Data suggest that the novel dual-action agent, tapentadol, is a
useful addition to the options available to fight severe, chronic pain
Lucy A Bee
Anthony H Dickenson
Neuropharmacology of Pain Group
University College London, London, UK
Multiple mechanisms at multiple sites can underlie chronic pain in patients, which provides the basis for a standard of care that uses more than one agent, either sequentially or in combination, for its treatment. New and emerging drugs heed this multimodal approach by combining different mechanisms of action within a single molecule, so-called ‘directed polypharmacology’,(1) with the different components often working synergistically to achieve pain relief. Tapentadol hydrochloride (Palexia; Grünenthal) is a case in point, combining potent agonist activity at the mu-opioid receptor (MOR) with noradrenaline reuptake inhibition (NRI) in the central nervous system (CNS), and which was approved in June 2009 by the US Food and Drug Administration (FDA) for treatment in the US of moderate-to-severe acute pain in adults (which can be adequately managed only with opioids). Tapentadol is a schedule II controlled oral analgesic, available in immediate release 50-, 75- and 100mg tablets. However, phase I/II clinical trial data, in line with results from preclinical animal studies, have indicated the efficacy of tapentadol in managing severe chronic pain, and so in such circumstances prolonged-released tablets are available but are currently restricted for use in NHS Scotland and Wales.
Pathways of pain
Pain is a unique, conscious experience that comprises sensory-discriminative, cognitive-evaluative and affective-emotional components. These different aspects of pain are the product of pathways that run from the periphery to cortical and limbic areas of the brain, relaying through the spinal cord and brainstem areas,(2,3) and, as such, the brainstem and spinal cord are key targets for the actions of many analgesic drugs. In particular, opioids act on MORs expressed on afferent pain fibres to reduce transmitter release within the spinal cord, which subdues spinal neuronal activity.
Opioids also act at targeted sites within the brainstem to switch descending excitatory controls off while switching descending inhibitory controls on.(4) Another way in which inhibition can be restored in hyperexcitable pain states is by increasing the synaptic availability of noradrenaline in the spinal cord by blocking its reuptake, because noradrenaline released from brainstem neurones typically inhibits spinal cord activity via actions at α2-adrenoceptors, and in particular α2A-adrenoceptors that are expressed alongside opioid receptors on the central terminals of C-fibres (therefore mediating presynaptic inhibition),(5) and α2C-adrenoceptors that are expressed on the axons of spinal projection neurones (therefore mediating postsynaptic inhibition).
Furthermore, noradrenaline inhibits spinal neuronal activity by activating excitatory α1-adrenoceptors on inhibitory interneurones within the spinal cord. Alterations in noradrenergic inhibitory control during pathological pain have been widely reported;(3) for example, in an animal model of nerve injury, the selective α2-adrenoceptor antagonist atipamezole was shown to have no effect on spinal cord neuronal responses to peripheral stimuli, which suggests a downregulation of this endogenous inhibitory system in chronic pain.(6) The restoration of this important inhibitory drive explains the antinociceptive capacity of α2-adrenoceptor activation in preclinical models of acute and persistent pain, and moreover explains the clinical analgesia produced by clonidine’s partial agonism of spinal α2-adrenoceptors in patients with neuropathic pain.(7)
Differentiation of tapentadol from tramadol
Inhibitory synergy between agonists working at α2-adrenoceptors and MORs has been widely reported,(8) and combined with serotonin reuptake inhibition, provides the empirical basis for the actions of tramadol. Tramadol’s analgesia is provided collectively by the enantiomers of the parent drug and a stronger metabolite,(9) whereas the pharmacological actions of tapentadol reside within the single enantiomer parent molecule and not its metabolites.(10) This enantiomeric purity is preferable because the alternative relies on enzymatic metabolism of the drug to its active compounds, which varies widely between individuals. The minor differences in the structure of tapentadol compared with that of tramadol not only results in stereoselectivity but also generates major differences in the pharmacological and pharmacokinetic profiles of these two drugs, which necessarily extends to differences in their clinical efficacy, tolerability and application.(9) In particular, tapentadol has MOR agonist activity that is significantly greater than that of tramadol (although it has significantly weaker activity at these receptors than morphine),(11,12) has higher affinity for the noradrenaline reuptake transporter and thus increases noradrenaline content, both spinally and supraspinally, to a greater extent than tramadol.
Moreover, tapentadol has significantly lower affinity for the serotonin (5-HT) reuptake transporter.(12,13) This relative lack of effect on synaptic 5-HT content might be expected to improve the analgesic capacity of tapentadol (compared with tramadol) in certain pain states because there is considerable preclinical data that shows a pathophysiological role of 5-HT, acting at excitatory 5-HT3 receptors, in certain animal pain models.(14) Indeed, the anti-hyperalgesic effect of milnacipran, an antidepressant agent that blocks the reuptake of both noradrenaline and 5-HT, is mediated principally via activation of the spinal noradrenergic system because its analgesia is lost after noradrenergic denervation, but not after serotonergic denervation, in nerve-injured animals.(15) Tapentadol’s lack of serotonergic effect does not only improve analgesia relative to tramadol but also reduces nausea and gastrointestinal side-effects because 5-HT has key involvement in these functions, with levels in the enteric nervous system exceeding those in the CNS.
The variable capacity of 5HT to differentially inhibit(16,17) or facilitate(17,18) nociception within the CNS is a function of the multiple 5-HT receptor subtypes that are expressed throughout the sensory neuraxis, which may mediate reciprocal and even antagonistic actions, depending on the membrane and intracellular mechanics to which they are coupled. As such, it has been shown in naïve mice that the application of tramadol engages 5-HT receptors in the spinal cord, including the 5-HT7 receptors, to evoke antinociception in various measures of acute pain.(19) By contrast, in situations of chronic pain, it is thought that excitatory 5-HT3 receptors in the spinal cord become the preferential target of 5-HT released from descending neurones, resulting in an augmented pain state.(3,20) This shift from a predominance of serotonergic inhibition to excitation could be time-dependent, because in the early aftermath of nerve injury, exogenous 5HT delivered spinally to nerve-injured animals transiently reduced mechanical hypersensitivities,(21) yet the more enduring effect of enhanced serotonergic output from the brainstem in this model of chronic pain was spinal facilitation. This latency correlates well with developing plasticity in the brainstem following the induction of injury,(22) and infers an analgesic superiority of noradrenaline over serotonin in situations of ongoing pain. This therefore suggests a role for tapentadol in the management of severe chronic pain.
Tapentadol can be described as ‘opioid-sparing’ because, despite having a 50-fold lower binding affinity to MOR than morphine,(12) it has just a slightly lower analgesic potency in animal models of pain, a shift which likely results from its parallel effect on α2-adrenoceptors. This dual MOR-NRI mechanism is demonstrated by the reversal of tapentadol’s analgesia in an animal model of nerve injury by the MOR antagonist naloxone, or by the α2-adrenoceptor antagonist atipamezole.(23) More recently, tapentadol has demonstrated dose-dependent analgesic effects in a low-intensity acute pain test as well as in a model of chronic pain, with clear demonstration of synergistic interaction between occupied MORs and noradrenaline transporters by the single tapentadol molecule.(24)
The presence of neuropathy enhances the actions of tapentadol at low doses,(23) in contrast to morphine, which is thought to lose efficacy following nerve injury, possibly due to a reduced number of opioid receptors on primary afferent fibres and/or due to the upregulation of excitatory neurotransmitters that physiologically antagonise morphine’s inhibitory actions.(25) It is suggested, therefore, that the MOR analgesic actions of tapentadol may dominate in acute or milder pain complaints, with NRI actions gaining dominance in the presence of more persistent pain, thereby giving it an advantage over tramadol.(23,26) Therefore, in murine models of acute or chronic (neuropathic) pain, morphine did not elicit analgesia in knock-out mice lacking MORs (yet was effective in wild-type littermates possessing MORs), whereas tapentadol had clear analgesia with respect to both chronic and acute complaints in both knock-out and wild-type mice.
The reduction in pain scores could be abolished by the α2-adrenoceptor antagonist, yohimbine, demonstrating once more that the analgesic effect of tapentadol is only partly due to MOR activation in acute and chronic pain.(27) Furthermore, in preclinical studies of diabetic neuropathy, morphine was shown to be slightly less potent than tapentadol on behavioural measures of thermal hyperalgesia, yet in normal control animals 1mg/kg tapentadol had minimal inhibitory effects in contrast to the full anti-nociceptive actions of morphine. This seems to indicate that, whereas tapentadol is an analgesic at suitable doses, it can act as a selective anti-hyperalgesic after diabetic neuropathy, possibly through a greater contribution of α2-adrenoceptors.(28) This potential sparing of normal transmission while attenuating abnormal pathophysiological activity is clearly advantageous in a clinical setting, particularly with respect to the treatment of ongoing severe pain. Furthermore, the ability of tapentadol to retain considerable effectiveness in the absence of MOR would fit with the concept that the molecule, at effective doses, would have less opioid load than a pure MOR agonist.
Key clinical trials
Preclinical promise translates well to clinical practice, because a number of trials looking at the actions of tapentadol in patients with severe pain have indicated good analgesic potential. The nature of this pain varied from that caused acutely by dental extraction and bunionectomy,(29) and that which endured as a result of diabetic neuropathy or osteoarthritis of the hip or knee.(30) In the osteoarthritis study, immediate-release tapentadol produced significant reductions in pain intensity compared with placebo, and was non-inferior to oxycodone. Furthermore, tapentadol’s tolerability was enhanced relative to oxycodone owing to reduced side-effects such as nausea, vomiting and constipation, and a lower incidence of discontinuation. In a second and longer osteoarthritis study, which also included patients with low back pain, tapentadol similarly showed favourable tolerability over oxycodone.(31)
Furthermore, in a clinical trial focusing on patients with painful diabetic neuropathy, prolonged-release tapentadol provided a statistically and clinically significant improvement in pain intensity compared to placebo, and was once again well-tolerated by patients.(32) The prolonged-release formulation of tapentadol could also be applied for the treatment of chronic low back pain (with or without a neuropathic component) following recent encouraging open-label trial outcomes in affected patients.(33)
From estimates based on prices in the Drug Tariff, the cost of four doses of tapentadol for seven days’ treatment in the surgical or non-surgical setting far exceed those of oxycodone, codeine, tramadol and morphine.(34) However, this increase is offset by a reduction in the expense incurred for the treatment of unwanted effects and treatment discontinuation, which evens out the cost per patient of tapentadol relative to the abovementioned opioid alternatives.
The MOR-NRI concept has been established from a number of preclinical and clinical studies in a range of severe pain conditions. Whereas non-steroidal anti-inflammatory drugs have efficacy in inflammatory pain conditions (yet are contraindicated in patients with peptic ulcer disease, severe renal impairment or bleeding tendency, and may be associated with cardiovascular side-effects) and anticonvulsants reduce neuropathic pain, tapentadol appears to bridge the gap because the opioid and noradrenaline uptake effects allow it to work across the boundaries of different pain states. Clinical experience of its use over longer periods is evidently needed, but early data suggest that this novel dual-action agent should be useful in the fight against severe pain.
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