Background Neuropathic pain (NP), defined as pain caused by a lesion or disease of the somatosensory system, affects 6.9 – 10 % of people worldwide. Pregabalin is currently recommended as a first line drug for NP in South Africa. Methods A cross-sectional retrospective descriptive medicines usage evaluation (MUE) of Pregabalin at Groote Schuur Chronic Pain clinic for the year 2017 was conducted. A MUE using a standardized data collection form was performed on 100 randomly selected folders. Data are summarized using descriptive statistics. Results The majority of cases were women (76) with a mean age of 55.9y (SD12.49). A diagnosis of NP was recorded in 58 folders and a “possible” diagnosis recorded in 7 folders. In 79 cases there was no mention of a tool/method used to diagnose NP. The most common condition diagnosed was chronic post-surgical pain with a neuropathic component (n=16), followed by NP (n=15). The most common initiating and current dose of Pregabalin was 75mg twice daily. In 56 patients, Pregabalin was prescribed in conjunction with a tricyclic antidepressant (TCA) or selective noradrenaline reuptake inhibitor (SNRI). Patient education was documented as having taken place in 76 of cases. Conclusions Based on this MUE we recommend the use of screening tools for the diagnosis of neuropathic pain, and a focus on the initiating dose of Pregabalin. The use of a standardized assessment document and the interdisciplinary team input at this clinic appears to optimize prescribing of Pregabalin in line with practice guidelines.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第23141号 / 薬科博第140号 / 新制||薬科||15(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 金子 周司, 教授 髙倉 喜信, 准教授 中川 貴之 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

La douleur neuropathique centrale est une affection fréquente dont le traitement est complexe. En raison d’un important taux de résistance aux traitements pharmacologiques, des techniques de neuromodulation ont été développées. Parmi elles, on retrouve les stimulations du cortex moteur primaire (ou gyrus précentral), invasive (i.e. stimulation électrique épidurale, eMCS) et non-invasive (i.e. stimulation magnétique transcrânienne répétitive, rTMS). Ces techniques restent limitées par différents paramètres. La rTMS a principalement été étudiée à travers des séances uniques, et son efficacité comme moyen thérapeutique au long cours reste mal connue. La eMCS souffre d’un manque de prédicteurs individuels d’efficacité suffisamment robustes pour sélectionner à bon escient les candidats à la chirurgie. Enfin, le cortex moteur primaire est une cible de découverte empirique, et d’autres cibles sont à envisager pour améliorer les résultats de ces neuromodulations corticales. Notre travail avait pour objectif l’amélioration des connaissances vis à vis de ces différentes limites. Il s’est articulé autour de 3 axes principaux :- L’étude de la rTMS en séances répétées, au long cours, comme moyen thérapeutique à part entière. - L’étude de la rTMS en séances répétées comme moyen de prédiction de la réponse antalgique à la eMCS.- Le développement de méthodes permettant la localisation fiable et reproductible du cortex pré-frontal dorsolatéral comme cible alternative de stimulation. / Central neuropathic pain is a frequent and hard to treat condition. Because of a large amount of drug-refractoriness, neuromodulation techniques have been developed. Among them, the mostly used is motor cortex stimulation, which can be both invasive (epidural motor cortex stimulation (eMCS)) and non-invasive (repetitive magnetic transcranial stimulation (rTMS)). These techniques remain limited by different problems: On one side, rTMS has been mainly studied through unique session practice and its use for pain therapy in a long-term scale remains not well understood. On the other side, eMCS suffers from a lack of predictability: A great proportion of patients present an insufficient relief, making eMCS less and less used. Finally, the motor cortex target is a chance discovery, and some other targets could be intended to improve the results. This work had the increase of knowledge about cortical stimulations as a main goal, especially about their different limitations. This work concentrated on 3 aims: - The study of chronic, repeated sessions of rTMS, used as a long-term tool for pain therapy. - The study of repeated rTMS sessions to predict eMCS.- The development of reliable tool to help to localize others cortical targets.

We are still unable to effectively suppress neuropathic pain, therefore it remains a serious problem. Ghrelin, the orexigenic hormone released by enteroendocrine stomach cells, could contribute to alleviation of the neuropathic pain by its antinociceptive effect. Previous studies have shown that ghrelin prevents development of nociceptive symptoms of neuropathic pain. The aim of our study was to determine whether chronic administration of ghrelin will affect the already fully developed neuropathic pain and differentiate its antinociceptive and analgesic effect. We used a model of chronic constriction injury of the sciatic nerve. We have proven that ghrelin suppressed the already developed thermal and mechanical hyperalgesia, so ghrelin not only prevents the development, but also suppresses the already developed nociceptive symptoms. However analgesia test showed that ghrelin did not affect the temperature preference, neither did induce the place preference. We suppose that ghrelin does not cause analgesia in neuropathic pain and its antinociceptive effect could be caused by anti- inflammatory or neuroprotective action. Key words: Ghrelin, neuropathic pain, chronic constriction injury, preference methods

(English) Modulation of synaptic transmission in dorsal horn of spinal cord plays a key role in nociceptive signalling. Recent studies have indicated a great importance of presynaptic TRPV1 receptors (transient receptor potential vanilloid) in spinal cord. These receptors act as molecular integrator of nociceptive stimulation on periphery. The way of their activation and the effect on modulation of the synaptic transmission are not clarified yet. Previous studies demonstrated the influence of many inflammatory mediators and cytokins on TRPV1 receptors. The aim of our research was to show changes in activation of presynaptic TRPV1 receptors in the spinal cord following the application of endogenous agonist N-oleoyl dopamine (OLDA) in a model of peripheral neuropathy, after incubation with cytokine TNFα and to show the effect of precursor of anandamide N-acylphosphatidylethanolamine (NAPE). In our experiments, we have recorded miniature excitatory postsynaptic currents (mEPSC) from neurons of acute spinal cord slices by the patch-clamp method. The first series of experiments tested sensitivity to application of the endogenous agonist OLDA 5 days after evoking peripheral neuropathy. The frequency of mEPSC increased significantly - to 250 % of base level after applying a low concentration of OLDA (0,2...

Trigeminal neuropathic pain (TNP) is a condition that occurs when one or more branches of the trigeminal nerve are insulted. Trigeminal neuropathic pain has been shown to be refractory to treatment. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability in both the peripheral and central nerve systems. Emerging evidence indicates that HCN channels are involved in the development and maintenance of chronic pain, however, the impact of thalamic HCN channel activity on TNP has yet to be elucidated. In this report, we used a chronic constriction of the distal infraorbital nerve (dIoN-CCI) to induce TNP in rats. By infusing HCN channel blockers into the ventral posteromedial (VPM) nucleus of the thalamus in dIoN-CCI rats, we demonstrated that inhibition of HCN channel activity ameliorated TNP. We found that the HCN blocker ZD7288 and the clinical drug ivabradine dose-dependently attenuated both evoked and none-evoked nociceptive behaviors in dIoN-CCI rats. Electrophysiological measurements showed the expression of HCN current (Ih) in the thalamocortical neurons in the VPM was sensitive to the HCN channel modulator cyclic adenosine monophosphate (cAMP), suggesting a contribution of the HCN2 subunit in thalamic HCN current. In the thalamus, surface expression of the HCN2 subunit was increased in dIoN-CCI rats. Taken together, we propose that an increase in HCN channel activity in the thalamus in the ascending nociceptive pathway contributed to trigeminal neuropathic pain.

Alexithymia represents a deficit in identifying and expressing emotions, paucity of fantasies, and an externally oriented cognitive style. Currently, numerous studies document that alexithymia and several mental and somatic disorders are significantly related. Several findings also indicate that this association might be caused by alexithymia related dysregulation of neuroendocrine and immune functions. Together these findings indicate that stressors related to alexithymia could underlie the process of neuroendocrine and immune dysregulation that likely may present a significant risk, sustaining and mediating pathogenesis of several disorders and particulary psychosomatic illnesses. In this context, it is also known that several proinflammatory cytokines may play a role in pain generation and that alexithymia is significantly associated with pain symptoms in several pain disorders. Following these findings this study includes several new data developing current state of the art and showing some alexithymia specific changes in patients with neurological disorders. Main finding of this study shows that alexithymia and anxiety in their specific interactions are linked to increased levels of interleukine-8 (IL-8) in cerebrospinal fluid (CSF) in the group of patients with non-inflammatory neurological...

Neuropathic pain in a common problem encountered in palliative care. When neuropathic pain is diagnosed, appropriate treatment is important in limiting the severe psychosocial impairment that can ensue with undertreated pain. Proper evaluation of the patient to clarify the type of pain experienced is the first step to determine appropriate management. Tapentadol is an oral mu-opioid receptor agonist and a noradrenaline reuptake inhibitor developed by Ortho-McNeil Janssen Pharmaceuticals and approved by the Food and Drug Administration in November 2008 for the treatment of moderate-to-severe acute pain in adult patients and for chronic pain in August 2011 in an extended release form. Tapentadol has been studied for use in nociceptive pain but few studies have yet been done to assess its efficacy in the treatment of neuropathic pain.

Revealing causal structures from observational data is an essential task in many data analysis issues across various domains, such as natural sciences, business, and healthcare. In healthcare, neuropathic pain is one of the most common medical problems, whose diagnosis process has well-understood causal structures. Causal structures are commonly visualized as a directed acyclic graph (DAG) or a node-link diagram, in which nodes represent variables, and edges represent causal relationships between data dimensions. However, these simple static graphs do not convey sufficient information for either an intuitive interpretation for novel viewers, or an in-depth exploration for experts. In this study, the visualization of causal structures for neuropathic pain diagnosis is set into context. An interactive system that integrates application-specific visualization, i.e. a discomfort drawing and a spinal cord diagram, into causality visualization is developed. It is further evaluated by a domain expert on neuropathic pain and a researcher in causal discovery through semi-structured interviews. The results show that the system reveals the causal structures for neuropathic pain diagnosis in a more intuitive, efficient way, and conveys more focused information compared to traditional node-link diagrams. The system is also demonstrated to be helpful to the medical community in neuropathic pain diagnosis, not only for doctors but also for patients. / Att upptäcka kausala strukturer från observationsdata är en viktig uppgift i många dataanalysfrågor inom olika områden, t.ex. naturvetenskap, affärsverksamhet och sjukvård. Inom hälso- och sjukvården är neuropatisk smärta ett av de vanligaste medicinska problemen. Dess diagnosprocess har väl förstådda kausala strukturer. Kausala strukturer visualiseras vanligtvis som en riktad acyklisk graf (DAG) eller nätverksdiagram, där noder representerar variabler och kanter representerar kausala relationer mellan datadimensioner. Dessa enkla statiska grafer förmedlar dock inte tillräckligt information för att ge en intuitiv tolkning för nya betraktare eller en djupgående utforskning för experter. I den här studien sätts visualiseringen av kausala strukturer för diagnostisering av neuropatisk smärta i ett sammanhang. Ett interaktivt system som integrerar applikationsspecifik visualisering, dvs. en smärtteckning och ett ryggmärgsdiagram, i kausalitetsvisualisering utvecklas. Det utvärderas av en domänexpert på neuropatisk smärta och en forskare inom kausal upptäckt genom semistrukturerade intervjuer. Resultaten visar att systemet avslöjar kausalstrukturer för diagnos av neuropatisk smärta på ett mer intuitivt och effektivt sätt och förmedlar mer fokuserad information jämfört med traditionella diagrammer. Systemet har också visat sig vara till hjälp för det medicinska samfundet vid diagnostisering av neuropatisk smärta, inte bara för läkare utan även för patienter.

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