The last years have witnessed major advances in the knowledge of the basic mechanisms
underlying the onset and the chronification of pain. In particular, it has emerged
that pain signaling and modulatory mechanisms change following physiopathological
events, such as the two major types of pain, neuropathic and inflammatory pains. Very
different chemical events and ion channel changes, respectively, underlie these pains
at peripheral levels, so treatments have to differ. Low back pain and cancer pain
can be one or the other or a combination of these different mechanisms, so-called
mixed pains. The final pain experience is a combination of all these peripheral and
central events, but within the central nervous system, the pain controlling systems
are more common so that therapies acting on central modulation can span a range of
pain conditions. Descending controls link the brain back to the spinal cord, where
noradrenaline (NRI) is a key inhibitory transmitter in pain control in these pathways.
Descending controls run from the brain to the spinal cord and can be gaged in patients
– the balance between excitations and facilitations’ shift to the latter in persistent
pain states, reinforcing pain transmission.1
Understanding the mechanisms for pain enhancement and modulation can help to explain
these altered pain states in patients and will lead to better treatments.
What if there was a single drug with more than one mechanism that had the efficacy
of a strong opioid, yet, with a reduced opioid load? Tapentadol is the only member
of the new mu opioid receptor (MOR)–NRI class of analgesic agents. Indeed, it presents
an MOR activity, although much less than that of morphine, but with a simultaneous
ability to inhibit the reuptake of NA (NRI), a key inhibitory transmitter in pain
control.2
The extensive preclinical data on tapentadol reveal an efficacy equal to that of morphine
but with a major noradrenergic component in behavioral and neuronal measures in models
of nerve injury, arthritis, and cancer-induced bone pain.3,4
There is a positive synergy between the MOR and NRI actions and an ability to control
central sensitization. The MOR action inhibits pain messages at the spinal cord levels
and in the brain, and the NRI provides a powerful inhibitory action on spinal events.
The prediction from the animal data that tapentadol should be effective in pain from
tissue and nerve damage, and so also mixed pain, has translated excellently to the
patient.5
Indeed, in rats and humans, tapentadol restores the failed NA inhibitions as measured
directly in patients through conditioned pain modulation.6 These actions occur with
reduced opioid load and so there are fewer MOR side effects. A failure of descending
inhibitions and the presence of central sensitization are predictors of chronic pain
in patients. The ability of a drug to restore normal modulation in the central nervous
system restores normal transmission, although it does not remove the cause of the
pain.
Of note, the pharmacological profile of tapentadol, combining synergistically MOR
agonism and NRI in one molecule, appears to be unique and it seems reasonable to propose
for tapentadol, a new class of centrally acting analgesics, designated MOR-NRI.7 Experimental
evidence showing that NRI is a key mechanism that can be predominant in chronic/neuropathic
pain reinforces the concept that tapentadol is different to classical opioids and
may therefore be an a priori choice for the treatment of chronic, neuropathic, and
mixed pains.5 Moreover, this concept has been strengthened and expanded to other drugs
(tramadol, buprenorphine, loperamide, and cebranopadol), suggesting that inclusion
of all analgesics that have any component of opioid mechanism of action into the same
class is misleading. On the other hand, the recognition of subclasses of opioids seems
warranted scientifically and beneficial to health care providers, payers, and regulators.
To date, some definitions have been proposed such as atypical and multigesic.8,9
Indeed, the umbrella terms “chronic noncancer pain” and “cancer pain” do not tell
much about their different underlying pathologies and pain mechanisms. The assessment
of individual nature, site, and mechanisms of pain is essential for effective multimodal
treatment with invasive and/or noninvasive and, often, pharmacological options. Whereas
the WHO analgesic ladder using nonopioids, opioids, and adjuvant analgesics has remained
the mainstay of pain management in cancer patients,10 no such universal guideline
for the pharmacological management of chronic noncancer pain exists.
Besides morphine, other MOR agonists, such as fentanyl and buprenorphine, including
their transdermal delivery systems, hydromorphone and oxycodone, have been developed
for improved efficacy and safety. However, truly innovative analgesics that utilize
combined mechanisms of action are required for generating better response rates, fewer
side effects, and improved tolerability, particularly in elderly patients. As comprehensively
reviewed by the expert authors of this supplement, the innovative centrally acting
analgesic tapentadol (Palexia®) represents such a new class of analgesic7 with two
synergistic mechanisms of action in one molecule, MOR agonism and NRI.11,12
Registration studies in thousands of nononcological patients have shown tapentadol
being effective and well tolerated for the management of moderate-to-severe chronic
noncancer pain with comparable efficacy but significantly superior gastrointestinal
tolerability to oxycodone controlled release (CR).13–15 Two clinical trials in patients
with painful diabetic polyneuropathy have proven the efficacy of tapentadol prolonged
release (PR) even in typical neuropathic pain conditions, and preliminary evidence
also exists for its effectiveness in chronic low back pain and other mixed pain conditions
characterized by a concomitant neuropathic pain component.16
Opioid analgesics, in particular morphine, have an established role in the management
of moderate-to-severe cancer pain.17–19 International, multicenter, placebo- or active-controlled,
double-blind, Phase III studies20,21 and several open-label or observational trials
demonstrated at least comparable efficacy, safety, and better tolerability of the
MOR–NRI tapentadol PR or extended release (ER) (PR in Europe = ER in USA) for the
management of moderate-to-severe chronic cancer pain.22
For physicians treating elderly patients with various co-morbidities, it is important
that tapentadol is characterized by a predictable and reliable pharmacokinetic profile
that makes pharmacokinetic drug–drug interactions unlikely to occur. No pharmacologically
active metabolites are generated, and no inhibition or induction potential on CYP/CYP450
enzymes has been demonstrated. Explicitly, there was a lack of clinically undesired
interactions with paracetamol, acetylsalicylic acid, naproxen, probenecid, omeprazole,
or metoclopramide.
The present supplement summarizes current clinical evidence on tapentadol in the treatment
of different types of pain and provides a robust practical guidance for the beneficial
use of this innovative centrally acting analgesic in chronic cancer and noncancer
pain patients.