Tapentadol

Tapentadol is used for the treatment of moderate to severe pain for both acute (following e.g. injury or surgery) and chronic musculoskeletal pain.{{cite journal | vauthors = Polati E, Canonico PL, Schweiger V, Collino M | title = Tapentadol: an overview of the safety profile | language = English | journal = Journal of Pain Research | volume = 12 | pages = 1569–1576 | date = 2019-05-16 | pmid = 31190968 | pmc = 6529613 | doi = 10.2147/JPR.S190154 | doi-access = free }} It is also specifically indicated for controlling the pain of diabetic neuropathy when around-the-clock opioid medication is required.

Extended-release formulations of tapentadol are not indicated for use in the management of acute pain and are instead indicated only for the relief of severe, disabling pain, that is long-term in nature and cannot be controlled by any other pharmacological means.{{cite journal |vauthors=Smit JW, Oh C, Rengelshausen J, Terlinden R, Ravenstijn PG, Wang SS, Upmalis D, Mangold B |title=Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies |journal=Pharmacotherapy |volume=30 |issue=1 |pages=25–34 |date=January 2010 |pmid=20030470 |pmc=2888545 |doi=10.1592/phco.30.1.25}}{{cite web|url=http://reference.medscape.com/drug/nucynta-tapentadol-999202|title=Medscape-Nucynta|access-date=2012-12-09|archive-date=2017-12-22|archive-url=https://web.archive.org/web/20171222105739/https://reference.medscape.com/drug/nucynta-tapentadol-999202|url-status=live}}

Tapentadol is pregnancy category C. There are no adequate and well-controlled studies of tapentadol in pregnant women, and tapentadol is not recommended for use in women during and immediately prior to labor and delivery.{{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022304s014s015lbl.pdf | title = Nucynta Label | archive-url = https://web.archive.org/web/20210330050011/https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022304s014s015lbl.pdf | archive-date=2021-03-30 }}

There are no adequate and well-controlled studies of tapentadol in children.

Tapentadol is contraindicated in people with epilepsy or who are otherwise prone to seizures. It raises intracranial pressure so should not be used in people with head injuries, brain tumors, or other conditions which increase intracranial pressure. It increases the risk of respiratory depression so should not be used in people with asthma.

As with other μ-opioid agonists, tapentadol may cause spasms of the sphincter of Oddi, and is therefore discouraged for use in patients with biliary tract disease such as both acute and chronic pancreatitis. People who are rapid or ultra rapid metabolizers for the CYP2C9, CYP2C19, and CYP2D6 enzymes may not respond adequately to tapentadol therapy. Due to reduced clearance, tapentadol should be administered with caution to people with moderate liver disease and not at all in people with severe liver disease.

The most commonly reported side effects of tapentadol therapy are constipation, nausea, vomiting, headaches, loss of appetite, drowsiness, dizziness, itching, dry mouth, and sweating. Tapentadol has also been noted to induce feelings of relaxation and euphoria,{{cite journal | vauthors = Roulet L, Rollason V, Desmeules J, Piguet V | title = Tapentadol Versus Tramadol: A Narrative and Comparative Review of Their Pharmacological, Efficacy and Safety Profiles in Adult Patients | journal = Drugs | volume = 81 | issue = 11 | pages = 1257–1272 | date = July 2021 | pmid = 34196947 | pmc = 8318929 | doi = 10.1007/s40265-021-01515-z }} and it may cause serious side effects such as respiratory depression, serotonin syndrome, addiction and substance dependence.

Several studies have found that tapentadol causes less constipation and nausea compared with oxycodone.{{Cite journal | vauthors = Oliveira M, Moisés MC, Dias EC, dos Santos MV, Schmidt AP |date= January 2024 |title=Treatment-emergent adverse events of tapentadol or oxycodone in pain management after orthopedic surgeries: A systematic review and meta-analysis of randomized clinical trials |journal=JCA Advances |volume=1 |issue=3 |pages=100024 |doi=10.1016/j.jcadva.2024.100024 |issn=2950-5534|doi-access=free }} It has been noted that due to this, treatment adherence may be improved, with fewer people discontinuing tapentadol (when compared with oxycodone).

Tapentadol has been demonstrated to reduce the seizure threshold in patients. Tapentadol should be used cautiously in patients with a history of seizures, and in patients who are also taking one or more other drugs which have also been demonstrated to reduce the seizure threshold. Patients at high risk include those using other serotogenic and adrenergic medications, as well as patients with head trauma, metabolic disorders, and those in alcohol and/or drug withdrawals.{{cite web |title=Nucynta CR |url=https://www.janssen.com/canada/sites/www_janssen_com_canada/files/product/pdf/nuccr08052014cpm_nc.pdf |url-status=live |archive-url=https://web.archive.org/web/20160815114732/https://www.janssen.com/canada/sites/www_janssen_com_canada/files/product/pdf/nuccr08052014cpm_nc.pdf |archive-date=2016-08-15 |access-date=2016-06-21 |website=Janssen Inc.}}

Tapentadol has been demonstrated to potentially produce hypotension (low blood pressure), and should be used with caution in patients with low blood pressure, and patients who are taking one or more other medications which are also known to reduce blood pressure.

{{See also|Opioid use disorder|Drug addiction}}

The World Health Organization determined that there was little evidence to judge the abuse potential of tapentadol when it was introduced.{{cite web|url=https://www.who.int/medicines/areas/quality_safety/5.2ExpertreviewTapentadolpre-review.pdf|publisher=World Health Organization|access-date=16 March 2014|title=Tapentadol: Expert peer review on pre-review report|vauthors=((35th Expert Committee on Drug Dependence, Hammamet, Tunisia))|date=June 2012|archive-date=16 March 2014|archive-url=https://web.archive.org/web/20140316105831/http://www.who.int/medicines/areas/quality_safety/5.2ExpertreviewTapentadolpre-review.pdf|url-status=live}} Although early pre-clinical animal trials suggested that tapentadol had a reduced abuse liability compared to other opioid analgesics, the US Drug Enforcement Agency placed tapentadol into Schedule II,{{cite journal|vauthors = Leonhart MM,((Deputy Administrator, Drug Enforcement Administration))|title=Schedules of Controlled Substances: Placement of Tapentadol Into Schedule II|journal=Federal Register|date=May 2009|volume=74|issue=97|pages=23790–93}} the same category as stronger opioids more commonly used recreationally, such as morphine, oxycodone, and fentanyl.{{cite web|title=DEA Diversion Control – Controlled Substances Schedules|url=http://www.deadiversion.usdoj.gov/schedules/index.html|publisher=US Federal Government|access-date=2012-05-16|archive-date=2021-04-25|archive-url=https://web.archive.org/web/20210425032741/https://www.deadiversion.usdoj.gov/schedules/index.html|url-status=live}} Since these initial trials, however, evidence has shown that tapentadol is commonly abused, misused and diverted, that it is addictive,{{cite journal | vauthors = Butler SF, McNaughton EC, Black RA | title = Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment | journal = Pain Medicine | volume = 16 | issue = 1 | pages = 119–130 | date = January 2015 | pmid = 25243972 | doi = 10.1111/pme.12524 }} and that it poses a high risk of physical and/or mental dependence.

Given that tapentadol is a highly selective full agonist of the μ-opioid receptor, and given that is not a pro-drug, with no ceiling effect, studies have found that it is significantly more abusable than tramadol, and similar to hydrocodone and other full agonists of the μ-opioid receptor (such as oxycodone and hydromorphone) in terms of addiction and dependence liability.{{cite journal | vauthors = Vosburg SK, Severtson SG, Dart RC, Cicero TJ, Kurtz SP, Parrino MW, Green JL | title = Assessment of Tapentadol API Abuse Liability With the Researched Abuse, Diversion and Addiction-Related Surveillance System | journal = The Journal of Pain | volume = 19 | issue = 4 | pages = 439–453 | date = April 2018 | pmid = 29224919 | doi = 10.1016/j.jpain.2017.11.007 | doi-access = free }} Tapentadol is water soluble, which creates the potential for further abuse of the drug. There have been reports of users crushing, chewing, inhaling or injecting immediate-release tapentadol tablets, which can lead to respiratory depression, coma and death.{{cite journal | vauthors = Dart RC, Bartelson BB, Adams EH | title = Nonmedical use of tapentadol immediate release by college students | language = en-US | journal = The Clinical Journal of Pain | volume = 30 | issue = 8 | pages = 685–692 | date = August 2014 | pmid = 24042351 | doi = 10.1097/AJP.0000000000000001 }}

{{See also|Opioid use disorder|Opioid withdrawal}}

The risk of experiencing severe withdrawal symptoms is high if a patient has become physically or mentally dependent and discontinues tapentadol abruptly.{{cite journal | vauthors = Sánchez Del Águila MJ, Schenk M, Kern KU, Drost T, Steigerwald I | title = Practical considerations for the use of tapentadol prolonged release for the management of severe chronic pain | language = English | journal = Clinical Therapeutics | volume = 37 | issue = 1 | pages = 94–113 | date = January 2015 | pmid = 25108647 | doi = 10.1016/j.clinthera.2014.07.005 | doi-access = free }} These symptoms can range from mild discomfort to more serious health issues, making abrupt cessation dangerous.{{Cite web |title=Tapentadol Dependence: A Case Series |url=https://www.psychiatrist.com/pcc/tapentadol-dependence/ |access-date=2025-04-05 |website=Psychiatrist.com |language=en-US}} When a person has been using tapentadol regularly for an extended period of time, tapering off the drug gradually is generally recommended.{{cite journal | vauthors = Vellucci R, Fornasari D | title = Appropriate use of tapentadol: focus on the optimal tapering strategy | journal = Current Medical Research and Opinion | volume = 39 | issue = 1 | pages = 123–129 | date = January 2023 | pmid = 36427080 | doi = 10.1080/03007995.2022.2148459 | hdl = 2434/948379 | hdl-access = free }}{{cite journal | vauthors = Vinik AI, Shapiro DY, Rauschkolb C, Lange B, Karcher K, Pennett D, Etropolski MS | title = A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy | journal = Diabetes Care | volume = 37 | issue = 8 | pages = 2302–2309 | date = August 2014 | pmid = 24848284 | doi = 10.2337/dc13-2291 }} This approach allows the body to adjust to lower doses over time, minimizing the risk of withdrawal symptoms and ensuring a safer transition away from tapentadol. Gradual withdrawal helps to avoid the shock to the system that comes with abrupt discontinuation, ultimately making the process more manageable for a person who has developed a dependence.{{Cite web |date=2020-01-31 |title=5 steps to tapering opioids for patients with chronic non-cancer pain |url=https://www.nps.org.au/news/5-steps-to-tapering-opioids |access-date=2025-04-05 |website=NPS MedicineWise |language=en}}

The symptoms of tapentadol withdrawal are typical of other opioids and can include anxiety, restlessness, fever or chills, joint pain, nausea or vomiting, loss of appetite, runny nose, stomach cramps, sweating, tremor, or insomnia.{{Cite web |title=Tapentadol (oral route) |url=https://www.mayoclinic.org/drugs-supplements/tapentadol-oral-route/description/drg-20072580 |access-date=2025-04-05 |website=Mayo Clinic |language=en}}

However, tapentadol withdrawal symptoms may be more intense and prolonged when compared with more typical opioids such as codeine or oxycodone, in some respects, due to the fact that tapentadol acts also as norepinephrine reuptake inhibitor (NRI). People withdrawing from a tapentadol dependency may experience both typical opioid withdrawal symptoms, such as fever or nausea, along with symptoms associated more commonly with the discontinuation of drugs which block the reuptake of norepinephrine.

Combination with selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, serotonin releasing agents, and serotonin receptor agonists may lead to potentially lethal serotonin syndrome.{{cite journal | vauthors = Nossaman VE, Ramadhyani U, Kadowitz PJ, Nossaman BD | title = Advances in perioperative pain management: use of medications with dual analgesic mechanisms, tramadol & tapentadol | journal = Anesthesiology Clinics | volume = 28 | issue = 4 | pages = 647–666 | date = December 2010 | pmid = 21074743 | doi = 10.1016/j.anclin.2010.08.009 }} Combination with MAOIs may also result in an adrenergic storm. Use of tapentadol with alcohol or other central nervous system depressants such as benzodiazepines, barbiturates, nonbenzodiazepines, phenothiazines, gabapentinoids and other opiates may result in increased impairment, sedation, respiratory depression, and death.

Tapentadol is partially metabolized by the hepatic enzymes CYP2C9, CYP2C19, and CYP2D6 so it innately has interactions with drugs that enhance or repress the activity/expression of one or more of these enzymes, as well as with substrates of these enzymes (due to competition for the enzyme); some enzyme mediators/substrates require dosing adjustments to one or both medications.{{cite journal | vauthors = Ramaswamy S, Chang S, Mehta V | title = Tapentadol--the evidence so far | journal = Anaesthesia | volume = 70 | issue = 5 | pages = 518–522 | date = May 2015 | pmid = 25866038 | doi = 10.1111/anae.13080 }}

The combination of tapentadol and alcohol may result in increased plasma concentrations of tapentadol and produce respiratory depression to a degree greater than the sum of the two drugs when administered separately; patients should be cautioned against alcohol consumption when taking tapentadol as the combination may be fatal.

Tapentadol should be used with caution in patients who are taking one or more anticholinergic drugs, as this combination may result in urine retention (which can result in serious renal damage and is considered a medical emergency).

Tapentadol is a synthetic opioid with a dual mechanism of action: it acts as a full agonist of the μ-opioid receptor (MOR) and as a norepinephrine reuptake inhibitor (NRI).{{cite journal | vauthors = Schröder W, Tzschentke TM, Terlinden R, De Vry J, Jahnel U, Christoph T, Tallarida RJ | title = Synergistic interaction between the two mechanisms of action of tapentadol in analgesia | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 337 | issue = 1 | pages = 312–320 | date = April 2011 | pmid = 21262850 | pmc = 3364495 | doi = 10.1124/jpet.110.175042 }} This unique pharmacological profile allows it to treat both nociceptive and neuropathic pain, and it is theorised that the effects on norepinephrine are a substantial benefit for people taking it.{{cite journal | vauthors = Alshehri FS | title = Tapentadol: A Review of Experimental Pharmacology Studies, Clinical Trials, and Recent Findings | journal = Drug Design, Development and Therapy | volume = 17 | pages = 851–861 | date = 2023 | pmid = 36974332 | pmc = 10039632 | doi = 10.2147/DDDT.S402362 | doi-access = free }} Tapentadol does not affect serotonin, unlike tramadol, which prevents the reuptake of serotonin and norepinephrine, similarly to certain antidepressants known as serotonin–norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine and duloxetine.{{cite journal |vauthors=Kokilambigai KS, Irina VM, Sheba Mariam KC, Adila K, Kathirvel S |date=September 2024 |title=Comprehensive overview of analytical and bioanalytical methodologies for the opioid analgesics - Tramadol and combinations |url= |journal=Anal Biochem |volume=692 |issue= |pages=115579 |doi=10.1016/j.ab.2024.115579 |pmid=38797485}}

Tapentadol exhibits high binding selectivity and affinity for MOR, which is the principal target of the endogenous neuropeptide β-endorphin.{{cite book |url=https://books.google.com/books?id=0Zq9BwAAQBAJ&pg=PA491 |title=Essentials of Internal Medicine 3e |vauthors=Talley NJ, Frankum B, Currow D |date=10 February 2015 |publisher=Elsevier Health Sciences |isbn=978-0-7295-8081-6 |pages=491–}} It has significantly lower affinity for the δ-opioid receptor (DOR) and κ-opioid receptor (KOR).{{cite journal | vauthors = Chang EJ, Choi EJ, Kim KH | title = Tapentadol: Can It Kill Two Birds with One Stone without Breaking Windows? | journal = The Korean Journal of Pain | volume = 29 | issue = 3 | pages = 153–157 | date = July 2016 | pmid = 27413479 | pmc = 4942642 | doi = 10.3344/kjp.2016.29.3.153 }} MOR binding sites are distributed throughout the human brain, with higher densities in regions such as the amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and select cortical areas.{{cite book | vauthors = Herman TF, Cascella M, Muzio MR | chapter = Mu Receptors |date=2025 | title = StatPearls | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK551554/ |access-date=2025-04-06 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31855381 }}

Opioids like tapentadol are believed to mediate analgesia primarily through MOR activation in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), thereby inhibiting ascending pain pathways.{{cite journal | vauthors = Roulet L, Rollason V, Desmeules J, Piguet V | title = Tapentadol Versus Tramadol: A Narrative and Comparative Review of Their Pharmacological, Efficacy and Safety Profiles in Adult Patients | journal = Drugs | volume = 81 | issue = 11 | pages = 1257–1272 | date = July 2021 | pmid = 34196947 | pmc = 8318929 | doi = 10.1007/s40265-021-01515-z }} MOR activation in the intestine contributes to common opioid-related side effects such as constipation.{{cite journal | vauthors = Faria J, Barbosa J, Moreira R, Queirós O, Carvalho F, Dinis-Oliveira RJ | title = Comparative pharmacology and toxicology of tramadol and tapentadol | journal = European Journal of Pain | volume = 22 | issue = 5 | pages = 827–844 | date = May 2018 | pmid = 29369473 | doi = 10.1002/ejp.1196 }}

As noted, tapentadol is structurally similar to tramadol, and both drugs utilize a dual mechanism involving the opioid and norepinephrine systems. However, unlike tramadol, tapentadol exerts minimal influence on serotonin reuptake and is approximately 2–3 times more potent as an opioid. Tapentadol also lacks active metabolites, which distinguishes it from tramadol and may contribute to a more predictable pharmacokinetic profile.{{Cite web |title=Tramadol and Tapentadol: Clinical and Pharmacologic Review |url=https://resources.wfsahq.org/atotw/tramadol-and-tapentadol-clinical-and-pharmacologic-review/ |access-date=2025-04-02 |website=WFSA Resource Library |language=en-US}}

Following oral administration, tapentadol typically provides onset of analgesia within 32 minutes, with effects lasting approximately 4 to 6 hours.{{cite journal | vauthors = Mateos RG, Bernal DS, Morera LM, Ferri CM, Escobar AE | title = Long-Term Effectiveness and Tolerability of Pain Treatment with Tapentadol Prolonged Release | journal = Pain Physician | volume = 24 | issue = 1 | pages = E75–E85 | date = January 2021 | pmid = 33400440 | url = https://pubmed.ncbi.nlm.nih.gov/33400440 }} Approximately 32% of an oral dose of tapentadol escapes first-pass metabolism in the liver, entering systemic circulation to exert pharmacological effects on both the central nervous system (CNS) and peripheral nervous system (PNS).{{cite journal | vauthors = Terlinden R, Ossig J, Fliegert F, Lange C, Göhler K | title = Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 32 | issue = 3 | pages = 163–169 | date = 2007 | pmid = 18062408 | doi = 10.1007/BF03190478 }}

The free base conversion factor for tapentadol hydrochloride is 0.86.{{cite web |url=http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |title=2014 - Final Adjusted Aggregate Production Quotas for Schedule I and II Controlled Substances and Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2014 |publisher=Deadiversion.usdoj.gov |access-date=2018-09-22 |archive-date=2016-03-04 |archive-url=https://web.archive.org/web/20160304053357/http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |url-status=live }} Food intake has a minor impact on the drug’s peak plasma concentration: increasing it by approximately 8% for immediate-release (IR) and 18% for extended-release (ER) formulations. These differences are not clinically significant, and tapentadol may be taken with or without food.{{cite journal | vauthors = Zannikos PN, Smit JW, Stahlberg HJ, Wenge B, Hillewaert VM, Etropolski MS | title = Pharmacokinetic evaluation of tapentadol extended-release tablets in healthy subjects | journal = Journal of Opioid Management | volume = 9 | issue = 4 | pages = 291–300 | date = 2013-07-01 | pmid = 24353023 | doi = 10.5055/jom.2013.0171 }}

Tapentadol displays dose-dependent plasma concentrations; however, higher doses (e.g., 250 mg) may produce disproportionately elevated Cmax values relative to lower doses, suggesting non-linear pharmacokinetics at higher concentrations.

In receptor binding studies, tapentadol demonstrated a Ki of 60 nM for cloned human μ-opioid receptors, with strong agonist activity comparable to morphine, as measured by [35S]GTPγS binding assays.{{cite web |date=4 November 2008 |title=Tapentadol Post Marketing Requirement |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022304s000_OtherR.pdf |work=Center for Drug Evaluation and Research (CDER) |publisher=FDA}} Its inhibitory effect on norepinephrine reuptake (Ki = 480 nM) complements its opioid activity, while its weak serotonergic effects distinguish it from dual-acting agents like tramadol. In vitro studies using human tissue indicate that tapentadol has approximately one-third the binding affinity of morphine for the human μ-opioid receptor, reflecting its comparatively lower opioid potency.{{cite web |title=Tapentadol |url=https://pubchem.ncbi.nlm.nih.gov/compound/Tapentadol#section=Pharmacology-and-Biochemistry |url-status=live |archive-url=https://web.archive.org/web/20160809000959/https://pubchem.ncbi.nlm.nih.gov/compound/Tapentadol#section=Pharmacology-and-Biochemistry |archive-date=August 9, 2016 |access-date=June 14, 2016 |work=PubChem |publisher=U.S. National Library of Medicine}}{{PD-notice}}{{cite journal |vauthors=Wiffen PJ, Derry S, Naessens K, Bell RF |date=September 2015 |title=Oral tapentadol for cancer pain |journal=The Cochrane Database of Systematic Reviews |volume=2015 |issue=9 |pages=CD011460 |doi=10.1002/14651858.CD011460.pub2 |pmc=6483480 |pmid=26403220}}{{Cite web |date=2020-06-23 |title=Tapentadol use and harms in Australia: Analysis of opioid sales data and sentinel survey data from people who inject drugs |url=https://www.unsw.edu.au/research/ndarc/resources/tapentadol-use-and-harms-in-australia--analysis-of-opioid-sales- |access-date=2025-04-02 |website=UNSW Sites |language=en}} Nonetheless, it retains clinically meaningful opioid activity, contributing to its analgesic effects.

Commercial formulations contain only the (R,R)-stereoisomer, which is the weakest in terms of opioid receptor activation. Drugs with high MOR affinity, such as tapentadol, carry an abuse potential comparable to other strong opioids like morphine, oxycodone, and hydromorphone.

File:Nucynta.jpg

Tapentadol was invented at the German pharmaceutical company Grünenthal in the late 1980s led by Helmut Buschmann;{{cite patent | country = US | number = 6248737 | title = 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects | inventor = Buschmann H, Strassburger W, Friderichs E | assign = Gruenenthal GmbH | gdate = 19 June 2001 | url = https://patents.google.com/patent/US6248737B1/en?oq=US6248737 }} the team started by analyzing the chemistry and activity of tramadol, which had been invented at the same company in 1962.{{cite book | vauthors = Buschmann H | chapter = Tapentadol – From Morphine and Tramadol to the Discovery of Tapentadol. Chapter 12 | title = Analogue-based Drug Discovery | volume = III | edition = First | veditors = Fischer J, Ganellin CR, Rotella DP | publisher = Wiley-VCH Verlag GmbH & Co. KGaA | date = 2013 | isbn = 9783527651108}}

Tramadol has several enantiomers, and each forms metabolites after processing in the liver. These tramadol variants have varying activities at the μ-opioid receptor, the norepinephrine transporter, and the serotonin transporter, and differing half-lives, with the metabolites having the best activity. Using tramadol as a starting point, the team aimed to discover a single molecule that minimized the serotonin activity, had strong μ-opioid receptor agonism and strong norepinephrine reuptake inhibition, and would not require metabolism to be active; the result was tapentadol.{{rp|301–302}}

In 2003 Grünenthal partnered with two Johnson & Johnson subsidiaries, Johnson & Johnson Pharmaceutical Research and Development and Ortho-McNeil Pharmaceutical to develop and market tapentadol; Johnson & Johnson had exclusive rights to sell the drug in the US, Canada, and Japan while Grünenthal retained rights elsewhere.{{cite book | vauthors = Froicu D, Sinatra RS | chapter = Tapentadol. Chapter 31 | title = The Essence of Analgesia and Analgesics | veditors = Sinatra RS, Jahr JS, Michael Watkins-Pitchford J | publisher = Cambridge University Press| date = 2010 | isbn = 9781139491983 }} In 2008 tapentadol received approval by the US Food and Drug Administration; in 2009 it was classified by US Drug Enforcement Agency as a Schedule II drug, and entered the US market. Tapentadol was reported to be the "first new molecular entity of oral centrally acting analgesics" class approved in the United States in more than 25 years.{{cite news |url= http://www.prnewswire.co.uk/cgi/news/release?id=172601|title=Grünenthal GmbH Presents Tapentadol, a Novel Centrally Acting Analgesic, at the 25th Annual Scientific Meeting of The American Pain Society|newspaper=PR Newswire|date=6 June 2006|access-date=2007-09-20|archive-date=2012-02-07|archive-url=https://web.archive.org/web/20120207164810/http://www.prnewswire.co.uk/cgi/news/release?id=172601|url-status=live}}

In 2010 Grünenthal granted Johnson & Johnson the right to market tapentadol in about 80 additional countries.{{cite web | work = J&J Press Release | date = 7 June 2010 | url = http://www.investor.jnj.com/releasedetail.cfm?releaseid=477026 | title = Janssen Pharmaceutica N.V. Announces Expansion of Licensing Agreement for Tapentadol | archive-url = https://web.archive.org/web/20180923010201/http://www.investor.jnj.com/releasedetail.cfm?releaseid=477026 | archive-date=2018-09-23 }} Later that year, tapentadol was approved in Europe.{{cite web | vauthors = Dutton G | work = Genetic Engineering & Biotechnology News | date = 1 June 2012 | url = http://www.genengnews.com/gen-articles/pain-management-market-ripe-with-immediate-opportunities/4123/ | title = Pain Management Market Ripe with Immediate Opportunities | archive-url = https://web.archive.org/web/20180923052648/https://www.genengnews.com/gen-articles/pain-management-market-ripe-with-immediate-opportunities/4123/ | archive-date=2018-09-23 }} In 2011, Nucynta ER, an extended release formulation of tapentadol, was released in the United States for management of moderate to severe chronic pain and received Food and Drug Administration approval the following year for the treatment of neuropathic pain associated with diabetic peripheral neuropathy.{{cite web|url=https://www.drugs.com/history/nucynta.html|title=Nucynta (tapentadol) FDA Approval History – Drugs.com|website=www.drugs.com|access-date=2016-03-09|archive-date=2015-04-12|archive-url=https://web.archive.org/web/20150412010317/http://www.drugs.com/history/nucynta.html|url-status=live}}{{cite web|url=https://www.drugs.com/newdrugs/fda-approves-nucynta-er-tapentadol-extended-release-oral-management-neuropathic-pain-associated-3461.html|title=FDA Approves Nucynta ER (tapentadol) Extended-Release Oral Tablets for the Management of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy|access-date=2018-01-23|archive-date=2021-03-05|archive-url=https://web.archive.org/web/20210305170434/https://www.drugs.com/newdrugs/fda-approves-nucynta-er-tapentadol-extended-release-oral-management-neuropathic-pain-associated-3461.html|url-status=live}}

After annual sales of $166 million, in January 2015, Johnson & Johnson sold its rights to market tapentadol in the US to Depomed for $1 billion.{{cite web | author = Staff | work = The Pharma Letter | date = 16 January 2015 | url =http://www.thepharmaletter.com/article/depomed-pays-over-1-billion-for-us-rights-to-janssen-s-nucynta-franchise | title = Depomed pays over $1 billion for US rights to Janssen's Nucynta franchise | archive-url = https://web.archive.org/web/20160308225343/http://www.thepharmaletter.com/article/depomed-pays-over-1-billion-for-us-rights-to-janssen-s-nucynta-franchise | archive-date = 2016-03-08 }} The drug was manufactured at a plant located on the island of Puerto Rico that was hit by Hurricane Maria in 2017 causing a major shortage in the drug's availability.{{Cite web | vauthors = Byrne M, Pallaria F |url=https://www.iwpharmacy.com/blog/dealing-with-prescription-drug-shortages-|title=Dealing with Prescription Drug Shortages |website= www.iwpharmacy.com |language=en-us|access-date=2019-10-15|archive-date=2019-10-15|archive-url=https://web.archive.org/web/20191015203617/https://www.iwpharmacy.com/blog/dealing-with-prescription-drug-shortages-|url-status=live}} In January 2018 Depomed sold off the manufacturing of the drug and licensed it to Collegium Pharmaceutical for $10 million up front with an annual royalty payment of a minimum $135 million for the next 4 years.{{Cite web|url=https://www.fiercepharma.com/pharma/troubled-depomed-sells-off-nucynta-axes-40-workforce-to-pare-down-costs|title=Troubled Depomed sells off Nucynta, axes 40% of workforce to pare down costs|website=FiercePharma|date=5 December 2017 |language=en|access-date=2019-10-15|archive-date=2019-10-15|archive-url=https://web.archive.org/web/20191015203618/https://www.fiercepharma.com/pharma/troubled-depomed-sells-off-nucynta-axes-40-workforce-to-pare-down-costs|url-status=live}} This combination of events has caused additional short supply of the drug leaving patients who depend on it to seek alternative treatments.

File:Palexia IR 50mg (Australia).jpg

There have been calls for Tapentadol to be only marketed in countries where appropriate controls exist,{{cite web|url=https://www.who.int/medicines/areas/quality_safety/TAPENTADOL_IFPMA_Comments.pdf|title=Supplemental data for World Health Organization (Expert Committee on Drug Dependence) Critical Review on drug dependence of tapentadol|date=23 May 2014|website=World Health Organization|page=18|access-date=12 March 2014|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829075834/https://www.who.int/medicines/areas/quality_safety/TAPENTADOL_IFPMA_Comments.pdf|url-status=live}} but after performing a critical review, the United Nations Expert Committee on Drug Dependence in 2014 advised that tapentadol not be placed under international control but remain under surveillance.{{cite web|url=http://apps.who.int/gb/ebwha/pdf_files/EB136/B136_48Rev1-en.pdf|title=World Health Organization: Reports of advisory bodies|date=22 January 2015|website=World Health Organization|pages=2, 4|access-date=12 March 2016|archive-date=8 September 2015|archive-url=https://web.archive.org/web/20150908103807/http://apps.who.int/gb/ebwha/pdf_files/EB136/B136_48Rev1-en.pdf|url-status=live}}

As mentioned, the enhanced potency of tapentadol makes it considerably more susceptible to abuse compared to other opioids. This increased potency is one of the key factors that contribute to its higher potential for misuse.{{cite journal | vauthors = Vosburg SK, Beaumont J, Dailey-Govoni ST, Butler SF, Green JL | title = Evaluation of Abuse and Route of Administration of Extended-Release Tapentadol Among Treatment-Seeking Individuals, as Captured by the Addiction Severity Index-Multimedia Version (ASI-MV) | journal = Pain Medicine | volume = 21 | issue = 9 | pages = 1891–1901 | date = September 2020 | pmid = 31617931 | pmc = 7553020 | doi = 10.1093/pm/pnz250 }} Furthermore, tapentadol is water soluble, which allows for a variety of methods to ingest or administer the drug.{{cite journal | vauthors = Sharma M, Soni R | title = Improved therapeutic potential of tapentadol employing cationic exchange resins as carriers in neuropathic pain: evidence from pharmacokinetic and pharmacodynamics study | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 2812 | date = February 2018 | pmid = 29434240 | doi = 10.1038/s41598-018-21214-2 | bibcode = 2018NatSR...8.2812S | pmc = 5809392 }} It can be snorted, inhaled, or even delivered delivered rectally, all of which significantly increase the risk of abuse and the potential for dangerous consequences. These factors combined make tapentadol a particularly risky substance when it comes to misuse, posing serious concerns for both individuals and public health.

[https://web.archive.org/web/20240818154859/https://www.fda.gov/about-fda/cder-offices-and-divisions/controlled-substance-staff#:~:text=Controlled%20Substance%20Staff%20%7C%20FDA,The%20.gov%20means%20it%27s%20official. CSS] recognizes that tapentadol is available as an immediate-release formula, and that in the past there was no requirement of a medication guide for immediate-release opioids. However, tapentadol exhibits several distinctive properties that makes it highly abusable. According to them:

1. Tapentadol is a novel opioid that displays high affinity and selectivity for the μ-opioid receptor;
2. In a human liability pharmacology study conducted by the sponsor, it was found that tapentadol displays a high abuse potential similar to hydromorphone, a controlled substance with a similar risk of abuse, misuse and diversion; and
3. Based on a human abuse liability study, 50 mg of tapentadol produces comparable opioid effects to that of 4 mg of hydromorphone.

Since 2009 the drug has been categorized in the US as a Schedule II Controlled Substance with ACSCN 9780; in 2014 it was allocated a 17,500 kg aggregate manufacturing quota.

In 2010, Australia made tapentadol a S8 controlled drug.{{cite web|url=https://www.tga.gov.au/file/1392/download|title=Australian Public Assessment Report for Tapentadol|date=February 2011|website=Therapeutic Goods Administration|format=PDF|access-date=12 March 2016|archive-date=23 September 2018|archive-url=https://web.archive.org/web/20180923005945/https://www.tga.gov.au/file/1392/download|url-status=live}} The following year, tapentadol was classified as a Class A controlled drug in the United Kingdom, and was also placed under national control in Cyprus, Estonia, Finland, Greece, Latvia and Spain.{{cite web|url=http://www.legislation.gov.uk/uksi/2011/744/contents/made|title=The Misuse of Drugs Act 1971 (Amendment) Order 2011|website=www.legislation.gov.uk|access-date=2011-03-26|archive-date=2021-05-03|archive-url=https://web.archive.org/web/20210503073943/https://www.legislation.gov.uk/uksi/2011/744/contents/made|url-status=live}}{{cite web|url=https://www.incb.org/documents/Publications/AnnualReports/AR2012/AR_2012_E.pdf|title=International Narcotics Control Board Report 2012|date=5 March 2013|website=International Narcotics Control Board|page=99|access-date=12 March 2016|archive-date=18 August 2016|archive-url=https://web.archive.org/web/20160818140629/http://www.incb.org/documents/Publications/AnnualReports/AR2012/AR_2012_E.pdf|url-status=live}}

More recently, Canada made the opioid a Schedule I controlled drug, putting it in the same class as other prescription opioids such as morphine, fentanyl, tramadol, and heroin.{{cite web|url=http://gazette.gc.ca/rp-pr/p2/2015/2015-07-29/html/sor-dors189-eng.php|title=Canada Gazette – Regulations Amending the Narcotic Control Regulations (Tapentadol) – (Archived) | publisher = Government of Canada, Public Works and Government Services Canada, Public Services and Procurement Canada, Integrated Services Branch, Canada|website=Canada Gazette|date=29 July 2015|access-date=2016-03-12|archive-date=2016-03-13|archive-url=https://web.archive.org/web/20160313070916/http://gazette.gc.ca/rp-pr/p2/2015/2015-07-29/html/sor-dors189-eng.php|url-status=live}}

In India (except the state of Punjab), multiple brands of Tapentadol remain available over the counter. Recent reports have suggested increasing Tapentadol abuse and dependence in India, where users have improvised injections with 50 and 100 mg tablets.{{cite journal |vauthors=Mukherjee D, Shukla L, Saha P, Mahadevan J, Kandasamy A, Chand P, Benegal V, Murthy P |date=March 2020 |title=Tapentadol abuse and dependence in India |url=http://osf.io/xsu2q/ |url-status=live |journal=Asian Journal of Psychiatry |volume=49 |pages=101978 |doi=10.1016/j.ajp.2020.101978 |pmid=32120298 |s2cid=211834859 |archive-url=https://web.archive.org/web/20211220041459/https://osf.io/xsu2q/ |archive-date=2021-12-20 |access-date=2021-10-10}} Furthermore, a large number of listings for Tapentadol sourced from India can be found internationally on illicit marketplaces on the dark web. There have been several reports of Tapentadol from Indian pharmacies being smuggled to the US, the EU, and Bangladesh, where they are distributed via the black market.{{Cite web| work = BanglaNews24.com|date=2021-12-14|title=71 arrested in DMP's anti-narcotics drive|url=https://www.banglanews24.com/english/national/news/bd/92669.details|access-date=2021-12-30 |language=bn|archive-date=2021-12-30|archive-url=https://web.archive.org/web/20211230064925/https://www.banglanews24.com/english/national/news/bd/92669.details|url-status=live}}

Tapentadol has been demonstrated as a potentially effective analgesic in experimental studies however, further research is needed before it can be recommended for clinical use. Tapentadol is mainly metabolised as tapentadol-O-glucuronide in dogs and tapentadol-O-sulfate in cats. Intravenous, but not oral, administration has been shown to be effective in the dog, inducing sedation, salivation, ataxia, diarrhoea, and thermal antinociception. In cats intravenous, intramuscular, and subcutaenous administration has resulted in mild sedation and salivation. IV produced longer and greater sedation in the cat than IM and SC.{{cite book | vauthors = Simon BT, Lizarraga I | chapter = Opioids | title = Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones | pages = 384–385 | isbn = 978-1-119-83027-6 | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C | publisher = Wiley Blackwell }}

{{Reflist}}

{{Analgesics}}

{{Neuropathic pain and fibromyalgia pharmacotherapies}}

{{Monoamine reuptake inhibitors}}

{{Opioid receptor modulators}}

Category:Mu-opioid receptor agonists

Category:3-Hydroxyphenyl compounds

Category:Serotonin–norepinephrine reuptake inhibitors

Category:Drugs developed by Johnson & Johnson

Category:Tertiary amines

Category:Dimethylamino compounds