Tapentadol
Encyclopedia
Tapentadol is a centrally acting analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 with a dual mode of action as an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

 at the μ-opioid receptor
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...

 and as a norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...

. While its analgesic actions have been compared to tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...

 and oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

, its general potency
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...

 is somewhere between tramadol and morphine in effectiveness. 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
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...

 and diabetic neuropathy. One selective serotonin and norepinephrine reuptake inhibitor (SNRI) often used as an adjunct, atypical & potentiator is duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...

 (Cymbalta). Another opioid with selective norepinephrine reuptake inhibitor effects is levorphanol
Levorphanol
Levorphanol is an opioid medication used to treat severe pain. It is the levorotatory stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic...

 (Levo-Dromoran).

Its dual mode of action provides analgesia at similar levels of more potent narcotic analgesics such as hydrocodone
Hydrocodone
Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...

, oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

, and pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...

 (meperidine) with a more tolerable side effect profile.

History

Tapentadol was developed by Grünenthal
Grünenthal
Grünenthal GmbH is a German pharmaceutical company in Stolberg near Aachen, which holds the patent to Ultram , and its much stronger derivative Nucynta , both used as analgesics with Norepinephrine Reuptake Inhibition...

 in conjunction with Johnson & Johnson Pharmaceutical Research and Development
Johnson & Johnson Pharmaceutical Research and Development
Johnson & Johnson Pharmaceutical Research and Development is a subsidiary of Johnson & Johnson that is responsible for discovering and developing pharmaceutical drugs...

. 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. 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 23 January 2008, a New Drug Application (NDA) for tapentadol was submitted to the United States
    United States
    The United States of America is a federal constitutional republic comprising fifty states and a federal district...

     Food and Drug Administration
    Food and Drug Administration
    The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

    .

  • On 17 February 2009 the Drug Enforcement Administration proposed a rule which would add tapentadol to Schedule II of the Controlled Substances Act
    Controlled Substances Act
    The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...

     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 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
    United Kingdom
    The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

     made tapentadol a Class A controlled drug
    Misuse of Drugs Act 1971
    The Misuse of Drugs Act 1971 is an Act of Parliament which represents UK action in line with treaty commitments under the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic...

    .

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).

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).

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.

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, the same category as the most powerful and frequently abused narcotics, such as morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...

, oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

 and fentanyl, could therefore be seen as overly cautious. 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
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

.

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
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

 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
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...

.

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

May cause hallucinations to patients on anti-depressants.

External links

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