View source for Tramadol

{{Short description|Opioid pain medication}}
{{Use American English|date=February 2024}}
{{Use dmy dates|date=February 2024}}
{{CS1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 451973921
| image = Tramadol as a racemic mixture.svg
| image_class = skin-invert-image
| width = 250
| alt = 
| caption = 
| width2 = 200
| alt2 = 
| imageL = (1S,2S)-Tramadol molecule ball.png
| altL = 
| imageR = (1R,2R)-Tramadol molecule spacefill.png
| altR = 

<!-- Clinical data -->
| pronounce = /ˈtræməˌdɒl/
| tradename = Tramal, others<ref name=generics/>
| Drugs.com = {{drugs.com|monograph|tramadol-hydrochloride}}
| MedlinePlus = a695011
| DailyMedID = Tramadol
| pregnancy_AU = C
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web |title=Tramadol Use During Pregnancy |website=Drugs.com |date=14 October 2019 |url=https://www.drugs.com/pregnancy/tramadol.html |access-date=7 February 2020 |url-status=live |archive-url=https://web.archive.org/web/20200413050449/https://www.drugs.com/pregnancy/tramadol.html |archive-date=13 April 2020}}</ref>
| pregnancy_category = 
| routes_of_administration = [[Oral administration|By mouth]], [[intravenous]], [[intramuscular]], [[rectal administration|rectal]]
| class = {{plainlist|
*[[Opioid]];<ref name="MedlinePlus"/>
*[[Serotonin–norepinephrine reuptake inhibitor]]}}
| ATC_prefix = N02
| ATC_suffix = AX02
| ATC_supplemental = {{ATC|N02|AJ13}}

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Tramadol Lupin tramadol hydrochloride 50 mg capsule blister pack (441970) | website=Therapeutic Goods Administration (TGA) | date=3 August 2024 | url=https://www.tga.gov.au/resources/artg/441970 | access-date=12 April 2025}}</ref>
| legal_BR = A2
| 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 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023 |url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |access-date=3 August 2023 |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}}</ref>
| legal_CA = Schedule I
| legal_CA_comment = <ref>{{cite web |title=Ralivia Product information |website=Health Canada |date=25 April 2012 |url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=78458 |access-date=3 July 2022 |url-status=live |archive-url=https://web.archive.org/web/20210508123729/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=78458 |archive-date=8 May 2021}}</ref>
| legal_DE = <!-- Anlage I, II, III, or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = Class C
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = /{{nbsp}}Class C<ref name="Tramadol SmPC">{{cite web | title=Summary of Product Characteristics (SmPC) | website=(emc) | date=4 July 2024 | url=https://www.medicines.org.uk/emc/product/7123/smpc | access-date=7 January 2025}}</ref><ref name="UK scheduling" />
| legal_US = Schedule IV
| legal_US_comment = <ref name="Ultram FDA label">{{cite web |title=Ultram- tramadol hydrochloride tablet, coated |website=DailyMed |date=7 June 2022 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=45f59e6f-1794-40a4-8f8b-3a9415924468 |access-date=3 July 2022 |url-status=live |archive-url=https://web.archive.org/web/20211201045354/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=45f59e6f-1794-40a4-8f8b-3a9415924468 |archive-date=1 December 2021}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web |title=List of nationally authorized medicinal products |publisher=European Medicines Agency |date=28 January 2021 |url=https://www.ema.europa.eu/en/documents/psusa/tramadol-list-nationally-authorised-medicinal-products-psusa00003002202005_en.pdf |access-date=10 April 2024 |url-status=live |archive-url=https://web.archive.org/web/20210715150111/https://www.ema.europa.eu/en/documents/psusa/tramadol-list-nationally-authorised-medicinal-products-psusa/00003002/202005_en.pdf |archive-date=15 July 2021}}</ref>
| legal_UN = Unscheduled<!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability = 68% (by mouth),<ref name="FiresteinBudd2016">{{cite book| vauthors= Polsten GR, Wallace MS | chapter = Analgesic Agents in Rheumatic Disease | veditors = Firestein GS, Budd R, Gabriel SE, McInnes IB, O'Dell JR |title=Kelley and Firestein's Textbook of Rheumatology | chapter-url = https://books.google.com/books?id=kBZ6DAAAQBAJ&pg=PA1081 |date=21 June 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-41494-4|pages=1081–}}</ref> 77% (rectal), 100% (IM)<ref name=MD>{{cite web |title=Tramadol Hydrochloride |work=Martindale: The Complete Drug Reference |publisher=Pharmaceutical Press |date=13 December 2013 | veditors = Brayfield A |url= https://www.medicinescomplete.com/mc/martindale/current/6263-c.htm |access-date=5 April 2014 |url-status=live |archive-url=https://web.archive.org/web/20210829092614/https://about.medicinescomplete.com/wp-content/plugins/revslider/public/assets/js/extensions/revolution.extension.slideanims.min.js?version=5.4.5 |archive-date=29 August 2021}}</ref>
| protein_bound = 20%<ref name=AHFS2014/>
| metabolism = [[Liver]]-mediated [[demethylation]] and [[glucuronidation]] via [[CYP2D6]] & [[CYP3A4]]<ref name=MD/><ref name=MSR/>
| metabolites = [[O-desmethyltramadol]]<br>N-desmethyltramadol
| onset = < 1 hour (by mouth)<ref name=AHFS2014/>
| elimination_half-life = 6.3 ± 1.4&nbsp;h<ref name=MSR>{{cite web |title=Ultram, Ultram ER (tramadol) dosing, indications, interactions, adverse effects, and more |work=Medscape Reference |publisher=WebMD |url=https://reference.medscape.com/drug/ultram-conzip-tramadol-343324#showall |access-date=10 April 2024 |url-status=live |archive-url=https://web.archive.org/web/20131203022453/http://reference.medscape.com/drug/ultram-er-tramadol-343324#showall |archive-date=3 December 2013}}</ref>
| duration_of_action = 6 hours<ref name="Pharmacology of tramadol">{{cite journal |vauthors=Dayer P, Desmeules J, Collart L |title=[Pharmacology of tramadol] |journal=Drugs |volume=53 |issue=Suppl 2 |pages=18–24 |date=1997 |doi=10.2165/00003495-199700532-00006 |pmid=9190321 |s2cid=46970093}}</ref>
| excretion = Urine (95%)<ref name=TGAIR>{{cite web |title=Australian Label: Tramadol Sandoz 50 mg capsules |publisher=TGA eBusiness Services |date=4 November 2011 |format=PDF |url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03844-3 |access-date=6 April 2014 |url-status=live |archive-url=https://web.archive.org/web/20160801015150/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03844-3 |archive-date=1 August 2016}}</ref>
<!-- Identifiers -->| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 27203-92-5
| CAS_supplemental = 
| PubChem = 33741
| IUPHAR_ligand = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00193
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 31105
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 39J1LGJ30J
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08623
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D01355
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 9648
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1066
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = <!-- Chemical and physical data -->
| IUPAC_name = 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol
| C = 16
| H = 25
| N = 1
| O = 2
| SMILES = CN(C)C[C@H]1CCCC[C@@]1(C2=CC(=CC=C2)OC)O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H25NO2/c1-17(2)12-14-7-4-5-10-16(14,18)13-8-6-9-15(11-13)19-3/h6,8-9,11,14,18H,4-5,7,10,12H2,1-3H3/t14-,16+/m1/s1
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = TVYLLZQTGLZFBW-ZBFHGGJFSA-N
| density = 
| density_notes = 
| melting_point = 180
| melting_high = 181
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Tramadol''', sold under the brand name '''Tramal''' among others,<ref name=PHR2009/><ref name=generics/> is an [[opioid]] [[analgesic|pain medication]] and a [[serotonin–norepinephrine reuptake inhibitor]] (SNRI) used to treat moderately severe [[pain]].<ref name=AHFS2014>{{cite web |title=Tramadol Hydrochloride |publisher=The American Society of Health-System Pharmacists |url=https://www.drugs.com/monograph/tramadol.html |access-date=10 April 2024 |url-status=live |archive-url=https://web.archive.org/web/20201112015421/https://www.drugs.com/monograph/tramadol-hydrochloride.html |archive-date=12 November 2020}}</ref><ref name="PHR2009"/> When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour.<ref name=AHFS2014/> It is also available by injection.<ref name=BNF74>{{cite book |title=British national formulary: BNF 74 |date=2017 |publisher=British Medical Association |isbn=978-0857112989 |pages=447–448 |edition=74}}</ref> It is available in combination with [[paracetamol]] (acetaminophen).

<!-- Side effects and mechanism -->
As is typical of opioids, common side effects include [[constipation]], [[pruritis|itchiness]], and [[nausea]].<ref name=AHFS2014/> Serious side effects may include [[hallucination]]s, [[seizure]]s, increased risk of [[serotonin syndrome]], decreased alertness, and [[drug addiction]].<ref name=AHFS2014/> A change in dosage may be recommended in those with [[chronic kidney disease|kidney]] or liver problems.<ref name=AHFS2014/> It is not recommended in those who are at risk of [[suicide]] or in those who are [[pregnant]].<ref name=AHFS2014/><ref name=BNF74/> While not recommended in women who are [[breastfeeding]], those who take a single dose should not generally have to stop breastfeeding.<ref>{{cite web |title=Tramadol Pregnancy and Breastfeeding Warnings |website=Drugs.com |url=https://www.drugs.com/pregnancy/tramadol.html |access-date=5 September 2016 |url-status=live |archive-url=https://web.archive.org/web/20200413050449/https://www.drugs.com/pregnancy/tramadol.html |archive-date=13 April 2020}}</ref> Tramadol is converted in the liver to [[O-desmethyltramadol|''O''-desmethyltramadol (desmetramadol)]], an opioid with a stronger affinity for the [[μ-opioid receptor]].<ref name=AHFS2014/><ref name=Raf2012>{{cite journal |vauthors=Raffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM, Hertrampf T, Kögel B, Schiene K, Straßburger W, Terlinden R, Tzschentke TM |title=Mechanistic and functional differentiation of tapentadol and tramadol |journal=Expert Opinion on Pharmacotherapy |volume=13 |issue=10 |pages=1437–1449 |date=July 2012 |doi=10.1517/14656566.2012.696097 |pmid=22698264 |s2cid=24226747}}</ref>

Tramadol was patented in 1972 and launched under the brand name Tramal in 1977 by the West German [[pharmaceutical company]] [[Grünenthal|Grünenthal GmbH]].<ref name=PHR2009/><ref name=Fis2006>{{cite book |vauthors=Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=528 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA528 |access-date=3 September 2020 |url-status=live |archive-url=https://web.archive.org/web/20210829111648/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA528 |archive-date=29 August 2021}}</ref> In the mid-1990s, it was approved in the United Kingdom and the United States.<ref name=PHR2009>{{cite journal |vauthors=Leppert W |title=Tramadol as an analgesic for mild to moderate cancer pain |journal=Pharmacological Reports |volume=61 |issue=6 |pages=978–992 |date=November–December 2009 |doi=10.1016/s1734-1140(09)70159-8 |pmid=20081232 |s2cid=4731268}}</ref> It is available as a [[generic medication]] and marketed under many brand names worldwide.<ref name=generics>{{cite web |title=Tramadol |website=Drugs.com |url=https://www.drugs.com/international/tramadol.html |access-date=22 December 2018 |url-status=live |archive-url=https://web.archive.org/web/20180723182517/https://www.drugs.com/international/tramadol.html |archive-date=23 July 2018}}</ref><ref name=AHFS2014/> In 2022, it was the 55th most commonly prescribed medication in the United States, with more than 12{{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 = Tramadol Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Tramadol | access-date = 30 August 2024 }}</ref>
{{TOC limit}}

==Medical uses==
[[File:50 mg Tramadol HCl tablets (generic Ultram) marketed by Amneal Pharmaceuticals (rotated).jpg|thumb|Generic tramadol HCl tablets marketed by Amneal Pharmaceuticals]]
[[File:Tramadol HCl.jpg|thumb|Tramadol HCl for injection]]

Tramadol is used primarily to treat mild to severe pain, both acute and chronic.<ref name=AMH/><ref name="pmid15509185">{{cite journal |vauthors=Grond S, Sablotzki A |title=Clinical pharmacology of tramadol |journal=Clinical Pharmacokinetics |volume=43 |issue=13 |pages=879–923 |year=2004 |doi=10.2165/00003088-200443130-00004 |pmid=15509185 |s2cid=32347667}}</ref> There is moderate evidence for use as a second-line treatment for [[fibromyalgia]], but it is not [[FDA]]-approved for this use.<ref name=Mac2015>{{cite journal |vauthors=MacLean AJ, Schwartz TL |title=Tramadol for the treatment of fibromyalgia |journal=Expert Review of Neurotherapeutics |volume=15 |issue=5 |pages=469–475 |date=May 2015 |doi=10.1586/14737175.2015.1034693 |pmid=25896486 |s2cid=26613022}}</ref> Its use is approved for treatment of fibromyalgia as a secondary [[analgesic|painkiller]] by the [[National Health Service|NHS]].<ref>{{cite web |author=<!--Not stated--> |date=20 February 2019 |title=Treatment – Fibromyalgia (NHS) |website=NHS |url=https://www.nhs.uk/conditions/fibromyalgia/treatment/ |access-date=4 September 2020 |url-status=live |archive-url=https://web.archive.org/web/20200904005917/https://www.nhs.uk/conditions/fibromyalgia/treatment/ |archive-date=4 September 2020}}</ref>

Its [[analgesic]] effects take approximately an hour to be realized, and it takes from two to four hours to reach peak effect after oral administration with an immediate-release formulation.<ref name=AMH/><ref name="pmid15509185"/> On a dose-by-dose basis, tramadol has about one-tenth the potency of [[morphine]] (thus 100&nbsp;mg is commensurate with 10&nbsp;mg morphine but may vary) and is practically equally potent when compared with [[pethidine]] and [[codeine]].<ref name="pmid7691519">{{cite journal |vauthors=Lee CR, McTavish D, Sorkin EM |title=Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states |journal=Drugs |volume=46 |issue=2 |pages=313–340 |date=August 1993 |doi=10.2165/00003495-199346020-00008 |pmid=7691519 |s2cid=218465760}}</ref> For moderate pain, its effectiveness is roughly equivalent to that of codeine in low doses and [[hydrocodone]] at very high doses. For severe pain, it is less effective than morphine.<ref name="AMH"/>

Pain-reducing effects last approximately six hours. The potency of analgesia varies considerably as it depends on an individual's genetics. People with specific variants of [[CYP2D6]] enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control.<ref name="TGAIR"/><ref name="AMH"/>

Sleep medicine physicians sometimes prescribe tramadol (or other opioid medications) for [[disease#Refractory disease|refractory]] [[restless legs syndrome]] (RLS);<ref>{{cite journal |vauthors=Silber MH, Becker PM, Buchfuhrer MJ, Earley CJ, Ondo WG, Walters AS, Winkelman JW |title=The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome |journal=Mayo Clinic Proceedings |volume=93 |issue=1 |pages=59–67 |date=January 2018 |doi=10.1016/j.mayocp.2017.11.007 |doi-access=free |pmid=29304922 |quote=In summary, a number of opioid medications in low dose appear effective in refractory RLS. The risks of opioid use are relatively low, taking into account the much lower doses used for RLS compared with those in patients with pain syndromes. As long as reasonable precautions are taken, the risk-benefit ratio is acceptable and opioids should not be unreasonably withheld from such patients.}}</ref><ref>{{cite journal |vauthors=Winkelmann J, Allen RP, Högl B, Inoue Y, Oertel W, Salminen AV, Winkelman JW, Trenkwalder C, Sampaio C |title=Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)<sup>§</sup> |journal=Movement Disorders |volume=33 |issue=7 |pages=1077–1091 |date=July 2018 |doi=10.1002/mds.27260 |pmid=29756335 |s2cid=21669996 |url=https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=54361 |access-date=13 December 2021 |url-status=live |archive-url=https://web.archive.org/web/20220703052408/https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=54361 |archive-date=3 July 2022|url-access=subscription }}</ref> that is, RLS that does not respond adequately to treatment with first-line medications such as [[dopamine agonists]] (e.g., [[pramipexole]]) or [[gabapentinoid]]s, often due to augmentation.<ref>{{cite journal |vauthors=Lipford MC, Silber MH |title=Long-term use of pramipexole in the management of restless legs syndrome |journal=Sleep Medicine |volume=13 |issue=10 |pages=1280–1285 |date=December 2012 |doi=10.1016/j.sleep.2012.08.004 |pmid=23036265 |quote=For the purposes of this study, augmentation was defined as earlier onset, increased severity, [increased] duration, or new anatomic distribution of RLS symptoms during treatment.}}</ref>

==Contraindications==
===Pregnancy and lactation===
Use of tramadol during [[pregnancy]] is generally avoided, as it may cause some reversible withdrawal effects in the newborn.<ref name="pregrev">{{cite journal |vauthors=Bloor M, Paech MJ, Kaye R |title=Tramadol in pregnancy and lactation |journal=International Journal of Obstetric Anesthesia |volume=21 |issue=2 |pages=163–167 |date=April 2012 |doi=10.1016/j.ijoa.2011.10.008 |pmid=22317891}}</ref> A small prospective study in France found, while an increased risk of [[miscarriage]]s existed, no major malformations were reported in the newborn.<ref name=pregrev/> Its use during [[lactation]] is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. No evidence of this dose harming the newborn was seen.<ref name=pregrev/>

===Labor and delivery===
Its use as an analgesic during labor is not advised due to its long onset of action (1 hour).<ref name=pregrev/> The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labor pains has been estimated to be 1:94.<ref name=pregrev/>

===Children===
Its use in children is generally advised against, although it may be done under the supervision of a specialist.<ref name=AMH/> On 21 September 2015, the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing.<ref>{{cite web |title=FDA Drug Safety Communication: FDA evaluating the risks of using the pain medicine tramadol in children aged 17 and younger |website=FDA |publisher=FDA Drug Safety and Availability |url=https://www.fda.gov/Drugs/DrugSafety/ucm462991.htm |access-date=21 September 2015 |url-status=dead |archive-url=https://web.archive.org/web/20150923222101/http://www.fda.gov/Drugs/DrugSafety/ucm462991.htm |archive-date=23 September 2015}}</ref> The FDA lists age under 12 years old as a contraindication.<ref>{{cite web |author=Office of the Commissioner |title=Press Announcements – FDA statement from Douglas Throckmorton, M.D., deputy center director for regulatory programs, Center for Drug Evaluation and Research, on new warnings about the use of codeine and tramadol in children & nursing mothers |website=fda.gov |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm553285.htm |access-date=21 April 2017 |url-status=dead |archive-url=https://web.archive.org/web/20170420225410/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm553285.htm |archive-date=20 April 2017}}</ref><ref>{{cite web |title=FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women |publisher=Food and Drug Administration |date=9 February 2019 |url=https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm |access-date=9 May 2017 |url-status=dead |archive-url=https://web.archive.org/web/20190423133633/https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm |archive-date=23 April 2019}}</ref>

===Elderly===
The risk of opioid-related adverse effects such as [[hypoventilation|respiratory depression]], falls, cognitive impairment, and sedation is increased.<ref name=AMH/> Tramadol may interact with other medications and increase the risk for adverse events.<ref name=":1">{{cite journal |author2-link=Arthur K. Cho |vauthors=Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R |date=January 2017 |title=Trends in Tramadol: Pharmacology, Metabolism, and Misuse |journal=Anesthesia and Analgesia |volume=124 |issue=1 |pages=44–51 |doi=10.1213/ANE.0000000000001683 |pmid=27861439 |s2cid=24224625}}</ref>

===Liver and kidney failure===
The drug should be used with caution in those with liver or kidney failure, due to metabolism in the liver (to the active molecule desmetramadol) and elimination by the kidneys.<ref name=AMH/>

==Side effects==
{{Main|List of side effects of tramadol}}
The most common [[adverse effect]]s of tramadol include [[nausea]], [[dizziness]], [[xerostomia|dry mouth]], [[indigestion]], abdominal pain, [[vertigo]], [[vomiting]], [[constipation]], drowsiness, and [[headache]].<ref name="AEP">{{cite journal |vauthors=Langley PC, Patkar AD, Boswell KA, Benson CJ, Schein JR |title=Adverse event profile of tramadol in recent clinical studies of chronic osteoarthritis pain |journal=Current Medical Research and Opinion |volume=26 |issue=1 |pages=239–251 |date=January 2010 |doi=10.1185/03007990903426787 |pmid=19929615 |s2cid=20703694}}</ref><ref name="drugs06">{{cite journal |vauthors=Keating GM |title=Tramadol sustained-release capsules |journal=Drugs |volume=66 |issue=2 |pages=223–230 |year=2006 |doi=10.2165/00003495-200666020-00006 |pmid=16451094 |s2cid=22620947}}</ref> Other side effects may result from interactions with other medications. Tramadol has the same dose-dependent adverse effects as morphine including respiratory depression.<ref>{{cite journal |title="Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine |journal=Prescrire International |volume=25 |issue=168 |pages=45–50 |date=February 2016 |pmid=27042732}}</ref>
[[File:Side effects of Tramadol.png|thumb|280px|right|Main side effects of tramadol: Red color denotes more serious effects, requiring immediate contact with health provider.<ref name="MedlinePlus">{{cite web |title=Tramadol |work=[[MedlinePlus]] |publisher=[[American Society of Health-System Pharmacists]] |date=1 September 2008 |url=https://medlineplus.gov/druginfo/meds/a695011.html |access-date=10 April 2024 |url-status=live |archive-url=https://web.archive.org/web/20090924092832/http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695011.html |archive-date=24 September 2009}}</ref>]]

===Dependence and withdrawal===
Long-term use of high doses of tramadol causes [[physical dependence]] and withdrawal syndrome.<ref name="pmid12825576">{{cite journal |title=Withdrawal syndrome and dependence: tramadol too |journal=Prescrire International |volume=12 |issue=65 |pages=99–100 |date=June 2003 |pmid=12825576}}</ref> These include both symptoms typical of [[opioid withdrawal]] and those associated with [[serotonin–norepinephrine reuptake inhibitor]] (SNRI) withdrawal; symptoms include numbness, tingling, [[paresthesia]], and tinnitus.<ref name=BP06>{{cite journal |vauthors=Epstein DH, Preston KL, Jasinski DR |title=Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol |journal=Biological Psychology |volume=73 |issue=1 |pages=90–99 |date=July 2006 |pmc=2943845 |doi=10.1016/j.biopsycho.2006.01.010 |pmid=16497429}}</ref> Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.<ref name="pmid12633909">{{cite journal |vauthors=Senay EC, Adams EH, Geller A, Inciardi JA, Muñoz A, Schnoll SH, Woody GE, Cicero TJ |title=Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur |journal=Drug and Alcohol Dependence |volume=69 |issue=3 |pages=233–241 |date=April 2003 |citeseerx=10.1.1.524.5426 |doi=10.1016/S0376-8716(02)00321-6 |pmid=12633909}}</ref> In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary.<ref name=BP06/> Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogs.<ref name=BP06/>

==Overdose==
The clinical presentation in overdose cases can vary but typically includes neurological, cardiovascular, and gastrointestinal manifestations.<ref>{{cite journal |vauthors=Marquardt KA, Alsop JA, Albertson TE |title=Tramadol exposures reported to statewide poison control system |journal=The Annals of Pharmacotherapy |volume=39 |issue=6 |pages=1039–1044 |date=June 2005 |doi=10.1345/aph.1e577 |pmid=15870139 |s2cid=20959808}}</ref> The predominant neurological symptoms are [[seizure]]s and altered levels of consciousness, ranging from [[somnolence]] to [[coma]]. Seizures are particularly notable due to tramadol's lowering of the [[seizure threshold]], occurring in approximately half of acute poisoning cases.<ref>{{cite journal |vauthors=Jovanović-Cupić V, Martinović Z, Nesić N |title=Seizures associated with intoxication and abuse of tramadol |journal=Clinical Toxicology |volume=44 |issue=2 |pages=143–146 |date=1 August 2012 |doi=10.1080/1556365050014418 |pmid=16615669 |s2cid=25269342}}</ref> Patients often exhibit [[tachycardia]] and mild [[hypertension]]. Gastrointestinal disturbances such as nausea and vomiting are common, and agitation, anxiety, and cold and clammy skin may also be present.<ref>{{cite journal |vauthors=Manouchehri A, Nekoukar Z, Malakian A, Zakariaei Z |title=Tramadol poisoning and its management and complications: a scoping review |journal=Annals of Medicine and Surgery |volume=85 |issue=8 |pages=3982–3989 |date=August 2023 |pmc=10406095 |doi=10.1097/ms9.0000000000001075 |doi-access=free |pmid=37554850}}</ref>

While less common, severe complications like respiratory depression and [[serotonin syndrome]] can occur, particularly in [[polysubstance use|polydrug overdoses]] involving other CNS depressants (such as [[benzodiazepine]]s, opioids, and [[alcohol (drug)|alcohol]]) and agents with [[serotonergic agent|serotonergic]] activity.<ref name=":2">{{cite journal |vauthors=Beakley BD, Kaye AM, Kaye AD |date=14 July 2015 |title=Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review |journal=Pain Physician |volume=18 |issue=4 |pages=395–400 |issn=2150-1149 |doi=10.36076/ppj.2015/18/395 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Ryan NM, Isbister GK |title=Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely |journal=Clinical Toxicology |volume=53 |issue=6 |pages=545–550 |date=July 2015 |doi=10.3109/15563650.2015.1036279 |pmid=25901965 |s2cid=23813622}}</ref> Additionally, individuals with genetic variations leading to [[CYP2D6]] enzyme duplication (rapid metabolizers) may have an increased risk of adverse effects, due to faster conversion of tramadol to its active [[metabolite]].<ref>{{cite journal |vauthors=Taghaddosinejad F, Mehrpour O, Afshari R, Seghatoleslami A, Abdollahi M, Dart RC |title=Factors related to seizure in tramadol poisoning and its blood concentration |journal=Journal of Medical Toxicology |volume=7 |issue=3 |pages=183–188 |date=September 2011 |pmc=3550210 |doi=10.1007/s13181-011-0168-0 |doi-access=free |pmid=21735309}}</ref>

Acute tramadol overdose is generally not life-threatening, with most fatalities resulting from polysubstance overdose.<ref>{{cite journal |vauthors=Nakhaee S, Mehrpour O |title=Tramadol poisoning-associated mortality |journal=Journal of Affective Disorders |volume=255 |pages=187 |date=August 2019 |doi=10.1016/j.jad.2019.04.069 |pmid=30987745 |s2cid=116863581}}</ref> Management includes cardiovascular monitoring, [[activated charcoal (medication)|activated charcoal]] administration, hydration, and treatment of seizures.<ref>{{cite journal |vauthors=Nakhaee S, Hoyte C, Dart RC, Askari M, Lamarine RJ, Mehrpour O |date=24 March 2021 |title=A review on tramadol toxicity: mechanism of action, clinical presentation, and treatment |journal=Forensic Toxicology |volume=39 |issue=2 |pages=293–310 |issn=1860-8965 |doi=10.1007/s11419-020-00569-0 |doi-access=free}}</ref> [[Naloxone]], an opioid antagonist, can partially reverse some effects of tramadol overdose, particularly respiratory depression. However, its use may increase the risk of seizures due to unopposed [[alpha-adrenergic]] stimulation.<ref name="AMH"/> For suspected serotonin syndrome, [[cyproheptadine]], a [[serotonin antagonist]], is considered an effective antidote.<ref name=":2"/>

The incidence of tramadol-related overdose deaths has been on the rise in certain regions. For instance, Northern Ireland has reported an increased frequency of such cases.<ref name="JFLM14">{{cite journal |vauthors=Randall C, Crane J |title=Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012 |journal=Journal of Forensic and Legal Medicine |volume=23 |pages=32–36 |date=March 2014 |doi=10.1016/j.jflm.2014.01.006 |pmid=24661703}}</ref> In 2013, England and Wales recorded 254 tramadol-related deaths, while Florida reported 379 cases in 2011.<ref>{{cite web |title=Tramadol Deaths in the United Kingdom |publisher=Public Health England |format=pdf_e |vauthors=White M |url=https://www.emcdda.europa.eu/system/files/attachments/3236/Martin%20White-UK-Tramadol%20deaths%20in%20the%20United%20Kingdom%20EMCDDA.pdf_en |access-date=25 February 2018 |url-status=live |archive-url=https://web.archive.org/web/20210407011422/https://www.emcdda.europa.eu/system/files/attachments/3236/Martin%20White-UK-Tramadol%20deaths%20in%20the%20United%20Kingdom%20EMCDDA.pdf_en |archive-date=7 April 2021}}</ref><ref>{{cite web |date=22 December 2013 |title=Killing Pain: Tramadol the 'Safe' Drug of Abuse |vauthors=Fauber J |url=https://www.medpagetoday.com/painmanagement/painmanagement/43554 |access-date=28 February 2018 |url-status=live |archive-url=https://web.archive.org/web/20200919094239/https://www.medpagetoday.com/painmanagement/painmanagement/43554 |archive-date=19 September 2020}}</ref> In 2011, 21,649 emergency room visits in the United States were related to tramadol.<ref>{{cite web |date=19 October 2016 |title=Tramadol: The Opioid Crisis for the rest of the World |website=The Wall Street Journal |publisher=Dow Jones & Co |vauthors=Scheck J |url=https://www.wsj.com/articles/tramadol-the-opioid-crisis-for-the-rest-of-the-world-1476887401 |access-date=4 January 2019 |url-status=live |archive-url=https://web.archive.org/web/20200830113252/https://www.wsj.com/articles/tramadol-the-opioid-crisis-for-the-rest-of-the-world-1476887401 |archive-date=30 August 2020}}</ref> The likely explanation for these observations is due to increase in frequency of prescriptions and use due to easier access due to lighter [[drug schedule|regulatory scheduling]] by authorities<ref>{{cite journal |vauthors=Kostev K, Von Vultée C, Usinger DM, Reese JP |title=Tramadol prescription patterns in patients followed by general practitioners and orthopedists in Germany in the year 2015 |journal=Postgraduate Medicine |volume=130 |issue=1 |pages=37–41 |date=January 2018 |doi=10.1080/00325481.2018.1407205 |pmid=29157058 |s2cid=32933111}}</ref> but this is starting to change. In 2021, [[Health Canada]] announced tramadol would be added to Schedule I of the [[Controlled Drugs and Substances Act]] and to the Narcotic Control Regulations due to tramadol being suspected of having contributed to 18 reported deaths in Canada between 2006 and 2017.<ref>{{cite web |publisher=Government of Canada |work=Public Works and Government Services Canada |date=31 March 2021 |title=Canada Gazette, Part 2, Volume 155, Number 7: Regulations Amending the Narcotic Control Regulations (Tramadol) |url=https://canadagazette.gc.ca/rp-pr/p2/2021/2021-03-31/html/sor-dors43-eng.html |access-date=10 November 2023}}</ref>

==Interactions==
[[File:Tramadol capsules - 2022-09-22 - Andy Mabbett.jpg|thumb|Tramadol hydrochloride (50mg) capsules made by Bristol Laboratories and provided by a pharmacy in England]]

Tramadol can have [[pharmacodynamics|pharmacodynamic]], [[pharmacokinetics|pharmacokinetic]], and [[pharmacogenomics|pharmacogenetic]] interactions.

Tramadol is metabolized by [[cytochrome P450|CYP2D6 enzymes]] which contributes to the metabolism of approximately 25% of all medications.<ref>{{cite journal |vauthors=Bernard S, Neville KA, Nguyen AT, Flockhart DA |title=Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications |journal=The Oncologist |volume=11 |issue=2 |pages=126–135 |date=February 2006 |doi=10.1634/theoncologist.11-2-126 |pmid=16476833}}</ref> Any medications with the ability to inhibit or induce these enzymes may interact with tramadol. These include common antiarrhythmics, antiemetics, antidepressants ([[sertraline]], [[paroxetine]], and [[fluoxetine]] in particular),<ref>{{cite web |title=CPIC® Guideline for Serotonin Reuptake Inhibitor Antidepressants and CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A – CPIC |url=https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/ |access-date=23 November 2023}}</ref> antipsychotics, analgesics, and tamoxifen.<ref name="Trends in Tramadol">{{cite journal |vauthors=Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R |title=Trends in Tramadol: Pharmacology, Metabolism, and Misuse |journal=Anesthesia and Analgesia |volume=124 |issue=1 |pages=44–51 |date=January 2017 |doi=10.1213/ANE.0000000000001683 |pmid=27861439 |s2cid=24224625}}</ref>

Due to tramadol's serotonergic effects, tramadol has the potential to contribute to the development of an acute or chronic hyper-serotonin state called [[serotonin syndrome]] when used concurrently with other pro-serotonergic medications such as antidepressants ([[selective serotonin reuptake inhibitor|SSRI]]s, [[serotonin–norepinephrine reuptake inhibitor|SNRIs]], [[tricyclic antidepressant|tricyclics]], [[monoamine oxidase inhibitor|MAOIs]]), [[antipsychotic]]s, [[triptan]]s, cold medications containing [[dextromethorphan]], and some herbal products such as [[St. John's wort]].<ref name="Trends in Tramadol"/><ref>{{cite journal |vauthors=Nelson EM, Philbrick AM |title=Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors |journal=The Annals of Pharmacotherapy |volume=46 |issue=12 |pages=1712–1716 |date=December 2012 |doi=10.1345/aph.1q748 |pmid=23212934 |s2cid=23707808}}</ref>

Concurrent use of [[5-HT3 antagonist]]s such as [[ondansetron]], [[dolasetron]], and [[palonosetron]] may reduce the effectiveness of both drugs.<ref>{{cite journal |vauthors=Stevens AJ, Woodman RJ, Owen H |title=The effect of ondansetron on the efficacy of postoperative tramadol: a systematic review and meta-analysis of a drug interaction |journal=Anaesthesia |volume=70 |issue=2 |pages=209–218 |date=February 2015 |doi=10.1111/anae.12948 |pmid=25490944 |s2cid=38180309}}</ref>

Tramadol also acts as an opioid agonist and thus can increase the risk for side effects when used with other opioid and opioid-containing [[analgesic]]s (such as [[morphine]], [[pethidine]], [[tapentadol]], [[oxycodone]], [[fentanyl]], and [[Tylenol 3]]).<ref name="opioid-combination">{{cite journal |vauthors=Pasternak GW |title=Preclinical pharmacology and opioid combinations |journal=Pain Medicine |volume=13 |issue=1 |pages=S4-11 |date=March 2012 |pmc=3307386 |doi=10.1111/j.1526-4637.2012.01335.x |pmid=22420604}}</ref>

Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold - such as [[antipsychotic|antipsychotic medications]], [[bupropion]] (an anti-depressant and smoking cessation drug), and [[amphetamine]]s - can further increase this risk.<ref>{{cite journal |vauthors=Sansone RA, Sansone LA |title=Tramadol: seizures, serotonin syndrome, and coadministered antidepressants |journal=Psychiatry |volume=6 |issue=4 |pages=17–21 |date=April 2009 |pmc=2714818 |pmid=19724727}}</ref>

==Pharmacology==

===Mechanism of action===
Tramadol induces analgesic effects through a variety of different targets on the [[norepinephrine|noradrenergic system]], [[serotonin|serotonergic system]], and [[opioid receptor]]s system.<ref>{{cite book |vauthors=Hitchings A, Lonsdale D, Burrage D, Baker E |title=Top 100 drugs: clinical pharmacology and practical prescribing |date=2015 |publisher=Churchill Livingstone Elsevier |isbn=978-0-7020-5516-4 |pages=168–169}}</ref> Tramadol affects serotonin and norepinephrine reuptake inhibition similarly to certain antidepressants known as serotonin–norepinephrine reuptake inhibitors (SNRIs), such as [[venlafaxine]] and [[duloxetine]].<ref name="pmid38797485">{{cite journal |vauthors=Kokilambigai KS, Irina VM, Sheba Mariam KC, Adila K, Kathirvel S |title=Comprehensive overview of analytical and bioanalytical methodologies for the opioid analgesics - Tramadol and combinations |journal=Anal Biochem |volume=692 |issue= |pages=115579 |date=September 2024 |pmid=38797485 |doi=10.1016/j.ab.2024.115579 |url=}}</ref> Tramadol exists as a [[racemic mixture]], the positive [[enantiomer]] inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters.<ref name="pmid25776506">{{cite journal |vauthors=Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia ML, Silva AM, Souto EB |title=Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems |journal=Biomedicine & Pharmacotherapy |volume=70 |pages=234–238 |date=March 2015 |doi=10.1016/j.biopha.2015.01.022 |doi-access=free |pmid=25776506}}</ref><ref name="Pharmacology of tramadol"/> Both enantiomers of tramadol are agonists of the [[m-opioid receptor|μ-opioid receptor]] and its M1 metabolite, O-[[desmetramadol]], is also a μ-opioid receptor agonist but is 6 times more potent than tramadol itself.<ref>{{cite web |title=Tramadol |website=drugbank.ca |url=https://www.drugbank.ca/drugs/DB00193 |access-date=21 January 2019 |url-status=live |archive-url=https://web.archive.org/web/20190528121148/https://www.drugbank.ca/drugs/DB00193 |archive-date=28 May 2019}}</ref> All of these actions may work synergistically to induce analgesia.

{| class="wikitable floatright" style="font-size:small;"
|+ Tramadol (and metabolite)<ref name="PDSP">{{cite web |title=PDSP K<sub>i</sub> Database |work=Psychoactive Drug Screening Program (PDSP) |vauthors=Roth BL, Driscol J |author1-link=Bryan Roth |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |url=https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testDDRadio=testDDRadio&testLigandDD=4928&testLigand=&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query |access-date=14 August 2017 |url-status=live |archive-url=https://web.archive.org/web/20210829092605/https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testDDRadio=testDDRadio&testLigandDD=4928&testLigand=&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query |archive-date=29 August 2021}}</ref><ref name="pmid17380034">{{cite journal |vauthors=Minami K, Uezono Y, Ueta Y |title=Pharmacological aspects of the effects of tramadol on G-protein coupled receptors |journal=Journal of Pharmacological Sciences |volume=103 |issue=3 |pages=253–260 |date=March 2007 |doi=10.1254/jphs.cr0060032 |doi-access=free |pmid=17380034}}</ref><ref name="pmid26292636">{{cite journal |vauthors=Minami K, Ogata J, Uezono Y |title=What is the main mechanism of tramadol? |journal=Naunyn-Schmiedeberg's Archives of Pharmacology |volume=388 |issue=10 |pages=999–1007 |date=October 2015 |doi=10.1007/s00210-015-1167-5 |pmid=26292636 |s2cid=9066672}}</ref>
|-
! Site !! Tramadol !! {{abbrlink|DSMT|Desmetramadol}} !! Species !! Ref
|-
| {{abbrlink|MOR|μ-Opioid receptor}} || 1,600–12,486<br>2,120–8,300<br>≥1,000 ([[EC50|EC<sub>50</sub>]]) || 5.4–18.6<br>17 ({{abbr|(+)|(+)-desmetramadol}})<br>≥240 (EC<sub>50</sub>) || Human<br>Rat<br>Human || <ref name="pmid19027293">{{cite journal |vauthors=Wentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM |title=Syntheses and opioid receptor binding properties of carboxamido-substituted opioids |journal=Bioorganic & Medicinal Chemistry Letters |volume=19 |issue=1 |pages=203–208 |date=January 2009 |doi=10.1016/j.bmcl.2008.10.134 |pmid=19027293}}</ref><ref name="pmid27096047">{{cite journal |vauthors=Shen Q, Qian Y, Huang X, Xu X, Li W, Liu J, Fu W |title=Discovery of Potent and Selective Agonists of δ Opioid Receptor by Revisiting the "Message-Address" Concept |journal=ACS Medicinal Chemistry Letters |volume=7 |issue=4 |pages=391–396 |date=April 2016 |pmc=4834657 |doi=10.1021/acsmedchemlett.5b00423 |pmid=27096047}}</ref><ref name="pmid21215785">{{cite journal |vauthors=Volpe DA, McMahon Tobin GA, Mellon RD, Katki AG, Parker RJ, Colatsky T, Kropp TJ, Verbois SL |title=Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs |journal=Regulatory Toxicology and Pharmacology |volume=59 |issue=3 |pages=385–390 |date=April 2011 |doi=10.1016/j.yrtph.2010.12.007 |pmid=21215785 |url=https://zenodo.org/record/1259503 |access-date=1 July 2019 |url-status=live |archive-url=https://web.archive.org/web/20210829092607/https://zenodo.org/record/1259503/preview/article.pdf |archive-date=29 August 2021}}</ref><br><ref name="pmid10991912"/><ref name="pmid7562497"/><br><ref name="pmid10961373">{{cite journal |vauthors=Gillen C, Haurand M, Kobelt DJ, Wnendt S |title=Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor |journal=Naunyn-Schmiedeberg's Archives of Pharmacology |volume=362 |issue=2 |pages=116–121 |date=August 2000 |doi=10.1007/s002100000266 |pmid=10961373 |s2cid=10459734}}</ref><ref name=Raf2012/>
|-
| {{abbrlink|DOR|δ-Opioid receptor}} || >10,000<br>57,600–100,000 || ≥2,900<br>690 {{abbr|(+)|(+)-desmetramadol}}) || Human<br>Rat || <ref name="pmid19027293"/><ref name="pmid27096047"/><ref name="pmid8955860"/><br><ref name="pmid7562497"/><ref name="pmid10991912"/>
|-
| {{abbrlink|KOR|κ-Opioid receptor}} || >10,000<br>42,700–81,000 || ≥450<br>1,800 {{abbr|(+)|(+)-desmetramadol}}) || Human<br>Rat || <ref name="pmid19027293"/><ref name="pmid27096047"/><ref name="pmid8955860"/><br><ref name="pmid7562497"/><ref name="pmid10991912"/>
|-
| {{abbrlink|SERT|Serotonin transporter}} || ~900 ([[IC50|IC<sub>50</sub>]])<br>992–1,190 || >20,000 (IC<sub>50</sub>)<br>2,980 ({{abbr|(−)|(−)-desmetramadol}}) (IC<sub>50</sub>) || Human<br>Rat || <ref name="pmid16427041">{{cite journal |vauthors=Barann M, Urban B, Stamer U, Dorner Z, Bönisch H, Brüss M |title=Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis |journal=European Journal of Pharmacology |volume=531 |issue=1–3 |pages=54–58 |date=February 2006 |doi=10.1016/j.ejphar.2005.11.054 |pmid=16427041}}</ref><br><ref name="pmid7562497">{{cite journal |vauthors=Codd EE, Shank RP, Schupsky JJ, Raffa RB |title=Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=274 |issue=3 |pages=1263–1270 |date=September 1995 |doi=10.1016/S0022-3565(25)10630-7 |pmid=7562497}}</ref><ref name=Raf2012/>
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 14,600<br>785 || 1,080 {{abbr|(−)|(−)-tramadol}} (IC<sub>50</sub>)<br>860 (IC<sub>50</sub>) || Human<br>Rat || <ref name=Raf2012/><br><ref name="pmid7562497"/><ref name=Raf2012/>
|-
| {{abbrlink|DAT|Dopamine transporter}} || >100,000 || >20,000 || Rat || <ref name="pmid1309873">{{cite journal |vauthors=Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL |title=Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=260 |issue=1 |pages=275–285 |date=January 1992 |doi=10.1016/S0022-3565(25)11227-5 |pmid=1309873}}</ref><ref name="pmid8955860">{{cite journal |vauthors=Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B |title=Influence of tramadol on neurotransmitter systems of the rat brain |journal=Arzneimittel-Forschung |volume=46 |issue=11 |pages=1029–1036 |date=November 1996 |pmid=8955860}}</ref>
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || >20,000 || >20,000 || Rat || <ref name="pmid8955860"/>
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || >20,000 || >20,000 || Rat || <ref name="pmid8955860"/>
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 1,000 (IC<sub>50</sub>) || 1,300 (IC<sub>50</sub>) || Rat || <ref name="pmid15105221">{{cite journal |vauthors=Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y |title=The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes |journal=Anesthesia and Analgesia |volume=98 |issue=5 |pages=1401–6, table of contents |date=May 2004 |doi=10.1213/01.ANE.0000108963.77623.A4 |doi-access=free |pmid=15105221 |s2cid=41718739}}</ref><ref name="pmid16679816">{{cite journal |vauthors=Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A |title=The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes |journal=Pharmacology |volume=77 |issue=2 |pages=93–99 |year=2006 |doi=10.1159/000093179 |pmid=16679816 |s2cid=23775035}}</ref>
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || >20,000 || >20,000 || Rat || <ref name="pmid8955860"/>
|-
| [[Tachykinin receptor 1|NK<sub>1</sub>]] || {{abbr|IA|Inactive}} || ? || Rat || <ref name="pmid12818951">{{cite journal |vauthors=Okamoto T, Minami K, Uezono Y, Ogata J, Shiraishi M, Shigematsu A, Ueta Y |title=The inhibitory effects of ketamine and pentobarbital on substance p receptors expressed in Xenopus oocytes |journal=Anesthesia and Analgesia |volume=97 |issue=1 |pages=104–10, table of contents |date=July 2003 |doi=10.1213/01.ANE.0000066260.99680.11 |doi-access=free |pmid=12818951 |s2cid=35809206}}</ref><ref name="pmid21372504">{{cite journal |vauthors=Minami K, Yokoyama T, Ogata J, Uezono Y |title=The tramadol metabolite O-desmethyl tramadol inhibits substance P-receptor functions expressed in Xenopus oocytes |journal=Journal of Pharmacological Sciences |volume=115 |issue=3 |pages=421–424 |year=2011 |doi=10.1254/jphs.10313sc |doi-access=free |pmid=21372504}}</ref>
|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || >20,000<br>3,400 ([[IC50|IC<sub>50</sub>]]) || >20,000<br>2,000 (IC<sub>50</sub>) || Rat<br>Multiple || <ref name="pmid8955860"/><br><ref name="pmid11561087">{{cite journal |vauthors=Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A |title=Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=299 |issue=1 |pages=255–260 |date=October 2001 |doi=10.1016/S0022-3565(24)29325-3 |pmid=11561087}}</ref><ref name="pmid15976229">{{cite journal |vauthors=Nakamura M, Minami K, Uezono Y, Horishita T, Ogata J, Shiraishi M, Okamoto T, Terada T, Sata T |title=The effects of the tramadol metabolite O-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 or M3 receptors |journal=Anesthesia and Analgesia |volume=101 |issue=1 |pages=180–6, table of contents |date=July 2005 |doi=10.1213/01.ANE.0000154303.93909.A3 |doi-access=free |pmid=15976229 |s2cid=23861688}}</ref>
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] || 1,000 (IC<sub>50</sub>) || {{abbr|IA|Inactive}} || Human || <ref name="pmid15976229"/><ref name="pmid12401609">{{cite journal |vauthors=Shiga Y, Minami K, Shiraishi M, Uezono Y, Murasaki O, Kaibara M, Shigematsu A |title=The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors |journal=Anesthesia and Analgesia |volume=95 |issue=5 |pages=1269–73, table of contents |date=November 2002 |doi=10.1097/00000539-200211000-00031 |doi-access=free |pmid=12401609 |s2cid=39621215}}</ref>
|-
| [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[alpha-7 nicotinic receptor|α7]] || 7,400 || {{abbr|ND|No data}} || Chicken || <ref name="pmid12010769">{{cite journal |vauthors=Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I |title=Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha 7 receptors |journal=British Journal of Pharmacology |volume=136 |issue=2 |pages=207–216 |date=May 2002 |pmc=1573343 |doi=10.1038/sj.bjp.0704703 |pmid=12010769}}</ref>
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]] || >10,000 || {{abbr|ND|No data}} || Rat || <ref name="PDSP"/><ref name="pmid24155346">{{cite journal |vauthors=Sánchez-Fernández C, Montilla-García Á, González-Cano R, Nieto FR, Romero L, Artacho-Cordón A, Montes R, Fernández-Pastor B, Merlos M, Baeyens JM, Entrena JM, Cobos EJ |title=Modulation of peripheral μ-opioid analgesia by σ1 receptors |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=348 |issue=1 |pages=32–45 |date=January 2014 |doi=10.1124/jpet.113.208272 |pmid=24155346 |s2cid=6884854}}</ref>
|-
| [[Sigma-2 receptor|σ<sub>2</sub>]] || >10,000 || {{abbr|ND|No data}} || Rat || <ref name="PDSP"/>
|-
| [[NMDA receptor|{{abbr|NMDAR|N-Methyl-D-aspartate receptor}}]] || 16,400 (IC<sub>50</sub>) || 16,500 (IC<sub>50</sub>) || Human || <ref name="pmid15845694">{{cite journal |vauthors=Hara K, Minami K, Sata T |title=The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes |journal=Anesthesia and Analgesia |volume=100 |issue=5 |pages=1400–1405 |date=May 2005 |doi=10.1213/01.ANE.0000150961.24747.98 |doi-access=free |pmid=15845694 |s2cid=35342038}}</ref>
|-
| [[NMDA receptor|{{abbr|NMDAR|N-Methyl-D-aspartate receptor}}<br>(MK-801)]] || >20,000 || >20,000 || Rat || <ref name="pmid8955860"/>
|-
| {{abbrlink|GABA<sub>A</sub>|GABAA receptor}} || >100,000 (IC<sub>50</sub>) || >100,000 (IC<sub>50</sub>) || Human || <ref name="pmid15845694"/>
|-
| {{abbrlink|GlyR|Glycine receptor}} || >100,000 (IC<sub>50</sub>) || >100,000 (IC<sub>50</sub>) || Human || <ref name="pmid15845694"/>
|-
| [[TRPA1|{{abbr|TRPA1|Transient receptor potential channel ankyrin 1}}]] || 100–<br>10,000 ({{abbr|SI|significant inhibition}}) || 1,000–<br>10,000 ({{abbr|SI|significant inhibition}}) || Human || <ref name="pmid25642661"/>
|-
| [[TRPV1|{{abbr|TRPV1|Transient receptor potential channel vanilloid 1}}]] || >10,000 (IC<sub>50</sub>) || >10,000 (IC<sub>50</sub>) || Human || <ref name="pmid25642661">{{cite journal |vauthors=Miyano K, Minami K, Yokoyama T, Ohbuchi K, Yamaguchi T, Murakami S, Shiraishi S, Yamamoto M, Matoba M, Uezono Y |title=Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity |journal=Anesthesia and Analgesia |volume=120 |issue=4 |pages=790–798 |date=April 2015 |doi=10.1213/ANE.0000000000000625 |doi-access=free |pmid=25642661 |s2cid=8082654}}</ref><ref name="pmid18499628">{{cite journal |vauthors=Marincsák R, Tóth BI, Czifra G, Szabó T, Kovács L, Bíró T |title=The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1 |journal=Anesthesia and Analgesia |volume=106 |issue=6 |pages=1890–1896 |date=June 2008 |doi=10.1213/ane.0b013e318172fefc |doi-access=free |pmid=18499628 |s2cid=45854233}}</ref>
|- class="sortbottom"
| colspan="5" style="width: 1px;" |Values are K<sub>i</sub> (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.
|}

{| class="wikitable floatright"
|+<br>Tramadol and mono-<br>amine&nbsp;reuptake/release<ref name="pmid17017961"/>
|-
! Action !! Value
|-
| [[Serotonin reuptake inhibitor|{{abbr|5-HT|Serotonin}} reuptake]] || 1,820
|-
| [[Serotonin releasing agent|{{abbr|5-HT|Serotonin}} release]] || >10,000
|-
| [[Norepinephrine reuptake inhibitor|{{abbr|NE|Norepinephrine}} reuptake]] || 2,770
|-
| [[Norepinephrine releasing agent|{{abbr|NE|Norepinephrine}} release]] || >10,000
|-
| [[Dopamine reuptake inhibitor|{{abbr|DA|Dopamine}} reuptake]] || >10,000
|-
| [[Dopamine releasing agent|{{abbr|DA|Dopamine}} release]] || >10,000
|- class="sortbottom"
| colspan="2" style="width: 1px;" |<small>Values for reuptake inhibition are K<sub>i</sub> (nM) and for release induction are [[EC50|EC<sub>50</sub>]] (nM)</small>
|}

Tramadol has been found to possess these actions:<ref name="pmid17380034"/><ref name="pmid26292636"/><ref name="pmid25776506"/>
* [[Agonist]] of the [[μ-opioid receptor]] (MOR) and to a far lesser extent of the [[δ-opioid receptor]] (DOR) and [[κ-opioid receptor]] (KOR)
* [[Serotonin reuptake inhibitor]] (SRI) and [[norepinephrine reuptake inhibitor]]; hence, an SNRI
* [[Serotonin receptor|Serotonin]] [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] [[receptor antagonist|antagonist]]
* [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] and [[muscarinic acetylcholine receptor M3|M<sub>3</sub>]] [[muscarinic acetylcholine receptor]] antagonist
* [[alpha-7 nicotinic receptor|α7]] [[nicotinic acetylcholine receptor]] antagonist
* [[NMDA receptor antagonist]] (very weak)
* [[TRPA1]] [[channel blocker|inhibitor]]

Tramadol acts on the [[opioid receptor]]s through its major [[active metabolite]] [[desmetramadol]], which has as much as 700-fold higher affinity for the MOR relative to tramadol.<ref name=Raf2012/> Moreover, tramadol itself has been found to possess no [[intrinsic activity|efficacy]] in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity ([[intrinsic activity|E<sub>max</sub>]] equal to that of [[morphine]]).<ref name="pmid10961373"/><ref name=Raf2012/><ref name="pmid25394761">{{cite journal |vauthors=Minami K, Sudo Y, Miyano K, Murphy RS, Uezono Y |title=μ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1) |journal=Journal of Anesthesia |volume=29 |issue=3 |pages=475–479 |date=June 2015 |doi=10.1007/s00540-014-1946-z |pmid=25394761 |s2cid=7091648}}</ref> As such, desmetramadol is exclusively responsible for the opioid effects of tramadol.<ref name="pmid18958460">{{cite journal |vauthors=Coller JK, Christrup LL, Somogyi AA |title=Role of active metabolites in the use of opioids |journal=European Journal of Clinical Pharmacology |volume=65 |issue=2 |pages=121–139 |date=February 2009 |doi=10.1007/s00228-008-0570-y |pmid=18958460 |s2cid=9977741}}</ref> Both tramadol and desmetramadol have pronounced [[binding selectivity|selectivity]] for the MOR over the DOR and KOR in terms of binding affinity.<ref name="pmid8955860"/><ref name="pmid27096047"/><ref name="pmid10991912"/>

Tramadol is well-established as an SRI.<ref name="pmid17380034"/><ref name="pmid26292636"/> In addition, a few studies have found that it also acts as a [[serotonin releasing agent]] (1–10&nbsp;μM), similar in effect to [[fenfluramine]].<ref name="pmid1596676">{{cite journal |vauthors=Driessen B, Reimann W |title=Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro |journal=British Journal of Pharmacology |volume=105 |issue=1 |pages=147–151 |date=January 1992 |pmc=1908625 |doi=10.1111/j.1476-5381.1992.tb14226.x |pmid=1596676}}</ref><ref name="pmid9389855">{{cite journal |vauthors=Bamigbade TA, Davidson C, Langford RM, Stamford JA |title=Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus |journal=British Journal of Anaesthesia |volume=79 |issue=3 |pages=352–356 |date=September 1997 |doi=10.1093/bja/79.3.352 |doi-access=free |pmid=9389855 |s2cid=15630689}}</ref><ref name="pmid9671098">{{cite journal |vauthors=Reimann W, Schneider F |title=Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine |journal=European Journal of Pharmacology |volume=349 |issue=2–3 |pages=199–203 |date=May 1998 |doi=10.1016/S0014-2999(98)00195-2 |pmid=9671098}}</ref><ref name="pmid12354291">{{cite journal |vauthors=Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T |title=p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro |journal=Journal of Neurochemistry |volume=82 |issue=6 |pages=1435–1443 |date=September 2002 |hdl-access=free |hdl=10533/173421 |doi=10.1046/j.1471-4159.2002.01073.x |pmid=12354291 |s2cid=13397864}}</ref> The serotonin releasing effects of tramadol could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor [[6-nitroquipazine]], which is in accordance with other serotonin releasing agents such as fenfluramine and [[MDMA]].<ref name="pmid1596676"/><ref name="pmid9671098"/><ref name="pmid12354291"/> However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30&nbsp;μM.<ref name="pmid10323276">{{cite journal |vauthors=Gobbi M, Mennini T |title=Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser |journal=European Journal of Pharmacology |volume=370 |issue=1 |pages=23–26 |date=April 1999 |doi=10.1016/s0014-2999(99)00123-5 |pmid=10323276}}</ref><ref name="pmid12354291"/><ref name="pmid17017961">{{cite journal |vauthors=Rothman RB, Baumann MH |title=Therapeutic potential of monoamine transporter substrates |journal=Current Topics in Medicinal Chemistry |volume=6 |issue=17 |pages=1845–1859 |year=2006 |doi=10.2174/156802606778249766 |pmid=17017961 |url=https://zenodo.org/record/1235860 |access-date=3 September 2020 |url-status=live |archive-url=https://web.archive.org/web/20201023101936/https://zenodo.org/record/1235860 |archive-date=23 October 2020}}</ref> In addition to serotonergic activity, tramadol is also a [[norepinephrine reuptake inhibitor]].<ref name="pmid17380034"/><ref name="pmid26292636"/> It is not a [[norepinephrine releasing agent]].<ref name="pmid8467366">{{cite journal |vauthors=Driessen B, Reimann W, Giertz H |title=Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro |journal=British Journal of Pharmacology |volume=108 |issue=3 |pages=806–811 |date=March 1993 |pmc=1908052 |doi=10.1111/j.1476-5381.1993.tb12882.x |pmid=8467366}}</ref><ref name="pmid8031323">{{cite journal |vauthors=Reimann W, Hennies HH |title=Inhibition of spinal noradrenaline uptake in rats by the centrally acting analgesic tramadol |journal=Biochemical Pharmacology |volume=47 |issue=12 |pages=2289–2293 |date=June 1994 |doi=10.1016/0006-2952(94)90267-4 |pmid=8031323}}</ref><ref name="pmid10700792">{{cite journal |vauthors=Halfpenny DM, Callado LF, Hopwood SE, Bamigbade TA, Langford RM, Stamford JA |title=Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry |journal=British Journal of Anaesthesia |volume=83 |issue=6 |pages=909–915 |date=December 1999 |doi=10.1093/bja/83.6.909 |doi-access=free |pmid=10700792 |s2cid=17830312}}</ref><ref name="pmid17017961"/> Tramadol does not inhibit the reuptake or induce the release of [[dopamine]].<ref name="pmid8467366"/><ref name="pmid17017961"/>

A [[positron emission tomography]] [[medical imaging|imaging]] study found that single oral 50-mg and 100-mg doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the [[serotonin transporter]] (SERT) in the [[thalamus]].<ref name="pmid24423243">{{cite journal |vauthors=Ogawa K, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y |title=Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB |journal=The International Journal of Neuropsychopharmacology |volume=17 |issue=6 |pages=845–850 |date=June 2014 |doi=10.1017/S1461145713001764 |doi-access=free |pmid=24423243}}</ref> The estimated [[effective dose (pharmacology)#ED50|median effective dose]] (ED<sub>50</sub>) for SERT occupancy hence was 98.1&nbsp;mg, which was associated with a plasma tramadol level of about 330&nbsp;ng/mL (1,300&nbsp;nM).<ref name="pmid24423243"/> The estimated maximum daily dosage of tramadol of 400&nbsp;mg (100&nbsp;mg {{abbr|q.i.d.|four times per day}}) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220&nbsp;ng/mL or 4,632&nbsp;nM).<ref name="pmid24423243"/> This is close to that of SSRIs, which occupy the SERT by 80% or more.<ref name="pmid24423243"/>

[[Cmax (pharmacology)|Peak plasma concentrations]] during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592&nbsp;ng/mL (266–2,250&nbsp;nM) for tramadol and 55 to 143&nbsp;ng/mL (221–573&nbsp;nM) for desmetramadol.<ref name="pmid15509185"/> The highest levels of tramadol were observed with the maximum oral daily dosage of 400&nbsp;mg per day divided into one 100-mg dose every 6&nbsp;hours (i.e., four 100-mg doses evenly spaced out per day).<ref name="pmid15509185"/><ref name="Drugs.com-Dosage">{{cite web |title=Tramadol Dosage Guide with Precautions |url=https://www.drugs.com/dosage/tramadol.html |access-date=4 September 2017 |url-status=live |archive-url=https://web.archive.org/web/20200621004147/https://www.drugs.com/dosage/tramadol.html |archive-date=21 June 2020}}</ref> Some accumulation of tramadol occurs with chronic administration; peak plasma levels with the maximum oral daily dosage (100&nbsp;mg {{abbr|q.i.d.|four times per day}}) are about 16% higher and the [[area under the curve (pharmacokinetics)|area-under-the-curve]] levels 36% higher than following a single oral 100-mg dose.<ref name="pmid15509185"/> [[Positron emission tomography]] imaging studies have reportedly found that tramadol levels are at least four-fold higher in the [[brain]] than in [[blood plasma|plasma]].<ref name="pmid8467366"/><ref name="pmid11975693">{{cite journal |vauthors=Tao Q, Stone DJ, Borenstein MR, Codd EE, Coogan TP, Desai-Krieger D, Liao S, Raffa RB |title=Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally |journal=Journal of Clinical Pharmacy and Therapeutics |volume=27 |issue=2 |pages=99–106 |date=April 2002 |doi=10.1046/j.1365-2710.2002.00384.x |doi-access=free |pmid=11975693 |s2cid=42370985}}</ref> Conversely, brain levels of desmetramadol "only slowly approach those in plasma".<ref name="pmid8467366"/> The [[plasma protein binding]] of tramadol is only 4–20%; hence, almost all tramadol in circulation is free, thus bioactive.<ref name="pmid8764760">{{cite journal |vauthors=Gibson TP |title=Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl |journal=The American Journal of Medicine |volume=101 |issue=1A |pages=47S–53S |date=July 1996 |doi=10.1016/s0002-9343(96)00138-6 |pmid=8764760}}</ref><ref name="pmid7517823"/><ref name="NobilisKopecký2002">{{cite journal |vauthors=Nobilis M, Kopecký J, Kvetina J, Chládek J, Svoboda Z, Vorísek V, Perlík F, Pour M, Kunes J |title=High-performance liquid chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma. Application to a bioequivalence study in humans |journal=Journal of Chromatography A |volume=949 |issue=1–2 |pages=11–22 |date=March 2002 |doi=10.1016/S0021-9673(01)01567-9 |pmid=11999728}}</ref>

====Correspondence to effects====
Co-administration of [[quinidine]], a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers.<ref name=Raf2012/><ref name="pmid7517823">{{cite journal |vauthors=Dayer P, Collart L, Desmeules J |title=The pharmacology of tramadol |journal=Drugs |volume=47 |issue=Suppl 1 |pages=3–7 |year=1994 |doi=10.2165/00003495-199400471-00003 |pmid=7517823 |s2cid=33474225}}</ref> However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers.<ref name=Raf2012/><ref name="pmid18958460"/> The analgesic effects of tramadol are only partially reversed by [[naloxone]] in human volunteers,<ref name=Raf2012/> hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by [[alpha-2 adrenoceptor|α<sub>2</sub>-adrenergic receptor]] antagonists such as [[yohimbine]], the [[5-HT3 receptor|5-HT<sub>3</sub> receptor]] antagonist [[ondansetron]], and the [[5-HT7 receptor|5-HT<sub>7</sub> receptor]] antagonists [[SB-269970]] and [[SB-258719]].<ref name="pmid15509185"/><ref name="pmid20179508">{{cite journal |vauthors=Yanarates O, Dogrul A, Yildirim V, Sahin A, Sizlan A, Seyrek M, Akgül O, Kozak O, Kurt E, Aypar U |title=Spinal 5-HT7 receptors play an important role in the antinociceptive and antihyperalgesic effects of tramadol and its metabolite, O-Desmethyltramadol, via activation of descending serotonergic pathways |journal=Anesthesiology |volume=112 |issue=3 |pages=696–710 |date=March 2010 |doi=10.1097/ALN.0b013e3181cd7920 |doi-access=free |pmid=20179508 |s2cid=11913166}}</ref> Pharmacologically, tramadol is similar to [[tapentadol]] and [[methadone]] in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine<ref name=MD/> due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.<ref name="pmid16762426">{{cite journal |vauthors=Micó JA, Ardid D, Berrocoso E, Eschalier A |title=Antidepressants and pain |journal=Trends in Pharmacological Sciences |volume=27 |issue=7 |pages=348–354 |date=July 2006 |doi=10.1016/j.tips.2006.05.004 |pmid=16762426}}</ref>

Tramadol has inhibitory actions on the 5-HT<sub>2C</sub> receptor. Antagonism of 5-HT<sub>2C</sub> could be partially responsible for tramadol's reducing effect on depressive and [[obsessive–compulsive disorder|obsessive–compulsive symptoms]] in patients with pain and co-morbid neurological illnesses.<ref name="pmid15105221"/> 5-HT<sub>2C</sub> blockade may also account for its lowering of the [[seizure threshold]], as 5-HT<sub>2C</sub> [[knockout mouse|knockout mice]] display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of [[GABAA receptor|GABA<sub>A</sub> receptors]] at high doses (significant inhibition at 100&nbsp;μM).<ref name="pmid15845694"/><ref name="pmid25776506"/> In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.<ref name="pmid10991912">{{cite journal |vauthors=Potschka H, Friderichs E, Löscher W |title=Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy |journal=British Journal of Pharmacology |volume=131 |issue=2 |pages=203–212 |date=September 2000 |pmc=1572317 |doi=10.1038/sj.bjp.0703562 |pmid=10991912}}</ref>

[[Nausea]] and [[vomiting]] caused by tramadol are thought to be due to activation of the [[5-HT3 receptor|5-HT<sub>3</sub> receptor]] via increased serotonin levels.<ref name="pmid16427041"/> In accordance, the 5-HT<sub>3</sub> receptor antagonist [[ondansetron]] can be used to treat tramadol-associated nausea and vomiting.<ref name="pmid16427041"/> Tramadol and desmetramadol themselves do not bind to the 5-HT<sub>3</sub> receptor.<ref name="pmid16427041"/><ref name="pmid26292636"/>

===Pharmacokinetics===
[[File:O-desmethyltramadol racemate2DACS2.svg|thumb|350px|class=skin-invert-image|[[Desmetramadol]]]]

Tramadol is metabolised in the [[liver]] via the [[cytochrome P450]] [[isozyme]] [[CYP2B6]], [[CYP2D6]], and [[CYP3A4]], being ''O''- and ''N''-demethylated to five different metabolites. Of these, [[desmetramadol]] (''O''-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.<ref name="pmid21494059">{{cite journal |vauthors=Leppert W |title=CYP2D6 in the metabolism of opioids for mild to moderate pain |journal=Pharmacology |volume=87 |issue=5–6 |pages=274–285 |year=2011 |doi=10.1159/000326085 |doi-access=free |pmid=21494059}}</ref><ref name="pmid23588782">{{cite journal |vauthors=Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA |title=Applications of CYP450 testing in the clinical setting |journal=Molecular Diagnosis & Therapy |volume=17 |issue=3 |pages=165–184 |date=June 2013 |pmc=3663206 |doi=10.1007/s40291-013-0028-5 |pmid=23588782}}</ref>

Phase II [[liver|hepatic]] metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in [[renal]] and [[hepatic]] impairment.<ref name="pmid15509185"/>

Its [[volume of distribution]] is around 306 L after oral administration and 203 L after parenteral administration.<ref name="pmid15509185"/>

==Chemistry==
Tramadol is marketed as a [[racemic mixture]] of both ''R''- and ''S''-[[stereoisomer]]s,<ref name=MD/> because the two isomers complement each other's analgesic activities.<ref name=MD/> The (+)-isomer is predominantly active as an opiate with a higher affinity for the μ-opiate receptor (20 times higher affinity than the (-)-isomer).<ref name="Tramadol SmPC" />

===Synthesis and stereoisomerism===
{| style="text-align: center;" class="floatright"
|[[File:(1R,2R)-Tramadol.svg|150x150px|class=skin-invert-image]]
|[[File:(1S,2S)-Tramadol gespiegelt.svg|150x150px|class=skin-invert-image]]
|-
|(1''R'',2''R'')-tramadol
|(1''S'',2''S'')-tramadol
|-
|[[File:(1R,2S)-Tramadol.svg|150x150px|class=skin-invert-image]]
|[[File:(1S,2R)-Tramadol gespiegelt.svg|150x150px|class=skin-invert-image]]
|-
|(1''R'',2''S'')-tramadol
|(1''S'',2''R'')-tramadol
|}
The chemical synthesis of tramadol is described in the literature.<ref name="Kleemann">{{cite book |title=Pharmaceutical Substances |veditors=Kleemann A, Engel J, Kutscher B, Reichert D |edition=4th |date=2000 |publisher=Thieme-Verlag |location=Stuttgart (Germany) |pages=2085–2086 |isbn=978-1-58890-031-9}}; since 2003 online with biannual actualizations.</ref> Tramadol {{nowrap|[2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol]}} has two stereogenic centers at the [[cyclohexane]] ring. Thus, {{nowrap|2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol}} may exist in ''four'' different configurational forms:
* (1''R'',2''R'')-isomer
* (1''S'',2''S'')-isomer
* (1''R'',2''S'')-isomer
* (1''S'',2''R'')-isomer
The synthetic pathway leads to the [[racemate]] (1:1 mixture) of (1''R'',2''R'')-isomer and the (1''S'',2''S'')-isomer as the main products. Minor amounts of the racemic mixture of the (1''R'',2''S'')-isomer and the (1''S'',2''R'')-isomer are formed as well. The isolation of the (1''R'',2''R'')-isomer and the (1''S'',2''S'')-isomer from the [[diastereomer]]ic minor racemate [(1''R'',2''S'')-isomer and (1''S'',2''R'')-isomer] is realized by the recrystallization of the [[hydrochloride]]s.
The drug tramadol is a racemate of the hydrochlorides of the (1''R'',2''R'')-(+)- and the (1''S'',2''S'')-(−)-enantiomers.
The resolution of the racemate [(1''R'',2''R'')-(+)-isomer / (1''S'',2''S'')-(−)-isomer] was described<ref name="Zynovy">{{cite journal |vauthors=Zynovy Z, Meckler H |year=2000 |title=A Practical Procedure for the Resolution of (+)- and (−)-Tramadol |journal=Organic Process Research & Development |volume=4 |issue=4 |pages=291–294 |doi=10.1021/op000281v}}</ref> employing (''R'')-(−)- or (''S'')-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects<ref name="pmid12066734">{{cite journal |vauthors=Burke D, Henderson DJ |title=Chirality: a blueprint for the future |journal=British Journal of Anaesthesia |volume=88 |issue=4 |pages=563–576 |date=April 2002 |doi=10.1093/bja/88.4.563 |doi-access=free |pmid=12066734}}</ref> of the (1''R'',2''R'')- and (1''S'',2''S'')-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals<ref name="pmid8229760">{{cite journal |vauthors=Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N |title=Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=267 |issue=1 |pages=331–340 |date=October 1993 |doi=10.1016/S0022-3565(25)39454-1 |pmid=8229760}}</ref> and in humans.<ref name="pmid8657431">{{cite journal |vauthors=Grond S, Meuser T, Zech D, Hennig U, Lehmann KA |title=Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia |journal=Pain |volume=62 |issue=3 |pages=313–320 |date=September 1995 |doi=10.1016/0304-3959(94)00274-I |pmid=8657431 |s2cid=34150137}}</ref>

===Detection in biological fluids===
Tramadol and desmetramadol may be quantified in blood, plasma, serum, or saliva to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantify these substances. The concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% that of the parent drug.<ref name="pmid17575561">{{cite journal |vauthors=Karhu D, El-Jammal A, Dupain T, Gaulin D, Bouchard S |title=Pharmacokinetics and dose proportionality of three Tramadol Contramid OAD tablet strengths |journal=Biopharmaceutics & Drug Disposition |volume=28 |issue=6 |pages=323–330 |date=September 2007 |doi=10.1002/bdd.561 |pmid=17575561 |s2cid=22720069}}</ref><ref name="pmid17350197">{{cite journal |vauthors=Tjäderborn M, Jönsson AK, Hägg S, Ahlner J |title=Fatal unintentional intoxications with tramadol during 1995-2005 |journal=Forensic Science International |volume=173 |issue=2–3 |pages=107–111 |date=December 2007 |doi=10.1016/j.forsciint.2007.02.007 |pmid=17350197}}</ref><ref>{{cite book |vauthors=Baselt R |date=2017 |title=Disposition of Toxic Drugs and Chemicals in Man |edition=11th |publisher=Biomedical Publications, Seal Beach, CA |pages=2185–2188 |isbn=978-0-692-77499-1}}</ref>

===Discrepant reports on natural agency===
{{more science citations needed|section|date = May 2024}}
In 2013, researchers [[Michel de Waard]] (then at [[Université Joseph Fourier]], [[Grenoble, France|Grenoble]] and [[Grenoble Institute of Neuroscience]], [[La Tronche]]<ref name=crosscont>{{cite journal |vauthors=Kusari S, Tatsimo SJ, Zühlke S, Talontsi FM, Kouam SF, Spiteller M |title=Tramadol--a true natural product? |journal=Angewandte Chemie |volume=53 |issue=45 |pages=12073–12076 |date=November 2014 |doi=10.1002/anie.201406639 |pmid=25219922}}</ref>) reported in ''[[Angewandte Chemie]]'' that tramadol was found in relatively high concentrations (>1%) in the roots of the African [[pin cushion tree]], ''Nauclea latifolia'', concluding that it was a natural product in addition to its being a later human synthetic, and presenting a putative biosynthetic hypothesis for its origin.<ref name=Nauc>{{cite journal |vauthors=Boumendjel A, Sotoing Taïwe G, Ngo Bum E, Chabrol T, Beney C, Sinniger V, Haudecoeur R, Marcourt L, Challal S, Ferreira Queiroz E, Souard F, Le Borgne M, Lomberget T, Depaulis A, Lavaud C, Robins R, Wolfender JL, Bonaz B, De Waard M |title=Occurrence of the synthetic analgesic tramadol in an African medicinal plant |journal=Angewandte Chemie |volume=52 |issue=45 |pages=11780–11784 |date=November 2013 |doi=10.1002/anie.201305697 |doi-access=free |pmid=24014188}}</ref> 

In 2014, [[Michael Spiteller]] ([[Technical University of Dortmund|Technische Universität Dortmund]]) and collaborators reported results, also in ''[[Angewandte Chemie]]'', that supported the conclusion that the presence of tramadol in those tree roots was the result of tramadol having been ingested by humans and having been administered to cattle (by farmers in the region); Spiteller et al. presented data that tramadol and its [[metabolites]] were present in animal excreta, which they then argue contaminated soil around the trees.<ref name=crosscont/> They further observed that tramadol and its mammalian metabolites were found in tree roots in the far north of [[Cameroon]] where the commercial drug was in use, but not in the south where it was not being administered.<ref name=crosscont/>

A news report appearing in ''[[Lab Times]]'' at the time of the latter, 2014  paper, and reporting on its contents, also reported that Michel de Waard (communicating author of the original paper) continued to contest the notion that tramadol in tree roots was the result of anthropogenic contamination.<ref name=LabTimes>[http://www.labtimes.org/editorial/e_546.lasso Who Really did it First? Nature or a Pharmacist?] {{Webarchive|url=https://web.archive.org/web/20151122041341/http://www.labtimes.org/editorial/e_546.lasso |date=22 November 2015}}, in ''Lab Times online''; by Nicola Hunt; published 22 September 2014; retrieved 21 November 2015</ref> The point was made that samples were taken from trees that grew in national parks, where livestock were forbidden, and it quoted de Waard extensively, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating" would be required to produce the concentrations discovered.<ref name=LabTimes/>{{better source|date = May 2024}}<!--Has de Waard only voiced opinion, and not published anything?-->

In 2016, Spiteller and colleagues followed up their preceding work with a [[carbon-14|radiocarbon]] analysis that supported their contention that the tramadol found in ''N. latifolia'' roots was of human synthetic origin rather being plant-derived.<ref name="pmid26473295">{{cite journal |vauthors=Kusari S, Tatsimo SJ, Zühlke S, Spiteller M |title=Synthetic Origin of Tramadol in the Environment |journal=Angewandte Chemie |volume=55 |issue=1 |pages=240–243 |date=January 2016 |doi=10.1002/anie.201508646 |pmid=26473295 |s2cid=39558505}}</ref>

==Society and culture==

===Formulations===
Available dosage forms include liquids, syrups, drops, elixirs, effervescent tablets, and powders for mixing with water, capsules, tablets including extended-release formulations, suppositories, compounding powder, and injections.<ref name=AMH/>

===Patent history===
The U.S. [[Food and Drug Administration]] (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005.<ref>{{cite journal |vauthors=McCarberg B |title=Tramadol extended-release in the management of chronic pain |journal=Therapeutics and Clinical Risk Management |volume=3 |issue=3 |pages=401–410 |date=June 2007 |pmc=2386353 |pmid=18488071}}</ref> ER Tramadol was protected by US patents nos. 6,254,887<ref>{{cite patent |country=US |number=6254887 |status=patent |title=Controlled Release Tramadol |gdate=3 July 2001 |inventor=Miller RB, Leslie ST, Malkowska ST, Smith KJ, Wimmer S, Winkler H, Hahn U, Prater DA}}</ref> and 7,074,430.<ref name=FDAaccessdata>FDA AccessData entry for [http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=021692&TABLE1=OB_Rx Tramadol Hydrochloride] {{Webarchive|url=https://web.archive.org/web/20161025134225/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=021692&TABLE1=OB_Rx |date=25 October 2016}}. Retrieved 17 August 2009.</ref><ref>{{cite patent |country=US |number=7074430 |status=patent |title=Controlled Release Tramadol Tramadol Formulation |gdate=11 July 2006 |inventor=Miller RB, Malkowska ST, Wimmer S, Hahn U, Leslie ST, Smith KJ, Winkler H, Prater DA}}</ref> The FDA listed the patents' expiration as 10 May 2014.<ref name=FDAaccessdata/> However, in August 2009, the US District Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was therefore permitted before the expiration of the patents.<ref>{{cite court |litigants=Purdue Pharma Prods. L.P. v. Par Pharm., Inc. |vol=377 |reporter=Fed.Appx. |opinion=978 |court=Fed. Cir. |date=2010 |url=https://cases.justia.com/federal/appellate-courts/cafc/09-1553/09-1553-2011-03-27.pdf}}</ref>

===Legal status===
Effective August 2014, tramadol has been placed into [[Controlled Substances Act#Schedule IV|Schedule IV]] of the federal Controlled Substances Act in the United States.<ref>{{cite web | vauthors = Gilbert Jr JA, Houck LK |title=DEA controls tramadol as a schedule IV controlled substance effective August 18, 2014 |date=2 July 2014 |website=FDA Law Blog |url=https://www.thefdalawblog.com/2014/07/dea-controls-tramadol-as-a-schedule-iv-controlled-substance-effective-august-18-2014/ |access-date=10 April 2024 |url-status=live |archive-url=https://web.archive.org/web/20171107020014/http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2014/07/dea-controls-tramadol-as-a-schedule-iv-controlled-substance-effective-august-18-2014.html |archive-date=7 November 2017 }}</ref><ref>{{cite web |title=Federal Registrar |publisher=gpo.gov |url=https://www.govinfo.gov/content/pkg/FR-2014-07-02/pdf/2014-15548.pdf |access-date=10 April 2024 |url-status=live |archive-url=https://web.archive.org/web/20180814124803/https://www.gpo.gov/fdsys/pkg/FR-2014-07-02/pdf/2014-15548.pdf |archive-date=14 August 2018}}</ref> Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.<ref>"[https://web.archive.org/web/20110417095837/http://www.deadiversion.usdoj.gov/drugs_concern/tramadol.pdf TRAMADOL (Trade Names: Ultram, Ultracet)]". Drug Enforcement Administration (February 2011)</ref><ref>"[https://archive.today/20130222125410/http://www.nabp.net/news/tennessee-news-tramadol-and-carisoprodol-now-classified-schedule-iv Tennessee News: Tramadol and Carisoprodol Now Classified Schedule IV]". National Association of Boards of Pharmacy (8 June 2011). Retrieved on 26 December 2012.</ref><ref>{{cite web |title=State of Ohio Board of Pharmacy |publisher=Pharmacy.ohio.gov |date=18 August 2014 |url=https://pharmacy.ohio.gov/Documents/Notices/Tramadol%20Is%20A%20Schedule%20IV%20Controlled%20Substance%20Effective%20August%2018,%202014.pdf |access-date=8 November 2016 |url-status=dead |archive-url=https://web.archive.org/web/20161229024318/http://pharmacy.ohio.gov/Documents/Notices/Tramadol%20Is%20A%20Schedule%20IV%20Controlled%20Substance%20Effective%20August%2018%2C%202014.pdf |archive-date=29 December 2016}}</ref>

Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as a [[Standard for the Uniform Scheduling of Drugs and Poisons#Schedule 8|Schedule 8 Controlled Drug]] (Possession without authority illegal) like most other [[opioid]]s.<ref name="AMH">{{cite book | veditors = Rossi S |isbn=978-0-9805790-9-3 |title=Australian Medicines Handbook |place=Adelaide |publisher=The Australian Medicines Handbook Unit Trust |year=2013 |edition=2013}}</ref>

Effective May 2008, Sweden classified tramadol as a [[controlled substance]] in the same category as [[codeine]] and [[dextropropoxyphene]], but allows a normal [[medical prescription|prescription]] to be used.<ref>{{cite web |title=Substansen tramadol nu narkotikaklassad på samma sätt som kodein och dextropropoxifen |publisher=[[Medical Products Agency (Sweden) |Lakemedelsverket]] |date=14 May 2008 |language=sv |url=https://lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/ |access-date=12 August 2019 |url-status=live |archive-url=https://web.archive.org/web/20190812094919/https://lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/ |archive-date=12 August 2019}}</ref>

In June 2014, the United Kingdom's Home Office classified tramadol as a Class C, Schedule 3 controlled drug, but exempted it from the safe custody requirement.<ref name="UK scheduling">{{cite web |title=Scheduling of tramadol and exemptions for temazepam prescriptions |website=UK Government |date=22 July 2013 |url=https://www.gov.uk/government/consultations/scheduling-of-tramadol-and-exemptions-for-temazepam-prescriptions |access-date=27 March 2023}}</ref>

In October 2023, New Zealand's Medsafe reclassified tramadol as a Class C2 Controlled Drug (in addition to its existing status as a prescription only medication).<ref>{{cite web |title=Upcoming reclassification of fentanyl, tramadol, zopiclone and zolpidem |website=NZ Government |date=19 June 2023  |url=https://www.nzoa.org.nz/sites/default/files/Upcoming%20reclassification%20of%20fentanyl%2C%20tramadol%2C%20zopiclone%20and%20zolpidem%20(19%20June%202023).pdf |access-date=10 March 2024}}</ref>

===Misuse===
Illicit use of the drug is thought to be a major factor in the success of the [[Boko Haram]] terrorist organization.<ref name=":0">{{cite web |title=If you take Tramadol away, you make Boko Haram weak. |date=15 March 2019 |website=African Arguments |url=https://africanarguments.org/2019/03/15/if-you-take-tramadol-away-you-make-boko-haram-weak/ |access-date=18 March 2019 |url-status=live |archive-url=https://web.archive.org/web/20200923085154/https://africanarguments.org/2019/03/15/if-you-take-tramadol-away-you-make-boko-haram-weak/ |archive-date=23 September 2020}}</ref><ref>{{cite news |title=Drugs for war: Opioid abuse in West Africa |work=BBC News |url=https://www.bbc.com/news/av/world-africa-44325649/tramadol-emboldens-vigilantes-to-fight-boko-haram |access-date=18 March 2019 |url-status=live |archive-url=https://web.archive.org/web/20200702061435/https://www.bbc.com/news/av/world-africa-44325649/tramadol-emboldens-vigilantes-to-fight-boko-haram |archive-date=2 July 2020}}</ref><ref>{{cite journal |website=csis.org |title=The Dangerous Opioid from India |date=23 March 2018 |vauthors=Tecimer N |url=https://www.csis.org/npfp/dangerous-opioid-india |access-date=18 March 2019 |url-status=live |archive-url=https://web.archive.org/web/20201101090942/https://www.csis.org/npfp/dangerous-opioid-india |archive-date=1 November 2020}}</ref> When used at higher doses, the drug "can produce similar effects to heroin."<ref name=":0"/> One former member said, "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it."<ref name=":0"/> Tramadol is also used as a coping mechanism in the [[Gaza Strip]] under [[Gaza genocide|Israeli siege]].<ref>{{cite news |title=Gaza's Opioid Problem |vauthors=Berger M |journal=The Nation |date=7 January 2019 |issn=0027-8378 |url=https://www.thenation.com/article/archive/gaza-opioid-problem/ |access-date=12 July 2024 |url-status=live |archive-url=https://web.archive.org/web/20190920231739/https://www.thenation.com/article/gaza-opioid-problem/ |archive-date=20 September 2019}}</ref> It is also abused in the [[United Kingdom]].<ref>{{cite journal |vauthors=Winstock AR, Borschmann R, Bell J |title=The non-medical use of tramadol in the UK: findings from a large community sample |journal=International Journal of Clinical Practice |volume=68 |issue=9 |pages=1147–1151 |date=September 2014 |doi=10.1111/ijcp.12429 |doi-access=free |pmid=24734958 |s2cid=21883884}}</ref><ref>{{cite web |title=Tramadol Abuse & Addiction Causes |date=8 August 2018 |website=UK Addiction Treatment Centres |url=https://www.ukat.co.uk/opiates/tramadol/ |access-date=20 December 2021 |url-status=live |archive-url=https://web.archive.org/web/20211220134110/https://www.ukat.co.uk/opiates/tramadol/ |archive-date=20 December 2021}}</ref>

From March 2019, the [[Union Cycliste Internationale]] (UCI) banned the drug, after riders were using the painkiller to improve their performance.<ref>{{cite web |vauthors=Ballinger A |date=22 May 2019 |title=UCI tests 117 riders for tramadol after painkiller banned in professional cycling |website=cyclingweekly.com |url=https://www.cyclingweekly.com/news/racing/uci-tests-117-riders-tramadol-painkiller-banned-professional-cycling-424536 |access-date=17 August 2022}}</ref><ref>{{cite web |vauthors=Robertshaw H |date=2 November 2017 |title=Tramadol could provide performance enhancement for cyclists, study finds |website=cyclingweekly.com |url=https://www.cyclingweekly.com/news/tramadol-found-enhance-cycling-performance-study-finds-357365 |access-date=17 August 2022}}</ref>

==Research==
{{See also|List of investigational antidepressants}}

===Investigational uses===
* [[Diabetic neuropathy]]&nbsp;<ref name="pmid9633738">{{cite journal |vauthors=Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M |title=Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy |journal=Neurology |volume=50 |issue=6 |pages=1842–1846 |date=June 1998 |doi=10.1212/WNL.50.6.1842 |pmid=9633738 |s2cid=45709223}}</ref><ref name="pmid10959067">{{cite journal |vauthors=Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, Donofrio P, Cornblath D, Olson WH, Kamin M |title=Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy |journal=Journal of Diabetes and Its Complications |volume=14 |issue=2 |pages=65–70 |year=2000 |doi=10.1016/S1056-8727(00)00060-X |pmid=10959067}}</ref>
* [[Antidepressant]]<ref name="pmid21463069">{{cite journal |vauthors=Barber J |title=Examining the use of tramadol hydrochloride as an antidepressant |journal=Experimental and Clinical Psychopharmacology |volume=19 |issue=2 |pages=123–130 |date=April 2011 |doi=10.1037/a0022721 |pmid=21463069}}</ref>
* [[Postherpetic neuralgia]]&nbsp;<ref name="pmid9190323">{{cite journal |vauthors=Göbel H, Stadler T |title=[Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine] |language=fr |journal=Drugs |volume=53 |issue=Suppl 2 |pages=34–39 |year=1997 |doi=10.2165/00003495-199700532-00008 |pmid=9190323 |s2cid=46986791}}</ref><ref name="pmid12855342">{{cite journal |vauthors=Boureau F, Legallicier P, Kabir-Ahmadi M |title=Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial |journal=Pain |volume=104 |issue=1–2 |pages=323–331 |date=July 2003 |doi=10.1016/S0304-3959(03)00020-4 |pmid=12855342 |s2cid=42979548}}</ref>
* [[Premature ejaculation]]<ref name="pmid22840860">{{cite journal |vauthors=Wu T, Yue X, Duan X, Luo D, Cheng Y, Tian Y, Wang K |title=Efficacy and safety of tramadol for premature ejaculation: a systematic review and meta-analysis |journal=Urology |volume=80 |issue=3 |pages=618–624 |date=September 2012 |doi=10.1016/j.urology.2012.05.035 |pmid=22840860}}</ref><ref name="pmid23102445">{{cite journal |vauthors=Wong BL, Malde S |title=The use of tramadol "on-demand" for premature ejaculation: a systematic review |journal=Urology |volume=81 |issue=1 |pages=98–103 |date=January 2013 |doi=10.1016/j.urology.2012.08.037 |pmid=23102445}}</ref>
* Adjunct to local anesthesia<ref>{{cite journal |vauthors=Ryan T, Hodge A, Holyoak R, Vlok R, Melhuish T, Binks M, Hurtado G, White L |title=Tramadol as an adjunct to intra-articular local anaesthetic infiltration in knee arthroscopy: a systematic review and meta-analysis |journal=ANZ Journal of Surgery |volume=89 |issue=7–8 |pages=827–832 |date=July 2019 |doi=10.1111/ans.14920 |pmid=30684306 |s2cid=59275648}}</ref>

==Veterinary medicine==
Tramadol was the most common opioid prescribed by American veterinarians from 2014 to 2019; however, usage has declined in subsequent years due to more recent evidence suggesting that dogs do not metabolise tramadol into O-desmethyltramadol effectively. As metabolisation of tramadol relies on [[cytochrome P450]] enzymes, it is species dependent and even individual genetics can have a profound impact on the efficacy of tramadol.<ref name="lamont">{{cite book | vauthors = Simon BT, Lizarraga I | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C | chapter = Opioids | title = Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones | pages = 384–385 | isbn = 978-1-119-83027-6 | publisher = Wiley Blackwell }}</ref> A 2021 meta-analysis of tramadol use in dogs found that although tramadol was more effective than [[nalbuphine]] and [[codeine]], it was less effective than [[methadone]], [[COX inhibitor]]s and [[multimodal analgesia]] with poor evidence to support the use of it is an analgesic for dogs.<ref>{{cite journal | vauthors = Tarragona L, Franco JV, Kreil V, Fravega R, Diaz A, Verdier N, Otero PE, Donati PA | title = Efficacy of tramadol for postoperative pain management in dogs: systematic review and meta-analysis | journal = Veterinary Anaesthesia and Analgesia | volume = 48 | issue = 3 | pages = 283–296 | date = 2021 | pmid = 33745825 | doi = 10.1016/j.vaa.2021.01.003 | doi-access = free | url = http://www.vaajournal.org/article/S1467298721000143/pdf }}</ref><ref name="lamont" /> The [[mean alveolar concentration]] sparing effect of tramadol is negligible and with a high likelihood of rescue analgesia being required thus tramadol monotherapy is not recommended for the dog.<ref name="lamont" /> One study looking at tramadol and [[meloxicam]] administered preoperatively provided no benefit compared to meloxican given alone.<ref>{{cite journal | vauthors = Panti A, Mazeri S, Fernandes KA, Handel IG, Bronsvoort BM, Gamble L, Mellanby RJ, Meunier NV | title = Randomised trial of perioperative tramadol for canine sterilisation pain management | journal = Veterinary Record | volume = 185 | issue = 13 | pages = 406–406 | date = 2019 | pmid = 31320545 | doi = 10.1136/vr.105009 | issn = 0042-4900 | doi-access = free | hdl = 20.500.11820/ad9cec44-ac63-4f9a-a3ab-25978c896365 | hdl-access = free }}</ref><ref name="lamont" /> Another study looking at [[cimicoxib]] versus tramadol for long-term post-operative pain following a [[tibial-plateau-levelling osteotomy]] found that although the level of analgesia was similar cimicoxib resulted in better mobility and a lower incidence of [[hock (anatomy)|hock]] [[oedema]].<ref>{{cite journal | vauthors = Mancusi D, Olimpo M, Gastaldi L, Rosso V, Panero E, Staffieri F, Peirone B, Piras L | title = Post-operative analgesia following TPLO surgery: A comparison between cimicoxib and tramadol | journal = Research in Veterinary Science | volume = 136 | pages = 351–359 | date = 2021 | pmid = 33773391 | doi = 10.1016/j.rvsc.2021.03.010 | doi-access = free | url = https://iris.unito.it/bitstream/2318/1835518/1/Main%20document1.pdf }}</ref><ref name="lamont" /> These studies and other evidence suggest that [[non-steroidal anti-inflammatory drugs]] provide superior analgesia to tramadol in dogs.<ref name="lamont" />

Tramadol is more effective in cats although oral tramadol is poorly tolerated leading to low compliance. A transdermal gel was formulated to address this but plasma concentrations were undetectable.<ref name="lamont" /> In cats oral tramadol at 6 mg/kg provides equivalent analgesia to intramuscular tramadol at 4 mg/kg.<ref name="lamont" /><ref>{{cite journal | vauthors = Bauquier SH | title = Randomised clinical trial comparing the perioperative analgesic efficacy of oral tramadol and intramuscular tramadol in cats | journal = Journal of Feline Medicine and Surgery | volume = 24 | issue = 8 | pages = 683–690 | date = 2022 | pmid = 34493100 | pmc = 10812277 | doi = 10.1177/1098612X211040406 | issn = 1098-612X | doi-access = free }}</ref> One study comparing tramadol to [[meperidine]] found tramadol to be more effective at providing analgesia for cats undergoing ovariohysterectomy.<ref>{{cite journal | vauthors = Silva RA, Cardozo LB, Kahvegian MA, Rossetto TC, Matera JM, Fantoni DT, Evangelista MC | title = Comparison of preoperative tramadol and pethidine on postoperative pain in cats undergoing ovariohysterectomy | journal = BMC Veterinary Research | volume = 10 | issue = 1 | pages = 252 | date = 2014 | pmid = 25310968 | pmc = 4200196 | doi = 10.1186/s12917-014-0252-1 | issn = 1746-6148 | doi-access = free }}</ref><ref name="lamont" /> A study looking at treatment of [[osteoarthritis]] in geriatric cats found owner-reported improvements but also significant adverse effects.<ref>{{cite journal | vauthors = Meadows J, Pypendop B, Johnson E, Guedes A | title = Evaluation of tramadol in osteoarthritic geriatric cats | journal = Veterinary Anaesthesia and Analgesia | volume = 44 | issue = 1 | pages = 195.e13 | date = 2017 | doi = 10.1016/j.vaa.2016.12.056 }}</ref><ref name="lamont" /> Reported adverse effects of tramadol include: [[diarrhoea]], [[dysphoria]], [[anorexia (symptom)|anorexia]], [[tachycardia]], [[pyrexia]], [[tachypnoea]], and increased levels of [[sertonin]] leading to agitation. Tramadol has the potential to cause [[serotonin syndrome]] when administered alongside [[SSRI|serotonin re-uptake inhibitor]]s, [[monoamine oxidase inhibitor]]s, and [[tricyclic antidepressant]]s.<ref name="lamont" />

In horses tramadol is ineffective by itself.<ref name="lamont" /> Two studies looking at intravenous tramadol found it provided no thermal or mechanical [[antinociception]],<ref>{{cite journal | vauthors = Wilson DV, Robinson E, Tobin TT, Dirokulu L, Dhanjal JK | title = Intravenous tramadol: effects, nociceptive properties, and pharmacokinetics in horses | journal = Veterinary Anaesthesia and Analgesia | volume = 36 | issue = 6 | pages = 581–590 | date = 2009 | pmid = 19845931 | doi = 10.1111/j.1467-2995.2009.00492.x }}</ref><ref name="Azarnoosh_2018">{{cite journal | vauthors = Azarnoosh A, Ashar FS, Dehghan MM, Mohebbi Z, Akbarinejad V, Corley K, Tavanaeimanesh H | title = Comparison of Analgesic Effects of a Constant Rate Infusion of Both Tramadol and Acetaminophen Versus those of Infusions of Each Individual Drug in Horses | journal = Journal of Equine Veterinary Science | volume = 64 | pages = 101–106 | date = 2018 | pmid = 30973144 | doi = 10.1016/j.jevs.2018.02.015 | url = https://linkinghub.elsevier.com/retrieve/pii/S0737080617304379 | access-date = 2025-06-05 | url-access = subscription }}</ref><ref name="lamont" /> another study looking at oral tramadol for chronic [[laminitis]] found it provided minimal analgesia,<ref name="Matthews_2012">{{cite journal | vauthors = Matthews NS, Hood DM, Guedes AG | title = Effect of ketamine hydrochloride on the analgesic effects of tramadol hydrochloride in horses with signs of chronic laminitis-associated pain | journal = American Journal of Veterinary Research | volume = 73 | issue = 5 | pages = 610–619 | date = 2012 | pmid = 22533391 | doi = 10.2460/ajvr.73.5.610 | issn = 0002-9645 | doi-access = free | url = https://avmajournals.avma.org/downloadpdf/journals/ajvr/73/5/ajvr.73.5.610.pdf }}</ref><ref name="lamont" /> and another study looking at [[intraarticular]] tramadol found it provided no post-operative analgesia following [[arthroscopy]];<ref>{{cite journal | vauthors = Chiaradia E, della Rocca G, Giorgi M, Mancini F, Marenzoni ML, Conti MB, Nannarone S, Di Salvo A | title = Efficacy, chondrotoxicity and plasma concentrations of tramadol following intra-articular administration in horses undergoing arthroscopy: preliminary findings | journal = The Veterinary Quarterly | volume = 38 | issue = 1 | pages = 129–137 | date = 2018-01-01 | pmid = 30773122 | pmc = 6831008 | doi = 10.1080/01652176.2018.1546963 | issn = 0165-2176 | doi-access = free | url = https://www.tandfonline.com/doi/pdf/10.1080/01652176.2018.1546963 }}</ref><ref name="lamont" /> however, when administered with [[paracetamol]] (acetaminophen) tramadol provides short-acting mechanical antinociception<ref name="Azarnoosh_2018" /><ref name="lamont" /> and when administered with [[ketamine]] oral tramadol provides adequate analgesia for chronic laminitis.<ref name="Matthews_2012" /><ref name="lamont" /> Based on this evidence tramadol is not recommended to be provided on its own for analgesia in horses.<ref name="lamont" />

{| class=wikitable
|+ Pharmacokinetics of tramadol across the species<ref name=Zoo>{{cite journal |vauthors=Souza MJ, Cox SK |title=Tramadol use in zoologic medicine |journal=The Veterinary Clinics of North America. Exotic Animal Practice |volume=14 |issue=1 |pages=117–130 |date=January 2011 |doi=10.1016/j.cvex.2010.09.005 |pmid=21074707}}</ref>
! Species !! Half-life (h) for parent drug !! Half-life (h) for desmetramadol !! Maximum plasma concentration (ng/mL) for parent drug !! Maximum plasma concentration (ng/mL) for desmetramadol

|-
| [[Camel]] || 3.2 (IM), 1.3 (IV) || – || 0.44 (IV) || –
|-
| [[Cat]] || 3.40 (oral), 2.23 (IV) || 4.82 (oral), 4.35 (IV) || 914 (oral), 1323 (IV) || 655 (oral), 366 (IV)
|-
| [[Dog]] || 1.71 (oral), 1.80 (IV), 2.24 (rectal) || 2.18 (oral), 90-5000 (IV) || 1402.75 (oral) || 449.13 (oral), 90–350 (IV)
|-
| [[Donkey]] || 4.2 (oral), 1.5 (IV) || – || 2817 (oral) || –
|-
| [[Goat]] || 2.67 (oral), 0.94 (IV) || – || 542.9 (oral) || –
|-
| [[Horses]] || 1.29–1.53 (IV), 10.1 (oral) || 4 (oral) || 637 (IV), 256 (oral) || 47 (oral)
|-
| [[Llama]] || 2.54 (IM), 2.12 (IV) || 7.73 (IM), 10.4 (IV) || 4036 (IV), 1360 (IM) || 158 (IV), 158 (IM)
|}

==See also==
* [[Tramadol/paracetamol]]

==References==
{{Reflist}}

==Further reading==
{{Refbegin}}
* {{cite book |title=Medical Genetics Summaries |chapter=Tramadol Therapy and CYP2D6 Genotype |veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ |display-editors=3 |publisher=[[National Center for Biotechnology Information]] (NCBI) |year=2015 |id=Bookshelf ID: NBK315950 |vauthors=Dean L |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK315950/ |pmid=28520365 |url=https://www.ncbi.nlm.nih.gov/books/NBK61999/}}
{{Refend}}

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