Doses Of Tapentadol Research Articles

Analgesic Efficacy and Safety of Tapentadol Immediate Release in Bunionectomy: A Meta-Analysis.

The aim of this systematic review and meta-analysis was to evaluate the analgesic effect of different doses of tapentadol immediate release (IR) and its adverse effects after a bunionectomy. Pubmed, Cochrane, Lilacs, Medline, and Imbiomed were used to identify abstracts of scientific publications related to the keywords of this systematic review (PROSPERO ID CRD42023437295). Moreover, the risk of bias in all included articles was assessed using the Cochrane Collaboration risk of bias tool. Data on the sum of pain intensity, total pain relief, global assessment, and adverse effects were extracted. The statistical method of inverse variance with means difference was used to evaluate the numerical data and the Mantel-Haenszel and Odd Ratio test to analyze the dichotomous data. In addition, the number needed to treat, the number needed to harm, and the 95% confidence intervals were calculated. A qualitative evaluation (n = 2381) was carried out according to the conclusions of the authors. Tapentadol (n = 1772) was more effective in relieving postoperative pain than the placebo (n = 609) after a bunionectomy. In addition, the analgesic efficacy of IR tapentadol (n = 1323) versus the placebo (n = 390) was evaluated in a total of 1713 patients using a global evaluation of the treatments. All three doses of IR tapentadol showed better results compared to the placebo after a bunionectomy. Finally, the adverse effects have a direct relationship with the dose, and the greatest number of adverse effects are most observed with tapentadol IR 100 mg (n = 2381). It is concluded that tapentadol IR (100 mg) leads to the best satisfaction score in this meta-analysis.

Multiple Dose Pharmacokinetics of Tapentadol Oral Solution for the Treatment of Moderate to Severe Acute Pain in Children Aged 2 to

BackgroundThis prospective, open-label trial was conducted to fulfil a post-approval commitment made to the competent authorities to extend the indication of the strong opioid analgesic tapentadol hydrochloride oral solution (OS) to the pediatric population.Patients and MethodsThe trial assessed the pharmacokinetic (PK) profile of tapentadol, tapentadol-O-glucuronide and tapentadol-O-sulfate after administration of multiple doses of tapentadol OS (1.25 mg tapentadol/kg bodyweight every 4 h for up to 72 h) in children aged 2 to <7 years after a painful event that produces acute pain requiring treatment with a strong analgesic. The obtained PK data were integrated into a previously developed population PK (popPK) model based on single-dose data and then a model-based PK evaluation was performed. The primary trial endpoint was the area under the concentration-time curve at steady state for the dosing interval (AUCτ,ss) for tapentadol.ResultsTen children received tapentadol OS; all completed the trial. Multiple administrations of the trial medication resulted in tapentadol serum concentrations within the concentration range predicted by the previously developed popPK model. The estimated model-based AUCτ,ss values for tapentadol ranged from 142 to 321 h•ng/mL. They were within the predicted exposure range with no higher than expected accumulation for the employed dosing regimen and also within the targeted steady state exposure range observed in adults receiving multiple doses of immediate release tapentadol 50 to 100 mg. The treatment regimen was safe and well tolerated.ConclusionThe findings confirm the linear and predictable PK profile of tapentadol hydrochloride. The good agreement between the observed data and the model predictions shows the value of modelling and simulations in the planning and analysis of pediatric clinical trials and the ability to utilize the established PK models to predict multiple dose exposure.

Pain response and quality of life assessment in patients with moderate/severe neuropathic pain due to bone metastasis undergoing treatment with palliative radiotherapy and tapentadol: A prospective multicentre pilot study.

To assess pain response rate (RR) and quality of life (QoL), in patients with moderate/severe neuropathic pain (NP) due to bone metastasis (BM) undergoing palliative 3D radiotherapy plus tapentadol. We conducted a prospective multicentre pilot study. Patients were assessed before radiotherapy using the validated questionnaire (Douleur Neuropathique en 4 questions). Response to radiotherapy (8Gy-30Gy/1-10fr) at one and two months was assessed according the International Bone Metastases Consensus criteria. radiological evidence of BM, NP according to DN4 (cut-off score≥4), no spinal cord compression, worst pain score≥5/10. Nonparametric Mann-Whitney U test compared changes in QoL among response groups. Seventeen patients (13 men, 4 woman), median age 67years (42-81), were included. Pre-treatment median pain severity was 7.5 (5-10). Median dose of tapentadol administered before radiotherapy was 100mg/24h (100-300mg). Overall RR 1month after radiotherapy was 10/16=62.5%: 3/16 (18.8%) achieving a complete response (CR) and 7/16 (43.8%) a partial response (PR). Overall RR 2months after RT was 5/10 (50%): 10% a CR and 40% a PR. ITT RR for this study at 1 and 2months was 10/17=59% and 5/17=29%, respectively. Patients responding to radiotherapy had significant improvement in EORTC QLQ-C30 emotional functioning (EF) (p=0.025) and fatigue symptom scale scores (p=0.035) one month after radiotherapy. Painful site symptom QLQ-BM22 scores improved 2months after radiotherapy (p=0.024). Palliative radiotherapy plus tapentadol shows an acceptable pain response and QoL improvement especially regarding EF, fatigue and painful site symptom scales in patients with moderate/severe NP due to BM. Therefore, it could be an alternative to manage NP in daily practice.

Acute colonic pseudo‐obstruction leading to perforation: a case‐control study investigating associations to tapentadol

AbstractBackgroundAcute colonic pseudo‐obstruction (ACPO) is an uncommon syndrome where the large bowel dilates in the absence of mechanical obstruction and may progress to perforation. A recent increase in the incidence of ACPO complicated by colonic perforation had been noted at the Alfred Hospital, coinciding with the introduction of the analgesic tapentadol. This led to an investigation of potential associations between complicated ACPO and tapentadol, together with other identifiable factors.MethodsThis was a retrospective case‐control study. Eight cases were identified and confirmed radiologically. Four matched controls were identified for each case based on age, sex and comparable diagnosis at the time of presentation.ResultsThirty‐five male and five female patients of similar age and comorbid disease were reviewed. Tapentadol use (p = 0.42) and duration (p = 0.81) and mean tapentadol dose (p = 0.07) did not differ between groups. Other associations included alcohol use of greater than three standard drinks per day (p = 0.031) and ondansetron use (p = 0.039) among cases. Mean (± SD) duration of opioid use was significantly longer in the cases than controls (7.6 ± 1.6 vs 5.0 ± 3.1 days respectively; p = 0.023; odds ratio 2.57, 95% confidence interval 1.1–5.8). Mean opioid dose (p = 0.68) did not differ between groups.ConclusionPseudo‐obstruction causing colonic perforation was associated with alcohol use of greater than three standard drinks per day, longer in‐hospital opioid use and ondansetron use, but not with the use, duration or mean dose of tapentadol. Data should be combined with data from other sites to strengthen associations.

Pharmacokinetics, safety, and efficacy of tapentadol oral solution for treating moderate to severe pain in pediatric patients.

Background: This trial is part of the global pediatric clinical development program investigating the administration of the strong analgesic tapentadol in children and adolescents.Patients and methods: The single site, open-label phase 2 trial evaluated the pharmacokinetic profile of tapentadol and its major metabolite, tapentadol-O-glucuronide, as well as safety and tolerability and efficacy of a single dose of tapentadol oral solution (1 mg/kg) in patients (2 to <18 years) undergoing dental, ear, nose, or throat surgery. Blood sampling and pain intensity measurements were conducted using age-appropriate schedules and rating scales, respectively. Adverse events were monitored throughout the trial.Results: Sixty-six patients were treated. They were stratified by age: Group 1 (12 to <18 years), n=21; Group 2 (6 to <12 years), n=28; and Groups 3 (3 to <6 years) and 4 (2 to <3 years), n=17. Serum tapentadol concentrations observed in these pediatric patients were within the range observed in adults after administration of a single tapentadol immediate-release dose (50–100 mg), whereas those of the metabolite tapentadol-O-glucuronide were within the same range or lower than in adults who received comparable single doses of tapentadol. Pain intensity improved over time across all age groups. The most common treatment-emergent adverse events were nausea (24.2%), vomiting (16.7%), dizziness (9.1%), and headache (6.1%).Conclusion: A single dose of tapentadol oral solution (1 mg/kg) administered to pediatric patients (2 to <18 years) resulted in serum tapentadol concentrations within the targeted range shown to be safe and efficacious in adults. Tapentadol demonstrated good tolerability and safety; within the limitations of the trial design, improvements in postsurgical pain intensity were observed across the age groups. Tapentadol may provide a new treatment option in the management of moderate to severe pediatric pain.

A randomized controlled trial comparing tapentadol with oxycodone in non-breastfeeding women post elective cesarean section

Background: Tapentadol may allow greater pain relief with reduced “opioid load” compared to oxycodone. Its use has not been studied in the obstetric population. The objective of this study was to compare the efficacy and side effect profile of tapentadol with oxycodone in patients who received spinal anesthesia for elective cesarean section. The trial was registered with EU Clinical Trials Register with CT number 2016-001621-33.Methods: This was a multicenter, randomized controlled trial. Randomized patients (n = 68) received either 50 mg tapentadol or oxycodone 10 mg 12 hourly postoperatively. The primary endpoint was the sum of pain intensity difference over the first 48 hours of treatment (SPID48). Secondary outcomes included time to rescue medications, SPID36, total pain relief (TOTPAR) scores, patient satisfaction scores, sum of total pain relief and pain intensity difference (SPRID) scores, time to rescue medications and side effects experienced. An analysis of covariance model with baseline pain intensity score as a covariate was used for statistical analysis.Results: There was no significant difference in the primary endpoint of SPID48 with adjusted mean difference -11.45 (95% CI -35.35, 12.45) p = .34). Oxycodone showed significantly greater SPID36 scores compared to tapentadol with increased time to rescue medication. Side effects experienced were similar between groups.Conclusion: Tapentadol did not provide superior pain control or improved tolerability compared to oxycodone post cesarean section. Results should be interpreted however with consideration of administration of intrathecal opioids to all patients in this study and debate over the optimal dose of tapentadol for acute pain.Trial registration: EU Clinical Trials Register identifier: 2016-001621-33.

Multiple effectiveness aspects of tapentadol for moderate-severe cancer-pain treatment: an observational prospective study.

BackgroundPrevious studies have shown the efficacy of tapentadol (TP) for chronic cancer pain. We evaluated multiple effectiveness aspects of TP prolonged release on moderate–severe cancer-related pain, neuropathic pain (NeP), patient satisfaction, and quality of life.MethodsAn observational prospective study was conducted on 80 cancer patients. Opioid-naïve patients received a starting dose of prolonged-release TP 50 mg twice daily, and opioid-experienced patients were switched to TP, not to exceed 500 mg/day. Treatment response was evaluated at 3, 6, 30–40, and 60–70 days through response rate, numeric rating-scale scoring, survival analysis (time to event for response), pain-intensity difference, TP escalation-index percentage, and effects on NeP. The drug-sparing effect on concomitant therapies was evaluated.ResultsSeventy of 80 patients (88%) were responders to treatment (95% CI 78%–94%). Compared to T0, pain-intensity reductions were statistically significant for all intervals (P<0.01), with better results at T3/T4. NeP was significantly reduced at T4 (P<0.01). The probability of response was low at the initial stages and increased during the study. Pain-intensity differences decreased during the study, though without significance. Two patients (2.5%) left the study for TP-induced side effects. A significant improvement in quality of life was observed after 30–40 days (P<0.01). The majority of patients were “satisfied”, “very satisfied”, or “extremely satisfied” (T3–T4).ConclusionTP was effective in terms of drug-sparing effect, response rate, TP escalation-index percentage, and NeP management. By comparing data from the survival analysis with the response rate and time to response (numeric rating scale from T0 to T4), we found that although TP induced a quick response, a longer period of therapy and higher doses were needed to improve the positive result.

Pharmacokinetics and pharmacodynamics after oral administration of tapentadol hydrochloride in dogs.

OBJECTIVE To evaluate pharmacokinetic and pharmacodynamic characteristics of 3 doses of tapentadol hydrochloride orally administered in dogs. ANIMALS 6 healthy adult mixed-breed dogs. PROCEDURES In a prospective, randomized crossover study, dogs were assigned to receive each of 3 doses of tapentadol (10, 20, and 30 mg/kg, PO); there was a 1-week washout period between subsequent administrations. Plasma concentrations and physiologic variables were measured for 24 hours. Samples were analyzed by use of high-performance liquid chromatography-tandem mass spectrometry. RESULTS Tapentadol was rapidly absorbed after oral administration. Mean maximum plasma concentrations after 10, 20, and 30 mg/kg were 10.2, 19.7, and 31 ng/mL, respectively. Geometric mean plasma half-life of the terminal phase after tapentadol administration at 10, 20, and 30 mg/kg was 3.5 hours (range, 2.7 to 4.5 hours), 3.7 hours (range, 3.1 to 4.0 hours), and 3.7 hours (range, 2.8 to 6.5 hours), respectively. Tapentadol and its 3 quantified metabolites (tapentadol sulfate, tapentadol-O-glucuronide, and desmethyltapentadol) were detected in all dogs and constituted 0.16%, 2.8%, 97%, and 0.04% of the total area under the concentration-time curve (AUC), respectively. Plasma AUCs for tapentadol, tapentadol sulfate, and tapentadol-O-glucuronide increased in a dose-dependent manner. Desmethyltapentadol AUC did not increase in a linear manner at the 30-mg/kg dose. Sedation scores and heart and respiratory rates were not significantly affected by dose or time after administration. CONCLUSIONS AND CLINICAL RELEVANCE Oral administration of tapentadol was tolerated well, and the drug was rapidly absorbed. Adverse events were not apparent in any dogs at any doses in this study.

Tapentadol in neuropathic pain cancer patients: a prospective open label study.

Many chemotherapy treatments induce peripheral neuropathy (CIPN). These patients often experience neuropathic pain (NP) that reduces the quality of life. The aim of this prospective, open label study was to evaluate the efficacy and tolerability of tapentadol (TP) in patients affected by CIPN. CIPN were consecutively enrolled in a prospective open label study at the Neuro-Oncology Unit of the Regina Elena National Cancer Institute in Rome. During the titration phase, each patient initially received doses of TP 50mg twice a day. All patients underwent pain intensity (NRS) and DN4. For evaluation of quality of life, patients underwent EORTC QLQ-C30 and EORTC QLQ-CIPN2 QLQ-CIPN20. We enrolled 31 patients, 19 were females with a median age of 60years. After 3months of treatment with TP, 22 patients completed the statistical package for social sciences (SPSS). Nineteen patients out of 22 showed a response to treatment (86%). We also observed that TP reduced the NRS and DN4 values from baseline to the last visit in a significant way (p<0.001, respectively). Seven patients (22.5%) discontinued the TP therapy after the first week of occurrence of side effects. Furthermore, we observed that TP improved also the global health status measured by EORT QLQ-C30. TP is well tolerated and efficacy in the treatment of NP. The important reduction of neuropathic pain, the improvement in NRS and QoL scores after therapy with TP makes it a candidate in the management of patients suffering from neuropathic pain of CIPN also as a first line of therapy.

Thermal antinociception following oral administration of tapentadol in conscious cats

ObjectiveTo evaluate the onset, magnitude and duration of thermal antinociception after oral administration of two doses of tapentadol in cats. Study designProspective, randomized, blinded, experimental study. AnimalsSix healthy adult cats weighing 4.4 ± 0.4 kg. MethodsSkin temperature (ST) and thermal threshold (TT) were evaluated using a wireless TT device up to 12 hours after treatment. Treatments included placebo (PBO, 50 mg dextrose anhydrase orally), buprenorphine (BUP, 0.02 mg kg−1) administered intramuscularly, low-dose tapentadol (LowTAP, 25 mg orally; mean 5.7 mg kg−1) and high-dose tapentadol (HighTAP, 50 mg orally; mean 11.4 mg kg−1) in a blinded crossover design with 7 day intervals. Statistical analysis was performed using anova with appropriate post hoc test (p ≤ 0.05). ResultsSalivation was observed immediately following 11 out of 12 treatments with tapentadol. The ST was significantly increased at various time points in the opioid treatments. Hyperthermia (≥ 39.5 °C) was not observed. Baseline TT was 45.4 ± 1.4 °C for all treatments. Maximum TT values were 48.8 ± 4.8 °C at 1 hour in LowTAP, 48.5 ± 3.0 °C at 2 hours in HighTAP and 50.2 ± 5.3 °C at 1 hour in BUP. TT significantly increased after LowTAP at 1 hour, after HighTAP at 1–2 hours, and after BUP at 1–2 hours compared with baseline values. TTs were significantly increased in BUP at 1–2 hours compared with PBO. Conclusion and clinical relevanceOral administration of tapentadol increased ST and TT in cats. The durations of thermal antinociception were similar between HighTAP and BUP, both of which were twice as long as that in LowTAP. Studies of different formulations may be necessary before tapentadol can be accepted into feline practice.

Role of preemptive tapentadol in reduction of postoperative analgesic requirements after laparoscopic cholecystectomy.

Background and Aims:Poorly managed acute postoperative pain may result in prolonged morbidity. Various pharmacotherapies have targeted this, but research on an ideal preemptive analgesic continues, taking into account drug-related side effects. Considering the better tolerability profile of tapentadol, we assessed its role as a preemptive analgesic in the reduction of postoperative analgesic requirements, after laparoscopic cholecystectomy.Material and Methods:In a prospective-double-blinded fashion, sixty patients posted for above surgery, were randomized to receive tablet tapentadol 75 mg (Group A) or starch tablets (Group B) orally, an hour before induction of general anesthesia. Perioperative analgesic requirement, time to first analgesia, pain, and sedation score were compared for first 24 h during the postoperative period and analyzed by one-way analysis of variance test. A P < 0.05 was considered significant.Results:Sixty patients were analyzed. The perioperative analgesic requirement was significantly lower in Group A. Verbal numerical score was significantly lower in Group A at the time point, immediately after shifting the patient to the postanesthesia care unit. Ramsay sedation scores were similar between the groups. No major side effects were observed except for nausea and vomiting in 26 cases (10 in Group A, 16 in Group B).Conclusion:Single preemptive oral dose of tapentadol (75 mg) is effective in reducing perioperative analgesic requirements and acute postoperative pain, without added side effects. It could be an appropriate preemptive analgesic, subjected to future trials concentrating upon its dose-response effects.

Pharmacokinetic and Pharmacodynamic Assessments of Tapentadol in Yellow-Bellied Slider Turtles (Trachemys Scripta Scripta) after a Single Intramuscular Injection

In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. Tapentadol (TAP) is a novel atypical opioid drug labelled for human use. The objective of this study was to evaluate the pharmacokinetics and the pharmacodynamics of this drug in yellow-bellied sliders, after a single intramuscular (IM) injection of 5mg/kg of TAP. Turtles (n = 9) were randomly assigned to 2 treatment groups, according to a single-dose, single-treatment, unpaired, 2-period crossover design. Group A (n = 5) received a single IM (proximal front limb) dose of TAP (5mg/mL) at 5mg/kg. Group B (n = 4) received a single IM injection of saline (equivalent volume to opioid volumes) of TAP at the same site. After a 1-month washout period, groups were rotated and the experiment repeated. TAP plasma concentrations were determined by a validated high-performance liquid chromatography-fluorescence method, and an infrared thermal stimuli was applied to the plantar surface of the turtles’ hind limbs to evaluate the thermal withdrawal latency (TWL). TAP plasma concentrations were detectable between 1 and 24 hour(s) (1619 and 37ng/mL, respectively). The TAP-treated group showed an increase in TWL 1 hour after drug administration (13.32 ± 6.40 seconds). Subsequently, TWL decreased with time and significant differences between treatment and control groups were apparent up to 10 hours following treatment. A linear relationship (r2 = 0.99) between TAP plasma concentration and effect was found. Given these findings, TAP appears to be an attractive option for antinociception in turtles, owing to its rapid onset and acceptable duration of effect.

PII: S1557-5063(15)00022-1

In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. Tapentadol (TAP) is a novel atypical opioid drug labelled for human use. The objective of this study was to evaluate the pharmacokinetics and the pharmacodynamics of this drug in yellow-bellied sliders, after a single intramuscular (IM) injection of 5 mg/kg of TAP. Turtles (n = 9) were randomly assigned to 2 treatment groups, according to a single-dose, single-treatment, unpaired, 2-period crossover design. Group A (n = 5) received a single IM (proximal front limb) dose of TAP (5 mg/mL) at 5 mg/kg. Group B (n = 4) received a single IM injection of saline (equivalent volume to opioid volumes) of TAP at the same site. After a 1-month washout period, groups were rotated and the experiment repeated. TAP plasma concentrations were determined by a validated high-performance liquid chromatography-fluorescence method, and an infrared thermal stimuli was applied to the plantar surface of the turtles’ hind limbs to evaluate the thermal withdrawal latency (TWL). TAP plasma concentrations were detectable between 1 and 24 hour(s) (1619 and 37 ng/mL, respectively). The TAP-treated group showed an increase in TWL 1 hour after drug administration (13.32 ± 6.40 seconds). Subsequently, TWL decreased with time and significant differences between treatment and control groups were apparent up to 10 hours following treatment. A linear relationship (r2 = 0.99) between TAP plasma concentration and effect was found. Given these findings, TAP appears to be an attractive option for antinociception in turtles, owing to its rapid onset and acceptable duration of effect.

The influence of μ-opioid and noradrenaline reuptake inhibition in the modulation of pain responsive neurones in the central amygdala by tapentadol in rats with neuropathy

Treatments for neuropathic pain are either not fully effective or have problematic side effects. Combinations of drugs are often used. Tapentadol is a newer molecule that produces analgesia in various pain models through two inhibitory mechanisms, namely central μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. These two components interact synergistically, resulting in levels of analgesia similar to opioid analgesics such as oxycodone and morphine, but with more tolerable side effects. The right central nucleus of the amygdala (CeA) is critical for the lateral spinal ascending pain pathway, regulates descending pain pathways and is key in the emotional-affective components of pain. Few studies have investigated the pharmacology of limbic brain areas in pain models. Here we determined the actions of systemic tapentadol on right CeA neurones of animals with neuropathy and which component of tapentadol contributes to its effect. Neuronal responses to multimodal peripheral stimulation of animals with spinal nerve ligation or sham surgery were recorded before and after two doses of tapentadol. After the higher dose of tapentadol either naloxone or yohimbine were administered. Systemic tapentadol resulted in dose-dependent decrease in right CeA neuronal activity only in neuropathy. Both naloxone and yohimbine reversed this effect to an extent that was modality selective.The interactions of the components of tapentadol are not limited to the synergy between the MOR and α2-adrenoceptors seen at spinal levels, but are seen at this supraspinal site where suppression of responses may relate to the ability of the drug to alter affective components of pain.

Polyneuropathic Pain Th erapy with a Patient Suffering from Generalized Castrate- Resistant Prostate Cancer – Clinical Case Report

Tapentadol is a µ -opioid receptors agonist as well as an inhibitor of noradrenaline reuptake. This pharmacologic profile of tapentadol makes it a suitable drug of choice in nociceptive and neuropathic pain control. This clinical report pressents a 65year old man with poorly differentiated prostate cancer - Gleason score 8 (4 + 4) with metastatic bone disease. Besides the initial application of bisphosphonates, the patient had been treated with androgen deprivation therapy (cyproterone acetate + leuprolide acetate) for the period of 18 months. This therapy was terminated due to an increase of PSA levels. Subsequently, the patient underwent palliative docetaxelbased chemotherapy. There were eight cycles applied with positive clinical and laboratory effect. However, the further application was limited by the averse effects, namely the peripheral neuropathy manifested by pain in arms and legs. The peripheral neuropathy had progressive tendency even after the end of chemotherapy, and supportive treatment with gabapentin and amitryptiline failed to succeed. Four months after zoledronic acid monotherapy, the patient was started on tapentadol in 50-mg dose b.i.d., consequently escalated to 100 mg b.i.d. (to this point, 25 µg of transdermal fentanyl were used for pain management). Significant relief from neuropathic discomfort was observed three weeks from the onset of tapentadol therapy. Patients state of health normalized within three months after the initiation of therapy. Consequently, the patient was able to receive docetaxel chemotherapy again, without any neuropathic pain exacerbation on the maintenance dose of tapentadol 50 mg b.i.d. Tapentadol administration resulted in stable and longtime relief from neuropathic pain which is a frequent side effect in the course of castrate-resistant prostate cancer therapy with taxanes.

Spinal-Supraspinal and Intrinsicµ-Opioid Receptor Agonist-Norepinephrine Reuptake Inhibitor (MOR-NRI) Synergy of Tapentadol in Diabetic Heat Hyperalgesia in Mice

Tapentadol is a μ-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1-3.16 µg/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED50 0.42 µg/animal i.t., 0.18 µg/animal i.c.v.). Combined administration of equianalgesic doses revealed spinal-supraspinal synergy (ED50 0.053 µg/animal i.t. + i.c.v.). Morphine (0.001-10 µg/animal) also showed central efficacy and synergy (ED50 0.547 µg/animal i.t., 0.004 µg/animal i.c.v., 0.014 µg/animal i.t. + i.c.v.). Supraspinal potencies of tapentadol and morphine correlated with the 50-fold difference in their MOR affinities. In contrast, spinal potencies of both drugs were similar and correlated with their relative systemic potencies (ED50 0.27 mg/kg i.p. tapentadol, 1.1 mg/kg i.p. morphine). Spinal administration of the opioid antagonist naloxone or the α2-adrenoceptor antagonist yohimbine before systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive toward both antagonists than was morphine, with median effective dose values of 0.75 and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated MOR-NRI synergy.

Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations

To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol immediate release (IR) compared with tapentadol prolonged release (PR). Three randomized, open-label, crossover studies were conducted in subjects under fasted conditions. Studies 1 and 2 determined the absolute bioavailability and pharmacokinetics of oral tapentadol IR 86 mg and tapentadol PR 86 mg, respectively, relative to a 34-mg intravenous (IV) dose of tapentadol. Study 3 determined the relative bioavailability of tapentadol PR 86 mg vs. tapentadol IR 86 mg. Pharmacokinetic parameters were calculated using non-compartmental analysis and relative bioavailability using dose-adjusted, log-transformed analysis of variance models for maximum concentration (Cmax) and areas under the serum concentration-time curve (AUC0-t and AUC). Adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), and laboratory parameters were assessed. Absolute bioavailability was estimated to be 32% (95% confidence interval (CI), 29.4 - 34.8%; n = 24) for tapentadol IR 86 mg and 32% (95% CI, 28.0 - 35.9%; n = 18) for tapentadol PR 86 mg. Based on AUC, the relative bioavailability of tapentadol PR vs. tapentadol IR was 96% (90% CI, 87.8 - 104.4%; n = 16). Following IV administration, tapentadol had an elimination half-life of about 4 hours; in Studies 1 and 2, respectively, mean tapentadol volumes of distribution were 540 and 471 l, and mean clearance was 1,531 and 1,603 ml/min. Compared to tapentadol IR 86 mg, the prolonged-release characteristics of tapentadol PR 86 mg were evident with a lower Cmax (22.5 ng/ml vs. 64.2 ng/ml), a longer time to Cmax (5.0 h vs. 1.5 h), a higher half-value duration (HVD: 12.5 h vs. 3.6 h), and a longer mean residence time (MRT: 10.6 h vs. 6.0 h). The most common AEs reported were dizziness, headache, fatigue, nausea, somnolence, and dry mouth; most AEs were mild. No clinically relevant changes in vital signs, ECG parameters, or laboratory values were observed. Absolute bioavailability for both tapentadol IR and tapentadol PR was ~ 32% under fasted conditions. Extent of exposure (AUC) for tapentadol PR was very similar to tapentadol IR, whereas Cmax was lower and HVD/MRT longer for the prolonged-release formulation. Overall, the pharmacokinetic characteristics of tapentadol PR enable a twice-daily dosing regimen to be used; such a regimen is expected to improve patient compliance during chronic use.

Miotic and subject-rated effects of therapeutic doses of tapentadol, tramadol, and hydromorphone in occasional opioid users

Tapentadol is a novel analgesic that activates mu-opioid receptors and blocks norepinephrine reuptake. There is very little information available regarding the non-analgesic pharmacodynamic effects of tapentadol. This outpatient study evaluated the physiological, subject-rated, and performance effects of therapeutic doses of tapentadol compared to two control drugs in humans. This double-blind, within-subject study examined the effects of oral placebo, tapentadol (25, 50, and 75 mg), tramadol (50, 100, and 150 mg), and hydromorphone (2, 4, and 6 mg). Nine occasional opioid users completed the study. Pharmacodynamic drug effects were measured before and for 6 h after drug administration. All three doses of the tested drugs produced comparable, time-dependent decreases in pupil diameter, but the effects were generally not dose dependent. The high dose of tapentadol, as well as all three doses of tramadol and hydromorphone, increased positive subject-rated effects (e.g., "Good Effects" and "Like the Drug") as a function of time. Only tramadol increased negative subject-rated effects (e.g., "Bad Effects" and "Nauseous"); however, these were of low magnitude. The highest tested dose of tapentadol produced a profile of positive effects comparable to that of hydromorphone, whereas tramadol produced positive and negative subject-rated effects. The mixed findings for tramadol are consistent with previous findings indicating that it has a distinct profile of effects relative to prototypic opioids. Future research should examine the effects of higher tapentadol doses, as well as the factors contributing to the different subject-rated profile of effects observed for tramadol relative to tapentadol and hydromorphone.

Tapentadol in cancer pain management: a prospective open-label study

Objectives:The aim of this prospective, open-label study was to evaluate the efficacy and tolerability of tapentadol (TP) in the management of cancer pain.Methods:A 4 weeks’ prospective study was carried out in 50 opioid-naive cancer patients with moderate–severe pain. Each patient initially received twice-daily doses of slow-release TP 50 mg. Doses were then managed to maintain adequate relief or dose-limiting toxicity, on the basis of the clinical response. The following parameters were recorded at weekly intervals for 4 weeks: pain and opioid-related adverse effects, quality of life measured with the Spitzer score, TP escalation index percent (TPEI%) and TP escalation index in mg (TPEImg), calculated at the end of the study, pain mechanisms, and PainDETECT at baseline.Results:Of 50 patients, 39 completed the entire study and 11 discontinued the treatment for different reasons. Pain intensity significantly decreased from baseline to all the week intervals (p < 0.0005), and adverse effects did not changed significantly, while quality of life improved. TP escalation indexes were low and no relationship was found with age, gender, and pain mechanisms.Conclusion:Tapentalol started in doses of 100 mg/day was well-tolerated and effective in opioid-naive patients with cancer pain, regardless of the pain mechanism. It can be considered as a flexible drug to be used in patients with moderate–severe pain.Limitations:This was an open-label study for exploratory purposes. Data should be confirmed in controlled studies with a larger number of patients.

Tapentadol increases levels of noradrenaline in the rat spinal cord as measured by in vivo microdialysis

Spinal noradrenaline is thought to play an important role in descending pain inhibitory pathways and the modulation of nociceptive information at the spinal level. Tapentadol is a μ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). We showed previously that tapentadol, in contrast to morphine, elevates levels of noradrenaline, but not serotonin, in the ventral hippocampus of rats. The aim of this study was to examine the effects of tapentadol, morphine and venlafaxine on spinal monoamine levels. Rats were implanted with spinal microdialysis probes. Drugs were administered intraperitoneally, and samples were collected for 3 h in isoflurane-anesthetized animals and analysed for monoamine content using HPLC–MS/MS. In terms of area-under-curve (AUC, 0–180 min), tapentadol (4.64–21.5 mg/kg) produced a dose-dependent, significant increase in extracellular spinal noradrenaline levels (9275 ± 4346 min % at the highest dose versus −1047 ± 889 min % for vehicle). A maximum increase of 182 ± 32% of baseline was reached 60 min after administration of 10 mg/kg tapentadol. Venlafaxine (10 mg/kg) produced an effect of similar magnitude. In contrast, tapentadol decreased extracellular spinal serotonin levels (non-significantly compared to vehicle), while venlafaxine increased spinal serotonin to 267 ± 74% of baseline. In contrast to tapentadol and venlafaxine, morphine slightly decreased levels of noradrenaline and serotonin. This study demonstrates that analgesic doses of tapentadol (and venlafaxine), but not morphine, increase spinal noradrenaline levels and that tapentadol is devoid of a relevant serotonergic effect. It supports the suggestion that the NRI component of tapentadol is functionally relevant and contributes to its mechanism of action.