Placebo and nocebo effects, positive and negative effects experienced after both real and sham interventions, putatively due to positive or negative outcome expectancies, can shape our sensory... Show morePlacebo and nocebo effects, positive and negative effects experienced after both real and sham interventions, putatively due to positive or negative outcome expectancies, can shape our sensory experience. Although placebo and nocebo effects are known to occur reliably in many individuals for sensations like pain and itch, our understanding of psychological learning processes and methodological factors that influence these effects remains limited. Chapters 2, 3, and 4 investigate this topic with meta-analysis, narrative review, and a behavioral study. Similarly, our characterization of the neural markers of nocebo effects is incomplete. A better grasp of how these effects form is necessary to contextualize them within the larger framework of bottom-up and top-down integration. Chapters 5, 6, and 7 investigate this topic in a series of EEG and fMRI studies. Advancing both psychological and neural accounts of placebo and nocebo effects will aid in applying findings from this field of study to everyday life; particularly in clinical settings, and potentially any setting in which expectations regarding one’s future experiences come into play. Show less
Complex Regional Pain Syndrome (CRPS) is a severely disabling pain syndrome. Patients report a poorer quality of life than patients with other chronic pain conditions, particularly in the physical... Show moreComplex Regional Pain Syndrome (CRPS) is a severely disabling pain syndrome. Patients report a poorer quality of life than patients with other chronic pain conditions, particularly in the physical domains (chapter 2). Sex differences are small, although male patients experience a higher psychological burden than female CRPS patients (chapter 3).Considering the pathophysiology CRPS, we could not reproduce previous MRI findings of altered brain function and structure in rest (Chapter 4). We did find increased salience detecting during the application of a painful stimulus with opposite activation of brain regions involved in reducing the affected burden of pain (chapter 5). Lastly, cortical motor activations during motor tasks differ from previously published results in patients with functional movement disorders (chapter 6). Show less
Within the field of pain but especially neuropathic pain there is still much to be gained, as illustrated by the unmet medical need and limitedly efficacious drug treatments currently available. A... Show moreWithin the field of pain but especially neuropathic pain there is still much to be gained, as illustrated by the unmet medical need and limitedly efficacious drug treatments currently available. A key contributor to chronification of neuropathic pain is central sensitization, which may manifest clinically as hyperalgesia, a symptom non-existent in healthy individuals. Models that can induce hyperalgesia and tools that can appropriately assess altered nociceptive functioning in early-phase drug studies are sought-after, as they may aid in examining the potential of drugs as (neuropathic) pain treatment. Continuing efforts are made to expand and improve our knowledge in this field. This thesis describes our contribution, and was based on two main objectives. One was to develop and validate methods for early-phase clinical drug studies with improved accuracy or resemblance to clinical pathophysiology, to improve the evaluation of a drug’s mechanism of action and analgesic potential. The other objective was to actually test novel drugs that are proposed to have superior clinical utility, using methods we believed to be appropriate for evaluating those drugs’ analgesic effects. Show less
This PhD research dealt with neurobiological and behavioral aspects of pain. Previous research has demonstrated that pain sensitivity can be worsened as a result of learned negative expectations, a... Show moreThis PhD research dealt with neurobiological and behavioral aspects of pain. Previous research has demonstrated that pain sensitivity can be worsened as a result of learned negative expectations, a phenomenon termed nocebo hyperalgesia –a counterpart to placebo analgesia. This PhD dissertation describes neuroimaging and biobehavioral experimental studies as well as a review and a meta-analysis concerned with such learned effects on pain. The research adds to a growing literature that has been challenging antiquated understandings of pain as a bottom-up process. We conducted a series of biobehavioral studies to further our understanding of how bottom-up pain signaling can be influenced by top-down processing. We examined the types of experiences, such as receiving negative information or experiencing a negative effect first-hand, that may lead to stronger nocebo effects. Behavioral paradigms were used to model real-life pain experiences, through validated methods, novel learning manipulations, as well as a close examination of emotional correlates such as fear. Concurrently, innovative neuroscientific methods –including pharmacological manipulations– were used to examine the biobehavioral underpinnings of learned nocebo responses. Our findings add to the growing knowledgebase from the field of nocebo hyperalgesia, demonstrating that learning by experience can decisively influence the processing and perception of noxious stimuli. Show less
The primary aim of this thesis was to investigate the complex relationship between pain, neuropsychiatric symptoms, and ADL functioning in persons with dementia. Furthermore, we studied the... Show moreThe primary aim of this thesis was to investigate the complex relationship between pain, neuropsychiatric symptoms, and ADL functioning in persons with dementia. Furthermore, we studied the psychometric properties of a new and universal observational pain assessment instrument Pain Assessment In Impaired Cognition: PAIC.The results of this thesis show that pain in nursing home residents with dementia is related to a decline in ADL functions, independent of dementia severity. Specifically, a decline in the ADL activities transferring and bathing.Additionally, the psychometric evaluation of the PAIC presented in this thesis not only results in a promising measurement instrument, but also provides useful information for the development and improvement of educational programmes that contribute to the utilization of the PAIC15. 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 dissertation covered several relevant cycles of placebo research with the main aim to optimize placebo effects in medical contexts. Firstly, a literature review described how the immune system... Show moreThis dissertation covered several relevant cycles of placebo research with the main aim to optimize placebo effects in medical contexts. Firstly, a literature review described how the immune system can be impacted by placebo effects and their underlying learning theories. In the following chapter, these learning theories were integrated to form an optimal research design by means of pharmacological conditioning to fit a specific patient group: children with juvenile idiopathic arthritis. Secondly, this dissertation focused on developing placebo information strategies to harness placebo beliefs and educate persons about the relevancy of placebo effects in practice. These insights are valuable because treatment expectations can have a positive or negative effect on treatment outcomes. Finally, insights from placebo learning theories and placebo information strategies were combined in an integrative experimental research design. This research design employed a more ethical form of placebo use because participants were made aware of placebos, called open-label placebos. In this last study we demonstrated that open-label placebo analgesia can be induced by combining learning theories and placebo information strategies. Altogether, this dissertation provided insights in learning mechanisms, communication strategies, and research paradigms that involve the optimization of placebo effects in medical context. Show less
The shoulder joint is a frequent anatomic site of musculoskeletal pain. Most middle-aged adults with shoulder pain have been diagnosed with subacromial bursitis, or subacromial impingement syndrome... Show moreThe shoulder joint is a frequent anatomic site of musculoskeletal pain. Most middle-aged adults with shoulder pain have been diagnosed with subacromial bursitis, or subacromial impingement syndrome. Attrition underneath the acromion have been presumed to cause painful inflammation of subacromial tissues for years, but scientific evidence was limited. The real cause for subacromial pain is still unknown, which resulted in the diagnostic label “subacromial pain syndrome”. In this thesis, we focused on the effectiveness of acromioplasty in the treatment of patients with subacromial pain. We found no effect of acromioplasty over bursectomy alone on long-term shoulder pain and function. We also examined shoulder kinematics and muscle activation in patients with subacromial pain. We found an association between the size of rotator cuff tears as well as subacromial pain syndrome with shoulder kinematics, and described an increase in teres major muscle activity in subacromial pain syndrome. The project contributed to changed recommendations in guidelines regarding the treatment of subacromial pain syndrome. Our kinematic and biomechanical studies may create a biomechanical rationale for physiotherapeutic strategies targeted at the teres major muscle in the treatment of subacromial pain. Show less
The thesis describes the use of extensive pharmacodynamic effect profiling to characterise the clinical pharmacology of classic and non-classical analgesia. Analgesic drugs that modulate widespread... Show moreThe thesis describes the use of extensive pharmacodynamic effect profiling to characterise the clinical pharmacology of classic and non-classical analgesia. Analgesic drugs that modulate widespread targets in the nervous system can be expected to affect numerous CNS functions, which requires multimodal characterisation of pain processing and neurocognition. This is illustrated on the basis of two case studies of pharmacological agents that target cannabinoid CB1 and GABA-ergic GABAA receptors: two of the most widely distributed systems of receptors and neurotransmitters that are involved in a myriad of physiological functions. The distribution of receptors throughout the central nervous system render an oral formulation of ∆9-THC and a positive allosteric modulator of α2/3/5 subunit-containing GABAA receptors, ideal candidates for extensive neurophysiological and analgesic effect profiling in early phase clinical research. Profiling human pharmacology with a strong focus on pharmacodynamics may help to better understand the therapeutic potential and safety limitations of a compound before selection of doses and patient populations for phase II proof-of-concept studies. Show less
This thesis focuses on several aspects of quality of life in patients with painful bone metastases, treated with palliative radiotherapy within the randomized Dutch Bone Metastasis Study.The... Show moreThis thesis focuses on several aspects of quality of life in patients with painful bone metastases, treated with palliative radiotherapy within the randomized Dutch Bone Metastasis Study.The detailed course of quality of life after treatment was studied, as was the relation between a pain response and quality of life. Also prognostic factors predicting a pain response, psychological distress, side-effects and survival were studied. Show less
Placebo effects are health improvements, for example pain reduction, due to an inert treatment. These effects are typically ascribed to a person’s expectations about the beneficial outcomes of... Show morePlacebo effects are health improvements, for example pain reduction, due to an inert treatment. These effects are typically ascribed to a person’s expectations about the beneficial outcomes of the placebo. The literature and experimental research in the current dissertation shows that expectancies, and thereby placebo effects, can be induced via verbal suggestion, conditioning, and mental imagery. Especially verbal suggestions may enhance analgesic treatments for patients. We found, for the first time, that mental imagery of reduced pain can induce analgesia via its effects on pain expectancies. We also observed that people’s expectations about the effectiveness of medications depend on the route of administration and targeted symptom. These findings suggest that harnessing placebo effects by targeting expectancies is promising for enhancing standard clinical care of physical symptoms. Show less
Drug development scientists are on a search for suitable biomarkers that can assist in predicting the therapeutic potential of analgesic medication and, therefore, it’s efficacy in the target... Show moreDrug development scientists are on a search for suitable biomarkers that can assist in predicting the therapeutic potential of analgesic medication and, therefore, it’s efficacy in the target population. This is particularly appropriate for human pain where models can assist to bridge the preclinical and clinical findings. These models can provide valuable information about the mechanism of action of existing and new drugs. However, a single human pain model cannot be used exclusively to screen the pharmacological mechanism of a compound as it inherently only tests a single mechanism. In this thesis the performance of a battery of pain models (PainCart) was investigated. Three main topics were investigated. (1) The validation of the PainCart was described in which the effects of different classes of analgesics on this battery of pain models were explored. (2) The PainCart was used in different chronic pain populations. (3) The performance of the battery during the development of new analgesic compounds was studied. The battery of pain models can act as biomarker to assess the effect of analgesics on pain. It can be used to benchmark analgesic properties of new drugs against established analgesics in early phase clinical studies. Show less
Osteoarthritis is a prevalent disease causing pain and disability. It__s aetiology is unknown and no curative treatment is available. Osteoarthritis research is complicated due to heterogeneity of... Show moreOsteoarthritis is a prevalent disease causing pain and disability. It__s aetiology is unknown and no curative treatment is available. Osteoarthritis research is complicated due to heterogeneity of the disease, slow progression and poor association of clinical features with radiographic abnormalities, imaging modality of choice until now. In this thesis the role of synovitis in osteoarthritis is studied in relationship with clinical features and structural damage. The studies described made especially use of data derived a prospective follow-up study in symptomatic hand osteoarthritis patients. Synovitis detected on ultrasound was associated with clinical features and with progression of structural damage after 2.3 years in hand osteoarthritis. In erosive osteoarthritis, a subtype of hand osteoarthritis, more synovitis was found in all hand joints, even in non-erosive joints, when compared to joints of patients without erosive osteoarthritis. Also, associations were found between synovitis and erosive development at follow-up. All analyses were performed on joint level, using GEE analyses, thereby taking into account patient effects. Associations were poor/absent when analyses were done on patient level. This is important for further research. These results indicate that synovitis plays a role in pain and in development of structural damage in osteoarthritis and could be a therapeutic target. Show less
In the chronic stage of Complex Regional Pain Syndrome (CRPS), motor disturbances are common and cause significant disability. The motor dysfunction of CRPS is a poorly understood phenomenon that... Show moreIn the chronic stage of Complex Regional Pain Syndrome (CRPS), motor disturbances are common and cause significant disability. The motor dysfunction of CRPS is a poorly understood phenomenon that is characterized predominantly by a decrease or loss of voluntary muscle control. This thesis aims to obtain a better understanding of the pathophysiology underpinning the motor dysfunction of CRPS by examining the potential roles of decreased inhibition of the motor system, changes in sensory processing and problems in sensory-motor integration. In specific, characteristics of muscle activity recordings are scrutinized in order to determine whether the loss of voluntary motor control and abnormal postures in CRPS exhibit characteristics of dystonia that are associated with reduced inhibition of the motor system (i.e., excessive muscle activation and enhanced mirror activity). The potential role of impaired processing of proprioceptive information related to wrist orientation and force production is examined, as well as the involuntary and voluntary (sensory-)motor interactions between the affected and unaffected arm. Furthermore, a systematic review of the literature on the motor consequences of experimental pain in healthy humans is presented in order to gain insight into the potential role of pain-related processes in the motor and sensory and motor disturbances of CRPS. Show less
Obesity is a major risk factor of osteoarthritis development and progression. Theoretically, obesity is a factor that can be modified. While obesity epidemic is difficult to reverse because we live... Show moreObesity is a major risk factor of osteoarthritis development and progression. Theoretically, obesity is a factor that can be modified. While obesity epidemic is difficult to reverse because we live in lipogenic environment, personal approach in modify obesity may avail. Therefore, understanding how obesity leads to osteoarthritis is needed. The first three chapters of this thesis investigate several aspects of osteoarthritis: what structures are damaged, what factors are associated with worsening of osteoarthritis and how to measure worsening of osteoarthritis. The other four chapters investigate the link between obesity and osteoarthritis. We show that obesity is associated with hand osteoarthritis. Since we do not walk on our hand, there must be another factor than mechanical that cause joint damage in osteoarthritis. One of the factors is adipokines, protein produced mainly by fat tissue. We showed that adiponectin, one of the adipokines, prevents worsening of hand osteoarthritis. We concluded that obesity plays role in osteoarthritis not only due to added mechanical force but also due to added metabolic force (adipokines). These adipokines might be used as target in modifying the effect of obesity on osteoarthritis. However, we still need more studies on how obesity links with osteoarthritis Show less
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
The clinical characteristics of Complex Regional Pain Syndrome (CRPS) are defined by pain and various combinations of sensory disturbances, autonomic features, and sudomotor and trophic changes.... Show moreThe clinical characteristics of Complex Regional Pain Syndrome (CRPS) are defined by pain and various combinations of sensory disturbances, autonomic features, and sudomotor and trophic changes. Furthermore, patients with CRPS may suffer from movement disorders, of which dystonia is the most prevalent. Dystonia of CRPS can affect multiple extremities, is often resistant to treatment and seems to have a poor prognosis. Reliable information on the nature, chronology and clinical determinants of dystonia in CRPS patients is lacking but could provide better insight in the underlying pathophysiological mechanism. The results of our studies on clinical and neurophysiologic aspects of patients with multiple CRPS and MDs in CRPS provided data that suggest disturbances at multiple levels of the CNS. Maladaptive neural plasticity likely is an important mechanism underpinning the MDs that may occur in CRPS. The presence of disturbances at multiple levels of the central nervous system parallels recent hypotheses on the underlying mechanisms suggested for other types of dystonia. Finally, the study on intrathecal baclofen administration in patients with CRPS and dystonia showed marked improvement of dystonia and pain scores after one year. Show less
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
The main objective of the research described in this thesis is to demonstrate the relevance of biomarkers on the selection of the dose range of COX inhibitors for effective analgesic and anti... Show moreThe main objective of the research described in this thesis is to demonstrate the relevance of biomarkers on the selection of the dose range of COX inhibitors for effective analgesic and anti-inflammatory response, as opposed to the focus on behavioural measures of pain and inflammation advocated by the current paradigm for the development of non-steroidal anti-inflammatory drugs (NSAIDs). To this end, the relationship between drug concentration and the corresponding inhibition of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was investigated for a range of COX inhibitors with varying degrees of selectivity, and hence with differential effects on the selected biomarkers. Thanks to the use of a mechanism-based approach, attention is also given to translational pharmacology in drug development. We evaluate whether 1) estimates of drug action in vitro are predictive of the effect in vivo, 2) animal data in vivo reflect drug effect on biomarkers in humans and 3) whether inflammatory conditions modify the extent of drug effect as compared to healthy conditions. A recommendation and guideline for best practices in the development of COX inhibitors is anticipated from this analysis. Show less
This thesis deals with emotional and social influences on childhood somatic complaints. Strong support is provided for the idea that negative affect contributes to the development of somatic... Show moreThis thesis deals with emotional and social influences on childhood somatic complaints. Strong support is provided for the idea that negative affect contributes to the development of somatic complaints in childhood. In addition, the studies described give information about the type and levels of negative affect associated with somatic complaints in childhood. When appraisal is characterized by the experience of little control over negative situations and emotions, this is likely to directly cause more feelings of negative affect and also to contribute to a more negative processing of emotions: children who feel little control evidently use more maladaptive emotion regulation strategies. This negative emotional processing further contributes to negative affect and subsequent somatic complaints. These relationships between negative affect and somatic complaints are even present at subclinical levels of emotional problems. With regard to social problems, it is found that they have an effect on somatic complaints that is fully mediated by aspects of children’s emotional functioning: self-perceived social problems indicate lower feelings of control and more maladaptive emotion regulation. Show less
