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Revision as of 12:08, 15 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank', 'CAS_number').← Previous edit Latest revision as of 17:59, 21 December 2024 edit undoMaxim Masiutin (talk | contribs)Extended confirmed users, IP block exemptions, Pending changes reviewers31,050 edits Rescuing 2 sources and tagging 0 as dead.) #IABot (v2.0.9.5Tag: IABotManagementConsole [1.3] 
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{{Short description|Antidepressant medication used also for the treatment of anxiety and chronic pain}}
{{Distinguish|dapoxetine}}
{{Distinguish|Dapoxetine|Dulcolax (disambiguation){{!}}Dulcolax}}
{{drugbox
{{Use dmy dates|date=August 2024}}
| verifiedrevid = 443715024
{{cs1 config|name-list-style=vanc|display-authors=6}}
| IUPAC_name = (+)-(''S'')-''N''-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine
{{Infobox drug
| image = Duloxetine.png
| Verifiedfields = changed
| width = 150
| verifiedrevid = 460765928
| image = Duloxetine.svg
| alt =
| image2 = Duloxetine-hydrochloride-from-xtal-3D-bs-17.png
| alt2 =


<!--Clinical data--> <!--Clinical data-->
| tradename = Cymbalta | tradename = Cymbalta, others<ref name="Drugs.com-Duloxetine-Generics"/>
| Drugs.com = {{drugs.com|monograph|duloxetine}} | Drugs.com = {{drugs.com|monograph|duloxetine}}
| MedlinePlus = a604030 | MedlinePlus = a604030
| DailyMedID = Duloxetine
| licence_EU = Ariclaim
| pregnancy_AU = B3
| licence_US = duloxetine
| routes_of_administration = ]
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| class = ]
| pregnancy_US = C
| ATC_prefix = N06
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| ATC_suffix = AX21
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_AU = S4
| legal_BR = C1
| legal_BR_comment = <ref name="Diário Oficial da União-2023">{{cite web |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only | legal_US = Rx-only
| legal_US_comment = <ref name="Cymbalta FDA label" />
| routes_of_administration = Oral
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Cymbalta EPAR" /><ref name="Cymbalta PI">{{cite web | title=Cymbalta PI | website=Union Register of medicinal products | date=22 December 2004 | url=https://ec.europa.eu/health/documents/community-register/html/h296.htm | access-date=19 December 2024 | archive-date=19 December 2024 | archive-url=https://web.archive.org/web/20241219203448/https://ec.europa.eu/health/documents/community-register/html/h296.htm | url-status=live }}</ref><ref name="Yentreve EPAR" /><ref name="Yentreve PI">{{cite web | title=Yentreve PI | website=Union Register of medicinal products | date=13 August 2004 | url=https://ec.europa.eu/health/documents/community-register/html/h280.htm | access-date=19 December 2024 | archive-date=19 December 2024 | archive-url=https://web.archive.org/web/20241219160658/https://ec.europa.eu/health/documents/community-register/html/h280.htm | url-status=live }}</ref>


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = ~ 50% (32% to 80%) | bioavailability = ~ 50% (32% to 80%)<ref name="pmid21366359"/>
| protein_bound = ~ 95% | protein_bound = ~ 95%
| metabolism = Liver, two P450 isozymes, ] and ] | metabolism = ], two P450 isozymes, ] and ]
| elimination_half-life = 12.1 hours | elimination_half-life ={{val|10|-|12|u=hours}}<ref name="pmid21366359"/><ref name="Cymbalta FDA label" />
| excretion = 70% in urine, 20% in feces | excretion = 70% in urine, 20% in feces


<!--Identifiers--> <!--Identifiers-->
| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = <!-- blanked - oldvalue: 116539-59-4 -->
| CAS_number = 116539-59-4
| CAS_supplemental = (free base)<br>{{CAS|136434-34-9}} (])
| CAS_number2_Ref = {{cascite|correct|CAS}}
| ATC_prefix = N06
| CAS_number2 = 136434-34-9
| ATC_suffix = AX21
| PubChem = 60835 | PubChem = 60835
| IUPHAR_ligand = 202 | IUPHAR_ligand = 202
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| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = O5TNM5N07U | UNII = O5TNM5N07U
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = 9044SC542W
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07880 | KEGG = D07880
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D01179
| ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 36795 | ChEBI = 36795
| ChEBI2_Ref = {{ebicite|correct|EBI}}
| ChEBI2 = 31526
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1175 | ChEMBL = 1175
| ChEMBL2_Ref = {{ebicite|correct|EBI}}
| ChEMBL2 = 1200328
| PDB_ligand = 29E


<!--Chemical data--> <!--Chemical data-->
| IUPAC_name = (+)-(''S'')-''N''-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine
| C=18 | H=19 | N=1 | O=1 | S=1
| C=18 | H=19 | N=1 | O=1 | S=1
| molecular_weight = 297.41456 g/mol
| smiles = CNCC(C1=CC=CS1)OC2=CC=CC3=CC=CC=C32 | smiles = CNCC(C1=CC=CS1)OC2=CC=CC3=CC=CC=C32
| InChI = 1/C18H19NOS/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19H,11-12H2,1H3/t17-/m0/s1
| InChIKey = ZEUITGRIYCTCEM-KRWDZBQOBW
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C18H19NOS/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19H,11-12H2,1H3/t17-/m0/s1 | StdInChI = 1S/C18H19NOS/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19H,11-12H2,1H3/t17-/m0/s1
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}} }}


<!-- Definition and medical uses -->
'''Duloxetine''' (sold under the brand names '''Cymbalta''', '''Ariclaim''', '''Xeristar''', '''Yentreve''', '''Duzela''') is a ] manufactured and marketed by ]. It is effective for ] and has been shown to be as effective as ] for ] (GAD). Duloxetine failed the US approval for ] amidst concerns over liver toxicity and suicidal events; however, it was approved for this indication in Europe. Duloxetine alleviates pain associated with ] and ]. Its efficacy relative to established treatments such as ]s and ]s has not yet been studied.


'''Duloxetine''', sold under the brand name '''Cymbalta''' among others,<ref name="Drugs.com-Duloxetine-Generics">{{cite web |title=Duloxetine |url=https://www.drugs.com/international/duloxetine.html |website=Drugs.com |access-date=24 December 2018 |archive-date=29 September 2018 |archive-url=https://web.archive.org/web/20180929233319/https://www.drugs.com/international/duloxetine.html |url-status=live }}</ref> is a medication used to treat ], ], ], ], ] and ].<ref name=AHFS2018>{{cite web | title = Duloxetine | work = Monograph | url = https://www.drugs.com/monograph/duloxetine.html | publisher = The American Society of Health-System Pharmacists | access-date = 24 December 2018 | archive-date = 26 November 2018 | archive-url = https://web.archive.org/web/20181126162525/https://www.drugs.com/monograph/duloxetine.html | url-status = live }}</ref><ref name="International OCD Foundation-2024">{{Cite web |title=Medications for OCD |url=https://iocdf.org/about-ocd/treatment/meds/ |access-date=25 February 2024 |website=International OCD Foundation |language=en-US |archive-date=27 January 2024 |archive-url=https://web.archive.org/web/20240127115230/https://iocdf.org/about-ocd/treatment/meds/ |url-status=live }}</ref> It is taken ].<ref name=AHFS2018/>
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<ref name="pmid16400743">{{cite journal |author= |title=Duloxetine: new drug. For stress urinary incontinence: too much risk, too little benefit |journal=Prescrire Int |volume=14 |issue=80 |pages=218–20 |year=2005 |month=December |pmid=16400743 |doi= |url=}}</ref> and "currently has no place in the treatment of depression or diabetic neuropathy."<ref name="pmid17121211">{{cite journal |author= |title=Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects |journal=Prescrire Int |volume=15 |issue=85 |pages=168–72 |year=2006 |month=October |pmid=17121211 |doi= |url=}}</ref><ref name="pmid17451072">{{cite journal |author= |title=Is there a place for duloxetine? |journal=Drug Ther Bull |volume=45 |issue=4 |pages=29–32 |year=2007 |month=April |pmid=17451072 |doi= 10.1136/dtb.2007.45429|url=http://dtb.bmj.com/cgi/pmidlookup?view=long&pmid=17451072 | quote=There is insufficient published evidence of its comparative efficacy to judge its duloxetine place in depression among many other longer-established antidepressant drugs, or how it compares with other therapy for diabetic peripheral neuropathic pain. Therefore we can see no place for it in either indication.}}</ref> At the same time, some professional guidelines recommend duloxetine in chronic neuropathic pain, especially diabetic polyneuropathy for which it is first-line treatment,<ref>{{NICE|96|Neuropathic pain - pharmacological management|2010}}</ref><ref>{{cite journal | author=Bril V, England J, Franklin GM ''et al'' | title=Evidence-based guideline: Treatment of painful diabetic neuropathy | journal=Neurology | year=2011 | volume=Online | pages= | doi=10.1212/WNL.0b013e3182166ebe | pmid=21482920}}</ref> and as an add-on medication in stress urinary incontinence instead of surgery.<ref>{{NICE|40|Urinary incontinence|2006}}</ref>


<!-- Type and mechanism -->
==Medical uses==
Duloxetine is a ] (SNRI).<ref name="Pharmaceutical Press-2018">{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=364–365|edition=76}}</ref> The precise mechanism for its antidepressant and anxiolytic effects is not known.<ref name=AHFS2018/>
The main uses of duloxetine are in ], ], ], painful ], ], and chronic musculoskeletal pain associated with ] and chronic lower back pain. It is being studied for various other indications.


<!-- Side effects -->
=== Major depressive disorder ===
Common side effects include ], nausea, feeling tired, dizziness, agitation, sexual problems, and increased sweating.<ref name=AHFS2018/> Severe side effects include an increased risk of ], ], ], and ].<ref name=AHFS2018/> ] may occur if stopped.<ref name=AHFS2018/> There are concerns that use during the later part of ] can harm the developing fetus.<ref name=AHFS2018/>
Duloxetine has demonstrated efficacy for the treatment of ]. In three out of six well-designed properly controlled pre-marketing trials duloxetine performed better than placebo; the three other trials were inconclusive.<ref name="FDA-1">{{cite web |url=http://www.fda.gov/cder/foi/nda/2004/021427_s000_Cymbalta_Medr_P1.pdf |title=Clinical review for NDA 21-427 Cymbalta (duloxetine). |author= Andreason PJ|date= |format=PDF |work=CDER approval package for application number 21-427. Medical review # 3. |publisher=FDA |page=12|accessdate=2008-05-22}} {{Dead link|date=November 2010|bot=H3llBot}}</ref> Recently, duloxetine was shown to be effective in elderly with recurrent major depressive disorder where it improved cognition, depression, and some pain measures.<ref>http://ajp.psychiatryonline.org/cgi/content/abstract/164/6/900?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=duloxetine&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT</ref> A ] of these trials indicated that the ] of duloxetine as compared with placebo was weak-to-moderate, and similar to other 11 antidepressants studied.<ref name="pmid18199864">{{cite journal |author=Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R |title=Selective publication of antidepressant trials and its influence on apparent efficacy |journal=N. Engl. J. Med. |volume=358 |issue=3 |pages=252–60 |year=2008 |month=January |pmid=18199864 |doi=10.1056/NEJMsa065779 |url=}}</ref> The rationale behind the development of duloxetine was that ] of both serotonin and norepinephrine would make it work better than ]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.<ref name="pmid17588546">{{cite journal |author=Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC |title=Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents |journal=Biol. Psychiatry |volume=62 |issue=11 |pages=1217–27 |year=2007 |month=December |pmid=17588546 |doi=10.1016/j.biopsych.2007.03.027 |url=}}</ref> A head-to-head comparison of duloxetine with an SSRI ] (Lexapro) found duloxetine to be both less tolerable and less effective.<ref name="pmid18545055">{{cite journal |author=Lam RW, Andersen HF, Wade AG |title=Escitalopram and duloxetine in the treatment of major depressive disorder: a pooled analysis of two trials |journal=Int Clin Psychopharmacol |volume=23 |issue=4 |pages=181–7 |year=2008 |month=July |pmid=18545055 |doi=10.1097/YIC.0b013e3282ffdedc |url=}}</ref> Another analysis of the comparative efficacy of modern antidepressants found duloxetine to be significantly, by 30-40%, less efficacious than ] (Remeron), escitalopram, ] (Effexor) and ] (Zoloft). Duloxetine was similar to ] (Prozac), ] (Luvox) and ] (Paxil). The tolerability of duloxetine was significantly worse than the tolerability of escitalopram and sertraline.<ref name="pmid19185342">{{cite journal |author=Cipriani A, Furukawa TA, Salanti G, ''et al.'' |title=Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis |journal=Lancet |volume= 373|issue= 9665|pages= 746|year=2009 |month=January |pmid=19185342 |doi=10.1016/S0140-6736(09)60046-5 |url=}}</ref>


<!-- Society and culture -->
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.<ref name="pmid17121211"/> Similar analysis was presented by ], which is a part of the respected ].<ref>{{cite journal |author= |title=Is there a place for duloxetine? |journal=Drug Ther Bull |volume=45 |issue=4 |pages=29–32 |year=2007 |month=April |pmid=17451072 |doi= 10.1136/dtb.2007.45429|url=http://dtb.bmj.com/cgi/pmidlookup?view=long&pmid=17451072}}</ref>
Duloxetine was approved for medical use in the United States<ref name=AHFS2018/><ref name="FDA Cymbalta Approval Package" /> and the European Union in 2004.<ref name="Cymbalta EPAR">{{cite web | title=Cymbalta EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/cymbalta | access-date=30 September 2020 | archive-date=20 October 2020 | archive-url=https://web.archive.org/web/20201020121232/https://www.ema.europa.eu/en/medicines/human/EPAR/cymbalta | url-status=live }}</ref><ref name="Yentreve EPAR" /> It is available as a ].<ref name="Pharmaceutical Press-2018"/> In 2022, it was the 31st most commonly prescribed medication in the United States, with more than 18{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Duloxetine Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Duloxetine | access-date = 30 August 2024 | archive-date = 1 September 2024 | archive-url = https://web.archive.org/web/20240901011320/https://clincalc.com/DrugStats/Drugs/Duloxetine | url-status = live }}</ref>


==Medical uses==
===Stress urinary incontinence===
]
Duloxetine was first reported to improve outcomes in ] (SUI) in 1998.<ref>{{cite journal |author=Voelker R |title=International group seeks to dispel incontinence "taboo" |journal=JAMA |volume=280 |issue=11 |pages=951–3 |year=1998 |month=September |pmid=9749464 |doi= 10.1001/jama.280.11.951|url=http://jama.ama-assn.org/cgi/content/full/280/11/951}}</ref> ]s with meta-analysis, conducted in 2005 by ]<ref name=cochrane>{{cite journal |author=Mariappan P, Ballantyne Z, N'Dow JM, Alhasso AA |editor1-last=Mariappan |editor1-first=Paramananthan |title=Serotonin and noradrenaline reuptake inhibitors (SNRI) for stress urinary incontinence in adults |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD004742 |year=2005 |pmid=16034945 |doi=10.1002/14651858.CD004742.pub2 |url=http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004742/frame.html}}</ref> and in 2008 by ],<ref name=UM>{{cite journal |author=Shamliyan TA, Kane RL, Wyman J, Wilt TJ |title=Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women |journal=Ann. Intern. Med. |volume=148 |issue=6 |pages=459–73 |year=2008 |month=March |pmid=18268288}}</ref> 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 ] measurements.<ref name=cochrane/> According to the University of Minnesota review, duloxetine performed worse than ] (Ditropan) or ] (Detrol) that cured 18% of the cases, or than ] + bladder training, which cured 13% of the cases. In terms of "improvement", that is incomplete cure, duloxetine showed improvement in 11% of patients while ] muscle training + bladder training showed improvement in 36% of the cases.<ref name=UM/> 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.<ref name=cochrane/>
The main uses of duloxetine are in ], ], ], chronic ], and ].<ref name="Cymbalta FDA label">{{cite web | title=Cymbalta- duloxetine hydrochloride capsule, delayed release | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba | access-date=29 September 2020 | archive-date=13 August 2020 | archive-url=https://web.archive.org/web/20200813211636/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba | url-status=live }}</ref><ref name=AHFS2018/><ref name="nice-2010">{{NICE|96|Neuropathic pain – pharmacological management|2010}}</ref><ref name="pmid21482920">{{cite journal | vauthors = Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, Feldman E, Iverson DJ, Perkins B, Russell JW, Zochodne D | title = Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation | journal = Neurology | volume = 76 | issue = 20 | pages = 1758–65 | date = May 2011 | pmid = 21482920 | pmc = 3100130 | doi = 10.1212/WNL.0b013e3182166ebe }}</ref>


Duloxetine is recommended as a first-line agent for the treatment of chemotherapy-induced neuropathy by the ],<ref name="pmid24733808">{{cite journal | vauthors = Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner-Johnston N, Bak K, Loprinzi CL | title = Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline | journal = Journal of Clinical Oncology | volume = 32 | issue = 18 | pages = 1941–1967 | date = June 2014 | pmid = 24733808 | doi = 10.1200/JCO.2013.54.0914 | s2cid = 11183183 | doi-access = free }}</ref> as a first-line therapy for fibromyalgia in the presence of mood disorders by the German Interdisciplinary Association for Pain Therapy,<ref name="pmid22760463">{{cite journal | vauthors = Sommer C, Häuser W, Alten R, Petzke F, Späth M, Tölle T, Uçeyler N, Winkelmann A, Winter E, Bär KJ | title = | language = de | journal = Schmerz | volume = 26 | issue = 3 | pages = 297–310 | date = June 2012 | pmid = 22760463 | doi = 10.1007/s00482-012-1172-2 | s2cid = 1348989 }}</ref> as a Grade B recommendation for the treatment of diabetic neuropathy by the American Association for Neurology<ref name="pmid21484835">{{cite journal | vauthors = Bril V, England JD, Franklin GM, Backonja M, Cohen JA, Del Toro DR, Feldman EL, Iverson DJ, Perkins B, Russell JW, Zochodne DW | title = Evidence-based guideline: treatment of painful diabetic neuropathy--report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation | journal = Muscle & Nerve | volume = 43 | issue = 6 | pages = 910–7 | date = June 2011 | pmid = 21484835 | doi = 10.1002/mus.22092 | hdl = 2027.42/84412 | s2cid = 15020212 | hdl-access = free }}</ref> and as a level A recommendation in certain neuropathic states by the ].<ref name="pmid20402746">{{cite journal | vauthors = Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T | title = EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision | journal = European Journal of Neurology | volume = 17 | issue = 9 | pages = 1113–e88 | date = September 2010 | pmid = 20402746 | doi = 10.1111/j.1468-1331.2010.02999.x | s2cid = 14236933 | doi-access = free }}</ref>
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.<ref name=ahrq>http://www.ahrq.gov/downloads/pub/evidence/pdf/fuiad/fuiad.pdf</ref> 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.<ref name=ahrq/>


===Painful diabetic peripheral neuropathy===
The only clinical trial, which directly compared duloxetine with the gold standard of the SUI treatment pelvic floor muscle training (PFMT) was conducted by ] 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.<ref name=2615a>{{cite web |url=http://www.clinicalstudyresults.org/drugdetails/viewfile.php?study_name=Trial+2615a++Efficacy+and+Safety+of+Duloxetine+compared+with+Placebo%2C+Pelvic+Floor+Muscle+Training%2C+and+Combined+Duloxetine%2FPelvic+Floor+Muscle+Training+in+Subjects+with+Moderate+to+Severe+Stress+Urinary+Incontinence&file=http%3A%2F%2Fpdf.clinicalstudyresults.org%2Fdocuments%2Fcompany-study_4001_0.pdf |title=Trial 2615a Efficacy and Safety of Duloxetine compared with Placebo, Pelvic Floor Muscle Training, and Combined Duloxetine/Pelvic Floor Muscle Training in Subjects with Moderate to Severe Stress Urinary Incontinence|author= |authorlink= |coauthors= |date= |format=PDF |work= |publisher=www.clinicalstudyresults.org |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=02-03-09}}</ref> In the continuation of this trial more than 91% of the patients on duloxetine experienced side effects.<ref name=2615b>{{cite web |url=http://www.clinicalstudyresults.org/drugdetails/viewfile.php?study_name=Trial+2615b+Efficacy+and+Safety+of+Duloxetine+compared+with+Placebo%2C+Pelvic+Floor+Muscle+Training%2C+and+Combined+Duloxetine%2FPelvic+Floor+Muscle+Training+in+Subjects+with+Moderate+to+Severe+Stress+Urinary+Incontinence&file=http%3A%2F%2Fpdf.clinicalstudyresults.org%2Fdocuments%2Fcompany-study_2356_0.pdf |title=Trial 2615b. Efficacy and Safety of Duloxetine compared with Placebo, Pelvic Floor Muscle Training, and Combined Duloxetine/Pelvic Floor Muscle Training in Subjects with Moderate to Severe Stress Urinary Incontinence |author= |authorlink= |coauthors= |date= |format=PDF |work= |publisher=www.clinicalstudyresults.org |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=02-03-09}}</ref>
A 2014 ] review concluded that duloxetine is beneficial in the treatment of diabetic neuropathy and fibromyalgia but that more comparative studies with other medicines are needed.<ref name="pmid24385423">{{cite journal | vauthors = Lunn MP, Hughes RA, Wiffen PJ | title = Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD007115 | date = January 2014 | pmid = 24385423 | doi = 10.1002/14651858.CD007115.pub3 | pmc = 10711341 }}</ref> The French medical journal '']'' concluded that duloxetine is no better than other available agents and has a greater risk of side effects.<ref name="pmid25121155">{{cite journal | title = Towards better patient care: drugs to avoid in 2014 | journal = Prescrire International | volume = 23 | issue = 150 | pages = 161–5 | date = June 2014 | pmid = 25121155 | url = http://english.prescrire.org/en/81/168/49342/0/NewsDetails.aspx | access-date = 28 June 2014 | archive-date = 14 July 2014 | archive-url = https://web.archive.org/web/20140714192809/http://english.prescrire.org/en/81/168/49342/0/NewsDetails.aspx | url-status = live }}</ref> Whereas duloxetine has shown efficacy in treating painful diabetic peripheral neuropathy by blocking late Nav 1.7 sodium ion channels and increasing norepinephrine, serotonin, and dopamine in the ] (CNS) and while improving mean NPRS scores and achieving a ≥50% pain response in more patients compared to placebo, it has been associated with potentially serious adverse reactions including hepatotoxicity, serotonin syndrome, severe skin reactions, increased risk of bleeding, increased blood pressure and sexual dysfunction.<ref name="pmid38505500">{{cite journal |vauthors=Mallick-Searle T, Adler JA |title=Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options |journal=J Pain Res |volume=17 |issue= |pages=1005–1028 |date=2024 |pmid=38505500 |pmc=10949339 |doi=10.2147/JPR.S442595|doi-access=free }}</ref>


===Major depressive disorder===
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."<ref name="pmid16400743"/>
Duloxetine was approved for the treatment of major depression in 2004.<ref name="Cymbalta FDA label" /><ref name="Cymbalta EPAR" /> While duloxetine has demonstrated improvement in depression-related symptoms compared to ], comparisons of duloxetine to other antidepressant medications have been less successful. A 2012 Cochrane Review did not find greater efficacy of duloxetine compared to SSRIs and newer antidepressants. Additionally, the review found evidence that duloxetine has increased side effects and reduced tolerability compared to other antidepressants. It thus did not recommend duloxetine as a first-line treatment for major depressive disorder, given the (then) high cost of duloxetine compared to inexpensive off-patent antidepressants and lack of increased efficacy.<ref name="pmid23076926">{{cite journal | vauthors = Cipriani A, Koesters M, Furukawa TA, Nosè M, Purgato M, Omori IM, Trespidi C, Barbui C | title = Duloxetine versus other anti-depressive agents for depression | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | pages = CD006533 | date = October 2012 | issue = 10 | pmid = 23076926 | pmc = 4169791 | doi = 10.1002/14651858.cd006533.pub2 }}</ref> Duloxetine appears less tolerable than some other antidepressants.<ref name="pmid29477251">{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR | title = Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis | journal = Lancet | volume = 391 | issue = 10128 | pages = 1357–1366 | date = April 2018 | pmid = 29477251 | pmc = 5889788 | doi = 10.1016/S0140-6736(17)32802-7 }}</ref> Generic duloxetine became available in 2013.<ref name="Swiatek-2013">{{cite journal |title=Loss of Cymbalta patent a major blow for Eli Lilly |journal=Indianapolis Star |date=13 October 2013 |vauthors=Swiatek J |url=http://www.indystar.com/story/money/2013/12/10/loss-of-cymbalta-patent-a-major-blow-for-eli-lilly/3956997/ |access-date=27 February 2015 |archive-date=15 January 2014 |archive-url=https://web.archive.org/web/20140115091916/http://www.indystar.com/story/money/2013/12/10/loss-of-cymbalta-patent-a-major-blow-for-eli-lilly/3956997/ |url-status=live }}</ref>


===Diabetic peripheral neuropathy=== ===Generalized anxiety disorder===
Duloxetine is more effective than placebo in the treatment of ] (GAD).<ref name="pmid19480470">{{cite journal | vauthors = Carter NJ, McCormack PL | title = Duloxetine: a review of its use in the treatment of generalized anxiety disorder | journal = CNS Drugs | volume = 23 | issue = 6 | pages = 523–41 | year = 2009 | pmid = 19480470 | doi = 10.2165/00023210-200923060-00006 | s2cid = 30897102 }}</ref> A review from the '']'' lists duloxetine among the first line drug treatments along with ], ], ], ], and ].<ref name="pmid24297210">{{cite journal | vauthors = Patel G, Fancher TL | title = Generalized anxiety disorder | journal = Annals of Internal Medicine | volume = 159 | issue = 11 | pages = ITC6–1, ITC6–2, ITC6–3, ITC6–4, ITC6–5, ITC6–6, ITC6–7, ITC6–8, ITC6–9, ITC6–10, ITC6–11; quiz ITC6–12 | date = December 2013 | pmid = 24297210 | doi = 10.7326/0003-4819-159-11-201312030-01006 | s2cid = 42889106 }}</ref>
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.<ref name =FDA_DPN>{{cite web | url = http://www.fda.gov/cder/foi/nda/2004/021733s000_Cymbalta_medr.pdf | title =Application number 21-733. Medical review(s).| accessdate = 2009-04-14 | author = Josefberg H | date = 2004-09-03| format =PDF | publisher = FDA}} {{Dead link|date=November 2010|bot=H3llBot}}</ref><ref>{{cite journal |author=Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S |title=Duloxetine vs. placebo in patients with painful diabetic neuropathy |journal=Pain |volume=116 |issue=1-2 |pages=109–18 |year=2005 |month=July |pmid=15927394 |doi=10.1016/j.pain.2005.03.029}}</ref><ref>{{cite journal |author=Raskin J, Pritchett YL, Wang F, ''et al.'' |title=A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain |journal=Pain Med |volume=6 |issue=5 |pages=346–56 |year=2005 |pmid=16266355 |doi=10.1111/j.1526-4637.2005.00061.x |url=}}</ref> 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".<ref name =FDA_DPN/>


===Neuropathic pain===
Duloxetine was not effective for the numbness or tingling, nor for the other ]. It reduced the pain without treating the underlying nerve damage.<ref></ref> Only tight glycemic control was unequivocally demonstrated to slow the progression of neuropathy.<ref name="pmid17562735"/><ref name="pmid17593238">{{cite journal |author=Várkonyi T, Kempler P |title=Diabetic neuropathy: new strategies for treatment |journal=Diabetes Obes Metab |volume=10 |issue=2 |pages=99–108 |year=2008 |month=February |pmid=17593238 |doi=10.1111/j.1463-1326.2007.00741.x |url=}}</ref> ], ], and ] have also shown some promise.<ref name="pmid17593238"/>
Duloxetine was approved for the pain associated with diabetic ] (DPN) by the US FDA.<ref name="pmid37670573">{{cite journal |vauthors=Jang HN, Oh TJ |title=Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy |journal=Diabetes Metab J |volume=47 |issue=6 |pages=743–756 |date=November 2023 |pmid=37670573 |pmc=10695723 |doi=10.4093/dmj.2023.0018 |url=}}</ref><ref name="pmid15927394">{{cite journal | vauthors = Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S | title = Duloxetine vs. placebo in patients with painful diabetic neuropathy | journal = Pain | volume = 116 | issue = 1–2 | pages = 109–18 | date = July 2005 | pmid = 15927394 | doi = 10.1016/j.pain.2005.03.029 | s2cid = 10291281 }}</ref><ref name="pmid16266355">{{cite journal | vauthors = Raskin J, Pritchett YL, Wang F, D'Souza DN, Waninger AL, Iyengar S, Wernicke JF | title = A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain | journal = Pain Medicine | volume = 6 | issue = 5 | pages = 346–56 | year = 2005 | pmid = 16266355 | doi = 10.1111/j.1526-4637.2005.00061.x | doi-access = free }}</ref> The response is achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting ].<ref name="U.S. Food and Drug Administration (FDA)-Application-Number-21-733-2004">{{cite web | url = https://www.fda.gov/cder/foi/nda/2004/021733s000_Cymbalta_medr.pdf | title =Application number 21-733. Medical review(s).| access-date = 14 April 2009 | date = 3 September 2004| publisher = U.S. ] (FDA)}} {{Dead link|date=November 2010|bot=H3llBot}}</ref>


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.<ref name="pmid17562735">{{cite journal |author=Wong MC, Chung JW, Wong TK |title=Effects of treatments for symptoms of painful diabetic neuropathy: systematic review |journal=BMJ |volume=335 |issue=7610 |pages=87 |year=2007 |month=July |pmid=17562735 |pmc=1914460 |doi=10.1136/bmj.39213.565972.AE |url=}}</ref> 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.<ref name="pmid17451072"/> 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.<ref name="pmid17121211"/> 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.<ref name="pmid18673529">{{cite journal |author=Sultan A, Gaskell H, Derry S, Moore RA |title=Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials |journal=BMC Neurol |volume=8|pages=29 |year=2008 |pmid=18673529 |pmc=2529342 |doi=10.1186/1471-2377-8-29 |url=}}</ref> The comparative efficacy of duloxetine and established pain-relief medications for diabetic peripheral neuropathy is unclear. A systematic review noted that ]s (] and ]), traditional ]s and ]s have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants, and anticonvulsants have similar tolerability while opioids cause more side effects.<ref name="pmid17562735">{{cite journal | vauthors = Wong MC, Chung JW, Wong TK | title = Effects of treatments for symptoms of painful diabetic neuropathy: systematic review | journal = BMJ | volume = 335 | issue = 7610 | pages = 87 | date = July 2007 | pmid = 17562735 | pmc = 1914460 | doi = 10.1136/bmj.39213.565972.AE }}</ref> Another 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.<ref name="pmid17121211">{{cite journal | title = Duloxetine: new indication. Depression and diabetic neuropathy: too many adverse effects | journal = Prescrire International | volume = 15 | issue = 85 | pages = 168–72 | date = October 2006 | pmid = 17121211 }}</ref> The comparative data collected by reviewers in '']'' indicated that amitriptyline, other tricyclic antidepressants, and venlafaxine may be more effective. The authors noted that the evidence in favor of duloxetine is much more solid, however.<ref name="pmid18673529">{{cite journal | vauthors = Sultan A, Gaskell H, Derry S, Moore RA | title = Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials | journal = BMC Neurology | volume = 8 | pages = 29 | date = August 2008 | pmid = 18673529 | pmc = 2529342 | doi = 10.1186/1471-2377-8-29 | doi-access = free }}</ref> A Cochrane review concluded that the evidence in support of duloxetine's efficacy in treating painful diabetic neuropathy was adequate and that further trials should focus on comparisons with other medications.<ref name="pmid24385423"/> A crossover trial found that duloxetine, pregabalin, and amitriptyline offered similar levels of pain relief.<ref name="NIHR-Evidence"/> Duloxetin also has similar effect on pain relief in diabetic neuropathic pain as ].<ref name="pmid39065707">{{cite journal |vauthors=Valenzuela-Fuenzalida JJ, López-Chaparro M, Barahona-Vásquez M, Campos-Valdes J, Cordero Gonzalez J, Nova-Baeza P, Orellana-Donoso M, Suazo-Santibañez A, Oyanedel-Amaro G, Gutiérrez Espinoza H |title=Effectiveness of Duloxetine versus Other Therapeutic Modalities in Patients with Diabetic Neuropathic Pain: A Systematic Review and Meta-Analysis |journal=Pharmaceuticals (Basel) |volume=17 |issue=7 |date=June 2024 |page=856 |pmid=39065707 |pmc=11280092 |doi=10.3390/ph17070856 |doi-access=free |url=}}</ref> Comparing at various doses, the strongest effect on relieving diabetic neuropatic pain is on {{val|120|u=mg/d}} dose.<ref name="pmid39065707"/> ] of duloxetine and pregabalin offered additional pain relief for people whose pain is not adequately controlled with one medication and was safe.<ref name="NIHR-Evidence">{{cite journal |date=6 April 2023 |title=Combination therapy for painful diabetic neuropathy is safe and effective |url=https://evidence.nihr.ac.uk/alert/combination-therapy-for-painful-diabetic-neuropathy-is-safe-and-effective/ |journal=NIHR Evidence |language=en |doi=10.3310/nihrevidence_57470 |s2cid=258013544 |url-access=subscription |access-date=28 April 2023 |archive-date=28 April 2023 |archive-url=https://web.archive.org/web/20230428104720/https://evidence.nihr.ac.uk/alert/combination-therapy-for-painful-diabetic-neuropathy-is-safe-and-effective/ |url-status=live }}</ref><ref name="pmid36007534">{{cite journal | vauthors = Tesfaye S, Sloan G, Petrie J, White D, Bradburn M, Julious S, Rajbhandari S, Sharma S, Rayman G, Gouni R, Alam U, Cooper C, Loban A, Sutherland K, Glover R, Waterhouse S, Turton E, Horspool M, Gandhi R, Maguire D, Jude EB, Ahmed SH, Vas P, Hariman C, McDougall C, Devers M, Tsatlidis V, Johnson M, Rice AS, Bouhassira D, Bennett DL, Selvarajah D | title = Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial | journal = Lancet | volume = 400 | issue = 10353 | pages = 680–690 | date = August 2022 | pmid = 36007534 | pmc = 9418415 | doi = 10.1016/s0140-6736(22)01472-6 }}</ref>


Duloxetine is also an option for the management of neuropathic pain in ] patients.<ref name="pmid38421578">{{cite journal |vauthors=Shkodina AD, Bardhan M, Chopra H, Anyagwa OE, Pinchuk VA, Hryn KV, Kryvchun AM, Boiko DI, Suresh V, Verma A, Delva MY |title=Pharmacological and Non-pharmacological Approaches for the Management of Neuropathic Pain in Multiple Sclerosis |journal=CNS Drugs |volume=38 |issue=3 |pages=205–224 |date=March 2024 |pmid=38421578 |doi=10.1007/s40263-024-01072-5 |url=}}</ref>
=== Generalized anxiety disorder ===
Duloxetine is just as effective as ] in the treatment of ] 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, ] have demonstrated that duloxetine is well tolerated both in the short-term and the long-term.<ref name="pmid18416656">One of the authors, HJ Möller "has participated in speakers bureau for Eli Lilly, has been a member of advisory board for Eli Lilly and has received grant/research support from Eli Lilly {{cite journal |author=Müller N, Schennach R, Riedel M, Möller HJ |title=Duloxetine in the treatment of major psychiatric and neuropathic disorders |journal=Expert Rev Neurother |volume=8 |issue=4 |pages=527–36 |year=2008 |month=April |pmid=18416656 |doi=10.1586/14737175.8.4.527 |url=}}</ref> Other Eli Lilly dependent researchers suggested that duloxetine should be considered a first-line treatment for generalized anxiety disorder.<ref name="pmid19210191">{{cite journal |author=Kornstein SG, Russell JM, Spann ME, Crits-Christoph P, Ball SG |title=Duloxetine in the treatment of generalized anxiety disorder |journal=Expert Rev Neurother |volume=9 |issue=2 |pages=155–65 |year=2009 |month=February |pmid=19210191 |doi=10.1586/14737175.9.2.155}}</ref><ref name="pmid17934551">Disclosure information for Susan Kornstein, see: {{cite journal |author=Wohlreich MM, Wiltse CG, Desaiah D, ''et al.'' |title=Duloxetine in Practice-Based Clinical Settings: Assessing Effects on the Emotional and Physical Symptoms of Depression in an Open-Label, Multicenter Study |journal=Prim Care Companion J Clin Psychiatry |volume=9 |issue=4 |pages=271–279 |year=2007 |pmid=17934551 |pmc=2018841 |doi= }}</ref> Although this view was repeated in a recent independent review,<ref name="pmid19480470">{{cite journal |author=Carter NJ, McCormack PL |title=Duloxetine: a review of its use in the treatment of generalized anxiety disorder |journal=CNS Drugs |volume=23 |issue=6 |pages=523–41 |year=2009 |pmid=19480470 |doi=10.2165/00023210-200923060-00006 |url=}}</ref> the major guidelines such as Maudsley Prescribing Guidelines,<ref name="isbn0-415-42416-X">{{cite book |author=Kerwin, Robert; Taylor, David H.; Carol Paton |title=Maudsley Prescribing Guidelines |publisher=Informa Healthcare |location= |year=2007 |pages=254 |isbn=0-415-42416-X }}</ref> Mayo Clinic Health Information<ref name="urlGeneralized anxiety disorder: Treatments and drugs - MayoClinic.com">{{cite web |url=http://www.mayoclinic.com/health/generalized-anxiety-disorder/DS00502/DSECTION=treatments-and-drugs |title=Generalized anxiety disorder: Treatments and drugs - MayoClinic.com |format= |work= |accessdate=2009-11-28}}</ref> and Canadian Psychiatric Association Guidelines<ref name="pmid16933543">{{cite journal |author= |title=Clinical practice guidelines. Management of anxiety disorders |journal=Can J Psychiatry |volume=51 |issue=8 Suppl 2 |pages=52S–55S |year=2006 |month=July |pmid=16933543 |doi= |url= |last1= Canadian Psychiatric |first1= Association}}</ref> do not mention duloxetine among the recommended treatment options.


===Fibromyalgia=== ===Fibromyalgia and chronic pain===
A review of duloxetine found that it reduced pain and fatigue, and improved physical and mental performance compared to placebo.<ref name="pmid19137126">{{cite journal | vauthors = Acuna C | title = Duloxetine for the treatment of fibromyalgia | journal = Drugs of Today | volume = 44 | issue = 10 | pages = 725–34 | date = October 2008 | pmid = 19137126 | doi = 10.1358/dot.2008.44.10.1269675 }}</ref>
On October 19, 2006, Eli Lilly issued a press release saying they had done trials which found that Cymbalta (duloxetine), at 60&nbsp;mg once or twice daily, significantly reduced pain in more than half of women treated for ] (FM), with and without major depression, according to 12-week data presented at the annual meeting of the ]. 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.<ref name=Arnold2004>{{cite journal |author=Arnold LM, Lu Y, Crofford LJ, ''et al.'' |title=A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder |journal=Arthritis Rheum. |volume=50 |issue=9 |pages=2974–84 |year=2004 |month=September |pmid=15457467 |doi=10.1002/art.20485 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/109609649/HTMLSTART}}</ref>


The US ] (FDA) approved the drug for the treatment of fibromyalgia in June 2008.<ref name="FDA-Fibromyalgia-2008">{{cite press release |url=http://newsroom.lilly.com/ReleaseDetail.cfm?ReleaseID=316740 |title=FDA Approves Cymbalta for the Management of Fibromyalgia |date=16 June 2008 |work=Eli Lilly Co. |access-date=17 June 2008 |archive-date=30 July 2008 |archive-url=https://web.archive.org/web/20080730063358/http://newsroom.lilly.com/ReleaseDetail.cfm?ReleaseID=316740 |url-status=dead }}</ref><ref name="FDA-Drug-Approval-Package-022148">{{cite web | title=Drug Approval Package: Cymbalta (duloxetine hydrochloride) NDA #022148 | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022148_cymbalta_toc.cfm | access-date=30 September 2020 | archive-date=31 October 2020 | archive-url=https://web.archive.org/web/20201031223436/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022148_cymbalta_toc.cfm | url-status=live }}</ref>
Duloxetine is superior to many other medications for the treatment of fibromyalgia due to its freedom from ], ] and ] adverse reactions. Its effectiveness in pain relief is believed to be due to its modulation of the ] system. A ] of clinical trials has confirmed its pain relief, fatigue reducing properties as well as its effectiveness in improving physical and mental performance.<ref name="pmid19137126">{{cite journal |author=Acuna C |title=Duloxetine for the treatment of fibromyalgia |journal=Drugs Today |volume=44 |issue=10 |pages=725–34 |year=2008 |month=October |pmid=19137126 |doi=10.1358/dot.2008.44.10.1269675 |url=http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=1269675}}</ref>


It may be useful for ] from ].<ref name="pmid22314118">{{cite journal | vauthors = Citrome L, Weiss-Citrome A | title = A systematic review of duloxetine for osteoarthritic pain: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed? | journal = Postgraduate Medicine | volume = 124 | issue = 1 | pages = 83–93 | date = January 2012 | pmid = 22314118 | doi = 10.3810/pgm.2012.01.2521 | s2cid = 20599116 }}</ref><ref name="pmid24618328">{{cite journal | vauthors = Myers J, Wielage RC, Han B, Price K, Gahn J, Paget MA, Happich M | title = The efficacy of duloxetine, non-steroidal anti-inflammatory drugs, and opioids in osteoarthritis: a systematic literature review and meta-analysis | journal = BMC Musculoskeletal Disorders | volume = 15 | pages = 76 | date = March 2014 | pmid = 24618328 | pmc = 4007556 | doi = 10.1186/1471-2474-15-76 | doi-access = free }}</ref>
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.<ref name=Arnold2004/>


In November 2010, the US ] (FDA) approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.<ref name="Food and Drug Administration-Press-Release-2010">{{cite press release |url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm232708.htm |title = FDA clears Cymbalta to treat chronic musculoskeletal pain |publisher = Food and Drug Administration |date = 4 November 2010 |website = U.S. ] (FDA) |access-date = 19 August 2013 |archive-date = 7 August 2013 |archive-url = https://web.archive.org/web/20130807032223/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm232708.htm |url-status = dead }}</ref><ref name="FDA-Drug-Approval-Package-022516">{{cite web | title=Drug Approval Package: Cymbalta (duloxetine hydrochloride) NDA #022516 | website=U.S. ] (FDA) | date=16 September 2011 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022516_cymbalta_tocEDT.cfm | access-date=29 September 2020 | archive-date=5 April 2021 | archive-url=https://web.archive.org/web/20210405153136/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022516_cymbalta_tocEDT.cfm | url-status=live }}</ref>
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.<ref name=Arnold2004/>


===Stress urinary incontinence===
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.<ref name=Arnold2004/>
Duloxetine failed to receive US approval for ] amid concerns over liver toxicity and suicidal events; it was approved for this use in the ], however, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery.<ref name="NICE-urinary">{{NICE|40|Urinary incontinence|2006}}</ref>


The safety and utility of duloxetine in the treatment of incontinence have been evaluated in a series of meta-analyses and practice guidelines.
The Food and Drug Administration regulators approved the drug for the treatment of fibromyalgia in June 2008.<ref>{{cite web |url=http://newsroom.lilly.com/ReleaseDetail.cfm?ReleaseID=316740 |title=FDA Approves Cymbalta for the Management of Fibromyalgia |date=2008-06-16 |work=Eli Lilly Co. |accessdate=2008-06-17}}</ref>
* A 2017 meta-analysis found that the harms are at least as great if not greater than the benefits.<ref name="pmid28246265">{{cite journal | vauthors = Maund E, Guski LS, Gøtzsche PC | title = Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports | journal = CMAJ | volume = 189 | issue = 5 | pages = E194–E203 | date = February 2017 | pmid = 28246265 | pmc = 5289870 | doi = 10.1503/cmaj.151104 }}</ref>
* A 2013 ] concluded that duloxetine decreased incontinence episodes more than placebo with people about 56% more likely than placebo to experience a 50% decrease in episodes. Adverse effects were experienced by 83% of duloxetine-treated subjects and by 45% of placebo-treated subjects.<ref name="pmid23504618">{{cite journal | vauthors = Li J, Yang L, Pu C, Tang Y, Yun H, Han P | title = The role of duloxetine in stress urinary incontinence: a systematic review and meta-analysis | journal = International Urology and Nephrology | volume = 45 | issue = 3 | pages = 679–86 | date = June 2013 | pmid = 23504618 | doi = 10.1007/s11255-013-0410-6 | s2cid = 10788312 }}</ref>
* A 2012 review and practice guideline published by the ] concluded that the clinical trial data provides Grade 1a evidence that duloxetine improves but does not cure urinary incontinence and that it causes a high rate of gastrointestinal side effects (mainly nausea and vomiting) leading to a high rate of treatment discontinuation.<ref name="uroweb-2014">{{cite web|url=http://www.uroweb.org/gls/pdf/20%20Urinary%20Incontinence_LR.pdf|title=www.uroweb.org|url-status=dead|archive-url=https://web.archive.org/web/20140504105841/http://www.uroweb.org/gls/pdf/20%20Urinary%20Incontinence_LR.pdf|archive-date=4 May 2014}}</ref>
* The National Institute for Clinical and Health Excellence recommends (as of September 2013) that duloxetine not be routinely offered as first-line treatment, and that it only be offered as second-line therapy in women wishing to avoid therapy. The guideline further states that women should be counseled regarding the drug's side effects.<ref name="Urinary incontinence Introduction CG171-2014">{{cite web|url=http://publications.nice.org.uk/urinary-incontinence-cg171|title=Urinary incontinence Introduction CG171|url-status=dead|archive-url=https://web.archive.org/web/20140504105632/http://publications.nice.org.uk/urinary-incontinence-cg171|archive-date=4 May 2014}}</ref>


==Contraindications==
=== Chronic fatigue syndrome ===
The following ]s are listed by the manufacturer:<ref name="Eli Lilly and Company-2010">{{cite web|url=http://www.cymbalta.com/learnaboutcymbalta/importantsafetyinformation.jsp|title=Eli Lilly and Company|access-date=15 May 2010|archive-date=13 April 2010|archive-url=https://web.archive.org/web/20100413180157/http://www.cymbalta.com/learnaboutcymbalta/importantsafetyinformation.jsp|url-status=live}}</ref>
{{Out of date|section|date=November 2011}}
* Hypersensitivity: duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
As of January 11, 2007, Eli Lilly is currently enrolling patients for ] Phase II and Phase III trials of Cymbalta for the use of ] (CFS) in conjunction with the ].<ref> Clinicaltrials.gov</ref> CFS is characterized by severe disabling fatigue of at least six months' duration which cannot be fully explained by an identifiable medical condition.
* ]s (MAOIs): concomitant use in patients taking MAOIs is contraindicated.
* Uncontrolled narrow-angle ]: in ], Cymbalta use was associated with an increased risk of ] (dilation of the pupil); therefore, its use should be avoided in patients with uncontrolled narrow-angle ], in which mydriasis can cause sudden worsening.
* ] (CNS) acting drugs: given the primary 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.
* Duloxetine and ] should not be co-administered.{{refn|group=note|name=first|Duloxetine moderately inhibits CYP2D6, decreasing the rate of metabolism and thereby increasing the concentration of thioridazine. This raises the patient's risk of lethal ventricular arrhythmias.<ref name="pmid17577103">{{cite journal | vauthors = Derby MA, Zhang L, Chappell JC, Gonzales CR, Callaghan JT, Leibowitz M, Ereshefsky L, Hoelscher D, Leese PT, Mitchell MI | title = The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate | journal = Journal of Cardiovascular Pharmacology | volume = 49 | issue = 6 | pages = 384–393 | date = June 2007 | pmid = 17577103 | doi = 10.1097/FJC.0b013e31804d1cce| s2cid = 2356196 | doi-access = free }}</ref>}}


In addition, the FDA has reported on life-threatening drug interactions that may be possible when co-administered with ]s and other drugs acting on serotonin pathways leading to increased risk for ].<ref name="FDA-2013">{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124915.htm |title=Information for Healthcare Professionals: Duloxetine (marketed as Cymbalta) – Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and 5-Hydroxytryptamine Receptor Agonists (Triptans) |publisher=U.S. ] (FDA) |date=14 August 2013 |access-date=18 September 2013 |archive-date=7 March 2013 |archive-url=https://web.archive.org/web/20130307052542/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124915.htm |url-status=live }}</ref>
=== Interstitial cystitis ===


Duloxetine should also be avoided in hepatic impairment such as cirrhosis.<ref name="pmid37918778">{{cite journal |vauthors=Ma J, Björnsson ES, Chalasani N |title=The Safe Use of Analgesics in Patients with Cirrhosis: A Narrative Review |journal=Am J Med |volume=137 |issue=2 |pages=99–106 |date=February 2024 |pmid=37918778 |doi=10.1016/j.amjmed.2023.10.022 |s2cid=264888110 |url=}}</ref>
There is a U.S. Patent 6150396 for the use of duloxetine for treatment of ] although one study found positive outcomes in only a small proportion of cases.<ref>(Journal of Urology 2007 Feb;177(2):552-5)</ref> 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.


==Adverse effects==
=== Musculoskeletal Pain ===
], ], ], and ] are the main ], reported by about 10% to 20% of patients.<ref name="Cymbalta package insert-2004">Cymbalta package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.</ref>
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.


In a trial for major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were ] (34.7%), ] (22.7%), ] (20.0%) and ] (18.7%), and except for ], these were reported significantly more often than in the placebo group.<ref name="pmid16700869">{{cite journal | vauthors = Perahia DG, Kajdasz DK, Walker DJ, Raskin J, Tylee A | title = Duloxetine 60 mg once daily in the treatment of milder major depressive disorder | journal = International Journal of Clinical Practice | volume = 60 | issue = 5 | pages = 613–20 | date = May 2006 | pmid = 16700869 | pmc = 1473178 | doi = 10.1111/j.1368-5031.2006.00956.x }}</ref> In a long-term study of fibromyalgia patients receiving duloxetine, frequency and type of adverse effects was similar to that reported in the MDD trial above. Side effects tended to be mild-to-moderate, and tended to decrease in intensity over time.<ref name="pmid19454869">{{cite journal | vauthors = Chappell AS, Littlejohn G, Kajdasz DK, Scheinberg M, D'Souza DN, Moldofsky H | title = A 1-year safety and efficacy study of duloxetine in patients with fibromyalgia | journal = The Clinical Journal of Pain | volume = 25 | issue = 5 | pages = 365–75 | date = June 2009 | pmid = 19454869 | doi = 10.1097/ajp.0b013e31819be587 | s2cid = 12208795 }}</ref><ref name="Drugs.com-FDA-prescribing-information">{{cite news|url=https://www.drugs.com/pro/cymbalta.html|title=Cymbalta - FDA prescribing information, side effects and uses|work=Drugs.com|access-date=14 September 2018|archive-date=14 September 2018|archive-url=https://web.archive.org/web/20180914203656/https://www.drugs.com/pro/cymbalta.html|url-status=live}}</ref>
== Contraindications ==
The following contraindications are listed by the manufacturer:<ref>http://www.cymbalta.com/learnaboutcymbalta/importantsafetyinformation.jsp?type=print></ref>
* Hypersensitivity - duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
* ]s - concomitant use in patients taking ]s is contraindicated.
* Uncontrolled narrow-angle ] - in clinical trials, Cymbalta use was associated with an increased risk of ] (dilation of the pupil); therefore, its use should be avoided in patients with uncontrolled narrow-angle ], in which mydriasis can cause sudden worsening.
* CNS acting drugs - given the primary ] (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 ] 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 (e.g. CNS stimulants may include ], ], ], ], ], ], and ] leading to increased risk for ]<ref>http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124915.htm</ref>.


===Sexual dysfunction===
== Adverse effects ==
In four clinical trials of duloxetine for the treatment of MDD, ] occurred significantly more frequently in patients treated with duloxetine than those treated with placebo, and this difference occurred only in men.<ref name="pmid16964316">{{cite journal | vauthors = Nelson JC, Lu Pritchett Y, Martynov O, Yu JY, Mallinckrodt CH, Detke MJ | title = The safety and tolerability of duloxetine compared with paroxetine and placebo: a pooled analysis of 4 clinical trials | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 8 | issue = 4 | pages = 212–9 | date = 2006 | pmid = 16964316 | pmc = 1557468 | doi = 10.4088/pcc.v08n0404 }}</ref><ref name="Drugs.com-FDA-prescribing-information" /> Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and ] (trouble achieving orgasm). Loss of or decreased response to sexual stimuli and ejaculatory ] are also reported.<ref name="pmid17627739">{{cite journal | vauthors = Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M | title = Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder | journal = The Journal of Sexual Medicine | volume = 4 | issue = 4 Pt 1 | pages = 917–29 | date = July 2007 | pmid = 17627739 | doi = 10.1111/j.1743-6109.2007.00520.x }}</ref> Frequency of treatment-emergent sexual dysfunction were similar for duloxetine and SSRIs when compared in a 6-month observational study in depressed patients.<ref name="pmid22121997">{{cite journal | vauthors = Dueñas H, Brnabic AJ, Lee A, Montejo AL, Prakash S, Casimiro-Querubin ML, Khaled M, Dossenbach M, Raskin J | title = Treatment-emergent sexual dysfunction with SSRIs and duloxetine: effectiveness and functional outcomes over a 6-month observational period | journal = International Journal of Psychiatry in Clinical Practice | volume = 15 | issue = 4 | pages = 242–54 | date = November 2011 | pmid = 22121997 | doi = 10.3109/13651501.2011.590209 | s2cid = 23153099 }}</ref> Rates of sexual dysfunction in MDD patients treated with duloxetine versus ] did not differ significantly at 4, 8, and 12 weeks of treatment, although the trend favored duloxetine (33.3% of duloxetine patients experienced sexual side effects compared to 43.6% of those receiving escitalopram and 25% of those receiving placebo).<ref name="pmid17627739"/>


===Increased sweating===
], ], ], and ] are the main side effects, reported by about 10% to 20% of patients.<ref>Cymbalta package insert. Indianapolis, IN: Eli Lilly Pharmaceuticals; 2004, September.</ref>
Duloxetine may also cause sweating more than usual (]).<ref name="DuloxetineMayo-Clinic">{{cite web |url=https://www.mayoclinic.org/drugs-supplements/duloxetine-oral-route/side-effects/drg-20067247 |title=Duloxetine (Oral Route) Side Effects - Mayo Clinic |website=] |access-date=1 October 2023 |archive-date=19 October 2023 |archive-url=https://web.archive.org/web/20231019032525/https://www.mayoclinic.org/drugs-supplements/duloxetine-oral-route/side-effects/drg-20067247 |url-status=live }}</ref><ref name="pmid25576334">{{cite journal |vauthors=Štuhec M |title=Excessive sweating induced by interaction between agomelatine and duloxetine hydrochloride: case report and review of the literature |journal=Wien Klin Wochenschr |volume=127 |issue=17–18 |pages=703–6 |date=September 2015 |pmid=25576334 |doi=10.1007/s00508-014-0688-0 |s2cid=184484229 |url=}}</ref>


The exact mechanism behind why duloxetine increases sweating is still not fully understood. However, a possible explanation is in duloxetine's action on the sympathetic nervous system. Sympathetic nerves control thermoregulation and sweating in humans; when increased levels of noradrenaline are present (as seen with SNRIs), this can stimulate sweat gland activity, leading to an increase in perspiration. Noradrenaline release may also cause increased serotonin availability that results from inhibiting reuptake. Such release enhances and further facilitates the activation of post-synaptic α-adrenoceptors by noradrenaline, which can stimulate sweat gland activity, leading to more significant amounts of copious liquid secretion mainly at higher duloxetine dosages above certain thresholds. The amount of sweating experienced may be influenced by the noradrenergic tone, which is determined by the interaction between noradrenergic and serotonergic neurons.<ref name="pmid19664885"/><ref>{{cite journal|url=https://opinvisindi.is/bitstream/handle/20.500.11815/4065/Journal_of_Sleep_Research_2022_Idiaquez_Hyperhidrosis_in_sleep_disorders_A_narrative_review_of_mechanisms_and.pdf|doi=10.1111/jsr.13660 |title=Hyperhidrosis in sleep disorders – A narrative review of mechanisms and clinical significance |date=2023 |journal=Journal of Sleep Research |volume=32 |issue=1 |pages=e13660 |pmid=35706374 |hdl=20.500.11815/4065 | vauthors = Idiaquez J, Casar JC, Arnardottir ES, August E, Santin J, Iturriaga R }}</ref> Therefore, at higher serum doses or concentrations (above certain thresholds) resulting from therapeutic antidepressant treatment, patients may show more perspiration than at lower doses.<ref name="pmid19664885">{{cite journal |vauthors=Demling J, Beyer S, Kornhuber J |title=To sweat or not to sweat? A hypothesis on the effects of venlafaxine and SSRIs |journal=Med Hypotheses |volume=74 |issue=1 |pages=155–7 |date=January 2010 |pmid=19664885 |doi=10.1016/j.mehy.2009.07.011}}</ref>
In a trial for mild major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were ] (34.7%), ] (22.7%), ] (20.0%) and ] (18.7%), and except for ], these were reported significantly more often than in the placebo group.<ref>{{cite journal |author=Perahia DG, Kajdasz DK, Walker DJ, Raskin J, Tylee A |title=Duloxetine 60 mg once daily in the treatment of milder major depressive disorder |journal=Int. J. Clin. Pract. |volume=60 |issue=5 |pages=613–20 |year=2006 |month=May |pmid=16700869 |doi=10.1111/j.1368-5031.2006.00956.x |url=http://www.blackwell-synergy.com/doi/full/10.1111/j.1368-5031.2006.00956.x?cookieSet=1 |pmc=1473178}}</ref>


===Discontinuation syndrome===
Duloxetine and SSRIs have been shown to cause sexual side effects in some patients, both males and females.
{{Further|SSRI discontinuation syndrome}}
During marketing of other ] and ], there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: ], irritability, agitation, dizziness, sensory disturbances (e.g., ] such as ] electric shock sensations), anxiety, confusion, headache, lethargy, ], ], ], ], and seizures. The ] syndrome from duloxetine resembles the ].


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.
=== 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: ] increased, ] increased, ] reaction, ], ] increased, ] increased, ], ], ], ], ] (especially at the initiation of treatment), ], ] (especially at initiation of treatment), and ].<ref> Cymbalta Side Effects, and Drug Interactions - RxList Monographs</ref>


In placebo-controlled clinical trials of up to nine weeks' duration of patients with MDD, a systematic evaluation of 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.<ref name="pmid16266753">{{cite journal | vauthors = Perahia DG, Kajdasz DK, Desaiah D, Haddad PM | title = Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder | journal = Journal of Affective Disorders | volume = 89 | issue = 1–3 | pages = 207–12 | date = December 2005 | pmid = 16266753 | doi = 10.1016/j.jad.2005.09.003 }}</ref>
===Discontinuation syndrome===
{{See|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: ], irritability, agitation, dizziness, sensory disturbances (e.g., ] such as electric shock sensations), anxiety, confusion, headache, lethargy, ], ], ], ], and seizures. Although these events are generally ], some have been reported to be severe. The ] syndrome from duloxetine resembles the ].


In 2012 The Institute for Safe Medical Practices (ISMP) published a report: "Duloxetine and Serious Withdrawal Symptoms".{{cn|date=December 2024}} The report highlights early clinical studies which found "abrupt discontinuation showed that withdrawal effects occurred in 40-50% of patients, that 10% of those were severe and approximately half were not resolved when side effects monitoring had ended after one or two weeks".
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."<ref>duloxetine patient information sheet. Indianapolis, IN: Eli Lilly Pharmaceuticals; July 2006</ref>


Withdrawal symptoms listed in 48 case reports (in the first quarter of 2012) included anger, crying, dizziness, and suicidal ideation.
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.<ref>{{cite journal |author=Perahia DG, Kajdasz DK, Desaiah D, Haddad PM |title=Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder |journal=J Affect Disord |volume=89 |issue=1-3 |pages=207–12 |year=2005 |month=December |pmid=16266753 |doi=10.1016/j.jad.2005.09.003}}</ref>


The report concluded there was insufficient information and a lack of clear warnings about the effects of discontinuing duloxetine and that in many cases withdrawal symptoms may be "severe, persistent, or both", adding "the prescribing information for physicians and pharmacists does not provide realistic schedules for tapering or a clear picture of the likely incidence of these reactions".
=== Suicidality ===
The FDA requires all antidepressants, including duloxetine, to carry a ] 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.<ref name="FDA">{{cite web | author = Levenson M, Holland C| title =Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)|accessdate = 2007-05-13 | url = http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt}}</ref><ref name="FDA2">{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = CLINICAL REVIEW: RELATIONSHIP BETWEEN ANTIDEPRESSANT DRUGS AND SUICIDALITY IN ADULTS| accessdate = 2007-09-22 | author = Stone MB, Jones ML | authorlink = | coauthors = | date = 2006-11-17| format =PDF | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 11–74| language = | archiveurl = | archivedate = | quote = }}</ref><ref name="FDA3">{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | accessdate = 2007-09-22 | author = Levenson M, Holland C | authorlink = | coauthors = | date = 2006-11-17| format =PDF | work =Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 75–140| language = | archiveurl = | archivedate = | quote = }}</ref>


===Suicidality===
To obtain ] results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As ] 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%<ref name="FDA2" /> or 20%<ref name="FDA3" /> 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.<ref name="FDA2" /> There have been no trials of duloxetine in minors.
In the United States all antidepressants, including duloxetine carry a ] 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 FDA experts that found a 2-fold increase in the risk of suicidal ideation and behavior in children and adolescents, and a 1.5-fold increase in suicidality in the 18–24 age group.<ref name="Levenson">{{cite web| vauthors = Levenson M, Holland C| title = Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)| website = ]| access-date = 13 May 2007| url = https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt| archive-date = 27 September 2007| archive-url = https://web.archive.org/web/20070927214932/https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt| url-status = live}}</ref><ref name="Stone-2006">{{cite web | url = https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Clinical review: relationship between antidepressant drugs and suicidality in adults | access-date = 22 September 2007 | vauthors = Stone MB, Jones ML | date = 17 November 2006 | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = U.S. ] (FDA) | pages = 11–74 | archive-date = 16 March 2007 | archive-url = https://web.archive.org/web/20070316092329/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | url-status = live }}</ref><ref name="Levenson-2006">{{cite web | url = https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | access-date = 22 September 2007 | vauthors = Levenson M, Holland C | date = 17 November 2006 | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = U.S. ] (FDA) | pages = 75–140 | archive-date = 16 March 2007 | archive-url = https://web.archive.org/web/20070316092329/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | url-status = live }}</ref>
To obtain ] results the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications. As ] and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance.


In 2005, the United States FDA released a public health advisory noting that there had been eleven reports of suicide attempts and three reports of suicidality within the mostly middle-aged women participating in the open-label extension trials of duloxetine for the treatment of stress urinary incontinence (SUI). The FDA described the potential role of confounding social stressors as "unclear". The suicide attempt rate in the SUI study population (based on 9,400 patients) was calculated to be 400 per 100,000 person-years. This rate is greater than the suicide attempt rate among middle-aged US women that has been reported in published studies, i.e., 150 to 160 per 100,000 person-years. In addition, one death from suicide was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer without SUI. No increase in suicidality was reported in controlled trials of Cymbalta for depression or diabetic neuropathic pain.<ref name="FDA-Historical">{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm114970.htm |title=Historical Information on Duloxetine hydrochloride (marketed as Cymbalta) |website=U.S. ] (FDA) |access-date=16 December 2019 |archive-date=22 July 2017 |archive-url=https://web.archive.org/web/20170722190849/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm114970.htm |url-status=dead }}</ref>
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."<ref name="pmid17453659">{{cite journal |author=Khan A, Schwartz K |title=Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports |journal=Ann Clin Psychiatry |volume=19 |issue=1 |pages=31–6 |year=2007 |pmid=17453659 |doi=10.1080/10401230601163550}}</ref> Jeanne Lenzer wrote in ] and ], 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 ], have not been reported to the FDA.<ref name="Slate">{{cite web |url=http://www.slate.com/id/2126918/ |title=What the FDA isn't telling.|accessdate=2008-01-20 |author=Jeanne Lenzer |authorlink= |coauthors= |date=2005-09-27 |work= |publisher=Slate Magazine |pages= |language= |archiveurl= |archivedate= |quote=}}</ref><ref name="independent">{{cite web |url=http://news.independent.co.uk/health/article226432.ece |title=Was Traci Johnson driven to suicide by anti-depressants? That's a trade secret, say US officials|accessdate=2008-01-20 |author=Jeanne Lenzer and Nicholas Pyke |authorlink= |coauthors= |date=2005-06-05 |work= |publisher=Independent Online Edition |pages= |language= |archiveurl= |archivedate= |quote=}}</ref> 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.<ref name="independent" /> 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.<ref>{{cite web |url=http://www.fda.gov/cder/drug/infopage/duloxetine/historical.htm |title=Historical Information on Duloxetine hydrochloride (marketed as Cymbalta) |accessdate=2008-01-20 |author= |authorlink= |coauthors= |date=2005-06 |work= |publisher= FDA|pages= |language= |archiveurl= http://web.archive.org/web/20070929150541/http://www.fda.gov/cder/drug/infopage/duloxetine/historical.htm <!-- Bot retrieved archive -->|archivedate=2007-09-29|quote=}}</ref>


===Postmarketing reports===
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.<ref>{{cite journal |author=Parikh AR; Thatcher BT; Tamano EA; Liskow BI |title=Suicidal Ideation Associated With Duloxetine Use: A Case Series |journal=J Clin Psychopharmacolgy |volume=28 |issue=1 |pages=102 |year=2008}}</ref>
Reported adverse events that were temporally correlated to duloxetine therapy include rash, reported rarely, and the following adverse events, reported very rarely: ] increased, ] increased, ] reaction, ], ] increased, ] increased, ], ], ], ], ] (especially at the initiation of treatment), ], ] (especially at initiation of treatment), and ].<ref name="RxList Monographs-Duloxetine-Side-Effects-2008">{{cite web | url = http://www.rxlist.com/cgi/generic/cymbalta_ad.htm | archive-url= https://web.archive.org/web/20080912150829/http://www.rxlist.com/cgi/generic/cymbalta_ad.htm | archive-date=12 September 2008 | title = Duloxetine Side Effects, and Drug Interactions | work = RxList Monographs }}</ref>


==Pharmacology==
A suicide of 19-year-old Traci Johnson, a healthy volunteer in a duloxetine ] 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.<ref>{{cite web |url=http://www.philly.com/mld/inquirer/news/local/7932602.htm |title=Drug test altered in wake of suicide|accessdate=2008-01-20 |author=Walter F. Naedele |authorlink= |coauthors= |date=2004-02-12 |work= |publisher= Philadelphia Inquirer|pages= |language= |archiveurl= |archivedate= |quote=}} {{Dead link|date=November 2010|bot=H3llBot}}</ref><ref name="NYT">{{cite web |url=http://query.nytimes.com/gst/fullpage.html?res=9C03E5D8133AF931A25751C0A9629C8B63 |title=Student, 19, in Trial of New Antidepressant Commits Suicide|accessdate=2008-01-20 |author=Gardiner Harris |authorlink= |coauthors= |date=2004-02-12 |work= |publisher=New York Times |pages= |language= |archiveurl= |archivedate= |quote=}}</ref> The ] article mentioned a withdrawal syndrome as a possible reason for this suicide.<ref name="NYT" />


===Mechanism of action===
== Pharmacology ==
{| class="wikitable" style="float:right;width:200px;margin:10px;"
===Pharmacodynamics===
|+Binding profile<ref name="pmid11750180">{{cite journal | vauthors = Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT | title = Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors | journal = Neuropsychopharmacology | volume = 25 | issue = 6 | pages = 871–80 | date = December 2001 | pmid = 11750180 | doi = 10.1016/S0893-133X(01)00298-6 | doi-access = free }} {{open access}}</ref><ref name="Li-2015">{{cite book|vauthors=Li JJ|url=https://books.google.com/books?id=qOHXCQAAQBAJ&q=duloxetine+0.7+ki&pg=PA127|title=Top Drugs: Their History, Pharmacology, and Syntheses|date=2015|publisher=Oxford University Press|isbn=978-0-19-936258-5|access-date=20 October 2020|archive-date=25 February 2024|archive-url=https://web.archive.org/web/20240225123331/https://books.google.com/books?id=qOHXCQAAQBAJ&q=duloxetine+0.7+ki&pg=PA127#v=snippet&q=duloxetine%200.7%20ki&f=false|url-status=live}}</ref>
|-
! Receptor !! K<sub>i</sub> (nM)
|-
| ] || 0.7~0.8
|-
| ] || 7.5
|-
| ] || 240
|-
| ] || 504
|-
| ] || 916
|-
| ] || 419
|}


Duloxetine inhibits the reuptake of serotonin and norepinephrine (NE) in the central nervous system. Duloxetine increases dopamine (DA) specifically in the prefrontal cortex, where there are few DA reuptake pumps, via the inhibition of NE reuptake pumps (NET), which is believed to mediate the reuptake of DA and NE.<ref name="Stahl-2013">{{cite book | vauthors = Stahl S | date = 2013 | title = Stahl's Essential Pharmacology | edition = 4th | publisher = Cambridge University Press | location = New York | pages = 305, 308, 309 }}</ref> Duloxetine has no significant affinity for dopaminergic, cholinergic, histaminergic, opioid, glutamate, and GABA reuptake transporters, however, and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NE transporters. Duloxetine undergoes extensive ], but the major circulating metabolites do not contribute significantly to the pharmacologic activity.<ref name="pmid16142213">{{cite journal | vauthors = Stahl SM, Grady MM, Moret C, Briley M | title = SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants | journal = CNS Spectrums | volume = 10 | issue = 9 | pages = 732–47 | date = September 2005 | pmid = 16142213 | doi=10.1017/s1092852900019726| s2cid = 40022100 }}</ref><ref name="pmid15892657">{{cite journal | vauthors = Bymaster FP, Lee TC, Knadler MP, Detke MJ, Iyengar S | title = The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression | journal = Current Pharmaceutical Design | volume = 11 | issue = 12 | pages = 1475–93 | year = 2005 | pmid = 15892657 | doi = 10.2174/1381612053764805 }}</ref>
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 ]. Preclinical studies demonstrate that duloxetine potently inhibits neuronal serotonin and norepinephrine reuptake,<ref>Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT. "Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human ] subtypes, and other neuronal receptors". Neuropsychopharmacology. 2001 Dec;25(6):871-80</ref> 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).


In vitro binding studies using synaptosomal preparations isolated from rat cerebral cortex indicated that duloxetine was approximately 3 fold more potent at inhibiting ] than ] uptake.<ref name="pmid28913467">{{cite journal | vauthors = Onuţu AH | title = Duloxetine, an antidepressant with analgesic properties - a preliminary analysis | journal = Romanian Journal of Anaesthesia and Intensive Care | volume = 22 | issue = 2 | pages = 123–128 | date = October 2015 | pmid = 28913467 | pmc = 5505372 }}</ref>
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 ], but the major circulating metabolites do not contribute significantly to the pharmacologic activity.


===Pharmacokinetics=== ===Pharmacokinetics===
====Absorption====
Duloxetine is acid labile, and is formulated with an enteric coating to prevent degradation in the stomach. Duloxetine has good oral ], averaging 50% after one 60&nbsp;mg dose.<ref name="pmid21366359"/> There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post-dose. Food or bedtime administration has no significant impact on the C<sub>max</sub> of duloxetine, but delay time to reach peak concentration by 4 hours.<ref name="pmid15892657"/><ref name="pmid21366359"/> This delay is caused by reduced gastrointestinal motility, and reduce ] and half-life by only 11% and 18%, respectively; as such, no dose adjustments or time-of-day restrictions are necessary.<ref name="pmid21366359"/> Depending on condition being treated, duloxetine is taken once a day or twice a day.<ref name="Cymbalta FDA label" /><ref name="pmid21366359"//>


====Distribution====
Duloxetine has an ] of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the ]. Steady-state is usually achieved after 3 days.
Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to ] and ]. ] is about {{val|1640|u=liters}}.<ref name="pmid21366359"/><ref name="Cymbalta FDA label" />


====Metabolism====
Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.
Duloxetine undergoes predominately hepatic metabolism via two ] isozymes, ] and ]. Circulating metabolites are pharmacologically inactive. Duloxetine is a moderate CYP2D6 inhibitor.<ref name="Cymbalta FDA label" />


====Elimination====
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 C<sub>max</sub> 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.
Duloxetine, administered in a single oral dose of {{val|20|u=mg}} or {{val|40|u=mg}} has plasma elimination half-life of {{val|10|-|12|u=hours}}<ref name="pmid21366359"/><ref name="Cymbalta FDA label" /> and its pharmacokinetics are dose proportional over the ].<ref name="Cymbalta FDA label" /> ] is usually achieved after 3 days.<ref name="pmid21366359"/><ref name="Cymbalta FDA label" /> Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (approx. 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the feces.<ref name="Cymbalta FDA label" />


Smoking is associated with a decrease in duloxetine concentration.<ref name="pmid21366359">{{cite journal | vauthors = Knadler MP, Lobo E, Chappell J, Bergstrom R | title = Duloxetine: clinical pharmacokinetics and drug interactions | journal = Clinical Pharmacokinetics | volume = 50 | issue = 5 | pages = 281–294 | date = May 2011 | pmid = 21366359 | doi = 10.2165/11539240-000000000-00000 | s2cid = 207299455 }}</ref><ref name="pmid18651344">{{cite journal | vauthors = Fric M, Pfuhlmann B, Laux G, Riederer P, Distler G, Artmann S, Wohlschläger M, Liebmann M, Deckert J | title = The influence of smoking on the serum level of duloxetine | journal = Pharmacopsychiatry | volume = 41 | issue = 4 | pages = 151–155 | date = July 2008 | pmid = 18651344 | doi = 10.1055/s-2008-1073173 | s2cid = 22045964 }}</ref><ref name="medicines.org.uk-Duloxetine-60">{{cite web|url=https://www.medicines.org.uk/emc/product/1900/smpc|title=Duloxetine 60mg gastro-resistant capsules - Summary of Product Characteristics (SmPC) - (emc)|website=www.medicines.org.uk|access-date=21 March 2020|archive-date=21 March 2020|archive-url=https://web.archive.org/web/20200321015841/https://www.medicines.org.uk/emc/product/1900/smpc|url-status=dead}}</ref>
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 ==
]
Duloxetine was created by Lilly researchers. David Robertson, David Wong, a co-discoverer of ], and Joseph Krushinski are listed as inventors on the ] filed in 1986 and granted in 1990.<ref name="United States Patent: 4956388">{{cite web |url=http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4956388.PN.&OS=PN/4956388&RS=PN/4956388|title=United States Patent 4,956,388: 3-Aryloxy-3-substituted propanamines |author=Robertson DW, Wong DT, Krushinski JH|date=1990-09-11 |work= |publisher=USPTO |accessdate=2008-05-17}}</ref> The first publication on the discovery of the ]form of duloxetine known as LY227942, was made in 1988.<ref>{{cite journal |author=Wong DT, Robertson DW, Bymaster FP, Krushinski JH, Reid LR |title=LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug |journal=Life Sci. |volume=43 |issue=24 |pages=2049–57 |year=1988 |pmid=2850421 |doi=10.1016/0024-3205(88)90579-6}}</ref> The (+)-] 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.<ref name="pmid14643350">{{cite journal |author=Bymaster FP, Beedle EE, Findlay J, ''et al.'' |title=Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake |journal=Bioorg. Med. Chem. Lett. |volume=13 |issue=24 |pages=4477–80 |year=2003|month=December |pmid=14643350 |doi= 10.1016/j.bmcl.2003.08.079|url=http://linkinghub.elsevier.com/retrieve/pii/S0960894X03010072}}</ref>


==Research directions==
Initial trials conducted in patients using regimens of 20&nbsp;mg/day or less did not convincingly demonstrate its efficacy<ref>{{cite journal |author=Turcotte JE, Debonnel G, de Montigny C, Hébert C, Blier P |title=Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects |journal=Neuropsychopharmacology |volume=24 |issue=5|pages=511–21 |year=2001 |month=May |pmid=11282251 |doi=10.1016/S0893-133X(00)00220-7|url=http://www.nature.com/npp/journal/v24/n5/abs/1395628a.html}}</ref> and the dose was increased to as high as 120&nbsp;mg in subsequent ]s.<ref name="pmid11926722">For example, see: {{cite journal |author=Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA |title=Duloxetine in the treatment a double-blind clinical trial |journal=J Clin Psychiatry |volume=63 |issue=3|pages=225–31 |year=2002 |month=March |pmid=11926722 |doi= |url=}}</ref>
Major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system.<ref name="pmid25003554">{{cite journal |vauthors=Lotrich FE |title=Inflammatory cytokine-associated depression |journal=Brain Res |volume=1617 |issue= |pages=113–25 |date=August 2015 |pmid=25003554 |pmc=4284141 |doi=10.1016/j.brainres.2014.06.032 |url=}}</ref><ref name="pmid17433516">{{cite journal |vauthors=Kim YK, Na KS, Shin KH, Jung HY, Choi SH, Kim JB |title=Cytokine imbalance in the pathophysiology of major depressive disorder |journal=Prog Neuropsychopharmacol Biol Psychiatry |volume=31 |issue=5 |pages=1044–53 |date=June 2007 |pmid=17433516 |doi=10.1016/j.pnpbp.2007.03.004 |s2cid=22275879 |url=}}</ref> Antidepressants including ones with a similar mechanism of action as duloxetine, i.e., serotonin metabolism inhibition, cause a decrease in proinflammatory ] activity and an increase in anti-inflammatory cytokines;<ref name="pmid22981313">{{cite journal |vauthors=Fornaro M, Rocchi G, Escelsior A, Contini P, Martino M |title=Might different cytokine trends in depressed patients receiving duloxetine indicate differential biological backgrounds |journal=J Affect Disord |volume=145 |issue=3 |pages=300–7 |date=March 2013 |pmid=22981313 |doi=10.1016/j.jad.2012.08.007 |url=}}</ref> this mechanism may apply to duloxetine in its effect on depression but research on cytokines specific to duloxetine therapy is insufficient.<ref name="pmid20646337">{{cite journal | vauthors = De Berardis D, Conti CM, Serroni N, Moschetta FS, Olivieri L, Carano A, Salerno RM, Cavuto M, Farina B, Alessandrini M, Janiri L, Pozzi G, Di Giannantonio M | title = The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature | journal = International Journal of Immunopathology and Pharmacology | volume = 23 | issue = 2 | pages = 417–22 | year = 2010 | pmid = 20646337 | doi = 10.1177/039463201002300204 | s2cid = 656023 | doi-access = free }}</ref><ref name="pmid21796103">{{cite journal | vauthors = Hannestad J, DellaGioia N, Bloch M | title = The Effect of Antidepressant Medication Treatment on Serum Levels of Inflammatory Cytokines: A Meta-Analysis | journal = Neuropsychopharmacology | volume = 36 | issue = 12 | pages = 2452–59 | date = November 2011 | pmid = 21796103 | doi = 10.1038/npp.2011.132 | pmc = 3194072 }}</ref> Cytokines are immunoregulatory molecules that play a key role in the human immune response. Some cytokines are proinflammatory and contribute to the development of inflammation, while others are anti-inflammatory and help to control the proinflammatory response.<ref name="pmid10767254">{{cite journal |vauthors=Opal SM, DePalo VA |title=Anti-inflammatory cytokines |journal=Chest |volume=117 |issue=4 |pages=1162–72 |date=April 2000 |pmid=10767254 |doi=10.1378/chest.117.4.1162 |s2cid=2267250 |url=}}</ref> Duloxetine can reduce the production of pro-inflammatory cytokines such as ] (IL-1β), ] (TNF-α), and ] (IL-6) and may increase the production of anti-inflammatory cytokines such as ] (IL-10),<ref name="pmid22981313"/><ref name="pmid39392051">{{cite journal |vauthors=Suzuki E, Sueki A, Takahashi H, Ishigooka J, Nishimura K |title=Association between TNF-α & IL-6 level changes and remission from depression with duloxetine treatment |journal=Int J Neurosci |volume= |issue= |pages=1–6 |date=October 2024 |pmid=39392051 |doi=10.1080/00207454.2024.2414279 |url=}}</ref><ref name="pmid38877455">{{cite journal |vauthors=Gao W, Gao Y, Xu Y, Liang J, Sun Y, Zhang Y, Shan F, Ge J, Xia Q |title=Effect of duloxetine on changes in serum proinflammatory cytokine levels in patients with major depressive disorder |journal=BMC Psychiatry |volume=24 |issue=1 |pages=449 |date=June 2024 |pmid=38877455 |pmc=11179362 |doi=10.1186/s12888-024-05910-0|doi-access=free }}</ref> however, mechanisms behind these effects are not well elucidated, there have been mixed findings regarding duloxetine's impact on cytokine production in different contexts, and the results are inconclusive.<ref name="pmid35791513">{{cite journal |vauthors=Zhu J, Chen J, Zhang K |title=Clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine comorbidity of depression and anxiety disorder |journal=Brain Behav |volume=12 |issue=8 |pages=e2689 |date=August 2022 |pmid=35791513 |pmc=9392519 |doi=10.1002/brb3.2689 |url=}}</ref><ref name="pmid26556688">{{cite journal |vauthors=Maciukiewicz M, Marshe VS, Tiwari AK, Fonseka TM, Freeman N, Rotzinger S, Foster JA, Kennedy JL, Kennedy SH, Müller DJ |title=Genetic variation in IL-1β, IL-2, IL-6, TSPO and BDNF and response to duloxetine or placebo treatment in major depressive disorder |journal=Pharmacogenomics |volume=16 |issue=17 |pages=1919–29 |date=November 2015 |pmid=26556688 |doi=10.2217/pgs.15.136 |url=}}</ref><ref name="pmid31125145">{{cite journal |vauthors=Miyauchi T, Tokura T, Kimura H, Ito M, Umemura E, Sato Boku A, Nagashima W, Tonoike T, Yamamoto Y, Saito K, Kurita K, Ozaki N |title=Effect of antidepressant treatment on plasma levels of neuroinflammation-associated molecules in patients with somatic symptom disorder with predominant pain around the orofacial region |journal=Hum Psychopharmacol |volume=34 |issue=4 |pages=e2698 |date=July 2019 |pmid=31125145 |doi=10.1002/hup.2698 |s2cid=163168228 |url=}}</ref><ref name="pmid34174336">{{cite journal |vauthors=Qiu W, Go KA, Wen Y, Duarte-Guterman P, Eid RS, ((Galea LAM)) |title=Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin |journal=Brain Behav Immun |volume=97 |issue= |pages=394–409 |date=October 2021 |pmid=34174336 |doi=10.1016/j.bbi.2021.06.012 |s2cid=235620244 |url=}}</ref>


Duloxetine is being investigated for its potential to decrease opioid use in the perioperative period because duloxetine administration can help reduce opioid consumption and mitigate the risk of opioid-related side effects and dependence. In total hip arthroplasty (THA) or total knee arthroplasty (TKA), duloxetine is researched to provide pain relief; studies demonstrated that it can reduce pain for several weeks post-surgery without an increased risk of adverse drug events, suggesting that duloxetine could be a valuable component of a multimodal management regimen for patients undergoing THA or TKA.<ref name="pmid38481321"/> Also, duloxetine can reduce postoperative nausea and vomiting after THA or TKA, which are common side effects of anesthesia and opioids: this additional benefit could improve patient comfort and satisfaction, potentially enhancing recovery outcomes.<ref name="pmid38481321">{{cite journal |vauthors=Lin Y, Jiang M, Liao C, Wu Q, Zhao J |title=Duloxetine reduces opioid consumption and pain after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials |journal=J Orthop Surg Res |volume=19 |issue=1 |pages=181 |date=March 2024 |pmid=38481321 |pmc=10936099 |doi=10.1186/s13018-024-04648-5 |doi-access=free |url=}}</ref>
In 2001 Lilly filed a ] (NDA) for duloxetine with the US ] (FDA). However, in 2003 the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP (current ]) violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and ] 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 ] monitoring" at the new highest recommended dose of 120&nbsp;mg, "where 24% patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients."<ref name="reg history">{{cite web|url=http://www.fda.gov/cder/foi/nda/2004/021427_s000_Cymbalta_AdminCorres.pdf |title=Approval package for: application number NDA 721-427. Administrative/Correspondence #2 |author= |year=2003 |format=PDF |work= |publisher=The FDA Center for Drug Evaluation and Research |pages= |accessdate=2008-05-18}} {{Dead link|date=November 2010|bot=H3llBot}}</ref>


==History==
After the manufacturing issues were resolved, the ] 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.<ref></ref> In 2007] approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.<ref>. November 1, 2007, retrieved November 24, 2007.</ref>
]
Duloxetine was created by ] researchers. David Robertson; David Wong, a co-inventor of ]; and Joseph Krushinski are listed as inventors on the ] filed in 1986 and granted in 1990.<ref name="Robertson-1990">{{cite web |url=http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4956388.PN.&OS=PN/4956388&RS=PN/4956388 |title=United States Patent 4,956,388: 3-Aryloxy-3-substituted propanamines |vauthors=Robertson DW, Wong DT, Krushinski JH |date=11 September 1990 |publisher=USPTO |access-date=17 May 2008 |archive-date=7 January 2016 |archive-url=https://web.archive.org/web/20160107015057/http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4956388.PN.&OS=PN%2F4956388&RS=PN%2F4956388 |url-status=dead }}</ref> The first publication on the invention of the ] form of duloxetine known as LY227942, was made in 1988.<ref name="pmid2850421">{{cite journal | vauthors = Wong DT, Robertson DW, Bymaster FP, Krushinski JH, Reid LR | title = LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug | journal = Life Sciences | volume = 43 | issue = 24 | pages = 2049–57 | year = 1988 | pmid = 2850421 | doi = 10.1016/0024-3205(88)90579-6 }}</ref> The (+)-], assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes to twice the degree of the (–)-enantiomer. This molecule was subsequently named duloxetine.<ref name="pmid14643350">{{cite journal | vauthors = Bymaster FP, Beedle EE, Findlay J, Gallagher PT, Krushinski JH, Mitchell S, Robertson DW, Thompson DC, Wallace L, Wong DT | title = Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 24 | pages = 4477–80 | date = December 2003 | pmid = 14643350 | doi = 10.1016/j.bmcl.2003.08.079 }}</ref>


In 2001, Lilly filed a ] (NDA) for duloxetine with the US ]. In 2003, however, the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP (current ]) violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and ] 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 ] monitoring", since there was a dose-dependent increase in elevated blood pressure readings, including at the new highest recommended dose of 120&nbsp;mg "where 24% of patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients."<ref name="FDA-2003">{{cite report |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021427_s000_Cymbalta_AdminCorres.pdf |title=Approval package for: application number NDA 721-427. Administrative/Correspondence #2 |year=2003 |publisher=U.S. ] (FDA) |access-date=18 May 2008 |archive-date=12 February 2017 |archive-url=https://web.archive.org/web/20170212091852/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021427_s000_Cymbalta_AdminCorres.pdf |url-status=live }} {{PD-notice}}</ref><ref name="FDA Cymbalta Approval Package">{{cite web | title=Drug Approval Package: Cymbalta (Duloxetine Hydrochloride) NDA #021427 | website=U.S. ] (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021427_s000_Cymbalta.cfm | access-date=29 September 2020 | archive-date=24 September 2020 | archive-url=https://web.archive.org/web/20200924060238/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021427_s000_Cymbalta.cfm | url-status=live }}</ref>
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.<ref name=Yentreve>{{cite web|url=http://www.thestreet.com/_googlen/stocks/pharmaceuticals/10268662.html?cm_ven=GOOGLEN&cm_cat=FREE&cm_ite=NA |title=Lilly Won't Pursue Yentreve for U.S.|author=Steyer R |date=2006-02-15 |publisher=TheStreet.com |accessdate=2008-05-18}}</ref><ref>{{cite doi|10.1136/bmj.331.7508.70-b}}</ref>


After the manufacturing issues were resolved, the ] 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.<ref name="FDA-News-2009">{{cite web |url=https://www.fda.gov/bbs/topics/news/2004/NEW01113.html |title=FDA news |website=] |access-date=16 December 2019 |archive-date=13 May 2009 |archive-url=https://web.archive.org/web/20090513072618/http://www.fda.gov/bbs/topics/news/2004/NEW01113.html |url-status=dead }}</ref> In 2007, ] approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.<ref name="Health-Canada-2008">{{cite web|title=Summary Basis of Decision (SBD): Cymbalta|url=http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2008_cymbalta_110028-eng.php|publisher=Health Canada|date=5 May 2008|access-date=27 February 2015|archive-url=https://web.archive.org/web/20150301073033/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2008_cymbalta_110028-eng.php|archive-date=1 March 2015|url-status=dead}}</ref>
The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.<ref> News-Medical.Net February 26, 2007</ref>


Duloxetine was approved for use of stress urinary incontinence (SUI) in the EU in 2004.<ref name="Yentreve EPAR">{{cite web | title=Yentreve EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/yentreve | access-date=30 September 2020 | archive-date=24 September 2020 | archive-url=https://web.archive.org/web/20200924025504/https://www.ema.europa.eu/en/medicines/human/EPAR/yentreve | url-status=live }}</ref> In 2005, Lilly withdrew the duloxetine application for stress urinary incontinence (SUI) in the US, 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 US market.<ref name="TheStreet.com-2006">{{cite web |url=http://www.thestreet.com/_googlen/stocks/pharmaceuticals/10268662.html?cm_ven=GOOGLEN&cm_cat=FREE&cm_ite=NA |title=Lilly Won't Pursue Yentreve for U.S. |date=15 February 2006 |publisher=TheStreet.com |access-date=18 May 2008 |url-status=dead |archive-url=https://web.archive.org/web/20090202114300/http://www.thestreet.com/_googlen/stocks/pharmaceuticals/10268662.html?cm_ven=GOOGLEN&cm_cat=FREE&cm_ite=NA |archive-date=2 February 2009 }}</ref><ref name="pmid16002878">{{cite journal | vauthors = Lenzer J | title = FDA warns that antidepressants may increase suicidality in adults | journal = BMJ | volume = 331 | issue = 7508 | pages = 70 | date = July 2005 | pmid = 16002878 | pmc = 558648 | doi = 10.1136/bmj.331.7508.70-b }}</ref>
== References ==
{{Reflist|2}}


The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.<ref name="News-Medical-2007">{{cite web|url=http://www.news-medical.net/?id=22194|title=FDA approves antidepressant Cymbalta (duloxetine HCl) for treatment of generalized anxiety disorder|date=26 February 2007|work=News-Medical|access-date=25 December 2013|archive-date=15 January 2009|archive-url=https://web.archive.org/web/20090115204249/http://www.news-medical.net/?id=22194|url-status=live}}</ref>
== External links ==

*
Cymbalta generated sales of nearly {{US$|5 billion}} in 2012, with $4 billion of that in the US, but its patent protection terminated 1 January 2014. Lilly received a six-month extension beyond 30 June 2013, after testing for the treatment of depression in adolescents, which may produce {{US$|1.5 billion}} in added sales.<ref name="Staton-2012">{{cite web|url=http://www.fiercepharma.com/story/lilly-could-net-15b-plus-cymbalta-extension/2012-07-09|title=Lilly could net $1.5B-plus from Cymbalta extension| vauthors = Staton T |date=9 July 2012|work=FiercePharma|access-date=25 December 2013|archive-date=30 October 2013|archive-url=https://web.archive.org/web/20131030202603/http://www.fiercepharma.com/story/lilly-could-net-15b-plus-cymbalta-extension/2012-07-09|url-status=dead}}</ref><ref name="Palmer-2013">{{cite web|url=http://www.fiercepharma.com/story/eli-lilly-lay-hundreds-sales-cymbalta-nears-edge-patent-cliff/2013-04-11|title=Eli Lilly to lay off hundreds in sales as Cymbalta nears edge of patent cliff| vauthors = Palmer E |date=11 April 2013|work=FiercePharma|access-date=25 December 2013|archive-date=11 December 2013|archive-url= https://web.archive.org/web/20131211204149/http://www.fiercepharma.com/story/eli-lilly-lay-hundreds-sales-cymbalta-nears-edge-patent-cliff/2013-04-11|url-status=dead}}</ref>
*

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The first generic duloxetine was marketed by an Indian pharmaceutical company ].<ref name="Anson-2013">{{cite web|url=http://americannewsreport.com/nationalpainreport/generic-cheaper-versions-cymbalta-approved-8822633.html|title=Generic Cheaper Versions of Cymbalta Approved| vauthors = Anson P |date=12 December 2013|work=National Pain Report|access-date=2 January 2014|archive-date=2 January 2014 |archive-url=https://web.archive.org/web/20140102195512/http://americannewsreport.com/nationalpainreport/generic-cheaper-versions-cymbalta-approved-8822633.html|url-status=dead}}</ref>

== See also ==
* ]

== Explanatory notes ==
{{reflist|group=note}}

== References ==
{{Reflist}}


{{Antidepressants}} {{Antidepressants}}
{{Neuropathic pain and fibromyalgia pharmacotherapies}}
{{Serotonergics}}
{{Monoamine reuptake inhibitors}}
{{Eli Lilly and Company}}
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{{Authority control}}


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