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Mechanism Of Action Of Tapentadol- Understanding Its Analgesic Action

Mechanism Of Action Of Tapentadol- Understanding Its Analgesic Action


Tapentadol combines two mechanisms of action- μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Its dual mechanism of action makes it an effective treatment option for managing acute and chronic pain within 30 minutes of administration. 



Tapentadol is a potent opioid analgesic prescribed to manage moderate to severe pain. Its unique dual mechanism of action distinguishes it from traditional opioids. 

Understanding how Tapentadol works is crucial for both healthcare professionals and patients. This will help to optimize effective individual treatment regimens and ensure safety. 

This blog will delve into the detailed mechanism of action of Tapentadol, explaining how it relieves pain effectively while minimizing potential side effects and risks. Also, gaining insights on other factors, such as its pharmacokinetics and pharmacodynamics profile. 


Tapentadol- A Quick Insight

Tapentadol is a novel, centrally-acting medicine that was approved by the FDA in the USA in 2008. It belongs to the drug class of opioid analgesics. Tapentadol is a Schedule II controlled substance that has the potential for abuse and dependence.

Tapentadol is a synthetic analgesic that is available in two formulations- Immediate release (IR) tablets and Extended-release (ER) tablets. 

The trade names of Tapentadol include Aspadol, Nucynta, and Palexia. Tapentadol pills can be identified by their distinct orange color; hence, they are also known as orange pain pills.  Its recommended dosage strength is 100 mg; however, it is also available in 50 mg and 75 mg tablets. 



Purchase Guide-

This is to bring to your attention that generic Tapentadol tablets are not available on the market. People willing to get Tapentadol pain medication should either get Aspadol or Nucynta with a valid medical prescription.  



Tapentadol MOA (Mechanism Of Action)

The dual mechanism of action of Tapentadol allows it to be an effective treatment option for managing acute, chronic, and neuropathic body pain. 

Mu-Opioid Receptor Agonism

The action of Tapentadol functions by binding to the opioid receptors of the brain, similar to other pain-relieving medications. When these opioid receptors are activated, they help lower the pain sensation, thus providing relief. 

Norepinephrine Reuptake Inhibition 

The Tapentadol tablet works by inhibiting norepinephrine reuptake. This means that Tapentadol, in addition to providing effective pain relief, also affects the level of norepinephrine by blocking its reuptake. Thus, it potentially contributes to the analgesic’s pain-relieving effects and improves mood and stress responses.


Pharmacokinetics And Pharmacodynamics Of Tapentadol

Pharmacokinetics refers to the movement of drugs through the body after their administration. Whereas pharmacodynamics is the biological response of the body to the drug taken. 

The pharmacokinetic and pharmacodynamics profile of Tapentadol is discussed below-

  • Onset of Action- It takes about 30 minutes for Tapentadol to start working.

  • Absorption- It is rapidly absorbed in the body after administration. A steady plasma concentration is achieved in 25 to 30 hours when the medication is taken every 6 hours [1]. 

  • Metabolism- Tapentadol is metabolized in the liver to form inactive metabolites. The major metabolite of Tapentadol is tapentadol-O-glucuronide. 

  • Elimination- It follows first-order elimination kinetics, meaning a constant proportion of the medicine is eliminated per unit of time. The elimination of Tapentadol takes place in the kidneys and is mainly done via urine.  


Half-Life Of Tapentadol

The half-life determines the time needed by the body to reduce or eliminate the active compound of the medication to half the total amount administered. It depends on how the body processes and eliminates the medication and thus can vary from a few hours to a few days. 

The half-life of Tapentadol is 3.93 hours for its immediate-release formula, whereas, for its extended-release formula, it is 4.4 to 5.9 hours [2].

The half-life of the medication determines the following factors-

  • Dosage Gap

  • Elimination time of the medication. 

Based on the half-life, the elimination time of Tapentadol IR and ER is listed down below. 


Rate of Elimination

Tapentadol IR Elimination Time

Tapentadol ER (Calculated for the max half-life- 5.9 hours)


0.00 hrs

0.00 hrs


3.39 hrs

5.90 hrs


6.78 hrs

11.80 hrs


10.17 hrs

17.70 hrs


13.56 hrs

23.60 hrs


16.95 hrs

1.23 days


Based on the above calculations, it takes about 20 to 24 hours to eliminate Tapentadol IR and 1 and a half days to eliminate Tapentadol ER from the system [3]. 


Synergistic Tapentadol Mechanisms Of Action


Synergistic Tapentadol Mechanisms Of Action


The synergistic interaction between the working mechanism of Tapentadol was studied in 2011 by W. Schröder et al. The study tested Tapentadol alone and with the presence of an antagonist (a substance that stops the action or effect of another substance) [4]. 

  • Naloxone- It is the opioid antagonist that inhibits the action of the Mu-Opioid Receptor. 

  • Yohimbine- It is the adrenergic antagonist that acts as an antagonist for the Norepinephrine Reuptake Inhibition. 

The study suggests that the agonist weakens the activity of the pain medication, thus indicating that both the working mechanism of Tapentadol plays a key role in contributing to pain relief. This also reveals a synergistic activity between the two mechanisms of action of this opioid pain medicine.  


Clinical Tapentadol Use

The FDA approves the use of Tapentadol in the USA for treating acute and chronic body pain. 

The key benefits of Tapentadol include-

  • Tapentadol is a weak inhibitor of serotonin reuptake, so there have been fewer cases of vomiting and nausea. 

  • Tapentadol has a high tolerability. 

  • It has a much better safety profile.  

  • Tapentadol causes fewer gastrointestinal (digestive system) side effects than other opioid pain medications [5]. 



The pharmacological profile of Tapentadol suggests that it synergistically combines both MOR agonism and NRI in one molecule, thus making Tapentadol a new class of centrally acting analgesic (MOR-NRI). 

It works within 30 minutes of intake and is a safe treatment option for managing moderate to severe chronic body pain.


It works by targeting the opioid receptors in the central nervous system, thus helping reduce body pain.

Tapentadol, along with its brand drugs Aspadol and Nucynta, belongs to opiate (narcotic) analgesics.

Tapentadol is metabolized in the liver to form tapentadol-O-glucuronide by the enzymes CYP2C9, CYP2C19, and CYP2D6.

Tapentadol takes about 30 minutes to start acting.

The action of Tapentadol IR lasts for 4 to 6 hours, whereas the extended-release formula (Tapentadol ER) lasts for 12 hours.


  1. Tapentadol hydrochloride: A novel analgesic, NCBI. 

  2. Pharmacokinetic evaluation of tapentadol extended-release tablets in healthy subjects, PubMed. 

  3. Drug Half-life Explained, drugs. 

  4. Synergistic Interaction between the Two Mechanisms of Action of Tapentadol in Analgesia, aspetjournals. 

  5. Tapentadol for pain: a treatment evaluation, tandfonline.