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{{Short description|Antidepressant medication}}
{{drugbox
{{Use dmy dates|date=January 2024}}
| Verifiedfields = changed
{{cs1 config|name-list-style=vanc|display-authors=6}}
| verifiedrevid = 419802400
{{Infobox drug
| drug_name=Venlafaxine
| verifiedrevid = 459442662
| IUPAC_name = (''RS'')-1-cyclohexanol
| image = Venlafaxine.svg | image = Venlafaxine flat.svg
| chirality = ]
| imagename = 1 : 1 mixture (racemate)
| alt =
| width = 200
| caption =
| image2 = Venlafaxine-3D-balls.png
| image2 = Venlafaxine-3D-balls.png
| width2 = 200
| alt2 =
| CASNo_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = GRZ5RCB1QG
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 637
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H27NO2/c1-18(2)13-16(17(19)11-5-4-6-12-17)14-7-9-15(20-3)10-8-14/h7-10,16,19H,4-6,11-13H2,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PNVNVHUZROJLTJ-UHFFFAOYSA-N
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 93413-69-5
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5454
| ATC_prefix = N06
| ATC_suffix = AX16
| ATC_supplemental =
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 9943
| PubChem = 5656
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00285
| smiles = OC2(C(c1ccc(OC)cc1)CN(C)C)CCCCC2
| C=17 |H=27 |N=1 |O=2
| molecular_weight = 277.402 g/mol
| bioavailability = 10-45%<ref name="goodman-gilman">{{cite book | editor=Laurence L Brunton | title=Goodman & Gilman's The Pharmacological Basis of Therapeutics | edition=11th | year=2006 | publisher=McGraw-Hill Medical Publishing Division | location=New York | isbn=0-07-142280-3}}</ref>
| protein_bound = 27%
| metabolism = ]
| elimination_half-life = 4.9 ± 2.4 h (parent compound);<ref name="goodman-gilman" /> 10.3 ± 4.3 h (active metabolite)<ref name="goodman-gilman" />
| pregnancy_category = C
| legal_US = Rx-only
| legal_UK = POM
| legal_AU = S4
| routes_of_administration = Oral
| excretion = Renal
}}


<!-- Clinical data -->
'''Venlafaxine''' (]: '''Effexor''' or '''Efexor''') is an ] of the ] (SNRI) class.<ref name="pmid3790168">{{cite journal | author = Muth EA, Haskins JT, Moyer JA, Husbands GE, Nielsen ST, Sigg EB | title = Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative | journal = Biochemical Pharmacology | volume = 35 | issue = 24 | pages = 4493–7 | year = 1986 | month = December | pmid = 3790168 | doi = 10.1016/0006-2952(86)90769-0| url = http://linkinghub.elsevier.com/retrieve/pii/0006-2952(86)90769-0}}</ref><ref name="pmid1976813">{{cite journal | author = Yardley JP, Husbands GE, Stack G, ''et al.'' | title = 2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 10 | pages = 2899–905 | year = 1990 | month = October | pmid = 1976813 | doi = 10.1021/jm00172a035| url = }}</ref><ref name="pmid11750180">{{cite journal | author = Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, ''et al.'' | 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 | year = 2001 | month = December | pmid = 11750180 | doi = 10.1016/S0893-133X(01)00298-6 | unused_data = DUPLICATE DATA: doi = 10.1016/S0893-133X(01)00298-6}}</ref> First introduced by ] in 1993, now marketed by ], it is ] for the treatment of ] (MDD), as a treatment for ], and ] ] in certain ] with depression. In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions.<ref>The number of prescriptions was calculated as the total of prescriptions for the corresponding generic and brand-name drugs using data from the charts for generic and brand-name drugs. {{cite web | title = Top 200 generic drugs by units in 2007. | work = Drug Topics, Feb 18, 2008 | url = http://drugtopics.modernmedicine.com/drugtopics/Top200Drugs/ArticleStandard/article/detail/491194 | accessdate = 2008-10-23}} {{cite web | title = Top 200 brand drugs by units in 2007. | work = Drug Topics, Feb 18, 2008 | url = http://drugtopics.modernmedicine.com/drugtopics/PharmacyFactsAndFigures/ArticleStandard/article/detail/491210 | accessdate = 2008-10-23}}</ref>
| class = ]
| pronounce = {{IPAc-en|ˌ|v|ɛ|n|l|ə|ˈ|f|æ|k|s|iː|n}}<br />{{respell|VEN|lə|FAK|seen}}
| tradename = Effexor, others<ref name=brands />
| Drugs.com = {{drugs.com|monograph|Venlafaxine_Hydrochloride}}
| MedlinePlus = a694020
| DailyMedID = Venlafaxine
| pregnancy_AU = B2
| pregnancy_AU_comment = <ref name=TGA />
| pregnancy_category =
| routes_of_administration = ]
| ATC_prefix = N06
| ATC_suffix = AX16
| ATC_supplemental =


<!-- Legal status -->
==Medical uses==
| legal_AU = S4
Venlafaxine is used primarily for the treatment of ], ], ], ], and ].<ref name=AHFS>{{cite web|title=venlafaxine-hydrochloride|url=http://www.drugs.com/monograph/venlafaxine-hydrochloride.html|work=The American Society of Health-System Pharmacists|accessdate=3 April 2011}}</ref>
| legal_AU_comment = <ref name=TGA />
| legal_BR = C1
| legal_BR_comment = <ref>{{cite web |author=Anvisa |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_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Efexor XL 75 mg hard prolonged release capsules - Summary of Product Characteristics (SmPC) | website=(emc) | date=16 March 2020 | url=https://www.medicines.org.uk/emc/product/5474/smpc | access-date=15 April 2020 | archive-date=7 October 2020 | archive-url=https://web.archive.org/web/20201007180409/https://www.medicines.org.uk/emc/product/5474/smpc | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Effexor FDA label">{{cite web | title=Effexor XR- venlafaxine hydrochloride capsule, extended release | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c3e7ac-1852-4d70-d2b6-4fca819acf26 | access-date=11 May 2021 | archive-date=12 May 2021 | archive-url=https://web.archive.org/web/20210512072156/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c3e7ac-1852-4d70-d2b6-4fca819acf26 | url-status=live }}</ref><ref name="Venbysi XR FDA label">{{cite web | title=Venlafaxine tablet, extended release | website=DailyMed | date=30 June 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e81a2daf-b8b2-7c05-b532-bc775700b100 | access-date=7 January 2023}}</ref>
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->


<!-- Pharmacokinetic data -->
===Depression===
| bioavailability = 42±15%<ref name=TGA/>
Multiple double blind studies show venlafaxine's effectiveness in treating depression. Venlafaxine has similar efficacy to the ] ] (Elavil) and ], and is better tolerated than amitriptyline. Its efficacy is similar to or better than ] (Zoloft) and ] (Prozac), depending on the criteria and rating scales used. Higher doses of venlafaxine are more effective, and more patients achieved ] or were "very much improved". The efficacy was similar if the number of patients who achieved "response" or were "improved" was considered. A ] comparing venlafaxine and combined groups of ] or tricyclic antidepressants showed venlafaxine's superiority.<ref name="pmid11098413">{{cite journal |author=Golden RN, Nicholas L |title=Antidepressant efficacy of venlafaxine |journal=Depression and anxiety |volume=12 Suppl 1 |issue= |pages=45–9 |year=2000 |pmid=11098413 |doi=10.1002/1520-6394(2000)12:1 |doi_brokendate=2010-07-26}}</ref> Judged by the same criteria, venlafaxine was similar in efficacy to the atypical antidepressant ] (Wellbutrin); however, the remission rate was significantly lower for venlafaxine.<ref name="pmid16974189">{{cite journal |author=Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA |title=A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability |journal=Journal of clinical psychopharmacology |volume=26 |issue=5 |pages=482–8 |year=2006 |pmid=16974189 |doi=10.1097/01.jcp.0000239790.83707.ab}}</ref> In a double-blind study, patients who did not respond to an SSRI were switched to venlafaxine or ]. Similar improvement was observed in both groups.<ref name="pmid18408525">{{cite journal |author=Lenox-Smith AJ, Jiang Q |title=Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor |journal=] |volume=23 |issue=3 |pages=113–9 |year=2008 |pmid=18408525 |doi=10.1097/YIC.0b013e3282f424c2 |url= }}</ref>
| protein_bound = 27±2% (parent compound), 30±12% (active metabolite, ])<ref name="Effexor FDA label" />
| metabolism = Extensively metabolised by the ],<ref name=TGA/><ref name="Effexor FDA label" /> primarily via ]<ref>{{cite book | vauthors = Dean L |title=Venlafaxine Therapy and CYP2D6 Genotype |url=https://www.ncbi.nlm.nih.gov/books/NBK305561/#:~:text=Venlafaxine%20is%20metabolized%20into%20its,reduced%20or%20absent%20CYP2D6%20activity. |date=2015 |publisher=National Center for Biotechnology Information (US) | pmid=28520361 |access-date=28 December 2018 |archive-date=29 November 2017 |archive-url=https://web.archive.org/web/20171129181900/https://www.ncbi.nlm.nih.gov/books/NBK305561/#:~:text=Venlafaxine%20is%20metabolized%20into%20its,reduced%20or%20absent%20CYP2D6%20activity. |url-status=live | veditors = Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, Malheiro AJ }}</ref>
| metabolites = O-desmethylvenlafaxine (ODV), see ]
| elimination_half-life = 5±2 h (parent compound for immediate release preparations), 15±6 h (parent compound for extended-release preparations), 11±2 h (active metabolite)<ref name=TGA/><ref name="Effexor FDA label" />
| excretion = ] (87%; 5% as unchanged drug; 29% as ] and 53% as other metabolites)<ref name=TGA/><ref name="Effexor FDA label" />


<!-- Identifiers -->
===Other===
| index2_label = as HCl
Many doctors are starting to prescribe venlafaxine "off label" for the treatment of ] (in a similar manner to ]) and ] prophylaxis (in some people, however, venlafaxine can exacerbate or cause migraines). Studies have shown venlafaxine's effectiveness for these conditions.<ref>{{cite journal |author=Rowbotham M, Goli V, Kunz N, Lei D |title=Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study |journal=Pain |volume=110 |issue=3 |pages=697–706 |year=2004 |pmid=15288411 |doi=10.1016/j.pain.2004.05.010}}</ref><ref>{{cite journal |author=Ozyalcin S, Talu G, Kiziltan E, Yucel B, Ertas M, Disci R |title=The efficacy and safety of venlafaxine in the prophylaxis of migraine |journal=Headache |volume=45 |issue=2 |pages=144–52 |year=2005 |pmid=15705120 |doi=10.1111/j.1526-4610.2005.05029.x}}</ref>
| CAS_number_Ref = {{cascite|correct|??}}
It has also been found to reduce the severity of 'hot flashes' in ] women.<ref>{{cite web |author=Mayo Clinic staff |year=2005 |title=Beyond hormone therapy: Other medicines may help |work=Hot flashes: Ease the discomfort of menopause |publisher=Mayo Clinic |url=http://www.mayoclinic.com/invoke.cfm?id=HQ01409 |accessdate=19 August 2005}}</ref><ref>{{cite journal |author=Schober C, Ansani N |title=Venlafaxine hydrochloride for the treatment of hot flashes |journal=Ann Pharmacother |volume=37 |issue=11 |pages=1703–7 |year=2003 |pmid=14565812 |doi=10.1345/aph.1C483}}</ref>
| CAS_number = 93413-69-5
| CAS_number2 = 99300-78-4
<!-- | CAS_number3 = 609345-58-6 -->| CAS_supplemental =
| PubChem = 5656
| PubChem2 = 62923
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00285
| DrugBank2 = DBSALT000186
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5454
| ChemSpiderID2 = 56641
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = GRZ5RCB1QG
| UNII2 = 7D7RX5A8MO
<!-- | UNII3 = 1R8EN4W1EG -->| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08670
| KEGG2 = D00821
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9943
| ChEBI2 = 9944
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 637
| ChEMBL2 = 1201066
| NIAID_ChemDB =
| PDB_ligand =
| synonyms =


<!-- Chemical data -->
Substantial weight loss in patients with major depression, generalized anxiety disorder, and ] has been noted, but the manufacturer does not recommend use as an ] either alone or in combination with ] or other amphetamine-like drugs.<ref name="Medicinedatasheet-Wyeth"/> Venlafaxine hydrochloride is in the phenethylamine class of modern chemicals, which includes amphetamine, methylenedioxymethamphetamine (MDMA), and methamphetamine. This chemical structure likely lends to its activating properties; however, some patients find venlafaxine highly sedating, despite its more common stimulatory effects.
| IUPAC_name = (''RS'')-1-cyclohexanol
| C = 17
| H = 27
| N = 1
| O = 2
| SMILES = OC2(C(c1ccc(OC)cc1)CN(C)C)CCCCC2
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H27NO2/c1-18(2)13-16(17(19)11-5-4-6-12-17)14-7-9-15(20-3)10-8-14/h7-10,16,19H,4-6,11-13H2,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PNVNVHUZROJLTJ-UHFFFAOYSA-N
}}


<!-- Definition and medical uses -->
Venlafaxine is not approved for the treatment of depressive phases of ]; this has some potential danger as venlafaxine can induce ], ], rapid cycling and/or ] in some bipolar patients, particularly if they are not also being treated with a ].<ref name="Medicinedatasheet-Wyeth"/>
'''Venlafaxine''', sold under the brand name '''Effexor''' among others, is an ] medication of the ] (SNRI) class.<ref name="Effexor FDA label" /><ref name=AHFS2018/> It is used to treat ], ], ], and ].<ref name=AHFS2018/> Studies have shown that venlafaxine improves ] (PTSD).<ref>{{cite report |url=https://effectivehealthcare.ahrq.gov/topics/ptsd-adult-treatment-update/research-2018 |title=Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder: A Systematic Review Update |vauthors=Forman-Hoffman V, Middleton JC, Feltner C, Gaynes BN, Weber RP, Bann C, Viswanathan M, Lohr KN, Baker C, Green J |date=17 May 2018 |publisher=Agency for Healthcare Research and Quality (AHRQ) |doi=10.23970/ahrqepccer207 |pmid=30204376 |doi-access=free |access-date=29 July 2023 |archive-date=10 July 2018 |archive-url=https://web.archive.org/web/20180710011511/https://effectivehealthcare.ahrq.gov/topics/ptsd-adult-treatment-update/research-2018 |url-status=dead }}</ref> It may also be used for ].<ref>{{cite web |title=Antidepressants: Another weapon against chronic pain |url=https://www.mayoclinic.org/pain-medications/art-20045647 |website=Mayo Clinic |access-date=25 January 2020 |archive-date=26 October 2021 |archive-url=https://web.archive.org/web/20211026225927/https://www.mayoclinic.org/pain-medications/art-20045647 |url-status=live }}</ref> It is taken ] (swallowed by mouth).<ref name=AHFS2018/> It is also available as the salt venlafaxine besylate (venlafaxine ] monohydrate) in an extended-release formulation (Venbysi XR).<ref name="Venbysi XR FDA label" />


<!-- Side effects and mechanism -->
Due to its action on both the serotoninergic and ] systems, venlafaxine is also used as a treatment to reduce episodes of ], a form of muscle weakness, in patients with the ] ].<ref>{{cite web |last= |first= |authorlink= |coauthors= |title=Medications |work= |publisher=Stanford University School of Medicine, Center for Narcolepsy |date=Revised 02/07/2003 |url=http://med.stanford.edu/school/Psychiatry/narcolepsy/medications.html |doi= |accessdate=2007-09-03}}</ref>
Common side effects include loss of appetite, constipation, ], dizziness, sweating, insomnia, drowsiness and sexual problems.<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 baby.<ref name=AHFS2018/> How it works is not entirely clear, but it seems to be related to the potentiation of the activity of some neurotransmitters in the brain.<ref name=AHFS2018/>


<!-- History and culture -->
Venlafaxine was found in one study to be equal to ] (Clomipramine) in the treatment of ] with fewer side effects.<ref name="pmid12444814">{{cite journal |author=Albert U, Aguglia E, Maina G, Bogetto F |title=Venlafaxine versus clomipramine in the treatment of obsessive-compulsive disorder: a preliminary single-blind, 12-week, controlled study |journal=J Clin Psychiatry |volume=63 |issue=11 |pages=1004–9 |year=2002 |month=November |pmid=12444814 |doi= |url=http://www.psychiatrist.com/privatepdf/2002/v63n11/v63n1108.pdf |format=PDF}}</ref>
Venlafaxine was approved for medical use in the United States in 1993.<ref name=AHFS2018>{{cite web |title=Venlafaxine Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/venlafaxine-hydrochloride.html |website=Drugs.com |publisher=AHFS |access-date=24 December 2018 |archive-date=27 November 2020 |archive-url=https://web.archive.org/web/20201127001402/https://www.drugs.com/monograph/venlafaxine-hydrochloride.html |url-status=live }}</ref> It is available as a ].<ref name=AHFS2018/> In 2022, it was the 44th most commonly prescribed medication in the United States, with more than 13{{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 = Venlafaxine Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Venlafaxine | access-date = 30 August 2024 }}</ref>


== Medical uses ==
Due to its tendency to increase blood pressure and its modulative effects on the ], venlafaxine is often used to treat ] and ].<ref>{{cite web |last=Hain T |title=Orthostatic Hypotension |work= |publisher=www.dizziness-and-balance.com |date=Revised 12/30/2007 |url=http://www.dizziness-and-balance.com/disorders/medical/orthostatic.html |doi= |accessdate=2008-03-29}}</ref>
Venlafaxine is used primarily for the treatment of ], ], ], ], and ].<ref name=AHFS>{{cite web |title=venlafaxine-hydrochloride |url=https://www.drugs.com/monograph/venlafaxine-hydrochloride.html |work=The American Society of Health-System Pharmacists |access-date=3 April 2011 |archive-date=27 November 2020 |archive-url=https://web.archive.org/web/20201127001402/https://www.drugs.com/monograph/venlafaxine-hydrochloride.html |url-status=live }}</ref>


Venlafaxine has been used ] for the treatment of ]<ref>{{cite journal | vauthors = Grothe DR, Scheckner B, Albano D | title = Treatment of pain syndromes with venlafaxine | journal = Pharmacotherapy | volume = 24 | issue = 5 | pages = 621–629 | date = May 2004 | pmid = 15162896 | doi = 10.1592/phco.24.6.621.34748 | s2cid = 28187627 | doi-access = free }}</ref> and ] prevention.<ref>{{cite book | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK535363 | pmid=30570984 | year=2022 | vauthors = Singh D, Saadabadi A | chapter = Venlafaxine | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing }}</ref> It may work on pain via effects on the opioid receptor.<ref name="Academic Press">{{cite book |title=The Opioid System as the Interface between the Brain's Cognitive and Motivational Systems |date=2018 |publisher=Academic Press |isbn=978-0-444-64168-7 |page=73 |url=https://books.google.com/books?id=sEFyDwAAQBAJ&pg=PA73 |access-date=9 May 2020 |archive-date=27 August 2021 |archive-url=https://web.archive.org/web/20210827181238/https://books.google.com/books?id=sEFyDwAAQBAJ&pg=PA73 |url-status=live }}</ref> It has also been found to reduce the severity of 'hot flashes' in ] women and men on hormonal therapy for the treatment of prostate cancer.<ref>{{cite web |author=Mayo Clinic staff |year=2005 |title=Beyond hormone therapy: Other medicines may help |work=Hot flashes: Ease the discomfort of menopause |publisher=Mayo Clinic |url=http://www.mayoclinic.com/invoke.cfm?id=HQ01409 |access-date=19 August 2005 |archive-date=25 February 2005 |archive-url=https://web.archive.org/web/20050225032733/http://www.mayoclinic.com/invoke.cfm?id=HQ01409 |url-status=live }}</ref><ref>{{cite journal | vauthors = Schober CE, Ansani NT | title = Venlafaxine hydrochloride for the treatment of hot flashes | journal = The Annals of Pharmacotherapy | volume = 37 | issue = 11 | pages = 1703–1707 | date = November 2003 | pmid = 14565812 | doi = 10.1345/aph.1C483 | s2cid = 45334784 }}</ref>
==Contraindications==
Studies of venlafaxine in pediatric age groups have not established its efficacy.<ref>{{cite journal |author=Courtney D |title=Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: a systematic review of published randomized controlled trials |journal=Can J Psychiatry |volume=49 |issue=8 |pages=557–63 |year=2004 |pmid=15453105}}</ref> Venlafaxine is not recommended in patients ] to it, nor should it be taken by anyone who is allergic to the inactive ingredients, which include ], ], ethylcellulose, ], ] and ]. It should never be used with a ] (MAOI), as it can cause potentially fatal ]. Caution should also be used in those with a seizure disorder.


Due to its action on both the ]ergic and ] systems, venlafaxine is also used as a treatment to reduce episodes of ], a form of muscle weakness, in patients with the ] ].<ref>{{cite web |title=Medications |publisher=Stanford University School of Medicine, Center for Narcolepsy |date=7 February 2003 |url=http://med.stanford.edu/school/Psychiatry/narcolepsy/medications.html |access-date=3 September 2007 |archive-url=https://web.archive.org/web/20070821090305/http://med.stanford.edu/school/Psychiatry/narcolepsy/medications.html |archive-date=21 August 2007 |url-status=dead }}</ref> Some open-label and three double-blind studies have suggested the efficacy of venlafaxine in the treatment of ] (ADHD).<ref>{{cite journal | vauthors = Ghanizadeh A, Freeman RD, Berk M | title = Efficacy and adverse effects of venlafaxine in children and adolescents with ADHD: a systematic review of non-controlled and controlled trials | journal = Reviews on Recent Clinical Trials | volume = 8 | issue = 1 | pages = 2–8 | date = March 2013 | pmid = 23157376 | doi = 10.2174/1574887111308010002 }}</ref> Clinical trials have found possible efficacy in those with ] (PTSD).<ref>{{cite journal | vauthors = Pae CU, Lim HK, Ajwani N, Lee C, Patkar AA | title = Extended-release formulation of venlafaxine in the treatment of post-traumatic stress disorder | journal = Expert Review of Neurotherapeutics | volume = 7 | issue = 6 | pages = 603–615 | date = June 2007 | pmid = 17563244 | doi = 10.1586/14737175.7.6.603 | s2cid = 25215502 }}</ref> Case reports, open trials and blinded comparisons with established medications have suggested the efficacy of venlafaxine in the treatment of ].<ref>{{cite journal | vauthors = Phelps NJ, Cates ME | title = The role of venlafaxine in the treatment of obsessive-compulsive disorder | journal = The Annals of Pharmacotherapy | volume = 39 | issue = 1 | pages = 136–140 | date = January 2005 | pmid = 15585743 | doi = 10.1345/aph.1E362 | s2cid = 30973410 }}</ref>
===Glaucoma===
Venlafaxine can increase eye pressure, so those with ] may require more frequent eye checks.<ref name="Medicinedatasheet-Wyeth"/>


===Pregnant women=== === Depression ===
A comparative meta-analysis of 21 major antidepressants found that venlafaxine, ], ], ], ], ], and ] were more effective than other antidepressants, although the quality of many comparisons was assessed as low or very low.<ref name=pmid19185342>{{cite journal | vauthors = Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C | title = Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis | journal = Lancet | volume = 373 | issue = 9665 | pages = 746–758 | date = February 2009 | pmid = 19185342 | doi = 10.1016/S0140-6736(09)60046-5 | s2cid = 35858125 }}</ref><ref>{{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>
There are few, well-controlled studies of venlafaxine in pregnant women. A study released in May 2010 by the Canadian Medical Association Journal suggests use of venlafaxine doubles the risk of ].<ref>{{cite pmid|19863482}}</ref><ref>{{cite pmid|20513781}}</ref> Consequently, venlafaxine should only be used during pregnancy if clearly needed.<ref name="Medicinedatasheet-Wyeth"/> Prospective studies have not shown any statistically significant ]s.<ref>{{cite journal |author=Gentile S |title=The safety of newer antidepressants in pregnancy and breastfeeding |journal=Drug Saf |volume=28 |issue=2 |pages=137–52 |year=2005 |pmid=15691224 |doi=10.2165/00002018-200528020-00005}}</ref> There have, however, been some reports of self-limiting effects on newborn infants.<ref>{{cite journal |author=de Moor R, Mourad L, ter Haar J, Egberts A |title= |journal=Ned Tijdschr Geneeskd |volume=147 |issue=28 |pages=1370–2 |year=2003 |pmid=12892015}}</ref> As with other serotonin reuptake inhibitors, these effects are generally short-lived, lasting only 3 to 5 days,<ref>{{cite journal |author=Ferreira E, Carceller AM, Agogué C, Martin BZ, St-André M, Francoeur D, Bérard A |title= |journal=Pediatrics |volume=119 |issue=1 |pages=52–9 |year=2007 |pmid=17200271 |doi=10.1542/peds.2006-2133}}</ref> and rarely resulting in severe complications.<ref name="pmid15900008">{{cite journal |author=Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL |title= |journal=JAMA |volume=293 |issue=19 |pages=2372–83 |year=2005 |pmid=15900008 |doi=10.1001/jama.293.19.2372}}</ref>


Venlafaxine was similar in efficacy to the atypical antidepressant ]; however, the remission rate was lower for venlafaxine.<ref name="pmid16974189">{{cite journal | vauthors = Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA | title = A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability | journal = Journal of Clinical Psychopharmacology | volume = 26 | issue = 5 | pages = 482–488 | date = October 2006 | pmid = 16974189 | doi = 10.1097/01.jcp.0000239790.83707.ab | s2cid = 276619 }}</ref> In a double-blind study, patients who did not respond to an SSRI were switched to either venlafaxine or another SSRI (]); similar improvement was observed in both groups.<ref name="pmid18408525">{{cite journal | vauthors = Lenox-Smith AJ, Jiang Q | title = Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor | journal = International Clinical Psychopharmacology | volume = 23 | issue = 3 | pages = 113–119 | date = May 2008 | pmid = 18408525 | doi = 10.1097/YIC.0b013e3282f424c2 | s2cid = 34986490 }}</ref>
===Heart disease and hypertension===
The FDA asked the manufacturers of all SNRIs to include the risk of persistent ] (PPHN) in prescribing data as of July 19, 2006. Medications containing venlafaxine caused a mean heart rate increase of 4 bpm in clinical trials, along with a sustained increase in blood pressure in some.


Studies have not established its efficacy for use in pediatric populations.<ref>{{cite journal | vauthors = Courtney DB | title = Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: a systematic review of published randomized controlled trials | journal = Canadian Journal of Psychiatry | volume = 49 | issue = 8 | pages = 557–563 | date = August 2004 | pmid = 15453105 | doi = 10.1177/070674370404900807 | doi-access = free }}</ref> In children and adolescents with depression, venlafaxine increases the risk of suicidal thoughts or attempts.<ref name=":0">{{cite journal |date=3 November 2022 |title=Antidepressants for children and teenagers: what works for anxiety and depression? |url=https://evidence.nihr.ac.uk/collection/antidepressants-for-children-and-teenagers-what-works-anxiety-depression/ |journal=NIHR Evidence |type=Plain English summary |language=en |publisher=National Institute for Health and Care Research |doi=10.3310/nihrevidence_53342|s2cid=253347210 }}</ref><ref name=":1">{{cite journal | vauthors = Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, Li X, Cuijpers P, Coghill D, Xiang Y, Hetrick SE, Leucht S, Qin M, Barth J, Ravindran AV, Yang L, Curry J, Fan L, Silva SG, Cipriani A, Xie P | title = Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis | journal = The Lancet. Psychiatry | volume = 7 | issue = 7 | pages = 581–601 | date = July 2020 | pmid = 32563306 | pmc = 7303954 | doi = 10.1016/S2215-0366(20)30137-1 }}</ref><ref name=":2">{{cite journal | vauthors = Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N | title = New generation antidepressants for depression in children and adolescents: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 5 | pages = CD013674 | date = May 2021 | pmid = 34029378 | pmc = 8143444 | doi = 10.1002/14651858.CD013674.pub2 | collaboration = Cochrane Common Mental Disorders Group }}</ref><ref name=":3">{{cite journal | vauthors = Solmi M, Fornaro M, Ostinelli EG, Zangani C, Croatto G, Monaco F, Krinitski D, Fusar-Poli P, Correll CU | title = Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects | journal = World Psychiatry | volume = 19 | issue = 2 | pages = 214–232 | date = June 2020 | pmid = 32394557 | pmc = 7215080 | doi = 10.1002/wps.20765 }}</ref><ref name=":4">{{cite journal | vauthors = Boaden K, Tomlinson A, Cortese S, Cipriani A | title = Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment | journal = Frontiers in Psychiatry | volume = 11 | pages = 717 | date = 2 September 2020 | pmid = 32982805 | pmc = 7493620 | doi = 10.3389/fpsyt.2020.00717 | doi-access = free }}</ref><ref name=":5">{{cite journal | vauthors = Correll CU, Cortese S, Croatto G, Monaco F, Krinitski D, Arrondo G, Ostinelli EG, Zangani C, Fornaro M, Estradé A, Fusar-Poli P, Carvalho AF, Solmi M | title = Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review | journal = World Psychiatry | volume = 20 | issue = 2 | pages = 244–275 | date = June 2021 | pmid = 34002501 | pmc = 8129843 | doi = 10.1002/wps.20881 }}</ref>
==Adverse effects==
===Suicide===
The US Food and Drug Administration body (FDA) requires all antidepressants, including venlafaxine, to carry a ] with a generic warning about a possible suicide risk. In addition, the most recent research indicated that patients taking venlafaxine are at increased risk of suicide.


A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk 1.6-fold (statistically significant), as compared to no treatment. At the same time, ] (Prozac) halved the suicide risk.<ref name="pmid17146010">{{cite journal |author=Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J |title=Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort |journal=Arch. Gen. Psychiatry |volume=63 |issue=12 |pages=1358–67 |year=2006 |pmid=17146010 |doi=10.1001/archpsyc.63.12.1358}}</ref> Higher doses (e.g., 225&nbsp;mg and 375&nbsp;mg per day) of venlafaxine are more effective than lower doses (e.g., 75&nbsp;mg per day) but also cause more side effects.<ref name="Rudolph1998">{{cite journal | vauthors = Rudolph RL, Fabre LF, Feighner JP, Rickels K, Entsuah R, Derivan AT | title = A randomized, placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major depression | journal = The Journal of Clinical Psychiatry | volume = 59 | issue = 3 | pages = 116–122 | date = March 1998 | pmid = 9541154 | doi = 10.4088/jcp.v59n0305 }}</ref>


Studies have shown that the extended-release is superior to the immediate-release form of venlafaxine.<ref name="Thase Asami Wajsbrot Dorries 2017 pp. 317–326"/>
In another study, the data on more than 200,000 cases were obtained from the UK general practice research database. The patients taking venlafaxine had significantly higher risk of completed suicide than the ones on ] (Prozac) (2.8 times) or ] (Celexa) (2.4 times). Even after taking into consideration the fact that venlafaxine was generally prescribed for more severe depression, venlafaxine was associated with 1.6-1.7 times more suicides than fluoxetine or citalopram. This difference was no longer statistically significant due to the rarity of completed suicides. However, for the attempted suicides (more frequent event) the 1.2-1.3 times higher risk for venlafaxine still stayed statistically significant after the adjustment.<ref name="pmid17164297">{{cite journal |author=Rubino A, Roskell N, Tennis P, Mines D, Weich S, Andrews E |title=Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study |journal=BMJ |volume=334 |issue=7587 |pages=242 |year=2007 |pmid=17164297 |doi=10.1136/bmj.39041.445104.BE |pmc=1790752}}</ref>


A 2017 meta-analysis has showed that the efficacy of venlafaxine is not correlated with baseline severity of depression.<ref name="Thase Asami Wajsbrot Dorries 2017 pp. 317–326"/> In other words, regardless of how severe a person's depression is at treatment initiation, the efficacy of venlafaxine remains consistent and is not influenced by the severity of depression at the start of treatment.
An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behaviour among the adults on venlafaxine to be not significantly different from fluoxetine or ].<ref name=FDA>{{cite web |url=http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf |title=Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee |accessdate=2007-06-20 |author= |authorlink= |coauthors= |date=November 16, 2006 |format=PDF |work= |publisher= |pages= |language= |archiveurl= |archivedate= |quote=}}</ref> A possible explanation for this discrepancy is that suicidal patients are generally excluded from clinical trials, and so clinical trials do not represent the real population of patients.{{Citation needed|date=March 2009}}


== Contraindications ==
Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials<ref name=FDA/> venlafaxine caused a statistically significant 5-fold increase in suicidal ideation and behavior in persons younger than 25. In another analysis, venlafaxine was no better than placebo among children (7–11 years old), but improved depression in adolescents (12–17 years old). However, in both groups, hostility and suicidal behavior increased in comparison to those receiving a placebo.<ref name="pmid17420682">{{cite journal |author=Emslie GJ, Findling RL, Yeung PP, Kunz NR, Li Y |title=Venlafaxine ER for the treatment of pediatric subjects with depression: results of two placebo-controlled trials |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=46 |issue=4 |pages=479–88 |year=2007 |pmid=17420682 |doi=10.1097/chi.0b013e31802f5f03}}</ref> In a study involving antidepressants that had failed to produce results in depressed teenagers, teens whose ] treatment had failed who were randomly switched to either another SSRI or to venlafaxine showed an increased rate of suicide on venlafaxine. Among teenagers who were suicidal at the beginning of the study, the rate of suicidal attempts and self-harm was significantly higher, by about 60%, after the switch to venlafaxine than after the switch to an SSRI.<ref name="pmid19223438">{{cite journal |author=Brent DA, Emslie GJ, Clarke GN, ''et al.'' |title=Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of SSRI-resistant depression in adolescents (TORDIA) study |journal=Am J Psychiatry |volume=166 |issue=4 |pages=418–26 |year=2009 |month=April |pmid=19223438 |doi=10.1176/appi.ajp.2008.08070976 |url=}}</ref>
Venlafaxine is not recommended in patients ] to it, nor should it be taken by anyone who is allergic to the inactive ingredients, which include ], ], ethylcellulose, ], ] and ]. It should not be used in conjunction with a ] (MAOI), as it can cause potentially fatal serotonin syndrome.<ref name=TGA>{{cite web | title=Efexor-XR (venlafaxine hydrochloride) | website=TGA eBS | url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04889-3 | access-date=11 May 2021 | format=PDF | archive-date=12 May 2021 | archive-url=https://web.archive.org/web/20210512121509/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04889-3 | url-status=live }}</ref><ref name="Effexor FDA label" /><ref name=Maudsley>{{cite book |title=The Maudsley Prescribing Guidelines in Psychiatry | veditors = Taylor D, Paton C, Kapur S |edition=illustrated |publisher=John Wiley & Sons |year=2012 |isbn=978-0-470-97948-8}}</ref> Venlafaxine might interact with ] or other opioids, as well as ], so caution is needed while mixing multiple ] agents together.<ref>{{cite journal | vauthors = Ripple MG, Pestaner JP, Levine BS, Smialek JE | title = Lethal combination of tramadol and multiple drugs affecting serotonin | journal = The American Journal of Forensic Medicine and Pathology | volume = 21 | issue = 4 | pages = 370–374 | date = December 2000 | pmid = 11111800 | doi = 10.1097/00000433-200012000-00015 | url = https://pubmed.ncbi.nlm.nih.gov/11111800/ | access-date = 6 April 2022 | url-status = live | archive-url = https://web.archive.org/web/20220406120319/https://pubmed.ncbi.nlm.nih.gov/11111800/ | archive-date = 6 April 2022 }}</ref>


===Common side effects=== == Adverse effects ==
{{see also|List of adverse effects of venlafaxine}}
] is often a side effect of drugs that inhibit serotonin reuptake. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and ] (trouble achieving orgasm). Genital anesthesia,<ref>{{cite journal |author=Bolton JM, Sareen J, Reiss JP |title=Genital anaesthesia persisting six years after sertraline discontinuation |journal=J Sex Marital Ther |volume=32 |issue=4 |pages=327–30 |year=2006 |pmid=16709553 |doi=10.1080/00926230600666410 |url=http://www.informaworld.com/openurl?genre=article&doi=10.1080/00926230600666410&magic=pubmed |unused_data=1B69BA326FFE69C3F0A8F227DF8201D0}}</ref> loss of or decreased response to sexual stimuli, and ejaculatory ] are also possible. Although usually reversible, these sexual side effects can last for years after the drug has been completely withdrawn.<ref>{{cite journal |author=Csoka AB, Bahrick AS, Mehtonen O-P |title=Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs) |journal=J Sex Med. |volume=5 |issue= 1|pages=227–33 |year=2008 |doi= 10.1111/j.1743-6109.2007.00630.x|url=http://www.blackwell-synergy.com/doi/abs/10.1111/j.1743-6109.2007.00630.x |pmid=18173768}}</ref> This is known as ].


Venlafaxine can increase eye pressure, so those with ] may require more frequent eye checks.<ref name="Effexor FDA label" />
NOTE: The percentage of occurrences for each side effect listed comes from clinical trial data provided by Wyeth Pharmaceuticals Inc. The percentage of people experiencing the side effect using Effexor should be compared to those using a ], given in parentheses. The following list includes those side effects with a difference of 3% or more.<ref name="Medicinedatasheet-Wyeth"/>


A 2017 meta-analysis estimated venlafaxine discontinuation rate due to adverse effects to be 9.4%.<ref name="Thase Asami Wajsbrot Dorries 2017 pp. 317–326">{{cite journal | vauthors = Thase M, Asami Y, Wajsbrot D, Dorries K, Boucher M, Pappadopulos E | title = A meta-analysis of the efficacy of venlafaxine extended release 75-225 mg/day for the treatment of major depressive disorder | journal = Current Medical Research and Opinion | volume = 33 | issue = 2 | pages = 317–326 | date = February 2017 | pmid = 27794623 | doi = 10.1080/03007995.2016.1255185 | publisher = Informa UK Limited | s2cid = 4394404 }}</ref>
* ] - 37% (placebo 11%)
* ] - 23% (9%)
* ] - 22% (11%)
* ] - 19% (7%)
* ] - 18% (10%)
* ] - 15% (7%)
* ] - 13% (6%)
* Abnormal ejaculation/orgasm - 12% (0%)
* ] - 12% (3%)
* ] - 12% (6%)
* ] - 11% (2%)
* ] - 6% (0%)
* ] - 6% (3%)
* ] - 6% (2%)
* ] - 6% (2%)
* ] - 5% (1%)
* ] - 3% (0%)
* ] - 3% (0%)


=== Suicide ===
Difference of 1-2%: ], ], ], ],{{disambiguation needed|date=April 2011}} ], increased ]/], ], ], ], ]ing, ], upset stomach or indigestion (]), ], ], abnormal dreams, ], ], decreased ], ], ], abnormal thinking, ], ], ], ], ] perversion, ] (ringing in the ears), ].
The US ] (FDA) requires all antidepressants, including venlafaxine, to carry a ] with a generic warning about a possible suicide risk.{{citation needed|date=May 2021}}


A 2014 meta-analysis of 21 clinical trials of venlafaxine for the treatment of depression in adults found that compared to placebo, venlafaxine reduced the risk of suicidal thoughts and behavior.<ref>{{cite journal | vauthors = Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ | title = Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine | journal = Archives of General Psychiatry | volume = 69 | issue = 6 | pages = 580–587 | date = June 2012 | pmid = 22309973 | pmc = 3367101 | doi = 10.1001/archgenpsychiatry.2011.2048 }}</ref>
Other possible side effects can be found on pp.&nbsp;26–27 of the report used for the above data.<ref name="Medicinedatasheet-Wyeth"/> Note that these are from a combination of studies, not all of which were controlled, and so it is possible the individuals reporting the effects may have experienced them even if they had not taken Effexor.


A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk by 60% (statistically significant), as compared to no treatment. At the same time, ] (Prozac) halved the suicide risk.<ref name="pmid17146010">{{cite journal | vauthors = Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J | title = Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort | journal = Archives of General Psychiatry | volume = 63 | issue = 12 | pages = 1358–1367 | date = December 2006 | pmid = 17146010 | doi = 10.1001/archpsyc.63.12.1358 | doi-access = free }}</ref>
===Dose dependency of adverse events===
A comparison of adverse event rates in a fixed-dose study comparing venlafaxine 75, 225, and 375&nbsp;mg/day with ] revealed a dose dependency for some of the more common adverse events associated with venlafaxine use. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage test, with a criterion of exact 2-sided p-value <=0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.<ref name="Medicinedatasheet-Wyeth"/>


In a study sponsored by ], which produces and markets venlafaxine, the data on more than 200,000 cases were obtained from the UK general practice research database. At baseline, patients prescribed venlafaxine had a greater number of risk factors for suicide (such as prior suicide attempts) than patients treated with other anti-depressants. The patients taking venlafaxine had a significantly higher risk of suicide than the ones on ] or ] (Celexa). After adjusting for known risk factors, venlafaxine was associated with an increased risk of suicide relative to fluoxetine and ] which was not statistically significant. A statistically significant greater risk for attempted suicide remained after adjustment, but the authors concluded that it could be due to residual confounding.<ref name="pmid17164297">{{cite journal | vauthors = Rubino A, Roskell N, Tennis P, Mines D, Weich S, Andrews E | title = Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study | journal = BMJ | volume = 334 | issue = 7587 | pages = 242 | date = February 2007 | pmid = 17164297 | pmc = 1790752 | doi = 10.1136/bmj.39041.445104.BE }}</ref>
===Memory loss===
In a study of 70 patients that compared the tolerability of venlafaxine at standard doses, ranging from 75 to 300&nbsp;mg, against relatively high doses (rarely prescribed), ranging from 375 to 600&nbsp;mg per day, for treating DSM-IV major depressive disorder, "failing memory" was reported in 44% of cases. The severity of venlafaxine-induced memory loss was also noted to increase with dose and length of treatment.<ref name="pmid15260908">{{cite journal |author=Harrison CL, Ferrier N, Young AH |title=Tolerability of high-dose venlafaxine in depressed patients |journal=J. Psychopharmacol. (Oxford) |volume=18 |issue=2 |pages=200–4 |year=2004 |month=June |pmid=15260908 |doi=10.1177/0269881104042621 |url=}}</ref>


An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behaviour among the adults on venlafaxine to be not significantly different from fluoxetine or ].<ref name=FDA>{{cite web |url=https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf |title=Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee |access-date=20 June 2007 |date=16 November 2006 |publisher=Food and Drug Administration: Center for Drug Evaluation and Research |archive-url=https://web.archive.org/web/20070316092329/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf |archive-date=16 March 2007 |url-status=live}}</ref>
===Discontinuation syndrome===
{{Main|SSRI discontinuation syndrome}}
In vitro studies revealed venlafaxine has virtually no affinity for opiate, benzodiazepine, or N-methyl-D-aspartic acid (]) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.<ref name="Medicinedatasheet-Wyeth"/>


Venlafaxine is contraindicated in children, adolescents, and young adults. In children and adolescents with depression, venlafaxine increases the risk of suicidal thoughts or attempts.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" />
Many patients stopping venlafaxine use experience ], i.e. withdrawal symptoms. This is especially noted if a patient misses a dose, but can also occur when reduction of dosage is gradual. The high risk of discontinuation syndrome symptoms may reflect venlafaxine's short half-life.<ref name="pmid11347722">{{cite journal |author=Haddad PM |title=Antidepressant discontinuation syndromes |journal=Drug Saf |volume=24 |issue=3 |pages=183–97 |year=2001 |pmid=11347722 |doi=10.2165/00002018-200124030-00003 |url=}}</ref> Missing even a single dose can induce discontinuation effects in some patients.<ref name="ANZ JPsych1998-parker"/> Discontinuation is similar in nature to those of SSRIs such as ] (] or ]). Sudden discontinuation of venlafaxine particularly seemed to cause discontinuation symptoms during the first 3 days in a study of 18 patients.<ref name="AmJPsych1997-fava">{{cite journal |author=Fava M, Mulroy R, Alpert J, Nierenberg A, Rosenbaum J |title=Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine |journal=Am J Psychiatry |volume=154 |issue=12 |pages=1760–2 |year=1997 |pmid=9396960}}</ref> As reported in 2001 by Haddad in the journal ''Drug Safety'', "another strategy to consider is switching to fluoxetine, which may suppress the discontinuation symptoms, but which has little tendency to cause such symptoms itself," and then discontinuing that.<ref name="pmid11347722"/> Some psychiatrists actually prescribe the singular SSRIs to alleviate the symptoms of venlafaxine withdrawal.


=== Serotonin syndrome ===
Although many other drugs can cause withdrawal symptoms which are not associated with addiction or dependence, for example, ], ], nitrates, ]s, centrally acting antihypertensives, ]s, ], ], dopaminergic agents, ], and ],<ref name="pmid11347722"/> addiction or dependence is a more common effect described for drugs that (are thought to, or may) improve mental well-being.<ref
The development of a potentially life-threatening ] (also classified as "serotonin toxicity")<ref name="Dunkley">{{cite journal | vauthors = Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM | title = The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity | journal = QJM | volume = 96 | issue = 9 | pages = 635–642 | date = September 2003 | pmid = 12925718 | doi = 10.1093/qjmed/hcg109 | doi-access = free }}</ref> may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to ]s and ]s, many hallucinogens such as ]s and ]s (e.g., ]/], ], ], ]), ] (DXM), ], ], ] (meperidine) and ]s and with drugs that impair metabolism of serotonin (including ]s).{{Citation needed|date=January 2021}} Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination), or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose.<ref name="Kolecki">{{cite journal | vauthors = Kolecki P | title = Isolated venlafaxine-induced serotonin syndrome | journal = The Journal of Emergency Medicine | volume = 15 | issue = 4 | pages = 491–493 | date = July–August 1997 | pmid = 9279702 | doi = 10.1016/S0736-4679(97)00078-4 }}</ref> An abortive serotonin syndrome state, in which some but not all of the symptoms of the full serotonin syndrome are present, has been reported with venlafaxine at mid-range dosages (150&nbsp;mg per day).<ref>{{cite web |url=http://www.priory.com/psych/venhall.htm |title=Hallucinations as a side effect of venlafaxine treatment |access-date=17 June 2008 |vauthors=Ebert D, etal |publisher=Psychiatry On-line |archive-date=21 May 2008 |archive-url=https://web.archive.org/web/20080521183032/http://www.priory.com/psych/venhall.htm |url-status=live }}</ref> A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5&nbsp;mg per day) has also been reported.<ref name="pmid12549949">{{cite journal | vauthors = Pan JJ, Shen WW | title = Serotonin syndrome induced by low-dose venlafaxine | journal = The Annals of Pharmacotherapy | volume = 37 | issue = 2 | pages = 209–211 | date = February 2003 | pmid = 12549949 | doi = 10.1345/aph.1C021 }}</ref>
name="pmid9081020">{{cite journal |author=Double D |title=Prescribing antidepressants in general practice. People may become psychologically dependent on antidepressants |journal=BMJ |volume=314 |issue=7083 |pages=829 |year=1997 |pmid=9081020 |pmc=2126213}}</ref>


===Serotonin syndrome=== === Pregnancy ===
There are few well-controlled studies of venlafaxine in pregnant women. A study released in May 2010 by the Canadian Medical Association Journal suggests use of venlafaxine doubles the risk of ].<ref>{{cite journal | vauthors = Broy P, Bérard A | title = Gestational exposure to antidepressants and the risk of spontaneous abortion: a review | journal = Current Drug Delivery | volume = 7 | issue = 1 | pages = 76–92 | date = January 2010 | pmid = 19863482 | doi = 10.2174/156720110790396508 | s2cid = 28153571 }}</ref><ref>{{cite journal | vauthors = Nakhai-Pour HR, Broy P, Bérard A | title = Use of antidepressants during pregnancy and the risk of spontaneous abortion | journal = CMAJ | volume = 182 | issue = 10 | pages = 1031–1037 | date = July 2010 | pmid = 20513781 | pmc = 2900326 | doi = 10.1503/cmaj.091208 }}</ref> Consequently, venlafaxine should only be used during pregnancy if clearly needed.<ref name="Effexor FDA label" /> A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association between venlafaxine use during pregnancy and several birth defects including anencephaly, cleft palate, septal heart defects and coarctation of the aorta.<ref name="pmid23281074">{{cite journal | vauthors = Polen KN, Rasmussen SA, Riehle-Colarusso T, Reefhuis J | title = Association between reported venlafaxine use in early pregnancy and birth defects, national birth defects prevention study, 1997-2007 | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 97 | issue = 1 | pages = 28–35 | date = January 2013 | pmid = 23281074 | pmc = 4484721 | doi = 10.1002/bdra.23096 }}</ref> Prospective studies have not shown any statistically significant ]s.<ref>{{cite journal | vauthors = Gentile S | title = The safety of newer antidepressants in pregnancy and breastfeeding | journal = Drug Safety | volume = 28 | issue = 2 | pages = 137–152 | year = 2005 | pmid = 15691224 | doi = 10.2165/00002018-200528020-00005 | s2cid = 24798891 }}</ref> There have, however, been some reports of self-limiting effects on newborn infants.<ref>{{cite journal | vauthors = de Moor RA, Mourad L, ter Haar J, Egberts AC | title = | journal = Nederlands Tijdschrift voor Geneeskunde | volume = 147 | issue = 28 | pages = 1370–1372 | date = July 2003 | pmid = 12892015 }}</ref> As with other ]s (SRIs), these effects are generally short-lived, lasting only 3 to 5 days,<ref>{{cite journal | vauthors = Ferreira E, Carceller AM, Agogué C, Martin BZ, St-André M, Francoeur D, Bérard A | title = Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates | journal = Pediatrics | volume = 119 | issue = 1 | pages = 52–59 | date = January 2007 | pmid = 17200271 | doi = 10.1542/peds.2006-2133 | s2cid = 27443298 }}</ref> and rarely resulting in severe complications.<ref name="pmid15900008">{{cite journal | vauthors = Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL | title = Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications | journal = JAMA | volume = 293 | issue = 19 | pages = 2372–2383 | date = May 2005 | pmid = 15900008 | doi = 10.1001/jama.293.19.2372 | s2cid = 30284439 }}</ref>
The development of a potentially life-threatening ] (also more recently classified as "serotonin toxicity")<ref name="Dunkley">{{cite journal |author=Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM |title=The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity |journal=QJM |volume=96 |issue=9 |pages=635–42 |year=2003 |month=September |pmid=12925718 |doi= 10.1093/qjmed/hcg109|url=http://www.qjmed.oxfordjournals.org/cgi/content/full/96/9/635}}</ref> may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to ] and ]s, many hallucinogens such as ]s and ]s (]/], ], ], ], ] for example), ] (DXM)/] (DXO), ], ], ] and ]s and with drugs that impair metabolism of serotonin (including ]s). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose.<ref name="Kolecki">{{cite journal |author=Kolecki P |title=Isolated venlafaxine-induced serotonin syndrome |journal=J Emerg Med |volume=15 |issue=4 |pages=491–3 |year=1997 |pmid=9279702 |doi=10.1016/S0736-4679(97)00078-4 }}</ref> An abortive serotonin syndrome state, in which some but not all of the symptoms of the full serotonin syndrome are present, has been reported with venlafaxine at mid-range dosages (150&nbsp;mg per day)<ref>{{cite web |url=http://www.priory.com/psych/venhall.htm |title=Hallucinations as a side effect of venlafaxine treatment |accessdate=2008-06-17 |author=Ebert D. et al. |publisher=Psychiatry On-line}}</ref> A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5&nbsp;mg per day) has also been reported.<ref name="pmid12549949">{{cite journal |author=Pan JJ, Shen WW |title=Serotonin syndrome induced by low-dose venlafaxine |journal=Ann Pharmacother |volume=37 |issue=2 |pages=209–11 |year=2003 |month=February |pmid=12549949 |doi= 10.1345/aph.1C021|url=}}</ref>


=== Bipolar disorder ===
===Serotonin toxicity and discontinuation syndrome===
According to the ] Task Force report on antidepressant use in bipolar disorder,<ref>{{cite journal | vauthors = Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, Post RM, Berk M, Goodwin GM, Sachs GS, Tondo L, Findling RL, Youngstrom EA, Tohen M, Undurraga J, González-Pinto A, Goldberg JF, Yildiz A, Altshuler LL, Calabrese JR, Mitchell PB, Thase ME, Koukopoulos A, Colom F, Frye MA, Malhi GS, Fountoulakis KN, Vázquez G, Perlis RH, Ketter TA, Cassidy F, Akiskal H, Azorin JM, Valentí M, Mazzei DH, Lafer B, Kato T, Mazzarini L, Martínez-Aran A, Parker G, Souery D, Ozerdem A, McElroy SL, Girardi P, Bauer M, Yatham LN, Zarate CA, Nierenberg AA, Birmaher B, Kanba S, El-Mallakh RS, Serretti A, Rihmer Z, Young AH, Kotzalidis GD, MacQueen GM, Bowden CL, Ghaemi SN, Lopez-Jaramillo C, Rybakowski J, Ha K, Perugi G, Kasper S, Amsterdam JD, Hirschfeld RM, Kapczinski F, Vieta E | title = The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders | journal = The American Journal of Psychiatry | volume = 170 | issue = 11 | pages = 1249–1262 | date = November 2013 | pmid = 24030475 | pmc = 4091043 | doi = 10.1176/appi.ajp.2013.13020185 | doi-access = free }}</ref> during the course of treatment for depression with those suffering from bipolar I and II, venlafaxine "appears to carry a particularly high risk of inducing pathologically elevated states of mood and behavior." Because venlafaxine appears to be more likely than ] and ] to induce mania and mixed episodes in these patients, provider discretion is advised through "carefully evaluating individual clinical cases and circumstances."
Venlafaxine may be particularly hazardous to those individuals who are susceptible to both venlafaxine-induced serotonin toxicity (also known as serotonin syndrome) and ]. In such cases, individuals who have developed the potentially fatal serotonin toxicity and/or may be at risk of doing so, may find cessation or dose reduction unachievable, placing them at continuing risk. As it is not possible to determine which patients are likely to develop the most severe symptoms of the discontinuation syndrome before cessation or dose reduction is attempted, this dual risk requires that all patients be closely monitored during any increase in dosage (when the patient is most at risk of developing serotonin toxicity)<ref>Venlafaxine (marketed as Effexor) FDA Alert: SSRIs/SNRI/Triptan and Serotonin Syndrome </ref> and that such increases be carried out in the smallest incremental steps possible. Additionally, patients who recommence venlafaxine or revert to a higher dosage following a failed attempt to discontinue the drug or reduce dosage are another group with an increased risk of developing serotonin toxicity.<ref name="pmid9081020"/>


===Drug interactions=== === Liver injury ===
A rare but serious side effect of venlafaxine is liver injury. It appears to affect both male and female patients with a median age of 44. Cessation of venlafaxine is one of the appropriate measures of management. While the mechanism of venlafaxine-related liver injury remains unclear, findings suggest that it may be related to a CYP2D6 polymorphism.<ref name="Stadlmann Portmann Tschopp Terracciano 2012 pp. 1724–1728">{{cite journal | vauthors = Stadlmann S, Portmann S, Tschopp S, Terracciano LM | title = Venlafaxine-induced cholestatic hepatitis: case report and review of literature | journal = The American Journal of Surgical Pathology | volume = 36 | issue = 11 | pages = 1724–1728 | date = November 2012 | pmid = 23073329 | doi = 10.1097/pas.0b013e31826af296 | publisher = Ovid Technologies (Wolters Kluwer Health) }}</ref>
Venlafaxine should be taken with caution when using ].<ref>{{cite book |title=2006 Lippincott's Nursing Drug Guide |last=Karch |first=Amy |year=2006 |publisher=Lippincott Williams & Wilkins |location=Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo |isbn=1-58255-436-6}}</ref> Venlafaxine may lower the seizure threshold, and coadministration with other drugs that lower the seizure threshold such as ] and ] should be done with caution and at low doses.<ref name="pmid18072153">{{cite journal |author=Thundiyil JG, Kearney TE, Olson KR |title=Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System |journal=J Med Toxicol |volume=3 |issue=1 |pages=15–9 |year=2007 |month=March |pmid=18072153 |doi= 10.1007/BF03161033|url=}}</ref>


=== Overdose ===
There have been false positive ] (PCP) results caused by venlafaxine, with certain on-site routine urine-based drug tests.<ref name="pmid17267806">{{cite journal |author=Santos PM, López-García P, Navarro JS, Fernández AS, Sádaba B, Vidal JP |title=False positive phencyclidine results caused by venlafaxine |journal=Am J Psychiatry |volume=164 |issue=2 |pages=349 |year=2007 |month=February |pmid=17267806 |doi=10.1176/appi.ajp.164.2.349 |url=http://ajp.psychiatryonline.org/cgi/content/full/164/2/349}}</ref><ref name="pmid11901076">{{cite journal |author=Sena SF, Kazimi S, Wu AH |title=False-positive phencyclidine immunoassay results caused by venlafaxine and O-desmethylvenlafaxine |journal=Clin. Chem. |volume=48 |issue=4 |pages=676–7 |year=2002 |pmid=11901076 |doi= |url=http://clinchem.org/cgi/content/full/48/4/676}}</ref>
Most patients overdosing with venlafaxine develop only mild symptoms. Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24&nbsp;mg/L, while postmortem blood levels in fatalities are often in the 10–90&nbsp;mg/L range.<ref>{{cite book| vauthors = Baselt R |title=Disposition of Toxic Drugs and Chemicals in Man |edition=8th |publisher=Biomedical Publications |location=Foster City, CA |year=2008 |pages=1634–1637 |isbn=978-0-9626523-7-0}}</ref> Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.<ref>{{cite web |year=2006 |title=Wyeth Letter to Health Care Providers |publisher=Wyeth Pharmaceuticals Inc |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150546.htm |access-date=6 August 2009 |archive-date=27 August 2009 |archive-url=https://web.archive.org/web/20090827092615/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150546.htm |url-status=live }}</ref> It is usually reserved as a second-line treatment for depression due to a combination of its superior efficacy to the first-line treatments like fluoxetine, paroxetine and citalopram and greater frequency of side effects like nausea, headache, insomnia, drowsiness, dry mouth, constipation, sexual dysfunction, sweating and nervousness.<ref name=pmid19185342 /><ref>{{cite journal | vauthors = Taylor D, Lenox-Smith A, Bradley A | title = A review of the suitability of duloxetine and venlafaxine for use in patients with depression in primary care with a focus on cardiovascular safety, suicide and mortality due to antidepressant overdose | journal = Therapeutic Advances in Psychopharmacology | volume = 3 | issue = 3 | pages = 151–161 | date = June 2013 | pmid = 24167687 | pmc = 3805457 | doi = 10.1177/2045125312472890 }}</ref>


There is no specific ] for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration of ] can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with ]s or other anticonvulsants. ], ], ], or ] are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug's high ].<ref>{{cite journal | vauthors = Hanekamp BB, Zijlstra JG, Tulleken JE, Ligtenberg JJ, van der Werf TS, Hofstra LS | title = Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning: a case report | journal = The Netherlands Journal of Medicine | volume = 63 | issue = 8 | pages = 316–318 | date = September 2005 | pmid = 16186642 | url = http://www.njmonline.nl/getpdf.php?id=432 | access-date = 6 November 2013 | url-status = live | format = PDF | archive-url = https://web.archive.org/web/20160304231924/http://www.njmonline.nl/getpdf.php?id=432 | archive-date = 4 March 2016 }}</ref>
Although the ] may not be as bad as with other antidepressants, it is still not recommended to take venlafaxine with alcohol.<ref>http://www.nhs.uk/chq/Pages/863.aspx?CategoryID=73&SubCategoryID=103</ref>


=== Withdrawal syndrome ===
==Overdose==
{{Main|Antidepressant withdrawal syndrome}}
Most patients overdosing with venlafaxine develop only mild symptoms. However, severe toxicity is reported, with the most common symptoms being ], serotonin toxicity, ], or ] abnormalities.<ref>{{cite journal |author=Blythe D, Hackett L |title=Cardiovascular and neurological toxicity of venlafaxine |journal=Hum Exp Toxicol |volume=18 |issue=5 |pages=309–13 |year=1999 |pmid=10372752 |doi=10.1191/096032799678840165}}</ref> Venlafaxine's toxicity appears to be higher than other SSRIs, with a fatal toxic dose closer to that of the ]s than the SSRIs. Doses of 900&nbsp;mg or more are likely to cause moderate toxicity.<ref name="QJM2003-Whyte"/> Deaths have been reported following very large doses.<ref name="Pharmacotherapy2003-Mazur">{{cite journal |author=Mazur J, Doty J, Krygiel A |title=Fatality related to a 30-g venlafaxine overdose |journal=Pharmacotherapy |volume=23 |issue=12 |pages=1668–72 |year=2003 |pmid=14695048 |doi=10.1592/phco.23.15.1668.31951}}</ref><ref>{{cite journal |author=Banham N |title=Fatal venlafaxine overdose |journal=Med J Aust |volume=169 |issue=8 |pages=445, 448 |year=1998 |pmid=9830400}}</ref> Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24&nbsp;mg/l, while postmortem blood levels in fatalities are often in the 10–90&nbsp;mg/l range.<ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1634–1637.</ref>


People stopping venlafaxine commonly experience ] such as ], ]s, ], ], ], sensation of electric shocks (commonly called "brain zaps"<ref>{{cite journal | vauthors = Papp A, Onton JA | title = Brain Zaps: An Underappreciated Symptom of Antidepressant Discontinuation | journal = The Primary Care Companion for CNS Disorders | volume = 20 | issue = 6 | pages = 18m02311 | date = December 2018 | pmid = 30605268 | doi = 10.4088/PCC.18m02311 | s2cid = 58577252 }}</ref><ref>{{cite journal | vauthors = Rizkalla M, Kowalkowski B, Prozialeck WC | title = Antidepressant Discontinuation Syndrome: A Common but Underappreciated Clinical Problem | journal = The Journal of the American Osteopathic Association | volume = 120 | issue = 3 | pages = 174–178 | date = February 2020 | pmid = 32077900 | doi = 10.7556/jaoa.2020.030 }}</ref>), and ].<ref name="pmid22295261">{{cite journal | vauthors = Petit J, Sansone RA | title = A case of interdose discontinuation symptoms with venlafaxine extended release | journal = The Primary Care Companion for CNS Disorders | volume = 13 | issue = 5 | date = 2011 | pmid = 22295261 | pmc = 3267502 | doi = 10.4088/PCC.11l01140 }}</ref> Venlafaxine has a higher rate of moderate to severe withdrawal symptoms relative to other antidepressants (similar to the SSRI ]).<ref name="pmid21286371">{{cite journal | vauthors = Hosenbocus S, Chahal R | title = SSRIs and SNRIs: A review of the Discontinuation Syndrome in Children and Adolescents | journal = Journal of the Canadian Academy of Child and Adolescent Psychiatry | volume = 20 | issue = 1 | pages = 60–67 | date = February 2011 | pmid = 21286371 | pmc = 3024727 }}</ref>
On May 31, 2006, the ] (MHRA) UK concluded its review of the latest safety evidence relating to venlafaxine, and particularly looked at the risks associated with overdose. The advice was: the need for specialist supervision in those severely depressed or hospitalized patients who need doses 300&nbsp;mg or more; cardiac contraindications are more targeted towards high risk groups; patients with uncontrolled hypertension should not take venlafaxine, and blood pressure monitoring is recommended for all patients; and updated advice on possible drug interactions.<ref>{{cite journal |author=MHRA UK |title=Updated product information for venlafaxine |journal=Safeguarding public health |volume= 120|issue= 8|pages= 778|year=2006 |month=31 May |doi=10.1016/j.puhe.2006.03.006}}</ref>


The higher risk and increased severity of withdrawal symptoms relative to other antidepressants may be related to the short ] of venlafaxine and its active metabolite.<ref name="pmid11347722">{{cite journal | vauthors = Haddad PM | title = Antidepressant discontinuation syndromes | journal = Drug Safety | volume = 24 | issue = 3 | pages = 183–197 | date = March 2001 | pmid = 11347722 | doi = 10.2165/00002018-200124030-00003 | s2cid = 26897797 }}</ref> After stopping venlafaxine, the levels of both serotonin and ] decrease, leading to the hypothesis that the withdrawal symptoms could result from an overly rapid reduction of neurotransmitter levels.<ref name="PMC1681629">{{cite journal | vauthors = Campagne DM | title = Venlafaxine and serious withdrawal symptoms: warning to drivers | journal = MedGenMed | volume = 7 | issue = 3 | pages = 22 | date = July 2005 | pmid = 16369248 | pmc = 1681629 }}</ref>
On 17 October 2006, Wyeth and the FDA notified healthcare professionals of revisions to the Overdosage/Human Experience section of the prescribing information for Effexor (venlafaxine) indicated for treatment of major depressive disorder. In post-marketing experience, there have been reports of overdose with venlafaxine, occurring predominantly in combination with alcohol and/or other drugs. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.<ref>{{cite web |year=2006 |title=Wyeth Letter to Health Care Providers |publisher=Wyeth Pharmaceuticals Inc |url=http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150546.htm |accessdate=2009-08-06}}</ref>


=== Other ===
A report in the ] in 2002 by Dr. Nicholas Buckley and colleagues at the Department of Clinical Pharmacology and Toxicology, ] Hospital, ] studying fatal toxicity index (deaths per million prescriptions), found that venlafaxine's fatal toxicity is higher than that of other ], but it is similar to that of some of the less toxic ]. Overall, they found serious toxicity could occur following venlafaxine overdose with reports of deaths, arrythmias, and seizures. They did, however, state that this type of data is open to criticism, pointing out that mortality data may be influenced by previous literature and that "less toxic" drugs may be preferentially prescribed to patients at higher risk of poisoning and suicide, but they are also less likely to be listed as the sole cause of death from overdose. It also assumed that drugs are taken in overdose with similar frequency and in similar amounts. They suggested "clinicians need to consider whether factors in their patients reduce or compensate for this risk before prescribing venlafaxine."<ref>{{cite journal |author=Buckley N, McManus P |title=Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data |journal=BMJ |volume=325 |issue=7376 |pages=1332–3 |year=2002 |pmid=12468481 |doi=10.1136/bmj.325.7376.1332 |pmc=137809}}</ref>
In rare cases, drug-induced ] can occur after use in some people.<ref>{{cite web | title = Venlafaxine Side Effects in Detail | url = https://www.drugs.com/sfx/venlafaxine-side-effects.html | access-date = 3 January 2018 | archive-date = 3 October 2020 | archive-url = https://web.archive.org/web/20201003115943/https://www.drugs.com/sfx/venlafaxine-side-effects.html | url-status = live }}</ref>


Venlafaxine should be used with caution in ] patients. Venlafaxine must be discontinued if significant ] persists.<ref>{{cite journal | vauthors = Khurana RN, Baudendistel TE | title = Hypertensive crisis associated with venlafaxine | journal = The American Journal of Medicine | volume = 115 | issue = 8 | pages = 676–677 | date = December 2003 | pmid = 14656626 | doi = 10.1016/S0002-9343(03)00472-8 }}</ref><ref>{{cite journal | vauthors = Thase ME | title = Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients | journal = The Journal of Clinical Psychiatry | volume = 59 | issue = 10 | pages = 502–508 | date = October 1998 | pmid = 9818630 | doi = 10.4088/JCP.v59n1002 }}</ref><ref>{{cite journal | vauthors = Edvardsson B | title = Venlafaxine as single therapy associated with hypertensive encephalopathy | journal = SpringerPlus | volume = 4 | issue = 1 | pages = 97 | date = 26 February 2015 | pmid = 25763307 | pmc = 4348355 | doi = 10.1186/s40064-015-0883-0 | doi-access = free }}</ref> It can also have undesirable cardiovascular effects.<ref>{{cite journal | vauthors = Johnson EM, Whyte E, Mulsant BH, Pollock BG, Weber E, Begley AE, Reynolds CF | title = Cardiovascular changes associated with venlafaxine in the treatment of late-life depression | journal = The American Journal of Geriatric Psychiatry | volume = 14 | issue = 9 | pages = 796–802 | date = September 2006 | pmid = 16943176 | doi = 10.1097/01.JGP.0000204328.50105.b3 }}</ref>
The 27 February 2007 Vancouver Sun reported that the BC Drug and Poison Information Centre had alerted doctors that the drug poses a significant risk of death from overdose, saying that venlafaxine "appears more toxic than it was originally hoped".<ref>{{cite web |last=Fayerman |first=Pamela |title=Warning issued over drug |publisher=Vancouver Sun |date=February 27, 2007 |url=http://www.canada.com/vancouversun/news/story.html?id=83f35b4e-ac13-4c09-b8de-44d16750b70b&k=58837 |accessdate=2007-06-02}}</ref> A doctor from the Department of Pharmacy Services College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina, reported on the death of a 39-year-old patient with a 30 g overdose.<ref name="Pharmacotherapy2003-Mazur"/> To put this into perspective, a patient would have to take over 66 of the infrequently prescribed 450&nbsp;mg high dosage pills, or 400 of the commonly prescribed 75&nbsp;mg pills.


== Pharmacology ==
===Gastrointestinal effects===
{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"
Two cases are known of patients who deliberately overdosed on a huge quantity of venlafaxine, resulting in their stomach or intestines respectively being blocked by a mass of tablets (pharmaco-]). The first patient died; the second recovered after the blocked part of her colon was surgically removed. The second patient's physicians speculate that the vasoconstrictive effects of venlafaxine contributed to tissue ] (lack of blood supply) in the affected part of the intestine.<ref>{{Cite journal
!Transporter
| last = Lung
!''K''<sub>i</sub> <ref name="Bymaster">{{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 = 871–880 | date = December 2001 | pmid = 11750180 | doi = 10.1016/S0893-133X(01)00298-6 | doi-access = free }}</ref>
| first = Derrick
!] <ref>{{cite journal | vauthors = Sabatucci JP, Mahaney PE, Leiter J, Johnston G, Burroughs K, Cosmi S, Zhang Y, Ho D, Deecher DC, Trybulski E | title = Heterocyclic cycloalkanol ethylamines as norepinephrine reuptake inhibitors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 9 | pages = 2809–2812 | date = May 2010 | pmid = 20378347 | doi = 10.1016/j.bmcl.2010.03.059 }}</ref>
| coauthors = Cristina Cuevas, Uwais Zaid and Benedict Ancock
|-
| title = Venlafaxine Pharmacobezoar Causing Intestinal Ischemia Requiring Emergent Hemicolectomy
|]
| journal = Journal of Medical Toxicology
|82
| volume =
|27
| issue =
|-
| pages =
|]
| publisher =
|2480
| location =
|535
| date = 4 March 2011
|-
| url = http://www.springerlink.com/content/dx22wn16732u4628/fulltext.html
|]
| doi = 10.1007/s13181-011-0144-8
|7647
| accessdate = 14 March 2011}}</ref>
|{{abbr|ND|No data}}
|}
{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"
|-
! Receptor !! ''K''<sub>i</sub> <ref name="Bymaster"/><ref>{{cite journal | vauthors = Roth BL, Kroeze WK | title = Screening the ] yields validated molecular targets for drug discovery | journal = Current Pharmaceutical Design | volume = 12 | issue = 14 | pages = 1785–1795 | date = 2006 | pmid = 16712488 | doi = 10.2174/138161206776873680 | author1-link = Bryan Roth }}</ref>
! Species
|-
| ] || 2230 || Human
|-
| ] || 2004 || Human
|-
| ] || 2792 || Human
|-
| ] || >1000 || Human
|}


=== Pharmacodynamics ===
===Management of overdose===
Venlafaxine is usually categorized as a ] (SNRI), but it has also been referred to as a ] (SNDRI).<ref>{{ClinicalTrialsGov|NCT00001483|Acute Effectiveness of Additional Drugs to the Standard Treatment of Depression}}</ref><ref>{{cite journal | vauthors = Goeringer KE, McIntyre IM, Drummer OH | title = Postmortem tissue concentrations of venlafaxine | journal = Forensic Science International | volume = 121 | issue = 1–2 | pages = 70–75 | date = September 2001 | pmid = 11516890 | doi = 10.1016/S0379-0738(01)00455-8 }}</ref> It is described as 'synthetic phenethylamine bicyclic derivative with antidepressant activity'.<ref>{{cite web |url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/venlafaxine |title=venlafaxine |publisher=National Cancer Institute |archive-url=https://web.archive.org/web/20220124090908/https://www.cancer.gov/publications/dictionaries/cancer-drug/def/venlafaxine |archive-date=24 January 2022 }}</ref><ref>{{cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK535363/|title=StatPearls|chapter=Venlafaxine|year=2022|publisher=StatPearls|pmid=30570984 |access-date=24 January 2022|archive-date=30 June 2022|archive-url=https://web.archive.org/web/20220630225510/https://www.ncbi.nlm.nih.gov/books/NBK535363/|url-status=live| vauthors = Singh D, Saadabadi A }}</ref> It works by blocking the ] for key ]s affecting mood, thereby leaving more active neurotransmitters in the ]. The neurotransmitters affected are ] and ]. Additionally, in high doses, it weakly inhibits the reuptake of ].<ref name="CNSDrugs2001-Wellington">{{cite journal | vauthors = Wellington K, Perry CM | title = Venlafaxine extended-release: a review of its use in the management of major depression | journal = CNS Drugs | volume = 15 | issue = 8 | pages = 643–669 | year = 2001 | pmid = 11524036 | doi = 10.2165/00023210-200115080-00007 | s2cid = 26795121 }}</ref> The frontal cortex largely lacks dopamine transporters; therefore venlafaxine can increase dopamine neurotransmission in this part of the brain.<ref>{{cite web |url=http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c95_p539-544.html.therapeutics&name=Venlafaxine&title=Therapeutics |title=Stahl's Essential Psychopharmacology – Cambridge University Press |publisher=Stahlonline.cambridge.org |access-date=21 November 2013 |archive-date=27 February 2012 |archive-url=https://web.archive.org/web/20120227144244/http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c95_p539-544.html.therapeutics&name=Venlafaxine&title=Therapeutics |url-status=live }}</ref><ref>{{cite journal | vauthors = Delgado PL, Moreno FA | title = Role of norepinephrine in depression | journal = The Journal of Clinical Psychiatry | volume = 61 | issue = Suppl 1 | pages = 5–12 | year = 2000 | pmid = 10703757 }}{{full citation needed|date=November 2013}}</ref>
There is no specific ] for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration of ] can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with ]s or other anticonvulsants. ], ], ], or ] are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug's high ].<ref>{{cite journal |author=Hanekamp B, Zijlstra J, Tulleken J, Ligtenberg J, van der Werf T, Hofstra L |title=Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning: a case report |journal=Neth J Med |volume=63 |issue=8 |pages=316–8 |year=2005 |pmid=16186642}}</ref>


Venlafaxine selectively inhibits the serotonin transporter at lower doses, but at a dose of 225&nbsp;mg per day it additionally blocks the norepinephrine transporter (NET), as measured by the intravenous tyramine pressor test.<ref name="Aldosary2022">{{cite journal | vauthors = Aldosary F, Norris S, Tremblay P, James JS, Ritchie JC, Blier P | title = Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder | journal = The International Journal of Neuropsychopharmacology | volume = 25 | issue = 4 | pages = 283–292 | date = April 2022 | pmid = 34958348 | pmc = 9017767 | doi = 10.1093/ijnp/pyab086 }}</ref>
==Mechanism of action==

Venlafaxine is a ] antidepressant, and is usually categorized as a ] (SNRI), but it has been referred to as a ] (SNDRI).<ref>{{cite web |author= |year= |title=Acute Effectiveness of Additional Drugs to the Standard Treatment of Depression |publisher=ClinicalTrials.gov |url=http://www.clinicaltrials.gov/ct/show/NCT00001483 |accessdate=23 June 2005}}</ref><ref>{{cite journal |author=Goeringer K, McIntyre I, Drummer O |title=Postmortem tissue concentrations of venlafaxine |journal=Forensic Sci Int |volume=121 |issue=1–2 |pages=70–5 |year=2001 |pmid=11516890 |doi=10.1016/S0379-0738(01)00455-8}}</ref> It works by blocking the ] for key ]s affecting mood, thereby leaving more active neurotransmitters in the ]. The neurotransmitters affected are ] and ]. Additionally, in high doses it weakly inhibits the reuptake of ],<ref name="CNSDrugs2001-Wellington">{{cite journal |author=Wellington K, Perry C |title=Venlafaxine extended-release: a review of its use in the management of major depression |journal=CNS Drugs |volume=15 |issue=8 |pages=643–69 |year=2001 |pmid=11524036 |doi=10.2165/00023210-200115080-00007}}</ref> with recent evidence showing that the ] also transports some ] as well, since dopamine is inactivated by norepinephrine reuptake in the ], which largely lacks dopamine transporters, therefore venlafaxine can increase dopamine neurotransmission in this part of the brain.<ref>http://stahlonline.cambridge.org/prescribers_drug.jsf?page=0521683505c95_p539-544.html.therapeutics&name=Venlafaxine&title=Therapeutics</ref><ref>{{cite journal | last1 = Delgado | first1 = P.L. | last2 = Moreno | first2 = F.A. | year = 2000 | title = Role of norepinephrine in depression | url = | journal = Journal of Clinical Psychiatry | volume = 61 | issue = | pages = 5–12 | pmid = 10703757 }}</ref>
Venlafaxine indirectly affects ]s as well as the α<sub>2</sub>-adrenergic receptor, and was shown to increase pain threshold in mice. These benefits with respect to pain were reversed with ], an opioid antagonist, thus supporting an opioid mechanism.<ref>{{cite book | vauthors = Stern TA, Fava M, Wilens TE, Rosenbaum JF |title=Massachusetts General Hospital Comprehensive Clinical Psychiatry |date=2015 |publisher=Elsevier Health Sciences |isbn=978-0-323-29507-9 |page=860 |url=https://books.google.com/books?id=deR1BwAAQBAJ&pg=PA860 |access-date=9 May 2020 |archive-date=27 August 2021 |archive-url=https://web.archive.org/web/20210827181241/https://books.google.com/books?id=deR1BwAAQBAJ&pg=PA860 |url-status=live }}</ref><ref name="Academic Press"/>
Venlafaxine interacts with opioid receptors (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) as well as alpha2-adrenergic receptor, and was shown to increase pain threshold in mice. When mice were tested with a hotplate analgesia meter, both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following ip administration. These findings suggest venlafaxine's seemingly superior efficacy in severe depression.<ref>http://www.opioids.com/depression/antidepressants.html</ref>


===Pharmacokinetics=== ===Pharmacokinetics===
Venlafaxine is well absorbed, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the ] ] to ] (''O-desmethylvenlafaxine''), which is just as potent a serotonin-norepinephrine reuptake inhibitor as the parent compound, meaning that the differences in metabolism between extensive and ]s are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in ] poor metabolizers.<ref name="JCPT JClinPharmTher2006-shams">{{cite journal |author=Shams ME et al. |title=CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine |journal=J Clin Pharm Ther |volume=31 |issue=5 |pages=493–502 |year=2006 |pmid=16958828 |doi=10.1111/j.1365-2710.2006.00763.x}}</ref> Steady-state concentrations of venlafaxine and its ] are attained in the ] within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the ].<ref name="Medicinedatasheet-Wyeth">{{cite web |year=2006 |title=Effexor Medicines Data Sheet |publisher=Wyeth Pharmaceuticals Inc |url=http://www.wyeth.com/content/showlabeling.asp?id=99 |accessdate=17 September 2006}}</ref> The ] of venlafaxine is relatively short, and, therefore, patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in the withdrawal symptoms.<ref name="ANZ JPsych1998-parker">{{cite journal |author=Parker G, Blennerhassett J |title=Withdrawal reactions associated with venlafaxine |journal=Aust N Z J Psychiatry |volume=32 |issue=2 |pages=291–4 |year=1998 |pmid=9588310 |doi=10.3109/00048679809062742}}</ref> Venlafaxine is well absorbed, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the ] ] to ] (''O''-desmethylvenlafaxine, now marketed as a separate medication named Pristiq<ref>{{cite journal | vauthors = Pae CU | title = Desvenlafaxine in the treatment of major depressive disorder | journal = Expert Opinion on Pharmacotherapy | volume = 12 | issue = 18 | pages = 2923–2928 | date = December 2011 | pmid = 22098230 | doi = 10.1517/14656566.2011.636033 | s2cid = 33558428 }}</ref>), which is just as potent an SNRI as the parent compound, meaning that the differences in metabolism between extensive and ]s are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in ] poor metabolisers.<ref name="JCPT JClinPharmTher2006-shams">{{cite journal | vauthors = Shams ME, Arneth B, Hiemke C, Dragicevic A, Müller MJ, Kaiser R, Lackner K, Härtter S | title = CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 31 | issue = 5 | pages = 493–502 | date = October 2006 | pmid = 16958828 | doi = 10.1111/j.1365-2710.2006.00763.x | s2cid = 22236102 | doi-access = free }}</ref><ref>{{cite book | title=Medical Genetics Summaries | chapter=Venlafaxine Therapy and CYP2D6 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK305561/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=] (NCBI) | year=2015 | pmid=28520361 | id=Bookshelf ID: NBK305561 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=7 February 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }}</ref> Steady-state concentrations of venlafaxine and its ] are attained in the ] within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the ].<ref name="Effexor FDA label" /> The ] of venlafaxine is relatively short, so patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in withdrawal symptoms.<ref name="ANZ JPsych1998-parker">{{cite journal | vauthors = Parker G, Blennerhassett J | title = Withdrawal reactions associated with venlafaxine | journal = The Australian and New Zealand Journal of Psychiatry | volume = 32 | issue = 2 | pages = 291–294 | date = April 1998 | pmid = 9588310 | doi = 10.3109/00048679809062742 | s2cid = 34824025 }}</ref>


Venlafaxine is a substrate of ] (P-gp), which pumps it out of the brain. ABCB1, the gene encoding P-gp, has the ] rs2032583, with ]s C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant.<ref name="snpedia '583">{{cite web |url=http://www.snpedia.com/index.php/Rs2032583 |title=Rs2032583 - SNPedia}}</ref> A 2007 study<ref name="Neuron: ABCB1">{{cite doi|10.1016/j.neuron.2007.11.017}}</ref> found that carriers of at least one C allele (variant CC or CT) are 7.72 times more likely than non-carriers to achieve ] after 4 weeks of treatment with ], ], ] or venlafaxine (all P-gp substrates). The study included patients with ]s other than ], such as ]; the ratio is 9.4 if these other disorders are excluded. At the 6-week mark, 75% of C-carriers had remitted, compared to only 38% of non-carriers. Venlafaxine is a substrate of ] (P-gp), which pumps it out of the brain. The gene encoding P-gp, ABCB1, has the ] rs2032583, with ]s C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant.<ref name="snpedia '583">{{cite web |url=http://www.snpedia.com/index.php/Rs2032583 |title=Rs2032583 -SNPedia |publisher=Snpedia.com |access-date=21 November 2013 |archive-date=11 December 2013 |archive-url=https://web.archive.org/web/20131211083916/http://www.snpedia.com/index.php/Rs2032583 |url-status=live }}</ref>{{unreliable source?|date=December 2013}} A 2007 study<ref name="Neuron: ABCB1">{{cite journal | vauthors = Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, Dose T, Ebinger M, Rosenhagen M, Kohli M, Kloiber S, Salyakina D, Bettecken T, Specht M, Pütz B, Binder EB, Müller-Myhsok B, Holsboer F | title = Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression | journal = Neuron | volume = 57 | issue = 2 | pages = 203–209 | date = January 2008 | pmid = 18215618 | doi = 10.1016/j.neuron.2007.11.017 | s2cid = 6772775 | doi-access = free }}</ref> found that carriers of at least one C allele (variant CC or CT) are 7.72 times more likely than non-carriers to achieve ] after 4 weeks of treatment with ], ], ] or venlafaxine (all P-gp substrates). The study included patients with ]s other than ], such as ]; the ratio is 9.4 if these other disorders are excluded. At the 6-week mark, 75% of C-carriers had remitted, compared to only 38% of non-carriers.{{citation needed|date=March 2017}}


==Chemistry==
==Physical/chemical properties==
The ] of venlafaxine is designated (R/S)-1- cyclohexanol hydrochloride or (±)-1- p-methoxybenzyl] cyclohexanol hydrochloride, and it has the ] of C<sub>17</sub>H<sub>27</sub>NO<sub>2</sub>. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid ] ], and more distantly the newly-released opioid ], but not to any of the conventional antidepressant drugs, including ]s, SSRIs, MAOIs, or ].<ref name="QJM2003-Whyte">{{cite journal |author=Whyte I, Dawson A, Buckley N |title=Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants |journal=QJM |volume=96 |issue=5 |pages=369–74 |year=2003 |pmid=12702786 |doi=10.1093/qjmed/hcg062}}</ref> The ] of venlafaxine is 1-cyclohexanol, though it is sometimes referred to as (±)-1--''p''-methoxybenzyl]cyclohexanol. It consists of two ]s present in equal quantities (termed a ]), both of which have the ] of C<sub>17</sub>H<sub>27</sub>NO<sub>2</sub>. It is usually sold as a mixture of the respective ] ]s, (''R''/''S'')-1-cyclohexanol hydrochloride, C<sub>17</sub>H<sub>28</sub>ClNO<sub>2</sub>, which is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid ] ], and more distantly to the newly released opioid ], but not to any of the conventional antidepressant drugs, including ]s, ], MAOIs, or ].<ref name="QJM2003-Whyte">{{cite journal | vauthors = Whyte IM, Dawson AH, Buckley NA | title = Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants | journal = QJM | volume = 96 | issue = 5 | pages = 369–374 | date = May 2003 | pmid = 12702786 | doi = 10.1093/qjmed/hcg062 | doi-access = free }}</ref>


Venlafaxine extended-release is chemically the same as normal venlafaxine. The extended-release (controlled release) version distributes the release of the drug into the ] over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended-release formula has a lower incidence of ] as a side effect, resulting in better compliance.<ref>{{cite journal | vauthors = DeVane CL | title = Immediate-release versus controlled-release formulations: pharmacokinetics of newer antidepressants in relation to nausea | journal = The Journal of Clinical Psychiatry | volume = 64 | issue = Suppl 18 | pages = 14–19 | year = 2003 | pmid = 14700450 }}</ref>
==Available forms==
]
]


=== Interactions ===
Effexor is distributed in pentagon-shaped, peach-colored tablets of 25&nbsp;mg, 37.5&nbsp;mg, 50&nbsp;mg, 75&nbsp;mg, and 100&nbsp;mg. There is also an extended-release version distributed in capsules of 37.5&nbsp;mg (gray/peach), 75&nbsp;mg (peach), and 150&nbsp;mg (brownish red).
Venlafaxine should be taken with caution when using ].<ref>{{cite book |title=2006 Lippincott's Nursing Drug Guide |url=https://archive.org/details/2006lippincottsn0000karc |url-access=registration | vauthors = Karch A |year=2006 |publisher=Lippincott Williams & Wilkins |location=Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo |isbn=978-1-58255-436-5}}</ref> Venlafaxine may lower the seizure threshold, and coadministration with other drugs that lower the seizure threshold such as ] and ] should be done with caution and at low doses.<ref name="pmid18072153">{{cite journal | vauthors = Thundiyil JG, Kearney TE, Olson KR | title = Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System | journal = Journal of Medical Toxicology | volume = 3 | issue = 1 | pages = 15–19 | date = March 2007 | pmid = 18072153 | pmc = 3550124 | doi = 10.1007/BF03161033 }}</ref>


==Society and culture==
===Extended release===
=== Recreational use ===
Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release (controlled release) version distributes the release of the drug into the ] over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of patients suffering from ] as a side effect, resulting in a lower number of patients stopping their treatment due to ].<ref>{{cite journal |author=DeVane CL. |title=Immediate-release versus controlled-release formulations: pharmacokinetics of newer antidepressants in relation to nausea |journal=J Clin Psychiatry |volume=64 |issue=Suppl 18 |pages=14–9 |year=2003 |pmid=14700450}}</ref> In Australia, New Zealand and Switzerland, ] sells their venlafaxine XR tablets under the name "Efexor-XR" (note the spelling with one 'f', rather than "Effexor-XR"). In Brazil, Medley sells a venlafaxine XR capsule under the brand name Alenthus XR. In September 2008, Osmotica Pharmaceuticals began marketing venlafaxine extended release tablets in the United States to compete with Wyeth's capsule-form, Effexor-XR. Sales of branded Efexor XR have remained strong, at US$2.7bn.<ref></ref> Teva may begin to offer generic Effexor XR in the US on July 1, 2010, per a settlement agreement with Wyeth, but will have to pay Wyeth a portion of the sale price, driving up the cost.<ref>http://www.wyeth.com/irj/servlet/prt/portal/prtroot/com.sap.km.cm.docs//wyeth_xml/home/news/announcements/1153395074748.pdf (Archived by WebCite at http://www.webcitation.org/5pXQuFykU) p. 3, 4</ref>
Venlafaxine can be abused as a recreational drug, with damages that can manifest within a month.<ref name="pmid30811375">{{cite journal | vauthors = Iliou T, Casta P, Lequeux J, Pochard L, Frauger E, Spadari M, Micallef J | title = Venlafaxine Abuse in a Patient With a History of Methylphenidate Abuse: A Case Report | journal = Journal of Clinical Psychopharmacology | volume = 39 | issue = 2 | pages = 172–174 | date = 2019 | pmid = 30811375 | doi = 10.1097/JCP.0000000000001011 | s2cid = 73496502 }}</ref>
Impax may begin to offer generic Effexor XR in the US on July 1, 2011, per a settlement agreement with Wyeth, but, like Teva, will have to pay Wyeth a portion of the sale price.<ref>http://www.wyeth.com/irj/portal/news/archive?nav=display&navTo=/wyeth_html/home/news/pressreleases/2008/1216240549738.html</ref>


===Generic=== === Brand names ===
]
Generic venlafaxine is available in the ] as of August 2006 and in Canada as of December 2006 due to patent expiry. Generic forms of the extended-release version have been available in Canada as of January 2007 and currently include Co Venlafaxine XR (Cobalt Pharmaceuticals Inc.), Gen-Venlafaxine XR (Genpharm), Riva-Venlafaxine XR (Laboratoire Riva Inc.), Novo Venlafaxine XR (Novopharm Limited), PMS-Venlafaxine XR (Pharmascience Inc.), Ratio-Venlafaxine XR (ratiopharm), Viepax (in Israel) and Sandoz Venlafaxine XR (Sandoz Canada Inc.). Generic versions of both drug forms are available now in India. Generic versions are also available in the UK such as Vaxalin manufactured by RatioPharm GmbH.<ref>http://www.mhra.gov.uk/home/groups/l-reg/documents/licensing/con025694.pdf</ref> On May 7, 2010 the Canadian pharmaceutical company ] announced that the FDA had accepted its filing for a generic version of Venlafaxine XR utilizing its own proprietary technologies.<ref>http://www.intellipharmaceutics.com/releasedetail.cfm?ReleaseID=467633</ref>
]


Venlafaxine was originally marketed as Effexor in most of the world; generic venlafaxine has been available since around 2008 and extended-release venlafaxine has been available since around 2010.<ref>{{cite news| vauthors = Staton T |title=Drugstores accuse Pfizer, Teva of blocking Effexor generics|url=http://www.fiercepharma.com/sales-and-marketing/drugstores-accuse-pfizer-teva-of-blocking-effexor-generics|work=FiercePharma|date=13 June 2012|access-date=22 June 2017|archive-date=26 November 2020|archive-url=https://web.archive.org/web/20201126124935/https://www.fiercepharma.com/sales-and-marketing/drugstores-accuse-pfizer-teva-of-blocking-effexor-generics|url-status=live}}</ref>
==References==
;Notes
{{Reflist|2}}


Venlafaxine is sold under many brand names worldwide.<ref name="brands">{{cite web|url=https://www.drugs.com/international/venlafaxine.html|title=Venlafaxine (International)|date=January 2020|website=Drugs.com|access-date=24 January 2020|archive-date=6 September 2020|archive-url=https://web.archive.org/web/20200906074924/https://www.drugs.com/international/venlafaxine.html|url-status=live}}</ref> In some countries, Effexor is marketed by ] after Upjohn was spun off from Pfizer.<ref>{{cite press release | title=Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan | publisher=Pfizer | via=Business Wire | date=16 November 2020 | url=https://www.businesswire.com/news/home/20201116005378/en/ | access-date=17 June 2024}}</ref><ref>{{cite web | title=Brands | website=Viatris | date=16 November 2020 | url=https://www.viatris.com/en/products/brands | access-date=17 June 2024}}</ref>
==External links==
;Drug information
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== Veterinary uses ==
;Diagnostic tools
Veterinary overdose in ]s is very well treated by ] HCl.<ref name="Gupta-2012">{{cite book | edition=2 | year=2012 | publisher=] | publication-place=] ] | veditors = Gupta RC | title=Veterinary Toxicology : Basic and Clinical Principles | isbn=978-0-12-385926-6 | oclc=794491298 | pages=xii+1438}}</ref>{{rp|page=1371}}
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Venlafaxine is highly toxic to ] and ] phytoplankton.<ref name="Runoff">{{cite journal | vauthors = Chia MA, Lorenzi AS, Ameh I, Dauda S, Cordeiro-Araújo MK, Agee JT, Okpanachi IY, Adesalu AT | title = Susceptibility of phytoplankton to the increasing presence of active pharmaceutical ingredients (APIs) in the aquatic environment: A review | journal = Aquatic Toxicology | volume = 234 | pages = 105809 | date = May 2021 | pmid = 33780670 | doi = 10.1016/j.aquatox.2021.105809 | publisher = ] | bibcode = 2021AqTox.23405809C | s2cid = 232419482 }}</ref> Cats are drawn to the smell of venlafaxine and tend to ingest the pills, which is highly toxic to them.<ref>{{cite web |title=The Top 5 Cat Toxins |url=https://www.pethealthnetwork.com/cat-health/cat-toxins-poisons/top-5-cat-toxins |access-date=3 May 2023 |website=Pet Health Network |language=en}}</ref>
===Patient experiences===
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== References ==
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{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | title=Medical Genetics Summaries | chapter=Venlafaxine Therapy and CYP2D6 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK305561/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=] (NCBI) | date=July 2015 | pmid=28520361 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}
{{refend}}


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