Tramadol: Difference between revisions

{{Drugbox

| verifiedrevid = 451407431

| IUPAC_name = (1''R'',2''R'')-''rel''-2-[(dimethylamino)methyl]- 1-(3-methoxyphenyl)cyclohexanol

| image = (1R,2R)- & (1S,2S)-Tramadol Enantiomers Structural Formulae.png

| image2 = Tramadol_3d_balls.png

<!--Clinical data-->

| tradename = Ryzolt, Ultram

| Drugs.com = {{drugs.com|monograph|ultram}}

| MedlinePlus = a695011

| pregnancy_AU = C

| pregnancy_US = C

| legal_AU = S4

| legal_UK = POM

| legal_US = Rx

| legal_status = Rx-only

| routes_of_administration = Oral, [[intravenous|IV]], [[intramuscular|IM]], rectal, sublingual, buccal, intranasal

<!--Pharmacokinetic data-->

| bioavailability = 68–72%(Increases with repeat dosing.)

| protein_bound = 20%

| metabolism = [[Hepatic]] [[demethylation]] and [[glucuronidation]]

| elimination_half-life = 5.5–7 hours

| excretion = [[Renal]]

<!--Identifiers-->

| CASNo_Ref = {{cascite|correct|CAS}}

| CAS_number = 27203-92-5

| ATC_prefix = N02

| ATC_suffix = AX02

| PubChem = 33741

| 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

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1066

<!--Chemical data-->

| C=16 | H=25 | N=1 | O=2

| molecular_weight = 263.4 g/mol

| smiles = O[C@]2(c1cc(OC)ccc1)CCCC[C@@H]2CN(C)C

| InChI = 1/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_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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = TVYLLZQTGLZFBW-ZBFHGGJFSA-N

}}

'''Tramadol hydrochloride''' ('''Ultram''', '''Tramal''') is a centrally acting [[opioid]] [[analgesic]], used in treating moderate to severe pain. The drug has a wide range of applications, including treatment for [[restless legs syndrome]] and [[fibromyalgia]]. It was developed by the [[pharmaceutical company]] [[Grünenthal|Grünenthal GmbH]] in the late 1970s.<ref>{{Ref patent |country=US |number=3652589 |status=patent |title=1-(m-Substituted Phenyl)-2-Aminomethyl Cyclohexanols |gdate=28 March 1972 |inventor=Flick, Kurt; Frankus, Ernst}}</ref><ref>[http://www.3dchem.com/moremolecules.asp?ID=429&othername=Tramal Tramal, What is Tramal? About its Science, Chemistry and Structure]{{Verify credibility|date=September 2009}}</ref>

Tramadol possesses weak [[agonist]] actions at the [[μ-opioid receptor]], releases [[serotonin]], and inhibits the reuptake of [[norepinephrine]].<ref name="pmid9671098">{{cite journal|author = 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|year = 1998|month = May|pmid = 9671098|doi = 10.1016/S0014-2999(98)00195-2| url = http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(98)00195-2}}</ref><ref name="pmid12354291">{{cite journal |author=Gobbi M, Moia M, Pirona L, ''et al.'' |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=1435–43 |year=2002 |month=September |pmid=12354291 |doi=10.1046/j.1471-4159.2002.01073.x}}</ref>

While its action is not like that of other opioids, Tramadol is a synthetic analog of the [[phenanthrene]] alkaloid [[codeine]]. Tramadol is converted to [[O-Desmethyltramadol|''O''-desmethyltramadol]]). Opioids are chemical compounds which act upon one or more of the human opiate receptors. The euphoria and respiratory depression of opioids are mainly caused by the μ₁ and μ₂ receptors; the addictive nature of opioids is due to these effects as well as its serotonergic/noradrenergic effects.{{Citation needed|date=July 2011}} The opioid agonistic effect of tramadol and its major metabolite(s) are almost exclusively mediated by the substance's action at the μ-opioid receptor. This characteristic distinguishes tramadol from many other substances (including [[morphine]]) of the opioid drug class, which generally do not possess tramadol's degree of subtype selectivity.

==Medical uses==

Tramadol is used similarly to [[codeine]], to treat moderate to moderately severe pain.<ref name=AHFS>{{cite web|title=Tramadol Hydrochloride

|url=http://www.drugs.com/monograph/tramadol-hydrochloride.html|work=The American Society of Health-System Pharmacists|accessdate=27 April 2011}}</ref> Tramadol is somewhat pharmacologically similar to [[levorphanol]] (albeit with much lower μ-agonism), as both opioids are also NMDA-antagonists which also have [[Serotonin-norepinephrine reuptake inhibitor|SNRI]] activity (other such opioids to do the same are [[dextropropoxyphene]] (Darvon) & M1-like molecule [[tapentadol]] (Nucynta, a new synthetic atypical opioid made to mimic the agonistic properties of tramadol's metabolite, M1(O-Desmethyltramadol). Tramadol is also molecularly similar to [[venlafaxine]] (Effexor) and has similar SNRI effects, with antinociceptive effects also observed. It has been suggested that tramadol could be effective for alleviating symptoms of depression, anxiety, and phobias<ref>{{cite journal |doi=10.1177/026988110401800305 |pmid=15358985 |year=2004 |last1=Rojas-Corrales |first1=MO |last2=Berrocoso |first2=E |last3=Gibert-Rahola |first3=J |last4=Micó |first4=JA |title=Antidepressant-like effect of Tramadol and its enantiomers in reserpinized mice: comparative study with desipramine, fluvoxamine, venlafaxine and opiates |volume=18 |issue=3 |pages=404–11 |journal=Journal of psycho-pharmacology}}</ref> because of its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.<ref>{{cite journal |pmid=16762426 |year=2006 |last1=Micó |first1=JA |last2=Ardid |last3=Berrocoso |last4=Eschalier |title=Antidepressants and pain |volume=27 |issue=7 |pages=348–54 |doi=10.1016/j.tips.2006.05.004 |journal=Trends in pharmacological sciences |first2=D |first3=E |first4=A}}</ref> However, health professionals have not endorsed its use for these disorders,<ref>{{cite journal |pmid=9749830 |year=1998 |last1=Rojas-Corrales |first1=MO |last2=Gibert-Rahola |last3=Micó |title=Tramadol induces antidepressant-type effects in mice |volume=63 |issue=12 |pages=PL175–80 |journal=Life sciences |doi=10.1016/S0024-3205(98)00369-5 |first2=J |first3=JA}}</ref><ref>{{cite journal |pmid=11565620 |year=2001 |last1=Hopwood |first1=SE |last2=Owesson |last3=Callado |last4=Mclaughlin |last5=Stamford |title=Effects of chronic Tramadol on pre- and post-synaptic measures of mono-amine function |volume=15 |issue=3 |pages=147–53 |journal=Journal of psycho-pharmacology |first2=CA |first3=LF |first4=DP |first5=JA |doi=10.1177/026988110101500301}}</ref> claiming it may be used as a unique treatment (only when other treatments failed), and must be used under the control of a psychiatrist.<ref>{{cite journal |author=Rojas-Corrales MO, Gibert-Rahola J, Micó JA |title=Tramadol induces antidepressant-type effects in mice |journal=Life Sciences |volume=63 |issue=12 |pages=PL175–80 |year=1998 |pmid=9749830 |doi=10.1016/S0024-3205(98)00369-5}}</ref><ref>{{cite journal |author=Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA |title=Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function |journal=Journal of Psychopharmacology |volume=15 |issue=3 |pages=147–53 |year=2001 |month=September |pmid=11565620 |url=http://jop.sagepub.com/cgi/pmidlookup?view=long&pmid=11565620 |doi=10.1177/026988110101500301}}</ref>

In May 2009, the United States Food and Drug Administration issued a [[FDA Warning Letter|Warning Letter]] to Johnson & Johnson, alleging that a promotional website commissioned by the manufacturer had "overstated the efficacy" of the drug, and "minimized the serious risks".<ref>Thomas W. Abrams [http://www.fda.gov/downloads/Drugs/guidanceComplianceRegulatoryinformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM153130.pdf Warning Letter to William C. Weldon, Chairman of the Board and Chief Executive Officer, Johnson & Johnson]. 5/12/2009</ref> The company which produced it, the German pharmaceutical company Grünenthal GmbH, were alleged to be guilty of "minimizing" the addictive nature and proposed efficacy of the drug, although it showed little abuse liability in preliminary tests. The 2010 [[Physicians Desk Reference]] contains several warnings from the manufacturer, which were not present in prior years. The warnings include more compelling language regarding the addictive potential of tramadol, the possibility of difficulty breathing while on the medication, a new list of more serious side effects, and a notice that tramadol is not to be used in place of opiate medications for addicts. Tramadol is also not to be used in efforts to wean addict patients from opiate drugs, nor to be used to manage long-term opiate addiction.

===Availability and usage===

[[File:50mgtramadolhclakyma.jpg|thumb|50 mg Tramadol HCl tablets (generic Ultram) marketed by Akyma Pharmaceuticals. Immediate release tramadol HCl is available in many generic preparations.]]

[[File:200mgTramadol.jpg|thumb|Bottle of 30 tablets of 200 mg extended-release tramadol HCl (generic Ultram ER) marketed by Patriot. Extended-release tramadol is commonly available in 100, 200, and 300 mg strengths to be taken once daily. It is often prescribed with tramadol-APAP (Ultracet) or regular immediate-release tramadol HCl (Ultram/Tramal/Rybix) for breakthrough pain.<ref>http://www.ultram-er.com/sites/default/files/ultramer.pdf</ref>]]

Tramadol is classified as a central nervous system drug usually marketed as the hydrochloride salt (tramadol hydrochloride); the tartrate is seen on rare occasions, and rarely (in the US at least) tramadol is available for both [[injection (medicine)|injection]] ([[intravenous]] and/or [[intramuscular]]) and oral administration. The most well known dosing unit is the 50&nbsp;mg generic tablet made by several manufacturers. It is also commonly available in conjunction with APAP ([[paracetamol]], acetaminophen) as Ultracet, in the form of a smaller dose of 37.5&nbsp;mg tramadol and 325&nbsp;mg of APAP. The solutions suitable for injection are used in patient-controlled analgesia pumps under some circumstances, either as the sole agent or along with another agent such as morphine.

Tramadol comes in many forms, including:

*capsules (regular and extended release)

*tablets (regular, extended release, chewable, low-residue and/or uncoated tablets that can be taken by the sublingual and buccal routes)

*suppositories

*effervescent tablets and powders

*ampules of sterile solution for SC, IM, and IV injection

*preservative-free solutions for injection by the various spinal routes (epidural, intrathecal, caudal, and others)

*powders for compounding

*liquids both with and without alcohol for oral and sub-lingual administration, available in regular phials and bottles, dropper bottles, bottles with a pump similar to those used with liquid soap and phials with droppers built into the cap

*tablets and capsules containing ([[acetaminophen]]/APAP), [[aspirin]] and other agents.

Tramadol has been regularly used in the form of an ingredient in multi-agent topical gels, creams, and solutions for nerve pain, rectal foam, concentrated retention enema, and a skin plaster (transdermal patch) quite similar to those used with lidocaine.

Tramadol has a characteristic and unpleasant taste which is mildly bitter but much less so than morphine and codeine. Oral and sublingual drops and liquid preparations come with and without added flavoring. Its relative effectiveness via transmucosal routes (i.e. sublingual, buccal, rectal) is similar to that of codeine, and, like codeine, it is also metabolized in the liver to stronger metabolites (see below).

The maximum dosage per day is 400&nbsp;mg for oral use and 600&nbsp;mg for parenteral use. Certain manufacturers or formulations have lower maximum doses. For example, Ultracet (37.5&nbsp;mg/325&nbsp;mg tramadol/APAP tablets) is capped at 8 tablets per day (300&nbsp;mg/day) due to its acetaminophen content. Ultram ER is available in 100, 200, and 300&nbsp;mg/day doses and is explicitly capped at 300&nbsp;mg/day as well.

Patients taking SSRIs (Prozac, Zoloft, etc.), SNRIs (Effexor, etc.), TCAs, MAOIs, or other strong opioids (oxycodone, methadone, fentanyl, morphine), as well as the elderly (> 75 years old), pediatric (< 18 years old), and those with severely reduced renal (kidney) or hepatic (liver) function should consult their doctor regarding adjusted dosing or whether to use Tramadol at all.

===Investigational uses===

* [[diabetic neuropathy]]&nbsp;<ref name="pmid9633738">{{cite journal |pmid=9633738 |year=1998 |last1=Harati |first1=Y |last2=Gooch |last3=Swenson |last4=Edelman |last5=Greene |last6=Raskin |last7=Donofrio |last8=Cornblath |last9=Sachdeo |title=Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy |volume=50 |issue=6 |pages=1842–6 |journal=Neurology |first2=C |first3=M |first4=S |first5=D |first6=P |first7=P |first8=D |first9=R}}</ref><ref name="pmid10959067">{{cite journal |pmid=10959067 |doi=10.1016/S1056-8727(00)00060-X |year=2000 |last1=Harati |first1=Y |last2=Gooch |last3=Swenson |last4=Edelman |last5=Greene |last6=Raskin |last7=Donofrio |last8=Cornblath |last9=Olson |title=Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy |volume=14 |issue=2 |pages=65–70 |journal=Journal of diabetes and its complications |first2=C |first3=M |first4=SV |first5=D |first6=P |first7=P |first8=D |first9=WH}}</ref>

*[[postherpetic neuralgia]]&nbsp;<ref name="pmid9190323">{{cite journal |pmid=9190323 |year=1997 |last1=Göbel |first1=H |last2=Stadler |title=Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine |volume=53 Suppl 2 |pages=34–9 |journal=Drugs |first2=T}}</ref><ref name="pmid12855342">{{cite journal |pmid=12855342|doi=10.1016/S0304-3959(03)00020-4 |year=2003 |last1=Boureau |first1=F |last2=Legallicier |last3=Kabir-Ahmadi |title=Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial |volume=104 |issue=1–2 |pages=323–31 |journal=Pain |first2=P |first3=M}}</ref>

*acute [[Opioid_dependence#Symptoms_of_withdrawal|opioid withdrawal]] management<ref name="pmid147253475">{{cite journal |pmid=14723475 |year=2003 |last1=Sobey |first1=PW |last2=Parran Tv |last3=Grey |last4=Adelman |last5=Yu |title=The use of tramadol for acute heroin withdrawal: a comparison to clonidine |volume=22 |issue=4 |pages=13–25 |journal=Journal of addictive diseases |first2=TV |first3=SF |first4=CL |first5=J}}</ref><ref name="pmid16595358">{{cite journal |pmid=16595358 |doi=10.1080/10550490500528712 |year=2006 |last1=Threlkeld |first1=M |last2=Parran |last3=Adelman |last4=Grey |last5=Yu |title=Tramadol versus buprenorphine for the management of acute heroin withdrawal: a retrospective matched cohort controlled study |volume=15 |issue=2 |pages=186–91 |journal=The American journal on addictions |first2=TV |first3=CA |first4=SF |first5=J |last6=Yu |first6=Jaehak}}</ref>

*[[SSRI discontinuation syndrome|antidepressant withdrawal]] aid (proven to be effective, especially with withdrawal from its distant relative [[venlafaxine]] (Effexor)).{{Citation needed|date=May 2011}}

*[[obsessive-compulsive disorder]]&nbsp;<ref name="pmid10200754">{{cite journal |pmid=10200754 |url=http://ajp.psychiatryonline.org/cgi/content/full/156/4/660a |journal=American Journal of Psychiatry |title=Rapid Remission of OCD with Tramadol Hydrochloride |volume=156 |issue=4 |page=660 |year=1999 |author1=Goldsmith, Toby D |author2=Shapira, Nathan A |author3=Keck, Paul E}}</ref>

*[[premature ejaculation]]&nbsp;<ref name="pmid17362279">{{cite journal |pmid=17362279|doi= 10.1111/j.1743-6109.2006.00424.x |year=2008 |last1=Salem |first1=EA |last2=Wilson |last3=Bissada |last4=Delk |last5=Hellstrom |last6=Cleves |title=Tramadol HCL has promise in on-demand use to treat premature ejaculation |volume=5 |issue=1 |pages=188–93 |journal=The journal of sexual medicine |first2=SK |first3=NK |first4=JR |first5=WJ |first6=MA}}</ref>

==Adverse effects==

{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"

|+Probability of adverse effects<ref>{{cite journal |journal=Clinical Therapeutics |title=Tramadol/Acetaminophen Combination Tablets and Codeine/Acetaminophen Combination Capsules for the Management of Chronic Pain: A Comparative Trial |volume=23 |issue=9 |year=2001 |author1=Mullican, W. S. |author2=Lacy, J. R. |pmid=11589258 |last3=Tramap-Anag-006 Study |first3=Group |pages=1429–45}}</ref>

! style="width:115px;"| Effect

! style="width:40px;"| Probability (%)

| Any adverse effect

| style="text-align:right;"| 71

| Drowsiness

|align="right"| 17

| Nausea

|align="right"| 17

| Dizziness

|align="right"| 15

| Constipation

|align="right"| 11

| Headache

|align="right"| 11

| Vomiting

|align="right"| 7

| Diarrhea

|align="right"| 6

| Dry Mouth

|align="right"| 5

| Fatigue

|align="right"| 5

| Indigestion

|align="right"| 5

| Seizure<ref name="pharmocotherapy2000"/>

|align="right"| <1

[[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>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695011.html |title=Tramadol |work=[[MedlinePlus]] |publisher=[[American Society of Health-System Pharmacists]] |accessdate=29 September 2009 |date=1 September 2008}}</ref>]]

The most commonly reported [[adverse drug reaction]]s are nausea, vomiting, sweating, itching and [[constipation]]. Drowsiness is reported, although it is less of an issue than for non-synthetic opioids. Patients prescribed tramadol for general pain relief with or without other agents have reported withdrawal symptoms including uncontrollable nervous tremors, muscle contracture, and 'thrashing' in bed (similar to restless leg syndrome) if weaning off the medication happens too quickly. Anxiety, 'buzzing', 'electrical shock' and other sensations may also be present, similar to those noted in Effexor withdrawal. [[Respiratory depression]], a common side-effect of most opioids, is not clinically significant in normal doses. By itself, it can decrease the [[seizure|seizure threshold]]. When combined with SSRIs, [[tricyclic antidepressant]]s, or in patients with epilepsy, the seizure threshold is further decreased. Seizures have been reported in humans receiving excessive single oral doses (700&nbsp;mg) or large intravenous doses (300&nbsp;mg). However, there have been several rare cases of people having grand-mal seizures at doses as low as 100–400&nbsp;mg orally.<ref>{{cite web|author=Pseudome |url=http://www.erowid.org/experiences/exp.php?ID=81951 |title=Erowid Experience Vaults: Tramadol (Ultram) – Overdose – 81951 |publisher=Erowid.org |date=2009-10-28 |accessdate=2010-04-18}}</ref><ref>{{cite web|author=by Rifter |url=http://www.erowid.org/experiences/exp.php?ID=63922 |title=Erowid Experience Vaults: Tramadol (Ultram) – My Seizures – 63922 |publisher=Erowid.org |date=2007-06-25 |accessdate=2010-04-18}}</ref><ref>{{cite web|author=by angelsigh |url=http://www.erowid.org/experiences/exp.php?ID=13574 |title=Erowid Experience Vaults: Tramadol (Ultram) – My Four Months On It... – 13574 |publisher=Erowid.org |date=2003-07-24 |accessdate=2010-04-18}}</ref> An Australian study found that of 97 confirmed new-onset seizures, eight were associated with tramadol, and that in the authors' First Seizure Clinic, "tramadol is the most frequently suspected cause of provoked seizures".<ref>{{cite journal |pmid=15651948 |year=2005 |last1=Labate |first1=A |last2=Newton |first2=MR |last3=Vernon |first3=GM |last4=Berkovic |first4=SF |title=Tramadol and new-onset seizures [letter] |volume=182 |issue=1 |pages=42–43 |journal=Medical Journal of Australia}}</ref> There appears to be growing evidence that Tramadol use may have serious risks in some individuals and it is contra-indicated in patients with uncontrolled epilepsy (BNF 59). Seizures caused by tramadol are most often [[tonic-clonic seizures]], more commonly known in the past as grand mal seizures. Also when taken with [[SSRIs]], there is an increased risk of [[serotonin syndrome|serotonin toxicity]], which can be fatal. Fewer than 1% of users have a presumed incident seizure claim after their first tramadol prescription. Risk of seizure claim increases two- to six-fold among users adjusted for selected comorbidities and concomitant drugs. Risk of seizure is highest among those aged 25–54 years, those with more than four tramadol prescriptions, and those with a history of alcohol abuse, stroke, or head injury.<ref name="pharmocotherapy2000">{{cite journal |journal=Pharmocotherapy |title=Tramadol and Seizures: A Surveillance Study in a Managed Care Population |volume=20 |issue=12 |year=2000 |author1=Gardner, J. S. |author2=Blough, D. |author3=Drinkard, C. R. |author4=Shatin, D. |author5=Anderson, G. |author6=Graham, D. |author7=Alderfer, R.}}</ref> Dosages of [[warfarin]] may need to be reduced for anticoagulated patients to avoid bleeding complications. [[Constipation]] can be severe especially in the elderly requiring manual evacuation of the bowel.{{Citation needed|date=August 2008}} Furthermore, there are suggestions that chronic opioid administration may induce a state of [[immune tolerance]],<ref>Bryant et al. 1988;{{Verify source|date=September 2009}} Rouveix 1992;{{Verify source|date=September 2009}} cited by {{cite journal |pmid=11460802 |year=2001 |last1=Collett |first1=BJ |title=Chronic opioid therapy for non-cancer pain |volume=87 |issue=1 |pages=133–43 |journal=British journal of anaesthesia |doi=10.1093/bja/87.1.133}}</ref> although tramadol, in contrast to typical opioids may enhance immune function.<ref>{{cite journal |pmid=10825330 |url=http://www.anesthesia-analgesia.org/cgi/content/abstract/90/6/1411 |journal=Anesthesia & Analgesia |title=The Effects of Tramadol and Morphine on Immune Responses and Pain After Surgery in Cancer Patients |volume=90 |issue=6 |page=1411 |year=2000 |author1=Sacerdote, Paola |author2=Bianchi, Mauro |author3=Gaspani, Leda |author4=Manfredi, Barbara |author5=Maucione, Antonio |author6=Terno, Giovanni |author7=Ammatuna, Mario |author8=Panerai, Alberto E |doi=10.1097/00000539-200006000-00028}}</ref><ref>{{cite journal |pmid=17120754 |year=2006 |last1=Liu |first1=Z |last2=Gao |last3=Tian |title=Effects of morphine, fentanyl and tramadol on human immune response |volume=26 |issue=4 |pages=478–81 |journal=Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban |first2=F |first3=Y}}</ref><ref>{{cite journal |pmid=9313273 |year=1997 |last1=Sacerdote |first1=P |last2=Bianchi |last3=Manfredi |last4=Panerai |title=Effects of tramadol on immune responses and nociceptive thresholds in mice |volume=72 |issue=3 |pages=325–30 |journal=Pain |doi=10.1016/S0304-3959(97)00055-9 |first2=M |first3=B |first4=AE}}</ref> Some have also stressed the negative effects of opioids on cognitive functioning and personality.<ref>Maruta 1978;{{Verify source|date=September 2009}} McNairy et al. 1984;{{Verify source|date=September 2009}} cited by {{cite journal |pmid=11460802 |year=2001 |last1=Collett |first1=BJ |title=Chronic opioid therapy for non-cancer pain |volume=87 |issue=1 |pages=133–43 |journal=British journal of anaesthesia |doi=10.1093/bja/87.1.133}}</ref>

===Physical dependence and withdrawal===

Tramadol is associated with the development of [[physical dependence]] and a severe withdrawal syndrome.<ref>{{cite journal |pmid=12563592 |doi=10.1053/ajem.2003.50039 |year=2003 |last1=Barsotti |first1=CE |last2=Mycyk |last3=Reyes |title=Withdrawal syndrome from tramadol hydrochloride |volume=21 |issue=1 |pages=87–8 |journal=The American journal of emergency medicine |first2=MB |first3=J}}</ref> Tramadol causes typical [[Opioid#Dependence|opiate-like withdrawal]] symptoms as well as atypical withdrawal symptoms including seizures. The atypical withdrawal symptoms are probably related to tramadol's effect on serotonin and norepinephrine re-uptake. Symptoms may include those of [[SSRI discontinuation syndrome]], such as [[anxiety]], [[Clinical depression|depression]], anguish, severe mood swings, aggressiveness, brain "zaps", electric-shock-like sensations throughout the body, [[paresthesias]], [[sweating]], [[palpitations]], [[restless legs syndrome]], sneezing, [[insomnia]], tremors, and headache among others. In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. Tramadol withdrawal lasts longer than that of other opioids; seven days or more of acute withdrawal symptoms can occur as opposed to typically three or four days for other codeine analogues. It is recommended that patients physically dependent on pain killers take their medication regularly to prevent onset of withdrawal symptoms and this is particularly relevant to tramadol because of its SSRI and SNRI properties, and, when the time comes to discontinue their tramadol, to do so gradually over a period of time that will vary according to the individual patient and dose and length of time on the drug.<ref>{{cite journal |pmid=18704211 |year=2008 |last1=Choong |first1=K |last2=Ghiculescu |title=Iatrogenic neuropsychiatric syndromes |volume=37 |issue=8 |pages=627–9 |journal=Australian family physician |first2=RA}}</ref><ref>{{cite journal |pmid=15569913 |doi=10.1176/appi.ajp.161.12.2326 |year=2004 |last1=Ripamonti |first1=C |last2=Fagnoni |last3=De Conno |title=Withdrawal syndrome after delayed tramadol intake |volume=161 |issue=12 |pages=2326–7 |journal=The American journal of psychiatry |first2=E |first3=F}}</ref><ref>{{cite journal |pmid=12825576 |year=2003 |title=Withdrawal syndrome and dependence: tramadol too |volume=12 |issue=65 |pages=99–100 |journal=Prescrire international}}</ref><ref>{{cite journal |pmid=12633909 |doi=10.1016/S0376-8716(02)00321-6 |year=2003 |last1=Senay |first1=EC |last2=Adams |last3=Geller |last4=Inciardi |last5=Muñoz |last6=Schnoll |last7=Woody |last8=Cicero |title=Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur |volume=69 |issue=3 |pages=233–41 |journal=Drug and alcohol dependence |first2=EH |first3=A |first4=JA |first5=A |first6=SH |first7=GE |first8=TJ}}</ref>

===Psychological dependence and recreational use===

Some controversy regarding the abuse potential of tramadol exists. Grünenthal has promoted it as an opioid with a lower risk of [[opioid dependence]] than that of traditional opioids, claiming little evidence of such dependence in clinical trials (which is true; Grünenthal never claimed it to be non-addictive). They offer the theory that, since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces abuse liability. The norepinephrine reuptake inhibitor effects may also play a role in reducing dependence.

It is apparent in community practice that dependence to this agent may occur after as little as three months of use at the maximum dose—generally depicted at 400&nbsp;mg per day. However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, and been rescheduled in Sweden rather than as a [[Standard for the Uniform Scheduling of Drugs and Poisons#Schedule 8 Controlled Drug (Possession without authority illegal)|Schedule 8 Controlled Drug]] like [[opioid]]s.<ref>Rossi, 2004{{Verify source|date=September 2009}}</ref> Similarly, tramadol is not currently scheduled by the U.S. [[Drug Enforcement Agency|DEA]], unlike opioid analgesics. It is, however, scheduled in certain states.<ref name=kwpr>{{cite press release |title = Tramadol Listed as Schedule IV Substance in Kentucky |publisher=Kentucky Board of Pharmacy |date=8 December 2008 |url=http://pharmacy.ky.gov/NR/rdonlyres/9A7E27E4-1D37-4F44-A542-C9DD5B487822/0/TramadolNotification.pdf |accessdate=8 February 2009}}</ref> Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type".

Dependence on Tramadol has been reported to be a major social problem in the Gaza Strip. The Hamas government has attempted to cut off supplies of the drug, and in April 2010 burnt 2 million tablets which had been intercepted while being smuggled into the territory.<ref>{{cite news|url=http://www.guardian.co.uk/world/2010/apr/20/hamas-burns-tramadol-painkillers-smuggled-gaza|title=Hamas burns Tramadol painkillers smuggled into Gaza|date=20 April 2010|last=McCarthy|first=Rory|work=The Guardian|location=London|publisher=Guardian Media Group|accessdate=8 February 2011}}</ref>

Because of the possibility of [[convulsions]] at high doses for some users, recreational use can be very dangerous.<ref>{{cite journal |pmid=16615669 |doi=10.1080/1556365050014418 |year=2006 |last1=Jovanović-Cupić |first1=V |last2=Martinović |last3=Nesić |title=Seizures associated with intoxication and abuse of tramadol |volume=44 |issue=2 |pages=143–6 |journal=Clinical toxicology |first2=Z |first3=N}}</ref> Tramadol can, however, via agonism of [[mu Opioid receptor|μ opioid receptor]]s, produce effects similar to those of other opioids (codeine and other weak opioids), although not nearly as intense due to tramadol's much lower affinity for this receptor. Tramadol can cause a higher incidence of [[nausea]], dizziness, loss of appetite compared with opiates which could deter abuse to some extent.<ref>{{cite journal |pmid=17298254 |doi=10.1089/jpm.2006.0117 |year=2007 |last1=Rodriguez |first1=RF |last2=Bravo |last3=Castro |last4=Montoya |last5=Castillo |last6=Castillo |last7=Daza |last8=Restrepo |last9=Rodriguez |title=Incidence of weak opioids adverse events in the management of cancer pain: a double-blind comparative trial |volume=10 |issue=1 |pages=56–60 |journal=Journal of palliative medicine |first2=LE |first3=F |first4=O |first5=JM |first6=MP |first7=P |first8=JM |first9=MF}}</ref> Tramadol can help alleviate withdrawal symptoms from opiates, and it is much easier to control the quantity of its usage than street drugs.<ref name="abusecomp">{{cite journal |doi=10.1016/j.jpainsymman.2005.10.006 |url=http://paincenter.wustl.edu/c/BasicResearch/documents/CiceroJPain2006.pdf |pmid=16716877 |year=2006 |last1=Adams |first1=EH |last2=Breiner |first2=S |last3=Cicero |first3=TJ |last4=Geller |first4=A |last5=Inciardi |first5=JA |last6=Schnoll |first6=SH |last7=Senay |first7=EC |last8=Woody |first8=GE |title=A comparison of the abuse liability of tramadol, NSAIDs, and Codeine in patients with chronic pain |volume=31 |issue=5 |pages=465–76 |journal=Journal of pain and symptom management}}</ref> It may also have large effect on sleeping patterns and high doses may cause insomnia. (Especially for those on methadone, both for maintenance and recreation. Though there is no scientific proof tramadol lessens effects or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and breakthrough pain.)<ref>{{cite journal |pmid=18557165 |year=2008 |last1=Vorsanger |first1=GJ |last2=Xiang |last3=Gana |last4=Pascual |last5=Fleming |title=Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain |volume=4 |issue=2 |pages=87–97 |journal=Journal of opioid management |first2=J |first3=TJ |first4=ML |first5=RR}}</ref>

===Detection in biological fluids===

Tramadol and ''O''-desmethyltramadol may be quantitated in blood, plasma or serum to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or 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 quantitate these substances. The concentrations of ''O''-desmethyltramadol in the blood or plasma of a person who has taken tramadol are generally 10–20% those of the parent drug.<ref>{{cite journal|pmid=17575561|year=2007|last1=Karhu|first1=D|last2=El-Jammal|first2=A|last3=Dupain|first3=T|last4=Gaulin|first4=D|last5=Bouchard|first5=S|title=Pharmacokinetics and dose proportionality of three Tramadol Contramid OAD tablet strengths|volume=28|issue=6|pages=323–30|doi=10.1002/bdd.561|journal=Biopharmaceutics & drug disposition}}</ref><ref>{{cite journal|pmid=17350197|year=2007|last1=Tjäderborn|first1=M|last2=Jönsson|first2=AK|last3=Hägg|first3=S|last4=Ahlner|first4=J|title=Fatal unintentional intoxications with tramadol during 1995-2005|volume=173|issue=2–3|pages=107–11|doi=10.1016/j.forsciint.2007.02.007|journal=Forensic science international}}</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1573–1576 ISBN 0962652377.</ref>

==Mechanism of action==

Tramadol acts as a [[mu-opioid receptor|μ-opioid receptor]] [[agonist]],<ref name="pmid2849950">{{cite journal|author = Hennies HH, Friderichs E, Schneider J|title = Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids|journal = Arzneimittel-Forschung|volume = 38|issue = 7|pages = 877–80|year = 1988|month = July|pmid = 2849950|doi =|url =}}</ref><ref name="pmid8955860">{{cite journal|author = 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 = 1029–36|year = 1996|month = November|pmid = 8955860|doi =|url =}}</ref> [[serotonin releasing agent]],<ref name="pmid9671098">{{cite journal |author=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 |year=1998 |month=May |pmid=9671098 |doi=10.1016/S0014-2999(98)00195-2}}</ref><ref name="pmid12354291"/><ref name="pmid1596676">{{cite journal|author = 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 = 147–51|year = 1992|month = January|pmid = 1596676|pmc = 1908625|doi =|url =}}</ref><ref name="pmid9389855">{{cite journal|author = 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 = 352–6|year = 1997|month = September|pmid = 9389855|doi =|url = http://bja.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9389855}}</ref> [[norepinephrine reuptake inhibitor]],<ref name="pmid8955860">{{cite journal |author=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=1029–36 |year=1996 |month=November |pmid=8955860}}</ref> [[NMDA receptor]] [[receptor antagonist|antagonist]],<ref name="pmid15845694">{{cite journal |author=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=1400–5, table of contents |year=2005 |month=May |pmid=15845694 |doi=10.1213/01.ANE.0000150961.24747.98}}</ref> [[5-HT2C receptor|5-HT_2C receptor]] antagonist,<ref name="pmid15105221">{{cite journal |author=Ogata J, Minami K, Uezono Y, ''et al.'' |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 |year=2004 |month=May |pmid=15105221 |url=http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=15105221 |doi=10.1213/01.ANE.0000108963.77623.A4}}</ref> [[alpha-7 nicotinic receptor|(α7)₅]] [[nicotinic acetylcholine receptor]] antagonist,<ref name="pmid12010769">{{cite journal |author=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=207–16 |year=2002 |month=May |pmid=12010769 |pmc=1573343 |doi=10.1038/sj.bjp.0704703}}</ref> [[TRPV1]] receptor agonist,<ref name="pmid18499628">{{cite journal|author = 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 = Anesth Analg.|volume = 106|issue = 6|pages = 1890–6|year = 2008|month = June|pmid = 18499628|doi =10.1213/ane.0b013e318172fefc|url = http://www.ncbi.nlm.nih.gov/pubmed/18499628}}</ref> and [[muscarinic acetylcholine receptor M1|M₁]] and [[muscarinic acetylcholine receptor M3|M₃]] [[muscarinic acetylcholine receptor]] antagonist.<ref name="pmid11561087">{{cite journal |author=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=255–60 |year=2001 |month=October |pmid=11561087 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11561087}}</ref><ref name="pmid12401609">{{cite journal |author=Shiga Y, Minami K, Shiraishi M, ''et al.'' |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 |year=2002 |month=November |pmid=12401609 |url=http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=12401609 |doi=10.1097/00000539-200211000-00031}}</ref>

The analgesic action of tramadol has yet to be fully understood, but it is believed to work through modulation of serotonin and norepinephrine in addition to its mild agonism of the μ-opioid receptor. The contribution of non-opioid activity is demonstrated by the fact that the analgesic effect of tramadol is not fully antagonised by the μ-opioid receptor antagonist [[naloxone]].

Tramadol is marketed as a [[racemic]] mixture of the (1''R'',2''R'')- and (1''S'',2''S'')-enantiomers with a weak affinity for the μ-opioid receptor (approximately 1/6000th that of [[morphine]]; Gutstein & Akil, 2006). The (1''R'',2''R'')-(+)-[[enantiomer]] is approximately four times more potent than the (1''S'',2''S'')-(–)-enantiomer in terms of [[Opioid receptor#The μ-opioid receptor|μ-opioid receptor]] affinity and [[5-HT]] reuptake, whereas the (1''S'',2''S'')-(–)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (1''R'',2''R'')-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1''S'',2''S'')-(–)-tramadol (Goeringer et al., 1997).

The [[serotonergic]]-modulating properties of tramadol give it the potential to interact with other serotonergic agents. There is an increased risk of [[serotonin syndrome|serotonin toxicity]] when tramadol is taken in combination with serotonin reuptake inhibitors (e.g., [[Selective serotonin reuptake inhibitor|SSRIs]]), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism.{{Citation needed|date=September 2009}} Tramadol is also thought to have some [[NMDA antagonist]]ic effects, which has given it a potential application in neuropathic pain states.

Tramadol has inhibitory actions on the 5-HT_2C receptor. Antagonism of 5-HT_2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses.<ref>{{cite journal |pmid=15105221 |year=2004 |last1=Ogata |first1=J |last2=Minami |last3=Uezono |last4=Okamoto |last5=Shiraishi |last6=Shigematsu |last7=Ueta |title=The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes |volume=98 |issue=5 |pages=1401–6, table of contents |journal=Anesthesia and analgesia |first2=K |first3=Y |first4=T |first5=M |first6=A |first7=Y |doi=10.1213/01.ANE.0000108963.77623.A4}}</ref> 5-HT_2C blockade may also account for its lowering of the [[seizure]] threshold, as 5-HT_2C 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 [[GABA-A]] receptors at high doses.<ref name="pmid15845694"/>

The overall [[analgesic]] profile of tramadol supports intermediate pain, especially chronic states. It is slightly less effective for acute pain than [[hydrocodone]], but more effective than [[codeine]]. It has a dosage ceiling similar to [[codeine]], a risk of seizures when overdosed, and a relatively long half-life making its potential for abuse relatively low amongst intermediate strength [[analgesics]].

Tramadol's primary active [[metabolite]], ''O''-desmethyltramadol, is a considerably more potent μ-opioid receptor agonist than tramadol itself, and is so much more so that tramadol can partially be thought of as a [[prodrug]] to ''O''-desmethyltramadol. Similarly to tramadol, ''O''-desmethyltramadol has also been shown to be a [[norepinephrine reuptake inhibitor]], 5-HT_2C receptor antagonist, and M₁ and M₃ muscarinic acetylcholine receptor antagonist.{{Citation needed|reason=Feb 2010|date=February 2010}}

===Characteristics===

Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and tramadol share the 3-methyl ether group, and both compounds are metabolized along the same hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this is morphine, and for tramadol, it is the ''O''-desmethyltramadol.

===Comparison with related substances===

Structurally, [[tapentadol]] is the closest chemical relative of tramadol in clinical use. Tapentadol is also an opioid, but unlike both tramadol and venlafaxine, tapentadol represents only one stereoisomer and is the weaker of the two, in terms of opioid effect. Both tramadol and venlafaxine are racemic mixtures. Structurally, tapentadol also differs from tramadol in being a phenol, and not an ether. Also, both tramadol and venlafaxine incorporate a cyclohexyl moiety, attached directly to the aromatic, while tapentadol lacks this feature. In reality, the closest structural chemical entity to tapentadol in clinical use is the over-the-counter drug phenylephrine. Both share a meta phenol, attached to a straight chain hydrocarbon. In both cases, the hydrocarbon terminates in an amine.

[[File:(1R,2R)-Tramadol.svg|150px|(1R,2R)-Tramadol]] &nbsp; [[File:(1S,2S)-Tramadol gespiegelt.svg|150px|(1S,2S)-Tramadol]]<br/>(1''R'',2''R'')-Tramadol &nbsp; &nbsp; (1''S'',2''S'')-Tramadol<br/>[[File:(1R,2S)-Tramadol.svg|150px|(1R,2S)-Tramadol]] &nbsp; [[File:(1S,2R)-Tramadol gespiegelt.svg|150px|(1S,2R)-Tramadol]]<br/>(1''R'',2''S'')-Tramadol &nbsp; &nbsp; (1''S'',2''R'')-Tramadol

The chemical synthesis of tramadol is described in the literature.<ref name="Kleemann">Pharmaceutical Substances, Axel Kleemann, Jürgen Engel, Bernd Kutscher and Dieter Reichert, 4. ed. (2000) 2 volumes, Thieme-Verlag Stuttgart (Germany), p. 2085 bis 2086, ISBN 978-1-58890-031-9; since 2003 online with biannual actualizations.</ref> Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the [[cyclohexane]] ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in ''four'' different configurational forms:

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|last1 = Zynovy|first1 = Zinovy| last2 = Meckler|first2 = Harold|year = 2000| title = A Practical Procedure for the Resolution of (+)- and (−)-Tramadol|url =|journal = Organic Process Research & Development|volume = 4| doi = 10.1021/op000281v|issue =4|pages = 291–294}}</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="Burke">{{cite journal |author=Burke D, Henderson DJ |title=Chirality: a blueprint for the future |journal=British Journal of Anaesthesia |volume=88 |issue=4 |pages=563–76 |year=2002 |month=April |pmid=12066734 |doi=10.1093/bja/88.4.563}}</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>{{cite pmid|8229760}}</ref> and in humans.<ref>{{cite pmid|8657431}}</ref>

==Metabolism==

Tramadol undergoes [[hepatic]] metabolism via the [[cytochrome P450]] [[isozyme]] [[CYP2B6]], [[CYP2D6]] and [[CYP3A4]], being ''O''- and ''N''-demethylated to five different metabolites. Of these, [[O-Desmethyltramadol|''O''-desmethyltramadol]] is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. As with codeine, in the 6% of the population that have increased CYP2D6 activity (increased metabolism), there is therefore an increased analgesic effect. Those with decreased CYP2D6 activity will experience less analgesia. Phase II 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>{{cite journal |author=Grond S, Sablotzki A |title=Clinical pharmacology of tramadol. La de la de da |journal=Clinical Pharmacokinetics |volume=43 |issue=13 |pages=879–923 |year=2004 |pmid= 15509185|doi=10.2165/00003088-200443130-00004}}</ref>

==Legal status==

Tramadol (as the racemic, ''cis''-hydrochloride salt), is available as a generic in the U.S. from any number of different manufacturers, including Amneal, Caraco, Mylan, Cor Pharma, Mallinckrodt, Pur-Pak, APO, Teva, and many more. Typically, the generic tablets are sold in 50&nbsp;mg tablets. Brand name formulations include Ultram ER, and the original Ultram from Ortho-McNeil (cross-licensed from [[Grünenthal|Grünenthal GmbH]]). The extended-release formulation of tramadol—which, amongst other factors—was intended to be more abuse-deterrent than the instant release) allegedly possesses more abuse liability than the instant release formulation.{{Citation needed|date=February 2010}} 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|author=USA |title=Tramadol extended-release in the management of chronic pain |publisher=Ncbi.nlm.nih.gov |date= |pmc=2386353|year=2007|volume=3|issue=3|pmid=18488071|pages=401–10|journal=Therapeutics and clinical risk management}}</ref> It is covered by U.S. patents nos. 6,254,887<ref>{{Ref patent |country=US |number=6254887 |status=patent |title=Controlled Release Tramadol |gdate=3 July 2001 |inventor=Miller, Ronald Brown, ''et al.''}}</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]. Retrieved August 17, 2009.</ref><ref>{{Ref patent |country=US |number=7074430 |status=patent |title=Controlled Release Tramadol Tramadol Formulation |gdate=11 July 2006 |inventor=Miller, Ronald Brown, ''et al.''}}</ref> The FDA lists the patents as scheduled for expiration on May 10, 2014.<ref name=FDAaccessdata/> However, in August 2009, U.S. District Court for the District of Delaware ruled the patents invalid, which, if it survives appeal, would permit manufacture and distribution of generic equivalents of Ultram ER in the United States.<ref>{{cite press release |title=Par Pharmaceutical Wins on Invalidity in Ultram(R) ER Litigation |publisher=[[Par Pharmaceutical]] |date=17 August 2009 |url=http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104&STORY=/www/story/08-17-2009/0005078446&EDATE= |accessdate=29 September 2009}}</ref>

Sweden, as of May 2008, has chosen to classify tramadol as a [[controlled substance]] in the same way as [[codeine]] and [[dextropropoxyphene]]. This means that the substance is a scheduled drug. But unlike codeine and [[dextropropoxyphene]], a normal [[medical prescription|prescription]] can be used at this time.<ref>{{cite web|url=http://www.lakemedelsverket.se/Tpl/NewsPage____7342.aspx |title=Substansen tramadol nu narkotikaklassad på samma sätt som kodein och dextropropoxifen – Läkemedelsverket |publisher=Lakemedelsverket.se |date= |accessdate=2010-04-18}}</ref> In [[Mexico]], combined with paracetamol and sold under the brand name Tramacet, it is widely available without a prescription. In most Asian countries such as the [[Philippines]], it is sold as a capsule under the brand name Tramal, where it is mostly used to treat labor pains.

==Proprietary preparations==

[[Grünenthal|Grünenthal GmbH]], which still owns the patent on Tramadol, has cross-licensed the drug to pharmaceutical companies internationally. Thus, Tramadol is marketed under many trade names around the world, including:

{{Multicol}}

* '''Acugesic''' (Malaysia, Singapore)

* '''Adolonta''' (Spain)

* '''Algifeno''' (Bolivia)

* '''Algesia''' (Philippines)

* '''Anadol''' (Bangladesh, Thailand)

* '''Boldol''' (Bosnia, Herzegovina)

* '''Calmador''' (Argentina)

* '''Campex''' (Pakistan)

* '''Contramal''' (Belgium, France, India, Italy, Turkey, Sudan)

* '''Crispin'''

* '''Dolcet''' (combined with paracetamol)(Philippines)

* '''Dolol''' (Denmark)

* '''Dolzam''' (Belgium, Luxembourg)

* '''Dromadol''' (United Kingdom)

* '''Exopen''' (South Korea)

* '''Ixprim''' (France, Ireland)

* '''Lumidol''' (Bosnia, Herzegowina, Croatia)

* '''Mabron''' (Bahrain, Bangladesh, Bulgaria, Czech Republic, Estonia, Iraq, Jordan, Latvia, Lithuania, Malaysia, Oman, Romania, Singapore, Slovakia, Sri Lanka, Sudan, Yemen)

* '''Mandolgin''' (Denmark)

* '''Mandolgine'''

* '''Mosepan'''

* '''Matrix''' (combined with [[paracetamol]]) (Honduras, Guatemala)

{{Multicol-break}}

* '''Nobligan''' (Argentina, Denmark, Iceland, Mexico, Norway, Portugal, Sweden)

* '''Osteodol''' (India)

* '''Oxxalgan PR''' (Greece)

* Palitex (India)

* '''Poltram''' (Poland)

* '''Pyredol''' (combined with [[paracetamol]]) (Vietnam, Bolivia)

* '''Ralivia''' (Canada)

* '''Ryzolt''' (United States)

* '''Sinergix''' (combined with [[ketorolac]]) (Mexico)

* '''Sintradon''' (Serbia)

* '''Siverol''' (Philippines)

* '''Tandol''' (South Korea)

* '''Tiparol''' (Sweden)

* '''Tonoflex''' (Pakistan)

* '''Topalgic''' (France)

* '''Tradol''' (Bangladesh, Ireland, Mexico, Singapore, Venezuela)

* '''Tradolan''' (Austria, Denmark, Finland, Iceland, Romania, Sweden)

* '''Tradolgesic''' (Thailand)

* '''Tradonal''' (Belgium, Indonesia, Italy, Luxembourg, Netherlands, Philippines, Spain, Switzerland)

* '''Tralgit''' (Czech Republic, [[Georgia (country)|Georgia]], Romania, Slovakia)

* '''Tralodie''' (Italy)

* '''Tramacet''' (combined with [[paracetamol]]) (Canada, Mexico, Costa Rica, South Africa)

* '''Tramacip''' (India)

* '''Tramadex''' (Israel)

* '''Tramadin''' (Finland)

* '''Tramadol HEXAL''' (Denmark, Finland, Germany)

* '''Trexol''' (Mexico)

* '''Trumen''' (Bangladesh)

{{Multicol-break}}

* '''Tramadol''' (Australia, Belgium, Chile, Estonia, France, Netherlands, Romania, New Zealand, Norway, Spain, United States)

* '''Tramadol Stada''' (Sweden)

* '''Tramadolor''' (Austria, Estonia, Germany, Hungary, Latvia, Lithuania, Luxembourg, Romania)

* '''Tramagit''' (Romania)

* '''Tramahexal''' (Australia)

* '''Tramake''' (United Kingdom)

* '''Trama-Klosidol''' (Argentina)

* '''Tramal''' (Pakistan, Netherlands, Finland, Croatia, Morocco, Slovenia, Austria, Poland, Brazil, Chile, Romania, Australia, New Zealand, Germany, Switzerland, Lebanon, Israel, Philippines, Egypt, Thailand)

* '''Tramalgic''' (Hungary)

* '''Tramal Gotas''' (Ecuador)

* '''Tramazac''' (India, Myanmar, Sri Lanka)

* '''Tramed'''

* '''Tramedo''' (Australia)

* '''Tramoda''' (Thailand)

* '''Tramól''' (Iceland)

* '''Tramundal''' (Austria)

* '''Tridol''' (South Korea)

* '''Tridural''' (Canada)

* '''Trodon''' (Serbia)

{{Multicol-break}}

* '''Ultracet''' (combined with [[paracetamol]])

* '''Ultradol'''

* '''Ultram''' and '''Ultram ER''' (United States)

* '''Ultramed''' (combined with [[paracetamol]]) (India)

* '''Veldrol''' (Mexico)

* '''VAMADOL PLUS''' (India)

* '''Volcidol''' (Thailand)

* '''Zafin''' (combined with [[paracetamol]]) (Chile)

* '''Zaldiar''' (combined with [[paracetamol]]) (Belgium, Chile, Croatia, the Czech Republic, Mexico, Poland, Portugal, Slovenia, Spain, Russia)

* '''Zaledor''' (combined with [[paracetamol]]) (Chile)

* '''Zamadol''' (United Kingdom)

* '''Zamudol''' (France)

* '''Zodol''' (Chile, Ecuador, Peru)

* '''Zydol''' (United Kingdom, Ireland, Australia)

* '''Zytram''' (Canada, Iceland, New Zealand, Spain)

* '''Zytrim''' (Spain)

{{Multicol-end}}

==Veterinary medicine==

Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats<ref>{{cite web |url=http://www.veterinarypartner.com/Content.plx?P=A&A=1815&S=1&SourceID=42 |title=Tramadol |work=The Pet Health Library |publisher=Veterinary Information Network |first=Wendy C. |last=Brooks |date=11 April 2008 |accessdate=29 September 2009}}</ref> as well as [[rabbit]]s, [[coatis]], many small mammals including [[rat]]s and [[flying squirrel]]s, [[guinea pig]]s, [[ferret]]s, and [[raccoon]]s. Tramadol comes in ampules in addition to the tablets, capsules, powder for reconstitution, and oral syrups and liquids; the fact that its characteristic taste is distasteful to dogs, but can be masked in food, makes for a means of administration. No data that would lead to a definitive determination of the efficacy and safety of tramadol in reptiles or amphibians is available at this time, and, following the pattern of all other drugs, it appears that tramadol can be used to relieve pain in [[marsupials]] such as North American [[opossum]]s, [[Gray Short-tailed Opossum|Short-Tailed Opossums]], [[sugar glider]]s, [[wallaby|wallabies]], and [[kangaroo]]s among others.

Tramadol for animals is one of the most reliable and useful active principles available to veterinarians for treating animals in pain. It has a dual mode of action: mu agonism and mono-amine reuptake inhibition, which produces mild anti-anxiety results. Tramadol may be utilized for relieving pain in cats and dogs. This is an advantage because the use of some non-steroidal anti-inflammatory substances in these animals may be dangerous.

When animals are administered tramadol, adverse reactions can occur. The most common are constipation, upset stomach, decreased heart rate. In case of overdose, mental alteration, pinpoint pupils and seizures may appear. In such case, veterinarians should evaluate the correct treatment for these events. Some contraindications have been noted in treated animals taking certain other drugs. Tramadol should not be co-administered with selegiline or any other psychoactive class of medication such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, or monoamine oxidase inhibitors. In animals, tramadol is removed from the body via liver and kidney excretion. Animals suffering from diseases in these systems should be monitored by a veterinarian, as it may be necessary to adjust the dose.

<!-- Needs clarification and proper refs: Dosage and administration of tramadol for animals: in dogs for sufficient analgesia: 1–4&nbsp;mg/kg PO q8-12h (Hardie, Lascelles et al. 2003) and to control chronic pain in cats: 4&nbsp;mg/kg PO twice daily (Note: Dose extrapolated from human medicine. Tramadol has not been evaluated for toxicity in cats and has not been used extensively, but early results encouraging) (Lascelles, Robertson et al. 2003).-->

==References==

{{Reflist|2}}

==External links==

* [http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695011.html Medline Plus – Patient Information] Medline Plus (A Service Of The U.S. National Library of Medicine)

* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Tramadol U.S. National Library of Medicine: Drug Information Portal – Tramadol]

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