175591-09-0

Agonism of the MOR is a common strategy for moderate to severe pain intervention. Opioid drugs, such as morphine, that modulate this receptor have demonstrated efficacy in acute situations; however, chronic conditions, particularly those of neuropathic or inflammatory etiology, suffer from inadequate pain management with this treatment. With a narrow therapeutic window, traditional MOR agonists flirt with side effects at optimal analgesia, and prolonged use increases the potential for physical dependency. Since extensive efforts to design activators of MOR have failed to dissociate the undesirable adverse effects from the analgesic properties, the focus has been on enhancing the analgesic efficacy through a dual mechanism of action. Tapentadol hydrochloride brings this concept to fruition; MOR agonism is coupled with noradrenaline reuptake inhibition in a combinatory contribution to analgesia. Compared to morphine, it is about 50-fold less potent for MOR (K_i = 100 nM for tapentadol versus 2 nM for morphine). The K_i for inhibition of noradrenaline reuptake was 500 nM while reuptake of serotonin was only weakly inhibited (K_i = 2.5μM). Despite its lower affinity for MOR, the dual mechanism has provided an efficacious profile in both acute and chronic conditions with fewer side effects.

Light Brown Solid

Grunenthal GmbH (Germany)

A novel, centrally acting oral analgesic with a dual mode of action that has demonstrated efficacy in preclinical and clinical models of pain relief.

Nucynta

Tapentadol was approved by the FDA in November 2008 for the treatment of moderate to severe acute pain. It is a centrally acting analgesic that acts as both an agonist at the l-opiod receptor and as a norepinephrine re-uptake inhibitor, allowing it to have efficacy similar to potent narcotic analgesics but without their side effects. The drug was developed by Grunenthal and Johnson & Johnson and was marketed starting in 2009.

The common adverse effects of tapentadol were nausea, vomiting, somnolence, dizziness, and itching. As with all opioid medications, constipation was also an issue. Tapentadol is contraindicated in patients taking monoamine oxidase inhibitors because of the potential for adverse cardiovascular events due to additive effects on norepinephrine levels. As with other MOR agonists, it is also contraindicated in patients with paralytic ileus. In patients with a history of epilepsy or seizure, tapentadol may induce seizures. Since tapentadol causes somnolence, its combination with other sleep aids could dangerously affect breathing. Similarly, patients with existing breathing or lung problems are cautioned about using tapentadol. Furthermore, patients with past or present substance abuse or drug addiction should consult the doctor prior to use since physical dependency and addiction is a risk with tapentadol. Alcohol should be avoided due to the potential additive effect on CNS depression.

The synthesis of tapentadol hydrochloride begins with diethyl ketone, which is subjected to a standard Mannich condition to provide a b-dimethylamino intermediate. A Grignard reaction with 3-bromoanisole was followed by the separation of diastereomers and racemic resolution. Treatment with thionyl chloride converts the hydroxy group to its corresponding chloride, which is removed by treatment with zinc borohydride (generated from zinc chloride and sodium borohydride), with overall retention of stereochemistry. The methyl ether is cleaved in refluxing HBr to afford the tapentadol salt that is ultimately converted to the hydrochloride for formulation into 50-, 75-, and 100-mg immediate-release (IR) oral tablets.

Potentially hazardous interactions with other drugs Analgesics: possible opioid withdrawal with buprenorphine and pentazocine.
Antidepressants: possible CNS excitation or depression with MAOIs - avoid concomitant use, and for 2 weeks after stopping MAOI; possible CNS excitation or depression with moclobemide; increased sedative effects with tricyclics.
Antihistamines: increased sedative effects with sedating antihistamines.
Antipsychotics: enhanced hypotensive and sedative effects.
Dopaminergics: avoid with selegiline.
Nalmefene: avoid concomitant use.
Sodium oxybate: enhanced effect of sodium oxybate - avoid concomitant use.

Approximately 97% of the parent compound is metabolised by conjugation with glucuronic acid to produce glucuronides. It is also metabolised, to a lesser extent, via the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and CYP2D6, before further conjugation.
None of the metabolites have analgesic activity.
Approximately 70% of the dose is excreted in the urine in the conjugated form and 3% as unchanged drug.