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Tramadol

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Tramadol, sold under the brand name Tramal among others,<ref name=PHR2009/><ref name=generics/> is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain.<ref name=AHFS2014>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="PHR2009"/> When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour.<ref name=AHFS2014/> It is also available by injection.<ref name=BNF74>Template:Cite book</ref> It is available in combination with paracetamol (acetaminophen).

As is typical of opioids, common side effects include constipation, itchiness, and nausea.<ref name=AHFS2014/> Serious side effects may include hallucinations, seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction.<ref name=AHFS2014/> A change in dosage may be recommended in those with kidney or liver problems.<ref name=AHFS2014/> It is not recommended in those who are at risk of suicide or in those who are pregnant.<ref name=AHFS2014/><ref name=BNF74/> While not recommended in women who are breastfeeding, those who take a single dose should not generally have to stop breastfeeding.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Tramadol is converted in the liver to O-desmethyltramadol (desmetramadol), an opioid with a stronger affinity for the μ-opioid receptor.<ref name=AHFS2014/><ref name=Raf2012>Template:Cite journal</ref>

Tramadol was patented in 1972 and launched under the brand name Tramal in 1977 by the West German pharmaceutical company Grünenthal GmbH.<ref name=PHR2009/><ref name=Fis2006>Template:Cite book</ref> In the mid-1990s, it was approved in the United Kingdom and the United States.<ref name=PHR2009>Template:Cite journal</ref> It is available as a generic medication and marketed under many brand names worldwide.<ref name=generics>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=AHFS2014/> In 2022, it was the 55th most commonly prescribed medication in the United States, with more than 12Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:TOC limit

Medical usesEdit

File:50 mg Tramadol HCl tablets (generic Ultram) marketed by Amneal Pharmaceuticals (rotated).jpg
Generic tramadol HCl tablets marketed by Amneal Pharmaceuticals
File:Tramadol HCl.jpg
Tramadol HCl for injection

Tramadol is used primarily to treat mild to severe pain, both acute and chronic.<ref name=AMH/><ref name="pmid15509185">Template:Cite journal</ref> There is moderate evidence for use as a second-line treatment for fibromyalgia, but it is not FDA-approved for this use.<ref name=Mac2015>Template:Cite journal</ref> Its use is approved for treatment of fibromyalgia as a secondary painkiller by the NHS.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Its analgesic effects take approximately an hour to be realized, and it takes from two to four hours to reach peak effect after oral administration with an immediate-release formulation.<ref name=AMH/><ref name="pmid15509185"/> On a dose-by-dose basis, tramadol has about one-tenth the potency of morphine (thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared with pethidine and codeine.<ref name="pmid7691519">Template:Cite journal</ref> For moderate pain, its effectiveness is roughly equivalent to that of codeine in low doses and hydrocodone at very high doses. For severe pain, it is less effective than morphine.<ref name="AMH"/>

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

Sleep medicine physicians sometimes prescribe tramadol (or other opioid medications) for refractory restless legs syndrome (RLS);<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> that is, RLS that does not respond adequately to treatment with first-line medications such as dopamine agonists (e.g., pramipexole) or gabapentinoids, often due to augmentation.<ref>Template:Cite journal</ref>

ContraindicationsEdit

Pregnancy and lactationEdit

Use of tramadol during pregnancy is generally avoided, as it may cause some reversible withdrawal effects in the newborn.<ref name="pregrev">Template:Cite journal</ref> A small prospective study in France found, while an increased risk of miscarriages existed, no major malformations were reported in the newborn.<ref name=pregrev/> Its use during lactation is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. No evidence of this dose harming the newborn was seen.<ref name=pregrev/>

Labor and deliveryEdit

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

ChildrenEdit

Its use in children is generally advised against, although it may be done under the supervision of a specialist.<ref name=AMH/> On 21 September 2015, the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The FDA lists age under 12 years old as a contraindication.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

ElderlyEdit

The risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment, and sedation is increased.<ref name=AMH/> Tramadol may interact with other medications and increase the risk for adverse events.<ref name=":1">Template:Cite journal</ref>

Liver and kidney failureEdit

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

Side effectsEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness, and headache.<ref name="AEP">Template:Cite journal</ref><ref name="drugs06">Template:Cite journal</ref> Other side effects may result from interactions with other medications. Tramadol has the same dose-dependent adverse effects as morphine including respiratory depression.<ref>Template:Cite journal</ref>

File:Side effects of Tramadol.png
CitationClass=web }}</ref>

Dependence and withdrawalEdit

Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome.<ref name="pmid12825576">Template:Cite journal</ref> These include both symptoms typical of opioid withdrawal and those associated with serotonin–norepinephrine reuptake inhibitor (SNRI) withdrawal; symptoms include numbness, tingling, paresthesia, and tinnitus.<ref name=BP06>Template:Cite journal</ref> Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.<ref name="pmid12633909">Template:Cite journal</ref> In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary.<ref name=BP06/> Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogs.<ref name=BP06/>

OverdoseEdit

The clinical presentation in overdose cases can vary but typically includes neurological, cardiovascular, and gastrointestinal manifestations.<ref>Template:Cite journal</ref> The predominant neurological symptoms are seizures and altered levels of consciousness, ranging from somnolence to coma. Seizures are particularly notable due to tramadol's lowering of the seizure threshold, occurring in approximately half of acute poisoning cases.<ref>Template:Cite journal</ref> Patients often exhibit tachycardia and mild hypertension. Gastrointestinal disturbances such as nausea and vomiting are common, and agitation, anxiety, and cold and clammy skin may also be present.<ref>Template:Cite journal</ref>

While less common, severe complications like respiratory depression and serotonin syndrome can occur, particularly in polydrug overdoses involving other CNS depressants (such as benzodiazepines, opioids, and alcohol) and agents with serotonergic activity.<ref name=":2">Template:Cite journal</ref><ref>Template:Cite journal</ref> Additionally, individuals with genetic variations leading to CYP2D6 enzyme duplication (rapid metabolizers) may have an increased risk of adverse effects, due to faster conversion of tramadol to its active metabolite.<ref>Template:Cite journal</ref>

Acute tramadol overdose is generally not life-threatening, with most fatalities resulting from polysubstance overdose.<ref>Template:Cite journal</ref> Management includes cardiovascular monitoring, activated charcoal administration, hydration, and treatment of seizures.<ref>Template:Cite journal</ref> Naloxone, an opioid antagonist, can partially reverse some effects of tramadol overdose, particularly respiratory depression. However, its use may increase the risk of seizures due to unopposed alpha-adrenergic stimulation.<ref name="AMH"/> For suspected serotonin syndrome, cyproheptadine, a serotonin antagonist, is considered an effective antidote.<ref name=":2"/>

The incidence of tramadol-related overdose deaths has been on the rise in certain regions. For instance, Northern Ireland has reported an increased frequency of such cases.<ref name="JFLM14">Template:Cite journal</ref> In 2013, England and Wales recorded 254 tramadol-related deaths, while Florida reported 379 cases in 2011.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2011, 21,649 emergency room visits in the United States were related to tramadol.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The likely explanation for these observations is due to increase in frequency of prescriptions and use due to easier access due to lighter regulatory scheduling by authorities<ref>Template:Cite journal</ref> but this is starting to change. In 2021, Health Canada announced tramadol would be added to Schedule I of the Controlled Drugs and Substances Act and to the Narcotic Control Regulations due to tramadol being suspected of having contributed to 18 reported deaths in Canada between 2006 and 2017.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

InteractionsEdit

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

Tramadol can have pharmacodynamic, pharmacokinetic, and pharmacogenetic interactions.

Tramadol is metabolized by CYP2D6 enzymes which contributes to the metabolism of approximately 25% of all medications.<ref>Template:Cite journal</ref> Any medications with the ability to inhibit or induce these enzymes may interact with tramadol. These include common antiarrhythmics, antiemetics, antidepressants (sertraline, paroxetine, and fluoxetine in particular),<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> antipsychotics, analgesics, and tamoxifen.<ref name="Trends in Tramadol">Template:Cite journal</ref>

Due to tramadol's serotonergic effects, tramadol has the potential to contribute to the development of an acute or chronic hyper-serotonin state called serotonin syndrome when used concurrently with other pro-serotonergic medications such as antidepressants (SSRIs, SNRIs, tricyclics, MAOIs), antipsychotics, triptans, cold medications containing dextromethorphan, and some herbal products such as St. John's wort.<ref name="Trends in Tramadol"/><ref>Template:Cite journal</ref>

Concurrent use of 5-HT3 antagonists such as ondansetron, dolasetron, and palonosetron may reduce the effectiveness of both drugs.<ref>Template:Cite journal</ref>

Tramadol also acts as an opioid agonist and thus can increase the risk for side effects when used with other opioid and opioid-containing analgesics (such as morphine, pethidine, tapentadol, oxycodone, fentanyl, and Tylenol 3).<ref name="opioid-combination">Template:Cite journal</ref>

Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold - such as antipsychotic medications, bupropion (an anti-depressant and smoking cessation drug), and amphetamines - can further increase this risk.<ref>Template:Cite journal</ref>

PharmacologyEdit

Mechanism of actionEdit

Tramadol induces analgesic effects through a variety of different targets on the noradrenergic system, serotonergic system, and opioid receptors system.<ref>Template:Cite book</ref> Tramadol affects serotonin and norepinephrine reuptake inhibition similarly to certain antidepressants known as serotonin–norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine.<ref name="pmid38797485">Template:Cite journal</ref> Tramadol exists as a racemic mixture, the positive enantiomer inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters.<ref name="pmid25776506">Template:Cite journal</ref><ref name="Pharmacology of tramadol"/> Both enantiomers of tramadol are agonists of the μ-opioid receptor and its M1 metabolite, O-desmetramadol, is also a μ-opioid receptor agonist but is 6 times more potent than tramadol itself.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> All of these actions may work synergistically to induce analgesia.

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Site Tramadol Template:Abbrlink Species Ref
Template:Abbrlink 1,600–12,486
2,120–8,300
≥1,000 (EC50)		 5.4–18.6
17 (Template:Abbr)
≥240 (EC50)		 Human
Rat
Human		 <ref name="pmid19027293">Template:Cite journal</ref><ref name="pmid27096047">Template:Cite journal</ref><ref name="pmid21215785">Template:Cite journal</ref>
<ref name="pmid10991912"/><ref name="pmid7562497"/>
<ref name="pmid10961373">Template:Cite journal</ref><ref name=Raf2012/>
Template:Abbrlink >10,000
57,600–100,000		 ≥2,900
690 Template:Abbr)		 Human
Rat		 <ref name="pmid19027293"/><ref name="pmid27096047"/><ref name="pmid8955860"/>
<ref name="pmid7562497"/><ref name="pmid10991912"/>
Template:Abbrlink >10,000
42,700–81,000		 ≥450
1,800 Template:Abbr)		 Human
Rat		 <ref name="pmid19027293"/><ref name="pmid27096047"/><ref name="pmid8955860"/>
<ref name="pmid7562497"/><ref name="pmid10991912"/>
Template:Abbrlink ~900 (IC50)
992–1,190		 >20,000 (IC50)
2,980 (Template:Abbr) (IC50)		 Human
Rat		 <ref name="pmid16427041">Template:Cite journal</ref>
<ref name="pmid7562497">Template:Cite journal</ref><ref name=Raf2012/>
Template:Abbrlink 14,600
785		 1,080 Template:Abbr (IC50)
860 (IC50)		 Human
Rat		 <ref name=Raf2012/>
<ref name="pmid7562497"/><ref name=Raf2012/>
Template:Abbrlink >100,000 >20,000 Rat <ref name="pmid1309873">Template:Cite journal</ref><ref name="pmid8955860">Template:Cite journal</ref>
5-HT1A >20,000 >20,000 Rat <ref name="pmid8955860"/>
5-HT2A >20,000 >20,000 Rat <ref name="pmid8955860"/>
5-HT2C 1,000 (IC50) 1,300 (IC50) Rat <ref name="pmid15105221">Template:Cite journal</ref><ref name="pmid16679816">Template:Cite journal</ref>
5-HT3 >20,000 >20,000 Rat <ref name="pmid8955860"/>
NK1 Template:Abbr ? Rat <ref name="pmid12818951">Template:Cite journal</ref><ref name="pmid21372504">Template:Cite journal</ref>
M1 >20,000
3,400 (IC50)		 >20,000
2,000 (IC50)		 Rat
Multiple		 <ref name="pmid8955860"/>
<ref name="pmid11561087">Template:Cite journal</ref><ref name="pmid15976229">Template:Cite journal</ref>
M2 Template:Abbr Template:Abbr Template:Abbr Template:Abbr
M3 1,000 (IC50) Template:Abbr Human <ref name="pmid15976229"/><ref name="pmid12401609">Template:Cite journal</ref>
M4 Template:Abbr Template:Abbr Template:Abbr Template:Abbr
M5 Template:Abbr Template:Abbr Template:Abbr Template:Abbr
α7 7,400 Template:Abbr Chicken <ref name="pmid12010769">Template:Cite journal</ref>
σ1 >10,000 Template:Abbr Rat <ref name="PDSP"/><ref name="pmid24155346">Template:Cite journal</ref>
σ2 >10,000 Template:Abbr Rat <ref name="PDSP"/>
[[NMDA receptor|Template:Abbr]] 16,400 (IC50) 16,500 (IC50) Human <ref name="pmid15845694">Template:Cite journal</ref>
[[NMDA receptor|Template:Abbr
(MK-801)]]		 >20,000 >20,000 Rat <ref name="pmid8955860"/>
Template:Abbrlink >100,000 (IC50) >100,000 (IC50) Human <ref name="pmid15845694"/>
Template:Abbrlink >100,000 (IC50) >100,000 (IC50) Human <ref name="pmid15845694"/>
[[TRPA1|Template:Abbr]] 100–
10,000 (Template:Abbr)		 1,000–
10,000 (Template:Abbr)		 Human <ref name="pmid25642661"/>
[[TRPV1|Template:Abbr]] >10,000 (IC50) >10,000 (IC50) Human <ref name="pmid25642661">Template:Cite journal</ref><ref name="pmid18499628">Template:Cite journal</ref>
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Tramadol and mono-
amine reuptake/release<ref name="pmid17017961"/>
Action Value
[[Serotonin reuptake inhibitor|Template:Abbr reuptake]] 1,820
[[Serotonin releasing agent|Template:Abbr release]] >10,000
[[Norepinephrine reuptake inhibitor|Template:Abbr reuptake]] 2,770
[[Norepinephrine releasing agent|Template:Abbr release]] >10,000
[[Dopamine reuptake inhibitor|Template:Abbr reuptake]] >10,000
[[Dopamine releasing agent|Template:Abbr release]] >10,000
Values for reuptake inhibition are Ki (nM) and for release induction are EC50 (nM)

Tramadol has been found to possess these actions:<ref name="pmid17380034"/><ref name="pmid26292636"/><ref name="pmid25776506"/>

Tramadol acts on the opioid receptors through its major active metabolite desmetramadol, which has as much as 700-fold higher affinity for the MOR relative to tramadol.<ref name=Raf2012/> Moreover, tramadol itself has been found to possess no efficacy in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity (Emax equal to that of morphine).<ref name="pmid10961373"/><ref name=Raf2012/><ref name="pmid25394761">Template:Cite journal</ref> As such, desmetramadol is exclusively responsible for the opioid effects of tramadol.<ref name="pmid18958460">Template:Cite journal</ref> Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.<ref name="pmid8955860"/><ref name="pmid27096047"/><ref name="pmid10991912"/>

Tramadol is well-established as an SRI.<ref name="pmid17380034"/><ref name="pmid26292636"/> In addition, a few studies have found that it also acts as a serotonin releasing agent (1–10 μM), similar in effect to fenfluramine.<ref name="pmid1596676">Template:Cite journal</ref><ref name="pmid9389855">Template:Cite journal</ref><ref name="pmid9671098">Template:Cite journal</ref><ref name="pmid12354291">Template:Cite journal</ref> The serotonin releasing effects of tramadol could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor 6-nitroquipazine, which is in accordance with other serotonin releasing agents such as fenfluramine and MDMA.<ref name="pmid1596676"/><ref name="pmid9671098"/><ref name="pmid12354291"/> However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30 μM.<ref name="pmid10323276">Template:Cite journal</ref><ref name="pmid12354291"/><ref name="pmid17017961">Template:Cite journal</ref> In addition to serotonergic activity, tramadol is also a norepinephrine reuptake inhibitor.<ref name="pmid17380034"/><ref name="pmid26292636"/> It is not a norepinephrine releasing agent.<ref name="pmid8467366">Template:Cite journal</ref><ref name="pmid8031323">Template:Cite journal</ref><ref name="pmid10700792">Template:Cite journal</ref><ref name="pmid17017961"/> Tramadol does not inhibit the reuptake or induce the release of dopamine.<ref name="pmid8467366"/><ref name="pmid17017961"/>

A positron emission tomography imaging study found that single oral 50-mg and 100-mg doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the serotonin transporter (SERT) in the thalamus.<ref name="pmid24423243">Template:Cite journal</ref> The estimated median effective dose (ED50) for SERT occupancy hence was 98.1 mg, which was associated with a plasma tramadol level of about 330 ng/mL (1,300 nM).<ref name="pmid24423243"/> The estimated maximum daily dosage of tramadol of 400 mg (100 mg Template:Abbr) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/mL or 4,632 nM).<ref name="pmid24423243"/> This is close to that of SSRIs, which occupy the SERT by 80% or more.<ref name="pmid24423243"/>

Peak plasma concentrations during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592 ng/mL (266–2,250 nM) for tramadol and 55 to 143 ng/mL (221–573 nM) for desmetramadol.<ref name="pmid15509185"/> The highest levels of tramadol were observed with the maximum oral daily dosage of 400 mg per day divided into one 100-mg dose every 6 hours (i.e., four 100-mg doses evenly spaced out per day).<ref name="pmid15509185"/><ref name="Drugs.com-Dosage">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some accumulation of tramadol occurs with chronic administration; peak plasma levels with the maximum oral daily dosage (100 mg Template:Abbr) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100-mg dose.<ref name="pmid15509185"/> Positron emission tomography imaging studies have reportedly found that tramadol levels are at least four-fold higher in the brain than in plasma.<ref name="pmid8467366"/><ref name="pmid11975693">Template:Cite journal</ref> Conversely, brain levels of desmetramadol "only slowly approach those in plasma".<ref name="pmid8467366"/> The plasma protein binding of tramadol is only 4–20%; hence, almost all tramadol in circulation is free, thus bioactive.<ref name="pmid8764760">Template:Cite journal</ref><ref name="pmid7517823"/><ref name="NobilisKopecký2002">Template:Cite journal</ref>

Correspondence to effectsEdit

Co-administration of quinidine, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers.<ref name=Raf2012/><ref name="pmid7517823">Template:Cite journal</ref> However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers.<ref name=Raf2012/><ref name="pmid18958460"/> The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers,<ref name=Raf2012/> hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by α2-adrenergic receptor antagonists such as yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719.<ref name="pmid15509185"/><ref name="pmid20179508">Template:Cite journal</ref> Pharmacologically, tramadol is similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine<ref name=MD/> due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.<ref name="pmid16762426">Template:Cite journal</ref>

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.<ref name="pmid15105221"/> 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).<ref name="pmid15845694"/><ref name="pmid25776506"/> In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.<ref name="pmid10991912">Template:Cite journal</ref>

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

PharmacokineticsEdit

File:O-desmethyltramadol racemate2DACS2.svg
Desmetramadol

Tramadol is metabolised in the liver via the cytochrome P450 isozyme CYP2B6, CYP2D6, and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, desmetramadol (O-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.<ref name="pmid21494059">Template:Cite journal</ref><ref name="pmid23588782">Template:Cite journal</ref>

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

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

ChemistryEdit

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

Synthesis and stereoisomerismEdit

File:(1R,2R)-Tramadol.svg File:(1S,2S)-Tramadol gespiegelt.svg
(1R,2R)-tramadol (1S,2S)-tramadol
File:(1R,2S)-Tramadol.svg File:(1S,2R)-Tramadol gespiegelt.svg
(1R,2S)-tramadol (1S,2R)-tramadol

The chemical synthesis of tramadol is described in the literature.<ref name="Kleemann">Template:Cite book; since 2003 online with biannual actualizations.</ref> Tramadol Template:Nowrap has two stereogenic centers at the cyclohexane ring. Thus, Template:Nowrap may exist in four different configurational forms:

  • (1R,2R)-isomer
  • (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)-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<ref name="Zynovy">Template:Cite journal</ref> employing (R)-(−)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects<ref name="pmid12066734">Template:Cite journal</ref> of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals<ref name="pmid8229760">Template:Cite journal</ref> and in humans.<ref name="pmid8657431">Template:Cite journal</ref>

Detection in biological fluidsEdit

Tramadol and desmetramadol may be quantified in blood, plasma, serum, or saliva to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantify these substances. The concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% that of the parent drug.<ref name="pmid17575561">Template:Cite journal</ref><ref name="pmid17350197">Template:Cite journal</ref><ref>Template:Cite book</ref>

Discrepant reports on natural agencyEdit

Template:More science citations needed In 2013, researchers Michel de Waard (then at Université Joseph Fourier, Grenoble and Grenoble Institute of Neuroscience, La Tronche<ref name=crosscont>Template:Cite journal</ref>) reported in Angewandte Chemie that tramadol was found in relatively high concentrations (>1%) in the roots of the African pin cushion tree, Nauclea latifolia, concluding that it was a natural product in addition to its being a later human synthetic, and presenting a putative biosynthetic hypothesis for its origin.<ref name=Nauc>Template:Cite journal</ref>

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

A news report appearing in Lab Times at the time of the latter, 2014 paper, and reporting on its contents, also reported that Michel de Waard (communicating author of the original paper) continued to contest the notion that tramadol in tree roots was the result of anthropogenic contamination.<ref name=LabTimes>Who Really did it First? Nature or a Pharmacist? Template:Webarchive, in Lab Times online; by Nicola Hunt; published 22 September 2014; retrieved 21 November 2015</ref> The point was made that samples were taken from trees that grew in national parks, where livestock were forbidden, and it quoted de Waard extensively, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating" would be required to produce the concentrations discovered.<ref name=LabTimes/>Template:Better source

In 2016, Spiteller and colleagues followed up their preceding work with a radiocarbon analysis that supported their contention that the tramadol found in N. latifolia roots was of human synthetic origin rather being plant-derived.<ref name="pmid26473295">Template:Cite journal</ref>

Society and cultureEdit

FormulationsEdit

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

Patent historyEdit

The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005.<ref>Template:Cite journal</ref> ER Tramadol was protected by US patents nos. 6,254,887<ref>Template:Cite patent</ref> and 7,074,430.<ref name=FDAaccessdata>FDA AccessData entry for Tramadol Hydrochloride Template:Webarchive. Retrieved 17 August 2009.</ref><ref>Template:Cite patent</ref> The FDA listed the patents' expiration as 10 May 2014.<ref name=FDAaccessdata/> However, in August 2009, the US District Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was therefore permitted before the expiration of the patents.<ref>Template:Cite court</ref>

Legal statusEdit

Effective August 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the United States.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.<ref>"TRAMADOL (Trade Names: Ultram, Ultracet)". Drug Enforcement Administration (February 2011)</ref><ref>"Tennessee News: Tramadol and Carisoprodol Now Classified Schedule IV". National Association of Boards of Pharmacy (8 June 2011). Retrieved on 26 December 2012.</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="AMH">Template:Cite book</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In June 2014, the United Kingdom's Home Office classified tramadol as a Class C, Schedule 3 controlled drug, but exempted it from the safe custody requirement.<ref name="UK scheduling">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In October 2023, New Zealand's Medsafe reclassified tramadol as a Class C2 Controlled Drug (in addition to its existing status as a prescription only medication).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

MisuseEdit

Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization.<ref name=":0">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref><ref>Template:Cite journal</ref> When used at higher doses, the drug "can produce similar effects to heroin."<ref name=":0"/> One former member said, "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it."<ref name=":0"/> Tramadol is also used as a coping mechanism in the Gaza Strip under Israeli siege.<ref>Template:Cite news</ref> It is also abused in the United Kingdom, inspiring the title of the TV show Frankie Boyle's Tramadol Nights (2010).<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

From March 2019, the Union Cycliste Internationale (UCI) banned the drug, after riders were using the painkiller to improve their performance.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

ResearchEdit

Template:See also

Investigational usesEdit

Veterinary medicineEdit

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.<ref name=Zoo>Template:Cite journal</ref>

Pharmacokinetics of tramadol across the species<ref name=Zoo/>
Species Half-life (h) for parent drug Half-life (h) for desmetramadol Maximum plasma concentration (ng/mL) for parent drug Maximum plasma concentration (ng/mL) for desmetramadol
Camel 3.2 (IM), 1.3 (IV) – 0.44 (IV) –
Cat 3.40 (oral), 2.23 (IV) 4.82 (oral), 4.35 (IV) 914 (oral), 1323 (IV) 655 (oral), 366 (IV)
Dog 1.71 (oral), 1.80 (IV), 2.24 (rectal) 2.18 (oral), 90-5000 (IV) 1402.75 (oral) 449.13 (oral), 90–350 (IV)
Donkey 4.2 (oral), 1.5 (IV) – 2817 (oral) –
Goat 2.67 (oral), 0.94 (IV) – 542.9 (oral) –
Horses 1.29–1.53 (IV), 10.1 (oral) 4 (oral) 637 (IV), 256 (oral) 47 (oral)
Llama 2.54 (IM), 2.12 (IV) 7.73 (IM), 10.4 (IV) 4036 (IV), 1360 (IM) 158 (IV), 158 (IM)

See alsoEdit

ReferencesEdit

Template:Reflist

Further readingEdit

Template:Refbegin

Template:Refend

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