Artículo de Revisión

Tapentadol a New Therapeutic Option

Mario Andrés Leotau Rodríguez*

* Médico y cirujano, Universidad Industrial de Santander. Estudiante de maestría. Máster en estudio y tratamiento del dolor, Universidad Rey Juan Carlos-Universidad de Cantabria, España. Correspondencia: Carrera 24 No. 156-106 Centro Médico Carlos Ardila Lulle, torre B piso 9 módulo 61, Aliviar Clinica de Dolor y Cuidado Paliativo, Bucaramanga, Colombia. Correo electrónico: ma.leotau@alumnos.urjc.es, leotau@gmail.com.

Recibido: marzo 1 de 2011. Enviado para modificaciones: mayo 15 de 2011. Aceptado: mayo 21 de 2011.

SUMMARY

Introduction: The peripheral dysfunction or illness is associated to the sensory phenomenon that includes both symptoms of loss of function as well as pain generation. Opioids provide relief from many pain settings; however they have reduced potency and efficacy for neuropathic pain.

Objective. Provide a current review of the literature about tapentadol that could be used as a guide.

Methodology. A literature search on the Cochrane, PubMed and Embase databases retrieved 66 papers, and from these, the papers with relevant information about tapentadol were selected.

Results and Conclusions. The therapeutic combination of the μ opioid receptor agonists with inhibitors of the norepinephrine reuptake have become more popular recently as an alternative to treat the mechanisms responsible for neuropathic pain. However, even though the inhibitors of the norepinephrine reuptake are well tolerated, their analgesic efficacy is usually unsatisfactory, and opioids usually have tolerability problems; the recent introduction of tapentadol, which combines in the same molecule both mechanisms of action can represent a novel, improved and efficient alternative for analgesia.

Key Words: Tramadol, pain, receptors, opioid, opioid analgesics, neuralgia. (Source: MeSH, NLM).

Introduction

There are several medications in the pharmaceutical arena that are effective for the treatment of neuropathic pain and which reduce neuronal excitability. Examples are lidocaine, pregabalin, gabapentin which blocks sodium channels (the first) and calcium channels (the last two), which are voltage dependent and therefore produce a reduction of the transmission of neuronal action potentials and the release of neurotransmitters (1-3). However, an alternative to restore neuronal excitability to physiological levels consists of stimulating the inhibitor mechanisms of the nociceptive pathways (4,5).

As in different regions within the same patient different mechanisms underlie neuropathic pain, in recent years more than one medication has been recommended for treatment, so commonly a combination therapy is prescribed when there is more than one partial analgesic response to medication (6).

The combination of μ opioid receptor agonists (MRA) with inhibitors of the norepinephrine reuptake (INR) or with α2 adrenergic receptor agonists, has been observed to produce analgesia after their intrathecal or systemic administration in models of nociceptive and neuropathic pain. The antinociceptive synergism of the spinal opioids and adrenergics is produced by the joint activation of the MRA and the α2A or α2C adrenergic receptors. Likewise the analgesic potency of the systemic administration of morphine has been observed to increase in KO rats for the norepinephrine transporter, and decreased with the administration of yohimbine (an α2 adrenergic receptor blocker) (6).

The activation of the MRA receptor is a very effective way to inhibit acute moderate to severe nociceptive pain; however their therapeutic efficacy of the MRA agonists is limited in somatic or inflammatory chronic pain conditions. The potency and efficacy of intrathecally administered morphine has been shown to be lesser in models of spinal nerve ligation, compared to that administered to control rats, and its prolonged use can lead to tolerance and to the need to increase doses over time (7-9).

The inhibitors of the reuptake of monoamines (inhibitors of the reuptake of serotonin, norepinephrine, tricyclic and non-tricyclic) are among the first-line treatment options for chronic pain (2,10,11).

Serotonin (5-HT) is released from the modulating pathways descending from the pons to the spinal cord, and the inhibition of its reuptake leads to an increase in the activation of the 5-HT receptors in spinal neurons, which helps to modulate the nociceptive spinal processing (12). Likewise, the inhibition of norepinephrine reuptake (INR) in the axonic endings of the inhibitory noradrenergic descending pathways, increases the extracellular concentration of norepinephrine (NE) in the spinal cord, which can also produce anti-nociception by the activation of the α2 adrenergic receptors which can be of particular interest in chronic neuropathic pain. Generally, these medications are usually well tolerated even though their analgesic efficacy is often unsatisfactory (13,14).

Combining both action mechanisms (MRA and INR agonist behavior) in the same molecule could produce according to that stated before, to an efficient strategy to treat chronic neuropathic pain. Tramadol binds to the μ,σ and κ receptors with low affinity, and therefore is less effective than other opioid agonists to treat severe pain; however this characteristic produces side effects not common for opioids although seizures, nausea, vomiting headache and dizziness are still possible (15). On the other hand, it is capable of inhibiting serotonin and norepinephrine reuptake and can bind to α2 adrenergic receptors as well as potentiating the neuronal release of serotonin (8,16,17). In the last two years tapentadol which is an analgesic medication that combines μ receptor agonist behavior and inhibits norepinephrine reuptake has been available (2,11,18,19).

Methods

A literature search on Cochrane, PubMed and Embase databases without time constraints with the keywords: tapentadol, opioid receptors, neuralgia and nociceptive pain. In the initial search 66 papers were found containing information about tapentadol. Both English and Spanish language papers were selected. Among these, clinical trials about the use of these new medication were analyzed and summarized; as well as review articles with relevant information to have a clearer vision of this new medication.

Results

The Tapentadol, 3–(3-dimethylamino–1–ethyl– 2–methylpropyl) phenol is a central action analgesic that combines in one molecule a weak μ opioid receptor agonist behavior and the inhibition of the norepinephrine reuptake (4,17,20,21) (a weak inhibition of in vitro serotonin reuptake has been observed, that does not contribute to the analgesic effects) (22). These two mechanisms have been shown in pharmacological studies responsible for the synergic effects of tapentadol (23).

The INR component can produce moderate opioid effect, enough to produce powerful analgesia and reduce the adverse effects of opioids (24, 25). The anti-hyperalgesic effect produced by high doses of intravenous tapentadol in rat models with ligation of the spinal nerve is clearly inhibited by yohimbine or atipamezol (both α2 adrenergic blockers), whereas naloxone (MRA blocker) produces only mild inhibition (14). On the other hand, the disappearance of the actions of tapentadol with intrathecal naloxone or atipamezol indicates that this agent combine in vivo actions mediated by μ opioid receptor with inhibition of norepinephrine reuptake in the spinal cord which supports the existence of the combined MRA – INR mechanism mentioned earlier (26, 27).

The disappearance of the effects of tapentadol with the use of atipamezol suggests that the INR leads to the activation of the α2 adrenergic receptors of the postsynaptic cells in the dorsal horns and the primary terminal afferents (3). In the cases where there is an injury of the peripheral nerves, the inhibition mediated by the α2 spinal adrenergic receptors of the activity of the dorsal horn neurons which is produced by low intensity mechanical stimuli (3,28). This in addition to the fact that an injury to a peripheral nerve decreases the MRA receptors in the dorsal horn neurons, explains why atipamezol is more effective than naloxone to revert the inhibitory effects of tapentadol in rat models of spinal nerve ligatures, whereas in sham rats naloxone is more effective (3,29-31). This finding is consonant with studies that question the potency of pure opioids in neuropathic pain (3,14).

As mentioned before, the use of animal models of spinal nerve ligature has demonstrated the role of monoamines in neuropathic pain and particularly the role of positive regulation of serotonin, which acts on the 5-HT3 spinal receptors. The negative regulatory role of norepinephrine which acts on α2 spinal adrenergic receptors has also been shown (23).

The decrease in the reuptake of norepinephrine by antidepressants could explain their effectiveness in pain as they increase of the availability of synaptic norepinephrine in the spinal cord even with the increases in serotonin (32).

Tapentadol has advantages over tramadol as the pro-nociceptive effect of a neuropathy diminishes with the increases in norepinephrine without the inconvenience of the adverse effects of the increases in 5-HT (as nausea and vomiting) (19); and its double action improves the therapeutic potential of opioids and decreases the adverse effects (like gastrointestinal, and vomiting among others), which could limit their doses. This new agent has a powerful inhibitory effect on the pain level of animals subject to mechanical thermal and electrical neuronal responses in models of spinal nerve ligatures Chan rats. And different from morphine, tapentadol maintains its efficacy after neuronal injury.

The presence of neuropathy potentiates its actions at lower doses, even though its affinity for the μ opioid receptors is 50 times less than morphine (8). Furthermore, even with this low affinity, tapentadol overlaps with morphine in its range of doses both in electrophysiological models as well as in neuropathic pain behavior (15,20,22), even if residual effects on other opioid receptors cannot be excluded (23).

It has been demonstrated in opioid receptor binding studies that tapentadol has a modest affinity for the μ opioid receptor when compared to other pure agonists (28,33). Even with this difference in affinity for the μ opioid receptor compared to morphine, tapentadol has shown an analgesic potency which is only 2-3 times less in acute and chronic pain in animal models (34). This discrepancy between potency and opioid receptor affinity is related to the impact of the second mechanism of analgesic action (inhibition of norepinephrine reuptake) of tapentadol (24,34-36).

Because of its combined action mechanisms, tapentadol offers a wide therapeutic spectrum for both nociceptive and neuropathic pain (15,28,27), and its high efficacy in acute nociceptive, acute and chronic inflammatory, and chronic neuropathic pain has been shown in several animal models. Compared with other medications with only one of the two modes of action, tapentadol albeit its potency has a better tolerability profile in animal models and its adverse effects are basically on the central nervous or gastrointestinal systems, and it has been shown that these effects are not as common as in patients treated with oxycodone and other pure opioid agonists (13,14,22, 37-39).

Tapentadol metabolism

Oral tapentadol is eliminated mainly by hepatic glucuronization by UGT1A9 and UGT2B7 transferases (uridina 5′-difosfo-glucuronosil transferases) (13,30). Its principal metabolite, tapentadol-O-gluroronide has no activity on opioid receptors, reuptake systems in synapses or other junctures. Tramadol is metabolized almost entirely by the enzyme of the P450, CYP26 cytochrome. CYP2D6 gene mutations occur in approximately 1 to 7% of the Caucasian population and can increase or decrease enzymatic activity and produce alterations of opioid analgesia.

Aside of the potential differences in individual responses to opioids metabolized by the P450 cytochrome there is a high-risk of pharmacological interactions as some of the substrates of CYP2D6 are antiarrhythmic medications, antidepressants, antipsychotics anti-parasite medications and tamoxifen. The analgesic activity of tramadol is affected by the inhibition of CYP2D6 as its analgesic effects are produced by its metabolite M1 (O-desmetiltramadol) (24,26,40).

In vitro studies to assess the inhibitory or inductor effects of tapentadol over the main seven isoforms of CYP implicated in the metabolism of medications (CYP2D6, CYP3A4, CYP1A2, CYP2A6, CYP2C9, CYP2C19 y CYP2E1) have revealed that tapentadol is not significantly metabolized by the CYP enzymes, and does not inhibit or induce the activity of any of the CYP isoforms assessed, except for the CYP2D6, which, however, is considered clinically irrelevant (12,24,26,41).

Clinical use of tapentadol

Tapentadol is currently approved by the FDA for moderate to severe acute pain management (34,35,42,43). Several studies in the medical literature are published with the use of this medication in pain management (41,44-46) , in acute postoperative pain (10,47,48), in patients with fibromyalgia (27,49), in lower back pain (50- 52), in articular pain like knee (24,50,53) and hip arthrosis (43,53), in peripheral neuropathy (37-39,54); all studies have shown great effectivity and avoidance of many side effects common with opioids (47,52,55,56).

Conclusions

The inhibition of the reuptake of the norepinephrine potentiates significantly the MRA receptor activation; however the inhibitory actions of tapentadol are not entirely noradrenergic, as naloxone is capable of reversing the effects of the agent both in “sham” or spinal nerve ligature in rat models. Therefore, both the μ opioid as well as the α2 adrenergic receptor are simultaneously required to achieve the efficacy of tapentadol which suggests synergy between the mechanisms.

The fact that the opioid and the noradrenergic analgesic systems not only interact at the spinal cord level, but at other supra spinal sites, supports the idea that the relative contribution of the MRA and INR agonist effects are different between neuropathic and nociceptive pain. That means that not only each mechanism can produce analgesia by themselves, but that they also interact in a synergic way at a spinal and supra spinal level.

As an example, the MRA agonists activate the noradrenergic inhibitory pathway which extends to the spinal cord, uninhibiting the gabaergic interneurons in the periaqueductal gray substance of the rat, which represents on its own, a great advantage over the action mechanism of tramadol, which is another agent with a dual action mechanism. Such medication has less side effects than other opioids although more than tapentadol, because of its action on 5-HT accumulation by the modification of the interneuronal activity in the digestive system and stimulation of smooth muscle contraction and relaxation. The result is that tramadol has more side effects and requires higher doses to achieve analgesia as its two actions, MRA activation and α2 adrenergic receptor binding are split between its two enantiomers (+) and (-) respectively.

On the other hand, different from tramadol, the analgesic effects of tapentadol are independent of its metabolic activation and has no active metabolites, which makes it very effective as an oral analgesic in variable pain scenarios; it's general ly well tolerated and has minimal pharmacological interactions as described in the published studies.

In conclusion, tapentadol has two mechanisms of action which are synergic with which it achieves efficacy in models of nociceptive and neuropathic pain its potency slightly higher in neuropathic compared to nociceptive pain.

Furthermore, this new analgesic profile is the result of dual action mechanisms which combine the MRA agonist behavior —more relevant in the inhibition of nociceptive pain— with INR —more relevant in the control of chronic neuropathic pain. This analgesic profile is superior than that of tramadol, and as with the rest of opioids, it's clinical efficacy is limited in neuropathic pain. This will allow in time to perform in-depth studies that could lead to the development of a new family of medications that are able to combine different analgesic actions in one single molecule for an improved treatment of both chronic and acute pain.

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