Tramadol - Wikipedia

9/3/2019 Tramadol - Wikipedia
Tramadol
Tramadol, sold under the brand name Ultram among others,[2] is an
Tramadol
opioid pain medication used to treat moderate to moderately severe pain.[1]
When taken by mouth in an immediate-release formulation, the onset of
pain relief usually begins within an hour.[1] It is also available by
injection.[8] It may be sold in combination with paracetamol
(acetaminophen) or as longer-acting formulations.[1][8]
Common side effects include constipation, itchiness, and nausea.[1] Serious

side effects may include seizures, increased risk of serotonin syndrome,
decreased alertness, and drug addiction.[1] A change in dosage may be
recommended in those with kidney or liver problems.[1] It is not
recommended in those who are at risk of suicide or in those who are
pregnant.[1][8] While not recommended in women who are breastfeeding,
those who take a single dose should not generally stop breastfeeding.[9]
Tramadol acts by binding to μ-opioid receptors on neurons.[1][10] It is also

a serotonin–norepinephrine reuptake inhibitor (SNRI).[1][10] It is
converted in the liver to O-desmethyltramadol, an opioid with stronger
binding to the μ-opioid receptor.[1][11]
Tramadol was patented in 1963 and launched under the name "Tramal" in
1977 by the West German pharmaceutical company Grünenthal
GmbH.[10][12] In the mid-1990s, it was approved in the United Kingdom
and the United States.[10] It is available as a generic medication and Clinical data
marketed under many brand names worldwide.[1][2] In the United States, Pronunciation tra' ma dole
the wholesale cost is less than US$0.05 per dose as of 2018.[13] In 2016, it
Trade names Ultram, Zytram,
was the 39th most prescribed medication in the United States, with more
others[2]
than 19 million prescriptions.[14]
AHFS/Drugs.com Monograph (https://w
ww.drugs.com/mono
graph/ultram.html)
Contents MedlinePlus a695011 (https://med
Medical uses lineplus.gov/druginfo/
Fibromyalgia meds/a695011.html)
Contraindications License data US FDA: Tramadol (h
Pregnancy and lactation
Labour and delivery ttps://www.accessdat
Children a.fda.gov/scripts/cde
Elderly r/drugsatfda/index.cf
Liver and kidney failure m?fuseaction=Searc
Side effects h.SearchAction&Sea
Dependence and withdrawal rchTerm=Tramadol&
Overdose
https://en.wikipedia.org/wiki/Tramadol#Pharmacodynamics 1/19
Interactions SearchType=BasicS
Pharmacology earch)
Pharmacodynamics
Pregnancy AU: C
Mechanism of action category
Pharmacokinetics US: C (Risk not ruled
Chemistry out)
Synthesis and stereoisomerism
Detection in biological fluids
Dependence Present[1]
liability
Society and culture Routes of By mouth, IV, IM,
Patent history administration rectal
Legal status
Misuse Drug class Opiate analgesic[3]
Research ATC code N02AX02 (WHO (htt
Investigational uses ps://www.whocc.no/a
False findings about sources in nature tc_ddd_index/?code
Veterinary medicine =N02AX02))
References
Legal status
External links
Legal status AU: S4 (Prescription
only)
Medical uses CA: ℞-only
NZ: Prescription
Tramadol is used primarily to treat mild to severe pain, both acute and
Medicine
chronic.[15][16]
UK: Class C –
Its analgesic effects take about one hour to come into effect and 2 to 4 h to Schedule 3 CD
peak after oral administration with an immediate-release
US: Schedule IV
formulation.[16][15] On a dose-by-dose basis, tramadol has about one-tenth
the potency of morphine and is practically equally potent when compared
In general:
with pethidine and codeine.[17]
℞ (Prescription only)
Pharmacokinetic data
For pain moderate in severity, its effectiveness is equivalent to that of
Bioavailability 70–75% (by mouth),
morphine; for severe pain it is less effective than morphine.[15] These
77% (rectal), 100%
painkilling effects last about 6 h.[16]
(IM)[4]
Available dosage forms include liquids, syrups, drops, elixirs, effervescent Protein binding 20%[1]
tablets and powders for mixing with water, capsules, tablets including
Metabolism Liver-mediated
extended-release formulations, suppositories, compounding powder, and
demethylation and
injections.[15]
glucuronidation via
CYP2D6 &
Fibromyalgia CYP3A4[4][5]
As of 2015, tramadol was not approved in the United States for

Metabolites O-
fibromyalgia.[18] Based on three small trials with weak study design, fair desmethyltramadol,
evidence was found for tramadol as a second-line treatment.[18] N-
desmethryltramadol
Contraindications Onset of action Less than 1 hour (by

mouth)[1]
Use of tramadol is not advised for people deficient in CYP2D6 enzymes.[7] Elimination 6.3 ± 1.4 h[5]
The enzymes are crucial to the therapeutic effects of tramadol, by means of
half-life
enabling tramadol's metabolism to desmetramadol.[15]
Duration of 6 hours[6]
action
Excretion Urine (95%)[7]
Pregnancy and lactation Identifiers
Tramadol's use in pregnancy is generally avoided, as it may cause some IUPAC name
reversible withdrawal effects in the newborn.[19] A small prospective study CAS Number 27203-92-5 (http://w
in France found, while an increased risk of miscarriages existed, no major
ww.commonchemistr
malformations were reported in the newborn.[19] Its use during lactation is
y.org/ChemicalDetail.
also generally advised against, but a small trial found that infants breastfed
aspx?ref=27203-92-
by mothers taking tramadol were exposed to about 2.88% of the dose the
5)
mothers were taking. No evidence of this dose having a harmful effect on
the newborn was seen.[19] PubChem CID 33741 (https://pubch
em.ncbi.nlm.nih.gov/
compound/33741)
Labour and delivery
DrugBank DB00193 (https://ww
Its use as an analgesic during labour is generally advised against due to its
w.drugbank.ca/drugs/
long onset of action (1 hour).[19] The ratio of the mean concentration of the
DB00193)
drug in the fetus compared to that of the mother when it is given
intramuscularly for labour pains has been estimated to be 1:94.[19]
ChemSpider 31105 (http://www.ch
emspider.com/Chemi
cal-Structure.31105.h
Children tml)
Its use in children is generally advised against, although it may be done UNII 39J1LGJ30J (https://f
under the supervision of a specialist.[15] On September 21, 2015, the FDA
dasis.nlm.nih.gov/sr
started investigating the safety of tramadol in use in persons under the age
s/srsdirect.jsp?regno
of 17. The investigation was initiated because some of these people have
=39J1LGJ30J)
experienced slowed or difficult breathing.[20] The FDA lists age under 12
KEGG D08623 (http://www.k
years old as a contraindication.[21][22]
egg.jp/entry/D08623)
Elderly
ChEBI CHEBI:9648 (https://
The risk of opioid-related adverse effects such as respiratory depression,
www.ebi.ac.uk/chebi/
falls, cognitive impairment and sedation is increased.[15]
searchId.do?chebiId
=CHEBI:9648)
Liver and kidney failure ChEMBL ChEMBL1066 (http
The drug should be used with caution in those with liver or kidney failure, s://www.ebi.ac.uk/ch
due to metabolism in the liver (to desmetramadol) and elimination by the embldb/index.php/co
kidneys.[15] mpound/inspect/ChE
MBL1066)
Side effects CompTox

Dashboard (EPA)
DTXSID90858931 (h
ttps://comptox.epa.g
The most common adverse effects of tramadol include nausea, dizziness,
ov/dashboard/DTXSI
dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation,
D90858931)
drowsiness, and headache.[24][25] Compared to other opioids, respiratory
depression and constipation are considered less of a problem with ECHA InfoCard 100.043.912 (https://
tramadol.[25] echa.europa.eu/subs
tance-information/-/s
Chronic opioid administration may induce a state of immune tolerance,[26]
ubstanceinfo/100.04
although in contrast to typical opioids, it may enhance immune
3.912)
function.[27][28][29]
Chemical and physical data
Formula C16H25NO2
Dependence and withdrawal Molar mass 263.381
Long-term use of high doses of tramadol causes physical dependence and g/mol g·mol−1
withdrawal syndrome.[30] These include both symptoms typical of opioid
3D model Interactive image (htt
withdrawal and those associated with serotonin–norepinephrine reuptake (JSmol)
ps://chemapps.stolaf.
inhibitor withdrawal; symptoms include numbness, tingling, paresthesia,
edu/jmol/jmol.php?m
and tinnitus.[31] Psychiatric symptoms may include hallucinations,
odel=CN%28C%29
paranoia, extreme anxiety, panic attacks, and confusion.[32] In most cases,
C%5BC%40H%5D1
tramadol withdrawal will set in 12–20 hours after the last dose, but this can
CCCC%5BC%40%4
vary.[31] Tramadol withdrawal typically lasts longer than that of other
0%5D1%28C2%3DC
opioids. Seven days or more of acute withdrawal symptoms can occur as
C%28%3DCC%3DC
opposed to typically 3 or 4 days for other codeine analogues.[31]
2%29OC%29O)
A 2014 report by the World Health Organizations Expert Committee on Melting point 180 to 181 °C (356 to
Drug Dependence found: 358 °F)
SMILES
... in many cases of tramadol dependence, a history of
substance abuse is present... but... the evidence for physical InChI
dependence was considered minimal. Consequently, (what is this?) (verify)
Tramadol is generally considered as a drug with low potential
for dependence. In a recent German study (including a
literature study, an analysis of two drug safety databases, and
questionnaires analyses), the low abuse and low dependence
potential of Tramadol were re-confirmed. The German expert
group found a low prevalence of abuse or dependence in
clinical practice in Germany, and concluded that Tramadol Generic tramadol HCl tablets
has a low potential for misuse, abuse, and dependence in marketed by Amneal
Germany.[33] Pharmaceuticals
Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous.[34]
Tramadol can cause a higher incidence of nausea, dizziness, and loss of appetite compared with opioids, which could deter
recreational use.[35] Compared to hydrocodone, fewer persons choose to use tramadol recreationally.[36]
Overdose
Recognised risk factors for tramadol overdose include depression, addiction, and seizures.[37] Naloxone only partially
reverses the toxic effects of tramadol overdose and may increase the risk of seizures.[15]
Deaths with tramadol overdose have been reported and are increasing in
frequency in Northern Ireland; the majority of these overdoses involves other
drugs including alcohol.[37] There were 254 tramadol-related deaths in
England and Wales in 2013, and 379 in Florida in 2011.[38][39] In 2011, 21,649
emergency room visits in the United States were related to tramadol.[40]
Interactions
Tramadol may interact with certain antidepressants and anxiolytics
(particularly selective serotonin reuptake inhibitors, serotonin–
norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and
tricyclic antidepressants) other opioid analgesics (pethidine, tapentadol,
oxycodone, and fentanyl), dextromethorphan, certain migraine medications
(triptans, ergots), certain antibiotics (namely, linezolid and isoniazid), certain
herbs (e.g. St. John's wort, passiflora, etc.), stimulants (including
amphetamines, phenethylamine, and phentermine), lithium, and methylene Tramadol HCl for injection
blue, as well as numerous other therapeutic agents.[7][15] As it is a substrate of
CYP3A4 and CYP2D6, any agents with the ability to inhibit or induce
these enzymes are likely to interact with tramadol. A pressor
response similar to the so-called "cheese effect" was noted in
combinations of amphetamine and tramadol, which appears to cause
dysfunction of or toxicity to epinephrine/norepinephrine
receptors.[15][25] Cyclobenzaprine, a commonly used muscle
relaxant, atypical analgesic adjunct, as well as a potentiator often
used with analgesics such as codeine, dihydrocodeine, hydrocodone
and the like, is structurally related to the tricyclic
antidepressants,[41] so should not be used with tramadol; this is also
the case for trazodone.[42]
Pharmacology
Main side effects of tramadol: Red color
denotes more serious effects, requiring
Pharmacodynamics
immediate contact with health provider.[23]
Tramadol induces analgesic effects through a variety of different
targets on the noradrenergic system, serotoninergic system and
opioid receptors system.[43] Tramadol exists as a racemic mixture, the positive enantiomer inhibits serotonin reuptake
while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters.[44][6]
Tramadol has also been shown to act as a serotonin releasing agent. Both enantiomers of tramadol are agonists of the mu-
opioid receptor and its M1 metabolite, O-demethylate, is also a mu-opoid receptor agonist but is 6 times more potent than
tramadol itself.[45] All these effects work synergistically to induce analgesia.
Mechanism of action
Tramadol has been found to possess these actions:[47][48][71]
Agonist of the μ-opioid receptor (MOR) and to a far lesser extent of the δ-opioid receptor (DOR) and κ-opioid receptor
(KOR)
Serotonin reuptake inhibitor (SRI) and Tramadol (and metabolite)[46][47][48]

norepinephrine reuptake inhibitor); hence,
an SNRI Site Tramadol DSMT Species Ref
Serotonin 5-HT2C receptor antagonist [49][50][51]
1,600–12,486 5.4–18.6 Human
M1 and M3 muscarinic acetylcholine MOR 2,120–8,300 17 ((+)) Rat [52][53]
receptor antagonist ≥1,000 (EC50) ≥240 (EC50) Human [54][11]
α7 nicotinic acetylcholine receptor
>10,000 ≥2,900 Human [49][50][55]
antagonist DOR
57,600–100,000 690 (+)) Rat [53][52]
NMDA receptor antagonist (very weak)
TRPA1 inhibitor >10,000 ≥450 Human [49][50][55]
KOR [53][52]
42,700–81,000 1,800 (+)) Rat
Tramadol acts on the opioid receptors through
its major active metabolite desmetramadol, ~900 (IC50) >20,000 (IC50) Human [56]
SERT [53][11]
which has as much as 700-fold higher affinity 992–1,190 2,980 ((−)) (IC50) Rat
for the MOR relative to tramadol.[11] Moreover, 14,600 1,080 (−) (IC50) Human [11]
NET [53][11]
tramadol itself has been found to possess no 785 >860 (IC50) Rat
efficacy in activating the MOR in functional DAT >100,000 >20,000 Rat [57][55]
activity assays, whereas desmetramadol
5-HT1A >20,000 >20,000 Rat [55]
activates the receptor with high intrinsic
5-HT2A >20,000 >20,000 Rat [55]
activity (Emax equal to that of
morphine).[54][11][72] As such, desmetramadol 5-HT2C 1,000 (IC50) 1,300 (IC50) Rat [58][59]
is exclusively responsible for the opioid effects

5-HT3 >20,000 >20,000 Rat [55]
of tramadol.[73] Both tramadol and
NK1 IA ? Rat [60][61]
desmetramadol have pronounced selectivity for
the MOR over the DOR and KOR in terms of >20,000 >20,000 Rat [55]
M1
binding affinity.[55][50][52] 3,400 (IC50) 2,000 (IC50) Multiple [62][63]
M2 ND ND ND ND
Tramadol is well-established as an SRI.[47][48]
In addition, a few studies have found that it M3 1,000 (IC50) IA Human [63][64]
also acts as a serotonin releasing agent (1– M4 ND ND ND ND

10 μM), similar in effect to
M5 ND ND ND ND
fenfluramine.[74][75][76][77] The serotonin
releasing effects of tramadol could be blocked α7 7,400 ND Chicken [65]
by sufficiently high concentrations of the σ1 >10,000 ND Rat [46][66]

serotonin reuptake inhibitor 6-nitroquipazine,
σ2 >10,000 ND Rat [46]
which is in accordance with other serotonin
NMDAR 16,400 (IC50) 16,500 (IC50) Human [67]
releasing agents such as fenfluramine and
MDMA.[74][76][77] However, two more recent NMDAR
>20,000 >20,000 Rat [55]
studies failed to find a releasing effect of (MK-801)
tramadol at respective concentrations up to 10 GABAA >100,000 (IC50) >100,000 (IC50) Human [67]
and 30 μM.[78][77][70] In addition to

GlyR >100,000 (IC50) >100,000 (IC50) Human [67]
serotonergic activity, tramadol is also a
norepinephrine reuptake inhibitor.[47][48] It is TRPA1
100– 1,000–
Human [68]
10,000 (SI) 10,000 (SI)
not a norepinephrine releasing
>10,000 (IC50) >10,000 (IC50) [68][69]
agent.[79][80][81][70] Tramadol does not inhibit TRPV1 Human
the reuptake or induce the release of Values are Ki (nM), unless otherwise noted. The smaller the value, the
dopamine.[79][70] more strongly the drug binds to the site.
A positron emission tomography imaging study found that single oral 50-mg and 100-mg
doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean Tramadol and mono-
amine reuptake/release[70]
occupation of the serotonin transporter (SERT) in the thalamus.[82] The estimated median
effective dose (ED50) for SERT occupancy hence was 98.1 mg, which was associated with a Action Value
plasma tramadol level of about 330 ng/ml (1,300 nM).[82] The estimated maximum daily 5-HT reuptake 1,820
dosage of tramadol of 400 mg (100 mg q.i.d.) would result in as much as 78.7% occupancy
5-HT release >10,000
of the SERT (in association with a plasma concentration of 1,220 ng/ml or 4,632 nM).[82]
NE reuptake 2,770
This is close to that of SSRIs, which occupy the SERT by 80% or more.[82]
NE release >10,000
Peak plasma concentrations during treatment with clinical dosages of tramadol have
DA reuptake >10,000
generally been found to be in the range of 70 to 592 ng/ml (266–2,250 nM) for tramadol
DA release >10,000
and 55 to 143 ng/ml (221–573 nM) for desmetramadol.[83] The highest levels of tramadol
were observed with the maximum oral daily dosage of 400 mg per day divided into one 100- Values for reuptake inhibition
are Ki (nM) and for release
mg dose every 6 hours (i.e., four 100-mg doses evenly spaced out per day).[83][84] Some
induction are EC50 (nM).
accumulation of tramadol occurs with chronic administration; peak plasma levels with the
maximum oral daily dosage (100 mg q.i.d.) are about 16% higher and the area-under-the-curve levels 36% higher than
following a single oral 100-mg dose.[83] Positron emission tomography imaging studies have reportedly found that
tramadol levels are at least four-fold higher in the brain than in plasma.[79][85] Conversely, brain levels of desmetramadol
"only slowly approach those in plasma".[79] The plasma protein binding of tramadol is only 4 to 20%; hence, almost all
tramadol in circulation is free, thus bioactive.[86][87][88]
Correspondence to effects
Co-administration of quinidine, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in
markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in
human volunteers.[11][87] However, other studies have found that the analgesic effects of tramadol are significantly
decreased or even absent in CYP2D6 poor metabolizers.[11][73] The analgesic effects of tramadol are only partially reversed
by naloxone in human volunteers,[11] hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic
effects are also partially reversed by α2-adrenergic receptor antagonists such as yohimbine, the 5-HT3 receptor antagonist
ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719.[16][89] Pharmacologically, tramadol is
similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and
norepinephrine[4] due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.[90]
Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for
tramadol's reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid
neurological illnesses.[58] 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout
mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death.
However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABAA receptors at
high doses (significant inhibition at 100 μM).[67][71] In addition, desmetramadol is a high-affinity ligand of the DOR, and
activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists
are well known for inducing seizures.[52]
Nausea and vomiting caused by tramadol are thought to be due to activation of the 5-HT3 receptor via increased serotonin
levels.[56] In accordance, the 5-HT3 receptor antagonist metoclopramide can be used to treat tramadol-associated nausea
and vomiting.[56] Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.[56][48]
Pharmacokinetics
Tramadol undergoes hepatic metabolism via the

cytochrome P450 isozyme CYP2B6, CYP2D6, and
CYP3A4, being O- and N-demethylated to five different
metabolites. Of these, desmetramadol (O-
desmethyltramadol) is the most significant, since it has
200 times the μ-affinity of (+)-tramadol, and
furthermore has an elimination half-life of 9 hours,
compared with 6 hours for tramadol itself. As with
codeine, in the 6% of the population who have reduced
CYP2D6 activity (hence reducing metabolism), a reduced
analgesic effect is seen. Those with decreased CYP2D6
activity require a dose increase of 30% to achieve the
Desmetramadol.
same degree of pain relief as those with a normal level of
CYP2D6 activity.[91][92]
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.[16]
Its volume of distribution is around 306 l after oral administration and 203 l after parenteral administration.[16]
Chemistry
Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers,[4] because the two isomers complement each
other's analgesic activities.[4] The (+)-isomer is predominantly active as an opiate with a higher affinity for the µ-opiate
receptor (20 times higher affinity than the (-)-isomer).[93]
Synthesis and stereoisomerism

The chemical synthesis of tramadol is described in the literature.[94]
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:
(1R,2R)-isomer (1R,2R)-tramadol (1S,2S)-tramadol

(1S,2S)-isomer
(1R,2S)-isomer
(1S,2R)-isomer
The synthetic pathway leads to the racemate (1:1 mixture) of
(1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor
amounts of the racemic mixture of the (1R,2S)-isomer and the
(1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-
(1R,2S)-tramadol (1S,2R)-tramadol
isomer and the (1S,2S)-isomer from the diastereomeric minor
racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol
is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(−)-enantiomers. The resolution of the racemate
[(1R,2R)-(+)-isomer / (1S,2S)-(−)-isomer] was described[95] 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[96]
of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in
animals[97] and in humans.[98]
Detection in biological fluids

Tramadol and desmetramadol may be quantified in blood, plasma or serum to monitor for abuse, confirm a diagnosis of
poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests
do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to
detect and quantitate these substances. The concentration of desmetramadol in the blood or plasma of a person who has
taken tramadol is generally 10–20% those of the parent drug.[99][100][101]
Society and culture
Patent history
The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER)
formulation in September 2005.[102] ER Tramadol was protected by US patents nos. 6,254,887[103] and
7,074,430.[104][105] The FDA listed the patents' expiration as 10 May 2014.[104] However, in August 2009, US District
Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals
for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was
therefore permitted prior to the expiration of the patents.[106]
Legal status
Effective August 18, 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the
United States.[107][108] Before that, some US states had already classified tramadol as a Schedule IV controlled substance
under their respective state laws.[109][110][111]
Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as a Schedule 8 Controlled Drug
(Possession without authority illegal) like most other opioids.[15]
Effective May 2008, Sweden classified tramadol as a controlled substance in the same category as codeine and
dextropropoxyphene, but allows a normal prescription to be used.[112]
The UK classified tramadol as a Class C, Schedule 3 controlled drug on 10 June 2014, but exempted it from the safe
custody requirement.[113]
Misuse
Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization.[114][115][116]
When used at higher doses, the drug "can produce similar effects to heroin."[114] Said one former member, “whenever we
took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very
bold, it was impossible to go on a mission without taking it.”[114] Tramadol misuse is also found as a coping mechanism in
the Gaza Strip.[117]
Research
Investigational uses
Diabetic neuropathy [118][119]
Antidepressant[120]
Postherpetic neuralgia [121][122]
Premature ejaculation[123][124]
Adjunct to local anaesthesia[125]
False findings about sources in nature

In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African
pin cushion tree (Nauclea latifolia).[126] In 2014, however, it was reported that the presence of tramadol in the tree roots
was the result of tramadol having been administered to cattle by farmers in the region:[127] tramadol and its metabolites
were present in the animals' excreta, which contaminated the soil around the trees. Therefore, tramadol and its
mammalian metabolites were found in tree roots in the far north of Cameroon, but not in the south where it is not
administered to farm animals.[127]
A 2014 editorial in Lab Times online contested the notion that tramadol in tree roots was the result of anthropogenic
contamination, stating that samples were taken from trees which grew in national parks, where livestock were forbidden;
it also quoted researcher Michel de Waard, who stated that "thousands and thousands of tramadol-treated cattle sitting
around a single tree and urinating there" would be required to produce the concentrations discovered.[128]
In 2015, radiocarbon analysis confirmed that the tramadol found in N.latifolia roots could not be plant-derived and was of
synthetic origin.[129]
Veterinary medicine
Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as
well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons.[130]
Pharmacokinetics of tramadol across the species[130]

Maximum plasma Maximum plasma
Half-life (h) for Half-life (h) for
Species concentration (ng/mL) for concentration (ng/mL) for
parent drug desmetramadol
parent drug desmetramadol
Camel 3.2 (IM), 1.3 (IV) – 0.44 (IV) –
3.40 (oral), 2.23 4.82 (oral), 4.35
Cat 914 (oral), 1323 (IV) 655 (oral), 366 (IV)
(IV) (IV)
1.71 (oral), 1.80 2.18 (oral), 90-
Dog 1402.75 (oral) 449.13 (oral), 90–350 (IV)
(IV), 2.24 (rectal) 5000 (IV)
4.2 (oral), 1.5
Donkey – 2817 (oral) –
(IV)
2.67 (oral), 0.94
Goat – 542.9 (oral) –
(IV)
1.29–1.53 (IV),
Horses 4 (oral) 637 (IV), 256 (oral) 47 (oral)
10.1 (oral)
2.54 (IM), 2.12 7.73 (IM), 10.4
Llama 4036 (IV), 1360 (IM) 158 (IV), 158 (IM)
(IV) (IV)
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External links
Medline Plus – Patient Information (https://www.nlm.nih.gov/medlineplus/druginfo/meds/a695011.html) Medline Plus
(A Service of the U.S. National Library of Medicine)
U.S. National Library of Medicine: Drug Information Portal – Tramadol (http://druginfo.nlm.nih.gov/drugportal/dpdirect.j
sp?name=Tramadol)
U.S. National Center for Biotechnology Information: Medical Genetics Summaries - Tramadol Therapy and CYP2D6
Genotype (https://www.ncbi.nlm.nih.gov/books/NBK315950/)
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Common side effects include constipation, itchiness, and nausea.[1] Serious

Tramadol acts by binding to μ-opioid receptors on neurons.[1][10] It is also

Medical uses CA: ℞-only

As of 2015, tramadol was not approved in the United States for

Contraindications Onset of action Less than 1 hour (by

Side effects CompTox

Serotonin reuptake inhibitor (SRI) and Tramadol (and metabolite)[46][47][48]

is exclusively responsible for the opioid effects

also acts as a serotonin releasing agent (1– M4 ND ND ND ND

by sufficiently high concentrations of the σ1 >10,000 ND Rat [46][66]

and 30 μM.[78][77][70] In addition to

Tramadol undergoes hepatic metabolism via the

Synthesis and stereoisomerism

(1R,2R)-isomer (1R,2R)-tramadol (1S,2S)-tramadol

Detection in biological fluids

Society and culture

False findings about sources in nature

Pharmacokinetics of tramadol across the species[130]

105. US patent 7074430 (https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US7074430), Miller RB,

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