Tapentadol and Dual Pain Inhibition: A New Strategy for Pain Relief in Australia

Research Article

Chronic Dis Int. 2015;2(1): 1011.

Tapentadol and Dual Pain Inhibition: A New Strategy for Pain Relief in Australia

Pergolizzi JV¹, Schug SA², Raffa RB³ and Taylor R4*

1Department of Medicine, Johns Hopkins University School of Medicine, USA

1Department of Pharmacology, Temple University School of Medicine, USA

1Department of Anesthesiology, Georgetown University School of Medicine, USA

1Association of Chronic Pain Patients, USA

2Anaesthesiology in Pharmacology, University of Western Australia, Australia

2Anaesthesia and Pain Medicine, Royal Perth Hospital, Australia

3Department of Pharmaceutical Sciences, Temple University School of Pharmacy, USA

4NEMA Research Inc., USA

*Corresponding author: Taylor R, NEMA Research Inc, 3384 Woods Edge Circle, #102, USA

Received: December 09, 2014; Accepted: January 05, 2015; Published: January 07, 2015


Although prevalent, pain is often under-treated, in part because pain can involve multiple physiological mechanisms. Pain signals are transmitted via ascending pathways and are modulated via descending pathways. The pathways are influenced by a complex interplay of inhibitory and excitatory actions involving the endogenous opioid and mono aminergic (e.g. nor adrenaline) systems. When pain involves multiple mechanisms, analgesics that inhibit only a single system will likely result in suboptimal pain relief, possibly initiating a vicious cycle of escalating doses, accelerated onset of dependence/tolerance, and excess side effects. Combining two agents with complementary mechanisms of action can be effective in treating such multi mechanistic pain, but taking multiple individual drugs can be inconvenient to the point of compromising compliance, and presaging a potentially dangerous poly pharmacy. The risk of drug-drug interactions increases dramatically as more drugs are added, and many patients who are in moderate to severe pain are already taking several other prescriptions for underlying disorders before analgesics are added. Tapentadol is a new analgesic agent that has a dual mechanism of action-it activates μ-opioid receptors and also inhibits the neuronal reuptake of norepinephrine, making it an attractive match for multi mechanistic pain syndromes. The dual mechanism of action was designed and observed using in vitro and animal testing, but now with 3 years in the clinic, we aim to present and evaluate the successful “translation” of these types of design strategies and preclinical data to the Australian clinic.

Keywords: Tapentadol; Dual inhibition; Analgesia; Pain; Chronic pain


More than 10 million Australians (67% of the population = 15 years of age) experience pain at least one time in the prior four weeks, of which 9% characterize the pain as severe to very severe [1]. About 20% of the population (including pediatric patients) have chronic pain, and in the senior population (>65 years), prevalence rates are about 33% [2]. As in other parts of the world, pain increases with advancing age, certain health conditions (for example, osteoporosis), and mental health conditions, such as depression. Risk factors for severe to very severe pain include smoking, obesity, and a sedentary lifestyle [3]. Only cardiovascular disease and musculoskeletal conditions cost the Australian healthcare system more than does chronic pain. Despite the availability of good clinical care, it is estimated that less than 10% of Australians suffering chronic noncancer pain receive adequate analgesia [4], and it is more likely to be available to city-dwelling Australians than to rural citizens [5].

The physiological/biochemical complexities of pain signal transmission cause many pain syndromes to be multi factorial, involving neurological activation of both ascending and descending pain pathways [6]. While the well-known helpful World Health Organization (WHO) pain ladder recommends treating pain based on intensity level [7], WHO treatment recommendations predated modern understanding of the mechanisms of pain and thus do not take multiple underlying pain mechanisms into account [8]. Pain signals are processed and modulated by a variety of interacting excitatory and inhibitory systems; analgesic agents work because they either block excitatory transmissions or activate inhibitory systems. Identifying the underlying mechanisms of chronic pain can be particularly difficult, in that symptoms do not necessarily correlate with the mechanism. In traditional clinical practice, patients tend to be identified by the initial cause or location of their pain, for example low back pain patients, rather than pain mechanism. However, one patient with low back pain might have purely nociceptive pain, while another might have mixed pain, including a neuropathic component. An effective treatment for the first patient will be inadequate for the second. Thus, pain should be treated mechanistically, and it is often necessary to treat it multi mechanistically.


This paper is a narrative review based on the most recent literature relating to tapentadol and the experiences and insights of the authors. The authors searched the PubMed database for the broad keyword “tapentadol,” which yielded over 200 results. The literature was then reviewed for those most relevant to a general discussion of the drug’s safety, efficacy, and potential role in the armamentarium against pain. In particular, the authors were seeking clinical trials, reviews, and other literature relating to tapentadol’s dual inhibition.

Rationale for mechanism-oriented treatment of pain

When treating multi mechanistic pain, each mechanism must be addressed. Drug efficacy can be mechanism-dependent, for example, a drug that is effective in treating nociceptive pain might provide little or no relief for neuropathic pain. For example, a chronic pain patient with nociceptive pain involving a neuropathic component (a common clinical presentation) is often best treated with a combination of drugs or one drug that has multiple mechanisms of action.

In addition to ascending pathways to the brain for processing and descending pathways for inhibitory modulation [9], peripheral and central sensitization can amplify or alter pain signals in an aberrant way, such that a mild noxious stimulus is perceived as very painful or a non-noxious stimulus is perceived as painful. Multi mechanistic pain may occur, for example, in osteoarthritis where central sensitization creates a neuropathic component that combines with nociceptive pain, creating the so-called “mixed pain state.” In such mixed pain states, both peripheral and central sensitization increase the excitability of the ascending pain pathways and decrease descending pain inhibition. Complicating the picture, psychosocial factors and mental health comorbidities may also come into play. Such chronic pain syndromes may not correlate with the extent of tissue damage or localized inflammatory zones [10].

The μ-opioid receptor system and the mono aminergic system are two important, closely interconnected pain modulatory systems. μ-opioid receptor agonists inhibit transmission of pain signals and influence higher brain centers (thus, both the sensation and perception of pain), whereas the noradrenergic system primarily modulates (attenuates) pain signal transmission via descending pathways that synapse in the dorsal horn of spinal cord [11,12]. For a schematic on the ascending and descending pain pathways please see reference [13]. μ-opioids inhibit presynaptic vesicular neurotransmitter release (by inhibiting Ca2+ influx) and hyperpolarize post-synaptic neurons (by altering K+ flux). Inhibition of neuronal noradrenaline reuptake results in an increased synaptic level of noradrenaline and an enhanced inhibitory action.

As pain persists, one system might become more dominant. For example, if acute pain transitions into neither chronic pain (chronification), noradrenaline-mediated inhibition can be increasingly important [14]. Chronic pain can also result in alteration of the opioideric system which, in turn, alters responsiveness to opioid analgesics [15]. Several possibilities are receptor up- or downregulation, opioid-induced hyperalgesia, and others [16]. Altered activity of the neither opioidergic system means that the balance shifts toward noradrenaline-mediated pain inhibition assuming greater importance [17]. The role of another monoamine in the descending pathways, 5-HT (5-hydroxytryptamine, serotonin) is less clear. For example, fluoxetine, a selective serotonin reuptake inhibitor (SSRI) has no clinically meaningful analgesic effect [18]. 5-HT can also have a pro-emetic effect, decreasing tolerability. An agent that targets the μ-opioid and noradrenaline, but not 5-HT, systems might strike the proper balance, with greater efficacy and reduced adverse effects.

Barriers to multi mechanistic pain therapy

In a survey of 415 physicians, 60% ‘agreed’ or ‘totally agreed’ that there is insufficient knowledge within the medical community about the pharmacological characteristics of different analgesic regimens, and 81% agreed or totally agreed with the statement that pain with a neuropathic component is often more severe and more difficult to treat [19]. While the identification of the underlying mechanism of pain can be important in the planning of a treatment strategy, identifying the specific mechanisms can be challenging, particularly since symptoms are not always reliable indicators of pain mechanism [20]. A single medication that could target multiple pain components (e.g., neuropathic and nociceptive) would eliminate the need to pinpoint exact pain mechanisms, simplifying prescribing.

Multidrug therapy guidelines

Practice guidelines for pain therapy advocate the use of combination therapy [21]. The American Society of Anesthesiologists Task Force on Acute Pain Management writes, “The literature supports the administration of two analgesic agents that act by different mechanisms via a single route for providing superior analgesic efficacy with equivalent or reduced adverse effects [22]”. Although the use of multidrug analgesic regimens is less well studied for chronic pain, the strategy has been endorsed for a variety of chronic pain syndromes [23].

The interruption of more than one mechanism of pain signaling increases the likelihood of successful pain treatment. For this, combination drug therapy should involve using agents with different, but complementary, mechanisms of action. Plus, when two or more agents are taken together, there is the possibility that they will have a synergistic effect (where the total effect is greater than the additive effects of the individual agents) [24,25]. Figure 1 (A. and B., it is also possible that combination therapy will amplify adverse effects).