|Systematic (IUPAC) name|
|Trade names||Nucynta, Palexia|
|Bioavailability||31.9 ± 6.8% (oral)|
|Metabolism||Hepatic (mostly via glucuronidation but also by CYP2C9, CYP2C19, CYP2D6)|
|Excretion||Urine (73%) and faeces|
|Mol. mass||221.339 g/mol|
|(what is this?)|
Tapentadol (brand names: Nucynta, Palexia, in India available as TAPAL by MSN Labs) is a centrally acting analgesic with a dual mode of action as an agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor. Its analgesic properties come into effect within thirty-two minutes of oral administration.
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. Unlike tramadol, it has only weak effects on the reuptake of serotonin, is a significantly more potent opioid and has no known active metabolites. Its general potency is somewhere between that of tramadol and morphine. Tapentadol's most recent potency evaluation equates 17mg of oral tapentadol to 10mg of oral morphine (1mg of I.V. morphine) and 10mg of oral oxycodone, giving the 50mg dose the relative potency of 30mg of oral morphine/oxycodone.
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, as well as extended release oral tablets of 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg under the brand name Nucynta ER.
Dosage for Nucynta immediate-release is initiated with 50-100 mg every 4 to 6 hours to a maximum of 700 mg on the first day of therapy. Thereafter the maximum recommended dose is 600 mg per day. Higher doses have not been clinically studied. Nucynta ER in non-tolerant patients is initiated at 50 mg twice daily (approximately every 12 hours). The maximum recommended daily dose for Nucynta ER is 500 mg.
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 23 January 2008, a New Drug Application (NDA) for tapentadol was submitted to the U.S. FDA.
- On 21 November 2008, Johnson & Johnson announced that it has received approval for immediate-release tapentadol tablets.
- On 17 February 2009 the U.S. 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 Administration approved the proposal to make tapentadol schedule II under the Controlled Substance Act. Tapentadol has a DEA Administrative Controlled Substances Control Number of 9780. As a Schedule II controlled substance, an annual aggregrate manufacturing quota is imposed by the DEA; in recent years it has held constant at 13 750 kilos. The aggregate manufacturing quota for 2014 has increased to 17,500 Kilos.
- 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 29 August 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.
The efficacy of tapentadol compared to a placebo was demonstrated in two phase III (and one phase II) randomized, double-blind, multi-center, placebo-controlled clinical trials submitted to the United States Food and Drug Administration. The phase III trials evaluated tapentadol multiple dosing following orthopedic surgery and in late-stage osteoarthritis (OA). The phase II study evaluated single dosing of tapentadol following a dental procedure. All trials utilized a zero-to-ten-point scale for pain intensity (none to worst) and a zero-to-five-point scale for pain relief (none to complete). Patients were assessed at intervals; 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 clinically relevant endpoints. These published phase II and phase III studies used active control medications, including oxycodone, morphine or NSAIDs.
Tapentadol demonstrated efficacy compared with a placebo in a phase III, three-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 every four to six hours. The sum of pain intensity difference (SPID) over the first 48 hours of study medication improved with all tapentadol strengths and oxycodone, compared with a placebo (p=<0.001). The percentage of patients requiring rescue medication was less for tapentadol and oxycodone, compared with a placebo (tapentadol 100 mg 10 percent, oxycodone 15 mg 9 percent, placebo 49 percent). The time to the first dose of rescue medication required was reduced with all strengths of tapentadol and oxycodone compared with a placebo (p=<0.001, no data given). Overall, more patients experienced at least a 50-percent improvement in pain from baseline levels with tapentadol and oxycodone compared with placebo (tapentadol 50, 75, 100 mg 58 percent, 56.7 percent, 70.3 percent, oxycodone 72.8 percent, placebo 30 percent, p=<0.001). Absolute risk reduction (ARR) was 40.3 percent for Tapentadol 100 mg and 42.8 percent for oxycodone. The number needed to treat (NNT) for 50-percent 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).
Tapentadol was effective in a phase III, 10-day, multiple-dosing assessment of patients awaiting knee-replacement surgery from late-stage OA. All patients were at a level of pain indicating opioid analgesics. Tapentadol 50 mg, 75 mg and oxycodone IR 10 mg was compared to a placebo. The SPID at 48 hours and 5 days improved with tapentadol 50 and 75 mg and oxycodone 10 mg compared to placebo (p=<0.001). More patients experienced at least a 50-percent improvement in pain from baseline with tapentadol and oxycodone compared to placebo (tapentadol=27, 26, oxycodone=25 percent, placebo=13 percent, p=<0.01). The number of doses needed (NNT) for 50-percent 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-day 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 reported a lower incidence of selected gastrointestinal adverse events with tapentadol (p=<0.001).
A phase II, single-dose trial of tapentadol 25 mg-200 mg, ibuprofen 400 mg and morphine IR 60 mg was evaluated for post-surgical dental pain. This patient population was younger than in the previous two studies (18–45 years old, mean age 23). The SPID at four and eight hours improved from baseline compared to placebo with doses of tapentadol that were>75 mg (p=<0.05). The time to noticeable, 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-percent reduction in pain from baseline. More patients reported a 50-percent 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, compared with an NNT for morphine 60 mg and ibuprofen 400 mg of 3 and 2, respectively. Ibuprofen appeared to work well compared to other medications in this model.
Non-published studies 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 the recall of a rescue medication, impacting the study's timeline). Results of these studies are not available. Studies recruiting subjects include tapentadol, morphine and placebo in chronic tumor-related pain and tapentadol, oxycodone and placebo in post-operative shoulder-surgery and vertebral compression-fracture pain. There have been no listed clinical trials involving tramadol or NSAIDs.
Tapentadol is indicated 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. Although tapentadol is not indicated for the treatment of non-diabetic neuropathic pain, it is often used off-label for this purpose. It also has the potential to treat depression like its close relative, tramadol, but it is not approved for this indication either.
Availability and dosage
Tapentadol is available in the United States in both immediate release and extended release formulations as Nucynta and Nucynta ER, respectively, from Janssen Pharmaceuticals. The immediate release formulation is provided in 50 mg (yellow), 75 mg (orange), and 100 mg (red/orange) tablets, to be used once every 4–6 hours as needed to control pain, up to a maximum dose of 600 mg per 24 hour period (700 mg on day one). The extended release formulation is provided in 50 mg (white), 100 mg (very light blue), 150 mg (light blue), 200 mg (blue), and 250 mg (dark blue). The extended release dosage starts at 50 mg twice a day, and is then slowly titrated to an effective and tolerable dose in the range of 100 mg-250 mg twice a day, with a maximum dose of 500 mg (250 mg twice a day) per 24 hour period. The dosage and preparation used should be frequently re-evaluated by the prescribing physician, and the dose should be lowered if possible to the lowest effective dose if pain decreases.
All preparations of Nucynta contain only the (R,R) stereoisomer, which is the weakest isomer in terms of opioid activity. (See "Tramadol" for more information on tapentadol's chemistry).
The safety and effectiveness of NUCYNTA® has not been established in patients with severe renal impairment (CLCR <30 mL/min). Use of NUCYNTA® in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.
In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), initiate NUCYNTA® at 50 mg no more frequently than once every 8 hours (maximum of 3 doses in 24 hours). Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or lengthening the dosing interval. Use of NUCYNTA® is not recommended in severe hepatic impairment (Child-Pugh Score 10 to 15).
In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses.
Safety and efficacy in pediatric patients younger than 18 years of age have not been established; therefore, use in this population is not recommended.
NUCYNTA® is Pregnancy Category C and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies of NUCYNTA® in pregnant women NUCYNTA® is not recommended for use in women during and immediately prior to labor and delivery. Because of the potential for adverse reactions in nursing infants from NUCYNTA®, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
As it is not currently available in generic form, Nucynta will cost the patient several hundred dollars per monthly supply without insurance ($2.96-$8.98 per pill). Nucynta is included in the formularies of most major insurance companies, although it is often a non-preferred drug so the cost to the patient tends to still be fairly high. To make Nucynta more competitive, Janssen Pharmaceuticals offers a Nucynta savings card to patients with valid health insurance (with the exception of medicare, medicaid, and other federally sponsored insurance plans) which enables them to pay no more than $25 per month for any preparation (up to 14 times per year for ER preparations, not to exceed 12 times per year for the same dosage, and up to 3 times per year for IR preparations).
Mechanism of action
Although the manufacturer currently lists Nucynta's mechanism of action as unknown, they state that it is most likely (as it is generally accepted to be) a combination of an agonistic effect at the mu-opioid receptor and the inhibition of norepinephrine re-uptake. Tapentadol has also been demonstrated to be sigma-2 receptor agonist, although whether or not sigma activity contributes to tapentadols analgesic effect is still a matter of contention and the function of the sigma-2 receptor has not yet been conclusively determined.
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.
Tapentadol may impair physical and cognitive abilities and should not be used when operating heavy machinery, especially during initial treatment and following increases in dosage. Patients should not attempt to operate any vehicle until they know how tapentadol affects them.
The regular use of Nucynta will generally result in dependence and can lead to addiction, producing unpleasant withdrawal symptoms when the dependent person attempts to abruptly discontinue use of the drug. Withdrawal may also be elicited in Nucynta users if they are administered an opioid antagonist such as naloxone, or mixed opioid agonist/antagonists such as buprenorphine.
Clinical studies cite there is less incidence of select adverse gastrointestinal effects with the administration of tapentadol when compared to oxycodone.
Combination with alcohol increases the risk for many of tapentadols side effects, including dizziness, somnolence, impaired motor skills and respiratory depression. Combination with alcohol also increases the Cmax of Nucynta ER® (250mg) by 48%. This indicates a greater risk of respiratory depression than the sum totals of both substances effects on respiration.
As with alcohol, the concomitant use of tapentadol with other sedatives such as benzodiazepines, barbiturates, nonbenzodiazepines, phenothiazines, and other opiates may result in increased impairment, sedation, respiratory depression, and death. This is a concern even when other sedatives are legitimately prescribed along with tapentadol, close clinical monitoring is necessary in such situation (especially following increases in either substances dosage) and patients should be advised of the risks of sedative combinations.
Tapentadol is partially metabolized by the hepatic enzymes CYP2C9, CYP2C19, and CYP2D6. Administering tapentadol along with other drugs which are metabolized by these enzymes, or drugs which inhibit these enzymes, may slow its metabolism, increasing its duration of effects and peak plasma concentration. Patients who are using such drugs should initiate tapentadol at the lowest possible dose and must be closely monitored for signs of overdose for at least two weeks following the initiation of tapentadol therapy and any increase in dose as accumulation can occur slowly over an extended period of time before presenting with overdose symptoms. Patients should be instructed to seek emergency medical treatment at the first signs of overdose and their tapentadol dose should be lowered upon presentation of symptoms. In some patients using multiple drugs, tapentadol therapy may not be feasible even at the lowest possible dose and an alternative analgesic agent should be initiated instead.
Patients using drugs which enhance the activity of the hepatic enzymes CYP2C9, CYP2C19, and CYP2D6 may not respond well to tapentadol therapy due to a reduction of tapentadols half-life and peak plasma concentration. Such patients may require higher doses of tapentadol than they would otherwise, and tapentadol therapy may not be feasible in these patients. If such patients do not respond to the maximum dose of tapentadol (600mg of the IR preparation or 500mg of the ER preparation per day) their tapentadol dose should not be increased further, they should instead discontinue tapentadol therapy and an alternative analgesic agent should be selected.
The absorption of tapentadol is not significantly impacted by the presence or absence of food in the stomach, patients may take tapentadol on either a full or empty stomach without reducing its effect or altering its course of distribution. Some patients may find that tapentadol is better tolerated when taken on either a full or empty stomach and are advised to take it in whichever way is more comfortable to them, but should be reminded that many medications are affected by the amount of food in the stomach and they should administer tapentadol accordingly. Patients should be discouraged from skipping meals in order to administer tapentadol, and may be alternatively instructed to adjust their eating schedule to correspond with their use of medications.
Tapentadol may increase the risk of seizures, and should be administered with care to epileptic patients and patients who are taking other drugs which lower the seizure threshold.
Since tapentadol may increase intracranial pressure by depressing respiration and increasing CO2 retention, it should not be administered to patients suffering from head injuries, brain tumors, or other conditions which increase intracranial pressure.
Tapentadol is contraindicated in patients with severe bronchial asthma, hypercapnia, and patients who have or are suspected to have paralytic ileus, due to the increased risk of respiratory depression.
Due to reduced clearance, tapentadol should be administered with caution to patients with moderate hepatic impairment (with reduced dosage), and not at all in patients with severe hepatic impairment.
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.
No human control studies have been conducted regarding the safety of tapentadol during pregnancy, although animal studies have suggested that it poses a risk of emryofetal toxicity. As such, the U.S. Food and Drug Administration (FDA) has placed it into pregnancy category C. Women should avoid taking tapentadol during pregnancy unless the benefit outweighs the risk to the fetus.
Patients who have reduced or absent CYP2C9, CYP2C19, and CYP2D6 enzyme activity should be monitored in the same manner as patients using other drugs which are metabolized by, or inhibit, these enzymes. In some such patients tapentadol therapy may not be feasible even at the lowest available dose, in this event the patient should discontinue tapentadol therapy and an alternative analgesic agent should be selected.
Patients who are rapid or ultra rapid metabolizers for the CYP2C9, CYP2C19, and CYP2D6 enzymes may not respond to tapentadol therapy, even at the maximum recommended daily dose (600mg for the IR preparation, and 500mg for the ER preparation). In such patients, the total daily tapentadol dose should not be increased beyond the maximum recommended daily dose, instead the patients should be instructed to discontinue tapentadol therapy and an alternative analgesic agent should be selected. The use of an adjunctive analgesic agent may be initiated instead but patients in this course of treatment must be closely monitored for interactions and signs of overdose for at least two weeks following the initiation of the second agent and any increase of its dose.
From Janssen Pharmaceuticals, Inc: "NUCYNTA is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty. NUCYNTA can be abused in a manner similar to other mu-opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. All patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction. NUCYNTA may be abused by crushing, chewing, snorting or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death." Patients with a history of drug or alcohol abuse are believed to have a higher risk of abusing NUCYNTA, as with other mu-opioid agonists.
Although early pre-clinical animal trials suggested that Nucynta has a reduced abuse liability compared to other opioid analgesics, it has since been determined to be no less abusable than other pure-form opioid preparations. The US DEA has placed tapentadol into Schedule II, the same category as the most powerful and frequently abused narcotics, such as morphine, oxycodone, and fentanyl.
According the World Health Organization there is little evidence to judge the abuse potential of Tapentadol. It is likely that the DEA placed it in schedule II with its politically motivated, newer heavy handed policy towards anything to do with opiate based pain killers. Despite this, doctors are advised to frequently monitor patients for signs of tapentadol abuse, particularly patients who have a history of drug abuse or are believed to be at an increased risk of drug abuse due to other factors.
Experience with Tapentadol overdose is very limited. Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to reestablishment of a patent airway and institution of assisted or controlled ventilation when overdose of Tapentadol is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
Due to its actions on norepinephrine, and to a lesser extent serotonin, a Tapentadol overdose may produce symptoms which are not typically present in opioid overdoses (symptoms of serotonin syndrome and adrenergic syndrome). This risk is greater if Tapentadol has been taken with other drugs of similar mechanisms. These additional symptoms should be addressed and treated symptomatically (after treating for mu-opioid agonism) if they are presented and must be taken into consideration prior to the administration of any medication. It may be necessary to treat the patients convulsions first in order to safely achieve intubation.
Tapentadol overdose is more likely to occur when it is combined with alcohol or other drugs. Alcohol administration has been demonstrated to increase the plasma levels of Tapentadol, thereby increasing the effect of the Tapentadol as well as acting synergistically with the depressant effects of alcohol. The concomitant use of Tapentadol and other depressants (including alcohol) significantly increases the risks of somnolence, hypotension, coma, and (potentially fatal) respiratory depression.
The risk of tapentadol overdose is also increased in patients who are taking other medications which are metabolized by, or inhibitors of, the CYP2C9, CYP2C19, and CYP2D6 enzymes as well as patients who have a reduced or absent activity of these enzymes.
Any accidental ingestion of tapentadol by a person or persons other than for whom it was prescribed is considered an emergency and medical treatment should be sought immediately before the presentation of overdose symptoms as overdoses may be fatal. The danger of death from accidental ingestion of tapentadol is greater in young children, the elderly, persons with acute or long term illnesses, persons under the influence of any other prescription or recreational drugs including alcohol, and persons who have consumed high dose tablets or multiple tablets of any dose, although any accidental consumption of tapentadol has the potential to result in death. Prompt medical attention is always necessary as the progression of overdose symptoms is often very rapid following initial symptoms and it may not be possible to receive medical treatment in time to prevent death once initial symptoms of overdose have presented.
- 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.
- Brayfield, A, ed. (14 November 2011). "Tapentadol". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 2 April 2014.
- 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.
- Raffa, RB; Buschmann, H; Christoph, T; Eichenbaum, G; Englberger, W; Flores, CM; Hertrampf, T; Kögel, B; Schiene, K; Straßburger, W; Terlinden, R; Tzschentke, TM (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.
- 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.
- Gandey, A (26 August 2011). "FDA Approves Tapentadol for Chronic Pain". Medscape Medical News. WebMD. Retrieved 2 April 2014.
- "Palexia film coated tablets". electronic Medicines Compendium. Grunenthal Ltd. 13 November 2013. Retrieved 2 April 2014.
- "PALEXIA® SR PRODUCT INFORMATION" (PDF). TGA eBusiness Services. CSL Limited. 26 June 2013. Retrieved 2 April 2014.
- 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.
- FDA Approves Tapentadol Immediate-Release Tablets for Relief of Moderate to Severe Acute Pain November 21, 2008. Retrieved on November 24, 2008.
- Proposed Rule - Schedules of Controlled Substances: Placement of Tapentadol Into Schedule II (February 17, 2009)
- Misuse of Drugs Act 1971 (Amendment) Order 2011
- "FDA Approves Nucynta ER (tapentadol) Extended-Release Oral Tablets for the Management of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy".
- Daniels, S.; Upmalis, D.; Okamoto, A.; Lange, C.; Haeussler, J. (2009). "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 25 (3): 765–76. doi:10.1185/03007990902728183. PMID 19203298.
- Hartrick, C.; van Hove, I.; Stegmann, J.-U.; Oh, C.; Upmalis, D. (2009). "Efficacy and Tolerability of Tapentadol Immediate Release and Oxycodone HCl Immediate Release in Patients Awaiting Primary Joint Replacement Surgery for End-Stage Joint Disease: A 10-Day, Phase III, Randomized, Double-Blind, Active and Placebo Controlled Study". Clinical Therapeutics 31 (2): 260–71. doi:10.1016/j.clinthera.2009.02.009. PMID 19302899.
- Kleinert, R.; Lange, C.; Steup, A.; Black, P.; Goldberg, J.; Dejardins, P. (2008). "Single Dose Analgesic Efficacy of Tapentadol in Postsurgical Dental Pain: The Results of a Randomized, Double-Blind, Placebo-Controlled Study". Anesthesia and Analgesia 107 (6): 2048–55. doi:10.1213/ane.0b013e31818881ca. PMID 19020157.
- Fidman, B; Nogid, A (2010). "NCBI Nucynta". Pharmacy and Therapeutics 35 (6): 330–357. PMC 2888545.
- "Nucynta.com D&A".
- "Nucynta.com D&A".
- Mary G. McMasters, MD, FASAM. "Universal Precautions for Prescribing Controlled Substances".
- Expert Committee on Drug Dependence. "Tapentadol Pre-Review Report".
- "DOSING NUCYNTA® IN SPECIFIC POPULATIONS".
- "Progressive Friday Fast Facts".
- "Nucynta Savings Card".
- "Nucynta.com-Mechanism of Action".
- Vlessides, M. (September 2006). "Two New Analgesics May Help Patients After Bunionectomy". Anesthesiology News 32 (9). ID 5326.
- "Nucynta". Nucynta.com. Retrieved 2012-12-08.
- "rxlist.com". rxlist.com. 2012.
- "Nucynta vs Morphine Sulfate, a side effect and efficacy comparison for a male patient aged 38".
- "Nucynta Related Hallucination".
- 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.
- "NUCYNTA ER (tapentadol hydrochloride) tablet, film coated, extended release [Janssen Pharmaceuticals, Inc.]".
- "Nucynta". Nucynta.com.
- "Tapentadol Pregnancy and Breastfeeing Warnings".
- 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.
- "DEA Diversion Control - Controlled Substances Schedules". US Federal Government. Retrieved 2012-05-16.
- "Nucynta - Abuse Potential Section". Nucynta.com. Retrieved 2012-05-16.
- . Wolrd Health Organization http://www.who.int/medicines/areas/quality_safety/5.2ExpertreviewTapentadolpre-review.pdf. Retrieved 16 March 2014. Missing or empty
- Merigian KS, Blaho K. "Diagnosis and management of the drug overdose patient.". PMID 10423599.
- "FDA Approves Nucynta ER (tapentadol) Extended-Release Oral Tablets for the Management of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy".
- PR Newswire: Phase II Data Show Efficacy and Tolerability of Tapentadol
- Nucynta dosing guide
- Nucynta dosing guide - special populations