Tapentadol: A Review of Experimental Pharmacology Studies, Clinical Trials, and Recent Findings.

Tapentadol is an analgesic compound that acts centrally to attenuate pain. Previous studies have shown that tapentadol has dual mechanisms of action as a mu-opioid receptor agonist and noradrenaline re-uptake inhibition. Therefore, tapentadol provides a great advantage over classic opioids in pain management from nociceptive to neuropathic. Cumulative evidence from in vitro data suggests that tapentadol effect of norepinephrine re-uptake could be a new target that overcomes other classic opioids in chronic neuropathic pain. Compared to tramadol and other opioids, tapentadol is associated with fewer adverse effects than tramadol. Tapentadol is a new alternative to treat acute, chronic, and neuropathic pain. Thus, this review article was focused on understanding the studies that led to the development of tapentadol as a novel analgesic drug and its advantages over conventional opioids. Thus, tapentadol is a good alternative with fewer adverse effects and is available for human use.

Tapentadol shows lower intrinsic efficacy at µ receptor than morphine and oxycodone.

Tapentadol is a centrally acting analgesic with a dual mechanism of action. It acts as an agonist at the µ receptor and inhibitor of noradrenaline reuptake. Clinical trials suggest similar analgesic efficacy of tapentadol, oxycodone, and morphine in acute and chronic pain. Given the limited information about the molecular actions of tapentadol at the µ receptor, we investigated the intrinsic efficacy of tapentadol and compared it with other opioids. ß-chlornaltrexamine (ß-CNA, 100 nM, 20 min) was used to deplete spare receptors in AtT20 cells stably transfected with human µ receptor wild-type (WT). Opioid-mediated changes in membrane potential were measured in real-time using a membrane potential-sensitive fluorescent dye. Using Black and Leff's operational model, intrinsic efficacy relative to DAMGO was calculated for each opioid. Tapentadol (0.05 ± 0.01) activated the GIRK channel with lesser intrinsic efficacy than morphine (0.17 ± 0.02) and oxycodone (0.16 ± 0.02). We further assessed the signaling of tapentadol in the common µ receptor variants (N40D and A6V) which are associated with altered receptor signaling. We found no difference in the response of tapentadol between these receptor variants.

Comparative study of dezocine, pentazocine and tapentadol on antinociception and physical dependence.

AIMS: Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting µ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol. MAIN METHODS: Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine. KEY FINDINGS: Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α2-adrenoceptor (α2-AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment. SIGNIFICANCE: Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI.

Tapentadol Versus Tramadol: A Narrative and Comparative Review of Their Pharmacological, Efficacy and Safety Profiles in Adult Patients.

We conducted a narrative review of the literature to compare the pharmacological, efficacy and safety profiles of tapentadol and tramadol, and to assess the clinical interest of tapentadol in adult patients. Tapentadol and tramadol share a mixed mechanism of action, including both mu-agonist and monoaminergic properties. Tapentadol is approximately two to three times more potent than tramadol and two to three times less potent than morphine. It has no identified analgesically active metabolite and is not significantly metabolised by cytochrome P450 enzymes, thus overcoming some limitations of tramadol, including the potential for pharmacokinetic drug-drug interactions and interindividual variability due to genetic polymorphisms of cytochrome P450 enzymes. The toxicity profiles of tramadol and tapentadol are similar; however tapentadol is likely to result in less exposure to serotoninergic adverse effects (nausea, vomiting, hypoglycaemia) but cause more opioid adverse effects (constipation, respiratory depression, abuse) than tramadol. The safety of tapentadol in real-world conditions remains poorly documented, particularly in at-risk patient subgroups and also in the ability to assess the risk associated with its residual serotonergic activity (serotonin syndrome, seizures). Because of an earlier market introduction, more real-world safety data are available for tramadol, including data from at-risk patient subgroups. The level of evidence on the efficacy of both tramadol and tapentadol for the treatment of chronic pain is globally low. The trials published to date show overall that tapentadol does not provide a clinically significant analgesic improvement compared to existing treatments, for which the safety profile is much better known. In conclusion, tapentadol is not a first-line opioid but represents an additional analgesic in the therapeutic choices, which some patients may benefit from after careful examination of their clinical situation, co-morbidities and co-medications.

Although tapentadol and oxycodone both increase colonic volume, tapentadol treatment resulted in softer stools and less constipation: a mechanistic study in healthy volunteers.

OBJECTIVES: Opioids are often used in treatment of severe pain, although many patients experience gastrointestinal side-effects like constipation. The aim of the current study was to investigate changes in colonic volume, as the result of both colonic motility and fluid transport, in healthy volunteers during opioid treatment with tapentadol as compared with oxycodone and placebo. METHODS: In a randomized, double-blind, cross-over study, 21 healthy male volunteers were administered equianalgesic dosages of oral tapentadol (50 mg bid), oxycodone (10 mg bid) or corresponding placebo for 14 days. Segmental colonic volumes were quantified using T2-weighted magnetic resonance images, and gastrointestinal side-effects were assessed with questionnaires. RESULTS: Total colonic volume increase during treatment was higher during tapentadol and oxycodone treatment (median 48 and 58 mL) compared to placebo (median -14 mL, both p≤0.003). Tapentadol (and placebo) treatment resulted in more bowel movements (both p<0.05) and softer stool consistency as compared with oxycodone (both p<0.01). Only oxycodone treatment was associated with increased constipation, straining during defecation, and tiredness (all p≤0.01). The colonic volume increase during treatment was directly associated with softer stools during tapentadol treatment (p=0.019). CONCLUSIONS: Tapentadol treatment increased colonic volume without leading to harder stools, likely as the opioid sparing effects result in less water absorption from the gut lumen. Oxycodone treatment also increased colonic volume, but with a simultaneous increase in stool dryness and gastrointestinal and central nervous system side-effects. The results confirm that tapentadol treatment may be advantageous to oxycodone regarding tolerability to pain treatment.

Quality of life and functional outcomes with tapentadol prolonged release in chronic musculoskeletal pain: post hoc analysis.

Aims: To investigate quality of life (QOL) and functionality changes in chronic pain during tapentadol prolonged release (PR) treatment. Patients & methods: Post hoc analysis of data from three Phase III trials in patients with osteoarthritis knee pain or low back pain. QOL and functionality changes were assessed by SF-36 scores. Results: All SF-36 subdomain scores improved progressively to week 3 of tapentadol titration and were sustained during 12-week maintenance treatment. Improvements in SF-36 scores were similar between tapentadol dose groups (e.g., 200 to <300 mg vs ≥500 mg), with no greater effect from higher doses. QOL and functionality improvements were consistently greater with tapentadol PR than oxycodone controlled release. Conclusion: Tapentadol PR provides consistent, clinically relevant improvements in QOL and functionality in chronic pain.

Antinociception and less gastric injury with the dexketoprofen-tapentadol combination in mice.

The purpose of this study was to evaluate the antinociceptive interaction between dexketoprofen and tapentadol in three different dose ratios, as well as the ulcerogenic activity of this combination. Dose-response curves were carried out for dexketoprofen, tapentadol, and dexketoprofen-tapentadol combinations in the acetic acid-induced writhing test in mice. On the other hand, the gastric damage of all treatments was assessed after the surgical extraction of the stomachs. Intraperitoneal administration of dexketoprofen and tapentadol induced a dose-dependent antinociceptive effect, reaching a maximal effect of about 58% and 99%, respectively. Isobolographic analysis and the interaction index showed that the three proportions produced an analgesic potentiation (synergistic interaction). Interestingly, the 1:1 and 1:3 ratios of the drugs combination produced minor gastric injury in comparison with the 3:1 proportion. Our data suggest that all proportions of the dexketoprofen-tapentadol combination produced a synergistic interaction in the acetic acid-induced visceral pain model in mice with a low incidence of gastric injury.

In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol.

Sorafenib (SR) is one of the most potent UGT (1A1, 1A9) inhibitors (in in vitro tests). The inhibition of UGT1A1 may cause hyperbilirubinaemia, whereas the inhibition of UGT1A9 and 1A1 may result in drug-drug interactions (DDIs). Tapentadol (TAP) is a synthetic µ-opioid agonist and is used to treat moderate to severe acute pain. Tapentadol is highly glucuronidated by the UGT1A9 and UGT2B7 isoenzymes. The aim of the study was to assess the DDI between SR and TAP. Wistar rats were divided into three groups, with eight animals in each. The rats were orally treated with SR (100 mg/kg) or TAP (4.64 mg/kg) or in combination with 100 mg/kg SOR and 4.64 TAP mg/kg. The concentrations of SR and sorafenib N-oxide, TAP and tapentadol glucuronide were respectively measured by means of high-performance liquid chromatography (HPLC) with ultraviolet detection and by means of ultra-performance liquid chromatography-tandem mass spectrometry. The co-administration of TAP with SR caused TAP maximum plasma concentration (Cmax) to increase 5.3-fold whereas its area under the plasma concentration-time curve (AUC0-∞) increased 1.5-fold. The tapentadol glucuronide Cmax increased 5.3-fold and whereas its AUC0-∞ increased 2.0-fold. The tapentadol glucuronide/TAP AUC0-∞ ratio increased 1.4-fold (p = 0.0118). TAP also increased SR Cmax 1.9-fold, whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide Cmax increased 1.9-fold whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide/SR AUC0-t ratio increased 1.4-fold (p = 0.0127). The results show that the co-administration of sorafenib and tapentadol increases the exposure to both drugs and changes their metabolism. In consequence, the pharmacological effect may be intensified, but the toxicity may increases, too.

Dual µ-opioid receptor and norepinephrine reuptake mechanisms contribute to dezocine- and tapentadol-induced mechanical antiallodynia in cancer pain.

Dezocine is an opioid analgesic widely used in China, occupying over 45% of the domestic market of opioid analgesics. We have recently demonstrated that dezocine produced mechanical antiallodynia and thermal antihyperalgesia through spinal µ-opioid receptor activation and norepinephrine reuptake inhibition in neuropathic pain. This study further explored the dual µ-opioid receptor and norepinephrine reuptake mechanisms underlying dezocine-induced mechanical antiallodynia in bone cancer pain, compared with tapentadol, the first recognized analgesic in this class. Dezocine and tapentadol, given subcutaneously, exerted profound mechanical antiallodynia in bone cancer pain rats in a dose-dependent manner, yielding similar maximal effects but different potencies: ED50s of 0.6 mg/kg for dezocine and 7.5 mg/kg for tapentadol, respectively. Furthermore, their mechanical antiallodynia was partially blocked by intrathecal injection of the specific µ-opioid receptor antagonist CTAP, but not κ-opioid receptor antagonists GNTI and nor-BNI or δ-opioid receptor antagonist naltrindole. Intrathecal administrations of the specific norepinephrine depletor 6-OHDA (but not the serotonin depletor PCPA) for three consecutive days and single injection of the α-adrenoceptor antagonist phentolamine/α2-adrenoceptor antagonist yohimbine partially blocked dezocine- and tapentadol-induced mechanical antiallodynia. Strikingly, the combination of CTAP and yohimbine nearly completely blocked dezocine- and tapentadol-induced mechanical antiallodynia. Our results illustrate that both dezocine and tapentadol exert mechanical antiallodynia in bone cancer pain through dual mechanisms of µ-opioid receptor activation and norepinephrine reuptake inhibition, and suggest that the µ-opioid receptor and norepinephrine reuptake dual-targeting opioids are effective analgesics in cancer pain.

Tapentadol prolonged release for severe chronic osteoarthritis pain in the elderly: improvements in daily functioning and quality of life.

Background: Chronic osteoarthritis (OA) pain leads to severe impairments in physical functioning and quality of life. Patients & methods: Data of patients with severe chronic knee and/or hip OA pain were extracted from the database of a prospective, noninterventional trial to assess the benefits of tapentadol prolonged release (PR) in elderly patients (>65 years of age; n = 1162) compared with younger patients (≤65 years of age; n = 498). Results: Tapentadol PR treatment (up to 3 months) significantly reduced pain intensity and pain-related restrictions on daily functioning and significantly improved physical and mental quality of life in both patient groups. The incidence of adverse drug reactions was low. Conclusion: Tapentadol PR is a useful strong analgesic to improve pain intensity, physical functioning and quality of life in elderly OA patients.

Tapentadol Suppresses Glutamatergic Transmission and Neuronal Firing in Rat Hippocampal CA3 Pyramidal Neurons.

BACKGROUND: Tapentadol, a centrally acting oral analgesic, activates µ-opioid receptor and inhibits norepinephrine reuptake. Given that glutamate plays a crucial role in mediating pain, this study investigated the influence of tapentadol on spontaneous glutamatergic synaptic transmission and evoked neuronal excitability in rat hippocampal CA3 pyramidal neurons, which has been suggested to be involved in nociceptive perception. METHODS: We used electrophysiological technique to determine the effect of tapentadol on spontaneous excitatory postsynaptic currents (sEPSC), glutamate-activated currents, and neuronal excitability in CA3 pyramidal neurons in rat hippocampal slices. We also used isolated nerve terminals (synaptosomes) prepared from the rat hippocampus to examine the effect of tapentadol on glutamate release. RESULTS: Whole-cell patch clamp recordings revealed that tapentadol effectively decreased the frequencies of sEPSCs and miniature EPSCs (mEPSCs) without changing their amplitudes in hippocampal CA3 pyramidal neurons. However, glutamate-evoked inward currents were not affected by tapentadol. Further, tapentadol decreased 4-aminopyridine-induced glutamate release from hippocampal synaptosomes, and this effect was prevented by chelating the extracellular Ca2+ ions and blocking the N- and P/Q-type Ca2+ channels. In addition, burst firing induced by 4-aminopyridine and tonic repetitive firing induced by depolarizing pulses were attenuated by tapentadol. CONCLUSIONS: We conclude that tapentadol inhibits glutamatergic synaptic transmission, without modifying postsynaptic receptor sensitivity, and that this decline of excitation consequently suppresses neuronal hyperexcitability in the hippocampal CA3 area.

Effect of tapentadol on experimental model of orofacial pain - a pilot study.

Acute orofacial pain is associated with significant disability and has a detrimental impact on quality of life. Although various origins of the pain in trigeminal territory can be identified an odontogenic pathology is the most common cause of acute orofacial pain in patients. Due to complex pathophysiology drugs with multitarget action might provide beneficial effect in pain management. The aim of the present study was to experimentally examine the anti-nociceptive effects of tapentadol, an opioid agonist and a norepinephrine reuptake inhibitor (MOR/NRI), in our animal model of orofacial pain. We tested the effect of tapentadol at gradual doses of 1, 2 and 5 mg/kg during thermal and mechanical stimulation in the trigeminal area of adult rats. We observed that tapentadol exhibits antinociceptive effect at dosages of 2 mg/kg and 5 mg/kg and only in association with mechanical stimulation.

Shining a Light on the Effects of the Combination of (-)-Epigallocatechin-3-gallate and Tapentadol on the Growth of Human Triple-negative Breast Cancer Cells.

BACKGROUND/AIM: Breast cancer is characterized by a high rate of mortality and is considered one of the deadliest types of cancer. It is of note that (-)-epigallocatechin-3-gallate (EGCG), the principal catechin of green tea, is able to hinder the growth of MDA-MB-231 breast cancer cells by influencing different signaling pathways, including apoptosis. Furthermore, EGCG is also used in the treatment of bone cancer pain. Tapentadol, an opioid drug acting at the level of noradrenaline (norepinephrine) reuptake inhibition and µ-opioid receptor, is able to modulate bone cancer pain and influence cancer cell viability by regulating apoptosis. MATERIALS AND METHODS: In vitro assays were performed on triple-negative MDA-MB-231 cells treated with tapentadol (1, 5, 10, 20, 40 and 80 µg/ml) and EGCG (1, 10, 20, 40, 80, 160 µmol/l), alone and in combination. The effects of EGCG and TAP on viability were determined by wound-healing and MTT assays, while cell migration was assessed by transwell migration. RESULTS: Cell proliferation, viability and apoptosis of MDA-MB-231 cells were impaired by the combination of EGCG and tapentadol. Specifically, our data show that EGCG and TAP reduced the proliferation of MDA-MB-231 cells by impairing cell-cycle progression (p<0.05). These findings suggest that the combination of these substances may represent a new strategy for the treatment of patients suffering from triple-negative breast cancer.

Cornea nerve fibre state determines analgesic response to tapentadol in fibromyalgia patients without effective endogenous pain modulation.

BACKGROUND: Tapentadol is a centrally acting analgesic with µ-agonistic activity combined with noradrenaline reuptake inhibition. Its mechanism of action relies on improvement of descending pain inhibition. In the current study, tapentadol's ability to enhance conditioned pain modulation (CPM, an experimental measure of descending pain inhibition) was evaluated in fibromyalgia patients with absent or reduced CPM responses. METHODS: A total of 34 fibromyalgia patients completed this double-blind trial. Patients were randomized to receive treatment with tapentadol sustained-release or placebo for a 3-month period with 1-month follow-up. At baseline, the cornea nerve fibre state (CNFS) was quantified to determine the presence of nerve fibre pathology and assess its value in the prediction of the analgesic response. RESULTS: Tapentadol significantly increased CPM responses during treatment with an average increase from baseline of 20.5 ± 12.5% (tapentadol) versus 3.0 ± 11.2% (placebo; p = 0.042). No treatment effect was observed for the absolute pain scores, however, analgesia responder rate analyses demonstrated a treatment effect in favour of tapentadol. Pain relief (a reduction in pain score ≥ 30%) was predicted by the presence of a normal CNFS (p = 0.035). Patients with an abnormal CNFS had no analgesic effect from tapentadol despite an increase in CPM. CONCLUSIONS: In chronic pain patients with fibromyalgia, the increase in endogenous pain inhibition by tapentadol was translated into analgesia in patients with a normal CNFS. In those with abnormal CNFS, tapentadol treatment was without analgesic effect. SIGNIFICANCE: In this double-blind randomized placebo-controlled trial, we showed that tapentadol significantly enhanced the descending pain inhibition in fibromyalgia patients. Tapentadol-induced pain relief was only present in patients with a normal CNFS.

A combination pharmacotherapy of tapentadol and pregabalin to tackle centrally driven osteoarthritis pain.

BACKGROUND: Many Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose-limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia. METHODS: Using electrophysiological single-unit recordings taken from spinal wide dynamic range neurons, Diffuse Noxious Inhibitory Controls (DNIC) were assessed as a marker of potential changes in descending controls in a monoiodoacetate (MIA) model of OA. We investigated if a subcutaneous injection of tapentadol or pregabalin, both alone and in combination, inhibited neuronal responses and restored the expression of DNIC, quantified as a reduction in neuronal firing in the presence of a conditioning noxious stimulus. RESULTS: Tapentadol restored DNIC-induced neuronal inhibition in MIA animals, while pregabalin inhibited pre-conditioned mechanically evoked neuronal responses but did not restore DNIC. Given in combination, tapentadol and pregabalin restored DNIC expression and also inhibited spinal neuronal responses. CONCLUSIONS: We propose that there is both central sensitization and an imbalance in inhibitory and facilitatory descending controls in MIA animals. The combination therapy of tapentadol and pregabalin restored descending noradrenergic inhibitory tone and also inhibited nociceptive transmission at the level of the spinal cord. SIGNIFICANCE: This study shows that pregabalin and tapentadol target different mechanisms of centrally driven chronic pain associated with osteoarthritis, and that when administered together can restore descending inhibitory tone whilst also tackling spinal neuronal hyperexcitability and may therefore provide superior analgesia.

Tapentadol: an analgesic that differs from classic opioids due to its noradrenergic mechanism of action.

Chronic pain treatment represents one of the most complex clinical challenges and even though opioids exhibit particular efficacy on nociceptive pain, their use must be controlled to avoid the risk of adverse reactions. A useful approach, aimed at maintaining analgesia and mitigating side effects, is represented by the use of a new class of analgesics endowed of µ-opioid (MOR) receptor agonism and noradrenaline reuptake inhibition (NRI) mechanisms. Tapentadol is the progenitor of this new class of drugs called MOP-NRI. A literature review has been conducted to gain information about the efficacy and the tolerability profile of tapentadol shifting from MOR agonism (acute pain) to NRI activity (chronic pain). The tolerability and therapeutic safety of tapentadol in neuropathic pain models, as well as in clinical settings, has been analyzed showing a good gastrointestinal tolerability profile, a moderate effect on hormone levels (in healthy volunteers and in patients) and on cognitive performance, a lack of significant alteration of the electrocardiogram recording and no changes of the QT/QTc interval, a minimal effect on serotonin reuptake in vivo with a low risk of serotonin syndrome, a longer time for the onset of analgesic tolerance and a less occurrence of abuse liability compared to formulations containing other comparator compounds. Tapentadol represents a great innovation in chronic pain therapy with a unique analgesic profile different form classical opioids, therefore, thanks to its synergistic MOR-NRI action, it may be a good option for the treatment of chronic, neuropathic and mixed pain.

Tapentadol Prolonged Release: A Review in Pain Management.

Tapentadol prolonged release (tapentadol PR) [Palexia® SR in EU] is a long-acting tablet formulation of the strong central analgesic tapentadol, which acts as both a µ-opioid receptor (MOR) agonist and a noradrenaline reuptake inhibitor. Tapentadol PR is approved for chronic pain in various countries, with its EU indication (severe chronic pain manageable only with opioid analgesics) being the focus here. Well-designed trials and clinical practice data support tapentadol PR use in this setting. Short term, tapentadol PR was an effective and generally well tolerated analgesic for moderate to severe pain of varying aetiologies, including neuropathic pain. It provided analgesia at least as good as that of conventional strong opioids and appeared more favourable in terms of gastrointestinal tolerability, likely due to less potent MOR binding. Severe back pain with a neuropathic component responded well to moderate-dose tapentadol PR in some patients, while for others, an increase to the maximum recommended tapentadol PR dosage provided analgesia at least as good as that of moderate-dose tapentadol PR plus pregabalin and appeared to have some CNS tolerability benefits. Data also support the use of tapentadol PR in opioid rotation, including when conventional opioids are intolerable. Longer-term data in musculoskeletal pain conditions indicate continued benefit over up to 2 years' treatment with tapentadol PR with no evidence of tolerance. Thus, tapentadol PR is a useful option for the management of severe chronic pain.

Does 'Strong Analgesic' Equal 'Strong Opioid'? Tapentadol and the Concept of 'µ-Load'.

INTRODUCTION: The distinct properties of the centrally-acting analgesic tapentadol derive from the combined contributions of an opioid component and a nonopioid component. However, the opioid component's relative contribution to analgesic and adverse effects has not previously been elucidated. Tapentadol's analgesic effect derives from the combined contribution of an opioid mechanism and a nonopioid mechanism, the extent of which can vary for different pains. Likewise, the interaction can vary for various adverse effects. Hence, the contribution of each mechanism to adverse effects can be different from the contribution to analgesia. We here estimate the percent contribution of each component of the mechanism of action to analgesia and to adverse effects. AREAS COVERED: Several approaches to in vitro and in vivo data to estimate the contribution of tapentadol's opioid component to analgesia and to the two important opioid adverse effects, respiratory depression and constipation. The results are then compared with clinical data. EXPERT OPINION: Traditional opioids, such as morphine, oxycodone, and others, produce their analgesic effects primarily through a single mechanism-the activation of µ-opioid receptors (MOR). Therefore, the contribution of the opioid component to adverse effects is 100%. In contrast, the newer strong analgesic tapentadol produces its analgesic effect via two separate and complementary analgesic mechanisms, only one of which is µ-opioid. We applied standard drug-receptor theory and novel techniques to in vitro and in vivo data to estimate by several different ways the µ-load of tapentadol (the % contribution of the opioid component to the adverse effect magnitude relative to a pure/classical µ-opioid at equianalgesia) in respiratory depression and constipation, and we compared the results to clinical evidence. The estimate is remarkably consistent over the various approaches and indicates that the µ-load of tapentadol is ≤ 40% (relative to pure MOR agonists, which have, by definition, a µ-load of 100%). FUNDING: Grünenthal GmbH.