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Duloxetine (brand names Cymbalta, Yentreve) is a serotonin-norepinephrine reuptake inhibitor (SNRI) used for major depressive disorder (MDD), generalized anxiety disorder (GAD), pain related to diabetic neuropathy and fibromyalgia and in some countries for stress urinary incontinence (SUI). It is manufactured and marketed by Eli Lilly. Large number of side effects occurring during duloxetine treatment and lack of clear advantage over existing medications prompted critical reviews concluding that duloxetine "should not be used" for stress urinary incontinence[1] and "currently has no place in the treatment of depression or diabetic neuropathy" as well.[2][

Contents

Duloxetine Systematic (IUPAC) name (+)-(S)-N-Methyl-3-(naphthalen-1-yloxy)- 3-(thiophen-2-yl)propan-1-amine Identifiers CAS number 116539-59-4 (free base). 136434-34-9 (hydrochloride) ATC code N06AX21 PubChem 60835 DrugBank APRD00060 Chemical data Formula C18H19NOS  Mol. mass 297.41456 g/mol SMILES eMolecules & PubChem Pharmacokinetic data Bioavailability ~ 50% (32% to 80%) Protein binding ~ 95% Metabolism Liver, two P450 isozymes, CYP2D6 and CYP1A2. Half life 12,1 hours Excretion 70% in urine, 20% in feces Therapeutic considerations Licence data EU, US Pregnancy cat. C(US) Legal status ℞-only(US) Routes Oral

1 History 2 Indications 2.1 Major depressive disorder 2.2 Stress urinary incontinence 2.3 Painful peripheral neuropathy 2.4 Generalized anxiety disorder 2.5 Fibromyalgia 2.6 Chronic fatigue syndrome 3 Contraindications 4 Adverse effects 4.1 Postmarketing spontaneous reports 4.2 Discontinuation syndrome 4.3 Suicidality 5 Pharmacology 6 See also 7 References 8 External links

History

Duloxetine was created by Lilly researchers. David Robertson, David Wong, a co-discoverer of fluoxetine (Prozac), and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990.[4] The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988.[5] The (+)-enantiomer of LY227942, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes two times more potently than (-)-enantiomer. This molecule was subsequently named duloxetine.[6]

Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant[7] and the dose was increased to as high as 120 mg in subsequent clinical trials.[8]

In 2001 Lilly filed a New Drug Application (NDA) for duloxetine for depression with the US Food and Drug Administration (FDA). However, in 2003 the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and QTc interval prolongation appeared as a concern. The FDA experts concluded that "Duloxetine can cause hepatotoxicity in the form of transaminase elevations. It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver." The FDA also recommended "routine blood pressure monitoring" at the new highest recommended dose of 120 mg, "where 24% patients had one or more [blood pressure] readings of 140/90 vs. 9% of placebo patients."[9]

After the manufacturing issues were resolved, the liver toxicity warning included in the prescribing information, and the follow-up studies showed that duloxetine does not cause QTc interval prolongation, duloxetine was approved by the FDA for depression and diabetic neuropathy in 2004.[10] In 2007 Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.[11]

Duloxetine was approved for use of stress urinary incontinence (SUI) in the EU in 2004. In 2005, Lilly withdrew the duloxetine application for stress urinary incontinence (SUI) in the U.S., stating that discussions with the FDA indicated "the agency is not prepared at this time to grant approval ... based on the data package submitted." A year later Lilly abandoned the pursuit of this indication in the U.S. market.[12]

Lorazepam serum levels are proportional to the dose administered. Giving 2 mg oral lorazepam will result in a peak total serum lorazepam level of around 20 nanograms/ml around two hours later,[24][23] half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide.[34] A similar dose given intravenously will result in an earlier and higher peak serum level, with a higher proportion of unmetabolised (active) lorazepam.[35] On regular administration, maximum lorazepam serum levels are attained after three days. Longer term use, up to six months, does not result in further accumulation.[24] On discontinuation, lorazepam serum levels become negligible after 3 days and undetectable after about a week. Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve hepatic oxidation and therefore is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more water-soluble than its precursor and therefore gets more widely distributed in the body leading to a longer half-life than lorazepam. Lorazepam-glucuronide is excreted by the kidneys[24] and remains detectable - particularly in the urine - for substantially longer than lorazepam.

Indications

The main uses of duloxetine are in major depressive disorder, general anxiety disorder, stress urinary incontinence and painful peripheral neuropathy. In addition, it is being studied for various other indication

Major depressive disorder

Duloxetine is efficacious for the treatment of major depression. In three out of six well-designed properly controlled pre-marketing trials duloxetine performed better than placebo; other three trials were inconclusive.[13] A meta-analysis of these trials indicated that the effect size of duloxetine as compared with placebo was weak-to-moderate, and similar to other 11 antidepressants studied.[14] The rationale behind the development of duloxetine was that inhibition of the reuptake of both serotonin and norepinephrine would make it work better than SSRIs, which inhibit only the reuptake of serotonin. However, in a comparative meta-analysis of clinical trials duloxetine appeared to be insignificantly less effective than SSRIs.[15] A head-to-head comparison of duloxetine with an SSRI escitalopram found duloxetine to be both less tolerable and less effective.[16]

Stress urinary incontinence

Please help improve this article or section by expanding it. Further information might be found on the talk page or at requests for expansion. (May 2008)Stress urinary incontinence is involuntary loss of urine when the bladder comes under strain, e.g. from coughing, sneezing or other movements that increase the intraabdominal pressure. Duloxetine was first reported to improve outcomes in SUI in 1998.[17] Systematic reviews with meta-analysis, conducted in 2005 (Cochrane)[18] and 2008 (University of Minnesota),[19] each found ten controlled trials. Both systematic reviews concluded that duloxetine did not lead to cure of stress urinary incontinence in the vast majority of people, but that episodes of incontinence were reduced by about 50%. This was associated with an improvement in quality of life measurements. Mild side-effects were common, and about a fifth had to discontinue the medication because of poor tolerance.

Painful peripheral neuropathy

Please help improve this article or section by expanding it. Further information might be found on the talk page or at requests for expansion. (May 2008)At 20mg per day Cymbalta showed no clinical improvement over placebo. At 60mg per day Cymbalta showed modest improvement for diabetic pain over baseline, with 51% of patients treated with Cymbalta reporting at least a 30% sustained reduction in pain. In comparison, 31% of patients treated with placebo reported this magnitude of sustained pain reduction. In one study Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events, another trial had a low dropout rate of 12.1 percent.[20][21] Duloxetine is also used to treat nerve pain in the feet, legs, or hands due to nerve damage caused by poorly controlled diabetes. Duloxetine is thought to enhance the nerve signals within the central nervous system which naturally inhibit pain. Duloxetine is not effective for the numbness or tingling, nor is it effective for the other complications of diabetes. It does not treat the underlying nerve damage, but can help reduce the pain.[22]

Generalized anxiety disorder

On May 11 2006, Eli Lilly and Company announced the recent submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for Cymbalta for the treatment of generalized anxiety disorder (GAD).

Eli Lilly said the FDA has approved Cymbalta for the treatment of GAD in February 2007.[23] Eli Lilly said that in clinical trials patients treated with Cymbalta for GAD experienced a 46% improvement in anxiety symptoms, compared to 32% for those who took placebo, as measured by the Hamilton Anxiety Scale.

Fibromyalgia

On October 19, 2006, Eli Lilly issued a press release saying they had done trials which found that Cymbalta, at 60 mg once or twice daily, significantly reduced pain in more than half of women treated for fibromyalgia (FM), with and without major depression, according to 12-week data presented at the annual meeting of the American College of Rheumatology. Eli Lilly is in Phase III of its FM trials and is expected to submit a sNDA to the FDA for approval of Cymbalta for FM within the next 12 months.

Critics argue that randomized controlled trials of FM are difficult due to factors such as a lack of understanding of the pathophysiology and a heterogeneous FM patient population. Although there is a lack of understanding of what causes FM, it is estimated that approximately 5-7% of the U.S. population has FM,[24] representing a large patient clientele. Eli Lilly hopes Cymbalta will be the first FDA approved medication for FM and had been promoting Cymbalta for FM since 2004.[25]

In the study testing the efficacy of Cymbalta for FM, participants completed several questionnaires to measure the amount of pain and discomfort the disease caused them at the beginning of the study, and then at the end of each of the first two weeks and every second week for the remaining 12 weeks of the study. Researchers also tested the participants for depression.[25]

Women who took Cymbalta had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11% of the study, there was no effect from taking the medication compared with a placebo. Reportedly, depression played no part in whether or not the drug worked to control pain. The change in the level of women's pain was particularly pronounced after a month of taking the drug, then leveled off a bit before dropping again near the end of the study.[25]

However, in one of the primary measures of pain there was no significant difference between the two groups at the end of the 12-week trial. Also, because the trial lasted only 12 weeks, it is impossible to tell how well the drug would control treatment for a longer period of time.[25]

The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008. [26]

Chronic fatigue syndrome

As of January 11 2007, Eli Lilly is currently enrolling patients for double blind Phase II and Phase III trials of Cymbalta for the use of Chronic Fatigue Syndrome (CFS) in conjunction with the University of Cincinnati.[27] CFS is characterized by severe disabling fatigue of at least six months' duration which cannot be fully explained by an identifiable medical condition. Eli Lilly has not publicly stated their hypothesis for use of Cymbalta for CFS.[citation needed

Contraindications

The following contraindications are listed by the manufacturer:[citation needed]

• Hypersensitivity - duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
• Monoamine oxidase inhibitors - concomitant use in patients taking monoamine oxidase inhibitors is contraindicated.
• Uncontrolled narrow-angle glaucoma - in clinical trials, Cymbalta use was associated with an increased risk of mydriasis (dilation of the iris); therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma, in which mydriasis can cause sudden worsening.
• CNS acting drugs - given the primary central nervous system (CNS) effects of duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.
• Cymbalta and thioridazine should not be co-administered.

  Adverse effects

  To meet Wikipedia's quality standards, this article or section may require cleanup because it is in a list format that may be better presented using prose. You can help by converting this section to prose, if appropriate. Editing help is available. (May 2008)

  Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.[28]

  In a trial for mild major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group:[29]

  Other side-effects include:

  • Orthostatic hypotension
  • Fatigue
  • Vivid nightmares
  • Increased sweating
  • Decreased appetite and weight loss
  • Blurred vision
  • Paresthesia
  • Disturbances of the gut, such as nausea, constipation, diarrhea, indigestion, vomiting
  • Tremor
  • Anxiety, nervousness, agitation
  • Palpitations
  • Decreased sex drive or difficulty achieving orgasm
  • Impotence or delayed ejaculation
  • Hot flashes
  • Taste disturbances
  • Difficulty passing urine
  • Increase in blood pressure or heart rate
  • Cold hands or feet
  • Jaundice
  • Inflammation of the liver or hepatitis
  • Depersonalization
  • Hypomania
  • Weight gain or loss

  Duloxetine and SSRIs have been shown to cause sexual side effects in some patients, both males and females. Although usually reversible, these sexual side effects can sometimes last for months, years, or longer, even after the drug has been completely withdrawn.[citation needed] This disorder is known as post-SSRI sexual dysfunction.

  Postmarketing spontaneous reports

  Reported adverse events which were temporally correlated to Cymbalta therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens-Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.[30]

  A number of more serious complications, in which duloxetine may have played a role, has been published in the form of case reports:

  • The Los Angeles County Department of Coroner released a report of the first post mortem studies of duloxetine; they identified twelve cases in which duloxetine was present on toxicologic analysis, but in no case was it deemed to be the ultimate cause of death. Five cases were declared multiple drug intoxication, and two were declared suicide.[31]
  • A case of hyponatremia induced by duloxetine was reported by doctors at Weill Cornell Medical College in New York. This is common to all SSRIs.[32]
  • A case of dyskinesia during treatment with duloxetine was reported in Germany.[33]
  • Two episodes of serotonin syndrome have been documented in the use of duloxetine in conjunction with other medications.[34][35]
  • A case of fulminant hepatic failure involving duloxetine which resulted in death was reported by the Department of Internal Medicine, Ohio State University, Columbus, Ohio.[36]
  • An attack of acute porphyria in a patient with known variegate porphyria who had been commenced on duloxetine.[37]

    Discontinuation syndrome

    Further information: SSRI discontinuation syndrome

    During marketing of other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. This withdrawal phenomenon is known as the SSRI discontinuation syndrome.

    When discontinuing treatment with Cymbalta, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate."[38] This tapering process may be ineffective for some patients.[citation needed]

    In MDD placebo-controlled clinical trials of up to nine weeks' duration, systematically evaluating discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.[39]

    Suicidality

    The FDA requires all antidepressants, including duloxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.[40][41][42]

    To obtain statistically significant results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As suicidal ideation and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance. In line with the general results, duloxetine use in depressed adults insignificantly decreased the odds of suicidality by 12%[41] or 20%[42] depending of the statistical technique used. However, in the subgroup of young adults (18-24 years old) duloxetine increased the odds of suicidality 5-fold, close to statistical significance.[41] There have been no trials of duloxetine in minors.

    Several commentators noted that the data FDA used in their analysis of duloxetine-associated suicidality may have been incomplete. According to Arif Khan, the Summary Basis of Approval used by the FDA to approve duloxetine for depression contained only the mention of two completed suicides out of 3490 patients, and the rest of the data was not sufficient to "conduct any meaningful analysis."[43] Jeanne Lenzer wrote in The Independent and Slate Magazine, and this fact was also confirmed by a Lilly spokesman, that another two completed suicides, which occurred in the depression studies ran by the Lilly's Japanese partner Shionogi, have not been reported to the FDA.[44][45] According to Lenzer, four completed suicides also occurred in the trials of duloxetine for stress urinary incontinence (SUI). As these trials failed, the FDA initially insisted that any information about them is a commercial secret and cannot be released.[45] Later, in a short statement the FDA acknowledged that in SUI trials eleven suicide attempts occurred in persons taking duloxetine vs none in the placebo group.[46]

    A series of four cases of duloxetine-associated suicidality has been reported. In all four cases depressed patients began having suicidal thoughts after starting on duloxetine or increasing its dose. These thoughts stopped, and the patients returned to normal after duloxetine was discontinued, and they were switched to another antidepressant.[47]

    A suicide of 19-year-old Traci Johnson, a healthy volunteer in a duloxetine clinical pharmacology study, was highly publicized. For about a month she had been given high doses of duloxetine, and then she was switched to placebo. Four days after the switch, she hanged herself with her scarf from a shower rod in the bathroom of Lilly Laboratory for Clinical Research.[48][49] The New York Times article mentioned a withdrawal syndrome as a possible reason for this suicide.[49]

    Pharmacology

    A study by Bymaster and colleagues found that duloxetine inhibited binding to the human norepinephrine (NE) and serotonin (5-HT) transporters. [50]

    See also

    • Serotonin-norepinephrine reuptake inhibitor (SNRI)
    • Neuropsychopharmacology
    • Neuropharmacology
    • Pharmacology
    • Psychoactive drug

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          External links

          • Manufacturer website
          • Duloxetine - medlineplus.org
          • Eli Lilly Cymbalta Prescribing Guide
          • FDA Alert for Healthcare Professionals - Cymbalta Serotonin Syndrome
          • FDA Patient Information Sheet on Cymbalta

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Pharmacodynamics

Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors,[36] which may also explain its marked[5] amnesic effects. The main pharmacological effects of lorazepam are the enhancement of GABA at the GABAA receptor.[37] Benzodiazepine drugs including lorazepam increase the inhibitory processes in the cerebral cortex.[38]

The magnitude and duration of lorazepam effects are dose related, meaning that larger doses have stronger and longer-lasting effects. This is because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors[39].

The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to get limited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation in mouse spinal cord cell cultures.[40]

Contraindications and special considerations

Contraindications

Lorazepam must be avoided in patients with the following conditions:

• Allergy or hypersensitivity. Past hypersensitivity or allergy to lorazepam, to any benzodiazepine or to any of the ingredients in lorazepam tablets or injections.

• Severe respiratory failure. Benzodiazepines, including lorazepam, may depress central nervous system respiratory drive and are contraindicated in severe respiratory failure. An example would be the inappropriate use to relieve anxiety associated with acute severe asthma. The anxiolytic effects may also be detrimental to a patient's willingness and ability to fight for breath. However, if mechanical ventilation becomes necessary, lorazepam may be used to facilitate deep sedation.

• Acute intoxication. Lorazepam may interact synergistically with the effects of alcohol, narcotics, or other psychoactive substances. It should therefore not be administered to a drunk or intoxicated person.

• Ataxia. This is a neurological clinical sign, consisting of unsteady and clumsy motion of the limbs and torso, due to failure of gross muscle movement coordination, most evident on standing and walking: it is the classic way in which acute alcohol intoxication may affect a person. Benzodiazepines should not be administered to already ataxic patients.

• Acute narrow-angle glaucoma. Lorazepam has pupil-dilating effects which may further interfere with the drainage of aqueous humour from the anterior chamber of the eye, thus worsening narrow-angle glaucoma.

• Sleep apnea. Sleep apnea may be worsened by lorazepam's central nervous system depressant effects. It may further reduce the patient's ability to protect his or her airway during sleep.

• Myasthenia gravis. This condition is characterised by muscle weakness and a muscle relaxant such as lorazepam may exacerbate symptoms.

• Pregnancy and breast feeding. Lorazepam belongs to the Food and Drug Administration (FDA) pregnancy category D which means that it is likely to cause harm to the unborn baby if taken during the first trimester of pregnancy. Lorazepam given to pregnant women antenatally may cause floppy infant syndrome in the neonate, respiratory depression necessitating ventilation, and neonatal withdrawal symptoms. There is inconclusive evidence that lorazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some new borns. Lorazepam when taken during late in pregnancy, the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apneic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.[41] Lorazepam may also imbibit foetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present in breast milk; so caution must be exercised about breast feeding.

Special groups and situations

• Children and the elderly. The safety and effectiveness of lorazepam is not well determined in children under 16 years of age, but it is used to treat serial seizures. Dose requirements have to be individualized, especially in the elderly and debilitated patients in whom the risk of oversedation is greater. Long-term therapy may lead to cognitive deficits, especially in the elderly, but this is reversible after a period of discontinuation. Benzodiazepines, including lorazepam, have been found to increase the risk of falls and fractures in the elderly.[42]

• Liver or Kidney failure. Lorazepam may be safer than most benzodiazepines in patients with impaired liver function. Like oxazepam it does not require hepatic oxidation, but only hepatic glucuronidation into lorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to an extent causing adverse reactions.[13] Lorazepam-glucuronide and a small amount of unchanged lorazepam are excreted by the kidneys, so in renal failure small increases in lorazepam levels may occur.

• Surgical Premedication. Informed consent which was given only after receiving lorazepam premedication could have its validity challenged later. Staff must use chaperones to guard against allegations of abuse during treatment. Such allegations may arise because of incomplete amnesia, disinhibition and impaired ability to process cues. Because of its relative long duration of residual effects (sedation, ataxia, hypotension and amnesia) lorazepam premedication is best suited for hospital inpatient use. Patients should not be discharged from hospital within 24 hours of receiving lorazepam premedication, unless accompanied by a caregiver. They should also not drive, operate machinery or use alcohol within this period.

• Pregnancy. Lorazepam rapidly penetrates membranes and therefore rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines including lorazepam in late pregnancy especially high doses may result in floppy infant syndrome.[43]

  Tolerance and dependence

  Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects, undesirable with anxiolytic, hypnotic and anticonvulsant effects. Patients at first experience drastic relief from anxiety and sleeplessness, but symptoms gradually return, relatively soon in the case of insomnia but more slowly in the case of anxiety symptoms. After four to six months of regular benzodiazepine use, there is little evidence of continued efficacy. If regular treatment is continued for longer than this, dose increases may be necessary to maintain effects, but treatment resistant symptoms may in fact be benzodiazepine withdrawal symptoms.[44]

  On abrupt, or overly rapid discontinuation of lorazepam, anxiety and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam as with other benzodiazepine drugs can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.[45]

  The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepam's relatively short serum half-life, its confinement mainly to the vascular space and its inactive metabolite results in interdose withdrawal phenomena and next dose cravings. This may reinforce psychological dependence. Because of its high potency, the smallest lorazepam tablet strength of 0.5 mg is also a significant dose reduction (in the UK, the smallest tablet strength is 1.0 mg, which further accentuates this difficulty). To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. If any benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, degree of dependence and the individual. Coming off long-term lorazepam may be more realistically achieved by a gradual switch to an equivalent dose of diazepam, a period of stabilization on this and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acutely, because of the longer half lives (20-200 hours) of diazepam and its active metabolites.[46]

  Withdrawal

  Withdrawal symptoms can occur after taking therapeutic doses of Ativan for as little as one week. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia. It takes approximately 18-36 hours for the benzodiazepine to remove itself from your body.[47]

  Abuse and misuse

  Prescribers of lorazepam must be alert to the possibility of abuse or diversion for illegitimate use when prescribing for unsupervised outpatients. This applies particularly to patients with past or present substance abuse disorders, as persons with addictive personalities are more likely to abuse medications such as lorazepam. In addition to recreational use, benzodiazepines may be diverted and used to facilitate crime: criminals may take them to deliberately seek disinhibition before committing crimes[48] (which increases their potential for violence) or they may give them to unwitting victims as date rape drugs, notably with alcohol.

  In Northern Ireland in cases where drivers had low or no alcohol readings but were thought to be impaired through drugs, benzodiazepines were found to be present in 87% of cases.[49]

  A large-scale, nationwide, U.S. government study of pharmaceutical-related ED visits by SAMHSA found that sedative-hypnotics in the United States are the most frequently abused pharmaceuticals, with 35% of drug-related emergency room visits involving sedative-hypnotics. In this category benzodiazepines are most commonly abused. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. Lorazepam was the third most commonly abused benzodiazepine in these ED visit statistics. [50]

  Adverse effects

  Any of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant, anxiolytic, amnesic and anticonvulsant) may be considered as "adverse effects", or "side effects", if unwanted.[5] Lorazepam's effects are dose-dependent, meaning that the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects.

  Lorazepam has an advantage of being non-sedative relative to its potent anxiolytic effects, but sedation is still the most complained-of side effect. In a group of around 3500 patients treated for anxiety, the most common side-effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Side-effects such as sedation and unsteadiness increased with age.[51]

  • Paradoxical effects. In some cases there can be paradoxical effects with benzodiazepines, such as increased hostility, aggression, angry outbursts and Psychomotor agitation.[52] Paradoxical effects are more likely to occur with higher doses, in patients with pre-existing personality disorders and those with a psychiatric illness. It is worth noting that frustrating stimuli may trigger such reactions, even though the drug may have been prescribed to help the patient cope with such stress and frustration in the first place. As paradoxical effects appear to be dose-related, they usually subside on dose reduction or on complete withdrawal of lorazepam.[53][54][55][48][56][57]
  • Suicidality. Benzodiazepines may sometimes unmask suicidal ideation in depressed patients, possibly through disinhibition or fear-reduction. Though relatively non-toxic in themselves, the concern is that benzodiazepines may inadvertently become facilitators of suicidal behaviour.[58] Lorazepam should therefore not be prescribed in high doses or as the sole treatment in depression but only together with an appropriate antidepressant.
  • Amnesic effects. Among benzodiazepines, lorazepam has relatively strong amnesic effects,[5][59] but patients soon develop tolerance to this with regular use. To avoid amnesia (or excess sedation) being a problem, the initial total daily lorazepam dose should not exceed 2 mg. This also applies to use for night sedation. Five participants in a sleep study were prescribed lorazepam 4 mg at night and the next evening three subjects unexpectedly volunteered memory gaps for parts of that day, an effect which subsided completely after 2-3 days use.[60] Amnesic effects cannot be estimated from the degree of sedation present, since the two effects are unrelated.

  Full lists of Lorazepam side effects:

  For lists of lorazepam side-effects, refer to the manufacturers' data sheets. Note, some may list side-effects for the entire benzodiazepine class, not the specific side-effect profile for lorazepam.

  Interactions

  • Alcohol. Lorazepam is not usually fatal in overdose, but may cause fatal respiratory depression if taken in overdose with alcohol. The combination also causes synergistic enhancement of the disinhibitory and amnesic effects of both drugs, with potentially embarrassing or forensic consequences. Some experts advise patients should be warned against taking alcohol while on lorazepam treatment,[5][61] but such clear warnings are not universal.[62]

    Overdose

    In cases of a suspected lorazepam overdose, it is important to establish if the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain if other drugs were also ingested.

    Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression and death.

    Early management of alert patients includes emetics, gastric lavage and activated charcoal. Otherwise, management is by observation, including of vital signs, support and — only if necessary, considering the hazards of doing so — giving intravenous flumazenil.

    Patients are ideally nursed in a kind, non-frustrating environment since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, patients may respond solicitously, but they may respond with disproportionate aggression to frustrating cues.[63] Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-induced anterograde amnesia

    History and legal status

    Historically, lorazepam is one of the "classical" benzodiazepines. Other classical benzodiazepines include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate.[64] Lorazepam was first introduced by Wyeth Pharmaceuticals in 1971 under the brand names of Ativan and Temesta. The drug was developed by President of Research, D.J. Richards. Wyeth's original patent on lorazepam is expired in the United States but the drug continues to be commercially viable. As a measure of its ongoing success, it has been marketed under more than seventy generic brands since then:

    Almazine, Alzapam, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen, Bonatranquan, Bonton, Control, Donix, Duralozam, Efasedan, Emotion, Emotival, Idalprem, Kalmalin, Larpose, Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin, Lorafen (PL), Lorazon, Lorenin, Loridem, Lorivan, Lorsedal, Lorzem, Lozepam, Merlit, Nervistop L, Nervistopl, NIC, Novhepar, Novolorazem, Orfidal, Piralone, Placidia, Placinoral, Punktyl, Quait, Renaquil, Rocosgen, Securit, Sedarkey, Sedatival, Sedizepan, Sidenar, Silence, Sinestron, Somnium, Stapam, Tavor, Titus, Tolid, Tranqil, Tranqipam, Trapax, Trapaxm, Trapex, Upan, Wintin and Wypax.

    In 2000, the U.S. drug company Mylan agreed to pay $147 million to settle accusations by the F.T.C. that they had raised the price of generic lorazepam by 2600 percent and generic clorazepate by 3200 percent in 1998 after having obtained exclusive licensing agreements for certain ingredients.[65]

    Lorazepam is a Schedule IV drug under the Controlled Substances Act in the U.S. and internationally under the United Nations Convention on Psychotropic Substances.[66] Lorazepam is a Schedule IV drug under the Controlled Drugs and Substances Act in Canada. In the United Kingdom, lorazepam is a Class 4 Controlled Drug under the Misuse of Drugs Regulations 2001.

    In popular culture

    Lorazepam has been mentioned in several contemporary media in recent years, with various clinical aspects highlighted. It is seen in medical situations, such as the TV series House, MD as the drug of choice for the cessation of seizures. Usage for seizures is also depicted in the movie Saw III where "Jigsaw" is being operated on and begins to convulse: the character performing the surgery yells many times for Ativan, but discovers that none is available in the limited operating area. Blue October mentions Lorazepam in their song "HRSA", where it is being prescribed in a psychiatric ward for a similar use. The dependency problem is portrayed in William Gibson's 2007 book Spook Country, in which the character Milgrim is addicted to Ativan and the character Brown exploits Milgrim's addiction, in order to control him, through a steady supply of Ativan and Rize (a brand of the benzodiazepine clotiazepam). In Martin Scorsese's recent film, The Departed, Billy Costigan--an edgy, bitter, intelligent undercover cop for the Massachusetts State Police--suffers from frequent anxiety and claims to have panic attacks and is occasionally seen in the film taking lorazepam.

    In 2005, Fall Out Boy member Pete Wentz attempted to overdose on lorazepam when trying to attempt suicide; he included references to the episode in the songs "I've Got a Dark Alley and a Bad Idea That Says You Should Shut Your Mouth (Summer Song)" and "7 Minutes in Heaven (Atavan Halen)",[67] on the album From Under the Cork Tree.

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    External links

  • inchem.org - Lorazepam data sheet
  • rxlist.com - Lorazepam data sheet
  • drugs.com - Lorazepam data sheet
  • Flash animation about how lorazepam works (mechanism of action)
  • baxter.com - Lorazepam Injection Data Sheet
  • NZ medsafe.govt.nz - Lorzem Data Sheet
  • benzo.org.uk - Genus/Wyeth 1998 UK Lorazepam Data Sheet
  • benzo.org.uk - Ashton H. Benzodiazepines: How They Work And How to Withdraw. August 2002 (The "Ashton Manual").
  • ndaa.org - Drummer, OH. 'Benzodiazepines: Effects on Human Performance and Behavior'(Central Police University Press, 2002).

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  v • d • e Antiemetics and antinauseants (A04) Serotonin (5-HT3) antagonists Azasetron · Dolasetron · Ondansetron · Granisetron · Palonosetron · Ramosetron · Tropisetron Dopamine antagonists Alizapride · Domperidone · Metoclopramide · Metopimazine · Prochlorperazine Antihistamines Cyclizine · Meclizine · Promethazine NK1 receptor antagonists Aprepitant · Casopitant · Fosaprepitant Cannabinoids Dronabinol · Nabilone Benzodiazepines Lorazepam · Midazolam Anticholinergics Scopolamine Corticosteroids Dexamethasone Other Cerium oxalate · Chlorobutanol · Propofol · Trimethobenzamide

  Retrieved from "http://en.wikipedia.org/wiki/Lorazepam"
  Categories: Benzodiazepines | Sedatives | Hypnotics | Anticonvulsants | Muscle relaxants | Anxiolytics | Antiemetics