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Tapentadol

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Tapentadol
Tapentadol.svg
Systematic (IUPAC) name
3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-
methylpropyl]phenol hydrochloride
Clinical data
Trade names Nucynta, Palexia
AHFS/Drugs.com monograph
MedlinePlus a610006
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
Legal status
Pharmacokinetic data
Bioavailability 32% (oral)[1]
Protein binding 20%[2]
Metabolism Hepatic (mostly via glucuronidation but also by CYP2C9, CYP2C19, CYP2D6)[1]
Biological half-life 4 hours<[1]
Excretion Urine and faeces (1%)[1]
Identifiers
CAS Number 175591-09-0 N
ATC code N02AX06
PubChem CID 9838022
IUPHAR/BPS 7477
ChemSpider 8013742 YesY
UNII H8A007M585 YesY
ChEMBL CHEMBL1201776 N
Synonyms BN-200
CG-5503
R-331333
Chemical data
Formula C14H23NO
Molar mass 221.339 g/mol
 NYesY (what is this?)  (verify)

Tapentadol (brand names: Nucynta, Palexia and Tapal) is a centrally acting opioid analgesic of the benzenoid class with a dual mode of action as an agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI).[1] Its analgesic properties come into effect within thirty-two minutes of oral administration, and last for 4–6 hours.[3]

It is similar to tramadol in its dual mechanism of action; namely, its ability to activate the mu opioid receptor and inhibit the reuptake of norepinephrine.[3] Unlike tramadol, it has only weak effects on the reuptake of serotonin and is a significantly more potent opioid with no known active metabolites.[3][4] Unlike most other opiates of similar potency (ex. tramadol, oxycodone, hydrocodone, codeine), tapentadol is not a pro-drug and therefor does not rely on metabolism to produce its therapeutic effects; this makes it a useful moderate-potency analgesic option for patients who do not respond adequately to more commonly used opiates due to genetic disposition (poor metabolizers of CYP3A4 and CYP2D6), as well as providing a more consistent dosage-response range among the patient population.

Its general potency is somewhere between that of tramadol and morphine,[5] with an analgesic efficacy comparable to that of oxycodone despite a lower incidence of side effects.[1] As such, it is generally regarded as a weak-moderate strength opioid.

It was approved by the US FDA on the 20th of November, 2008,[6] by the MHRA of the UK on the 4th of February 2011[7] and by the TGA of Australia on the 24th of December 2010.[8]

Medical use[edit]

Tapentadol is used for the treatment of moderate to severe pain for both acute (following injury, surgery, etc.) and chronic musculoskeletal pain. It is also specifically indicated for controlling the pain of diabetic neuropathy when around-the-clock opioid medication is required.[1][9]

Its general potency is somewhere between that of tramadol and morphine,[5] with an analgesic efficacy comparable to that of oxycodone despite a lower incidence of side effects.[1][10]

Tapentadol is Pregnancy Category C. There are no adequate and well-controlled studies of tapentadol in pregnant women, tapentadol is not recommended for use in women during and immediately prior to labor and delivery.[11]

There are no adequate and well-controlled studies of tapentadol in children.[11]

Contraindications[edit]

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 mu-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 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.[11]

Adverse effects[edit]

The most commonly reported side effects of tapentadol therapy in clinical trials were nausea, vomiting, dizziness, sleepiness, itchiness, dry mouth, headache, and fatigue.[1]

According to the World Health Organization there is little evidence to judge the abuse potential of tapentadol.[10] Although early pre-clinical animal trials suggested that Nucynta has a reduced abuse liability compared to other opioid analgesics.[1] The US DEA has placed tapentadol into Schedule II,[12] the same category as the most powerful and frequently abused narcotics, such as morphine, oxycodone, and fentanyl.[11][13]

Interactions[edit]

Combination with SSRIs/SNRIs, SRAs, serotonin receptor agonists and/or MAOIs may lead to potentially lethal serotonin syndrome.[14] Combination with MAOIs may also result in an adrenergic storm. Use of tapentadol with alcohol or other sedatives such as benzodiazepines, barbiturates, nonbenzodiazepines, phenothiazines, and other opiates may result in increased impairment, sedation, respiratory depression, and death.[1] Tapentadol is partially metabolized by the hepatic enzymes CYP2C9, CYP2C19, and CYP2D6 so has interactions with drugs that enhance or repress their activity.[1]

Mechanism of action[edit]

Tapentadol is an agonist of the μ-opioid receptor and a norepinephrine reuptake inhibitor (NRI).[1] Its analgesic properties come into effect within thirty-two minutes of oral administration, and last for 4–6 hours.[3]

It is similar to tramadol in its dual mechanism of action but unlike tramadol, it has only weak effects on the reuptake of serotonin and is a significantly more potent opioid with no known active metabolites.[3][4]

Commercial preparations contain only the (R,R) stereoisomer, which is the weakest isomer in terms of opioid activity.[10]

History[edit]

75 mg Nucynta (tapentadol) tablets.

Tapentadol was discovered by scientists at the German pharmaceutical company Grünenthal in the late 1980s led by Helmut Buschmann; the team started by analyzing the chemistry and activity of tramadol, which had been discovered at the same company in 1962.[15]:302 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.[15]:301–302

In 2003 Grünenthal partnered with two Johnson & Johnson subsidiaries, Johnson & Johnson Pharmaceutical Research and Development and Ortho-McNeil Pharmaceutical to develop and sell tapentadol; J&J had the right to sell the drug in the US, Canada, and Japan following approvals and Grünenthal retained the rest of the world.[16]:143 The partners won FDA approval for tapentadol in 2008 and a year later cleared the US Drug Enforcement Administration process, was classified as a Schedule II drug, and the drug entered the US market.[16]:143 It was the first new drug of the centrally acting analgesic class approved in the United States in more than 25 years.[17]

In 2010 Grünenthal granted J&J the right to market tapentadol in about 80 additional countries.[18] Later that year tapentadol was approved in Europe.[19] In 2011 the United Kingdom made tapentadol a Class A controlled drug.[20] and in 2012, Nucynta ER, an extended release formulation of tapentadol was released to the United States market in doses of 50, 100, 150, 200, and 250 mg for the treatment of neuropathic pain associated with diabetic peripheral neuropathy.[21]

In January 2015, J&J sold its rights to market tapentadol in the US to Depomed for around $1B.[22] In the last year before that deal, sales of the drug has been around $166 million.[22]

Tapentadol is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN 9780 with a 17 500 kilo aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.86 for the hydrochloride. [23] Regulation in other countries is variable.

See also[edit]

References[edit]

  1. ^ a b c d e f g h i j k l m Fidman, B; Nogid, A (2010). "Role of Tapentadol Immediate Release (Nucynta) in the Management Of Moderate-to-Severe Pain". Pharmacy and Therapeutics 35 (6): 330–357. PMC 2888545. 
  2. ^ Brayfield, A, ed. (14 November 2011). "Tapentadol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 2 April 2014. 
  3. ^ a b c d e Singh, DR; Nag, K; Shetti, AN; Krishnaveni, N (July 2013). "Tapentadol hydrochloride: A novel analgesic.". Saudi Journal of Anaesthesia 7 (3): 322–326. doi:10.4103/1658-354X.115319. PMC 3757808. PMID 24015138. 
  4. ^ a b Raffa, RB; et al. (July 2012). "Mechanistic and functional differentiation of tapentadol and tramadol.". Expert Opinion on Pharmacotherapy 13 (10): 1437–49. doi:10.1517/14656566.2012.696097. PMID 22698264. 
  5. ^ a b Tzschentke, TM; de Vry, J; Terlinden, R; Hennies, HH; Lange, C; Strassburger, W; Haurand, M; Kolb, J; Schneider, J; Buschmann, H; Finkam, M; Jahnel, U; Friedrichs, E (2006). "Tapentadol Hydrochloride". Drugs of the Future 31 (12): 1053. doi:10.1358/dof.2006.031.12.1047744. 
  6. ^ "Nucynta History". drugs.com. Retrieved April 5, 2015. 
  7. ^ "Palexia film coated tablets". electronic Medicines Compendium. Grunenthal Ltd. 13 November 2013. Retrieved 2 April 2014. 
  8. ^ "PALEXIA® SR PRODUCT INFORMATION" (PDF). TGA eBusiness Services. CSL Limited. 26 June 2013. Retrieved 2 April 2014. 
  9. ^ "Medscape-Nucynta". 
  10. ^ a b c 35th Expert Committee on Drug Dependence, Hammamet, Tunisia (June 2012). "Tapentadol: Expert peer review on pre-review report" (PDF). Wolrd Health Organization. Retrieved 16 March 2014. 
  11. ^ a b c d Nucynta Label, last updated October 2013. Main FDA index page is here to check for updates.
  12. ^ Leonhart, M. M., Deputy Administrator, Drug Enforcement Administration (May 2009). "Schedules of Controlled Substances: Placement of Tapentadol Into Schedule II". Federal Register 74 (97): 23790–93. 
  13. ^ "DEA Diversion Control - Controlled Substances Schedules". US Federal Government. Retrieved 2012-05-16. 
  14. ^ Nossaman, V. E.; Ramadhyani, U.; Kadowitz, P. J.; Nossaman, B. D. (2010). "Advances in Perioperative Pain Management: Use of Medications with Dual Analgesic Mechanisms, Tramadol & Tapentadol". Anesthesiology Clinics 28 (4): 647–66. doi:10.1016/j.anclin.2010.08.009. PMID 21074743. 
  15. ^ a b Helmut Buschmann. Tapentadol – From Morphine and Tramadol to the Discovery of Tapentadol. Chapter 12 in Analogue-based Drug Discovery III, First Edition. Edited by Janos Fischer, C. Robin Ganellin, and David P. Rotella. Wiley-VCH Verlag GmbH & Co. KGaA. 2013. ISBN 9783527651108
  16. ^ a b Dan Froicu and Raymond S Sinatra. Tapentadol. Chapter 31 in The Essence of Analgesia and Analgesics, Eds. Raymond S. Sinatra, Jonathan S. Jahr, J. Michael Watkins-Pitchford. Cambridge University Press, 2010. ISBN 9781139491983
  17. ^ Krüger-Hellwig, A. (6 June 2006). "Grünenthal GmbH Presents Tapentadol, a Novel Centrally Acting Analgesic, at the 25th Annual Scientific Meeting of The American Pain Society". PR Newswire. Retrieved 2007-09-20. 
  18. ^ J&J Press Release. June 7, 2010 Janssen Pharmaceutica N.V. Announces Expansion of Licensing Agreement for Tapentadol
  19. ^ Gail Dutton for GEN. Jun 1, 2012 Pain Management Market Ripe with Immediate Opportunities
  20. ^ Misuse of Drugs Act 1971 (Amendment) Order 2011
  21. ^ "FDA Approves Nucynta ER (tapentadol) Extended-Release Oral Tablets for the Management of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy". 
  22. ^ a b Staff, The Pharma Letter. January 16, 2015 Depomed pays over $1 billion for US rights to Janssen’s Nucynta franchise
  23. ^ http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm
Monoaminergics
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