. Methods: A cost-utility analysis was undertaken for duloxetine and seven oral post–first-line comparators, including nonsteroidal anti-inflammatory drugs (NSAIDs), weak and strong opioids, and an anticonvulsant. We created a Markov model on the basis of the National Institute for Health and Clinical Excellence model documented in its 2008 osteoarthritis clinical guidelines. Health states included treatment, death, and 12 states associated with serious adverse events (AEs). We estimated treatment-specific utilities by carrying out a meta-analysis of pain scores from CLBP clinical trials and developing a transfer-to-utility equation using duloxetine CLBP patient-level data. Probabilities of AEs were taken from the National Institute for Health and Clinical Excellence model or estimated from osteoarthritis clinical trials by using a novel maximum-likelihood simulation technique. Costs were gathered from Red Book, Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project database, the literature, and, for a limited number of inputs, expert opinion. The model performed one-way and probabilistic sensitivity analyses and generated incremental cost-effectiveness ratios (ICERs) and cost acceptability curves. Results: The model estimated an ICER of $59,473 for duloxetine over naproxen. ICERs under $30,000 were estimated for duloxetine over non-NSAIDs, with duloxetine dominating all strong opioids. In subpopulations at a higher risk of NSAID-related AEs, the ICER over naproxen was $33,105 or lower. Conclusions: Duloxetine appears to be a cost-effective post–first-line treatment for CLBP compared with all but generic NSAIDs. In subpopulations at risk of NSAID-related AEs, it is particularly cost-effective.
... Potentially serious AEs such as bleeding, hepatoxicity, and suicidality have been associated with the use of duloxetine or drugs in its class, and precautions or warnings for these AEs are found in the Food and Drug Administration package insert. The use of duloxetine in adult patients is not known to be associated with risk to a degree likely to produce economically relevant consequences, and quantifying the potential impact of additional AEs was not feasible from the limited description of these events in the published literature [19,[100][101][102][103][104]. ...
To assess the cost-effectiveness of duloxetine in the treatment of chronic low back pain (CLBP) from a US private payer perspective.
A cost-utility analysis was undertaken for duloxetine and seven oral post-first-line comparators, including nonsteroidal anti-inflammatory drugs (NSAIDs), weak and strong opioids, and an anticonvulsant. We created a Markov model on the basis of the National Institute for Health and Clinical Excellence model documented in its 2008 osteoarthritis clinical guidelines. Health states included treatment, death, and 12 states associated with serious adverse events (AEs). We estimated treatment-specific utilities by carrying out a meta-analysis of pain scores from CLBP clinical trials and developing a transfer-to-utility equation using duloxetine CLBP patient-level data. Probabilities of AEs were taken from the National Institute for Health and Clinical Excellence model or estimated from osteoarthritis clinical trials by using a novel maximum-likelihood simulation technique. Costs were gathered from Red Book, Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project database, the literature, and, for a limited number of inputs, expert opinion. The model performed one-way and probabilistic sensitivity analyses and generated incremental cost-effectiveness ratios (ICERs) and cost acceptability curves.
The model estimated an ICER of $59,473 for duloxetine over naproxen. ICERs under $30,000 were estimated for duloxetine over non-NSAIDs, with duloxetine dominating all strong opioids. In subpopulations at a higher risk of NSAID-related AEs, the ICER over naproxen was $33,105 or lower.
Duloxetine appears to be a cost-effective post-first-line treatment for CLBP compared with all but generic NSAIDs. In subpopulations at risk of NSAID-related AEs, it is particularly cost-effective.
A limited number of studies have reported an association between erectile dysfunction (ED) and chronic periodontitis (CP). The aim of the present study is to assess the association between CP and ED through a systematic review of published literature. To address the focused question, “Is there a relationship between ED and CP?” indexed databases were searched till December 2015 using various key words “erectile dysfunction,” “periodontal disease,” “periodontitis,” “dental infection,” and “impotence.” Letters to the editor, commentaries, historic reviews, and experimental studies were excluded. The pattern of the present systematic review was customized to primarily summarize the pertinent data. Nine studies were included. Seven studies had a cross-sectional design and two studies were randomized control trials. The number of study participants ranged between 53 and 513,258 individuals with age ranging between 20 years and 85 years (median age ranging between 34.9 ± 4.9 years and 50.9 ± 16.6 years). In all studies, a positive relationship between CP and ED was reported. In four studies, odds ratio were reported, ranging between 1.53 and 3.35. From the literature reviewed, there seems to be a positive association between ED and CP; however, further well-designed controlled clinical trials are needed in this regard. It is emphasized that physicians should refer patients with ED to oral health care providers for a comprehensive oral evaluation and treatment.
Duloxetine is a new antidepressant agent approved for use in major depressive disorder, generalized anxiety disorder and diabetic peripheral neuropathic pain. It potently inhibits the reuptake of serotonin and norepinephrine in the synaptic cleft. This dual mechanism of action is thought to provide a favorable pharmacological profile with regards to efficacy, onset of action and analgesic properties. Pilot studies on the efficacy of duloxetine in the treatment of dysthymia and other psychiatric disorders have also shown promising results. Duloxetine appears well tolerated and its safety profile is similar to that of the selective serotonin-reuptake inhibitors.
In the past 10-15 years, the diagnosis of mental diseases in the paediatric and adolescent population has risen significantly. This has resulted in paediatric dentists caring for a large number of children suffering from these conditions. For the safe care of these children, paediatric dentists need to be aware of not only the characteristics of mental diseases but also the medications used for their treatment. Becoming familiar with the plethora of psychoactive agents and their complex pharmacological properties and interactions poses a daunting but necessary challenge as they are likely to influence dental treatment. To help with this understanding, the present paper provides a comprehensive but simplified review of the major paediatric psychotropic drugs in terms of basic pharmacology, common indications, general and oral health-related adverse effects and interactions with other medications which may be prescribed in the course of dental treatment.
Blutungskomplikationen unter Serotonin-Noradrenalin-Wiederaufnahmehemmern sind ein bekanntes Phänomen. Wir berichten über
eine Patientin, die unter Duloxetin eine großflächige Hautblutung entwickelte. Als pathophysiologisches Korrelat konnte eine
transiente Thrombozytenfunktionsstörung nachgewiesen werden. Nach Umstellung der Therapie auf Venlafaxin, ebenfalls ein Antidepressivum
mit dualem Wirkmechanismus, zeigte die Patientin eine regelrechte Plättchenfunktion. Wir erreichten schließlich eine Remission
der Episode.
Bleeding complications during therapy with serotonin norepinephrine reuptake inhibitors are a well-known phenomenon. We report
a patient who developed ecchymosis during administration of duloxetine. As a correlate we detected a transient platelet dysfunction.
After converting to venlafaxine therapy, another antidepressant with a dual mechanism of action, the patient showed normal
platelet function. We finally achieved remission of the episode.
Among the antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are often preferred to other classes of antidepressants in the treatment of depression in the elderly because of their better safety profile. Most of the known effects of SSRIs, either beneficial or adverse, are linked to their inhibitory action on the serotonin reuptake transporter (5-HTT). This reuptake mechanism is present not only in neurons but also in other cells such as platelets.
Serotoninergic mechanisms seem to play an important role in haemostasis, and their importance in this regard has long been underestimated. Abnormal activation may lead to a pro-thrombotic state, as may occur in patients with major depressive disorder, whilst downregulation, as occurs in patients treated with SSRIs, may have two clinical consequences, both of particular interest in the elderly. On the one hand, there may be an increased risk of bleeding; on the other hand, a reduction in thrombotic risk may be possible. Polymorphism in the promoter region of the gene that transcribes the 5-HTT has been shown to have a relevant impact on its function and, in turn, on the beneficial and adverse effects of SSRIs.
Bleeding has been a concern since the introduction of SSRIs, with multiple case reports published and communicated to the pharmacovigilance systems. The first epidemiological study was published in 1999 and since then, 34 epidemiological studies from different areas, most of them including elderly patients in their study populations, have been published with a variety of results. Broadly, the epidemiological evidence supports a moderately increased risk of bleeding associated with the use of SSRIs, which may be critically dependent on patient susceptibility and the presence of risk factors.
The impairment of primary haemostasis induced by SSRIs may result, as a beneficial counterpart, in a reduction in the thrombotic risk. A small number of clinical trials and an increasing number of epidemiological studies that include elderly patients have been conducted to clarify whether SSRIs reduce the risk of primary and secondary ischaemic disorders. However, the results have been inconclusive with some studies suggesting a preventive effect and others no effect or even an increased risk. Behind such contradictory results may be the role of depression itself as a cardiovascular risk factor and, therefore, a major confounding factor. How to disentangle its effect from that of the antidepressants is the methodological challenge to be overcome in future studies.
In this complex scenario, the elderly seem to be at a crossroads, because they are the group in which both the risks and the benefits can be the greatest. Studies performed to date have provided us with some clues that can help orient clinicians in taking the most appropriate course of action. For instance, as the gastrointestinal bleeding risk appears to increase with age, prudent advice in patients with a previous history of upper-gastrointestinal bleeding or peptic ulcer, and in those who take NSAIDs, oral anticoagulants, antiplatelet drugs or corticosteroids, would be to suggest addition of an acid-suppressing agent to the drug regimen in those elderly patients in whom SSRIs are indicated.
Duloxetine, a dual acting norepinephrine serotonin reuptake inhibitor, is a relatively new pharmacologic agent utilized in the treatment of depression, as well as diabetic neuropathic pain, fibromyalgia, and female stress urinary incontinence. This expanding scope of usage will inevitably lead to its eventual appearance during routine post-mortem toxicologic assays. Currently there is a paucity of post-mortem toxicologic data concerning duloxetine. The current report provides six additional case reports of post-mortem duloxetine levels, along with a review of duloxetine's pharmacokinetics, and the toxicologic manifestations which have been reported in the literature. The post-mortem levels reported, including the highest level recorded to date, are integrated with previously published reports to generate a foundation for a nascent guide to the interpretation of post-mortem duloxetine levels that could be encountered during routine post-mortem toxicologic analyses, and establish a basis upon which the establishment of toxic and lethal thresholds for this compound can be further elucidated with greater clarity.
This study evaluated the pharmacodynamics and pharmacokinetics of once-daily dosing of warfarin at steady state when taken concomitantly with once-daily doses of duloxetine. Healthy subjects with a stable international normalized ratio (INR) of 1.5 to 2.0 on an individualized fixed dose of warfarin (2-9 mg) in period 1 received daily warfarin and duloxetine (60 mg for 14 days [n = 15] or 60 mg for 4 days, then 120 mg for 10 days [n = 15]) in period 2. Across the 14-day period when warfarin was coadministered with duloxetine, the least squares mean INR changes from baseline (warfarin alone) ranged from -0.05 to +0.07, and the 90% confidence intervals ranged from -0.12 to +0.14. Following coadministration of warfarin with 60 mg duloxetine, but not with 120 mg duloxetine, there was a statistically significant prolongation in bleeding time compared to warfarin alone. For both R- and S-warfarin, the 90% confidence interval for the geometric mean ratios of area under the curve (AUC(tau,ss)) and maximum plasma concentrations (C(max,ss)) between warfarin administered alone and with 60 or 120 mg duloxetine were contained within the bioequivalence limits of 0.8 to 1.25. In conclusion, duloxetine had no clinically or statistically significant effect on the pharmacodynamics or pharmacokinetics of warfarin at steady state.
Duloxetine is the first relatively balanced serotonin and noradrenaline re-uptake inhibitor to be widely available for three indications including: major depressive disorder, peripheral diabetic neuropathic pain and female stress urinary incontinence, although it is not currently approved for all indications in all countries. Generally, duloxetine is safe and well-tolerated across indications, with few reported serious side effects. Common adverse events are consistent with the pharmacology of the molecule and are mainly referable to the gastrointestinal and the nervous systems. The studied dose range is up to 400 mg/day (administered 200 mg b.i.d) but the maximum dose approved for marketing is 120 mg/day (administered 60 mg b.i.d). Duloxetine is eliminated (half-life = 12.1 hours) primarily in the urine after extensive hepatic metabolism by multiple oxidative pathways, methylation and conjugation. Duloxetine would not be expected to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by P450 (CYP)3A, (CYP)1A2, (CYP)2C9, or (CYP)2C19, but would be expected to cause some inhibition of CYP 2D6. Duloxetine should not be used in combination CYP 1A2 inhibitors or nonselective, irreversible monoamine oxidase inhibitors. The purpose of this review is to provide an overview of some of the most important information related to safety and tolerability of duloxetine.
BACKGROUND: Depression is underdiagnosed in the primary care setting. Physical symptoms such as aches, pains, and gastrointestinal disturbance are frequently associated with major depressive disorder (MDD) and are often the presenting symptoms. Duloxetine, a dual-reuptake inhibitor of serotonin and norepinephrine, may have a positive effect on physical symptoms in addition to efficacy in treating emotional symptoms of depression. METHOD: Efficacy was evaluated in 6 double-blind, placebo- and/or active comparator-controlled trials of duloxetine for patients with MDD (DSM-IV criteria). Efficacy in depression was determined primarily using the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Secondary efficacy measures included subscales of the HAM-D-17 and assessment of physical symptoms. Safety evaluations included adverse events, vital signs, laboratory analyses, and electrocardiograms. Safety was evaluated by pooling the data from the MDD trials and a study of duloxetine in nondepressed patients. RESULTS: Duloxetine demonstrated significant differences from placebo on core mood symptoms, physical symptoms (e.g., back pain), and global functioning as early as week 1 of treatment. The estimated probabilities of remission in the studies that demonstrated efficacy ranged from 43% to 57%. The most frequently observed adverse events for duloxetine-treated patients included nausea, dizziness, insomnia, fatigue, and somnolence. Duloxetine did not prolong corrected QT intervals, and the rate of sustained elevations of blood pressure did not differ significantly from placebo. CONCLUSION: In these studies, duloxetine was safe and effective in the treatment of both emotional and physical symptoms of MDD. Based on dose assessments, 60 mg q.d. appears to be the optimum starting and therapeutic dose.
Despite their safety, selective serotonin re-uptake inhibitors (SSRIs) are associated with bleeding. The authors critically reviewed the medical literature on SSRIs to identify subgroups of patients at risk of bleeding complications. The authors performed a literature search using MEDLINE from 1966 to 1st September 2004 using; 'haemorrhage, serotonin uptake inhibitors and antidepressive agents' as search terms and followed up on citations in each paper that was relevant to SSRI associated bleeding. The authors reviewed 7 retrospective analytical studies and 24 case reports of bleeding in 43 different people. Analytical studies support an association between SSRI consumption and upper gastrointestinal (GI) bleeding and perioperative bleeding. Little evidence links SSRI use with intracerebral haemorrhage. The risk of GI bleeding appeared to be highest among patients consuming SSRIs with NSAIDs. Combining aspirin or NSAIDs with SSRIs may further increase the risk of bleeding. Clinicians should caution patients about combining SSRIs with aspirin or NSAIDs. Pharmacotherapy to reduce the risk of GI bleeding should be considered in high risk patients.
Stress urinary incontinence (SUI) is a significant problem for millions of women, many of whom remain untreated for years, sometimes for life. One reason for this is the lack of effective pharmacologic therapy. The drugs used for urge incontinence have little or no effect on leakage occurring without detrusor contraction under conditions of increased intra-abdominal pressure. Recent studies suggest that extrinsic urethral sphincter closure may be controlled by enhancing neurotransmission in pudendal pathways. A new agent, duloxetine, which inhibits serotonin-norepinephrine re-uptake in these pathways, is now in clinical trials and appears to be the first effective pharmacologic therapy for SUI.