Tapentadol

Tapentadol

Systematic (IUPAC) name
3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2- methylpropyl]phenol hydrochloride
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a610006
Pregnancy cat.	C(AU) C(US)
Legal status	Schedule II
Routes	Oral, Other ROA Unknown
Pharmacokinetic data
Bioavailability	31.9 ± 6.8% (oral)[1]
Metabolism	Hepatic glucuronidation and sulfate conjugation
Half-life	4 hrs
Excretion	Renal (>95%) and fecal
Identifiers
CAS number	175591-23-8 N
ATC code	N02AX06
PubChem	CID 9838022
ChemSpider	8013742 Y
UNII	H8A007M585 Y
ChEMBL	CHEMBL1201776 N
Synonyms	BN-200 CG-5503 R-331333
Chemical data
Formula	C14H23NO
Mol. mass	221.339 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C14H23NO/c1-5-14(11(2)10-15(3)4)12-7-6-8-13(16)9-12/h6-9,11,14,16H,5,10H2,1-4H3/t11-,14+/m0/s1 Y Key:KWTWDQCKEHXFFR-SMDDNHRTSA-N Y
N(what is this?)  (verify)

Tapentadol (trade name Nucynta, Palexia, In India - ZYNTAP)^[2] is a centrally acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor.^[3] While its analgesic actions have been compared to tramadol and oxycodone,^[4] its general potency is somewhere between tramadol and morphine in effectiveness.^[5] Tapentadol is a new molecular entity that is structurally similar to Tramadol (Tramal). It has opioid and nonopioid acitivity in a single compound.

In the US, Tapentadol is FDA approved for the treatment of moderate to severe acute pain. Due to the dual mechanism of action as an opioid agonist and norepinephrine reuptake inhibitor, there is potential for off label use in chronic pain.

Doctors use serotonin and norepinephrine reuptake inhibitors in chronic pain management to increase the effectiveness of opioids and, to a lesser extent, NSAIDs (along with other analgesics) against neuropathic pain and from certain specific contributing causes such as fibromyalgia and diabetic neuropathy. One selective serotonin and norepinephrine reuptake inhibitor (SNRI) often used as an adjunct, atypical & potentiator is duloxetine (Cymbalta). Another opioid with selective norepinephrine reuptake inhibitor effects is levorphanol (Levo-Dromoran).

Its dual mode of action provides analgesia at similar levels of more potent narcotic analgesics such as hydrocodone, oxycodone, and pethidine (meperidine) with a more tolerable side effect profile.

History

75 mg Nucynta (tapentadol) tablets. Tapentadol is available as Nucynta in 50, 75, and 100 mg tablets from Ortho-McNeil-Janssen Pharmaceuticals

Tapentadol was developed by Grünenthal in conjunction with Johnson & Johnson Pharmaceutical Research and Development. It is being marketed as immediate release oral tablets of 50 mg, 75 mg, and 100 mg under the brand name Nucynta.

It is the first new drug of the centrally acting analgesic class approved in the United States in more than 25 years.^[6] Internationally, tapentadol's status is in various stages of development at this time.

• On 21 November 2008, Johnson & Johnson announced that it has received approval for immediate-release tapentadol tablets.^[7]

• On 23 January 2008, a New Drug Application (NDA) for tapentadol was submitted to the United States Food and Drug Administration.

• On 17 February 2009 the Drug Enforcement Administration proposed a rule which would add tapentadol to Schedule II of the Controlled Substances Act of 1970.^[8] The original commercial release date for tapentadol was planned for 17 March 2009; however, the placement of the compound in Schedule II interrupted commercial development. It was the manufacturer's intention to have tapentadol approved as a Schedule III compound, based upon limited preclinical animal data that show a reduced liability for abuse and tolerance compared with morphine.

• On 22 June 2009, the Drug Enforcement Agency approved the proposal to make tapentadol schedule II under the Controlled Substance Act.

• On 23 June 2009, after having received approval from the FDA and DEA, tapentadol became available for prescription on the US market. It is available in immediate-release oral doses of 50, 75, and 100 mg.

• On 10 August 2010, the European decentralised procedure regarding tapentadol concluded positively, which will result in the granting of national marketing authorisations in 26 European markets. Tapentadol will then be available as an oral, solid, immediate-release formulation (tablets) for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics, and an oral, solid, prolonged-release formulation (tablets) for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics.

• On 28 March 2011 the United Kingdom made tapentadol a Class A controlled drug.^[9]

Clinical trials

Efficacy of tapentadol compared to placebo was demonstrated in two phase III and one phase II, randomized, double-blind, multicenter, placebo controlled clinical trials submitted to the FDA. The phase III trials evaluated tapentadol multiple dosing post-orthopedic surgery and in late-stage OA. The phase II study evaluated single dosing of tapentadol post dental procedure. All trials utilized a 0-10 point scale for pain intensity (none to worst) and 0-5 point scale for pain relief (none to complete). Patients were assessed at time intervals and the sum of numerical values for these pain scales were the basis of evaluating efficacy. Secondary endpoints of total pain relief from baseline, time to pain relief, time to first rescue medication and the need for rescue medication are important clinically relevant endpoints. These published phase II and phase III studies used active control medications including oxycodone, morphine or NSAIDs.

Tapentadol demonstrated efficacy compared to placebo in a phase III, 3 day, multiple dosing assessment of post-surgical (bunionectomy) pain. The mean age of this patient population was 60–62 years. Participants had a post-operative baseline pain score of >4 on an 11 point scale and were randomized to placebo, tapentadol 50 mg, 75 mg, 100 mg or oxycodone IR 15 mg. All study medications including oxycodone were compared to placebo and given q4-6h. The sum of pain intensity (SPID) over the first 48 hours of study medication improved with all tapentadol strengths as well as oxycodone compared to placebo (p=<0.001). The percent of patients requiring rescue medication was less for tapentadol and oxycodone compared to placebo (tapentadol 100 mg=10%, oxycodone 15 mg =9%, placebo=49%). The time to the first dose of rescue medication required was reduced with all strengths of tapentadol as well as oxycodone when compared to placebo (p=<0.001, no data given). Overall, more patients experienced at least a 50% improvement in pain from baseline with tapentadol and oxycodone compared to placebo (tapentadol 50, 75, 100 mg=58%, 56.7%, 70.3%, oxycodone =72.8%, placebo = 30%, p=<0.001). Absolute risk reduction (ARR) was 40.3% for Tapentadol 100 mg and 42.8% for oxycodone. The number needed to treat (NNT) for 50% pain improvement at 48 hours was 3.6, 3.8 and 2.5 for tapentadol and 2.5 for oxycodone. Tapentadol was non-inferior to oxycodone IR 15 mg. Withdrawal due to adverse events was less with Tapentadol than oxycodone (NNH; Tapentadol 50, 75, 100 mg = 39, 23.8, n/a, oxycodone = 100).^[10]

Tapentadol was effective in a phase III, 10 day, multiple dosing assessments of patients awaiting knee replacement surgery from late stage OA. All patients were currently at a level of pain with an indication for opioid analgesics. Tapentadol 50 mg, 75 mg and oxycodone IR 10 mg was compared to placebo. The sum pain intensity difference (SPID) at 48 hours and 5 days improved with tapentadol 50 mg and 75 mg and oxycodone 10 mg as compared to placebo (p=<0.001). More patients experienced at least a 50% improvement in pain from baseline with tapentadol and oxycodone compared to placebo (tapentadol = 27, 26, oxycodone=25%, placebo=13%, p=<0.01). The NNT to achieve 50% pain relief was 7.1, 7.7 and 8.3 for tapentadol 50 and 75 mg doses and oxycodone. Tapentadol was non-inferior to oxycodone IR 15 mg. In this 10 days study, tapentadol had a lower incidence of discontinuation due to adverse events than oxycodone (NNH tapentadol 50,75 mg = 11.2, 6.9, oxycodone=3.6). The authors also state lower incidence of selected GI adverse events with tapentadol (p=<0.001).^[11]

A phase II single dose trial of tapentadol 25 mg-200 mg, ibuprofen 400 mg and morphine IR 60 mg was evaluated in post-surgery dental pain. This patient population was younger than in the previous 2 studies (18–45 years old, mean=23). The sum of total pain relief (SPID) at 4 and 8 hours and improved from baseline compared to placebo with doses of tapentadol that were >75 mg (p=<0.05). The time to perceptible (any noticeable relief) and clinically meaningful pain relief reported by patients was shorter for tapentadol 200 mg and ibuprofen 400 mg compared to morphine 60 mg IR (time to perceptible, meaningful pain relief: tapentadol 200 mg = 0.7 hours, 1.5 hours, morphine 60 mg = 0.8 hours, 2.6 hours, ibuprofen 400 mg = 0.8 hours, 1.5 hours). A minimum dose of 50 mg tapentadol was necessary to achieve statistical significance for a 50% reduction in pain from baseline. More patients reported a 50% improvement in pain from baseline with each increasing dose of tapentadol. The NNT for tapentadol 50, 75, 100, 200 mg was 13, 5, 2, and 3. NNT for morphine 60 mg and ibuprofen 400 mg was 3 and 2. Ibuprofen appeared to work well compared to other medications in this model.^[12]

Additional non-published have evaluated tapentadol with oxycodone and placebo in hip replacement surgery (terminated due to high discontinuation rates) and tapentadol with morphine and placebo in chronic tumor related pain (terminated due to recall of a rescue medication impacting timeline). Results of these studies are not available. Studies currently recruiting subjects include tapentadol, morphine and placebo in chronic tumor related pain, and tapentadol, oxycodone and placebo in post-op shoulder surgery and vertebral compression fracture. There are no listed clinical trials involving tramadol or NSAIDs.

Abuse potential

The abuse potential of tapentadol has not been fully elucidated due to limited clinical experience with this new drug. The preliminary information available from clinical use as well as close pharmacodynamic similarities with the class prototype drug tramadol indicate that tapentadol has a relatively limited potential for abuse, dependency and addiction compared to other strong opioid medications. The decision of the US DEA to place tapentadol into Schedule II,^[13] the same category as the most powerful and frequently abused narcotics, such as morphine, oxycodone and fentanyl, could therefore be seen as overly cautious. This highly restricted classification will likely drive the cost of tapentadol up and place unnecessarily high scrutiny on its clinical use, decreasing availability, inhibiting physicians from prescribing it and ultimately leaving patients that could benefit from its effects insufficiently treated. The DEA rarely (if ever) "down-grades" drugs placed in Schedule II into lower categories based upon empirical evidence, making it unlikely that tapentadol will see widespread utilization on the US market in the near future. This may additionally reduce the profitability of the drug to the parent manufacturing company. While Tapentadol is less abused than Oxycodone, the drug will remain in Schedule II since it is considered to have an abuse profile similar to hydromorphone.

Adverse effects

Nausea, dizziness, constipation, and CNS sedation are common side effects of opioid pain medications. In phase II trials, tapentadol has been shown to provide equianalgesic effect with a lower incidence of side effects compared to oxycodone and morphine. One trial, sponsored by Grünenthal, comparing tapentadol to morphine and ibuprofen for relief of postoperative pain found tapentadol to cause less nausea and dizziness than morphine, with no significant difference in the incidence of vomiting or drowsiness.^[14]

Clinical studies cite there is less incidence of select adverse gastrointestinal effects tapentadol compared to oxycodone.

May cause hallucinations to patients on anti-depressants.

See also

• Bromadol
• C-8813
• Ciramadol
• Faxeladol
• Profadol
• Tramadol

References

1. ^ Terlinden R, Ossig J, Fliegert F, Gohler K (2006). "Pharmacokinetics, excretion and metabolism of tapentadol HCl, a novel centrally acting analgesic in healthy subjects". Program and abstracts of the 25th Annual Scientific Meeting of the American Pain Society; May 3–6, 2006; San Antonio, Texas. Poster 689.
2. ^ US Patent 6248737 - 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects
3. ^ Tzschentke TM, Christoph T, Kögel B, Schiene K, Hennies HH, Englberger W, Haurand M, Jahnel U, Cremers TI, Friderichs E, De Vry J. (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol Hydrochloride (Tapentadol HCl): a Novel μ-Opioid Receptor Agonist/Norepinephrine Reuptake Inhibitor with Broad-Spectrum Analgesic Properties. Journal of Pharmacology and Experimental Therapeutics. 2007 Oct;323(1):265-76.
4. ^ Data Comparing Nucynta (tapentadol) Tablets to Oxycodone Immediate Release Tablets Presented at 2010 American Pain Society Annual Meeting
5. ^ Tschentke, T.M. et Tapentadol/Nucynta launched June 22, 2009 as an immediate release oral tablets, 50mg, 75mg, 100mg. "Tapentadol Hydrochloride." Drugs of the Future. 2006, Vol. 31, Issue 12, p. 1053. DOI: 10.1358/dof.2006.031.12.1047744
6. ^ Krüger-Hellwig, Anke. "Grünenthal GmbH Presents Tapentadol, a Novel Centrally Acting Analgesic, at the 25th Annual Scientific Meeting of The American Pain Society." PR Newswire. 6 June 2006. Retrieved on 20 September 2007.
7. ^ FDA Approves Tapentadol Immediate-Release Tablets for Relief of Moderate to Severe Acute Pain November 21, 2008. Retrieved on November 24, 2008.
8. ^ Proposed Rule - Schedules of Controlled Substances: Placement of Tapentadol Into Schedule II (February 17, 2009)
9. ^ Misuse of Drugs Act 1971 (Amendment) Order 2011
10. ^ Daniels, S; Upmalis, D; Okamoto, A; Lange, C; Haeussler, J. “A Randomized, Double-Blind, Phase III Study Comparing Multiple Doses of Tapentadol IR, Oxycodone IR, and Placebo for Postoperative (bunionectomy) Pain.” Current Medical Research and Opinion; Vol. 25; No. 3; 2009; 765-776.
11. ^ Hartrick, C; Van Hove, I; Stegmann, J; Oh, C; Upmalis, D. “Efficacy and Tolerability of tapentadol Immediate Release and Oxycodone HCl Immediate Release in Patients Awaiting Primary Join Replacement Surgery for End-Stage Joint Disease: A 10-day, Phase III, Randomized, Double-Blind, Active and Placebo Controlled Study”. Clinical Therapeutics. Vol 31; No.2; 2009.
12. ^ Kleinert, R; Lange, C; Steup, A; Black, P; Goldberg, J; Dejardins, P. “Single Dose Analgesic Efficacy of Tapentadol in Postsurgical Dental Pain: The Results of a Randomized, Double-Blind, Placebo-Controlled Study”. International Anesthesia Research Society Vol. 107, No. 6, December 2008
13. ^ Leonhart, MM, Deputy Administrator, Drug Enforcement Administration, Schedules of Controlled Substances: Placement of Tapentadol Into Schedule II, Fed Regist. 2009 May 21;74(97):23790-3.
14. ^ "Two New Analgesics May Help Patients After Bunionectomy". Journal of Anaesthesiology Clinical Pharmacology. September 26, 2006. http://www.joacp.org/index.php?option=com_content&task=view&id=48&Itemid=58. Retrieved 2007-09-20. 

External links

• PR Newswire: Phase II Data Show Efficacy and Tolerability of Tapentadol