Neuropathic pain is a significant and frequent outcome of spinal cord injury (SCI), and is often refractory to treatment. A better understanding of the pathological processes following injury that contribute to the development of neuropathic pain will aid the search for novel therapeutics. In the second chapter of this thesis a murine model of post-SCI below-lesion neuropathic pain was utilized to investigate changes in GABAergic tone. The gad1:GFP transgenic mouse line allowed the study of a subpopulation of GFPlabeled GABAergic neurons under control of the GABA synthesizing glutamate decarboxylase enzyme. SCI was observed to result in a loss of GABAergic neurons, and secondary markers of GABAergic tone supported this observation. This finding suggests that GABAergic interneuron cell death accounts for the decreased GABAergic tone previously reported post-SCI. In the third chapter of this thesis it was attempted to prevent the death of GABAergic neurons post-SCI using a transgenic mouse line expressing increased levels of the X-linked inhibitor of apoptosis (XIAP) under the ubiquitin C promoter. No differences were observed between ubXIAP and wildtype mice, indicating that increased expression of XIAP is not sufficient to prevent the development of neuropathic pain post- SCI. The fourth chapter of this thesis attempted to prevent the development of neuropathic pain through a novel treatment schedule of the drug pregabalin. Pregabalin administered shortly after SCI prevented the development of neuropathic pain. Pregabalin initiated 1 week post-SCI had no effect. Early pregabalin treatment did not appear to dramatically alter glial activation, or expression of the pregabalin receptor, but we observed changes in markers associated with synaptic plasticity. My findings build upon our knowledge of the mechanisms underlying post-SCI below-lesion neuropathic pain, and suggest new avenues of research, such as the uses of preemptive treatment with pregabalin, that offer promise for translation to clinical use.

Following spinal cord injury (SCI), up to 70% of patients develop a condition known as autonomic dysreflexia (AD). This study investigates the use of Pregabalin as a preemptive treatment to mitigate the development of AD following SCI in an animal model. Saline-treated and dPGB rats (first Pregabalin treatment 7 days post-SCI) demonstrated typical signs of AD, with mean arterial pressure (MAP) increases of 23.5% and 27.4% respectively, following colon distension. In contrast, iPGB animals (first Pregabalin treatment 1 hour post-SCI) had MAP increases of 14.6%; significantly lower than saline-treated animals. Additionally, iPGB animals had significantly lower urine volumes than saline-treated animals on days 9 and 10 post-SCI, indicating a more rapid return of spontaneous bladder voiding. It was concluded that only treatment with Pregabalin immediately following SCI can alleviate large increases in blood pressure that accompany AD episodes. Immunostaining for substance P revealed a significantly higher density in both the dorsal horn and central autonomic area in iPGB animals when compared to saline-treated and uninjured animals, indicating a possible mechanism of sympathetic inhibition following iPGB treatment.

No description available.

Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.

Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.

No description available.

Fibromyalgi är ett kroniskt smärtsyndrom med prevalens i Sverige och internationellt kring 2 %. Karakteristiskt är långvarig, utbredd och generaliserad smärta, dock förekommer andra psykiska och fysiska symtom som gör syndromets symtombild varierad. Syndromet har i decennier inte accepterats på grund av dess oklara etiologi. Avvikelser har beskrivits i centrala nervsystemet och i periferin hos fibromyalgipatienter. Det finns också teorier om att psykiska mekanismer kan vara involverade. Vad som saknas är kausalsamband mellan fynden som rapporterats. Behandlingen är symtomatisk i form av icke-farmakologiska eller farmakologiska alternativ. Val av intervention avgörs utefter patientens symtombild. I Europa finns idag inget godkänt läkemedel för behandling av fibromyalgi och läkemedelsterapi sker utanför godkänd indikation. I USA har tre läkemedel godkänts för behandling av fibromyalgi och två av dessa är duloxetin och pregabalin. Båda dessa läkemedel inkluderas i en nyligen uppdaterad europeisk rekommendation som ligger till grund för läkemedelsverkets rekommendationer i Sverige. Läkemedelsföretagen bakom duloxetin och pregabalin har år 2008 och 2009 ansökt om godkännande till försäljning av läkemedlen till fibromyalgipatienter i Europa, dock avslogs ansökningarna. Trots avslag fortsätter läkemedelsföretagen driva forskning om dessa läkemedel vid fibromyalgi. Denna litteraturundersöknings syfte var att utvärdera effekt och säkerhet för duloxetin och pregabalin vid symtomatisk behandling av smärta orsakad av fibromyalgi. Utvärderingen inkluderar åtta kliniska studier som publicerats från och med år 2008, fyra studier med duloxetin och fyra med pregabalin. Resultat från litteraturundersökningen visar att varken duloxetin eller pregabalin har någon stor effekt, jämfört med placebo, på fibromyalgins främsta symtom smärta. Placeboeffekten är relativt stor och dossamband saknas för läkemedlen. / Fibromyalgia is a chronic pain syndrome characterized by widespread generalized pain. Patients also experience other both mental and physical symptoms making the syndrome heterogeneous. Co-morbidity examples are somnolence, gastrointestinal problems and psychiatric conditions including depression and anxiety. The prevalence of fibromyalgia in Sweden is 2,0 % of the population and the international prevalence is similar. Of these 2,0 % almost 80 % are women and the average age of the patients is middle-age. For decades fibromyalgia has not been accepted because of its unknown etiology. Abnormalities have been found in both the central nervous system and in the periphery of fibromyalgia patients. There are also theories that a mental mechanism like poor well-being and stress can cause local pain that can spread and develop into widespread pain. Currently a causal relationship behind the clinical findings is missing.   The treatment of fibromyalgia is often symptomatic according to the patient’s symptoms and needs. The treatment can either be non-pharmacological or pharmacological. In Sweden and the rest of Europe there is no drug approved by the European Medicines Agency for the treatment of fibromyalgia. In the United States three drugs are approved by the Food and Drugs Administration, the two antidepressants milnacipran and duloxetine and the anticonvulsant pregabalin. In a recent update by the European League Against Rheumatism (EULAR) both duloxetine and pregabalin are listed as recommended drugs for the treatment of symptoms of fibromyalgia. The Swedish medical agency has in their recommendations for Swedish healthcare followed the update from EULAR. The pharmaceutical companies have applied for authorization to market the drugs in Europe for treatment of fibromyalgia but the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion to all applications on the grounds that there was poor benefit, due to poor evidence of effect from clinical trials, compared to the side effects of the drugs. Despite this assessment, the companies are supporting new clinical trials. This literature study examined eight clinical trials published from year 2008 and later, conducted to assess the effect and safety of the two drugs duloxetine and pregabalin compared to placebo. The aim of this literature study was to analyze the effect and safety of these drugs for symptomatic treatment of pain caused by fibromyalgia. The aggregated results show that neither duloxetine nor pregabalin had any major effect on pain caused by fibromyalgia, nor on other symptoms. There was a lack of dose response relationship and several parameters also improved with placebo treatment.

Red scrotum syndrome is a poorly understood, chronic dysesthetic erythema primarily involving the anterior scrotum. Previous reports have indicated that red scrotum syndrome is occasionally responsive to oral doxycycline and oral gabapentin. Otherwise, few therapies have proven successful in treating the disorder. We report two cases of red scrotum syndrome responding to oral pregabalin, an anticonvulsant medication commonly used for neuropathic pain. These two cases suggest pregabalin as an effective means for treating red scrotum syndrome and endorse a neuropathic etiology.

A Fibromialgia (FM) é uma síndrome que se caracteriza por dor crônica difusa, fadiga, transtornos do sono e alterações de humor. Embora sua fisiopatologia não esteja totalmente elucidada, o processo neurobiológico parece envolver alterações do córtex sensitivo e motor e de suas conexões com estruturas subcorticais que constituem a neuromatriz da dor, assim como alterações neuropáticas periféricas. Sabe-se que o aumento do cálcio intracelular acima de certo limiar, pode ser parte do processo dependente de atividade que leva à sensibilização central, por aumento do influxo de cálcio por meio de canais NMDA, AMPA, canais dependentes de voltagem, e por liberação de reservas intracelular microssomais. A sensibilização central pode ser também interpretada como um processo de plasticidade mal-adaptativa que sustenta circuitos da dor e de seus correlatos. Por tanto, o córtex sensitivo e motor tem sido alvo diagnóstico e terapêutico para o estudo e tratamento da dor crônica. Dentre as múltiplas estratégias farmacológicas tem sido preconizado o uso da pregabalina, aprovado pela Food and Drug Administration (FDA) dos EUA para uso no tratamento de fibromialgia em 2007. A pregabalina age inibindo os canais de cálcio pré sinápticos dependentes de voltagem por se ligar à proteína auxiliar alfa-2-delta. In vitro, este fármaco reduz a liberação de neurotransmissores cálcio-dependentes incluindo glutamato, norepinefrina, calcitonina e substância P, estes neurotransmissores têm sido associados à sensibilização do sistema nervoso. Portanto, considerando o potencial neuromodulador da pregabalina baseado no seu mecanismo de ação, é um fármaco atrativo para avaliar o papel da modulação do córtex sensitivo e motor na fisiopatolgia da FM. No entanto, para que se avance no conhecimento do efeito dos fármacos na função encefálica, necessitamos utilizar recursos de neuroimagem que sejam exequíveis em contextos diversos, e que permitam mensurar o efeito dos fármacos dinamicamente. Dentre os recursos de imagem existe a Functional Near Infrared Spectroscopy (fNIRS) que permite avaliar ativação cortical por meio da mudança no consumo local de oxigênio que acompanha o disparo neuronal regional, mensurado pelas mudanças na concetração da oxi- e desoxi-hemoglobina. Com estas considerações, hipotetizamos que a modulação farmacológica induzida pela pregabalina poderia ser mensurada, clinicamente por meio de testes psicofísicos da dor (que avaliam vias nociceptivas associadas a termoreceptores e barorreceptores) e à nível de neuroimagem por meio do fNIRS. Por se tratar de um mesmo sistema com potencial de ser avaliado de forma virtualmente simultânea, hipotetizamos também que existirá uma associação entre as modulações clínicas (testes psicofísicos) e neurológicas (fNIRS do córtex sensitivo e motor primários). Desta forma, neste estudo avaliou-se o efeito de pregabalina (150 mg) em dose única em fibromiálgicas e controles saudáveis. Em ambos os grupos a pregabalina foi comparada ao placebo, num desenho de estudo randomizado, duplo-cego, cruzado. Avaliou-se o efeito das intervenções, intra e inter-grupos, na ativação cortical de maneira indireta, pela concetração da oxi-hemoglobina durante testes psicofísicos da dor por meio meio do Quantitative Sensory Testing (QST) e algometria de pressão, que foram comparados com a ativação cortical durante uma tarefa motora de percussão dos dedos da mão (left hand finger tapping). Foram estudadas mulheres com idade entre 18 e 65 anos, 17 fibromiálgicas e 10 controles saudáveis. Os parâmetros do QST foram avaliados uma hora após dose única de 150 mg de pregabalina. Resultados: Na linha de base, as fibromiálgicas apresentaram alterações no QST sugestivas de lesão de fibras finas: o limiar de detecção de calor (HDT, do inglês Heat Detection Threshold) foi maior que nas controles (35,53 ºC ± 3,22 vs. 33,33 ºC ± 0,85; p<0,05), enquanto o limiar de dor por pressão (PPT, do inglês Pain Pressure Threshold) foi menor (2,44 kg/cm2 ± 1,08 vs. 4,32 kg/cm2 ± 1,45; P<0,01). Não foram observadas diferenças nos outros componentes do QST, nem mudanças com a pregabalina. Quando comparados com as saudáveis, nas fibromiálgicas o HDT, limiar de dor por calor (HPT) e a tolerância ao calor (HT) evocaram activação nos giros frontal médio, precentral e póscentral, porém, de menor amplitude do que as controles. Depois da administração da pregabalina, aumentou a ativação em responsta ao HDT, mas não teve correlação com o valor do limiar. Já o HPT mostrou se correlacionar de forma inversa com a ativação nos giros frontal superior (rs=-0,552, p=0,033) e precentral (rs=-0,545, p=0,036) na linha de base e após pregabalina (rs=-0,52, p=0,047). A HT também apresentou uma correlação inversa com os giros frontal superior (rs=-0,645, p=0,032) e precentral (rs=-0,655, p=0,029), mas neste caso, esta correlação desapareceu após ter recebido pregabalina. A ativação cortical pelo PPT não detectou diferenças entre fibromiálgicas e controles. Conclusões: O perfil nos testes psicofísicos nas pacientes apresenta correlação com sua ativação cortical. As alterações nos testes sugerem alterações de fibras finas nociceptivas, o que é explicado por um componente de neuropatia periférica, que na fibromialgia é acompanhado por diminuição da ativação em áreas sensitivas e motoras, e aumento da ativação em áreas associadas com processamento cognitivo da dor, cuja atividade foi elevada com a pregabalina. Quando comparadas às controles, nas fibromiálgicas a HT recrutou mais áreas associada ao processamento cognitivo da dor, o que fortalece a hipótese a favor da existência do componente de sensibilização central na fibromialgia. Desta forma, estes achados reforçam a provável coexistência de alterações periféricas e centrais na fisiopatologia da fibromialgia. / Fibromyalgia is a syndrome characterized by presenting chronic diffuse pain, fatigue, mood and sleep disturbances. Although its pathophysiology has not been totally elucidated yet, the neurobiological processes seems to involve funciontal alterations of the sensorimotor cortex and its conections with subcortical structures (related to the pain neuronal matrix), and also, with quantitative and qualitative alterations in fine sensitive fibers from the peripheral nervous system. It is known that increased intracellular calcium above certain threshold might be part of a process activity-dependant that leads to central sensitization, due to elevated calcium influx through NMDA and AMPA channels, as well as voltage-dependent channels, and also due to relase of intracellular microsomal reserves. Central sensitization can also be interpreted as a maladaptive plasticity that sustains pain circuits and its correlated. Thus, the sensorimotor cortex has been a diagnostic and therapeutic target for the study and treatment of chronic pain. Among the multiple pharmacological strategies, the use of pregabalin has been recommended and approved by the Food and Drug Administration (FDA) of the United States of America for treatment of patients with fibromyalgia since 2007. Pregabalin acts by inhibiting voltage-dependant pre-synaptic calcium channels by binding to the auxiliary protein alfa-2-delta. In vitro, this drug reduces the liberation of neurottransmissors that depend on calcium, and that include glutamate, norepinephrine, calcitonin and P-substance. All the latter mentioned neurotransmitters are associated with the central nervou system sensitization. Thus, considering its potential as neuronal modulation, taking into accout tis mechanisms of action, the pregabalin is an appealing drug to study the role of the modulation fo the sensorimotor cortex in the pathophysiology of fibromyalgia. Nevertheless, to incrase the knowledge about the effect of drugs on the cortical function, we need to use feasible neuroimaging resources able to be applied in diverse contexts, and that allow to measure the effect of the drugs in real time. Among the neuroimaging resources, there is the Functional Near Infrared Spectroscopy (fNIRS), which allows to assess cortical activation estimating the uptake of regional oxygen, that accompanies local neuronal firing. The fNIRS measures changes in the concentration of oxy and desoxy hemoglobin. Given these considerations, we hypothezise that the pharmacological modulation induced by pregabalin could be measured, clinically through psychophysical pain testing, and at the neuroimaging level using fNIRS. Given that it is about the same system with the potential to be assessed in complementary and virtually simultaneous ways, we also hypothesize that there still could exist an association between the clinical modulation (psychophysical tests) and cortical sensorimotor activation (assessed by fNIRS). In this way, this study appraised the effect of a single dose of pregabalin (150 mg) in the cortical activation and psicophysical pain testing in fibromyalgic and in healthy subjects. In both groups, pregabalin was compared to placebo, in a randomized, double-blinded, cross-over trial design. We assessed the effect of pregabalin, within and between-groups, on the cortical activity in an indirect way via the changes in oxy-hemoglobin upon heat and pressure stimuliation inside a protocol of QST, and also compared the psychophysical pain tests results with the performance during a Left Hand Fingertapping Task. We studied women aging 18 to 65, 17 of them with fibromyalgia and 10 healthy controls. QST parameters were assessed one hour after a single dose of 150 mg of pregabalin. Results: At baseline, patients with fibromyalgia presented QST alterations suggestive of fine nerve fibers lesion: baseline HDT was higher in fibromyalgia (35.53±3.22 vs. 33.33±0.85, P<0.05), while PPT was lower (2.44±1.08 vs. 4.32±1.45, P<0.01) than healthy volunteers, but did not change with pregabalin. When compared to healthy subjects, HDT, HPT, and HT evoked smaller activation in the middle frontal, pre- and post-central gyri in fibromyalgia, that increased after pregabalin (only for HDT-induced activation), but that was not correlated to the HDT. HPT was inversely correlated to the activation in the superior frontal (rs=-0.552, p=0.033) and precentral gyri (rs=-0.545, p=0.036), remaining unchanged after pregabalin (rs=-0.52, p=0.047). HT was inversely correlated to the middle frontal (rs=-0.645, p=0.032) and precentral gyri activation (rs=-0.655, p=0.029), but was no longer correlated after pregabalin. PPT cortical activation did not differ between fibromyalgia and healthy volunteers. Conclusions: The psychophysical pain testing profile in fibromyalgia has a cortical correlate. Alterations in tests for small fibers support its probable peripheral neuropathic component, and was accompanied by decreased activation in sensorimotor areas but increased in pain-related cognitive processing cortexes, and whose activity is increased by pregabalin. Also, upon HT fibromyalgia patients recruited more areas related to pain cognitive processing, which could favor the hypothesis of a component of central sensitization in fibromyalgia, and which was poorly modulated by pregabalin. Taken together, these findings support the co-existence of both, peripheral and central alterations in fibromyalgia.

Seizures containing large numbers of units of narcotics, goods dangerous to health and doping are often sent to the Swedish National Forensic Centre (NFC). Only a fraction of these capsules or tablets can be analyzed, therefore the samples need to represent the whole seizure. If the samples show content variations, Near Infrared (NIR) spectroscopy in combination with hyperspectral imaging has been shown to be a promising tool to gauge the homogeneity in the seizures based on chemical content. The objective of this thesis was to further develop and then validate a method for the separation of pregabalin and gabapentin capsules using NIR hyperspectral imaging and Principal Component Analysis (PCA). Capsules containing different amounts of pregabalin and gabapentin were prepared and analyzed. Additionally, authentic seizures were analyzed to confirm that the method fulfilled its purpose. The result of this study showed that use of hyperspectral data in the wavelength range 1650-1750 nm gave the best differentiation between pregabalin and gabapentin capsules. Capsules containing the ratio 70-30 % gabapentin and pregabalin could be separated distinctively from capsules containing pure gabapentin. Multiple authentic seizures could be separated into groups correctly depending on the capsules or tablets content.