Pain from bone metastases is multifaceted with clinical descriptors including ongoing pain, hypersensitivity to external stimuli and intermittent episodes of breakthrough pain characterized as a sudden and abrupt onset of severe pain on a background of well-controlled pain. Moreover, cancer-induced bone pain remains inadequately managed due to a myriad of side effects associated with the current pain relieving regimens, which primarily rely on administration of opiates. Despite advances made in cancer therapeutics, these patients experience an inferior quality of life with incapacitating pain with limited daily activities. Development of long-term novel, non-opiate mechanism-based therapeutics with limited side effects is considered beneficial in elevating the patients' quality of life. First part of this dissertation encompasses the role of p38 MAPK in a mouse model of cancer-induced bone pain in which breast cancer cells were injected and sealed into the femur. Our data demonstrated that both acute and prolonged inhibition of p38 MAPK blocked cancer-induced spontaneous pain but had no effect on the evoked pain indicating important differences in mechanisms mediating ongoing pain as opposed to evoked pain. Undermanaged control of breakthrough pain is attributed to poor understanding of underlying mechanisms and how they may differ from ongoing pain due, in part, to lack of a pre-clinical model in which these mechanisms can be studied. We have established a rat model of cancer-induced bone pain to examine ongoing pain and pain relief using conditioned place preference paradigm as well as breakthrough pain using palpation-induced conditioned place aversion. We have shown that while peripheral afferent input from the tumor-bearing tibia mediates cancer-induced ongoing pain and initiation of breakthrough pain, it does not contribute to the maintenance of breakthrough pain. These data suggest that molecular targets mediating these two mechanisms may be different. This hypothesis was confirmed by our findings in this model that acute blockade of interleukin-6 blocked movement-evoked breakthrough pain in tumor-bearing rats, but failed to block tumor-induced ongoing pain. Hence, we provide a platform to manipulate treatments that can be given alone or in combination with opiates in such a way that patients receive adequate control of breakthrough pain.

Cancer-induced bone pain is characterized by moderate to severe ongoing pain that commonly requires the use of opiates. Even when ongoing pain is well controlled, patients can suffer breakthrough pain (BTP), episodic severe pain that "breaks through" the medication. We developed a novel model of cancer-induced BTP using female rats with mammary adenocarcinoma cells sealed within the tibia. We demonstrated previously that rats with bone cancer learn to prefer a context paired with saphenous nerve block to elicit pain relief (i.e., conditioned place preference, CPP), revealing the presence of ongoing pain. Treatment with systemic morphine abolished CPP to saphenous nerve block, demonstrating control of ongoing pain. Here, we show that pairing BTP induced by experimenter-induced movement of the tumor-bearing hindlimb with a context produces conditioned place avoidance (CPA) in rats treated with morphine to control ongoing pain, consistent with clinical observation of BTP. Preventing movement-induced afferent input by saphenous nerve block before, but not after, hindlimb movement blocked movement-induced BTP. Ablation of isolectin B4 (IB4)-binding, but not TRPV1(+), sensory afferents eliminated movement-induced BTP, suggesting that input from IB4-binding fibers mediates BTP. Identification of potential molecular targets specific to this population of fibers may allow for the development of peripherally restricted analgesics that control BTP and improve quality of life in patients with skeletal metastases.

Pain is the most feared symptom of cancer and can impact patients' lives more than the cancer itself. Despite improvements in cancer prevention and detection, pain is often the first sign of cancer, with an estimated 70-75% of advanced stage cancer patients presenting with skeletal metastases. Cancer metastasis to the bone is associated with persistent pain that increases in intensity over time. Current treatments follow the World Health Organization (WHO) analgesic ladder for cancer pain management suggesting non-steroidal anti-inflammatory drugs (NSAIDs) for mild to moderate pain and opioids for moderate to severe pain. However, estimates indicate as many as 50-80% of cancer patients worldwide receive inadequate pain management. Moreover, opioid doses required for these patients are associated with adverse side effects further diminishing quality of life. Development of improved non-opioid therapies is dependent on increased understanding of mechanisms driving cancer pain and its relief. The objective of this dissertation was to characterize a rat model of cancer-induced bone pain, to develop approaches to measure both ongoing and breakthrough pain and to investigate the contribution of underlying inflammatory mechanisms to pain, bone destruction and bone remodeling. Using female Fischer F344/NhSD rats, histocompatible MAT B III mammary adenocarcinoma cells were sealed into the intramedullary space of the right rear tibia for a time course of 13 days. Ongoing pain was characterized based on the WHO 3-step ladder for pain management utilizing novel behavioral and neurochemical assays. Morphine and peripheral nerve block were sufficient to control ongoing pain, whereas NSAID treatment failed to provide pain relief. Cancer-bearing rats selectively displayed movement-induced breakthrough pain to a background of morphine-controlled ongoing pain. Furthermore, we determined that breakthrough pain is initiated, but not maintained, by peripheral afferent input from the tumor-bearing tibia using lidocaine administration prior to or following movement. For the final part of this study, we investigated the role of transient receptor potential vanilloid 1 (TRPV1) and interleukin-6 (IL-6) blockade, as these have been shown to be important mediators in animal models CIBP. Acute blockade of TRPV1 channels by AMG9810 selectively reversed inflammatory-induced pain, but failed to control evoked or ongoing CIBP. Acute blockade of interleukin-6 signaling by TB-2-081, an IL-6 receptor antagonist, successfully reversed evoke pain responses, but like AMG9810, failed to control ongoing pain. Sustained administration of TB-2-081 reversed cancer-induced tactile hypersensitivity and tumor-induced bone remodeling of the tibia. Further in vitro analysis revealed TB-2-081 functions by inhibiting the Jak/STAT cascade on both tumor cells and osteoblasts, suggesting that blockade of IL-6 signaling can effectively modulate the bone microenvironment to reduce tumor burden and pain. Combined, our data introduce a rat model of breast cancer bone metastasis, in which the underlying mechanisms of ongoing and breakthrough CIBP can be effectively studied. From this, novel therapeutic agents can be developed and investigated to help improve quality of life in patients suffering from this disease.

Background: The buprenorphine transdermal system (BTDS) is approved in the US for the management of chronic pain. Due to its high affinity for mu-opioid receptors with a slow dissociation profile, buprenorphine may potentially displace or prevent the binding of competing mu-opioid-receptor agonists, including immediate-release (IR) opioids, in a dose-dependent manner. Health care professionals may assume that the use of IR opioids for supplemental analgesia during BTDS therapy is not acceptable. Materials and methods: This post hoc analysis evaluated the use of IR opioids as supplemental analgesia during the management of moderate-severe chronic pain with BTDS at 52 US sites (BUP3015S, NCT01125917). Patients were categorized into IR-opioid and no-IR-opioid groups. At each visit of the extension phase, adverse events, concomitant medications, and information from the Brief Pain Inventory (BPI) were recorded. Results: The most common supplemental IR opioids prescribed during BTDS treatment (n=354) were hydrocodone-acetaminophen and oxycodone-acetaminophen. The mean daily dose of IR opioids (morphine equivalents) for supplemental analgesia was 22 mg. At baseline, BPI pain intensity and BPI - interference scores were higher for patients in the IR-opioid group. In both treatment groups, scores improved by week 4, and then were maintained throughout 6 months of the open-label extension trial. The incidence of treatment-emergent adverse events was similar in both groups. Conclusion: Patients who were prescribed IR opioids reported lower scores for BPI pain intensity and pain interference to levels similar to patients receiving BTDS without IR opioids, without increasing the rate or severity of treatment-emergent adverse events. Patients prescribed concomitant use of IR opioids with BTDS had greater treatment persistence. The results of this post hoc analysis provide support for the concomitant use of IR opioids for supplemental analgesia during the management of moderate-severe chronic pain with BTDS.

A dor como sintoma inicial do câncer de boca pode ser o primeiro e único indicador da neoplasia. Até o presente momento suas características, à fase do diagnóstico, ainda não são bem definidas, e nem sempre a dor é considerada como critério importante de diagnóstico para o câncer. OBJETIVO. Avaliar a prevalência e as características gerais de dor orofacial, bem como de outros sinais e sintomas, que levaram os pacientes a procurar atendimento à saúde e ao diagnóstico de câncer de cavidade oral ou orofaringe, comparativamente a um grupo controle composto por pacientes sem câncer. MATERIAL E MÉTODO. Dois grupos: a) Grupo Pacientes (GP), formado por 74 pacientes consecutivos do Ambulatório de Cirurgia de Cabeça e Pescoço do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, que foi dividido em dois subgrupos: cavidade oral (Ca boca - CaB) e orofaringe (Ca orofaringe - CaO) e b) Grupo Controles (CG), formado por 74 pacientes encaminhados para tratamento odontológico convencional no ambulatório da Divisão de Odontologia do HCFMUSP. Foram utilizados os seguintes instrumentos de avaliação: Ficha clínica da Equipe de Dor Orofacial da Divisão de Odontologia do HCFMUSP (EDOF-HC); Escala Visual Analógica (EVA), Escala Numérica de Dor (END), Escala Verbal de Dor (EVD), Questionário de dor McGill; Ficha de Dor Neuropática do Centro de Dor do HCFMUSP; Índice de disfunção de Helkimo; Índice CPOD; Questionário de Qualidade de Vida (UW-QOL) e o Índice de Desempenho de Karnofsky (IDK). RESULTADOS. Os dois grupos foram pareados em relação ao gênero (4:1 homens); idade (58,46 anos no GP e 58,61 GC), raça (2:1 leucoderma) e ocupação. As diferenças estatísticas predominantes no GP foram as seguintes: tabagista/ex-tabagista e etilista/ex-etilista (p < 0,001); motivos de procura por assistência: dor (p < 0,001), úlcera e aumento de volume (p < 0,001); queixa principal: dor (p < 0,001), aumento de volume (p < 0,001) e úlcera (p=0,016); localização da queixa principal: língua e garganta (p < 0,001), ouvido (p=0,033) e palato (p=0,028); prevalência de dor no momento do estudo (p<0,001); problema mais importante nos últimos sete dias (p < 0,001); motivo de procura por assistência médica (p < 0,001); dor constante muitas vezes explosiva em algum momento (p < 0,001); dor espontânea ou provocada (p < 0,001); fatores desencadeantes da dor: mastigação ou deglutição (p=0,001); dor acorda o paciente (p<0,001); dor moderada a forte (EVA=6; p<0,001), (END=7,5; p < 0,001); duração variável (p<0,001); indiferente quanto ao período do dia (p=0,001); múltiplos descritores, destacando-se: pontada, queimação, latejante (p < 0,001) e tipo \"dor de dente\" (p=0,006) e otalgia reflexa uni ou bilateral (p < 0,001). Os seguintes índices também foram piores no GP: índice de disfunção clínica de Helkimo (p < 0,001); índice CPOD (p=0,004); biofilme dental (p=0,002); questionário de dor McGill (p < 0,001); ficha de dor neuropática (p < 0,001); índice de qualidade de vida (p < 0,001) e IDK (p < 0,001). No GP, 25% estavam nos estádios 0, I ou II, e 75% nos III ou IV; o número de profissionais procurados variou de 1 a 9; cirurgião dentista e cirurgião de cabeça e pescoço fizeram os diagnósticos em ambos os subgrupos e o otorrinolaringologista no CaO; pacientes com CaO procuraram mais por médicos. Houve diferença estatística entre os subgrupos CaB e CaO nos seguintes tópicos; dor tipo \"dor de dente\" (p=0,044) e queimação (p=0,016) no CaB; peso (p=0,018), deglutição como desencadeante de dor (p=0,009), garganta como local de queixa principal (p < 0,001) e otalgia bilateral (p=0,004) no CaO. CONCLUSÃO. Os dados deste estudo mostram que a dor foi sintoma presente em toda a fase de diagnóstico dos cânceres de cavidade oral e orofaringe, inclusive nos estágios iniciais. Destacaram-se as seguintes características: gênero masculino, acima de 50 anos de idade, dor difusa (localização variada), intensidade moderada a forte, indiferente ao período do dia, podendo acordar o paciente, predominantemente em pontada, queimação, latejante ou tipo \"dor de dente\", desencadeada por mastigação ou deglutição, otalgia reflexa uni ou bilateral, limitação ou incapacitação da função mandibular, pacientes com a condição clínica claramente comprometida tanto em qualidade de vida como em funcionalidade. Esses dados podem auxiliar no diagnóstico diferencial dos cânceres de boca e orofaringe, principalmente quando há dor persistente e refratária aos tratamentos / Pain as an early symptom of oral cancer may be the first and only indicator of neoplasia. To date, its characteristics at the diagnostic stage are not still well defined, and pain is not always considered as an important diagnostic criterion for cancer. Objective. To evaluate the prevalence and general characteristics of orofacial pain, as well as other signs and symptoms, which led the patients to seek health care and the diagnosis of cancer of the mouth or oropharynx, compared to a control group composed of patients without cancer. Patients and Method: Two groups: a) Patient Group (PG), consisting of 74 consecutive patients from the Head and Neck Surgery Outpatient Clinic of the Hospital das Clínicas of the Medical School of the University of São Paulo, which was divided into two subgroups:oral cancer(CaB) and oropharynx cancer (CaO) and b) Control Group (CG), formed by 74 patients referred for conventional dental treatment in the outpatient clinic of the Dentistry Division of HCFMUSP. The following evaluation instruments were used: Clinical record form of the Orofacial Pain Team of the Dentistry Division of HCFMUSP (EDOF-HC); Visual Analogue Scale (VAS), Numerical Pain Scale (NPS), Verbal Pain Scale (VPS), McGill Pain Questionnaire; Neuropathic Pain chart of the HCFMUSP Pain Center; Helkimo dysfunction index; DFMT,Index; Quality of Life Questionnaire (UW-QOL) and the Karnofsky performance status (KPS).Results. The two groups were compared for gender (4:1 men); age (58.46 years in PG and 58.61 CG), race (2: 1 white) and occupation. The predominant statistical differences in PG were: smoker / ex-smoker and alcoholic/ex- alcoholic (p < 0.001); reasons for seeking care: pain (p < 0.001), ulcer and swelling (p < 0.001); main complaint: pain: (p < 0.001) swelling (p < 0.001) and ulcer (p=0.016). Location of the main complaint: Tongue and throat (p < 0.001), ear (p=0.033) and palate (p = 0.028); prevalence of pain at study time (p < 0.001); the most important issues in the past seven days (p < 0.001);reason for seeking medical care (p < 0.001); constant pain with attacks of explosions (p < 0.001); spontaneous or induced pain (p < 0.001); pain-triggering factors: chewing or swallowing (p=0.001); pain wakes up the patient (p < 0.001); moderate to severe pain (VAS=6, p < 0.001), (NPS=7.5, p < 0.001); variable duration (p < 0.001); regardless of the period of the day (p=0.001); multiple descriptors, such as: jumping, burning and throbbing (p < 0.001) and toothache type (p=0.006) and unilateral or bilateral reflex otalgia (p < 0.001). The following indexes were also worse in PG: Helkimo clinical dysfunction index (p < 0.001); DMFT index (p=0.004); dental biofilm (p = 0.002); McGill pain questionnaire (p < 0.001); neuropathic pain scale (p < 0.001); index of quality of life (p < 0.001) and KPS (p < 0.001). In PG, 25% were in stages 0, I or II, and 75% in stages III or IV; the number of professionals sought ranged from 1 to 9; dentist and head and neck surgeon made the diagnoses in both subgroups and the otolaryngologist in CaO; patients with CaO sought more physicians. There was a statistical difference between CaB and CaO subgroups in the following topics: toothache-like pain (p=0.044), CaB burning (p=0.016) in the CaB; heavy (p=0.018), swallowing as pain trigger (p=0.009), throat as the primary complaint site (p < 0,001) and bilateral otalgia in CaO (p=0.004). Conclusion. The data from this study show that pain was a symptom present throughout the diagnostic phase of oral cancer. The following characteristics were noted in the sample with oral cancer: male gender, over 50 years of age, diffuse pain (varied location), moderate to strong intensity, indifferent to the time of day, being able to awaken the patient, burning, throbbing, stabbing or toothache-like pain, triggered by chewing or swallowing, unilateral or bilateral reflex otalgia, limitation or incapacitation of mandibular function, patients with a clinical condition clearly compromised both in quality of life and in functionality. These data may aid in the differential diagnosis of oral cancer, especially when there is persistent and refractory orofacial pain