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Is Tapentadol a Glorified Tramadol?

Ask The Expert from January/February 2016
Page 1 of 2

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
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By NunyaSuperbarrel on 10/08/2017
17 yrs ago aged 24 I was diagnosed with possible MS after first being diagnosed with endocarditis and cerebral abscesses, but post attempt at draining, the biopsy showed a "demyelination process such as Ms". Large Frontal lobe lesions and temporal. Only cognitive symptoms. At the same time I started to get a severe aching in my left lower leg at night in bed about once every 6 months that I could relieve by walking. By 2005 the aching was 80% worse and about once a week. I was taking 120mg-180mg of codeine to get rid of it. In 2006 it was nightly. Oxycodene, transderm, gabapentin, did not work and due to now having lesion caused epilepsy I could not take tramadol after having a bad tonic clinic seizure with it. With doctors refusing to give me anything because of the "drug seeker" attitude, I was now taking up to 30 panadiene (450mg codeine and 1500mg paracetamol) every night. The aching was so severe I could not sleep but was sedated by the codeine and panadol so I was relieved. In 2007 I was given OxyContin 120mg and was finally able to be pain free. By 2015 I decreased the dose to 90mg because I wanted to stop taking it but could not tolerate taking less than that. My aching now started about lunch time when I took 30mg then 60mg at night. Now in 2017 after having a few seizures lasting 2 hours, my aching has changed. I am now able to take all 90mg at night again. Last month the aching was so severe I was up in tears at 3am one night and needed 150mg and had a seizure later in the afternoon that caused 2 hrs of complete left sided parasthesia, but am back to 90mg. My seizures always only afftect my left side, and have had one grand mal. I now feel that during the day, I can 'ignore' the aching but at night about 7pm on, I can't. I get periodical pins and needles in 3 toes. Sometimes I get a severe aching in an elastic band shap aground my calf. I am frustrated to no end with having to ask Dr's myself for possible diagnoses by tests frequently. I am then treated like an idiot by pharmacists who ask me if I have tried tens machines, physio, creams... of course I have! I went to a pain specialist who told me only to take magnesium!!! My pharmacist now is trying to get me to swap for short periods to other pain reliefs. The new option is this trapentadol. Tramadol, fentanyl cause me seizures and I refuse to try this option since the tramadol caused seizures but he is recommending a short change to my Doctor. I am an Intensive Care nurse so I lift patients a lot and get significant lower back and hip pain that is only relieved by codeine again- the OxyContin is useless for anything but the aching leg. I feel that the extra muscle pain makes life unbearable. Pain specialists say we shouldn't be pain free, but should have tolerable pain. Why should I not be pain free? There are days I can't walk for 2 days after working because of severe hip and leg bilateral pain. The ignorance of every pain specialist, and pharmacists is ridiculous! I am not a drug seeker, or a dependent, I have two very large lesions and a smaller temporal one that my last pain specialist (after 17yrs) dx as neuropathic pain. I found the prescribed gabapentin to help about 20-30% for the pain, but after 2 months I was still feeling confused and dangerous now as a nurse so I stopped taking it. It is about time people started teaching pain specialists to listen to people like myself. I am so sympathetic to my patient's pain and am currently doing my thesis on patients attitude to the pain relief the "pain team" of Doctors in my hospital will give them post coronary bypass grafts. Now that they are making codeine available by script only in 2018 here in Australia, I am getting anxious already. I think pain specialists or my GP should live with me for a week to see how my life is. I am angry as all hell to drug addicts, pharmacists, because they make my life hell and unbearable. Due to the amount of medications that cause me seizures, and a dangerous nurse, I am limited so I should be given opioids. My liver function tests are amazingly normal but when I get my hip and bone pain about 3-4 times a week, I need 8 panadiene each time. Experts do not suffer pain, nor do the studies people do describe the truth for everyone. The recent study by the university of Colorado that showed opioids CAUSE pain is absolute rubbish! They did the study on 10 MICE! Do studies on real people with real pain and don't just go by what some study on animals say, or a few hundred people. You can tell I am frustrated and angry but the government needs to wake up too. We are not all addicts or have a dependency- we SUFFER!
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