|Systematic (IUPAC) name|
|Mol. mass||257.799 g/mol|
|Bioavailability||31.9 ± 6.8% (oral)|
|Metabolism||Hepatic glucuronidation and sulfate conjugation|
|Half life||4 hrs|
|Excretion||Renal (>95%) and fecal|
|Pregnancy cat.||C(AU) C(US)|
|Legal status||Schedule II|
|Routes||Oral, Other ROA Unknown|
Tapentadol (trade name Nucynta) 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. It is considered to have a potency between tramadol and morphine.. Tapentadol is a new molecular entity that is structurally similar to tramadol (Ultram). It has opioid and nonopioid acitivity in a single compound.
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).
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 — posited by some commentators to be derived from the phrase "New Synthetic: Tapentadol" and/or an anagram of the name Cynthia with some letters missing.
It is the first new drug of the centrally-acting analgesic class approved in the United States in more than 25 years. 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.
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.  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 instant-release oral doses of 50, 75, and 100 mg.
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 50mg, 75mg, 100mg or oxycodone IR 15mg. 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 100mg=10%, oxycodone 15mg =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, 100mg=58%, 56.7%, 70.3%, oxycodone =72.8%, placebo = 30%, p=<0.001). Absolute risk reduction (ARR) was 40.3% for Tapentadol 100mg 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 15mg. Withdrawal due to adverse events was less with Tapentadol than oxycodone (NNH; Tapentadol 50, 75, 100mg = 39, 23.8, n/a, oxycodone = 100).
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 50mg, 75mg and oxycodone IR 10mg was compared to placebo. The sum pain intensity difference (SPID) at 48 hours and 5 days improved with tapentadol 50mg and 75mg and oxycodone 10mg 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 75mg doses and oxycodone. Tapentadol was non-inferior to oxycodone IR 15mg. In this 10 days study, tapentadol had a lower incidence of discontinuation due to adverse events than oxycodone (NNH tapentadol 50,75mg = 11.2, 6.9, oxycodone=3.6). The authors also state lower incidence of selected GI adverse events with tapentadol (p=<0.001).
A phase II single dose trial of tapentadol 25mg-200mg, ibuprofen 400mg and morphine IR 60mg 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 >75mg (p=<0.05). The time to perceptible (any noticeable relief) and clinically meaningful pain relief reported by patients was shorter for tapentadol 200mg and ibuprofen 400mg compared to morphine 60mg IR (time to perceptible, meaningful pain relief: tapentadol 200mg = 0.7 hours, 1.5 hours, morphine 60mg = 0.8 hours, 2.6 hours, ibuprofen 400mg = 0.8 hours, 1.5 hours). A minimum dose of 50mg 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, 200mg was 13, 5, 2, and 3. NNT for morphine 60mg and ibuprofen 400mg was 3 and 2. Ibuprofen appeared to work well compared to other medications in this model.
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.
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 very limited potential for abuse, dependency and addiction. The decision of the US DEA to place the drug into a Schedule II section is puzzling and appears to be overly cautious and poorly thought out, placing tapentadol into the same category of drugs of abuse such as Oxycontin and amphetamines. This will ultimately drive the costs up, place unnecessarily high scrutiny on the drugs utilization, decrease the drugs availability, inhibit physicians from prescribing it and ultimately will leave patients that could benefit from its effects shortchanged and their pain insufficiently treated. The DEA does not have a good track record of "down-grading" drugs it places into Schedule II into lower categories and the hopes of tapentadol becoming more widely available are dim. This will additionally significantly reduce the profitability of the drug to the parent manufacturing company. It is hoped that drugs from the same class will soon be reaching the wide market will avoid a similar unfortunate fate and will be ultimately much more useful both to clinicians and patients.
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.
Clinical studies cite there is less incidence of select adverse gastrointestinal effects tapentadol compared to oxycodone.
FDA approved package insert: Revised: 05/2009 by Ortho-McNeil-Janssen Pharmaceuticals, Inc.