Tapentadol dependence through intravenous injection ('shooting') of crushed tablets associated with cutaneous pseudoallergic reactions.

Tapentadol is a synthetic opioid analgesic with a low risk of abuse and diversion. The rising trend of abuse of tapentadol is largely attributable to its intrinsic pharmacological profile and easy availability due to poor regulatory control. We report a case of intravenous injection of crushed tapentadol tablets that presented with cutaneous adverse drug reactions. Cutaneous adverse reactions are common in injection drug abuse, and clinical examination is a must to inspect the injection sites. Stringent regulatory measures are required to restrict the increasing abuse of tapentadol in India.

Characteristics of fatal tapentadol-related toxicity in Australia.

INTRODUCTION: Tapentadol is a centrally acting opioid analgesic prescribed for the treatment of moderate to severe pain. The study aimed to determine the characteristics of Australian toxicity deaths related to tapentadol. METHODS: All cases in which tapentadol use was coded contributory to death (n = 159) were retrieved from the National Coronial Information System (1 July 2000-31 December 2020). RESULTS: The mean age was 48.5 (18-81) and 56% were female. Documented histories of problems with chronic pain (66%), mental health (60.4%), substance use (44%) and injecting drug use (23.3%) were common. The majority of deaths were deemed unintentional (76.1%) and in 18.9% pre-existing disease was co-contributory. The median peripheral blood tapentadol concentration was 1.00 mg L-1 (0.02-47.00), and the median aortic concentration was 2.05 mg L-1 (0.10-30.00). In all cases, psychoactive drugs other than tapentadol were also detected, most commonly antidepressants (72.3%), opioids (66.7%), hypnosedatives (64.2%) and gabapentinoids (43.4%). Of cases where autopsies were conducted, 27.7% were diagnosed with cardiomegaly and 18.5% with severe coronary artery stenosis. Pulmonary oedema (68.1%), aspiration of vomitus (39.5%) and acute pneumonia (26.9%) were common. DISCUSSION AND CONCLUSIONS: The typical tapentadol-related toxicity death involved unintentional death in the presence of multiple drugs, although a notable minority were intentional self-harm. Multiple morbidities were common. The identification and characteristics of these cases indicate that the adverse event profile of tapentadol needs to be considered in the setting of polypharmacy.

Web-Based Discussion and Illicit Street Sales of Tapentadol and Oxycodone in Australia: Epidemiological Surveillance Study.

BACKGROUND: Opioid use disorder and its consequences are a persistent public health concern for Australians. Web activity has been used to understand the perception of drug safety and diversion of drugs in contexts outside of Australia. The anonymity of the internet offers several advantages for surveilling and inquiring about specific covert behaviors, such as diversion or discussion of sensitive subjects where traditional surveillance approaches might be limited. OBJECTIVE: This study aims to characterize the content of web posts and compare reports of illicit sales of tapentadol and oxycodone from sources originating in Australia. First, post content is evaluated to determine whether internet discussion encourages or discourages proper therapeutic use of the drugs. Second, we hypothesize that tapentadol would have lower street price and fewer illicit sales than oxycodone. METHODS: Web posts originating in Australia between 2017 and 2019 were collected using the Researched Abuse, Diversion, and Addiction-Related Surveillance System Web Monitoring Program. Using a manual coding process, unstructured post content from social media, blogs, and forums was categorized into topics of discussion related to the harms and behaviors that could lead to harm. Illicit sales data in a structured format were collected through a crowdsourcing website between 2016 and 2019 using the Researched Abuse, Diversion, and Addiction-Related Surveillance System StreetRx Program. In total, 2 multivariable regression models assessed the differences in illicit price and number of sales. RESULTS: A total of 4.7% (28/600) of tapentadol posts discussed an adverse event, whereas 10.27% (95% CI 9.32-11.21) of oxycodone posts discussed this topic. A total of 10% (60/600) of tapentadol posts discussed unsafe use or side effects, whereas 20.17% (95% CI 18.92-21.41) of oxycodone posts discussed unsafe use or side effects. There were 31 illicit sales reports for tapentadol (geometric mean price per milligram: Aus $0.12 [US $0.09]) and 756 illicit sales reports for oxycodone (Aus $1.28 [US $0.91]). Models detected no differences in the street price or number of sales between the drugs when covariates were included, although the potency of the pill significantly predicted the street price (P<.001) and availability predicted the number of sales (P=.03). CONCLUSIONS: Australians searching the web for opinions could judge tapentadol as safer than oxycodone because of the web post content. The illicit sales market for tapentadol was smaller than that of oxycodone, and drug potency and licit availability are likely important factors influencing the illicit market.

Tapentadol in Cancer Patients with Neuropathic Pain: A Comparison of Methadone, Oxycodone, Fentanyl, and Hydromorphone.

Tapentadol has µ-opioid receptor stimulating and noradrenaline reuptake inhibiting properties, and should be effective for neuropathic pain (NP). However, the efficacy of tapentadol for NP in cancer patients is unclear. Ashiya Municipal Hospital (Hyogo, Japan) enrolled five groups of Japanese cancer patients between January 1, 2013, and December 31, 2019. Patients with NP were administered tapentadol (n = 29), methadone (n = 32), oxycodone (n = 20), fentanyl (n = 26), or hydromorphone (n = 20). The primary endpoint was the difference in the verbal rating scale (VRS) scores between days 0 and 7. The secondary endpoint was the tolerability of each opioid. Before administering opioids among the five groups, there was no significant difference in the VRS score (p = 0.99). The mean reduction in the VRS score on day 7 was significantly greater in the tapentadol group than in the oxycodone group (p = 0.0024) and was larger than that of the methadone, fentanyl, and hydromorphone groups. Regarding safety, the discontinuation rate in the tapentadol group was the lowest of all groups (tapentadol vs. methadone vs. oxycodone vs. fentanyl vs. hydromorphone, 0.0% vs. 6.3% vs. 5.0% vs. 3.8% vs. 10.0%, respectively). This study suggests that tapentadol could be efficacious for cancer patients with NP, and a preferred option in cases that require immediate dose adjustment or for those at high risk for adverse effects. However, the pain intensity was evaluated without pain assessment scales specific to NP. Thus, we think that it is desirable to validate our findings using assessment scales, such as the painDETECT questionnaire in future.

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.

Efectividad analgésica del tapentadol en el dolor neuropático secundario al síndrome postlaminectomía / Analgesic effectiveness of tapentadol in neuropathic pain secondary to post-laminectomy syndrome

Objetivo: El objetivo del presente estudio es evaluar la eficacia y seguridad de tapentadol de liberación a 100 o 200 mg vía oral cada 24 horas, de acción prolongada, para el tratamiento del síndrome postlaminectomía (SPL) en una serie de pacientes con dolor neuropático en tratamiento analgésico inefectivo. Material y métodos: Se realizó un estudio unicéntrico, longitudinal, prospectivo y observacional, en el que se reclutaron 30 pacientes a la clínica de dolor de un centro de referencia de tercer nivel que sufrían de SPL y que cumplían con todos los criterios de inclusión; a quienes se les aplicó el cuestionario Brief Pain Inventory en su versión en español y el test de Lanss antes y después de iniciar tratamiento con tapentadol, y se aplicó una t de Student para comparar la efectividad global del tratamiento del dolor neuropático. Resultado: Se analizaron datos de 30 pacientes, de los cuales 19 fueron mujeres (63,3 %) y 11 hombres (36,6 %) con diagnóstico de SPL confirmado y con características de dolor de tipo neuropático, quienes fueron divididos en dos grupos: el primer grupo de 13 pacientes (43,3 %) recibió tapentadol a 100 mg vía oral cada 24 horas y el segundo de 17 pacientes (56,6 %) recibió 200 mg vía oral cada 24 horas por cuatro semanas. Se les dio un seguimiento de 4 semanas y se encontró una disminución estadísticamente significativa (valor de p = 0,05) del dolor neuropático en la consulta subsecuente de la clínica del SPL.(AU)

Objective: The objective of this study is to eva­luate the efficacy and safety of long-acting tapentadol 100 or 200 mg orally every 24 hours for the treatment of Postlaminectomy Syndrome (SPL) in a series of patients with pain neuropathic in ineffective analgesic treatment. Material and methods: A single-center, longitudinal, prospective and observational study was conducted, in which 30 patients were recruited to the pain clinic of a third-level reference center who suffered from SPL and who met all the inclusion criteria; To whom the Brief Pain Inventory questionnaire in its Spanish version and the Lanss Test were applied before and after starting treatment with tapentadol and a student's t was applied to compare the overall effectiveness of the treatment of neuropathic pain. Results: Data from 30 patients were analyzed, of which 19 were women (63.3 %) and 11 were men (36.6 %) with a diagnosis of confirmed SPL and the presentation of neuropathic pain, who were divided into two groups. The first group of 13 patients (43.3 %) received tapentadol at 100 mg orally every 24 hours, and the second group of 17 patients (56.6 %) received 200 mg orally every 24 hours for four weeks. They were followed up for 4 weeks and statistically significant improvement (p value = 0.05) was found in the SPL clinic.(AU)

Fever in a patient with osteomyelitis: the diagnosis could be serotonin syndrome.

Awareness of rare differential diagnoses of common clinical presentations helps promote early detection and prompt management of serious conditions. A 54-year-old man, with an infected non-union following a high tibial osteotomy, presented with an acutely discharging abscess to his proximal tibia. He was generally unwell with a Staphylococcus aureus bacteraemia. The tibia was debrided, CERAMENT G used as dead space management and a spanning external fixator applied. Postoperatively, pregabalin and tapentadol were commenced in addition to amitriptyline and sertraline, which the patient was taking regularly. Overnight, the patient developed hyperthermia, inducible clonus, hyperreflexia, agitation, confusion and rigors. Prompt recognition of the possibility of serotonin syndrome resulted in early cessation of serotonergic medications and a positive outcome. From this case an important message is that fever in a patient taking serotonergic medications should prompt a screening neurological examination. Clinicians should also be wary when patients are commenced on multimodal analgesia, including tapentadol.

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.

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.

Safety of tapentadol compared with other opioids in chronic pain treatment: network meta-analysis of randomized controlled and withdrawal trials.

OBJECTIVE: To assess the relative safety of oral tapentadol PR and other opioid analgesics for moderate or severe chronic pain in adults, we conducted a systematic review and network meta-analysis (NMA). METHODS: A systematic review was conducted to identify randomized controlled trials (RCTs) and randomized withdrawal trials of tapentadol with other WHO stage II and III opioid analgesics in patients with moderate or severe chronic pain. Searches were conducted in MEDLINE, EMBASE, PubMed, Cochrane databases and trial registries. Feasibility assessment evaluated the trials' suitability for NMA. Outcomes assessed were overall AEs, overall serious adverse events, constipation, nausea, dizziness, somnolence, headache, and discontinuation due to AEs. Randomized withdrawal trials were analyzed separately to other RCTs. RESULTS: Searches conducted in April 2019 identified 16,604 records. Following screening and feasibility assessment, 29 RCTs and 19 randomized withdrawal trials were identified and included in the NMA. Consistent with existing research, evidence from RCTs suggested that tapentadol is associated with relatively lower odds of adverse events occurring than most active comparators. The withdrawal trial data were less clear, with higher uncertainty around the results, and results that appear to contradict the RCT evidence. There are a number of trial design factors that may be affecting these results. CONCLUSIONS: RCT evidence suggests that tapentadol can be a useful treatment option for patients suffering from chronic pain and in need of an opioid analgesic. Opioids should be prescribed by a qualified physician only after other analgesics have been considered, taking side effects and misuse risk into account.

Bone fractures in patients using tapentadol or oxycodone: an exploratory US claims database study.

Aim: To explore fracture outcomes with tapentadol or oxycodone, two opioids with differing mechanisms of action. Materials & methods: Retrospective cohort pilot study, using MarketScan® Commercial and Medicare Supplemental claims databases, on patients with postoperative pain, back pain, or osteoarthritis and ≥1 claim for tapentadol (n = 16,457), oxycodone (n = 1,356,920), or both (n = 15,893) between June 2009 and December 2015. Results: During 266,826 and 9,007,889 days of tapentadol and oxycodone treatment, patients evidenced 1080 and 72,275 fractures, respectively. Fracture rates per treatment-year were 1.512 for tapentadol and 3.013 for oxycodone. Conclusion: Examination of administrative claims has inherent limitations, but this exploratory analysis indicates a lower fracture rate with tapentadol than oxycodone in the analyzed dataset, which needs confirmation by further clinical trials.

Experiencia en la práctica clínica real de la efectividad y la tolerabi- lidad de tapentadol de liberación prolongada para el tratamiento de dolor crónico postraumático producido por accidentes de trabajo / Real-world clinical practice experience of the effectiveness and tolerability of pro- longed-release tapentadol for the treatment of chronic post-traumatic pain caused by occupational accidents

Se llevó a cabo un estudio observacional para analizar si tapentadol de liberación prolongada (LP) puede considerarse un tratamiento de primera línea para pacientes con dolor crónico postraumático (DCPT). Métodos: Se presenta una serie de casos de la práctica clínica real de pacientes con DCPT producido por accidentes de trabajo. Antes de ingresar al estudio, todos los pacientes recibían tramadol, que se interrumpió cuando se inició la administración de tapentadol LP. Las evaluaciones de dolor incluyeron una escala de valoración numérica, el cuestionario DN4 y la escala de Impresión Global de Cambio del Paciente (PGIC, Patients' Global Impression of Change). Se recuperaron y registraron los eventos adversos. Resultados: 94 pacientes participaron en el estudio y 77 (82 %) completaron todas las visitas predefinidas. Cerca de la mitad de los pacientes informaron dolor crónico que tenía una duración de al menos 3 años; se observó un componente neuropático en el 87 % de los pacientes. El puntaje de dolor se redujo en 1,5 puntos luego del primer mes de tratamiento con tapentadol LP y en 2,48 puntos luego de 4 meses (p<0,05). También se asoció la administración de tapentadol LP con una reducción del 28,9 % de la dosis concomitante de pregabalina (p<0,01). De acuerdo con el cuestionario PGIC, el 74 % y el 77,9 % de los pacientes informó mejoría luego de uno y cuatro meses de tratamiento, respectivamente. El perfil de seguridad fue consistente con los datos actuales sobre tapentadol LP. Conclusión: El dolor osteomuscular crónico es una enfermedad prevalente que se caracteriza por tener resultados terapéuticos deficientes y se asocia a una mayor discapacidad y una mala calidad de vida. En este estudio de la práctica clínica real en pacientes que trabajan y que cuentan con un componente de dolor neuropático elevado, se observó que tapentadol LP produce efectos beneficiosos en términos del control del DCPT, y se obtuvieron índices altos de eficacia y seguridad.

An observational study was carried out to analyze whether prolonged-release (PR) tapentadol may be considered a first-line treatment for patients with chronic post-traumatic pain (PTD). Methods: A case series of cases of patients with PTFE caused by work accidents in a real clinical practice setting is described. Before entering the study, all patients were receiving tramadol, which was discontinued when PR tapentadol was started. Pain assessments included a numerical rating scale, the DN4 questionnaire, and the Patients' Global Impression of Change (PGIC) scale. Adverse events were retrieved and described. Results: 94 patients participated in the study and 77 (82%) completed all the predefined visits. About half of the patients reported chronic pain that lasted for at least 3 years. A neuropathic component was reported in 87% of patients. The pain score was reduced by 1.5 points after the first month of treatment with PR tapentadol and by 2.48 points after 4 months (p < 0.05). Administration of PR tapentadol was also associated with a concomitant reduction of pregabalin dose of 28.9% (p < 0.01). According to the PGIC questionnaire, 74% and 77.9% of patients reported improvement after one and four months of treatment, respectively. The safety profile was consistent with current data on PR tapentadol. Conclusion: Chronic musculoskeletal pain is a prevalent disease characterized by poor therapeutic results and associated with increased disability and poor quality of life. In our study in a real clinical practice setting with patients with a high neuropathic pain component, PR tapentadol produced beneficial effects in terms of DCPT control, and high efficacy and safety rates were obtained. Keywords: tapentadol, chronic pain, pain caused by work accidents, chronic post-traumatic pain, evidence from real clinical practice.

Pharmacokinetic Analysis, Analgesic Effects, and Adverse Effects of Tapentadol in Cancer Patients with Pain.

In this study, we conducted a pharmacokinetic analysis of tapentadol (TP) in Japanese patients with cancer pain and identified covariates influencing pharmacokinetic parameters. In addition, the analgesic effects and adverse effects of TP were investigated. Data were collected from in-patients with cancer pain who had been administered TP as an extended-release formula. The median (range) estimated clearance (CL/F) and distribution volume (Vd/F) of TP were 86.7 (31.3-213.7) L/h and 1288 (189-6736) L, respectively. There was a strong negative correlation between CL/F and age, Child-Pugh score, and albumin-bilirubin (ALBI) score. The subjects were further divided into two groups according to the factors highly correlated with CL/F. The CL/F of patients in the Child-Pugh B group was 0.46-times that of patients in the Child-Pugh A group. In addition, the CL/F of patients with an ALBI score > -2.40 was 0.56-times that of patients with ALBI scores ≤-2.40, and both differences were statistically significant (p < 0.05). The mean intensity of pain over 24 h was investigated daily from before starting TP for the first 7 d of the treatment. TP reduced pain in six of nine patients; the mean pain visual analogue scale score decreased significantly from 59.2 mm before administration to 42.5 mm at days 5-7. Overall, the Child-Pugh and ALBI scores significantly affected the clearance of TP, which was reduced in patients with impaired liver function. These results suggest that TP is an opioid with a sufficient analgesic effect for cancer patients.

Opioid use and harms associated with a sustained-release tapentadol formulation: A post-marketing surveillance study.

AIMS: A sustained-release formulation (SRF) of tapentadol has been marketed in Australia since February 2013. This study examined tapentadol SRF extra-medical use, attractiveness for extra-medical use, and associated harms in Australia. METHODS: This post-marketing study comprises analyses of Australian community sales data (2011-2017) for eleven pharmaceutical opioids (prescription and over-the-counter codeine disaggregated); calls to three poisons information centres (covering five of the eight jurisdictions in Australia) related to pharmaceutical opioids and coded by the centres as 'misuse' or 'abuse' (2011-2017); and interviews with people who inject drugs (n = 888) recruited as part of the Illicit Drug Reporting System (IDRS) from all Australian capital cities (2017). RESULTS: Population-level availability of tapentadol SRF increased from market launch, comprising the sixth largest market share of all opioid unit sales, and third greatest share in oral morphine equivalent milligrams sold, in December 2017. Lifetime tapentadol SRF use among the IDRS sample (n = 888) was low (1.5%; 95%CI 0.9-2.5), with few reporting past-6 month non-prescribed use or injection. Non-fatal overdose following tapentadol use was self-reported by less than 1% (95%CI 0.1-0.8). Between 2013-2017, 1.1% (n = 25) of pharmaceutical opioid 'misuse/abuse' calls were related to tapentadol, and predominantly the SRF. CONCLUSIONS: Increasing utilisation of tapentadol sustained-release formulation was observed, along with indications of extra-medical use and harms associated with use, although on a smaller scale relative to other opioids. These findings need to be interpreted in the context of the low level of exposure to tapentadol sustained-release formulation among the sentinel population of people who inject drugs.

Current Status of Adverse Events Related with Opioid Analgesics in Japan: Assessment Based on Japanese Adverse Drug Event Report Database.

Opioid analgesics have greatly contributed to the advancement of pain management. However, although opioids have been appropriately used in Japan, they rarely induce serious adverse events, such as respiratory depression. The present study aimed to investigate the temporal changes in the occurrence of opioid-related adverse events and deaths between 2004 and 2017 in Japan using the Japanese Adverse Drug Event Report (JADER) database. We analyzed the following points using data extracted from JADER website: 1) temporal changes in the number and proportion of opioid-related adverse event reports; 2) temporal changes in the number of morphine-, oxycodone-, and fentanyl-related adverse event reports per annual consumption; and 3) cases in which the reported outcome following opioid-related adverse events was death. Our results showed no dramatic changes in the overall incidence of opioid-related adverse events, despite the temporal changes in the annual consumption and shared component of each opioid during the survey period. However, the number and rate of fentanyl-related adverse events and their outcome "death" increased since 2010, being the highest among all adverse event including those related to morphine and oxycodone. Outcome "death" by fentanyl-related adverse events was caused mainly due to respiratory depression. These findings suggest that, although opioid-related adverse events can be controlled through proper monitoring and management by medical personnel in Japan, extra caution should be continuously paid for the rare but serious fentanyl-induced adverse events.

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.

The Increasing Use and Abuse of Tapentadol and Its Incorporation Into a Validated Quantitative Method.

Tapentadol is a centrally acting synthetic analgesic which is prescribed for the treatment of a range of chronic pain conditions. Its use in treating various pain conditions is increasing and, as with other opioids, it has the potential to be abused. We describe a three-stage incorporation of tapentadol into validated screening and quantitative methods through: (i) addition of retention time/mass spectral data to a database, (ii) qualitative validation and (iii) quantitative validation. This represents an efficient and flexible approach to the incorporation of new compounds of interest to existing screening methods. Tapentadol was analyzed in blood and serum samples using alkaline liquid-liquid extraction with identification and quantitation by liquid chromatography/time-of-flight mass spectrometry. In a series of six post-mortem cases where tapentadol was detected but was not a primary causative factor in death, blood concentrations ranged from 0.01 to 1.0 mg/L. In two cases where tapentadol was a significant contributor to death, post-mortem blood concentrations were 1.7 and 3.9 mg/L. In one of these fatal cases, ante-mortem blood and serum were also analyzed. The tapentadol concentration in the post-mortem blood was 30% higher than in the ante-mortem blood after a post-mortem interval of 13 days, indicating some potential for post-mortem redistribution. The measured ante-mortem blood:serum ratio was 1.7, and is the first such ratio to be reported. Other drugs were detected in almost all cases, with the majority being prescription analgesics, sedatives and antidepressants. The number of cases in which tapentadol has been detected has increased in recent years, highlighting the importance of screening for this drug in forensic toxicological laboratories.

Review of Post-Marketing Safety Data on Tapentadol, a Centrally Acting Analgesic.

INTRODUCTION: Tapentadol is a centrally acting analgesic that has been available for the management of acute and chronic pain in routine clinical practice since 2009. METHODS: This is the first integrated descriptive analysis of post-marketing safety data following the use of tapentadol in a broad range of pain conditions relating to the topics overall safety, dose administration above approved dosages, administration during pregnancy, serotonin syndrome, respiratory depression, and convulsion. The data analyzed pertain to spontaneous reports from healthcare and non-healthcare professionals and were put in the context of safety information known from interventional and non-interventional trials. RESULTS: The first years of routine clinical practice experience with tapentadol have confirmed the tolerability profile that emerged from the clinical trials. Moreover, the reporting of expected side effects such as respiratory depression and convulsion was low and no major risks were identified. The evaluation of available post-marketing data did not confirm the theoretical risk of serotonin syndrome nor did it reveal unexpected side effects with administration of higher than recommended doses. CONCLUSION: More than 8 years after its first introduction, the favorable overall safety profile of tapentadol in the treatment of various pain conditions is maintained in the general population. FUNDING: Grünenthal GmbH.

Assessment of Tapentadol API Abuse Liability With the Researched Abuse, Diversion and Addiction-Related Surveillance System.

Tapentadol, a Schedule II opioid with a combination of µ-opioid activity and norepinephrine reuptake inhibition, is used for the management of moderate to severe acute and chronic pain. Its dual mechanism of action is thought to reduce opioid-related side effects that can complicate pain management. Since approval, tapentadol has been tracked across multiple outcomes suggesting abuse liability, and a pattern of relatively low, although not absent, abuse liability has been found. This retrospective cohort study further details the abuse liability of tapentadol as an active pharmaceutical ingredient (API) when immediate-release as well as extended-release formulations were on the market together (fourth quarter of 2011 to second quarter of 2016). Tapentadol (API) was compared with tramadol, hydrocodone, morphine, oxycodone, hydromorphone, and oxymorphone across Poison Center, Drug Diversion, and Treatment Center Programs Combined data streams from the Researched Abuse, Diversion and Addiction-Related Surveillance system. Findings suggest the public health burden related to tapentadol to date is low, but present. Event rates of abuse per population-level denominators were significantly lower than all other opioids examined. However, when adjusted for drug availability, event rates of abuse were lower than most Schedule II opioids studied, but were not the lowest. Disentangling these 2 sets of findings further by examining various opioid formulations, such as extended-release and the role of abuse-deterrent formulations, is warranted. PERSPECTIVE: This article presents the results from an examination of tapentadol API across the Researched Abuse, Diversion and Addiction-Related Surveillance System: a broad and carefully designed postmarketing mosaic. Data to date from Poison Center, Drug Diversion, and Treatment Centers combined suggest a low, but present public health burden related to tapentadol.

Pharmacokinetics of tapentadol in laying hens and its residues in eggs after multiple oral dose administration.

1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel opioid analgesic, in laying hens after intravenous (IV) and oral (PO) administration and to quantify the concentrations of TAP residues in eggs. 2. Twenty healthy laying hens were divided into three groups: A (n = 6), B (n = 6) and C (n = 8). The study was conducted in two phases. Groups A and B received TAP by IV and PO routes at the dose of 1 and 5 mg/kg, respectively. 3. No visible adverse effects were observed after administration of the drug. TAP plasma concentrations were detectable up to 4 h following administration. Following IV administration, TAP plasma concentrations were only higher than the minimal effective concentration (148 ng/ml) reported for humans for 1 h. After single PO administration, plasma concentrations of TAP would not conform to software algorithms and the PK parameters were not calculated. TAP concentration following multiple PO doses at 5 mg/kg for 5 d was found to be higher and more persistent (12 h vs. 7 h) in yolk compared with albumen. 4. This is the first PK study on the novel atypical opioid TAP in laying hens. Further studies are required to investigate the analgesic efficacy and actual effective plasma concentration of TAP in this species.