Tramadol: Difference between revisions

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{{Headerpanel|{{DepressantOD|opiates}}}}
{{Druginfo
{{SummarySheet}}
|author        = [[User:Km39|Km39]] 16:31, 21 March 2007 (PDT)
{{SubstanceBox/Tramadol}}
|certifier      = [[User:Lap22|Lap22]] 09:28, 28 March 2007 (PDT)
|drug name      = Tramadol
|image          = Tramadol
|Review Color  = green
|phonetics      = TRA ma dole
|brand          = Ultram, Ultram ER
|supplied      = Tablets: 50 mg<br>Extended-release tablets: 100 mg, 200 mg, 300 mg
|gen avail      = immediate-release form only
|patent exp    = September 2008 (Ultram ER)
|class          = opioid analgesic
|schedule      = Rx
|preg cat      = C
|breast feed    = Not indicated for mothers who are breast feeding.
|IUPAC name    = rac-(1R,2R)-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol
|emp formula    = (C<sub>16</sub>H<sub>25</sub>NO<sub>2</sub>)•HCl
|MW            = 299.8
|genomicsURL    = http://www.pharmgkb.org/do/serve?objId=PA451735&objCls=Drug
}}
 
== Description ==
Tramadol is a centrally-acting synthetic opioid analgesic that is not a controlled substance.<ref name=a/> Tramadol is used to treat moderate to moderately severe chronic pain. It can also be used to treat breakthrough pain.<ref name=B/> Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures), which can be exacerbated by the use of other medications such [[Selective serotonin reuptake inhibitor (SSRI)|SSRIs]], [[Tricyclic antidepressant (TCA)|TCAs]], and opioids. Additionally tramadol and [[sertraline]], when given in the same regimen, were found to cause a mild serotonin syndrome.<ref name=sert/> Tramadol does not cause GI bleeding, hypertension or heart failure.
 
There is a small chance of tramadol abuse. The rate is 0.75/100,000 patients and of these, 97% of patients who became addicted had a history of drug and alcohol abuse.<ref name=cicerot>Cicero TJ, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug and alcohol dependence. 1999 Nov 1;57(1):7-22</ref>
 
A number of studies have proven the efficacy of tramadol. It is more effective than placebo for osteoarthritis and comparable in efficacy to [[ibuprofen]] 2400 mg/day.<ref name=B/>  Osteoarthritis is an off-label use. Tramadol was found to be substandard to [[Hydrocodone Bitartrate and Acetaminophen|hydrocodone/acetaminophen]] for patients entering the emergency department with acute musculoskeletal pain.<ref name=hydroc>Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.]</ref>  Pain relief tyically begins about one hour after administration.<ref name=a/>
 
== Mechanism of Action ==
Tramadol is a synthetic analgesic which acts centrally through binding to the opioid µ-receptors and via a tricyclic-like mechanism whereby it inhibits neuronal reuptake of serotonin and norepinephrine within the CNS.<ref name=B>Stitik TP, Altschuler E, Foye PM, Stitik TP, Altschuler E, Foye PM. Pharmacotherapy of osteoarthritis. American Journal of Physical Medicine & Rehabilitation. 2006 Nov;85(11 Suppl):S15-28; quiz S9-31.</ref><ref name=C>Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol. 2000 Dec;21(4):370-4.</ref> The opioid activity of tramadol is due to tramadol binding to the µ-receptors and the M1 metabolite, which is O-demethylated, binding to the opioid µ-receptors. M1 is 6-times more potent than tramadol when compared for their analgesic qualities. M1 binds to the µ-receptors 200-times stronger than does tramadol. Additionally, tramadol inhibits the reuptake of serotonin and norepinephrine which is believed to contribute to its analgesic properties.<ref name=a/>
 
== Time Required for Therapeutic Response ==
* Initial: One hour<ref name=B/>
 
== Pharmacokinetics ==
'''Absorption'''<br>
Tramadol is almost completely absorbed. The bioavailability of a 100 mg dose is 75%. The peak plasma concentrations of racemic tramadol occur 2 hours after the dose. The peak plasma concentrations of M1 occur 3 hours after the dose is given. Steady state is realized 2 days after dosing tramadol four times a day. Food does not impact the rate or extent of absorption.<ref name=a>Ortho-McNeil Pharmaceutical INC. Ultram (tramadol hydrochloride tablets) prescribing information. 2004.</ref>
 
'''Distribution'''<br>
The volume of distribution was 2.6 L/kg in males and 2.9 L/kg in females. Tramadol binds to proteins about 20%. Saturation of plasma proteins is only of concern if one exceeds the recommended dosage.<ref name=a/>
 
'''Metabolism'''<br>
M1 (O-desmethyl-tramadol) is formed by CYP2D6.<ref name= old>Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.</ref> About 7% of the population are considered poor metabolizers of CYP2D6. The concnetrations of tramadol will be about 20% higher in these patients. The M1 concentrations will be about 40% lower when compared to patients who are considered extensive metabolizers of CYP2D6.<ref name=a/> A study looking at poor metabolizers of CYP2D6 versus extensive metabolizers found that for the positive (+) enantiomer, the AUC was 1.98-fold and the negative (-) enantiomer's AUC was 1.74-fold when compared to extensive metabolizers. The oral clearance was examined and was found to be 1.91-fold in poor metabolizers for the (+) enantiomer and 1.71-fold for the negative enantiomer when compared to extensive metabolizers.<ref name=enta>Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.</ref>
 
'''Excretion'''<br>
30% of tramadol will be excreted in the urine unchanged. 60% of the drug will be excreted in the urine as metabolites. The rest is unidentified or is a metabolite which could not be extracted. Tramadol itself is eliminated via the liver. The half-life of tramadol is 6.3 hours and the half-life of M1 is 7.4 hours. After repeated dosing of tramadol, the half-life of tramadol increases to about 7 hours.<ref name=a/>
<br>
<br>
 
== Special Population Pharmacokinetics ==
* '''Renal insufficiency:''' Renal insufficiency decreases the rate and extent of elimination of both tramadol and its metabolites. When a patient's creatinine clearance is less than 30 mL/min, a decreased dose of tramadol is recommended, and extended-release tramadol is not recommended.<ref name=a/> 
* '''Hepatic insufficiency:''' The metabolism of tramadol is lowered in patients with hepatic insufficiency. This causes a larger area-under the concentration-time curve for tramadol. Tramadol and M1 will have longer elimination half-lives which have been reported to extend to 13 hours for tramadol and 19 hours for M1. Extended-release tramadol is not recommended in this patient population.<ref name=a/>
* '''Hemodialysis:''' After a 4 hour hemodialysis session, less than 7% of the dose of tramadol is cleared from the blood. Extended-release tramadol is not recommended in this patient population.<ref name=a/>
* '''Geriatric:''' In patients over the age of 75, the peak serum concentrations increase from 162 to 208 ng/mL. Additionally, the elimination half-life of tramadol is increased by an hour, from 6 to 7 hours. Based on this pharmacokinetic data, the dosage of tramadol should be adjusted in patients over the age of 75. No PK differences were noted in the population from 65-75 years of age.<ref name=a/> A randomized controlled trial measured serum concentrations of M1 and tramadol in 100 patients. The 100 patients were split up into three groups, greater than or equal to 75 years, 65 to less than 75, and less than 65 years. There were no PK differences between the groups. The group greater than or equal to 75 years used 20% less tramadol than did the group which was less than 65 years of age.<ref name=old/>
* '''Pediatric:''' No data.
* '''Gender:''' The bioavailability was slightly different between males (73%) and females (79%). The plasma clearance was slightly greater in males at 6.4 mL/min/kg vs. 5.7 mL/min/kg in females. Females had a 12% higher peak tramadol concentration than males. Females also had a 35% greater area under the concentration-time curve than did males. Currently, the clinical significance is not known.<ref name=a/>
 
== Indications and Dosages ==
 
=== FDA Approved Indications ===


'''Tramadol''' (also known as '''Ultram''', '''Ralivia''' or '''Tramal''') is a synthetic [[psychoactive class::opioid]] substance of the [[chemical class::phenylpropylamine]] class that is structurally related to [[codeine]] and [[morphine]]. It acts as a weak [[μ-opioid]] [[receptor]] [[agonist]] and a [[reuptake inhibitor]] of [[norepinephrine]] and [[serotonin]].<ref>{{cite journal | vauthors=((Reimann, W.)), ((Schneider, F.)) | journal=European Journal of Pharmacology | title=Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine | volume=349 | issue=2 | pages=199–203 | date=22 May 1998 | url=https://www.sciencedirect.com/science/article/pii/S0014299998001952 | issn=0014-2999 | doi=10.1016/S0014-2999(98)00195-2}}</ref><ref name="Gobbi2002">{{cite journal | vauthors=((Gobbi, M.)), ((Moia, M.)), ((Pirona, L.)), ((Ceglia, I.)), ((Reyes-Parada, M.)), ((Scorza, C.)), ((Mennini, T.)) | journal=Journal of Neurochemistry | 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: Effects of MTA and mCPP in synaptosomes | volume=82 | issue=6 | pages=1435–1443 | date=19 September 2002 | url=http://doi.wiley.com/10.1046/j.1471-4159.2002.01073.x | issn=00223042 | doi=10.1046/j.1471-4159.2002.01073.x}}</ref>
'''Moderate to moderately-severe pain in patients 17 years of age and older'''<ref name=a/><ref name=chr>Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.</ref><ref name=com>Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.</ref>
* Starting dose for chronic pain:
** 25 mg daily in the morning
* Starting dose for acute pain:
** 50 to 100 mg daily every 4 to 6 hours as needed for pain
* Maintenance dose:
** 200 mg daily
** After the titration period is over, additional doses may be given as needed for pain every 4-6 hours.
** The maximum daily dose is 400 mg (300 mg for ages 75 and up).
* Titration schedule: titrate in 25 mg increments as separate doses every three days until 25 mg by mouth four times a day is reached. Then the total daily dosage of tramadol may be increased by 50mg every three days to 50 mg by mouth four times a day. Adverse effects will be more likely if tramadol is not titrated.


Tramadol was developed in 1962 and launched under the name "Tramal" by the German pharmaceutical company Grünenthal GmbH in 1977. In the mid-1990s, it was approved for use in the United Kingdom and the United States.<ref name="Leppert2009">{{cite journal | vauthors=((Leppert, W.)) | journal=Pharmacological Reports | title=Tramadol as an analgesic for mild to moderate cancer pain | volume=61 | issue=6 | pages=978–992 | date= November 2009 | url=https://linkinghub.elsevier.com/retrieve/pii/S1734114009701598 | issn=17341140 | doi=10.1016/S1734-1140(09)70159-8}}</ref> It is commonly prescribed to treat moderate to moderately severe pain.
=== Non-FDA Approved Indications ===
* arthralgia<ref name=arth>Akinci SB, Saricaoglu F, Atay OA, Doral MN, Kanbak M. Analgesic effect of intra-articular tramadol compared with morphine after arthroscopic knee surgery. Arthroscopy. 2005 Sep;21(9):1060-5.</ref>
* bone pain<ref name=ext>Cander B, Girisgin S, Koylu R, Gul M, Kocak S. The effectiveness of analgesics in traumatic injuries of the extremities. Advances in therapy. 2005 Sep-Oct;22(5):462-6.</ref><ref name=spine>Sekar C, Rajasekaran S, Kannan R, Reddy S, Shetty TA, Pithwa YK. Preemptive analgesia for postoperative pain relief in lumbosacral spine surgeries: a randomized controlled trial. Spine J. 2004 May-Jun;4(3):261-4.</ref>
* dental pain<ref name=tooth>Moore PA. Pain management in dental practice: tramadol vs. codeine combinations. Journal of the American Dental Association (1939). 1999 Jul;130(7):1075-9.</ref>
* headache<ref name=headache>Silberstein SD, Freitag FG, Rozen TD, Kudrow DB, Hewitt DJ, Jordan DM, et al. Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial. Headache. 2005 Nov-Dec;45(10):1317-27.</ref>
* fibromyalgia<ref name=fib>Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. The American journal of medicine. 2003 May;114(7):537-45.</ref>
* neuropathic pain<ref name=neuro>Chong MS, Hester J. Diabetic painful neuropathy : current and future treatment options. Drugs. 2007;67(4):569-85.</ref>
* osteoarthritis<ref name=B/><ref name=OA>Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. The Journal of rheumatology. 2007 Mar;34(3):543-55.</ref>
* postoperative shivering<ref name=shi>le Roux PJ, Coetzee JF. Tramadol today. Current opinion in anaesthesiology. 2000 Aug;13(4):457-61.</ref>
* premature ejaculation<ref name=premature>Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA. Tramadol HCL has Promise in On-Demand Use to Treat Premature Ejaculation. J Sex Med. 2007 Mar 14.</ref>
* restless legs syndrome <ref name=leg>Vetrugno R, La Morgia C, D'Angelo R, Loi D, Provini F, Plazzi G, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord. 2007 Feb;22(3):424-7.</ref>  


[[Subjective effects]] are largely consistent with that of traditional opioids and include [[sedation]], [[pain relief]], [[anxiety suppression]], [[muscle relaxation]], and [[euphoria]]. Tramadol is also known to produce mild to moderate [[entactogenic]] effects like [[increased music appreciation]] and [[empathy, affection, and sociability enhancement]], which is thought to be due to its [[serotonergic]] effects.  
=== Dosage Adjustment === <!--IF NO DOSAGE ADJUSTMENT NEEDED, ERASE THE LINE. KEEP THE BREAKS (<br>) BETWEEN LINES FOR STYLING PURPOSES-->
'''Renal insufficiency:''' For patients with a CrCl <30 mL/min, the dosage interval should be extended to 12 hours. The maximum daily dose should be lowered to 200 mg/day.<ref name=a/><br>
'''Hepatic insufficiency:''' The recommended dose is 50 mg every 12 hours for patients with hepatic cirrhosis. It is not recommended that patients with hepatic impairment receive extended-release tramadol.<ref name=a/><br>
'''Hemodialysis:''' Patients can receive their regular dose on dialysis days. Only 7% of the dose is removed by a four-hour hemodialysis session. No studies have been completed with hemodialysis patients taking extended-release tramadol, therefore it is not recommended it is given to this patient population.<br>
'''Geriatric:''' In patients over the age of 65, dosage should initially be lower than an adult patient. It is be titrated based on tolerability, not to exceed the rate of titration recommended for adult patients. Patients over the age of 75 years, should not exceed 300 mg of tramadol per day.<ref name=a/><br>
'''Pediatric:''' Not indicated.


Unlike other [[opioids]], tramadol has been established to lower the seizure threshold in humans<ref>{{cite journal | vauthors=((Talaie, H.)), ((Panahandeh, R.)), ((Fayaznouri, M. R.)), ((Asadi, Z.)), ((Abdollahi, M.)) | journal=Journal of Medical Toxicology | title=Dose-independent occurrence of seizure with tramadol | volume=5 | issue=2 | pages=63–67 | date= June 2009 | url=http://link.springer.com/10.1007/BF03161089 | issn=1556-9039 | doi=10.1007/BF03161089}}</ref> as well as increase the risk of [[serotonin syndrome]]. This makes its effects and interactions relatively unpredictable. As a result, high doses or combinations with other [[psychoactive substances]] are strongly advised against.
=== Dosage Limits ===
* '''Ages 17 to 75:''' 400 mg/day
* '''Elderly over age 75:''' 300 mg/day
* '''Adolescents under age 17 and children:''' Not indicated


It is highly advised to use [[harm reduction practices]] if using this substance.


==History and culture==
== Administration ==
{{historyStub}}
* '''Route:''' Oral
* '''Method:'''
** May be taken with or without food. Take with a drink of water or other beverage.
** Extended-release tablets should be swallowed whole and not crushed or chewed.


Tramadol was synthesized in 1962 by chemists employed by the German pharmaceutical company Grünenthal.<ref name="Leppert2009" /> However, it was not approved in Germany until 1977, entering the market as Tramal. It became the leading analgesic drug in Germany and during the past 38 years it has been approved in over 100 countries, including the UK, USA, Republic of China and Canada.<ref>{{cite journal | vauthors=((Lassen, D.)), ((Damkier, P.)), ((Brøsen, K.)) | journal=Clinical Pharmacokinetics | title=The Pharmacogenetics of Tramadol | volume=54 | issue=8 | pages=825–836 | date= August 2015 | url=http://link.springer.com/10.1007/s40262-015-0268-0 | issn=0312-5963 | doi=10.1007/s40262-015-0268-0}}</ref>
== Monitoring Parameters ==
* Not needed


For a period of time it was believed tramadol was not a purely synthetic drug after its apparent discovery in the roots of the pin cushion tree.<ref>{{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, J.-L.)), ((Bonaz, B.)), ((De Waard, M.)) | journal=Angewandte Chemie International Edition | title=Occurrence of the Synthetic Analgesic Tramadol in an African Medicinal Plant | volume=52 | issue=45 | pages=11780–11784 | date=4 November 2013 | url=https://onlinelibrary.wiley.com/doi/10.1002/anie.201305697 | issn=14337851 | doi=10.1002/anie.201305697}}</ref> These reports later proved to be erroneous; the tramadol had been excreted by cows treated with the drug, resulting in the tramadol having seeped into the roots through their urine.<ref>{{cite journal | vauthors=((Kusari, S.)), ((Tatsimo, S. J. N.)), ((Zühlke, S.)), ((Talontsi, F. M.)), ((Kouam, S. F.)), ((Spiteller, M.)) | journal=Angewandte Chemie International Edition | title=Tramadol-A True Natural Product? | volume=53 | issue=45 | pages=12073–12076 | date=3 November 2014 | url=https://onlinelibrary.wiley.com/doi/10.1002/anie.201406639 | issn=14337851 | doi=10.1002/anie.201406639}}</ref>
== Contraindications/Precautions  ==
=== Contraindications ===
* '''Hypersensitivity to tramadol or any of its components'''
* '''Hypersensitivity to opioids'''
* '''Patients acutely intoxicated with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs'''


==Chemistry==
=== Precautions ===
(+/-)Tramadol, or 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, is an atypical synthetic opioid. The chemical structure of tramadol consists of two rings that include a [[cyclohexane]] ring bonded to a [[phenyl]] ring at R<sub>1</sub>. This phenyl ring is substituted at R<sub>3</sub> with a methoxy group (CH<sub>3</sub>O-). At the same location (R<sub>1</sub>) the cyclohexane ring is bonded to the phenyl ring, an additional hydroxy group is found. Tramadol features a second substitution on its cyclohexane ring at R<sub>2</sub>. Here, the ring is bonded to a dimethylamine group connected through a methyl bridge.  
* Acute abdominal conditions
* Renal impairment (caution with immediate-release, extended-release not recommended in severe renal impairment)
* Hepatic impairment (caution with immediate-release, extended-release not recommended)
* Respiratory depression
* Patients receiving anesthetic medications
* Patients who consume alcohol
* Patients with epilepsy, a history of seizures, head trauma, metabolic disorder, alcohol withdrawal, drug withdrawal, or CNS infections: seizures may occur with tramadol, even within typical dosage limits. Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures).<ref name=d>Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. The Annals of pharmacotherapy. 1997 Feb;31(2):175-7.</ref> Risk of seizures increases when the following drugs are used concomitantly: [[Selective serotonin reuptake inhibitor (SSRI)|selective serotonin reuptake inhibitors (SSRIs)]], [[Tricyclic antidepressant (TCA)|tricyclic antidepressants (TCAs)]], tricyclic compounds ([[cyclobenzaprine]], [[promethazine]]), opioids, [[Monoamine oxidase inhibitor (MAOI)|monoamine oxidase inhibitors (MAOIs)]], neuroleptics, alcohol,<ref name=f>Jovanovic-Cupic V, Martinovic Z, Nesic N. Seizures associated with intoxication and abuse of tramadol. Clinical toxicology (Philadelphia, Pa. 2006;44(2):143-6.</ref> [[naloxone]] (given for overdose of tramadol), or any other drug which may lower the seizure threshold.
* Increased intracranial pressure
* Abrupt discontinuation: withdrawal may occur if tramadol is stopped without downward titration. Symptoms of withdrawal include anxiety, sweating, insomnia, pain, nausea, tremors, diarrhea, piloerection and hallucinations.


Tramadol is unique as it is found in a racemate (combination) of its stereoisomers. These are two molecules that share the same chemical structure, but are three-dimensional mirror images of each other. Tramadol is produced as a racemate of its two isomers because the combination is proven to be more effective. The picture seen above is the R- enantiomer of tramadol, switching the dashed and solid wedges seen on the molecule skeleton results in the S- enantiomer. It is produced as a hydrochloride salt.<ref>{{cite journal | vauthors=((Dayer, P.)), ((Desmeules, J.)), ((Collart, L.)) | journal=Drugs | title=[Pharmacology of tramadol] | volume=53 Suppl 2 | pages=18–24 | date= 1997 | issn=0012-6667 | doi=10.2165/00003495-199700532-00006}}</ref>
=== Pregnancy indications ===
'''Category C'''
Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits. Tramadol has not been shown to be teratogenic in mice, rats and rabbits.


Tramadol is a 4-phenylpiperidine analog of [[codeine]]. Notably, it is not a morphinan opiate.
=== Breast-feeding indications ===
Tramadol is not indicated for breastfeeding mothers. The excretion into breast milk is 0.1% of the maternal dose.<ref name=a/>


==Pharmacology==
The R- and S- enantiomers of tramadol act on different receptors in a complimentary manner. The R- enantiomer is a selective agonist of the mu receptors and inhibits serotonin reuptake while the S- enantiomer inhibits noradrenaline reuptake. Tramadol acts as an [[opioid|opioid]] [[receptor|receptor]] [[agonist|agonist]],<ref>{{cite journal | vauthors=((Hennies, H. H.)), ((Friderichs, E.)), ((Schneider, J.)) | journal=Arzneimittel-Forschung | title=Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids | volume=38 | issue=7 | pages=877–880 | date= July 1988 | issn=0004-4172}}</ref><ref name="Frink1996">{{cite journal | vauthors=((Frink, M. C.)), ((Hennies, H. H.)), ((Englberger, W.)), ((Haurand, M.)), ((Wilffert, B.)) | journal=Arzneimittel-Forschung | title=Influence of tramadol on neurotransmitter systems of the rat brain | volume=46 | issue=11 | pages=1029–1036 | date= November 1996 | issn=0004-4172}}</ref> [[serotonin]] [[releasing agent]],<ref name="Frink1996" /><ref name="Gobbi2002" /><ref>{{cite journal | vauthors=((Driessen, B.)), ((Reimann, W.)) | journal=British Journal of Pharmacology | title=Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. | volume=105 | issue=1 | pages=147–151 | date= January 1992 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908625/ | issn=0007-1188}}</ref><ref>{{cite journal | vauthors=((Bamigbade, T. A.)), ((Davidson, C.)), ((Langford, R. M.)), ((Stamford, J. A.)) | journal=British Journal of Anaesthesia | title=Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus | volume=79 | issue=3 | pages=352–356 | date= September 1997 | url=https://linkinghub.elsevier.com/retrieve/pii/S0007091217398598 | issn=00070912 | doi=10.1093/bja/79.3.352}}</ref> [[norepinephrine]] [[reuptake inhibitor]],<ref name="Frink1996" /> [[NMDA receptor antagonist]],<ref>{{cite journal | vauthors=((Hara, K.)), ((Minami, K.)), ((Sata, T.)) | journal=Anesthesia & Analgesia | title=The Effects of Tramadol and Its Metabolite on Glycine, γ-Aminobutyric Acid<sub>A</sub>, and N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes: | volume=100 | issue=5 | pages=1400–1405 | date= May 2005 | url=http://journals.lww.com/00000539-200505000-00037 | issn=0003-2999 | doi=10.1213/01.ANE.0000150961.24747.98}}</ref> 5-HT2C receptor antagonist,<ref name="Ogata2004">{{cite journal | vauthors=((Ogata, J.)), ((Minami, K.)), ((Uezono, Y.)), ((Okamoto, T.)), ((Shiraishi, M.)), ((Shigematsu, A.)), ((Ueta, Y.)) | journal=Anesthesia & Analgesia | title=The Inhibitory Effects of Tramadol on 5-Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes: | pages=1401–1406 | date= May 2004 | url=http://journals.lww.com/00000539-200405000-00038 | issn=0003-2999 | doi=10.1213/01.ANE.0000108963.77623.A4}}</ref> (α7)5 nicotinic acetylcholine receptor antagonist,<ref name="Ogata2004" /> and M1 and M3 muscarinic [[acetylcholine]] [[receptor]] [[antagonist]].<ref>{{cite journal | vauthors=((Shiraishi, M.)), ((Minami, K.)), ((Uezono, Y.)), ((Yanagihara, N.)), ((Shigematsu, A.)) | journal=The Journal of Pharmacology and Experimental Therapeutics | title=Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors | volume=299 | issue=1 | pages=255–260 | date= October 2001 | issn=0022-3565}}</ref><ref>{{cite journal | vauthors=((Shiga, Y.)), ((Minami, K.)), ((Shiraishi, M.)), ((Uezono, Y.)), ((Murasaki, O.)), ((Kaibara, M.)), ((Shigematsu, A.)) | journal=Anesthesia & Analgesia | title=The Inhibitory Effects of Tramadol on Muscarinic Receptor-Induced Responses in Xenopus Oocytes Expressing Cloned M3 Receptors | volume=95 | issue=5 | pages=1269–1273 | date= November 2002 | url=https://journals.lww.com/00000539-200211000-00031 | issn=0003-2999 | doi=10.1097/00000539-200211000-00031}}</ref>


Tramadol is metabolised to [[O-Desmethyltramadol]] ('''O-DSMT'''), a significantly more potent opioid.
== [[Tramadol drug interactions | Drug-Drug, -Food, -Herb Interactions]] ==
Click the link above to go to the drug interactions page.


The euphoric effects of tramadol stem from the way in which opioids bind to and activate the [[Opioid#Receptor_types|μ-opioid]] [[receptor]]. This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their [[physical euphoria|euphoria]], [[pain relief]] and [[anxiolytic]] effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.
== Adverse Reactions/Side Effects ==


==Subjective effects==
In a clinical trial of 550 patients with moderate pain (375 patients 65 years or older), the rates of side effects were comparable to acetaminophen with codeine, but the rate of withdrawal for side effects was greater in patients treated with tramadol.<ref name=a/> The most frequent adverse effects include constipation (38%), nausea (34%), dizziness (31%), headache (26%), somnolence (23%) and vomiting (13%).<ref name=B/>
{{Preamble/SubjectiveEffects}}
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{{effects/base
{| style="width:100%" border="1" align="center"
|+ '''Tramadol Adverse Reactions Chart'''
|- style="background:#EFEFFF" align="center"
| '''Incidence''' || '''Body System''' || '''Adverse Reactions'''
|- style="background:#FFFFCC" align="center"
| '''>10%''' || All || style="padding-left:0.5em" align="left"| Dizziness (26-33%), nausea (24-40%), constipation (24-46%), headache (18-32%), somnolence (16-25%), vomiting (9-25%), dyspepsia (5-13%), pruritis (8-11%), diarrhea (5-10%), CNS stimulation (7-14%), asthenia (6-12%), sweating (6-12%)
|- style="background:#FFFEDD" align="center"
| rowspan="7" | '''1-10%'''|| CNS || style="padding-left:0.5em" align="left"| Sleep changes (1-5%), anxiety, confusion, coordination disturbances, euphoria, nervousness
|- style="background:#FFFEDD" align="center"
| Cardiovascular || style="padding-left:0.5em" align="left"| Vasodilation (1-5%)
|- style="background:#FFFEDD" align="center"
| Dermatologic || style="padding-left:0.5em" align="left"| Rash (1-5%)
|- style="background:#FFFEDD" align="center"
| GI || style="padding-left:0.5em" align="left"| Dry mouth (5-10%), abdominal pain (1-5%), anorexia (1-5%), flatulence (1-5%)
|- style="background:#FFFEDD" align="center"
| Genitourinary || style="padding-left:0.5em" align="left"| Menopausal symptoms (1-5%), urinary frequency or retention (1-5%)
|- style="background:#FFFEDD" align="center"
| Neuromuscular/skeletal || style="padding-left:0.5em" align="left"| Hypertonia (1-5%)
|- style="background:#FFFEDD" align="center"
| Miscellaneous || style="padding-left:0.5em" align="left"| Malaise (1-5%)
|- style="background:#FEFEEF" align="center"
| '''<1%''' || All || style="padding-left:0.5em" align="left"| Accidental injury, allergic reaction, anaphylaxis, death, suicide, weight loss, serotonin syndrome, orthostatic hypotension, tachycardia, Stevens-Johnson syndrome, tremor, gait changes, amnesia, dysuria, dysgeusia, menstrual disorder, hallucinations, paresthesias
|}


|{{effects/physical|
== Overdosage Measures ==
*'''[[Effect::Sedation]]''' & '''[[Effect::Stimulation]]''' - At lower to common doses, tramadol is considerably more, and highly stimulating than traditional opiates like [[codeine]] and [[heroin]] due to its action as a [[norepinephrine]] [[reuptake inhibitor]]. Higher doses are marked by sedation and lethargy characteristic of traditional opiates.
Symptoms of overdosage include respiratory depression, lethargy, coma, seizure, or cardiac arrest.<ref name=a/>
*'''[[Effect::Pain relief]]'''{{citation needed}}
<br>
*'''[[Effect::Physical euphoria]]''' - Tramadol is considered as less intense in its physical euphoria when compared with that of [[morphine]] or [[heroin]].  The sensation itself can be described as extreme feelings of intense physical comfort, warmth, love and bliss.
'''Treatment:'''
*'''[[Effect::Itchiness]]''' - Itchiness is comparably greater than other opioids due to higher amounts of histamine release.
* Use general supportive measuresand maintain ventilation.
*'''[[Effect::Constipation]]'''{{citation needed}}
* Naloxone reverses some, but not all symptoms and can increase the risk for seizure.
*'''[[Effect::Cough suppression]]'''{{citation needed}}
* Convulsions can be suppressed with barbiturates or benzodiazepines.
*'''[[Effect::Dehydration]]'''{{citation needed}} - Tramadol can produce significant dehydration, particularly with higher doses. Users are advised to drink water throughout the experience to help mitigate the comedown and side effects like headaches.
*'''[[Effect::Difficulty urinating]]'''
*'''[[Effect::Nausea]]'''{{citation needed}}
*'''[[Effect::Pupil constriction]]'''{{citation needed}}
*'''[[Effect::Decreased libido]]'''{{citation needed}}
*'''[[Effect::Appetite suppression]]'''
*'''[[Effect::Orgasm suppression]]'''{{citation needed}}
*'''[[Effect::Seizure]]'''{{citation needed}}
*'''[[Effect::Teeth grinding]]''' - This effect typically occurs only at lower dosages where the stimulation is more pronounced, this is likely due to its action as a serotonin [[reuptake inhibitor]].
*'''[[Effect::Headaches]]''' - Headaches seem to occur more frequently on tramadol than other [[opiates]], although they don't occur for everyone. The underlying cause is unclear, although it may be related to its [[SNRI]] properties.
*'''[[Effect::Restless legs]]'''<ref>{{cite journal | vauthors=((Hoque, R.)), ((Chesson, A. L.)) | journal=Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine | title=Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis | volume=6 | issue=1 | pages=79–83 | date=15 February 2010 | issn=1550-9389}}</ref>


}}
== Product Information and Distribution ==
|{{effects/cognitive|


The general head space of tramadol is described by many as one of stimulation, euphoria, relaxation, anxiety suppression and pain relief.


*'''[[Effect::Disinhibition]]'''
{| style="width:100%;" border="1" align="center"
*'''[[Effect::Cognitive euphoria]]''' - This particular substance can be considered as less intense in its cognitive euphoria when compared with that of [[morphine]] or [[diacetylmorphine]] (heroin). The sensation itself can be described as powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
|+ '''Note: appearance only available for brand-name product'''
*'''[[Effect::Empathy, affection and sociability enhancement]]'''
|- style="background:#EFEFFF" align="center"
*'''[[Effect::Anxiety suppression]]'''
| '''Dose/form''' || '''Drug color(s)'''|| '''Drug shape''' || '''Markings or odor/flavor'''
*'''[[Effect::Anxiety]]''' - While tramadol has a greater tendency to suppress anxiety, it can also potentially cause it under certain conditions. This effect can possibly be attributed to the noradrenergic properties of this substance.
|- style="background:#FEFEEF" align="center"
*'''[[Effect::Irritability]]''' - While opioids are well known for their ability to improve mood, they can also have the paradoxical effect of increasing the user's sensitivity to irritable stimuli. This can manifest as aloofness and sudden outbursts of anger and aggression (colloquially known as "opiate rage"). It appears to occur more frequently during the comedown of the experience and/or with heavy use. Tramadol's noradrenergic properties may also have a part in this effect.
| style="background:#EFEFFF" | '''50 mg tablet''' || white || oblong || ULTRAM/06 59
*'''[[Effect::Thought acceleration]]'''
|- style="background:#FEFEEF" align="center"
*'''[[Effect::Compulsive redosing]]'''
| style="background:#EFEFFF" | '''100 mg extended-release tablet''' || white || round || '100' over 'ER'
*'''[[Effect::Motivation enhancement]]'''
|- style="background:#FEFEEF" align="center"
*'''[[Effect::Dream potentiation]]'''
| style="background:#EFEFFF" | '''200 mg extended-release tablet''' || white || round || '200' over 'ER'  
*'''[[Effect::Increased music appreciation]]''' Music may sound more immersive when under the influence of tramadol.
|- style="background:#FEFEEF" align="center"
*'''[[Effect::Wakefulness]]'''
| style="background:#EFEFFF" | '''300 mg extended-release tablet''' || white || round || '300' over 'ER'
}}
|}
}}


<br />
* '''Inactive ingredients for tablets:''' corn starch, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium glycolate, titanium dioxide, wax
===Experience reports===
* '''Inactive ingredients for extended-release tablets:''' colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium stearyl fumarate
Anecdotal reports which describe the effects of this compound within our [[experience index]] include:
{{#ask: [[Category:Tramadol]][[Category:Experience]]|format=ul|Columns=1}}
Additional experience reports can be found here:


*[https://www.erowid.org/experiences/subs/exp_Pharms_Tramadol.shtml Erowid Experience Vaults: Tramadol]
== Patient Information ==
* May be taken with or without food.
* May cause dizziness or drowsiness. Use caution when driving or operating heavy machinery.
* DO NOT take with alcohol.
* Extended-release tablets should be swallowed whole and not be crushed or chewed.
* Use caution when taking tranquilizers, hypnotics, or other opiate containing analgesics
* Contact your doctor if you are planning on becoming pregnant or think that you are pregnant
* Do not take more often than directed, this may cause respiratory depression, seizures and death
* Contact a health-care professional right away if: you are having difficulty breathing, have had a seizure, develop a rash, experience a change in vision, hallucinate, or have a fast heart beat.
* Other side-effects that you may notice include constipation or diarrhea, dry mouth, and headache.


==Toxicity and harm potential==
== References ==
{{toxicity}}
<references/>
Tramadol has a [[Toxicity::low toxicity]] relative to dose. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also [[Toxicity::potentially [[respiratory depression|lethal]] when mixed with [[depressants]] like [[alcohol]] or [[benzodiazepines]]]] and generally has a wider range of substances which it is [[Tramadol#Dangerous interactions|dangerous to combine with]] in comparison to other opioids. It should not be taken during [[Benzodiazepine#Discontinuation|benzodiazepine withdrawals]] as this can potentially cause [[seizure]]s.


It is strongly recommended that one use [[responsible drug use|harm reduction practices]] when using this drug.
== PUBMED References ==
=== Efficacy Trial Articles ===
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10743823&query_hl=19&itool=pubmed_docsum Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11029125&query_hl=17&itool=pubmed_docsum Pendeville PE, Von Montigny S, Dort JP, Veyckemans F. Double-blind randomized study of tramadol vs. paracetamol in analgesia after day-case tonsillectomy in children. European journal of anaesthesiology. 2000 Sep;17(9):576-82.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9676769&query_hl=17&itool=pubmed_DocSum Roth SH. Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis. The Journal of rheumatology. 1998 Jul;25(7):1358-63.]


===Dependence and abuse potential===
As with other [[opioids]], the chronic use of tramadol can be considered [[Addiction potential::moderately addictive with a high potential for abuse]] and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and [[Opioids#Discontinuation|withdrawal symptoms]] may occur if a person suddenly stops their usage.


Tolerance to many of the effects of tramadol [[Time to full tolerance::develops with prolonged and repeated use]]. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about [[Time to half tolerance::3 - 7 days]] for the tolerance to be reduced to half and [[Time to zero tolerance::1 - 2 weeks]] to be back at baseline (in the absence of further consumption). Tramadol presents cross-tolerance with [[Cross-tolerance::all other [[opioids]]]], meaning that after the consumption of tramadol all [[opioid]]s will have a reduced effect.
=== Therapeutic Class Comparison Articles ===
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9085303&query_hl=19&itool=pubmed_DocSum Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16731323&query_hl=17&itool=pubmed_DocSum Ng KF, Yuen TS, Ng VM. A comparison of postoperative cognitive function and pain relief with fentanyl or tramadol patient-controlled analgesia. Journal of clinical anesthesia. 2006 May;18(3):205-10.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16476920&query_hl=17&itool=pubmed_DocSum Ekman EF, Ruoff G, Kuehl K, Ralph L, Hormbrey P, Fiechtner J, et al. The COX-2 specific inhibitor Valdecoxib versus tramadol in acute ankle sprain: a multicenter randomized, controlled trial. The American journal of sports medicine. 2006 Jun;34(6):945-55.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9701294&query_hl=17&itool=pubmed_DocSum Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.]


===Dangerous interactions===
=== Pharmacokinetics Articles ===
{{DangerousInteractions/Intro}}
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17296459&query_hl=1&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17296459&query_hl=1&itool=pubmed_docsum Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.]
{{DangerousInteractions/PhenylpropylamineOpioids}}
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17288681&query_hl=1&itool=pubmed_docsum Murthy BP, Skee DM, Danyluk AP, Brett V, Vorsanger GJ, Moskovitz BL. Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol. Current medical research and opinion. 2007 Feb;23(2):275-84.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17175164&query_hl=1&itool=pubmed_DocSum Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16951997&query_hl=17&itool=pubmed_docsum Garrido MJ, Habre W, Rombout F, Troconiz IF. Population pharmacokinetic/pharmacodynamic modelling of the analgesic effects of tramadol in pediatrics. Pharmaceutical research. 2006 Sep;23(9):2014-23.]
 


===[[Serotonin syndrome]] risk===
=== Drug Interaction Articles ===
Combinations with the following substances can lead to dangerously high [[serotonin]] levels. Serotonin syndrome requires immediate medical attention and can be fatal if left untreated.
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16051647&query_hl=31&itool=pubmed_docsum Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British journal of anaesthesia. 2005 Oct;95(4):434-41.]
# [http://ajp.psychiatryonline.org/cgi/content/full/161/6/1129 Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. The American journal of psychiatry. 2004 Jun;161(6):1129.]
# [http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1297365&blobtype=pdf Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. Journal of the Royal Society of Medicine. 1999 Sep;92(9):474-5.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17064212&query_hl=2&itool=pubmed_docsum Dumo PA, Kielbasa LA. Successful anticoagulation and continuation of tramadol therapy in the setting of a tramadol-warfarin interaction. Pharmacotherapy. 2006 Nov;26(11):1654-7.]
# [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9692666&query_hl=2&itool=pubmed_docsum Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy. 1998 Jul-Aug;18(4):871-3.]


*'''[[DangerousInteraction::MAOIs|MAOIs]]''' such as '''[[syrian rue]]''', '''[[banisteriopsis caapi]]''', '''phenelzine''', '''selegiline''', and '''moclobemide'''<ref>{{cite journal | vauthors=((Gillman, P. K.)) | journal=British Journal of Anaesthesia | title=Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity | volume=95 | issue=4 | pages=434–441 | date= October 2005 | url=https://linkinghub.elsevier.com/retrieve/pii/S0007091217349565 | issn=00070912 | doi=10.1093/bja/aei210}}</ref>
==Proprietary preparations==
*'''[[Serotonin releasers]]''' such as '''[[DangerousInteraction::MDMA]]''', '''[[4-FA]]''', '''[[methamphetamine]]''', '''[[methylone]]''' and '''[[DangerousInteraction::aMT]]'''
Grünenthal, which still owns the patent to tramadol, has cross-licensed the agent to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:
*'''[[UnsafeInteraction::2C-T-x|2C-T-x]]'''
*'''[[DangerousInteraction::DXM|DXM]]'''


==Legal status==
* '''Acugesic''' (in [[Malaysia]] and [[Singapore]])
* '''Algifeno''' (in [[Bolivia]])
* '''Adolan'''
* '''Adolonta''' (in [[Spain]])
* '''Anadol''' (in [[Portugal]])
* '''Boldol''' (in [[Bosnia and Herzegovina]])
* '''Calmador''' (in [[Argentina]])
* '''Campex''' (in [[Pakistan]])
* '''Contramal''' (in [[India]] and [[Italy]])
* '''Crispin'''
* '''Dolcet''' (in the [[Philippines]])
* '''Dolol''' (in [[Denmark]])
* '''Dolzam''' (in [[Belgium]])
* '''Dromadol''' (in [[UK]])
* '''Exopen''' (in [[South Korea]])
* '''Ixprim''' (in [[France]])
* '''Lumidol''' (in [[Croatia]])
* '''Mandolgin''' (in [[Denmark]])
* '''Mandolgine'''
* '''Mosepan'''
* '''Nobligan'''
* '''Osteodol''' (Fem India)
* '''Poltram'''
* '''Ralivia''' (In [[Canada]])
* '''Sintradon'''
* '''Siverol''' (in the [[Philippines]])
* '''Tamool'''
* '''Tandol''' (in [[South Korea]])
* '''Tedool'''
* '''Tiparol'''
* '''Toplagic'''
* '''Tradol'''
* '''Tradolan'''
* '''Tradonal''' (in the [[Philippines]])
* '''Tralgit'''
* '''Tralodie''' (in [[Italy]])
* '''Tramacet''' (combined with [[paracetamol]])
* '''Tramacip'''
* '''Tramadex''' (in [[Israel]])
* '''Tramadin'''
* '''Tramadol'''
* '''Tramadolor'''
* '''Tramahexal'''
* '''Tramajack'''
* '''Tramake Insts''' (in [[United Kingdom]])
* '''Trama-Klosidol'''
* '''Tramal''' (in the [[Netherlands]], [[Finland]], [[Slovenia]], [[Chile]], [[Romania]], [[Australia]], [[New Zealand]] and [[Switzerland]])
* '''Tramalgic''' (in [[Hungary]])
* '''Tramal Gotas''' (in [[Ecuador]])
* '''Tramauydin'''
* '''Tramazac''' (in India)
* '''Tramedo'''
* '''Tramoda''' (in [[Thailand]])
* '''Tramundal''' (various Austrian solid and liquid forms manufacturd by Mundipharma Ges. m.b.H, in Vienna and available elsewhere in Central Europe as well)
* '''Tridol''' (in [[South Korea]])
* '''Tridural''' (in [[Canada]])
* '''Trodon''' (in [[Serbia]])
* '''Ultracet''' (combined with [[paracetamol]])
* '''Ultradol'''
* '''Ultram''' and '''Ultram ER''' (in the [[US]])
* '''Ultramed''' (combined with [[paracetamol]]) in [[India]]
* '''Veldrol''' (in [[Mexico]])
* '''Zafin''' (combined with [[paracetamol]], in [[Chile]])
* '''Zaldiar''' (combined with [[paracetamol]], in [[Spain]], [[Poland]], [[Russia]], [[Chile]])
* '''Zaledor''' (combined with [[paracetamol]], in [[Chile]])
* '''Zamadol''' (in UK)
* '''Zamudol'''
* '''Zodol''' (in [[Ecuador]])
* '''Zydol''' (in the [[UK]] and [[Australia]])
* '''Zytram'''
* '''Zytrim''' (in [[Spain]])


*'''Austria:''' Tramadol is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).{{citation needed}}
=== Adverse Effects Articles ===
*'''Malaysia:''' Tramadol is not listed as a First Schedule drug in the Dangerous Drugs Act 1952 of Malaysia.<ref>[https://www.pharmacy.gov.my/v2/sites/default/files/document-upload/first-schedule-05.07.2021_0.pdf ''First Schedule Drugs'']


[https://www.pharmacy.gov.my/v2/en/documents/dangerous-drugs-act-1952-and-regulations.html ''Dangerous Drugs Act 1952 and Regulations''] </ref>
*'''Germany:''' Tramadol is a prescription medicine, according to Anlage 1 AMVV.<ref>{{Citation | title=AMVV - Verordnung über die Verschreibungspflicht von Arzneimitteln | url=https://www.gesetze-im-internet.de/amvv/BJNR363210005.html}}</ref>
*'''South Africa:''' Tramadol is legal for prescribed medical use only and is considered a Schedule 5 controlled substance. Sale and possession is decriminalized and considered misdemeanor.<ref>https://strathprints.strath.ac.uk/71305/1/Fynn_etal_HP_2020_Drug_utilization_review_of_tramadol_hydrochloride_in_a_regional_hospital.pdf</ref>
*'''Sweden:''' As of May 2008, Sweden 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 prescription can be used at this time.<ref>http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/</ref>
*'''Switzerland:''' Tramadol is listed as a "Abgabekategorie A" pharmaceutical, which requires a prescription.{{citation needed}}
*'''Turkey''': Tramadol is a 'green prescription' only substance<ref>YEŞİL REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/01.04.2019%20SKRS%20Ye%C5%9Fil%20Re%C3%A7eteli%20%C4%B0la%C3%A7lar%20Aktif%20SON%20-%20G%C3%9CNCEL_58b1ff4a-2e1c-4867-bad7-eec855d6162a.pdf</ref> and illegal when sold or possessed without a prescription.{{citation needed}}
*'''United Kingdom:''' On June 10th, 2014, tramadol was made a Class C drug under the Misuse of Drugs Act.<ref>{{Citation | title=The Misuse of Drugs and Misuse of Drugs (Safe Custody) (Amendment) (England, Wales and Scotland) Regulations 2014 | url=https://www.legislation.gov.uk/uksi/2014/1275/regulation/5/made}}</ref>
*'''United States:''' Tramadol is a Schedule IV controlled substance in the United States.<ref>DEA Controlled Drugs | https://www.deadiversion.usdoj.gov/schedules/orangebook/e_cs_sched.pdf</ref>


==See also==
=== Compliance Articles ===


*[[Responsible use]]
=== Pharmacoeconomic Articles ===
*[[Depressants]]
*[[Opioids]]
*[[Serotonin]]
*[[Norepinephrine]]
*[[O-Desmethyltramadol]] (O-DSMT)


==External links==
== External Links ==
'''Clinical treatment guidelines'''
* [http://www.aapa.org/clinissues/pain/guidelines.html Pain Management Resource Center]


*[http://en.wikipedia.org/wiki/Tramadol Tramadol (Wikipedia)]
'''Patient information pages'''
*[https://www.erowid.org/pharms/tramadol/ Tramadol (Erowid Vault)]
* [http://www.nlm.nih.gov/medlineplus/pain.html Pain (Medline Plus)]
*[https://isomerdesign.com/PiHKAL/explore.php?id=10528 Tramadol (Isomer Design)]
* [http://www.mayoclinic.com/health/pain/PN00017 How you feel pain? (Mayo Clinic)]
*[https://go.drugbank.com/drugs/DB00193 Tramadol (DrugBank)]
*[https://www.drugs.com/tramadol.html Tramadol (Drugs.com)]


==References==
'''Other resources'''
{{reflist|2}}
* [http://www.vachronicpain.org/pages/pain_resources.htm VA pain resources]
{{#set:Featured=true}}
* [http://www.arthritis.org/ Arthritis Foundation]


[[Category:Psychoactive substance]]
[[Category:Drugs]]
[[Category:Cycloalkylamine]]
[[Category:Medicines]]
[[Category:Phenylpropylamine]]
[[sv:Läkemedel]]
[[Category:Opioid]]
[[es:Farmacos]]

Latest revision as of 21:21, 16 November 2025

Template:Druginfo

Description

Tramadol is a centrally-acting synthetic opioid analgesic that is not a controlled substance.[1] Tramadol is used to treat moderate to moderately severe chronic pain. It can also be used to treat breakthrough pain.[2] Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures), which can be exacerbated by the use of other medications such SSRIs, TCAs, and opioids. Additionally tramadol and sertraline, when given in the same regimen, were found to cause a mild serotonin syndrome.[3] Tramadol does not cause GI bleeding, hypertension or heart failure.

There is a small chance of tramadol abuse. The rate is 0.75/100,000 patients and of these, 97% of patients who became addicted had a history of drug and alcohol abuse.[4]

A number of studies have proven the efficacy of tramadol. It is more effective than placebo for osteoarthritis and comparable in efficacy to ibuprofen 2400 mg/day.[2] Osteoarthritis is an off-label use. Tramadol was found to be substandard to hydrocodone/acetaminophen for patients entering the emergency department with acute musculoskeletal pain.[5] Pain relief tyically begins about one hour after administration.[1]

Mechanism of Action

Tramadol is a synthetic analgesic which acts centrally through binding to the opioid µ-receptors and via a tricyclic-like mechanism whereby it inhibits neuronal reuptake of serotonin and norepinephrine within the CNS.[2][6] The opioid activity of tramadol is due to tramadol binding to the µ-receptors and the M1 metabolite, which is O-demethylated, binding to the opioid µ-receptors. M1 is 6-times more potent than tramadol when compared for their analgesic qualities. M1 binds to the µ-receptors 200-times stronger than does tramadol. Additionally, tramadol inhibits the reuptake of serotonin and norepinephrine which is believed to contribute to its analgesic properties.[1]

Time Required for Therapeutic Response

  • Initial: One hour[2]

Pharmacokinetics

Absorption
Tramadol is almost completely absorbed. The bioavailability of a 100 mg dose is 75%. The peak plasma concentrations of racemic tramadol occur 2 hours after the dose. The peak plasma concentrations of M1 occur 3 hours after the dose is given. Steady state is realized 2 days after dosing tramadol four times a day. Food does not impact the rate or extent of absorption.[1]

Distribution
The volume of distribution was 2.6 L/kg in males and 2.9 L/kg in females. Tramadol binds to proteins about 20%. Saturation of plasma proteins is only of concern if one exceeds the recommended dosage.[1]

Metabolism
M1 (O-desmethyl-tramadol) is formed by CYP2D6.[7] About 7% of the population are considered poor metabolizers of CYP2D6. The concnetrations of tramadol will be about 20% higher in these patients. The M1 concentrations will be about 40% lower when compared to patients who are considered extensive metabolizers of CYP2D6.[1] A study looking at poor metabolizers of CYP2D6 versus extensive metabolizers found that for the positive (+) enantiomer, the AUC was 1.98-fold and the negative (-) enantiomer's AUC was 1.74-fold when compared to extensive metabolizers. The oral clearance was examined and was found to be 1.91-fold in poor metabolizers for the (+) enantiomer and 1.71-fold for the negative enantiomer when compared to extensive metabolizers.[8]

Excretion
30% of tramadol will be excreted in the urine unchanged. 60% of the drug will be excreted in the urine as metabolites. The rest is unidentified or is a metabolite which could not be extracted. Tramadol itself is eliminated via the liver. The half-life of tramadol is 6.3 hours and the half-life of M1 is 7.4 hours. After repeated dosing of tramadol, the half-life of tramadol increases to about 7 hours.[1]

Special Population Pharmacokinetics

  • Renal insufficiency: Renal insufficiency decreases the rate and extent of elimination of both tramadol and its metabolites. When a patient's creatinine clearance is less than 30 mL/min, a decreased dose of tramadol is recommended, and extended-release tramadol is not recommended.[1]
  • Hepatic insufficiency: The metabolism of tramadol is lowered in patients with hepatic insufficiency. This causes a larger area-under the concentration-time curve for tramadol. Tramadol and M1 will have longer elimination half-lives which have been reported to extend to 13 hours for tramadol and 19 hours for M1. Extended-release tramadol is not recommended in this patient population.[1]
  • Hemodialysis: After a 4 hour hemodialysis session, less than 7% of the dose of tramadol is cleared from the blood. Extended-release tramadol is not recommended in this patient population.[1]
  • Geriatric: In patients over the age of 75, the peak serum concentrations increase from 162 to 208 ng/mL. Additionally, the elimination half-life of tramadol is increased by an hour, from 6 to 7 hours. Based on this pharmacokinetic data, the dosage of tramadol should be adjusted in patients over the age of 75. No PK differences were noted in the population from 65-75 years of age.[1] A randomized controlled trial measured serum concentrations of M1 and tramadol in 100 patients. The 100 patients were split up into three groups, greater than or equal to 75 years, 65 to less than 75, and less than 65 years. There were no PK differences between the groups. The group greater than or equal to 75 years used 20% less tramadol than did the group which was less than 65 years of age.[7]
  • Pediatric: No data.
  • Gender: The bioavailability was slightly different between males (73%) and females (79%). The plasma clearance was slightly greater in males at 6.4 mL/min/kg vs. 5.7 mL/min/kg in females. Females had a 12% higher peak tramadol concentration than males. Females also had a 35% greater area under the concentration-time curve than did males. Currently, the clinical significance is not known.[1]

Indications and Dosages

FDA Approved Indications

Moderate to moderately-severe pain in patients 17 years of age and older[1][9][10]

  • Starting dose for chronic pain:
    • 25 mg daily in the morning
  • Starting dose for acute pain:
    • 50 to 100 mg daily every 4 to 6 hours as needed for pain
  • Maintenance dose:
    • 200 mg daily
    • After the titration period is over, additional doses may be given as needed for pain every 4-6 hours.
    • The maximum daily dose is 400 mg (300 mg for ages 75 and up).
  • Titration schedule: titrate in 25 mg increments as separate doses every three days until 25 mg by mouth four times a day is reached. Then the total daily dosage of tramadol may be increased by 50mg every three days to 50 mg by mouth four times a day. Adverse effects will be more likely if tramadol is not titrated.

Non-FDA Approved Indications

Dosage Adjustment

Renal insufficiency: For patients with a CrCl <30 mL/min, the dosage interval should be extended to 12 hours. The maximum daily dose should be lowered to 200 mg/day.[1]
Hepatic insufficiency: The recommended dose is 50 mg every 12 hours for patients with hepatic cirrhosis. It is not recommended that patients with hepatic impairment receive extended-release tramadol.[1]
Hemodialysis: Patients can receive their regular dose on dialysis days. Only 7% of the dose is removed by a four-hour hemodialysis session. No studies have been completed with hemodialysis patients taking extended-release tramadol, therefore it is not recommended it is given to this patient population.
Geriatric: In patients over the age of 65, dosage should initially be lower than an adult patient. It is be titrated based on tolerability, not to exceed the rate of titration recommended for adult patients. Patients over the age of 75 years, should not exceed 300 mg of tramadol per day.[1]
Pediatric: Not indicated.

Dosage Limits

  • Ages 17 to 75: 400 mg/day
  • Elderly over age 75: 300 mg/day
  • Adolescents under age 17 and children: Not indicated


Administration

  • Route: Oral
  • Method:
    • May be taken with or without food. Take with a drink of water or other beverage.
    • Extended-release tablets should be swallowed whole and not crushed or chewed.

Monitoring Parameters

  • Not needed

Contraindications/Precautions

Contraindications

  • Hypersensitivity to tramadol or any of its components
  • Hypersensitivity to opioids
  • Patients acutely intoxicated with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs

Precautions

  • Acute abdominal conditions
  • Renal impairment (caution with immediate-release, extended-release not recommended in severe renal impairment)
  • Hepatic impairment (caution with immediate-release, extended-release not recommended)
  • Respiratory depression
  • Patients receiving anesthetic medications
  • Patients who consume alcohol
  • Patients with epilepsy, a history of seizures, head trauma, metabolic disorder, alcohol withdrawal, drug withdrawal, or CNS infections: seizures may occur with tramadol, even within typical dosage limits. Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures).[22] Risk of seizures increases when the following drugs are used concomitantly: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), tricyclic compounds (cyclobenzaprine, promethazine), opioids, monoamine oxidase inhibitors (MAOIs), neuroleptics, alcohol,[23] naloxone (given for overdose of tramadol), or any other drug which may lower the seizure threshold.
  • Increased intracranial pressure
  • Abrupt discontinuation: withdrawal may occur if tramadol is stopped without downward titration. Symptoms of withdrawal include anxiety, sweating, insomnia, pain, nausea, tremors, diarrhea, piloerection and hallucinations.

Pregnancy indications

Category C Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits. Tramadol has not been shown to be teratogenic in mice, rats and rabbits.

Breast-feeding indications

Tramadol is not indicated for breastfeeding mothers. The excretion into breast milk is 0.1% of the maternal dose.[1]


Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

In a clinical trial of 550 patients with moderate pain (375 patients 65 years or older), the rates of side effects were comparable to acetaminophen with codeine, but the rate of withdrawal for side effects was greater in patients treated with tramadol.[1] The most frequent adverse effects include constipation (38%), nausea (34%), dizziness (31%), headache (26%), somnolence (23%) and vomiting (13%).[2]

Tramadol Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Dizziness (26-33%), nausea (24-40%), constipation (24-46%), headache (18-32%), somnolence (16-25%), vomiting (9-25%), dyspepsia (5-13%), pruritis (8-11%), diarrhea (5-10%), CNS stimulation (7-14%), asthenia (6-12%), sweating (6-12%)
1-10% CNS Sleep changes (1-5%), anxiety, confusion, coordination disturbances, euphoria, nervousness
Cardiovascular Vasodilation (1-5%)
Dermatologic Rash (1-5%)
GI Dry mouth (5-10%), abdominal pain (1-5%), anorexia (1-5%), flatulence (1-5%)
Genitourinary Menopausal symptoms (1-5%), urinary frequency or retention (1-5%)
Neuromuscular/skeletal Hypertonia (1-5%)
Miscellaneous Malaise (1-5%)
<1% All Accidental injury, allergic reaction, anaphylaxis, death, suicide, weight loss, serotonin syndrome, orthostatic hypotension, tachycardia, Stevens-Johnson syndrome, tremor, gait changes, amnesia, dysuria, dysgeusia, menstrual disorder, hallucinations, paresthesias

Overdosage Measures

Symptoms of overdosage include respiratory depression, lethargy, coma, seizure, or cardiac arrest.[1]
Treatment:

  • Use general supportive measuresand maintain ventilation.
  • Naloxone reverses some, but not all symptoms and can increase the risk for seizure.
  • Convulsions can be suppressed with barbiturates or benzodiazepines.

Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
50 mg tablet white oblong ULTRAM/06 59
100 mg extended-release tablet white round '100' over 'ER'
200 mg extended-release tablet white round '200' over 'ER'
300 mg extended-release tablet white round '300' over 'ER'
  • Inactive ingredients for tablets: corn starch, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium glycolate, titanium dioxide, wax
  • Inactive ingredients for extended-release tablets: colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium stearyl fumarate

Patient Information

  • May be taken with or without food.
  • May cause dizziness or drowsiness. Use caution when driving or operating heavy machinery.
  • DO NOT take with alcohol.
  • Extended-release tablets should be swallowed whole and not be crushed or chewed.
  • Use caution when taking tranquilizers, hypnotics, or other opiate containing analgesics
  • Contact your doctor if you are planning on becoming pregnant or think that you are pregnant
  • Do not take more often than directed, this may cause respiratory depression, seizures and death
  • Contact a health-care professional right away if: you are having difficulty breathing, have had a seizure, develop a rash, experience a change in vision, hallucinate, or have a fast heart beat.
  • Other side-effects that you may notice include constipation or diarrhea, dry mouth, and headache.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 Ortho-McNeil Pharmaceutical INC. Ultram (tramadol hydrochloride tablets) prescribing information. 2004.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Stitik TP, Altschuler E, Foye PM, Stitik TP, Altschuler E, Foye PM. Pharmacotherapy of osteoarthritis. American Journal of Physical Medicine & Rehabilitation. 2006 Nov;85(11 Suppl):S15-28; quiz S9-31.
  3. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named sert
  4. ↑ Cicero TJ, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug and alcohol dependence. 1999 Nov 1;57(1):7-22
  5. ↑ Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.]
  6. ↑ Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol. 2000 Dec;21(4):370-4.
  7. ↑ 7.0 7.1 Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.
  8. ↑ Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.
  9. ↑ Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.
  10. ↑ Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.
  11. ↑ Akinci SB, Saricaoglu F, Atay OA, Doral MN, Kanbak M. Analgesic effect of intra-articular tramadol compared with morphine after arthroscopic knee surgery. Arthroscopy. 2005 Sep;21(9):1060-5.
  12. ↑ Cander B, Girisgin S, Koylu R, Gul M, Kocak S. The effectiveness of analgesics in traumatic injuries of the extremities. Advances in therapy. 2005 Sep-Oct;22(5):462-6.
  13. ↑ Sekar C, Rajasekaran S, Kannan R, Reddy S, Shetty TA, Pithwa YK. Preemptive analgesia for postoperative pain relief in lumbosacral spine surgeries: a randomized controlled trial. Spine J. 2004 May-Jun;4(3):261-4.
  14. ↑ Moore PA. Pain management in dental practice: tramadol vs. codeine combinations. Journal of the American Dental Association (1939). 1999 Jul;130(7):1075-9.
  15. ↑ Silberstein SD, Freitag FG, Rozen TD, Kudrow DB, Hewitt DJ, Jordan DM, et al. Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial. Headache. 2005 Nov-Dec;45(10):1317-27.
  16. ↑ Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. The American journal of medicine. 2003 May;114(7):537-45.
  17. ↑ Chong MS, Hester J. Diabetic painful neuropathy : current and future treatment options. Drugs. 2007;67(4):569-85.
  18. ↑ Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. The Journal of rheumatology. 2007 Mar;34(3):543-55.
  19. ↑ le Roux PJ, Coetzee JF. Tramadol today. Current opinion in anaesthesiology. 2000 Aug;13(4):457-61.
  20. ↑ Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA. Tramadol HCL has Promise in On-Demand Use to Treat Premature Ejaculation. J Sex Med. 2007 Mar 14.
  21. ↑ Vetrugno R, La Morgia C, D'Angelo R, Loi D, Provini F, Plazzi G, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord. 2007 Feb;22(3):424-7.
  22. ↑ Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. The Annals of pharmacotherapy. 1997 Feb;31(2):175-7.
  23. ↑ Jovanovic-Cupic V, Martinovic Z, Nesic N. Seizures associated with intoxication and abuse of tramadol. Clinical toxicology (Philadelphia, Pa. 2006;44(2):143-6.

PUBMED References

Efficacy Trial Articles

  1. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.
  2. Pendeville PE, Von Montigny S, Dort JP, Veyckemans F. Double-blind randomized study of tramadol vs. paracetamol in analgesia after day-case tonsillectomy in children. European journal of anaesthesiology. 2000 Sep;17(9):576-82.
  3. Roth SH. Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis. The Journal of rheumatology. 1998 Jul;25(7):1358-63.


Therapeutic Class Comparison Articles

  1. Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.
  2. Ng KF, Yuen TS, Ng VM. A comparison of postoperative cognitive function and pain relief with fentanyl or tramadol patient-controlled analgesia. Journal of clinical anesthesia. 2006 May;18(3):205-10.
  3. Ekman EF, Ruoff G, Kuehl K, Ralph L, Hormbrey P, Fiechtner J, et al. The COX-2 specific inhibitor Valdecoxib versus tramadol in acute ankle sprain: a multicenter randomized, controlled trial. The American journal of sports medicine. 2006 Jun;34(6):945-55.
  4. Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.

Pharmacokinetics Articles

  1. Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.
  2. Murthy BP, Skee DM, Danyluk AP, Brett V, Vorsanger GJ, Moskovitz BL. Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol. Current medical research and opinion. 2007 Feb;23(2):275-84.
  3. Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.
  4. Garrido MJ, Habre W, Rombout F, Troconiz IF. Population pharmacokinetic/pharmacodynamic modelling of the analgesic effects of tramadol in pediatrics. Pharmaceutical research. 2006 Sep;23(9):2014-23.


Drug Interaction Articles

  1. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British journal of anaesthesia. 2005 Oct;95(4):434-41.
  2. Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. The American journal of psychiatry. 2004 Jun;161(6):1129.
  3. Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. Journal of the Royal Society of Medicine. 1999 Sep;92(9):474-5.
  4. Dumo PA, Kielbasa LA. Successful anticoagulation and continuation of tramadol therapy in the setting of a tramadol-warfarin interaction. Pharmacotherapy. 2006 Nov;26(11):1654-7.
  5. Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy. 1998 Jul-Aug;18(4):871-3.

Proprietary preparations

Grünenthal, which still owns the patent to tramadol, has cross-licensed the agent to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:

Adverse Effects Articles

Compliance Articles

Pharmacoeconomic Articles

External Links

Clinical treatment guidelines

Patient information pages

Other resources

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