The studies described in this thesis investigate the effects of different pharmacotherapieson antinociception and ventilatory control. Additionally, inherent variabilities in patient phenotypes... Show moreThe studies described in this thesis investigate the effects of different pharmacotherapieson antinociception and ventilatory control. Additionally, inherent variabilities in patient phenotypes within the population were assessed to gain a deeper understanding of the individual effects of analgesics and the ventilatory effects of disease, particularly type 2 diabetes mellitus (T2DM). Show less
The circadian timing system is highly integrated with the sleep-wake regulation system. This thesis focuses on how different pharmacological treatments influence the sleep regulation system and the... Show moreThe circadian timing system is highly integrated with the sleep-wake regulation system. This thesis focuses on how different pharmacological treatments influence the sleep regulation system and the circadian timing rhythm in two murine models. In the first animal model, which is presented in Chapter 2 and 3, we implanted EEG/EMG electrodes in freely moving Brown Norway rats. We chose this rat strain because it is pigmented and therefore a more representative model than the more mainstream rat strains which are usually albino rats. This study aimed to investigate the effect of caffeine, sleep deprivation and ketamine on sleep and circadian-controlled activity under constant darkness. In the second animal model, which is presented in Chapter 4 and 5, we implanted EEG/EMG or Multi-unit electrodes in chemotherapy-induced fatigue mice. All the results from this thesis and future perspectives were discussed in Chapter 6. We are able to see how disruption of sleep and the circadian clock adversely affect health and may contribute to many diseases in modern society. In this thesis, these studies provide a better understanding of these drugs influence the circadian timing system and sleep-wake regulation and maybe new treatment approaches for antidepressant therapy and cancer related fatigue. Show less
Hoydonckx, Y.; Singh, M.; Gilron, I.; Khan, J.; Narouze, S.; Dahan, A.; ... ; Bhatia, A. 2023
BackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to... Show moreBackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to conventional medical management and/or patients cannot afford expensive treatments. It is stipulated that CDH share a mechanism of central sensitization in the trigeminocervical complex, mediated by activation of the N-methyl-d-aspartate (NMDA) receptors. Ketamine, a non-competitive NMDA antagonist, has been used in the treatment of chronic pain, but its role in CDH has not been completely established. This trial aims to evaluate the effect of high-dose IV ketamine infusions (compared to placebo) on the number of headache days at 28 days post-infusion.MethodsA multicenter, placebo-controlled, randomized controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessors. The study will include 56 adults with a CDH diagnosis as per ICHD-3 criteria. Participants will be randomized (1:1) to either ketamine (1 mg. kg−1 bolus followed by infusion of 1 mg. kg−1. h−1 for 6 h) or placebo (0.9% saline in the same volume and infusion rate as the trial medication) bolus and infusion for 6 h. The impact on the number of monthly headache days, headache intensity, physical activity, mood, sleep, quality of life, analgesic consumption, and adverse effects will be recorded at baseline, immediately post-infusion, and from 1 to 28 days, 29 to 56 days, and 57 to 84 days after the infusionDiscussionDespite advancements in treatment, many patients continue to suffer from CDH. This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion. This treatment could become a safe, affordable, and widely available option for patients living with refractory headache. Show less
Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile... Show moreEmotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep ( p < 0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience ( p < 0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) Show less
Velzen, M. van; Dahan, J.D.C.; Dorp, E.L.A. van; Mogil, J.S.; Hooijmans, C.R.; Dahan, A. 2021
In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed... Show moreIn humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous. Show less
Although ketamine can be considered to be an “old” drug, a definitive model explainingketamine pharmacokinetics for a wide range of patient populations, dosing regimens and ketamine administrations... Show moreAlthough ketamine can be considered to be an “old” drug, a definitive model explainingketamine pharmacokinetics for a wide range of patient populations, dosing regimens and ketamine administrations forms is lacking. Currently, a large number of ketamine population pharmacokinetic models is published. However, the large number of ketamine pharmacokinetic models based on data from all types of study populations,ketamine dosing regimens and administration forms, can prove to become a serious challenge for clinical decision makers, since it may not always be easy to pick the model that best suits their patient population. In this thesis, we focus on unraveling the complex pharmacokinetics and pharmacodynamics that characterize ketamine, in order to get a step closer to a final “all encompassing” pharmacokinetic-pharmacodynamic model. For the pharmacodynamic outcomes, we especially focus on the effects of ketamine on neuropathic pain, nociceptive pain (pressure pain) and psychedelic outcomes. Show less
In the thesis I present a series of studies that focus on the use and optimization of use of low-dose ketamine in clinical practice by:(1) reviewing the proof for its use in alleviation and... Show moreIn the thesis I present a series of studies that focus on the use and optimization of use of low-dose ketamine in clinical practice by:(1) reviewing the proof for its use in alleviation and prevention of acute and chronic (cancer and non-cancer) pain;(2) testing a possible novel administration route of ketamine, i.e. inhalation;(3) applying ketamine in a novel indication: the use of the S-enantiomer as respiratory stimulant during opioid-induced respiratory depression;(4) studying the effect of a nitric oxide donor on ketamine (the racemic and S-ketamine variants) typical side effects that hamper it’s use in chronic pain therapy Show less
Endogenous pain modulation is a complex phenomenon involved in the perception of pain. It consists of top-down inhibitory and facilitatory pathways that originate at higher sites within the central... Show moreEndogenous pain modulation is a complex phenomenon involved in the perception of pain. It consists of top-down inhibitory and facilitatory pathways that originate at higher sites within the central nervous system and converge at dorsal horn neurons in the spinal cord, to modulate incoming afferent nociceptive information. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. This thesis describes the effect of several central-acting drugs on descending control of pain in both healthy volunteers and chronic pain patients to further understand the underlying mechanism of endogenous pain control in health and disease. Show less
Neuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological... Show moreNeuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological treatment is often inadequate and coincides with intolerable side effects. The spared nerve injury animal model of neuropathic pain was employed as a method for evaluating the effect of the 11-amino acid tissue protective peptide ARA 290, and the NMDA receptor antagonist ketamine on behavioral and cellular responses after nerve injury and comparison of these two drugs. Clinically, pain is a subjective outcome that can be measured by numerical rating scales or questionnaires. Due to this subjectiveness it is not reliable for diagnosing small fiber neuropathy (SFN). Therefore, SFN is being diagnosed by invasive method of intra-epidermal nerve fiber density evaluated with microscopy. Alternatively, the cornea has a high density of small nerve fibers that can be evaluated by the non-invasive method of corneal confocal microscopy. Finally, the effect of ARA 290 on nerve fiber loss and corneal nerve fiber density in sarcoidosis patients in a double-blind-randomized clinical study was evaluated that showed that ARA 290 is a potential disease modifying agent for treatment of sarcoidosis-associated SNFLD. Show less
Noppers, I.; Niesters, M.; Swartjes, M.; Bauer, M.; Aarts, L.; Geleijnse, N.; ... ; Sarton, E. 2011
The balance between safety and efficacy is important in pharmacotherapy. When the indication of a registered drug shifts to another disease or a different patient population, studies on safety and... Show moreThe balance between safety and efficacy is important in pharmacotherapy. When the indication of a registered drug shifts to another disease or a different patient population, studies on safety and efficacy need to be performed. Ketamine is a relatively __old__ drug and used for almost 50 years as an anesthetic. Recently there has been a renewed interest for the treatment of therapy-resistant chronic pain with subanesthetic doses of ketamine. This thesis describes the effects of S-ketamine in patients with chronic pain (CRPS-1 and fibromyalgia patients) and healthy volunteers. In chronic pain patients (e.g. CRPS-1) pain relief can last for months after long-term intravenous ketamine infusions, but short-term S-ketamine had no long-term efficacy in fibromyalgia patients. S-ketamine can cause a wide range of side-effects which limits its use. Therefore studies were performed in healthy volunteers to expand the knowledge on S-ketamine and the main metabolite S-norketamine to further characterize side-effects (specifically neurocognitive effects). S-norketamine does not contribute to S-ketamine__s analgesic effects and can therefore not serve as an alternative. Show less
Niesters, M.; Dahan, A.; Swartjes, M.; Noppers, I.; Fillingim, R.B.; Aarts, L.; Sarton, E.Y. 2011
Chronic pain is a widespread condition in the general population. For this reason, chronic pain management has received increased attention in recent years, both in clinical practice and in... Show moreChronic pain is a widespread condition in the general population. For this reason, chronic pain management has received increased attention in recent years, both in clinical practice and in scientifi c research. This thesis describes a series of experiments which studied the effi cacy and safety of ketamine in subanesthetic doses. Both healthy volunteers and chronic pain patients were recruited for these studies. The specifi c chronic pain condition studied in these experiments was Complex Regional Pain Syndrome type 1, which is characterized by chronic pain affecting one or more extremities. It is very diffi cult to treat this condition with current pharmacotherapeutic interventions. However, one of the studies in this thesis showed that a continuous ketamine infusion, lasting for several days, can have a prolonged effect in reducing pain scores for up to several weeks (despite rapidly decreasing ketamine plasma concentrations after termination of the infusion). In addition, experiments in both healthy volunteers and patients were performed to study the pharmacokinetics and pharmacodynamics of ketamine in subanesthetic doses. Show less
