Pharmacological rationale for tapentadol/Nucynta

Pharmacological rationale for tapentadol therapy: a review of new evidence – free full-text /PMC6526917/ – 2019 May

Chronic pain could be considered as a neurological disorder.

Tapentadol is an analgesic drug which acts both as a μ-opioid receptor (MOR) agonistand as a noradrenaline reuptake inhibitor (NRI), thereby generating a synergistic action in terms of analgesic efficacy, but not for the burden of adverse effects.

Therefore, tapentadol can be defined as the first “MOR-NRI” drug. This molecule holds the potential to address at least some of the current limitations of analgesic therapy due to its unique mechanism of action and has shown to be safe and effective in the treatment of chronic pain of cancer and noncancer etiologies including nociceptive, neuropathic and mixed pain.  

In particular, the MOR component of tapentadol activity predominantly allows for analgesia in nociceptive pain; on the other hand, the NRI component contributes, now in a predominant manner, for analgesic efficacy in cases of neuropathic pain states.

This paper will discuss recent pieces of evidence on the pathophysiology of pain, the background on tapentadol and then present some new studies on how the unique mechanism of action of tapentadol provides a key role in its analgesic efficacy in a number of pain states and with a favorable safety profile.

Pathophysiology of pain: new evidence

The importance of central sensitization

The transmission of noxious stimuli along the ascending pathways is influenced by the action of descending modulatory pathways.

As recently reviewed, over the last few years mounting attention has been paid to the processes that lead to chronic pain, which encompasses a number of functional and structural modifications of the involved structures.

Indeed, from the very early stage of acute pain (few hours), the neural structures involved in pain start to undergo plastic modifications so that peripheral and central sensitization can ensue.

Tissue damage or nociceptor activation can lead to peripheral sensitization: peripheral nociceptors reduce their activation threshold and increase their responsivity to noxious stimuli.

If the cause of the inflammatory pain resolves within a few days, such plastic modifications also regress.

…if the stimulus persists, high-frequency transmission is upheld with massive spinal release of glutamates and neuro-modulating peptides. This release of neurotransmitters ultimately leads to modifications of the spinothalamic neurons and inter-neurons, promoting increased excitability, a phenomenon known as central sensitization.

Pain evolution

According to available evidence, the process of chronification of pain could be divided into three consecutive stages.

The first stage, acute pain, is characterized by localized pain, with intensity proportional to the stimulus or tissue damage. The pain usually resolves rapidly and often with anti-inflammatory drugs; lack of modulation of such episodes must not be underestimated, since they may ultimately trigger the more progressive stages.

In the second stage, defined as “progressive recurrent pain”, the pain has not yet become chronic. However, more frequent and intense episodes of pain may occur, with the interval between them being either entirely pain-free or characterized by mild persistent pain; central sensitization and altered descending control phenomena start developing leading to expanded areas of pain and more hyperalgesia and allodynia, and possibly even structural modifications may occur if pain is not adequately treated.

This type of pain is likely responsive to effective treatment, and therefore the early establishment of appropriate therapy is of paramount importance.

In the third and final stage, the changes in the processes of pain have become established in the periphery, spinal cord and higher centers and both transmission and modulation pathways now may present pathological properties with a gain of excitation and a loss of inhibition

In this phase, central sensitization and other changes becomes more and more established, contributing to a number of different pain conditions. (Table 1)

Moreover, as pain becomes chronic, quality of life reduces, and the patients may experience mood alterations, depression and/or anxiety, and diminished ability to carry out daily activities

Table 1:

Chronic pain conditions in which different aspects of the central sensitization phenomenon have been assessed and validated mechanistically with quantitative sensory testing

  • Chronic fatigue syndrome
  • Chronic low back pain
  • Chronic pancreatitis
  • Endometriosis
  • Fibromyalgia
  • Irritable bowel syndrome
  • Migraine
  • Multiple chemical sensitivity
  • Myofascial pain syndrome
  • Neurogenic pain
  • Non-cardiac chest pain
  • Osteoarthrosis
  • Pelvic pain/interstitial cystitis
  • Post-traumatic stress disorder
  • Postoperative chronic pain
  • Primary endometriosis/dysmenorrhea
  • Restless legs
  • Rheumatoid arthritis
  • Shoulder impingement syndrome
  • Temporomandibular disorders
  • Tension type headache/chronic tension type headache
  • Vulvodynia
  • Whiplash

Descending facilitatory and inhibitory pathways originating in supraspinal centers could influence the perception of pain and modulate the activity of spinal nociceptors through increased or decreased propagation of signals to the brain.

The release of neurotransmitters, including endogenous opioids, NA and 5-HT, underlies the modulation of the noxious stimulus.

MOR agonists inhibit transmission of pain signals along the ascending pathways and are involved in the modulation of supraspinal pain signals through their action in descending pathways.

Noradrenergic pathways exert an inhibitory effect on the transmission of acute pain, and changes in these systems appear to contribute to chronic pain.

An imbalance between amplified spinal ascending signals and inadequate activation of the descending inhibitory pathways has been suggested to lead to the development and maintenance of many chronic pain syndromes

Experimental evidence suggests that effective involvement of inhibitory descending pathways could protect against the development of chronic pain.

Moreover, the MOR activation is particularly relevant in acute nociceptive pain, while the inhibition of NA reuptake activity plays a crucial role in chronic neuropathic pain

Does this imply that opioids are required at this stage?

Mechanism of action

Tapentadol is a novel, centrally acting analgesic drug. It is the first representative of a new class of drugs, which can be referred to as MOR-NRI drugs, and it displays an analgesic efficacy comparable or superior to that of strong classical opioids such as oxycodone and morphine.

Despite a 50-fold lower affinity for MOR and relatively moderate NRI activity tapentadol potency is comparable to that of morphine across a variety of preclinical pain models.

 a synergistic interaction between the two distinct mechanisms of action within the single molecule. Thanks to this intricate interaction and mutual enhancement of the individual effects, relatively moderate receptor activities are sufficient for both mechanisms of action to achieve a strong analgesic effect by acting on both ascending and descending pathways (Figure 2).

Remarkably, a very recent study suggested that the “μ-load” of tapentadol is ≤40%, relative to pure MOR agonists, which have, by definition a μ-load of 100%.

This reduced μ-load likely translates into a more favorable tolerability profile of tapentadol compared with strong classical opioids.

This is pure speculation.

3 thoughts on “Pharmacological rationale for tapentadol/Nucynta

  1. canarensis

    I know one thing I’m certainly hypersensitized to is statements like “The [acute] pain usually resolves rapidly and often with anti-inflammatory drugs” Is this a sneaky way of saying “no opioids for acute pain treatment, or is it just my paranoia on the subject?

    Jeez, that list of conditions where “central sensitization phenomenon have been assessed and validated mechanistically” is a laundry list of my issues plus some other things I don’t have. Can’t decide whether I feel honored or doomed. Or damned. At least my endometriosis didn’t roar up after that surgery (tho I got great pain treatment for a week or so), despite the fact that he had to leave a chunk that was wrapped around my abdominal aorta.

    “This is pure speculation.”
    Yup. Again, they seem to be avoiding the issue of individual variability, genetics, etc etc. I also thought at the statement “it displays an analgesic efficacy comparable or superior to that of strong classical opioids such as oxycodone and morphine.” Strong for who? I can take oxycodone like tictacs without noticing any analgesia –or anything else. In fact, I’ve never gotten the teeniest high from any opioid, via any form of administration including IVs in hospitals after surgery.

    Liked by 1 person

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