Healthcare is under pressure: an ageing population, healthcare-staff shortage, quality (healthcare outcomes) must increase and costs must be reduced.Yet, what are the outcomes of healthcare?For... Show moreHealthcare is under pressure: an ageing population, healthcare-staff shortage, quality (healthcare outcomes) must increase and costs must be reduced.Yet, what are the outcomes of healthcare?For some conditions, quality of care is measured for every patient. Unfortunately, this is not the case for prostate cancer and lumbar disk herniation in the Netherlands. We used claims data to evaluate healthcare outcomes and volume-outcome relationships.Examples of our results:Prostate cancer:• More than 30% of patients is incontinent 1 year after radical prostatectomy• Large differences between hospitals (19%-85%)• Risk of incontinence is 52% lower at highest-volume hospitalsLumbar disk herniation:• One year after hernia surgery, 23% of patients have one or more undesirable outcomes (e.g. re-operation, use of opioids).• Wide variation in number of operations and outcomes per hospitalOur recommendations:• Reconsider the disproportionately strict interpretation of the GDPR (AVG) for healthcare research• Unlock the huge potential of healthcare research based on existing data • Make routine measurement of healthcare outcomes a national standard, for prostate cancer even on a per surgeon level• Centralization of care should be combined with outcome measurement• Hospitals should share healthcare outcomes with patients• Our results urge doctors, health insurers, patient organizations and policymakers to take action Show less
BackgroundThere is lack of data on opioid (over)use for migraine in Europe.MethodsWe performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use... Show moreBackgroundThere is lack of data on opioid (over)use for migraine in Europe.MethodsWe performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use in individuals with migraine. Primary outcome was to assess opioid use for the treatment of migraine attacks. As secondary outcomes we specified use of opioids (duration of use, type of opioids, prescriber) and compared between persons with episodic migraine versus chronic migraine. Descriptive statistics, unpaired T-tests, Chi-square and Mann-Whitney U tests were used.ResultsIn total n = 3712 patients participated, 13% ever used opioids for headache. In opioid users, 27% did this for >1 month, and 11% for >1 year, and 2% without prescription. The majority of prescribing physicians were general practitioners (46%), followed by neurologists (35%), other specialists (9%), or emergency room doctors (8%). Opioids were used as acute treatment in 63%, in 16% as preventive treatment, and in 21% for both indications. Chronic migraine patients reported more opioid use compared with episodic migraine (22% versus 12%, p < 0.001), with also more prolonged use (>1 month: 34% chronic migraine versus 24% episodic migraine, p < 0.003).ConclusionOpioid use is more frequent and prolonged in chronic migraine patients. Further education for both doctors and migraine subjects and providing multimodal pain management strategies are needed to reduce opioid use in persons with migraine. Show less
Dam, C.J. van; Velzen, M. van; Kramers, C.; Schellekens, A.; Olofsen, E.; Niesters, M.; Dahan, A. 2023
Background Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous... Show moreBackground Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous adverse effects, and are difficult to wean. As an alternative, we previously showed advantages of using pharmaceutical-grade cannabis in a population of chronic pain patients with fibromyalgia. It remains unknown whether combining an opioid with pharmaceutical-grade cannabis has advantages, such as fewer side effects from lesser opioid consumption in chronic pain.Methods Trial design: a single-center, randomized, three-arm, open-label, exploratory trial.Trial population: 60 patients with fibromyalgia according to the 2010 definition of the American College of Rheumatologists.Intervention: Patients will be randomized to receive up to 4 daily 5 mg oral oxycodone sustained release (SR) tablet, up to 5 times 150 mg inhaled cannabis (Bediol (R), containing 6.3% delta(9)-tetrahydrocannabinol and 8% cannabidiol), or the combination of both treatments. Treatment is aimed at self-titration with the daily maximum doses given. Treatment will continue for 6 weeks, after which there is a 6-week follow-up period.Main trial endpoint: The number of side effects observed during the course of treatment using a composite adverse effect score that includes the following 10 symptoms: dizziness (when getting up), sleepiness, insomnia, headache, nausea, vomiting, constipation, drug high, hallucinations, and paranoia.Secondary and tertiary endpoints include pain relief and number of oxycodone doses and cannabis inhalations.Discussion The trial is designed to determine whether self-titration of oxycodone and cannabis will reduce side effects in chronic pain patients with fibromyalgia. Show less
The last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in... Show moreThe last decades it is increasingly recognized that acute as well as chronic postoperative pain is an important problem. Treatment and prevention of postoperative pain is a challenge, especially in special patient populations where there is only limited guidance on how to optimally use opioids. In this thesis we focused on the perioperative use of opioids in three different populations. First, the influence of the opioids remifentanil versus fentanyl on acute and chronic postoperative pain was investigated in adult cardiac surgery patients. Second, pharmacodynamic modelling methods were applied to analyze the postoperative use of morphine in children after cardiac surgery. Finally, a pharmacokinetic model was developed to investigate the influence of obesity on the pharmacokinetics of morphine and its metabolites. Pain remains a complex puzzle among biological, psychological, behavioral and social-cultural factors. The high inter-individual variation in all of these factors results in postoperative pain still being a major issue while the ultimate goal is to stay without pain after a surgical procedure. Therefore, the answer to the question: “Does it still hurt?” is: YES unfortunately. This thesis adds pieces to this complex puzzle by focusing on the use of opioids in three different patient populations. Show less
This thesis aims to describe certain novel approaches and pharmacological interventions in the treatment of acute and chronic pain. It demonstrates that the efficacy of the mu-opioid receptor... Show moreThis thesis aims to describe certain novel approaches and pharmacological interventions in the treatment of acute and chronic pain. It demonstrates that the efficacy of the mu-opioid receptor agonist and noradrenaline reuptake inhibitor tapentadol in the treatment of chronic pain is highest in specific patient phenotypes. This highlights the importance of patient phenotyping to get a detailed indication of the characteristics of the different aspects of the pain syndrome (such as involvement and activity of excitatory versus inhibitory pathways) without the need for knowledge on underlying mechanisms or related illnesses. Additionally, it demonstrates that treatment with the non-conventional treatment option cannabis shows potential but efficacy in the chosen patient population was limited. This thesis is also designated to treatment of acute pain with sublingual sufentanil and a non-opioid alternative option (ice-popsicle). Both show efficacy and seem possible alternatives as part of the multimodal therapy of acute pain. Show less
This thesis assesses multiple monitoring modalities that can be used in the peri-operative period to reduce respiratory adverse events associated with the use of anesthetic drugs, particularly... Show moreThis thesis assesses multiple monitoring modalities that can be used in the peri-operative period to reduce respiratory adverse events associated with the use of anesthetic drugs, particularly opioids and neuromuscular blocking drugs. Monitors of analgesia, neuromuscular block and ventilation are studied in both healthy volunteers and surgical patient populations to assess proof of concept, efficacy, feasibility of clinical use and effect on clinical outcomes. Show less
Broens, S.J.L.; Prins, S.A.; Kleer, D. de; Niesters, M.; Dahan, A.; Velzen, M. van 2020
Although postoperative adverse respiratory events, defined by a decrease in respiratory rate (RR) and/or a drop in oxygen saturation (SpO(2)), occur frequently, many of such events are missed. The... Show moreAlthough postoperative adverse respiratory events, defined by a decrease in respiratory rate (RR) and/or a drop in oxygen saturation (SpO(2)), occur frequently, many of such events are missed. The purpose of the current study was to assess whether continuous monitoring of the integrated pulmonary index (IPI), a composite index of SpO(2), RR, end-tidal PCO(2)and heart rate, alters our ability to identify and prevent adverse respiratory events in postoperative patients. Eighty postoperative patients were subjected to continuous respiratory monitoring during the first postoperative night using RR and pulse oximetry and the IPI monitor. Patients were randomized to receive intervention based on standard care (observational) or based on the IPI monitor (interventional). Nurses were asked to respond to adverse respiratory events with an intervention to improve the patient's respiratory condition. There was no difference in the number of patients that experienced at least one adverse respiratory event: 21 and 16 in observational and interventional group, respectively (p = 0.218). Compared to the observational group, the use of the IPI monitor led to an increase in the number of interventions performed by nurses to improve the respiratory status of the patient (average 13 versus 39 interventions, p < 0.001). This difference was associated with a significant reduction of the median number of events per patient (2.5 versus 6, p < 0.05) and a shorter median duration of events (62 s versus 75 s, p < 0.001). The use of the IPI monitor in postoperative patients did not result in a reduction of the number of patients experiencing adverse respiratory events, compared to standard clinical care. However, it did lead to an increased number of nurse interventions and a decreased number and duration of respiratory events in patients that experienced postoperative adverse respiratory events. Show less
The ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve... Show moreThe ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve the mesocortical circuitry. Coping with stress increases VTA-DA excitability, but when the stressor becomes chronic the VTA-DA circuit is less active, which may lead to degeneration and local microglial activation. This switch between activation and inhibition of VTA-DA neurons is modulated by e.g. corticotropin-releasing hormone (CRH), opioids, brain-derived neurotrophic factor (BDNF), and the adrenal glucocorticoids. These actions are coordinated with energy-demanding stress-coping styles to promote behavioral adaptation. The VTA circuits show sexual dimorphism that is programmed by sex hormones during perinatal life in a manner that can be affected by glucocorticoid exposure. We conclude that insight in the role of stress in VTA-DA plasticity and connectivity, during reward processing and stress-coping, will be helpful to better understand the mechanism of resilience to breakdown of adaptation. Show less
Bruin, F. de; Hek, K.; Lieshout, J. van; Verduijn, M.; Langendijk, P.; Bouvy, M.; Teichert, M. 2019
This thesis describes the day to day interaction between propofol and midazolam as encountered in every day practice. The direct interaction of premedication given to patients before surgery has... Show moreThis thesis describes the day to day interaction between propofol and midazolam as encountered in every day practice. The direct interaction of premedication given to patients before surgery has profound implications. The propofol induction dose can be decreased with respect to the target BIS. Besides the interaction mechanisms of propofol and midazolam, the pharmacological backgrounds of propofol-opioid interactions are given. The future perspectives of PK-PD modeling and the use of additional informative techniques are given in the last chapter. Show less
The objective of the investigations described in this thesis was to characterize the in vivo pharmacological and PK-PD properties of buprenorphine relative to fentanyl with respect to: 1) kinetics... Show moreThe objective of the investigations described in this thesis was to characterize the in vivo pharmacological and PK-PD properties of buprenorphine relative to fentanyl with respect to: 1) kinetics of onset and offset of the pharmacological effects at the mu-opioid receptor, 2) selectivity of action (antinociception versus respiratory depression), 3) the interspecies extrapolation of the PK-PD correlation of the antinociceptive and respiratory depressant effect, 4) the role of active metabolites, 5) kinetics of antagonism of the respiratory depressant effect. Preclinical investigations were performed to develop and validate mechanism-based PK-PD models for the effects of opioids on antinociception and respiration. These PK-PD models were subsequently applied to characterize the effects of buprenorphine and fentanyl in humans. It was shown that the developed PK-PD model can be used to predict the efficacy and safety outcome of opioids in animals. Furthermore, the PK-PD model had excellent properties to enable animal-to-human extrapolation of the efficacy and safety outcome. Show less
The objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase... Show moreThe objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase distribution and target interaction kinetics. Several in vitro and in vivo studies have been performed to characterize the transport to the site of action in the brain, the receptor interaction and EEG effects. From the transport studies it could be concluded that the efflux transporter P-glycoprotein is involved in the transport of morphine, whereas for the other opioids no interaction could be identified, which was mainly due to the high passive permeability. Population modeling showed that the predicted morphine biophase concentration-time profiles in vivo were distinctly different from the brain ECF concentration-time profiles, as estimated by intracerebral microdialysis. In addition, for morphine, a complex biophase distribution model was required to describe the hysteresis between blood concentration and EEG effect whereas for the other opioids a simple one-compartment distribution model was sufficient. Investigation of the role of target interaction showed that based on the correlation between in vitro and in vivo receptor binding characteristics, two subpopulations existed. In conclusion, for the development of a predictive PK-PD model, the underlying processes should be investigated in great detail and supportive data are essential for model validation and prediction. Show less
