True facts: Is Tapentadol a glorified Tramadol?

In 1995, a chemical entity was released by Janssen pharmaceutical which is known as Tramadol (Ultram). Again in 2009, a similar entity was released by Janssen called Tapentadol (Nucynta). Tapentadol was released as a schedule II analgesic which was the first new opioid entity with controlled substance status. It was approved by the Food and Drug Administration (FDA) in several decades. In 2014, Tramadol was officially changed from a schedule V to a schedule IV drug by the Drug Enforcement Administration (DEA).

Tramadol

Tramadol is a centrally acting analgesic used to treat moderate to severe pain. It acts as both a reuptake inhibitor of the serotonin and monoamines norepinephrine and as a weak opioid agonist effect. Tramadol has mainly 2 chiral centres with a 1:1 racemic mixture of 2 diastereomeric enantiomers. The recommended total daily dosage of Tramadol is 25 to 100 mg whereas, for adults, the maximum daily dose is 400 mg. For patients with impaired renal function, dosage adjustment is necessary. There has been a controversy over the use of Tramadol during breastfeeding an infant. So, there is a necessity to closely observe for any signs of respiratory distress, feeding or lethargy in any mother who is taking opioid- based medications including Tramadol. There has been evidence where Tramadol is used in a variety of conditions which include neuropathic pain, cancer pain and osteoarthritis.

Tapentadol

Tapentadol is a unique, novel analgesic and centrally acting mu- opioid agonist of the aromatic hydrocarbon benzenoid class. It is a non-racemic molecule and not a prodrug unlike Tramadol. Its analgesic effect is produced through norepinephrine reuptake inhibition and moderate opioid receptor agonism. It has been shown by clinical trials that the analgesic potency of Tapentadol is very good and has also been seen that 50mg of Tapentadol has an analgesia which is equivalent to 10mg of oxycodone. Tapentadol is mostly available in the form of 25, 50, 75, and 100mg tablets. The recommended maximum Tapentadol dose for an adult is 600 to 700 mg daily. Tapentadol is not recommended in severe hepatic impairment but it can be used with caution in moderate hepatic impairment. Its analgesic benefit has been clinically demonstrated in orthopedic and cardiac surgery as well as in cancer related pain and chronic low back pain.

Tramadol and Tapentadol are both phenylpropylamines. Both the compounds differ in their mu binding affinity though are mu opioid receptors agonists. Tramadol is pharmacologically a ‘partial agonist’ whose mu binding affinity is 6000 times less than that of morphine. Tapentadol, in contrast, is a full mu agonist which has a binding affinity 18 times less than that of morphine and it is only 2- to 3- times less potent than morphine. It is probably because of its dual mechanism i.e. mu receptor agonist and norepinephrine reuptake inhibitor.

Both Tapentadol and Tramadol have been shown to have analgesic properties separate from opiate activity, but they inhibit the reuptake of norepinephrine from the synaptic cleft. There is no doubt that Tapentadol is far from a ‘glorified Tramadol’.

Tapentadol’s Metabolism

Basically, Tapentadol is metabolized hepatically by Phase 2 pathways which is primary conjugated with glucuronic acid to form glucuronides and by an oxidative pathway of minor Phase 1 through cytochrome P (CYP) 2C19 (13%) and CYP2D6 (2%) enzymes. Tapentadol is excreted through the kidneys and its terminal half-life is approximately 4.25 hours. Tapentadol, therefore, possesses less risk of drug-drug and cytochrome P450 interactions and has no active metabolites.

In contrast to Tapentadol, Tramadol is metabolized by CYP2D6 and CYP3A4 to which 2D6 produce the O- demethylated metabolite (M1) which has more analgesic properties than Tramadol itself but surprisingly, it doesn’t impact the pain relief. Even though M1 is a more important analgesic than Tramadol, the metabolite faces more difficulty passing into the central nervous system (CNS). The dose of Tramadol and the M1 metabolite is increased additionally. The ratio of Tramadol to M1 entering the CNS is increased which means that more of the weaker parent compound binds to the mu receptors.

If a patient is taking 2D6 inhibitors or is classified as a ‘poor’ metabolizer of 2D6, it can lead to decrease in analgesia and metabolism i.e. 40% decreased M1 compared with ‘extensive’ metabolizers and 20% higher blood concentration. Most common 2D6 inhibitors include doxepin, citalopram, sertraline, fluoxetine.

The average mean half-life for the M1 metabolite is 7.4 hours whereas the mean half-life of Tramadol is approximately 6 hours. Tramadol is metabolized by the liver while M1 is excreted by the kidneys. When compared with extensive metabolizers, ultra- rapid metabolizers are successful in converting Tramadol into M1 more quickly; capitulating improved analgesia but it can also cause toxicity at lower doses. Though the binding affinity of the M1 is greater than the parent compound Tramadol and that of Tapentadol, the actual effect of M1 on mu opioid receptors is more or less the same as that of Tapentadol. In comparison to Tapentadol, the parent drug Tramadol has 2 to 5 times less potency and has no activity by itself, across various animal pain models.

Serotonin syndrome

When there is a buildup of serotonin in the central and peripheral nervous systems, serotonin syndrome therefore occurs. The buildup in serotonin can be the result of the combination of the following: decreased serotonin metabolism, increased serotonin synthesis or release or reuptake. Certain symptoms of serotonin syndrome include altered mental status, seizures, autonomic hyperactivity and neuromuscular hyperactivity. Tramadol inhibits serotonin reuptake three times more than Tapentadol, though both of them inhibit reuptake of norepinephrine to the same degree. Generally, Tramadol-seizures appear to be generalized tonic-clonic seizures which occur within 24 hours of medication ingestion. These seizures have mostly occurred in patients who ingest alcohol, antipsychotics, antidepressant medications or illicit drugs. Patients with epilepsy or who have suffered head trauma tend to have frequent seizures while taking Tramadol at the recommended daily dose. Countries such as Iran, are seeing a higher incidence of the abuse of Tramadol which results in more opioid side effects and seizures.

Key points

Both of these medicines are considered opioid agonists but significantly, Tramadol is weaker than Tapentadol.

For the above reasons, Tapentadol should be associated with the lower incidence of superior analgesia and serotonin- related toxicities.