Introduction
The first opioids were plant-derived opiates, including morphine and codeine (which undergoes Phase 1 cytochrome P450-catalyzed metabolism to morphine). Their therapeutic pain-relieving effects were discovered serendipitously, and they were used for centuries without much rational scientific understanding of how they produced their beneficial effects. However, in addition to pain relief, the opiates unfortunately produce a spectrum of adverse effects such as constipation and respiratory depression that are inexorably linked to the analgesic effect, and they have abuse potential related to their activation of MOR (μ-opioid receptor) [
1,
2]. The explanation for the lack of dissociation between therapeutic and adverse effects is now understood—their major analgesic mechanism is the same as their adverse effect mechanism, namely MOR agonism, so they are in this regard in essence mono-modal or one-dimensional (albeit differences in pharmacology or pharmacokinetics can result in nuances in their clinical profile).
In the absence of a molecular target, subsequent semi-synthetic and synthetic opioids were discovered by structure–activity relationships in which the dependent variable was obtained from in vivo screening using animal models (such as abdominal constriction, hot plate, tail flick, etc., tests). Such screening led to a great number of useful opioids with individual differences [
3,
4], but, due to the way they were discovered, they are essentially pharmacologic ‘clones’, that is, they display fundamentally the same pharmacology as the predecessors that were used as the template and standards.
The discovery in the early 1970s that opioids produce their effects via binding to 7-transmembrane G protein-coupled opioid receptors [
2] and activating their 2nd-messenger transduction systems transformed the initial stages of drug discovery from screening through animal models to ‘directed’ in vitro high-throughput screening in selective assays for affinity for, and intrinsic activity at, opioid receptors and receptor subtypes expressed in specialized cells or modeled on computers using computational techniques [
5,
6].
Based on the discovery of opioid receptors, the logical hypothesis was reached that there must be endogenous ligands for these receptors, and endogenous opioid peptides were soon identified. The existence of opioid receptors and endogenous ligands for these receptors revealed for the first time a cellular-level mechanistic explanation for how the exogenous opioids produced both their analgesic, and their other receptor-mediated (side-) effects [
2]. It also helped to delineate what is now recognized as a major afferent nociceptive (pain-detecting/transmitting) pathway. For years, opioid pharmacology and drug discovery was directed toward compounds that had ever-greater selectivity and binding affinity for opioid receptors. There was thus a race to a more mono-modal mechanism of analgesic action. And with that came the more mono-modal opioid receptor-mediated adverse effects. As a result, with pure opioid drugs, the MOR contribution to adverse effects (e.g., constipation, respiratory depression, etc.) is 100%.
During the course of such drug discovery, however, it was inevitable that drugs with more than one pharmacologic mechanism of action were discovered [
7]. For such drugs, four outcomes are possible: the mechanisms contribute either positively or negatively to the analgesic effect, and positively or to a less extent to adverse effects [
8]. The latter category—drugs that have mechanisms of action that are either additive or synergistic on the analgesic endpoint, but less than additive on adverse effect endpoints—would possess clinically advantageous properties [
9,
10]. Two such drugs (buprenorphine [
11‐
15] and tramadol [
16,
17]) were recognized after discovery. One (tapentadol) was designed and discovered with a specific dual mechanism as the goal [
18‐
20].
Concurrent with the identification of analgesics with favorable clinical features was the discovery of pain modulatory pathways. Thus, in addition to long-known afferent (‘ascending’) pain-sensation transmitting pathways, there are ‘descending’ pain-sensation modulating pathways in the brain and spinal cord [
21]. Now collectively known as DNIC (diffuse noxious inhibitory control), activity in these pathways can modify the amplitude or temporal characteristics of pain signals [
22]. The monoamines, norepinephrine and serotonin, play prominent roles in the descending pathways, with variable contributions in different types of pain, at different anatomical sites, and at different periods in the progression or time course of pain. Furthermore, experience has shown that many pains involve more than one (patho)physiological process [
23,
24], having, for example, both a neuropathic component and a nociceptive component. Therefore, treatment of such pains with mono-mechanistic analgesics usually yields sub-optimal results (either insufficient pain relief or excess adverse effects). In such cases, better separation of therapeutic from adverse effects can be achieved by using analgesics with multiple mechanisms of action that match the multiple mechanisms of pain (patho)physiology [
25,
26].
Buprenorphine and tramadol are examples of analgesics that were found to have multiple mechanisms of analgesic action after their synthesis. Buprenorphine has very high affinity for MOR, which is a major mechanism of its analgesic action [
27]. It has recently been shown to have an additional supraspinal naloxone-, PTX- (pertussis toxin), and NOP (nociception/orphanin FQ peptide)-insensitive, Gz- and Ser/Thr-sensitive mechanism, and possibly other contributory mechanisms [
28]. Tramadol produces its analgesic effect by the combined action of the enantiomers of the parent drug and enantiomers of its
O-desmethyl (M1) metabolite. Tramadol has at least three mechanisms: affinity for MOR, inhibition of neuronal reuptake of norepinephrine (NRI), and inhibition of neuronal reuptake of serotonin (SRI).
Tapentadol is the only approved centrally-acting analgesic that was chemically engineered from the beginning to possess strong analgesic efficacy by combining two specific synergistic mechanisms of analgesic action (‘directed polypharmacology’) [
29,
30]. The two mechanisms are: activation of MOR and the inhibition of neuronal reuptake of NRI (MOR-NRI) [
18‐
20,
31‐
33]. The outcome of this approach is that tapentadol is more potent in a variety of animal models, and in clinical trials has been shown to have comparable efficacy to oxycodone, with more favorable tolerability [
34‐
40]. It is a single molecule, has no analgesically active metabolite [
41], and is metabolized primarily by glucuronidation (rather than CYP450) [
42].
Although tapentadol is a strong analgesic in animal models [
43] and humans [
44‐
46], it binds to recombinant human MOR with an affinity of 0.16 μM (
Ki value). For comparison, that is about 10- to 20-fold lower affinity than morphine or oxycodone for MOR [
18,
47,
48]. How does one account for a lower receptor affinity yet greater analgesic potency and efficacy of a molecule? In the case of tapentadol, the answer came from an animal study that demonstrated that tapentadol’s two mechanisms of analgesic action (MOR-NRI) independently contribute to the analgesic effect, and in fact produce a synergistic (greater than the expected additive)–analgesic effect [
49,
50]. The synergistic interaction can account for its greater functional (therapeutic effect) activity.
Importantly, though, the two mechanisms do not interact synergistically on an adverse effect endpoint (constipation) [
51]. There is thus a mechanistic explanation for a favorable separation between the analgesic effect and adverse effects [
51]. Nevertheless, such a separation needs to be demonstrated clinically. In fact, data from clinical trials demonstrate that tapentadol produces pain relief comparable to oxycodone, but that it has a better tolerability profile, i.e., a better balance of benefit (effective analgesia) and risk (adverse effects) [
52‐
55]. There is therefore compelling evidence that each component of tapentadol, opioid and non-opioid, independently contributes significantly to its analgesic effect; that is, the overall effect is a sort of hybrid of a polypharmacological ligand. It is also suggested by the data that the contribution of the opioid component to adverse effects might be less than its contribution to analgesia.
Two questions thus arise. First, what is the relative contribution of tapentadol’s opioid component to its analgesic effect? Second, what is the relative contribution of tapentadol’s opioid component to adverse effects? To date, there has been no formal attempt to answer these questions. In the case of a drug that has enantiomers, for example, tramadol, the assessment is facilitated by the ability to administer each enantiomer separately, and observing the effect of each independently, then together. In the case of a single molecule such as tapentadol, the analysis is less obvious or direct. We use available data to provide the first attempt at a quantitative answer to the question of the relative contribution of tapentadol’s opioid component to analgesia and to adverse effects. Since we are not aware of any prior attempt to answer such questions for any other drug, there is no definitive way to do so. We thus decided to take a variety of different approaches, and analyzed whether the answers would converge to an agreeably consistent answer. We selected approaches that we loosely label ‘in vitro and PK’, ‘in vivo’, and ‘clinical’. The ‘in vitro’ approach will be recognized as emanating directly from affinity, intrinsic activity, and pharmacokinetic data. The ‘in vivo’ approach involves novel analysis, but is essentially a type of component factor analysis. And the ‘clinical’ approach utilizes available clinical data. Both clinical and preclinical data are taken from previously conducted studies, and no studies with human participants or animals were performed by any of the authors for this analysis.
The remainder of the manuscript is designed so that the reader uninterested in the mathematical details can read the explanations and conclusions without loss of continuity.
Conclusion
The analyses described here, using a variety of different approaches, and a variety of in vitro, in vivo, and clinical data, lead to the following findings:
1.
Combining principles of drug–receptor binding and signal transduction (in vitro) data with available pharmacokinetic data suggests that the μ-load of tapentadol should theoretically be about 17–28%.
2.
From in vivo animal models, the opioid (MOR) component of tapentadol contributes slightly more than ½ (~ 54%) to analgesia in a nociceptive pain (LITF-r) model and about 1/3rd (~ 36%) in a neuropathic pain (SNL-r) model. This is consistent with available data on the in vivo activity of tapentadol.
3.
The contribution of tapentadol’s μ-opioid component of mechanism of action to the prototypical opioid adverse effect (μ-load) of respiratory depression (as modeled by inhibition of respiratory stimulatory effect of CO2 in rats and humans) is approximately 40% that of morphine and other single-mechanism opioids.
4.
The contribution of tapentadol’s μ-opioid component of action to the adverse effect of constipation (modeled by the inhibition of gastrointestinal transit of charcoal in rats) is approximately 30%, thus about 1/3rd that of morphine and other single-mechanism opioids.
From post hoc analysis of clinical trials in which constipation-related data were obtained, the μ-load of tapentadol for constipation in humans is in the range of 38–41%, very similar to the calculated estimates from the animal studies.
The results are summarized in Tables
1 and
2.
Table 1
Summary of the calculated estimates of the contribution of tapentadol’s opioid component to its analgesic (antinociceptive) action
Nociceptive | Animal model: LITF-r (low-intensity tail-flick test, rat) | 54 |
Neuropathic | Animal model: SNL-r (spinal nerve ligation test, rat) | 36 |
Table 2
Summary of the calculated estimates of the contribution of tapentadol’s opioid component to adverse effects relative to analgesia (its μ-load)
Constipation | Animal model (inhibition of GI transit, rat) | 30 |
Clinical trial (cLBP) | 40 |
Clinical trials (OA pain) | 33–41 |
Respiratory depression | Animal model (inhibition of CO2 stimulation) | 39–46 |
Clinical pharmacology (VE55)–100/150 mg vs. oxycodone | ~ 40 |
Expert Opinion
Prior to the introduction of a select few analgesics that produce their effects by the combined complementary contribution of an opioid and one or more non-opioid components, the class of opioid analgesics was rather monolithic. Despite subtle differences in pharmacodynamics or pharmacokinetics, they primarily produce their therapeutic and adverse effects which are for the most part mediated by the same receptors (MOR) [
4,
53]. It thus did not make sense to talk of a μ-load for this class of drugs, because the μ-load of all of the opioids was essentially 100%. However, the introduction of mixed agonists-antagonists (e.g., nalbuphine, pentazocine) and the three multi-mechanistic centrally-acting analgesics (buprenorphine, tramadol, and most recently tapentadol) raises the question of the relative contribution of the opioid component to their analgesia and to their adverse effects. Multimechanistic analgesic drugs can indeed be different, since the mechanisms can interact in an additive or synergistic way to produce analgesia, yet to a less than additive, even counteractive, way to produce adverse effects [
7]. Since tapentadol was the only one of the three that was designed (‘engineered’) to have its specific ‘polypharmacologic’ profile [
18,
29], it was of particular interest to determine the relative contribution of its opioid component to analgesia and to adverse effects relative to pure MOR agonists at equianalgesic doses (what we term here its μ-load) (see Table
3).
Table 3
Article Highlights
In terms of analgesic response, the main relevant receptor for most commonly-used opioids is MOR (μ-opioid receptor). Thus, when considering the balance between analgesia and opioid-typical adverse effects, the opioids are rather mono-mechanistic |
In contrast, tapentadol’s analgesic effect results from the combined contributions of an opioid and a non-opioid mechanism of action |
Tapentadol’s dual opioid (MOR) and non-opioid (norepinephrine reuptake inhibition; NRI) mechanisms of action combine in a complementary and synergistic manner to produce an antinociceptive effect (analgesia) in animal models, but in less than a synergistic manner to produce the adverse effect of constipation. The question is: to what extent does the opioid component contribute to analgesia on the one hand, and to adverse effects on the other hand? |
We here estimate, using drug–receptor theory and several different approaches, the μ-load of tapentadol for two classic opioid adverse effects (constipation and respiratory depression) |
The calculations confirm that both components of tapentadol’s mechanism of analgesic action contribute to its therapeutic effect |
However, unlike mono-mechanistic opioids, the μ-load (the MOR-related effect in comparison to the effect of a pure/classical opioid at equianalgesia) of tapentadol is substantially less than 100% (calculated estimates yield values of ≤ 40%) |
The μ-load varies somewhat by type of pain (neuropathic and nociceptive) and by type of adverse effect (constipation and respiratory depression) that is considered for the estimation |
Estimates using clinical trial data yield results similar to the estimates using in vitro and in vivo animal data |
The results of this analysis are consistent with, and help explain, the favorable clinical characteristics of tapentadol with regards to opioid-induced side effects. Because of the synergistic mechanism of action, tapentadol provides 100% of the analgesic efficacy of a pure strong opioid, but at < 40% of the µ-load |
The results of our analysis also suggest that for a drug to be a strong analgesic, it does not have to be a strong opioid, and that this distinction is particularly important when considering the side effects of strong analgesics |
Based on extensive in vitro and in vivo data in a large variety of assays and in a large variety of animal models, tapentadol (a single entity without an analgesically-active metabolite) produces its antinociceptive (analgesic) effect by the combined contribution of two components: one opioid and the other non-opioid [
18‐
20,
31‐
33]. The opioid component consists primarily of activation (an agonist action) at μ-opioid receptors, while the non-opioid component consists primarily of inhibition of the neuronal reuptake of norepinephrine. In addition, preclinical studies have demonstrated a (positive) synergistic interaction between the two components on pain relief, but less than synergistic interaction on an adverse effect endpoint (constipation). It is therefore clearly a mechanistic possibility that, unlike for mono-mechanistic opioids, the μ-load of tapentadol can be less than 100% [
34‐
40], as found here.
Since no study has been specifically designed to determine a drug’s μ-load, there was no precedence to follow, so we decided to intentionally use a variety of techniques and assumptions, some techniques more rigorous and quantitative than others, in order to obtain a broad overview of the range of estimates. We also decided to compare the results obtained from in vitro, in vivo (animal model), and clinical trial data. The reasoning was that diverse approaches would give a better estimate than would a single estimate. In fact, the estimates of μ-load obtained here using the diverse approaches and sources of data converged to a surprising degree, and rather consistently at ≤ 40%.
Given the inherent diversity of the sources and usability of the data, and the number of quite disparate approaches employed, it seems remarkable that the estimates fall within such a narrow range. The fact that they do enhances confidence in their estimates. The results also make sense. For example, tapentadol was designed to have dual contributions to analgesia, only one of which is opioid. So the calculations here that the opioid component is not the only contributor to analgesia, but that the non-opioid component also contributes to a significant extent, is consistent with the original design intent. It is therefore also reasonable to find here that the estimates of the μ-load of tapentadol are consistent from test tube to animal to human data, and yield values substantially less than 100%.
The estimates for tapentadol’s μ-load calculated here are consistent, not only with the intent from the inception of the drug’s design but also with the clinical experience with the drug. In several clinical trials, tapentadol has been shown to produce analgesia that is equivalent to oxycodone, but with greater gastrointestinal tolerability (greater separation of adverse from therapeutic effects). The results are also consistent with tapentadol’s activity against different types of pain [
34‐
40]. As mentioned above, preclinical data suggest that the NRI component instills in it a more potent effect against neuropathic pain than against acute nociceptive pain, another fact consistent with the present findings. Interestingly, this is also consistent with clinical evidence suggesting that tapentadol is more potent in chronic low back pain patients whose pain has a neuropathic component as opposed to pain of purely nociceptive origin [
60,
61].
Given the significant contribution of tapentadol’s non-opioid mechanism (NRI) of analgesic action, and its low μ-load for adverse effects estimated here, it might be worth consideration that it is more accurately called a ‘strong analgesic’ rather than a ‘strong opioid’. The results of our analysis suggest that for a drug to be a ‘strong analgesic’, it does not have to be a strong opioid, and that this distinction is particularly important when considering the side effects of strong analgesics.