Duloxetine
Encyclopedia
Duloxetine is a serotonin-norepinephrine reuptake inhibitor
manufactured and marketed by Eli Lilly
. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine
for generalized anxiety disorder (GAD). Duloxetine failed the US approval for stress urinary incontinence amidst concerns over liver toxicity and suicidal events; however, it was approved for this indication in Europe. Duloxetine alleviates pain associated with diabetic neuropathy
and fibromyalgia
. Its efficacy relative to established treatments such as anticonvulsant
s and tricyclic antidepressant
s has not yet been studied.
The role of duloxetine in the treatment of various conditions has led to divergent opinions. Owing to a large number of side effects and lack of clear advantage over existing medications, some reviews have concluded that duloxetine "should not be used" for stress urinary incontinence and "currently has no place in the treatment of depression or diabetic neuropathy." At the same time, some professional guidelines recommend duloxetine in chronic neuropathic pain, especially diabetic polyneuropathy for which it is first-line treatment, and as an add-on medication in stress urinary incontinence instead of surgery.
, stress urinary incontinence, painful peripheral neuropathy
, fibromyalgia
, and chronic musculoskeletal pain associated with osteoarthritis
and chronic lower back pain. It is being studied for various other indications.
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. The rationale behind the development of duloxetine was that inhibition of the reuptake
of both serotonin and norepinephrine would make it work better than selective serotonin reuptake inhibitor
s (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. A head-to-head comparison of duloxetine with an SSRI escitalopram
(Lexapro) found duloxetine to be both less tolerable and less effective. Another analysis of the comparative efficacy of modern antidepressants found duloxetine to be significantly, by 30-40%, less efficacious than mirtazapine
(Remeron), escitalopram, venlafaxine
(Effexor) and sertraline
(Zoloft). Duloxetine was similar to fluoxetine
(Prozac), fluvoxamine
(Luvox) and paroxetine
(Paxil). The tolerability of duloxetine was significantly worse than the tolerability of escitalopram and sertraline.
A review in Prescrire International summarizing the existing evidence noted that duloxetine has limited efficacy in depression and no advantages over other antidepressants. Prescribers observed that, taking into account the risk of hepatic disorders and drug interactions, there is no reason to choose duloxetine when so many other options are available. Similar analysis was presented by Drug and Therapeutics Bulletin
, which is a part of the respected BMJ Group.
s with meta-analysis, conducted in 2005 by Cochrane Collaboration
and in 2008 by University of Minnesota
, concluded that duloxetine failed to cure SUI better than placebo. According to the Cochrane review, some studies showed that episodes of incontinence were reduced by about 50%. This was associated with an improvement in quality of life
measurements. According to the University of Minnesota review, duloxetine performed worse than oxybutynin
(Ditropan) or tolterodine
(Detrol) that cured 18% of the cases, or than pelvic floor muscle training
+ bladder training, which cured 13% of the cases. In terms of "improvement", that is incomplete cure, duloxetine showed improvement in 11% of patients while pelvic floor
muscle training + bladder training showed improvement in 36% of the cases. Significant side effects were common with duloxetine; they were reported as acceptable and about a fifth had to discontinue the medication because of poor tolerance.
In addition, the full report prepared by Minnesota Evidence-based Practice Center for the U.S. government, on which the University of Minnesota review is based, notes that weight reduction would result in improved SUI in 990 adults per 1,000 treated. In the light of the cited data, the report does not mention duloxetine in its policy recommendations. The only recommended interventions are early behavioral changes in weight, physical activity, and pelvic floor muscle training.
The only clinical trial, which directly compared duloxetine with the gold standard of the SUI treatment pelvic floor muscle training (PFMT) was conducted by Eli Lilly
and gave mixed results. The incontinence episode frequency in duloxetine group decreased by 57% vs. 35% in the PFTM group. However, the differences in the pad use and quality of life were not statistically significant. To the contrary, 65% patients doing PFTM reported feeling better vs 54% of the patients on duloxetine. 31% of the patients on duloxetine discontinued the trial due to the side effects during the first 12 weeks. In the continuation of this trial more than 91% of the patients on duloxetine experienced side effects.
Summing up the existing evidence, a review in Prescrire International recommends pelvic floor exercises, which are "risk-free and effective in two-thirds to three-quarters of cases", as the first line treatment of SUI. Duloxetine use reduced the frequency of stress incontinence by one episode a day as compared with placebo. "The tangible effect of duloxetine on the quality of life is doubtful, with a maximum gain of five points on a 100-point scale." The review notes that, at best, duloxetine efficacy is "modest and transient, while its adverse effects are numerous and potentially severe."
Duloxetine was not effective for the numbness or tingling, nor for the other complications of diabetes
. It reduced the pain without treating the underlying nerve damage. Only tight glycemic control was unequivocally demonstrated to slow the progression of neuropathy. Benfotiamine
, alpha-lipoic acid, and ranirestat
have also shown some promise.
The comparative efficacy of duloxetine and established pain-relief medications for DPN is unclear. An independent systematic review in BMJ noted that tricyclic antidepressants (imimpramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants and anticonvulsants have similar tolerability while the opioids caused more side effects. A review in Drug and Therapeutic Bulletin saw no place for duloxetine in the treatment of DPN, based on its high cost and insufficient evidence of the comparative efficacy with tricyclic antidepressants. Another independent review in Prescrire International, considered the moderate pain relief achieved with duloxetine to be clinically insignificant and the results of the clinical trials—unconvincing. The reviewer saw no reason to prescribe duloxetine in practice. The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. However, the authors noted that the evidence in favor of duloxetine is much more solid.
in the treatment of generalized anxiety disorder with demonstrated improvements in function and quality of life for sufferers. Long-term use of duloxetine prevents relapse of generalized anxiety disorder. According to researchers linked to Eli Lilly, clinical trials have demonstrated that duloxetine is well tolerated both in the short-term and the long-term. Other Eli Lilly dependent researchers suggested that duloxetine should be considered a first-line treatment for generalized anxiety disorder. Although this view was repeated in a recent independent review, the major guidelines such as Maudsley Prescribing Guidelines, Mayo Clinic Health Information and Canadian Psychiatric Association Guidelines do not mention duloxetine among the recommended treatment options.
(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. Eli Lilly has been promoting Cymbalta for FM since 2004.
Duloxetine is superior to many other medications for the treatment of fibromyalgia due to its freedom from muscarinic, histaminergic and adrenergic
adverse reactions. Its effectiveness in pain relief is believed to be due to its modulation of the nociception
system. A meta-analysis
of clinical trials has confirmed its pain relief, fatigue reducing properties as well as its effectiveness in improving physical and mental performance.
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.
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.
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.
The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008.
Phase II and Phase III trials of Cymbalta for the use of chronic fatigue syndrome
(CFS) in conjunction with the University of Cincinnati
. CFS is characterized by severe disabling fatigue of at least six months' duration which cannot be fully explained by an identifiable medical condition.
although one study found positive outcomes in only a small proportion of cases. Interstitial cystitis is a bladder and urinary tract disorder which presents as chronic pelvic and perineal pain. It is speculated that duloxetine suppresses neural impulses related to pain below a threshold level sufficient to alleviate some or all neurological pain symptoms.
In addition, the FDA has reported on life threatening drug interactions that may be possible when co-administered with any CNS stimulant, such as phentermine
, diethylpropion, amphetamine
, sibutramine
, methylphenidate
, methamphetamine
, and cocaine
leading to increased risk for serotonin syndrome
.
, somnolence
, insomnia
, and dizziness
are the main side effects, reported by about 10% to 20% of patients.
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.
Duloxetine and SSRIs have been shown to cause sexual side effects in some patients, both males and females.
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
.
, 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. The withdrawal
syndrome from duloxetine resembles the SSRI discontinuation syndrome
.
When discontinuing treatment with duloxetine, 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. The use of a liquid form of the drug may facilitate more gradual tapering."
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 duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.
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.
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% or 20% 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. 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." 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. 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. 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.
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.
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 hung herself in the bathroom of Lilly Laboratory for Clinical Research. The New York Times article mentioned a withdrawal syndrome as a possible reason for this suicide.
. Preclinical studies demonstrate that duloxetine potently inhibits neuronal serotonin and norepinephrine reuptake, and it has been demonstrated that this inhibition is balanced throughout the dosing range (when compared to venlafaxine in which the inhibition of noradrenaline is low at low doses and raises as the dose escalates).
It is also considered a less potent inhibitor of dopamine reuptake. However, duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NA transporters. Duloxetine undergoes extensive metabolism
, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.
. Steady-state is usually achieved after 3 days.
Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.
When orally administered it is well absorbed. There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein.
Metabolism and Elimination — Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (aprox 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces.
Duloxetine was created by Lilly researchers. David Robertson, David Wong, a co-discoverer of fluoxetine
, and Joseph Krushinski are listed as inventors on the patent application
filed in 1986 and granted in 1990. The first publication on the discovery of the racemic
form of duloxetine known as LY227942, was made in 1988. 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.
Initial trials conducted in patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy and the dose was increased to as high as 120 mg in subsequent clinical trial
s.
In 2001 Lilly filed a New Drug Application
(NDA) for duloxetine 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 (current Good Manufacturing Practice
) 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."
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. In 2007Health Canada
approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.
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.
The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
manufactured and marketed by Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
for generalized anxiety disorder (GAD). Duloxetine failed the US approval for stress urinary incontinence amidst concerns over liver toxicity and suicidal events; however, it was approved for this indication in Europe. Duloxetine alleviates pain associated with diabetic neuropathy
Diabetic neuropathy
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
and fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
. Its efficacy relative to established treatments such as anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s and tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s has not yet been studied.
The role of duloxetine in the treatment of various conditions has led to divergent opinions. Owing to a large number of side effects and lack of clear advantage over existing medications, some reviews have concluded that duloxetine "should not be used" for stress urinary incontinence and "currently has no place in the treatment of depression or diabetic neuropathy." At the same time, some professional guidelines recommend duloxetine in chronic neuropathic pain, especially diabetic polyneuropathy for which it is first-line treatment, and as an add-on medication in stress urinary incontinence instead of surgery.
Medical uses
The main uses of duloxetine are in major depressive disorder, general anxiety disorderGeneral anxiety disorder
Generalized anxiety disorder is an anxiety disorder that is characterized by excessive, uncontrollable and often irrational worry about everyday things that is disproportionate to the actual source of worry...
, stress urinary incontinence, painful peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, and chronic musculoskeletal pain associated with osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
and chronic lower back pain. It is being studied for various other indications.
Major depressive disorder
Duloxetine has demonstrated efficacy for the treatment of major depressive disorder. In three out of six well-designed properly controlled pre-marketing trials duloxetine performed better than placebo; the three other trials were inconclusive. Recently, duloxetine was shown to be effective in elderly with recurrent major depressive disorder where it improved cognition, depression, and some pain measures. A meta-analysisMeta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
of these trials indicated that the effect size
Effect size
In statistics, an effect size is a measure of the strength of the relationship between two variables in a statistical population, or a sample-based estimate of that quantity...
of duloxetine as compared with placebo was weak-to-moderate, and similar to other 11 antidepressants studied. The rationale behind the development of duloxetine was that inhibition of the reuptake
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of both serotonin and norepinephrine would make it work better than selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s (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. A head-to-head comparison of duloxetine with an SSRI escitalopram
Escitalopram
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
(Lexapro) found duloxetine to be both less tolerable and less effective. Another analysis of the comparative efficacy of modern antidepressants found duloxetine to be significantly, by 30-40%, less efficacious than mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
(Remeron), escitalopram, venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor) and sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft). Duloxetine was similar to fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac), fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
(Luvox) and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil). The tolerability of duloxetine was significantly worse than the tolerability of escitalopram and sertraline.
A review in Prescrire International summarizing the existing evidence noted that duloxetine has limited efficacy in depression and no advantages over other antidepressants. Prescribers observed that, taking into account the risk of hepatic disorders and drug interactions, there is no reason to choose duloxetine when so many other options are available. Similar analysis was presented by Drug and Therapeutics Bulletin
Drug and Therapeutics Bulletin
Drug and Therapeutics Bulletin is a monthly scientific journal which evaluations of, and practical advice on, individual treatments and the overall management of disease...
, which is a part of the respected BMJ Group.
Stress urinary incontinence
Duloxetine was first reported to improve outcomes in stress urinary incontinence (SUI) in 1998. Systematic reviewSystematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
s with meta-analysis, conducted in 2005 by Cochrane Collaboration
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
and in 2008 by University of Minnesota
University of Minnesota
The University of Minnesota, Twin Cities is a public research university located in Minneapolis and St. Paul, Minnesota, United States. It is the oldest and largest part of the University of Minnesota system and has the fourth-largest main campus student body in the United States, with 52,557...
, concluded that duloxetine failed to cure SUI better than placebo. According to the Cochrane review, some studies showed that episodes of incontinence were reduced by about 50%. This was associated with an improvement in quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
measurements. According to the University of Minnesota review, duloxetine performed worse than oxybutynin
Oxybutynin
Oxybutynin is an anticholinergic medication used to relieve urinary and bladder difficulties, including frequent urination and inability to control urination , by decreasing muscle spasms of the bladder. It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholine...
(Ditropan) or tolterodine
Tolterodine
Tolterodine is an antimuscarinic drug that is used to treat urinary incontinence.It is marketed by Pfizer in Canada and the United States by its brand name Detrol. In Egypt it is also found under the trade names Tolterodine by Sabaa and Incont L.A...
(Detrol) that cured 18% of the cases, or than pelvic floor muscle training
Kegel exercise
A pelvic floor exercise, more commonly called a Kegel exercise , consists of contracting and relaxing the muscles that form part of the pelvic floor, which are now sometimes colloquially referred to as the "Kegel muscles". Several tools exist to help with these exercises, though many are ineffective...
+ bladder training, which cured 13% of the cases. In terms of "improvement", that is incomplete cure, duloxetine showed improvement in 11% of patients while pelvic floor
Pelvic floor
The pelvic floor or pelvic diaphragm is composed of muscle fibers of the levator ani, the coccygeus, and associated connective tissue which span the area underneath the pelvis. The pelvic diaphragm is a muscular partition formed by the levatores ani and coccygei, with which may be included the...
muscle training + bladder training showed improvement in 36% of the cases. Significant side effects were common with duloxetine; they were reported as acceptable and about a fifth had to discontinue the medication because of poor tolerance.
In addition, the full report prepared by Minnesota Evidence-based Practice Center for the U.S. government, on which the University of Minnesota review is based, notes that weight reduction would result in improved SUI in 990 adults per 1,000 treated. In the light of the cited data, the report does not mention duloxetine in its policy recommendations. The only recommended interventions are early behavioral changes in weight, physical activity, and pelvic floor muscle training.
The only clinical trial, which directly compared duloxetine with the gold standard of the SUI treatment pelvic floor muscle training (PFMT) was conducted by Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
and gave mixed results. The incontinence episode frequency in duloxetine group decreased by 57% vs. 35% in the PFTM group. However, the differences in the pad use and quality of life were not statistically significant. To the contrary, 65% patients doing PFTM reported feeling better vs 54% of the patients on duloxetine. 31% of the patients on duloxetine discontinued the trial due to the side effects during the first 12 weeks. In the continuation of this trial more than 91% of the patients on duloxetine experienced side effects.
Summing up the existing evidence, a review in Prescrire International recommends pelvic floor exercises, which are "risk-free and effective in two-thirds to three-quarters of cases", as the first line treatment of SUI. Duloxetine use reduced the frequency of stress incontinence by one episode a day as compared with placebo. "The tangible effect of duloxetine on the quality of life is doubtful, with a maximum gain of five points on a 100-point scale." The review notes that, at best, duloxetine efficacy is "modest and transient, while its adverse effects are numerous and potentially severe."
Diabetic peripheral neuropathy
Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN) based on the positive results of two clinical trials. The average daily pain was measured using 11-point scale, and duloxetine treatment resulted in an additional 1–1.7 points decrease of pain as compared with placebo. At least 50% pain relief was achieved in 40–45% of the duloxetine patients vs. 20–22% of placebo patients. The pain almost completely disappeared, decreasing by more than 90%, in 9–14% of duloxetine patients vs. 2–4% of placebo patients. Most of the response was achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose; however this effect was deemed to be of "minimal clinical significance".Duloxetine was not effective for the numbness or tingling, nor for the other complications of diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. It reduced the pain without treating the underlying nerve damage. Only tight glycemic control was unequivocally demonstrated to slow the progression of neuropathy. Benfotiamine
Benfotiamine
Benfotiamine is a synthetic S-acyl derivative of thiamine . After absorption, benfotiamine can be dephosphorylated by cells bearing an ecto-alkaline phosphatase to the lipid-soluble S-benzoylthiamine...
, alpha-lipoic acid, and ranirestat
Ranirestat
Ranirestat is an aldose reductase inhibitor being developed for the treatment of diabetic neuropathy by Dainippon Sumitomo Pharma and PharmaKyorin. It has been granted orphan drug status. The drug is to be used orally.-Trials:...
have also shown some promise.
The comparative efficacy of duloxetine and established pain-relief medications for DPN is unclear. An independent systematic review in BMJ noted that tricyclic antidepressants (imimpramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants and anticonvulsants have similar tolerability while the opioids caused more side effects. A review in Drug and Therapeutic Bulletin saw no place for duloxetine in the treatment of DPN, based on its high cost and insufficient evidence of the comparative efficacy with tricyclic antidepressants. Another independent review in Prescrire International, considered the moderate pain relief achieved with duloxetine to be clinically insignificant and the results of the clinical trials—unconvincing. The reviewer saw no reason to prescribe duloxetine in practice. The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. However, the authors noted that the evidence in favor of duloxetine is much more solid.
Generalized anxiety disorder
Duloxetine is as effective as venlafaxineVenlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
in the treatment of generalized anxiety disorder with demonstrated improvements in function and quality of life for sufferers. Long-term use of duloxetine prevents relapse of generalized anxiety disorder. According to researchers linked to Eli Lilly, clinical trials have demonstrated that duloxetine is well tolerated both in the short-term and the long-term. Other Eli Lilly dependent researchers suggested that duloxetine should be considered a first-line treatment for generalized anxiety disorder. Although this view was repeated in a recent independent review, the major guidelines such as Maudsley Prescribing Guidelines, Mayo Clinic Health Information and Canadian Psychiatric Association Guidelines do not mention duloxetine among the recommended treatment options.
Fibromyalgia
On October 19, 2006, Eli Lilly issued a press release saying they had done trials which found that Cymbalta (duloxetine), at 60 mg once or twice daily, significantly reduced pain in more than half of women treated for fibromyalgiaFibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
(FM), with and without major depression, according to 12-week data presented at the annual meeting of the American College of Rheumatology
American College of Rheumatology
The American College of Rheumatology is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with arthritis and rheumatic and...
. 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. Eli Lilly has been promoting Cymbalta for FM since 2004.
Duloxetine is superior to many other medications for the treatment of fibromyalgia due to its freedom from muscarinic, histaminergic and adrenergic
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
adverse reactions. Its effectiveness in pain relief is believed to be due to its modulation of the nociception
Nociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
system. A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
of clinical trials has confirmed its pain relief, fatigue reducing properties as well as its effectiveness in improving physical and mental performance.
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.
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.
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.
The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008.
Chronic fatigue syndrome
As of January 11, 2007, Eli Lilly is currently enrolling patients for double blindDouble-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
Phase II and Phase III trials of Cymbalta for the use of chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
(CFS) in conjunction with the University of Cincinnati
University of Cincinnati
The University of Cincinnati is a comprehensive public research university in Cincinnati, Ohio, and a part of the University System of Ohio....
. CFS is characterized by severe disabling fatigue of at least six months' duration which cannot be fully explained by an identifiable medical condition.
Interstitial cystitis
There is a U.S. Patent 6150396 for the use of duloxetine for treatment of interstitial cystitisInterstitial cystitis
Interstitial cystitis or bladder pain syndrome is a chronic, oftentimes severely debilitating disease of the urinary bladder...
although one study found positive outcomes in only a small proportion of cases. Interstitial cystitis is a bladder and urinary tract disorder which presents as chronic pelvic and perineal pain. It is speculated that duloxetine suppresses neural impulses related to pain below a threshold level sufficient to alleviate some or all neurological pain symptoms.
Musculoskeletal Pain
On November 4, 2010, the U.S. Food and Drug Administration approved Cymbalta to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.Contraindications
The following contraindications are listed by the manufacturer:- Hypersensitivity - duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
- MAOIMonoamine oxidase inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s - concomitant use in patients taking MAOIMonoamine oxidase inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s is contraindicated. - Uncontrolled narrow-angle glaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
- in clinical trials, Cymbalta use was associated with an increased risk of mydriasisMydriasisMydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
(dilation of the pupil); therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, in which mydriasis can cause sudden worsening. - CNS acting drugs - given the primary central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(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 thioridazineThioridazineThioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...
should not be co-administered.
In addition, the FDA has reported on life threatening drug interactions that may be possible when co-administered with any CNS stimulant, such as phentermine
Phentermine
Phentermine, a contraction of "phenyl-tertiary-butylamine", is a psychostimulant drug of the phenethylamine class, chemically related to amphetamine. It is used medically as an appetite suppressant....
, diethylpropion, amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
, sibutramine
Sibutramine
Sibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise...
, methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
, methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
, and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
leading to increased risk for serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
.
Adverse effects
NauseaNausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, and dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
are the main side effects, reported by about 10% to 20% of patients.
In a trial for mild major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
(34.7%), dry mouth (22.7%), headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
(20.0%) and dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
(18.7%), and except for headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, these were reported significantly more often than in the placebo group.
Duloxetine and SSRIs have been shown to cause sexual side effects in some patients, both males and females.
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 phosphataseAlkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
increased, glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, hyponatremia
Hyponatremia
Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. In the vast majority of cases, hyponatremia occurs as a result of excess body water diluting the serum sodium and is not due to sodium deficiency. Sodium is the dominant extracellular...
, jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, orthostatic hypotension
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
(especially at the initiation of treatment), Stevens–Johnson syndrome, syncope
Syncope (medicine)
Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
(especially at initiation of treatment), and urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
.
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 moodDysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, hypomania
Hypomania
Hypomania is a mood state characterized by persistent and pervasive elevated or irritable mood, as well as thoughts and behaviors that are consistent with such a mood state...
, tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
, and seizures. Although these events are generally self-limiting
Self-limiting
Self-limiting may refer to:*Self-limiting , an organism or colony of organisms which limits its own growth*Governor , used to control the speed of mechanical equipment to prevent it from operating at unsafe speeds...
, some have been reported to be severe. The withdrawal
Withdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
syndrome from duloxetine resembles the SSRI discontinuation syndrome
SSRI discontinuation syndrome
SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI antidepressant medications...
.
When discontinuing treatment with duloxetine, 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. The use of a liquid form of the drug may facilitate more gradual tapering."
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 duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.
Suicidality
The FDA requires all antidepressants, including duloxetine, to carry a black box warningBlack box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
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.
To obtain statistically significant results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
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% or 20% 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. 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." Jeanne Lenzer wrote in The Independent
The Independent
The Independent is a British national morning newspaper published in London by Independent Print Limited, owned by Alexander Lebedev since 2010. It is nicknamed the Indy, while the Sunday edition, The Independent on Sunday, is the Sindy. Launched in 1986, it is one of the youngest UK national daily...
and Slate Magazine
Slate (magazine)
Slate is a US-based English language online current affairs and culture magazine created in 1996 by former New Republic editor Michael Kinsley, initially under the ownership of Microsoft as part of MSN. On 21 December 2004 it was purchased by the Washington Post Company...
, 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
Shionogi
is a Japanese pharmaceutical company best known for developing Crestor. Medical supply and brand name also uses Shionogi .Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines produced are for hyperlipidaemia, antibiotics, and cancer medicines.In...
, have not been reported to the FDA. 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. 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.
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.
A suicide of 19-year-old Traci Johnson, a healthy volunteer in a duloxetine clinical pharmacology
Clinical pharmacology
Clinical pharmacology is the science of drugs and their clinical use. It is underpinned by the basic science of pharmacology, with added focus on the application of pharmacological principles and methods in the real world...
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 hung herself in the bathroom of Lilly Laboratory for Clinical Research. The New York Times article mentioned a withdrawal syndrome as a possible reason for this suicide.
Pharmacodynamics
Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, they are believed to be related to its potentiation of serotonergic and noradrenergic activity in the central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Preclinical studies demonstrate that duloxetine potently inhibits neuronal serotonin and norepinephrine reuptake, and it has been demonstrated that this inhibition is balanced throughout the dosing range (when compared to venlafaxine in which the inhibition of noradrenaline is low at low doses and raises as the dose escalates).
It is also considered a less potent inhibitor of dopamine reuptake. However, duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NA transporters. Duloxetine undergoes extensive metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.
Pharmacokinetics
Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic rangeTherapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
. Steady-state is usually achieved after 3 days.
Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.
When orally administered it is well absorbed. There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein.
Metabolism and Elimination — Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (aprox 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces.
History
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, and Joseph Krushinski are listed as inventors on the patent application
Patent application
A patent application is a request pending at a patent office for the grant of a patent for the invention described and claimed by that application. An application consists of a description of the invention , together with official forms and correspondence relating to the application...
filed in 1986 and granted in 1990. The first publication on the discovery of the racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
form of duloxetine known as LY227942, was made in 1988. The (+)-enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
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.
Initial trials conducted in patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy and the dose was increased to as high as 120 mg in subsequent clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
In 2001 Lilly filed a New Drug Application
New drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
(NDA) for duloxetine with the US Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA). However, in 2003 the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP (current Good Manufacturing Practice
Good Manufacturing Practice
"Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods,...
) violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and QTc interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
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
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
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."
After the manufacturing issues were resolved, the liver toxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
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. In 2007Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...
approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.
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.
The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.