Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0030193 (pain)
261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Duloxetine (Cymbalta) is manufactured by Eli Lilly and Company and is the newest antidepressant to be approved by the Food and Drug Administration (FDA). Duloxetine is a potent serotonin and norepinephrine reuptake inhibitor that is also used for the management of pain associated with diabetic peripheral neuropathy. With the introduction of any new drug, toxicology laboratories around the nation experience the same problems: lack of information about the chemical and physical properties of the new drug, detection methodologies from biological specimens, and interpretation of quantitative values. Since its FDA approval in 2002, the Los Angeles County Department of Coroner Toxicology Laboratory has detected and quantitated duloxetine in 12 postmortem cases. The isolation of duloxetine from postmortem specimens consisted of a basic, liquid-liquid (n-butylchloride) extraction procedure. Duloxetine was detected in our general, pharmaceutical, basic drugs screen that utilizes gas chromatography-nitrogen-phosphorus detection (GC-NPD) and GC-mass spectrometry (MS), and the quantitation was specifically by GC-MS. Linearity was achieved from 0.05 to 3.0 mg/L with the limit of detection at 0.03 mg/L. Presented are the case histories, demographics, cause/manner of death, and the postmortem tissue distribution ranges of duloxetine: central blood, not detected (ND)-0.59 mg/L (12 cases); femoral blood, ND-0.26 mg/L (9 cases); vitreous humor, ND-0.23 mg/L (4 cases); liver, 0.28-22 mg/kg (8 cases); gastric contents, 0.08-86 mg total (6 cases); bile, 0.57-3.1 mg/L (7 cases); and urine, 0.07-0.47 mg/L (6 cases). The detection and quantitation of duloxetine in these 12 case studies are considered the first to be reported in the literature; all are designed to aid the forensic toxicologist with the interpretation of his/her own casework.
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PMID:A first look at duloxetine (Cymbalta) in a postmortem laboratory. 1713 55

Diabetics develop numerous chronic associated diseases, among them sensory polyneuropathy. Diabetic polyneuropathy (DPN) often causes pain of various kinds, degree and duration. There are many pharmacological approaches: antidepressants are also important. Duloxetine is a recently approved dual action serotonin and noradrenaline re-uptake inhibitor that in its analgesic efficacy is comparable to established drugs. Duloxetine, in a dosage of 60 mg x 1 or x 2 daily, significantly reduces, from the first week of administration, the pain of DPN, when compared with a placebo. The most commonly observed side effects have been nausea, sleepiness, constipation and fatigue. On average duloxetine has not shown any clinically relevant increase in blood pressure, pulse rate and weight. It thus offers a new option as part of the treatment of pain caused by DPN. The various drugs should be considered individually in any treatment algorithm, also taking into account their side effects. Psychotherapeutic methods serve to support the overcoming of pain.
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PMID:[Duloxetine, a new therapeutic option for diabetic peripheral neuropathic pain]. 1713 88

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.
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PMID:Bleeding gums: duloxetine may be the cause. 1724 71

Diabetic painful neuropathy (DPN) is one of the most common causes of neuropathic pain. The management of DPN consists of excluding other causes of painful peripheral neuropathy, maximising diabetic control and using medications to alleviate pain. The precise relationship between glycaemic control and the development and severity of DPN remains controversial. In this context, drugs such as aldose reductase inhibitors, ACE inhibitors, lipid-lowering agents and alpha-lipoic acid (thioctic acid) may have a useful role to play. There is also evidence that a successful pancreatic transplant may improve symptoms over time, but the mainstay of management continues to be symptomatic control of pain with drugs. Evidence from placebo-controlled studies has shown that opioids, antiepileptic and antidepressant drugs together with capsaicin are effective for alleviating DPN. Tramadol and oxycodone have been shown to be effective in studies of limited duration but their adverse effects, such as constipation and physical dependency, may limit their usefulness as a first-line treatment for DPN. Of the antidepressant drugs, the tricyclic antidepressants have been shown to be effective for alleviating DPN. These medications are widely used but their anticholinergic and sedative properties may not be well tolerated by patients. There is also good evidence that the serotonin-noradrenaline reuptake inhibitor antidepressant drugs venlafaxine and duloxetine are effective for treating DPN. However, venlafaxine may cause cardiac dysrhythmias, and patients using this medication require careful cardiac monitoring. Duloxetine appears to be less cardiotoxic and is licensed in the US and EU for alleviating DPN. The gabapentinoid group of drugs, gabapentin and pregabalin, appear to be the most evidence-based of the antiepileptic drugs for treating DPN. Large placebo-controlled studies have been performed with both of these agents. For many patients, it is still unclear what advantages pregabalin has over gabapentin for DPN. Until better evidence emerges, the potential availability of less expensive generic formulations of gabapentin, together with greater experience with its use, favour gabapentin as the main antiepileptic drug for alleviating DPN. Topiramate, lamotrigine, sodium valproate and oxcarbazepine have been shown to be effective in smaller studies but do not have the same evidence base as the gabapentinoid group of drugs. Of the newer antiepileptic drugs, lacosamide appears to be the most promising for alleviating DPN. Capsaicin has the best evidence base of all the topical agents, but local anaesthetic patches may also have a useful therapeutic role. It is not possible to nominate a single drug as the first-line treatment for DPN and there is evidence that a low-dose combination of two or more drugs rather than a single agent may provide better symptomatic relief with fewer adverse effects. Further studies are necessary to clarify the best combination(s) of treatment for DPN.
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PMID:Diabetic painful neuropathy: current and future treatment options. 1735 15

Duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, is licensed in the UK under two brand names for a total of three different indications. It is available as Cymbalta (jointly promoted by Boehringer Ingelheim and Lilly) for the treatment of patients with major depression, or with diabetic peripheral neuropathic pain; and as Yentreve (Lilly) for the treatment of women with "moderate to severe" stress urinary incontinence. Here we consider whether duloxetine has a role in the treatment of patients with any of these conditions.
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PMID:Is there a place for duloxetine? 1745 Oct 72

Anxiety disorders often are accompanied by painful physical symptoms. This report assessed the effectiveness of duloxetine in improving anxiety symptoms, pain severity, and patient functioning in adults diagnosed with generalized anxiety disorder (GAD), who presented with clinically significant pain symptoms. Data were pooled from two multicenter, randomized, double-blind, placebo-controlled clinical studies evaluating the efficacy of duloxetine 60-120 mg once daily compared with placebo in the treatment of GAD. The primary patient population for these analyses was patients with baseline Visual Analog Scale (VAS) overall pain severity score > or =30. Of the 798 randomized patients that had baseline VAS scores, approximately 44.4% of GAD patients were identified as having baseline VAS overall pain severity score > or =30 (duloxetine N=208, placebo N=146). Duloxetine-treated patients had significantly greater improvement compared with placebo-treated patients on anxiety symptoms (measured by Hamilton Anxiety Scale total score), on patient functioning (measured by the Sheehan Disability Scale Global Functional Impairment Score and across all Sheehan Disability Scale domains), and on all VAS pain items. Patients achieving remission at endpoint, and patients with lower scores on the Clinical Global Impression of Improvement and Patient Global Impression of Improvement scales had greater improvement in VAS pain severity scores. These results suggest that in patients with GAD who present with clinically significant pain symptoms, duloxetine is effective in reducing anxiety symptoms, pain severity, and in improving patient functioning.
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PMID:Efficacy of duloxetine in the treatment of generalized anxiety disorder in patients with clinically significant pain symptoms. 1758 17

Altered functioning of monoamine-containing pathways descending from supraspinal structures to the spinal dorsal horn contributes to injury-induced sensitization of nociceptive transmission. Antidepressant drugs as typified by the dual serotonin (5-HT) and noradrenaline reuptake inhibitor duloxetine attenuate various signs and symptoms of persistent pain in animals and humans. The current study assessed whether dopamine receptor agonists could further enhance the antinociceptive activity of duloxetine in an animal model of injury-induced central sensitization, the rat formalin test. Duloxetine (3-100 mg/kg, s.c.), the dopamine D(1) receptor agonist SKF-82958 (0.1-1 mg/kg, s.c.) and the dopamine D(2) receptor agonist quinpirole (0.003-0.1 mg/kg, s.c.) all significantly attenuated spontaneous nociceptive behaviours during the second phase of the test; duloxetine and quinpirole also attenuated nociceptive behaviours during first phase and interphase. These antinociceptive actions of SKF-82958 and quinpirole were selectively antagonized by SCH 23390 and eticlopride respectively. Remarkably, when completely inactive doses of duloxetine (3 mg/kg) and SKF-82958 (0.3 mg/kg) were combined, a marked attenuation of second phase nociceptive behaviours occurred (P<0.05 vs vehicle), indicative of analgesic synergy. Similarly, when an active antinociceptive dose of quinpirole (0.03 mg/kg, P<0.05 vs vehicle) was combined with an inactive dose of duloxetine (3 mg/kg), a potentiation of duloxetine-mediated antinociception was observed (P<0.001 vs vehicle). Taken together, these results suggest that antidepressant drugs that can enhance the activity of 5-HT, noradrenaline and dopamine neurotransmission within nociceptive pathways should provide a broader spectrum of antinociception than dual mechanism of action reuptake inhibitors in animal models of injury-induced persistent nociception.
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PMID:Dopamine D(1) and D(2) receptor agonism enhances antinociception mediated by the serotonin and noradrenaline reuptake inhibitor duloxetine in the rat formalin test. 1772 28

Clinicians need to know whether duloxetine is effective in patients across a broad range of depressive symptoms and depression severity. Data were pooled from nine randomized, double-blind, placebo-controlled studies in major depressive disorder (total N=2227) comparing duloxetine (40-120 mg/day) with placebo for 8-9 weeks. Patients were retrospectively stratified by baseline score on the HAMD17 into mild (< or =19; n=682), moderate (n=1099), or severe (> or =25; n=446) groups. Duloxetine produced significantly greater baseline-to-endpoint mean change than placebo in HAMD17 total score, Maier and retardation subscales, and the Clinical Global Impressions-Severity of Illness scale in all three cohorts. Significant improvement was seen in HAMD17 items 1 (depressed mood), 3 (suicide), 7 (work and activities), and 10 (psychic anxiety) regardless of severity. The HAMD17 anxiety subscale and items 13 (somatic symptoms-general) and 15 (hypochondriasis) showed significant improvement only in moderately and severely ill patients. Significant improvement in the HAMD17 Maier subscale was seen in all groups by week 1. In all three groups, placebo was significantly superior to duloxetine at early visits on HAMD17 item 12 (somatic symptoms-GI). Mildly and severely ill patients exhibited significant reduction in visual analog scale overall pain severity at the study endpoint. The studies contained fewer patients with very mild or very severe illness, limiting our ability to draw conclusions in these patient populations. Duloxetine demonstrated superior efficacy in the treatment of major depressive disorder, when compared with placebo, regardless of the baseline severity of depressive symptoms, although effect sizes were largest in the most severely depressed patients.
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PMID:Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression. 1791 53

Depression and painful somatic symptoms commonly occur together. Depression and chronic pain can have devastating effects on a patient's health, productivity, and overall quality of life. When moderate-to-severe pain exists, it can impair patient function while making treatment more difficult or resistant, with increased severity in depressive symptoms and worse outcomes. A variety of chronic pain syndromes exist, including diabetic neuropathy. A high prevalence of patients with chronic pain display depressive symptoms. Treatment for these conditions relies on pharmacologic therapy coupled with diligent, periodic assessments of changes in symptom severity. The link between pain and depression lies in the central and peripheral nervous systems. The brain stem serves as an important connection between the higher brain centers and the spinal cord. In the brain stem, the neurotransmitters serotonin and norepinephrine modulate pain transmission through ascending and descending neural pathways. Both serotonin and norepinephrine are also key neurotransmitters involved with the pathophysiology of depression. Tricyclic antidepressants are effective treatments for pain and depression; selective serotonin reuptake inhibitors provide less benefit. Duloxetine and venlafaxine, which are serotonin and norepinephrine reuptake inhibitors, were shown in clinical trials to alleviate pain and depressive symptoms. Diabetic neuropathy and other chronic pain syndromes were also shown to benefit from duloxetine and venlafaxine. Antidepressants remain fundamental therapeutic agents for depression and anxiety disorders. Their extended use into chronic pain, depression with physical pain, physical pain with or without depression, and other potential medical conditions should be recognized.
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PMID:Antidepressant agents for the treatment of chronic pain and depression. 1796 65

Duloxetine is a balanced selective serotonin norepinephrine reuptake inhibitor (SNRI) which, in 2004, became the first agent to receive regulatory approval for the treatment of painful diabetic neuropathy in the US. This compound has no other significant receptor or channel activities other than the serotonin and norepinephrine reuptake inhibition mechanisms and works to diminish or control the symptoms of diabetic neuropathy. Duloxetine has no known neuroprotective or other effects which prevent the development of neuropathy in patients with diabetes. The purpose of this review article is to discuss the background of painful diabetic neuropathy, the pharmacology of duloxetine, and its safety and efficacy in clinical trials and long-term observations. The authors will also comment on its use in clinical practice. Results from controlled clinical trials reveal that duloxetine administered at 60 mg qd or 60 mg bid is efficacious in treating diabetic neuropathic pain relative to placebo. Positive treatment outcomes are also seen for other measures of pain and quality of life. A minor but statistically significant increase in blood glucose compared with placebo treated patients has been observed in controlled clinical trials. Otherwise, controlled and open-label clinical studies have demonstrated a high degree of safety and tolerability for the compound. These findings provide support for the proposed role of serotonin and norepinephrine as key mediators of the descending pain inhibition pathways of the brain stem and spinal cord.
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PMID:Review of duloxetine in the management of diabetic peripheral neuropathic pain. 1820 Aug 4


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