tramadol

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

File:Tramadol HCl.jpg

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

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. 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.{{cite journal |vauthors=Lee CR, McTavish D, Sorkin EM |title=Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states |journal=Drugs |volume=46 |issue=2 |pages=313–340 |date=August 1993 |doi=10.2165/00003495-199346020-00008 |pmid=7691519 |s2cid=218465760}} 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.

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.

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

Use of tramadol during pregnancy is generally avoided, as it may cause some reversible withdrawal effects in the newborn.{{cite journal |vauthors=Bloor M, Paech MJ, Kaye R |title=Tramadol in pregnancy and lactation |journal=International Journal of Obstetric Anesthesia |volume=21 |issue=2 |pages=163–167 |date=April 2012 |doi=10.1016/j.ijoa.2011.10.008 |pmid=22317891}} A small prospective study in France found, while an increased risk of miscarriages existed, no major malformations were reported in the newborn. 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.

Its use as an analgesic during labor is not advised due to its long onset of action (1 hour). 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.

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

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

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.

{{Main|List of side effects of tramadol}}

The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness, and headache.{{cite journal |vauthors=Langley PC, Patkar AD, Boswell KA, Benson CJ, Schein JR |title=Adverse event profile of tramadol in recent clinical studies of chronic osteoarthritis pain |journal=Current Medical Research and Opinion |volume=26 |issue=1 |pages=239–251 |date=January 2010 |doi=10.1185/03007990903426787 |pmid=19929615 |s2cid=20703694}}{{cite journal |vauthors=Keating GM |title=Tramadol sustained-release capsules |journal=Drugs |volume=66 |issue=2 |pages=223–230 |year=2006 |doi=10.2165/00003495-200666020-00006 |pmid=16451094 |s2cid=22620947}} Other side effects may result from interactions with other medications. Tramadol has the same dose-dependent adverse effects as morphine including respiratory depression.{{cite journal |title="Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine |journal=Prescrire International |volume=25 |issue=168 |pages=45–50 |date=February 2016 |pmid=27042732}}

File:Side effects of Tramadol.png |publisher=American Society of Health-System Pharmacists |date=1 September 2008 |url=https://medlineplus.gov/druginfo/meds/a695011.html |access-date=10 April 2024 |url-status=live |archive-url=https://web.archive.org/web/20090924092832/http://www.nlm.nih.gov/medlineplus/druginfo/meds/a695011.html |archive-date=24 September 2009}}]]

Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome.{{cite journal |title=Withdrawal syndrome and dependence: tramadol too |journal=Prescrire International |volume=12 |issue=65 |pages=99–100 |date=June 2003 |pmid=12825576}} 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.{{cite journal |vauthors=Epstein DH, Preston KL, Jasinski DR |title=Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol |journal=Biological Psychology |volume=73 |issue=1 |pages=90–99 |date=July 2006 |pmc=2943845 |doi=10.1016/j.biopsycho.2006.01.010 |pmid=16497429}} Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.{{cite journal |vauthors=Senay EC, Adams EH, Geller A, Inciardi JA, Muñoz A, Schnoll SH, Woody GE, Cicero TJ |title=Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur |journal=Drug and Alcohol Dependence |volume=69 |issue=3 |pages=233–241 |date=April 2003 |citeseerx=10.1.1.524.5426 |doi=10.1016/S0376-8716(02)00321-6 |pmid=12633909}} In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. 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.

The clinical presentation in overdose cases can vary but typically includes neurological, cardiovascular, and gastrointestinal manifestations.{{cite journal |vauthors=Marquardt KA, Alsop JA, Albertson TE |title=Tramadol exposures reported to statewide poison control system |journal=The Annals of Pharmacotherapy |volume=39 |issue=6 |pages=1039–1044 |date=June 2005 |doi=10.1345/aph.1e577 |pmid=15870139 |s2cid=20959808}} 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.{{cite journal |vauthors=Jovanović-Cupić V, Martinović Z, Nesić N |title=Seizures associated with intoxication and abuse of tramadol |journal=Clinical Toxicology |volume=44 |issue=2 |pages=143–146 |date=1 August 2012 |doi=10.1080/1556365050014418 |pmid=16615669 |s2cid=25269342}} 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.{{cite journal |vauthors=Manouchehri A, Nekoukar Z, Malakian A, Zakariaei Z |title=Tramadol poisoning and its management and complications: a scoping review |journal=Annals of Medicine and Surgery |volume=85 |issue=8 |pages=3982–3989 |date=August 2023 |pmc=10406095 |doi=10.1097/ms9.0000000000001075 |doi-access=free |pmid=37554850}}

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.{{cite journal |vauthors=Beakley BD, Kaye AM, Kaye AD |date=14 July 2015 |title=Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review |journal=Pain Physician |volume=18 |issue=4 |pages=395–400 |issn=2150-1149 |doi=10.36076/ppj.2015/18/395 |doi-access=free}}{{cite journal |vauthors=Ryan NM, Isbister GK |title=Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely |journal=Clinical Toxicology |volume=53 |issue=6 |pages=545–550 |date=July 2015 |doi=10.3109/15563650.2015.1036279 |pmid=25901965 |s2cid=23813622}} 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.{{cite journal |vauthors=Taghaddosinejad F, Mehrpour O, Afshari R, Seghatoleslami A, Abdollahi M, Dart RC |title=Factors related to seizure in tramadol poisoning and its blood concentration |journal=Journal of Medical Toxicology |volume=7 |issue=3 |pages=183–188 |date=September 2011 |pmc=3550210 |doi=10.1007/s13181-011-0168-0 |doi-access=free |pmid=21735309}}

Acute tramadol overdose is generally not life-threatening, with most fatalities resulting from polysubstance overdose.{{cite journal |vauthors=Nakhaee S, Mehrpour O |title=Tramadol poisoning-associated mortality |journal=Journal of Affective Disorders |volume=255 |pages=187 |date=August 2019 |doi=10.1016/j.jad.2019.04.069 |pmid=30987745 |s2cid=116863581}} Management includes cardiovascular monitoring, activated charcoal administration, hydration, and treatment of seizures.{{cite journal |vauthors=Nakhaee S, Hoyte C, Dart RC, Askari M, Lamarine RJ, Mehrpour O |date=24 March 2021 |title=A review on tramadol toxicity: mechanism of action, clinical presentation, and treatment |journal=Forensic Toxicology |volume=39 |issue=2 |pages=293–310 |issn=1860-8965 |doi=10.1007/s11419-020-00569-0 |doi-access=free}} 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. For suspected serotonin syndrome, cyproheptadine, a serotonin antagonist, is considered an effective antidote.

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.{{cite journal |vauthors=Randall C, Crane J |title=Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012 |journal=Journal of Forensic and Legal Medicine |volume=23 |pages=32–36 |date=March 2014 |doi=10.1016/j.jflm.2014.01.006 |pmid=24661703}} In 2013, England and Wales recorded 254 tramadol-related deaths, while Florida reported 379 cases in 2011.{{cite web |title=Tramadol Deaths in the United Kingdom |publisher=Public Health England |format=pdf_e |vauthors=White M |url=https://www.emcdda.europa.eu/system/files/attachments/3236/Martin%20White-UK-Tramadol%20deaths%20in%20the%20United%20Kingdom%20EMCDDA.pdf_en |access-date=25 February 2018 |url-status=live |archive-url=https://web.archive.org/web/20210407011422/https://www.emcdda.europa.eu/system/files/attachments/3236/Martin%20White-UK-Tramadol%20deaths%20in%20the%20United%20Kingdom%20EMCDDA.pdf_en |archive-date=7 April 2021}}{{cite web |date=22 December 2013 |title=Killing Pain: Tramadol the 'Safe' Drug of Abuse |vauthors=Fauber J |url=https://www.medpagetoday.com/painmanagement/painmanagement/43554 |access-date=28 February 2018 |url-status=live |archive-url=https://web.archive.org/web/20200919094239/https://www.medpagetoday.com/painmanagement/painmanagement/43554 |archive-date=19 September 2020}} In 2011, 21,649 emergency room visits in the United States were related to tramadol.{{cite web |date=19 October 2016 |title=Tramadol: The Opioid Crisis for the rest of the World |website=The Wall Street Journal |publisher=Dow Jones & Co |vauthors=Scheck J |url=https://www.wsj.com/articles/tramadol-the-opioid-crisis-for-the-rest-of-the-world-1476887401 |access-date=4 January 2019 |url-status=live |archive-url=https://web.archive.org/web/20200830113252/https://www.wsj.com/articles/tramadol-the-opioid-crisis-for-the-rest-of-the-world-1476887401 |archive-date=30 August 2020}} 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{{cite journal |vauthors=Kostev K, Von Vultée C, Usinger DM, Reese JP |title=Tramadol prescription patterns in patients followed by general practitioners and orthopedists in Germany in the year 2015 |journal=Postgraduate Medicine |volume=130 |issue=1 |pages=37–41 |date=January 2018 |doi=10.1080/00325481.2018.1407205 |pmid=29157058 |s2cid=32933111}} 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.{{cite web |publisher=Government of Canada |work=Public Works and Government Services Canada |date=31 March 2021 |title=Canada Gazette, Part 2, Volume 155, Number 7: Regulations Amending the Narcotic Control Regulations (Tramadol) |url=https://canadagazette.gc.ca/rp-pr/p2/2021/2021-03-31/html/sor-dors43-eng.html |access-date=10 November 2023}}

File:Tramadol capsules - 2022-09-22 - Andy Mabbett.jpg

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.{{cite journal |vauthors=Bernard S, Neville KA, Nguyen AT, Flockhart DA |title=Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications |journal=The Oncologist |volume=11 |issue=2 |pages=126–135 |date=February 2006 |doi=10.1634/theoncologist.11-2-126 |pmid=16476833}} 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),{{cite web |title=CPIC® Guideline for Serotonin Reuptake Inhibitor Antidepressants and CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A – CPIC |url=https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/ |access-date=23 November 2023}} antipsychotics, analgesics, and tamoxifen.{{cite journal |vauthors=Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R |title=Trends in Tramadol: Pharmacology, Metabolism, and Misuse |journal=Anesthesia and Analgesia |volume=124 |issue=1 |pages=44–51 |date=January 2017 |doi=10.1213/ANE.0000000000001683 |pmid=27861439 |s2cid=24224625}}

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.{{cite journal |vauthors=Nelson EM, Philbrick AM |title=Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors |journal=The Annals of Pharmacotherapy |volume=46 |issue=12 |pages=1712–1716 |date=December 2012 |doi=10.1345/aph.1q748 |pmid=23212934 |s2cid=23707808}}

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

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).{{cite journal |vauthors=Pasternak GW |title=Preclinical pharmacology and opioid combinations |journal=Pain Medicine |volume=13 |issue=1 |pages=S4-11 |date=March 2012 |pmc=3307386 |doi=10.1111/j.1526-4637.2012.01335.x |pmid=22420604}}

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.{{cite journal |vauthors=Sansone RA, Sansone LA |title=Tramadol: seizures, serotonin syndrome, and coadministered antidepressants |journal=Psychiatry |volume=6 |issue=4 |pages=17–21 |date=April 2009 |pmc=2714818 |pmid=19724727}}

Tramadol induces analgesic effects through a variety of different targets on the noradrenergic system, serotonergic system, and opioid receptors system.{{cite book |vauthors=Hitchings A, Lonsdale D, Burrage D, Baker E |title=Top 100 drugs: clinical pharmacology and practical prescribing |date=2015 |publisher=Churchill Livingstone Elsevier |isbn=978-0-7020-5516-4 |pages=168–169}} Tramadol affects serotonin and norepinephrine reuptake inhibition similarly to certain antidepressants known as serotonin–norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine.{{cite journal |vauthors=Kokilambigai KS, Irina VM, Sheba Mariam KC, Adila K, Kathirvel S |title=Comprehensive overview of analytical and bioanalytical methodologies for the opioid analgesics - Tramadol and combinations |journal=Anal Biochem |volume=692 |issue= |pages=115579 |date=September 2024 |pmid=38797485 |doi=10.1016/j.ab.2024.115579 |url=}} 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.{{cite journal |vauthors=Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia ML, Silva AM, Souto EB |title=Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems |journal=Biomedicine & Pharmacotherapy |volume=70 |pages=234–238 |date=March 2015 |doi=10.1016/j.biopha.2015.01.022 |doi-access=free |pmid=25776506}} 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.{{cite web |title=Tramadol |website=drugbank.ca |url=https://www.drugbank.ca/drugs/DB00193 |access-date=21 January 2019 |url-status=live |archive-url=https://web.archive.org/web/20190528121148/https://www.drugbank.ca/drugs/DB00193 |archive-date=28 May 2019}} All of these actions may work synergistically to induce analgesia.

Tramadol has been found to possess these actions:

• Agonist of the μ-opioid receptor (MOR) and to a far lesser extent of the δ-opioid receptor (DOR) and κ-opioid receptor (KOR)
• Serotonin reuptake inhibitor (SRI) and norepinephrine reuptake inhibitor; hence, an SNRI
• Serotonin 5-HT_2C receptor antagonist
• M₁ and M₃ muscarinic acetylcholine receptor antagonist
• α7 nicotinic acetylcholine receptor antagonist
• NMDA receptor antagonist (very weak)
• TRPA1 inhibitor

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. 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 (E_max equal to that of morphine).{{cite journal |vauthors=Minami K, Sudo Y, Miyano K, Murphy RS, Uezono Y |title=μ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1) |journal=Journal of Anesthesia |volume=29 |issue=3 |pages=475–479 |date=June 2015 |doi=10.1007/s00540-014-1946-z |pmid=25394761 |s2cid=7091648}} As such, desmetramadol is exclusively responsible for the opioid effects of tramadol.{{cite journal |vauthors=Coller JK, Christrup LL, Somogyi AA |title=Role of active metabolites in the use of opioids |journal=European Journal of Clinical Pharmacology |volume=65 |issue=2 |pages=121–139 |date=February 2009 |doi=10.1007/s00228-008-0570-y |pmid=18958460 |s2cid=9977741}} Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.

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

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.{{cite journal |vauthors=Ogawa K, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y |title=Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB |journal=The International Journal of Neuropsychopharmacology |volume=17 |issue=6 |pages=845–850 |date=June 2014 |doi=10.1017/S1461145713001764 |doi-access=free |pmid=24423243}} 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). The estimated maximum daily dosage of tramadol of 400 mg (100 mg {{abbr|q.i.d.|four times per day}}) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/mL or 4,632 nM). This is close to that of SSRIs, which occupy the SERT by 80% or more.

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

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.{{cite journal |vauthors=Dayer P, Collart L, Desmeules J |title=The pharmacology of tramadol |journal=Drugs |volume=47 |issue=Suppl 1 |pages=3–7 |year=1994 |doi=10.2165/00003495-199400471-00003 |pmid=7517823 |s2cid=33474225}} However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers. The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers, 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.{{cite journal |vauthors=Yanarates O, Dogrul A, Yildirim V, Sahin A, Sizlan A, Seyrek M, Akgül O, Kozak O, Kurt E, Aypar U |title=Spinal 5-HT7 receptors play an important role in the antinociceptive and antihyperalgesic effects of tramadol and its metabolite, O-Desmethyltramadol, via activation of descending serotonergic pathways |journal=Anesthesiology |volume=112 |issue=3 |pages=696–710 |date=March 2010 |doi=10.1097/ALN.0b013e3181cd7920 |doi-access=free |pmid=20179508 |s2cid=11913166}} 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 due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.{{cite journal |vauthors=Micó JA, Ardid D, Berrocoso E, Eschalier A |title=Antidepressants and pain |journal=Trends in Pharmacological Sciences |volume=27 |issue=7 |pages=348–354 |date=July 2006 |doi=10.1016/j.tips.2006.05.004 |pmid=16762426}}

Tramadol has inhibitory actions on the 5-HT_2C receptor. Antagonism of 5-HT_2C could be partially responsible for tramadol's reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT_2C blockade may also account for its lowering of the seizure threshold, as 5-HT_2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABA_A receptors at high doses (significant inhibition at 100 μM). 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.{{cite journal |vauthors=Potschka H, Friderichs E, Löscher W |title=Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy |journal=British Journal of Pharmacology |volume=131 |issue=2 |pages=203–212 |date=September 2000 |pmc=1572317 |doi=10.1038/sj.bjp.0703562 |pmid=10991912}}

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

File:O-desmethyltramadol racemate2DACS2.svg]]

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.{{cite journal |vauthors=Leppert W |title=CYP2D6 in the metabolism of opioids for mild to moderate pain |journal=Pharmacology |volume=87 |issue=5–6 |pages=274–285 |year=2011 |doi=10.1159/000326085 |doi-access=free |pmid=21494059}}{{cite journal |vauthors=Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA |title=Applications of CYP450 testing in the clinical setting |journal=Molecular Diagnosis & Therapy |volume=17 |issue=3 |pages=165–184 |date=June 2013 |pmc=3663206 |doi=10.1007/s40291-013-0028-5 |pmid=23588782}}

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.

Its volume of distribution is around 306 L after oral administration and 203 L after parenteral administration.

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

The chemical synthesis of tramadol is described in the literature.{{cite book |title=Pharmaceutical Substances |veditors=Kleemann A, Engel J, Kutscher B, Reichert D |edition=4th |date=2000 |publisher=Thieme-Verlag |location=Stuttgart (Germany) |pages=2085–2086 |isbn=978-1-58890-031-9}}; since 2003 online with biannual actualizations. Tramadol {{nowrap|[2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol]}} has two stereogenic centers at the cyclohexane ring. Thus, {{nowrap|2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol}} may exist in four different configurational forms:

• (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{{cite journal |vauthors=Zynovy Z, Meckler H |year=2000 |title=A Practical Procedure for the Resolution of (+)- and (−)-Tramadol |journal=Organic Process Research & Development |volume=4 |issue=4 |pages=291–294 |doi=10.1021/op000281v}} 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{{cite journal |vauthors=Burke D, Henderson DJ |title=Chirality: a blueprint for the future |journal=British Journal of Anaesthesia |volume=88 |issue=4 |pages=563–576 |date=April 2002 |doi=10.1093/bja/88.4.563 |doi-access=free |pmid=12066734}} of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals{{cite journal |vauthors=Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N |title=Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=267 |issue=1 |pages=331–340 |date=October 1993 |doi=10.1016/S0022-3565(25)39454-1 |pmid=8229760}} and in humans.{{cite journal |vauthors=Grond S, Meuser T, Zech D, Hennig U, Lehmann KA |title=Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia |journal=Pain |volume=62 |issue=3 |pages=313–320 |date=September 1995 |doi=10.1016/0304-3959(94)00274-I |pmid=8657431 |s2cid=34150137}}

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.{{cite journal |vauthors=Karhu D, El-Jammal A, Dupain T, Gaulin D, Bouchard S |title=Pharmacokinetics and dose proportionality of three Tramadol Contramid OAD tablet strengths |journal=Biopharmaceutics & Drug Disposition |volume=28 |issue=6 |pages=323–330 |date=September 2007 |doi=10.1002/bdd.561 |pmid=17575561 |s2cid=22720069}}{{cite journal |vauthors=Tjäderborn M, Jönsson AK, Hägg S, Ahlner J |title=Fatal unintentional intoxications with tramadol during 1995-2005 |journal=Forensic Science International |volume=173 |issue=2–3 |pages=107–111 |date=December 2007 |doi=10.1016/j.forsciint.2007.02.007 |pmid=17350197}}{{cite book |vauthors=Baselt R |date=2017 |title=Disposition of Toxic Drugs and Chemicals in Man |edition=11th |publisher=Biomedical Publications, Seal Beach, CA |pages=2185–2188 |isbn=978-0-692-77499-1}}

{{more science citations needed|section|date = May 2024}}

In 2013, researchers Michel de Waard (then at Université Joseph Fourier, Grenoble and Grenoble Institute of Neuroscience, La Tronche{{cite journal |vauthors=Kusari S, Tatsimo SJ, Zühlke S, Talontsi FM, Kouam SF, Spiteller M |title=Tramadol--a true natural product? |journal=Angewandte Chemie |volume=53 |issue=45 |pages=12073–12076 |date=November 2014 |doi=10.1002/anie.201406639 |pmid=25219922}}) 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.{{cite journal |vauthors=Boumendjel A, Sotoing Taïwe G, Ngo Bum E, Chabrol T, Beney C, Sinniger V, Haudecoeur R, Marcourt L, Challal S, Ferreira Queiroz E, Souard F, Le Borgne M, Lomberget T, Depaulis A, Lavaud C, Robins R, Wolfender JL, Bonaz B, De Waard M |title=Occurrence of the synthetic analgesic tramadol in an African medicinal plant |journal=Angewandte Chemie |volume=52 |issue=45 |pages=11780–11784 |date=November 2013 |doi=10.1002/anie.201305697 |doi-access=free |pmid=24014188}}

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. 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.

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.[http://www.labtimes.org/editorial/e_546.lasso Who Really did it First? Nature or a Pharmacist?] {{Webarchive|url=https://web.archive.org/web/20151122041341/http://www.labtimes.org/editorial/e_546.lasso |date=22 November 2015}}, in Lab Times online; by Nicola Hunt; published 22 September 2014; retrieved 21 November 2015 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.{{better source|date = May 2024}}

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.{{cite journal |vauthors=Kusari S, Tatsimo SJ, Zühlke S, Spiteller M |title=Synthetic Origin of Tramadol in the Environment |journal=Angewandte Chemie |volume=55 |issue=1 |pages=240–243 |date=January 2016 |doi=10.1002/anie.201508646 |pmid=26473295 |s2cid=39558505}}

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.

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

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

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.{{cite book |editor=Rossi, S |isbn=978-0-9805790-9-3 |title=Australian Medicines Handbook |place=Adelaide |publisher=The Australian Medicines Handbook Unit Trust |year=2013 |edition=2013}}

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.{{cite web |title=Substansen tramadol nu narkotikaklassad på samma sätt som kodein och dextropropoxifen |publisher=Lakemedelsverket |date=14 May 2008 |language=sv |url=https://lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/ |access-date=12 August 2019 |url-status=live |archive-url=https://web.archive.org/web/20190812094919/https://lakemedelsverket.se/Alla-nyheter/NYHETER-2008/Substansen-tramadol-nu-narkotikaklassad-pa-samma-satt-som-kodein-och-dextropropoxifen/ |archive-date=12 August 2019}}

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.{{cite web |title=Scheduling of tramadol and exemptions for temazepam prescriptions |website=UK Government |date=22 July 2013 |url=https://www.gov.uk/government/consultations/scheduling-of-tramadol-and-exemptions-for-temazepam-prescriptions |access-date=27 March 2023}}

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).{{cite web |title=Upcoming reclassification of fentanyl, tramadol, zopiclone and zolpidem |website=NZ Government |date=19 June 2023 |url=https://www.nzoa.org.nz/sites/default/files/Upcoming%20reclassification%20of%20fentanyl%2C%20tramadol%2C%20zopiclone%20and%20zolpidem%20(19%20June%202023).pdf |access-date=10 March 2024}}

Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization.{{cite web |title=If you take Tramadol away, you make Boko Haram weak. |date=15 March 2019 |website=African Arguments |url=https://africanarguments.org/2019/03/15/if-you-take-tramadol-away-you-make-boko-haram-weak/ |access-date=18 March 2019 |url-status=live |archive-url=https://web.archive.org/web/20200923085154/https://africanarguments.org/2019/03/15/if-you-take-tramadol-away-you-make-boko-haram-weak/ |archive-date=23 September 2020}}{{cite news |title=Drugs for war: Opioid abuse in West Africa |work=BBC News |url=https://www.bbc.com/news/av/world-africa-44325649/tramadol-emboldens-vigilantes-to-fight-boko-haram |access-date=18 March 2019 |url-status=live |archive-url=https://web.archive.org/web/20200702061435/https://www.bbc.com/news/av/world-africa-44325649/tramadol-emboldens-vigilantes-to-fight-boko-haram |archive-date=2 July 2020}}{{cite journal |website=csis.org |title=The Dangerous Opioid from India |date=23 March 2018 |vauthors=Tecimer N |url=https://www.csis.org/npfp/dangerous-opioid-india |access-date=18 March 2019 |url-status=live |archive-url=https://web.archive.org/web/20201101090942/https://www.csis.org/npfp/dangerous-opioid-india |archive-date=1 November 2020}} When used at higher doses, the drug "can produce similar effects to heroin." 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." Tramadol is also used as a coping mechanism in the Gaza Strip under Israeli siege.{{cite news |title=Gaza's Opioid Problem |vauthors=Berger M |journal=The Nation |date=7 January 2019 |issn=0027-8378 |url=https://www.thenation.com/article/archive/gaza-opioid-problem/ |access-date=12 July 2024 |url-status=live |archive-url=https://web.archive.org/web/20190920231739/https://www.thenation.com/article/gaza-opioid-problem/ |archive-date=20 September 2019}} It is also abused in the United Kingdom, inspiring the title of the TV show Frankie Boyle's Tramadol Nights (2010).{{cite journal |vauthors=Winstock AR, Borschmann R, Bell J |title=The non-medical use of tramadol in the UK: findings from a large community sample |journal=International Journal of Clinical Practice |volume=68 |issue=9 |pages=1147–1151 |date=September 2014 |doi=10.1111/ijcp.12429 |doi-access=free |pmid=24734958 |s2cid=21883884}}{{cite web |title=Tramadol Abuse & Addiction Causes |date=8 August 2018 |website=UK Addiction Treatment Centres |url=https://www.ukat.co.uk/opiates/tramadol/ |access-date=20 December 2021 |url-status=live |archive-url=https://web.archive.org/web/20211220134110/https://www.ukat.co.uk/opiates/tramadol/ |archive-date=20 December 2021}}

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

{{See also|List of investigational antidepressants}}

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

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.{{cite journal |vauthors=Souza MJ, Cox SK |title=Tramadol use in zoologic medicine |journal=The Veterinary Clinics of North America. Exotic Animal Practice |volume=14 |issue=1 |pages=117–130 |date=January 2011 |doi=10.1016/j.cvex.2010.09.005 |pmid=21074707}}

• Tramadol/paracetamol

{{Reflist}}

{{Refbegin}}

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

{{Refend}}

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