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Is Tapentadol a Glorified Tramadol?

Ask The Expert from January/February 2016
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In 1995, Janssen Pharmaceutical released a chemical entity known as tramadol (Ultram). In 2009, Janssen released a similar entity, tapentadol (Nucynta), as a Schedule II analgesic that was the first new opioid entity with controlled substance status approved by the U.S. Food and Drug Administration (FDA) in several decades. The drug was sold to DepoMed in April 2015.1 In 2014, the Drug Enforcement Administration (DEA) officially changed tramadol from a schedule V to a schedule IV drug.1 Both tramadol and tapentadol are phenylpropylamines (Figure 1).

Although both compounds are mu opioid receptors agonists, they differ in their mu binding affinity: tramadol has a mu binding affinity 6,000 times less than that of morphine. In fact, tramadol is pharmacologically a “partial agonist.”2 In contrast, tapentadol is a full mu agonist with a binding affinity 18 times less than that of morphine, but is only 2- to 3-times less potent than morphine. This is presumably because of its dual mechanism—a mu receptor agonist and norepinephrine reuptake inhibitor.3

Both tramadol and tapentadol inhibit the reuptake of norepinephrine from the synaptic cleft, which has been shown to have analgesic properties separate from opiate activity.2,4,5 Tramadol has been shown to inhibit serotonin reuptake, but tapentadol has not been shown to have any therapeutic serotonin activity.3

Despite this, the FDA-approved labeling requires both compounds to include the standard warning for risk of seizure and serotonin syndrome—especially when they are taken with antidepressants, other opioids, or neuroleptics, or are used in patients with a history of epilepsy or head injury.6,7

Without a doubt, tapentadol is far from a “glorified tramadol,” which has been suggested to one of the authors (JF) by many medical and pharmacy colleagues. But an important question remains: Are all of these warnings warranted for tapentadol?

Tapentadol’s Metabolism

Tapentadol is metabolized hepatically by Phase 2 pathways, primarily conjugating with glucuronic acid to form glucuronides, and by a minor Phase 1 oxidative pathway through cytochrome P (CYP) 2C19 (13%) and CYP2D6 (2%) enzymes.2,6 The terminal half-life of tapentadol is approximately 4.25 hours, and it is excreted through the kidneys.6,8 This means that tapentadol has no active metabolites, and, therefore, possesses less risk of drug-drug and cytochrome P450 interactions.3,9

In contrast, tramadol is metabolized by CYP2D6 and CYP3A4, with 2D6 producing the O-demethylated metabolite (M1) that has more analgesic properties than tramadol itself but interestingly doesn’t impact the pain relief.2,10-12 Here’s why: Although M1 is a more potent analgesic than tramadol, the metabolite has more difficulty passing into the central nervous system (CNS).3 Additionally, as the dose of tramadol is increased, so too is the M1 metabolite; however, the ratio of tramadol to M1 entering the CNS increases. This means that more of the weaker parent compound binds to the mu receptors.2

If a patient taking tramadol is classified as a “poor” metabolizer of 2D6 or is taking 2D6 inhibitors, it can result in decreased analgesia and metabolism—20% higher blood concentration and 40% decreased M1 compared with “extensive” metabolizers (ie, normal metabolic rate).7,12

Common 2D6 inhibitors include citalopram, doxepin, escitalopram, fluoxetine, paroxetine, and sertraline; common 3A4 inhibitors include amiodarone, amlodipine, cimetidine, ciprofloxacin, clarithromycin, diltiazem, erythromycin, and fluoxetine.6,7,11,13-16

In fact, studies have found that poor metabolizers of 2D6 had higher concentrations of tramadol (4.4 mcg/mL) than extensive metabolizers (0.8 mcg/mL), confirming that 2D6 was an important factor in drug metabolism.17 The mean half-life of tramadol is approximately 6 hours, whereas the mean half-life for the M1 metabolite is 7.4 hours—tramadol is metabolized by the liver and M1 is excreted by the kidneys.7,12 Compared with extensive metabolizers, ultra-rapid metabolizers are able to convert tramadol into M1 more quickly, yielding improved analgesia, but also can cause toxicity at lower doses.12

Other studies show another interesting difference between tramadol, M1, and tapentadol when evaluating the binding of recombinantly expressed human mu opioid receptor (hMOR). Tramadol has 15 times less binding affinity for the hMOR than tapentadol and about 700 times less than M1. Yet, functional activity studies indicate that tapentadol is analogous to M1, whereas tramadol showed no activity in an agonist-stimulated [35S]GTPγS binding assay in cells recombinantly expressing hMOR.2

In another words, although the binding affinity of the M1 is greater than that of tapentadol and the parent compound tramadol, the actual effect of M1 on mu opioid receptors is approximately the same as that of tapentadol. The parent drug tramadol itself has no activity, and therefore tramadol has 2 to 5 times less potency compared to tapentadol across various animal pain models.2

Serotonin Syndrome Risk Examined

What is the relative risk of seizure and serotonin syndrome between tramadol and tapentadol? Serotonin syndrome occurs when there is a buildup of serotonin in the central and the peripheral nervous systems or the serotonin receptors are activated. This buildup in serotonin can be due to a combination of the following: increased serotonin synthesis or release, or decreased serotonin metabolism or reuptake.11 The symptoms of serotonin syndrome include neuromuscular hyperactivity, autonomic hyperactivity, altered mental status, and seizures.11

Human affinity (measured by Ki values) of tapentadol and tramadol for human norepinephrine receptors (hNET) were 8.8 mcM and 14.6 mcM, respectively, wherease values for human serotonin (hSERT) were 5.28 mcM and 1.19 mcM, respectively. According to Raffa et al, this shows that tapentadol is slightly more potent than tramadol in blocking hNET and nearly 5-fold less potent than tramadol in blocking hSERT.2 In rats given an analgesic dose, tramadol increases norepinephrine 5 times baseline levels and serotonin 5 to 6 times baseline levels, whereas tapentadol increases norepinephrine 5 to 6 times and serotonin 2 times baseline levels.2 According to the authors, these changes would be equivalent in humans. Of note, another study of rats found that tapentadol only increased the cerebral spinal fluid (CSF) concentration of norepinephrine 50% to 60%, whereas the serotonin norepinephrine reuptake inhibitor duloxetine doubled the concentration.18

Most commonly, tramadol-induced seizures appear to be generalized tonic-clonic seizures that occur within 24 hours of medication ingestion. These seizures have occurred predominantly in patients ingesting alcohol, illicit drugs, antipsychotics, or antidepressant medications or some combination of these along with tramadol.19

Last updated on: February 9, 2016
First published on: January 1, 2016
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