Search

Abstract During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID‐19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight. We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normal‐weight versus obese COVID‐19 hospitalized patients. Two groups of patients were enrolled: normal‐weight and obese (body mass index [BMI] 18.5–25 and >30 kg/m2, respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured. The mean DEX AUC0–8 and Cmax were lower in the obese compared to the normal‐weight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs. 203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC0–8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC0–8 (p = 0.004, 95% CI 2–7%). In women, irrespective of the BMI, DEX AUC0–8 increased by 214% in comparison to men (p

Abstract The suitability of the endogenous 6‐hydroxymelatonin/melatonin urinary metabolic ratio as a surrogate for the paraxanthine/caffeine ratio to predict cytochrome P450 1A2 (CYP1A2) activity was assessed in this study. Twelve healthy volunteers completed four study sessions spread over 1 month (including overnight urine collection with first morning voids collected separately). Except for the third session, volunteers were asked to abstain from methylxanthine‐containing beverages and foods at least 24 h before urine collection. At the end of urine collection, subjects were given a caffeinated beverage and capillary blood samples were collected 2 h after the drink administration. A significant linear relationship between the 6‐hydroxymelatonin/melatonin ratios from 12‐h urine samples and first morning voids was observed (R2 = 0.876, p < 0.0001). In contrast to the paraxanthine/caffeine ratio, consumption of methylxanthine‐containing beverages during session three did not significantly influence the 6‐hydroxymelatonin/melatonin ratios compared with the other sessions requiring abstinence from caffeine. A larger intra‐ and interindividual variability in the 6‐hydroxymelatonin/melatonin ratios compared with the paraxanthine/caffeine ratio was also observed. A very weak correlation was observed between the paraxanthine/caffeine ratio and both of the endogenous 6‐hydroxymelatonin/melatonin ratios (Pearson r < 0.35, p < 0.05). All these results question whether this endogenous metric could adequately reflect CYP1A2 activity or substitute for the probe caffeine. Additional studies with larger study samples are needed to examine this endogenous metric in more details.

IntroductionThe use of massage therapy has received increased attention in the treatment of chronic pain. However, barriers can hinder its use in nursing care. This study uses a qualitative methodology to explore professionals' experiences regarding touch massage (TM) and identify barriers and facilitators for the implementation of this intervention.Materials and methodsThis study is part of a larger research program aimed at investigating the impact of TM on the experiences of patients with chronic pain hospitalized in two units of an internal medicine rehabilitation ward. Health care professionals (HCPs) were trained either to provide TM or to use of a massage-machine device according to their units. At the end of the trial, two focus groups were conducted with HCPs from each unit who took part in the training and agreed to discuss their experience: 10 caregivers from the TM group and 6 from the machine group. The focus group discussions were tape-recorded, transcribed and analyzed using thematic content analysis.ResultsFive themes emerged from thematic content analysis: perceived impact on patients, HCPs' affective and cognitive experiences, patient-professionals relationships, organizational tensions, and conceptual tensions. Overall, the HCPs reported better general outcomes with TM than with the machine. They described positive effects on patients, HCPs, and their relationships. Regarding interventions' implementation, the HCPs reported organizational barriers such as patients' case complexity, work overload, and lack of time. Conceptual barriers such as ambivalence around the legitimacy of TM in nursing care were reported. TM was often described as a pleasure care that was considered a complementary approach and was overlooked despite its perceived benefits.ConclusionDespite the perceived benefits of TM reported by the HCPs, ambivalence arose around the legitimacy of this intervention. This result emphasizes the importance of changing HCPs' attitudes regarding a given intervention to facilitate its implementation.

Abstract Opioid use and associated morbidity and mortality have increased in several countries during the past 20 years. We performed a study whose objective was to assess the frequency and causes of opioid‐related emergency division (ED) visits in an adult tertiary Swiss University Hospital over 9 weeks in 2018. We primarily assessed opioid‐related adverse drug reactions (ADR), secondary overdose, misuse, abuse, and insufficient pain relief. Current opioid use was identified in 1037 (8.3%) of the 12 470 included ED visits. In 64 opioid users, an ADR was identified as a contributing cause of the ED visit, representing 6.2% of opioid users, and 0.5% of the total ED visits. Moreover, we identified an overdose in 16 opioid users, misuse or abuse in 19 opioid users, and compatible withdrawal symptoms in 7 opioid users. After pooling all these events, we conclude that the ED visits could be related to opioid use in 10.2% of opioid users. Finally, in 201 opioid users, insufficient pain relief (pain not responding to the current pharmacological treatment) was identified as a contributing cause of ED visits. In these cases, other factors than simply pharmacological nonresponse may have been involved. In the context of an ever‐increasing opioid use to better control chronic pain situations, these results should reinforce emergency network epidemiological surveillance studies at a national level.

ContextThe management of behavioral symptoms and rigidity in patients with dementia constitutes a significant challenge. Short-term studies suggest an interest in the use of medical cannabis, but long-term data are lacking.ObjectivesThe objective of this study was to investigate the feasibility and long-term safety of administering tetrahydrocannabinol/cannabidiol (THC/CBD) treatment as an additional drug to a poly medicated population with severe dementia, evaluate clinical improvements, and collect information on the pharmacokinetics of cannabinoids and possible drug–drug interactions.MethodsA prospective observational study of patients with severe dementia living in a long-term care home to whom the physicians had prescribed a medical cannabis treatment. Data were collected over 2 years. We assessed the changes in medical cannabis dosages, safety parameters, variations in neuropsychiatric problems, agitation, rigidity, the most invalidating daily activity, and disabling behavior trouble scores. We evaluated the pharmacokinetics of cannabinoids by measuring plasma levels and analyzing the enzymatic activity.ResultsWe assessed 19 patients (81.4 years—17 women and two men) receiving an average of 12.4 mg THC/24.8 mg CBD per day for up to 13 months, with no reported problems related to the treatment and limited adverse drug reactions. Clinical scores showed a marked improvement that was stable over time, deprescription of other medications, and care facilitated. The pharmacokinetic evaluation showed an expected slight reduction in the enzymatic activity of CYP1A2 and CYP2C19.ConclusionA long-term THC/CBD (1:2) medication can be administered safely and with overall positive clinical improvement to poly medicated older adults with severe dementia and associated problems. The results must be confirmed in a randomized trial.

Following the contraindication of codeine use in children, increasing use of tramadol has been observed in pain management protocols. However, tramadol’s pharmacokinetics (PK) and pharmacodynamics are influenced by cytochrome P450 (CYP)2D6 activity, similarly to codeine. Previous studies in adults have demonstrated a correlation between pupillary response and tramadol PK. Our objective was to evaluate pupillometry as a phenotyping method to assess CYP2D6 activity in children treated with tramadol. We included 41 children (mean age 11 years) receiving a first dose of tramadol (2 mg/kg) in the emergency room (ER) as part of their routine care. CYP2D6 phenotyping and genotyping were performed. The concentrations of tramadol and its active metabolite, M1, were measured, and static and dynamic pupillometry was conducted using a handheld pupillometer at the time of tramadol administration and during the ER stay. Pupillometric measurements were obtained for 37 children. Tramadol affected pupillary parameters, with a decrease in pupil diameter in 83.8% of children (p = 0.002) (mean decrease 14.1 ± 16.7%) and a decrease in reflex amplitude constriction in 78.4% (p = 0.011) (mean decrease 17.7 ± 34.5%) at T150 compared to T0. We were unable to identify a correlation between pupillometry measurements and CYP2D6 activity. Likely confounding factors include light intensity, pain, and stress, making the procedure less feasible in paediatric emergency settings.

While morphine is the gold standard treatment for severe nociceptive pain in children, hydromorphone is increasingly prescribed in this population. This review aims to assess available knowledge about hydromorphone and explore the evidence for its safe and effective prescription in children. Hydromorphone is an opioid analgesic similar to morphine structurally and in its pharmacokinetic and pharmacodynamic properties but 5–7 times more potent. Pediatric pharmacokinetic and pharmacodynamic data on hydromorphone are sorely lacking; they are non-existent in children younger than 6 months of age and for oral administration. The current data do not support any advantage of hydromorphone over morphine, both in terms of efficacy and safety in children. Morphine should remain the treatment of choice for moderate and severe nociceptive pain in children and hydromorphone should be reserved as alternative treatment. Because of the important difference in potency, all strategies should be taken to avoid inadvertent administration of hydromorphone when morphine is intended.

Pharmacokinetic variability is a major source of differences in drug response and can be due to genetic variants and/or drug-drug interactions. Cytochromes P450 are among the most studied enzymes from a pharmacokinetic point of view. Their activity can be measured by phenotyping, and/or predicted by genotyping. Depending on the presence of drugs and/or diseases that can affect their in vivo activity, both approaches can be complementary. In 2014, the Geneva cocktail using dried blood spots was validated in healthy volunteers for CYP450 phenotyping. Since its clinical implementation, it has been used in approximately 500 patients in various clinical situations. Our study aims to report the concordance between CYP450 genotype and phenotype in real-life patients. The prospectively collected data from patients who were genotyped and/or phenotyped between January 2014 and December 2020 were reviewed. A total of 537 patients were genotyped and/or phenotyped for CYP450 during this period, and 241 underwent simultaneous genotyping and phenotyping allowing for genotype/phenotype concordance assessment. Genotyping correctly predicted poor metabolizer phenotypes for most CYPs isoenzymes studied, whereas agreement was more variable for intermediate, normal, and ultrarapid metabolizers. Discrepancies between the phenotype predicted on the basis of genotyping and the measured phenotype were not always explained by concurrent medication (phenotypic switch). Therefore genotyping and phenotyping tests are complementary approaches when aiming to individualize drug therapy. In the 537 patients, the majority of clinical situations were observed with analgesic/anesthetic drugs (n = 187), followed by antidepressants (n = 153), antineoplastics (n = 97), and immunosuppressants (n = 93). Inefficacy (or low drug levels) and adverse drug reaction (or high drug levels) were the main reasons for testing. Genotype and/or phenotype results explained or at least contributed to the clinical event in 44% of cases.

Background: Polypharmacy and inappropriate prescription are frequent in vulnerable and multi-morbid populations. Adults with intellectual disability (ID) are at risk of being polymedicated because they often present with multiple comorbidities and challenging behaviors.Aim: The objective of this study was thus to evaluate the prevalence of potentially inappropriate medications (PIM) and polypharmacy in a hospital unit dedicated to adults with ID.Methods: A 10-month prospective observational study took place at a hospital unit specializing in the care of adults with ID in Geneva, Switzerland. Once a week, health and prescription data were collected and screened for PIM according to preset definitions.Results: Fourteen patients consented to participate, leading to 20 hospitalization events assessed during the study. Hospitalizations lasted 12.8 weeks on average. ID severities ranged from mild to profound, all degrees of severity being equally represented. One hundred percent of the patients were polymedicated (defined as five drugs or more prescribed simultaneously). A mean number of 9.4 drugs were prescribed per week, including 5.3 psychotropic drugs. The number of prescribed drugs remained stable throughout the hospitalizations. Antipsychotics were the most prescribed drug class (19% of all prescribed drugs), followed by benzodiazepines (13%) and laxatives (12%). A total of 114 PIM were recorded with an average of 5.7 PIM per hospitalization.Conclusions: This study showed that polypharmacy and inappropriate prescription are very common in adults with ID, even though the literature and expert positions advocate for deprescription in these patients. Specific prescribing and deprescribing guidelines are needed for that specific population.

The aim of this work was to predict the extent of Cytochrome P450 2D6 (CYP2D6)‐mediated drug–drug interactions (DDIs) in different CYP2D6 genotypes using physiologically‐based pharmacokinetic (PBPK) modeling. Following the development of a new duloxetine model and optimization of a paroxetine model, the effect of genetic polymorphisms on CYP2D6‐mediated intrinsic clearances of dextromethorphan, duloxetine, and paroxetine was estimated from rich pharmacokinetic profiles in activity score (AS)1 and AS2 subjects. We obtained good predictions for the dextromethorphan–duloxetine interaction (Ratio of predicted over observed area under the curve (AUC) ratio (Rpred/obs) 1.38–1.43). Similarly, the effect of genotype was well predicted, with an increase of area under the curve ratio of 28% in AS2 subjects when compared with AS1 (observed, 33%). Despite an approximately twofold underprediction of the dextromethorphan–paroxetine interaction, an Rpred/obs of 0.71 was obtained for the effect of genotype on the area under the curve ratio. Therefore, PBPK modeling can be successfully used to predict gene–drug–drug interactions (GDDIs). Based on these promising results, a workflow is suggested for the generic evaluation of GDDIs and DDIs that can be applied in other situations.

Abstract Background Rebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature; however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder. Case presentation A 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal range. While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient’s psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200 mg daily. A cholinergic rebound syndrome was then evoked. The patient’s ability to speak recovered dramatically and fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of biperiden daily. Conclusions This case report underscores that cholinergic rebound syndrome may occur in patients suffering from bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.

Objectives Adults with an intellectual disability (AWID) are often polymedicated because of somatic and psychiatric health problems. Besides, they may display challenging behaviours, leading to off-label prescription of psychotropic drugs, without efficacy and with numerous adverse effects. In this context, a prescription/deprescription tool (Tool for Optimising Prescription in Intellectual Disability/TOP-ID) was developed to improve the care of AWID. This paper describes how TOP-ID was designed.Design Four-step consensus-based process involving a review of the literature, eight semistructured interviews and a two-round Delphi process.Setting Seventeen general practices and university and general hospitals from Belgium, France and Switzerland.Participants Eighteen French-speaking physicians from different domains of expertise participated in the Delphi process.Primary and secondary outcome measures For the Delphi iteration process, consensus was defined as at least a 65% agreement between the experts.Results Two rounds were needed for the Delphi process. Eighty-one items of the tool were submitted to 18 out of 35 recruited French-speaking experts during the first round. Sixty-nine per cent of the items reached a rate of agreement of 65% or more in that round. Thirteen questions were reformulated and resubmitted for the second Delphi iteration round. All of the statements reached a rate of agreement of 65% or more in the second round.Conclusion TOP-ID is the first prescription–deprescription tool developed specifically for AWIDs in French. It is intended to help prescribers document patient care in order to reduce prescription errors and to improve safety. The next steps of the project include the development of an electronic version of TOP-ID and a utility study.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide in both sexes. Despite considerable progress in better understanding the patterns of disease in women, they are still often undertreated and benefit less from evidence-based treatment. Hypertension is a key contributor to CVD and is also one of the most potent risk factors for heart failure in women. Even with the wide variety of available drugs, blood pressure control is globally suboptimal. Current guidelines do not suggest differential treatment of hypertension for women; however, a growing body of research suggests gender dimorphism in the pathophysiology of hypertension and pharmacological response to cardiovascular drugs. The clinical relevance of theses sex-divergent effects of drugs is still under investigation. Owing to the exponential relationship between blood pressure and cardiovascular mortality, even a modest decrease in blood pressure or therapeutic adhesion could be clinically \relevant. In this review, we explore the known pharmacological and pharmacokinetic sex differences with special attention to the main classes of antihypertensive treatment. Current data shows frequently higher drug exposures in women and more frequent adverse drug reactions in all antihypertensive drug groups. As far as cardiovascular prevention is concerned, sex-specific data is often lacking in clinical trials, highlighting the necessity to further study CVD and their treatment in both men and women.

Abstract Background It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the “in vivo” measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. Methods/design This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2–3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50–70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. Discussion By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. Trial registration ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

BackgroundIdentifying patients at high risk of hospital preventable readmission is an essential step towards selecting those who might benefit from specific transitional interventions.ObjectiveDerive and validate a predictive risk score for potentially avoidable readmission (PAR) based on analysis of readmissions, with a focus on medication.Design/setting/participantsRetrospective analysis of all hospital admissions to internal medicine wards between 2011 and 2014. Comparison between patients readmitted within 30 days and non-readmitted patients, as identified using a specially designed algorithm. Univariate and multivariate regression analyses of demographic data, clinical diagnoses, laboratory results, and the medication data of patients admitted during the first period (2011-2013), to identify factors associated with PAR. Using these, derive a predictive score with a regression coefficient-based scoring method. Subsequently, validate this score with a second cohort of patients admitted in 2013-2014. Variables were identified at hospital discharge.ResultsThe derivation cohort included 7,317 hospital stays. Multivariate logistic regressions found significant associations with PAR for: [adjusted OR (95% CI)] hospital length of stay > 4 days [1.3 (1.1-1.7)], admission in previous 6 months [2.3 (1.9-2.8)], heart failure [1.3 (1.0-1.7)], chronic ischemic heart disease [1.7 (1.2-2.3)], diabetes with organ damage [2.2 (1.3-3.8)], cancer [1.4 (1.0-1.9)], metastatic carcinoma [1.9 (1.3-3.0)], anemia [1.2 (1.0-1.5)], hypertension [1.3 (1.1-1.7)], arrhythmia [1.3 (1.0-1.6)], hyperkalemia [1.4 (1.0-1.7)], opioid drug prescription [1.3 (1.1-1.6)], and acute myocardial infarction [0.6 (0.4-0.9)]. The PAR-Risk Score, derived from these results, demonstrated fair discriminatory and calibration power (C-statistic = 0.699; Brier Score = 0.069). The results for the validation cohort's operating characteristics were similar (C-statistic = 0.687; Brier Score = 0.064).ConclusionThis study identified routinely-available factors that were significantly associated with PAR. A predictive score was derived and internally validated.

We report a case of carbamazepine withdrawal syndrome following in utero exposure to carbamazepine related to a pharmacogenetic predisposition factor. The infant was born at 37 1/7 weeks’ gestation by cesarean section to a mother treated for epilepsy with carbamazepine. One hour and thirty minutes after birth, the infant presented a respiratory distress with severe oxygen desaturation requiring intubation 5 h after birth. On the third day of life the infant developed clinical signs of a withdrawal syndrome which resolved progressively after 16 days and symptomatic treatment. The infant genotype analysis showed two low activity CYP2C9 allelic variants (∗2/∗3 heterozygote) predicting a CYP2C9 slow metabolizer phenotype which could explain reduced carbamazepine elimination and a late and long-lasting withdrawal symptoms observed 3 days after birth. The association of a withdrawal syndrome with carbamazepine exposure has not been previously reported and pharmacogenetic tests might therefore be useful in identifying patients at risk.

We report a patient who presented a non-ST segment elevation myocardial infarction in the context of severe normocytic hypochromic anemia related to gastrointestinal bleeding, three months after switching anticoagulant from the vitamin K antagonist acenocoumarol to the direct oral anticoagulant rivaroxaban. High levels of both anti-Xa activity and rivaroxaban plasma concentrations were measured despite rivaroxaban withdrawal, suggesting reduced elimination/drug clearance. Estimated half-life was 2 to 3 times longer than usually reported. The patient is a homozygous carrier of ABCB1 variant alleles, which could have participated to reduced elimination of rivaroxaban. Furthermore, CYP3A4/5 phenotyping showed moderately reduced enzyme activity. Drug-drug interaction with simvastatin may have contributed to decreased rivaroxaban elimination. Although in the present case moderate acute renal failure probably played a role, more clinical data are required to elucidate the impact of ABCB1 polymorphism on rivaroxaban pharmacokinetics and bleeding complications.

Parallel to an ever stronger advocacy for the use of generics, various sources of information report concerns regarding substitution. The literature indicates that information regarding substitution is not univocal. The aim of this qualitative study was to explore patients' representations regarding generics in patients suffering from non-specific disabling chronic musculoskeletal pain, as these patients are confronted with the issue of the prescription and/or substitution of original formulations with generics.Qualitative methods were selected because the aim was to access the range of patients' representations and to consider their conceptions. Standardized face-to-face semi-structured interviews were used, and transcripts were submitted to content analysis.Patients' representations suggest that they might be confident in taking a generic medication: when he/she has an understanding of generics as resulting from a development process that has become part of the public domain; the generic medication is prescribed by the physician; each prescription is discussed, i.e., the patient is prescribed the generic version of a given medication and not a generic medication.Economic arguments are not sufficient to justify substitution, and may even raise issues calling upon cognitive dissonance. Even in non-life-threatening diseases, negative cues require attention and need be de-emphasized - in particular lower price as an indication of lower quality, and generic status as contradictory with advocating individualization of medication.

Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p

A pharmacokinetic/pharmacodynamic, randomized, crossover, placebo-controlled study was conducted in healthy human volunteers with the primary objective of exploring the existence of a positive interaction between paracetamol 1 g and ketorolac 20 mg intravenously on experimental pain models. Further, the simplified UVB model was validated as a screening tool for analgesics or a combination of analgesics in clinical drug development. It was observed that the UVB irradiation induced primary hyperalgesia, evidenced by significant decreases of the heat pain threshold from (mean ± SD) 46.9 ± 1.1 °C to 40.1 ± 1.7 °C (p