Mediation of Movement-Induced Breakthrough Cancer Pain by IB4-Binding Nociceptors in Rats.

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.SIGNIFICANCE STATEMENT We present a novel preclinical measure of movement-induced breakthrough pain (BTP) that is observed in the presence of morphine controlling ongoing pain. Blockade of sensory input before movement prevented BTP, whereas nerve block after movement failed to reverse BTP. These observations indicate that blocking peripheral sensory input may prevent BTP and targeting central sites may be required for pain relief once BTP has been initiated. Preventing sensory input from TRPV1-expressing fibers failed to alter movement-induced BTP. In contrast, preventing sensory input from isolectin B4 (IB4)-binding fibers blocked movement-induced BTP. Therefore, examining molecular targets on this population of nociceptive fibers may prove useful for developing an improved strategy for preventing BTP in cancer patients with skeletal metastases.

Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats.

OBJECTIVES: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action. METHODS: Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry. RESULTS: Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1-4). Expression of SP was increased in the morphine + fosaprepitant group. CONCLUSIONS: The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals.

Advances in cancer pain from bone metastasis.

With the technological advances in cancer diagnosis and treatment, the survival rates for patients with cancer are prolonged. The issue of figuring out how to improve the life quality of patients with cancer has become increasingly prominent. Pain, especially bone pain, is the most common symptom in malignancy patients, which seriously affects the life quality of patients with cancer. The research of cancer pain has a breakthrough due to the development of the animal models of cancer pain in recent years, such as the animal models of mouse femur, humerus, calcaneus, and rat tibia. The establishment of several kinds of animal models related to cancer pain provides a new platform in vivo to investigate the molecular mechanisms of cancer pain. In this review, we focus on the advances of cancer pain from bone metastasis, the mechanisms involved in cancer pain, and the drug treatment of cancer pain in the animal models.

Relationship between performance status and satisfaction with fentanyl pectin nasal spray / Relación entre el estado de rendimiento medio con la escala ECOG y la satisfacción del paciente con el uso de fentanilo en pectina por vía nasal

Background: Patients with breakthrough pain in cancer (BTPc) experience impaired activities of daily living and quality of life. Both function and satisfaction with treatment can impact patients’ abilities to use products, and likely impact response to therapies. Objective: This exploratory analysis examined the relationship between functional status and satisfaction with ability to use fentanyl pectin nasal spray (FPNS) for BTPc. Methods: Treatment satisfaction data were analyzed from a multicenter, open-label, long-term study using FPNS for managing BTPc in patients with Eastern Cooperative Oncology Group (ECOG) grade ≤ 2. Satisfaction with ease of use, convenience, and reliability of FPNS were assessed on three-question, fourpoint scales (1 = not satisfied, 2 = not satisfied or dissatisfied, 3 = satisfied, 4 = very satisfied) at the end of 1, 4, 8, and 12 weeks. For each domain, percentage of patients who reported being "satisfied or very satisfied" (score 3 or 4) with FPNS was analyzed based on ECOG grade. Results: Overall, > 90 % of patients with ECOG 0-2 reported being satisfied or very satisfied with FPNS across all three domains. Differences in patient satisfaction with FPNS by ECOG grade were clinically small though statistically significant (ease of use: p = 0.0022, convenience: p = 0.0057, and reliability: p = 0.0012). Conclusion: The FPNS device was well accepted irrespective of ECOG grade (0-2). Statistically, patients with higher performance status (lower ECOG grades) reported higher satisfaction scores, though effect size was small. Results imply the FPNS device provides a high level of usability irrespective of functional status, which is likely to promote use and thus likelihood of success in controlling BTPc (AU)

Introducción: los pacientes con dolor irruptivo oncológico (BTPc) experimentan un deterioro de las actividades de la vida diaria y de la calidad de vida. Tanto la función como la satisfacción con el tratamiento pueden afectar a las capacidades de los pacientes para utilizar fármacos e impactar en sus respuestas a los mismos. Objetivo: este análisis exploratorio examina la relación entre el estado funcional y la satisfacción con la capacidad de usar el aerosol nasal de pectina de fentanilo (FPNS) para BTPc. Métodos: se analizaron datos de satisfacción del tratamiento de un estudio multicéntrico, abierto, a largo plazo usando FPNS para el tratamiento del BTPc en pacientes con Eastern Cooperative Oncology Group (ECOG) grado ≤ 2. Fueron evaluados la satisfacción con la facilidad de uso, comodidad y fiabilidad de FPNS en escalas tres preguntas y cuatro puntos (1 = nada satisfecho, 2 = no satisfecho o insatisfecho, 3 = satisfecho, 4 = muy satisfecho) al final de 1, 4, 8 y 12 semanas. Para cada dominio, el porcentaje de pacientes que informaron estar "satisfechos o muy satisfechos" (puntuación de 3 o 4) con FPNS se analizó basado en el grado ECOG. Resultados: en general, el 90 % de los pacientes con ECOG 0-2 dijo haber estado satisfecho o muy satisfecho con la FPNS en los tres dominios. Diferencias en la satisfacción del paciente con FPNS por grado ECOG fueron clínicamente pequeñas pero estadísticamente significativas (facilidad de uso: p = 0,0022, conveniencia: p = 0,0057 y fiabilidad: p = 0,0012). Conclusión: el dispositivo FPNS fue bien aceptado independientemente del grado ECOG (0-2). Estadísticamente, los pacientes con status de rendimiento superior (grados menores ECOG) informaron mayores puntuaciones de satisfacción, aunque el tamaño del efecto fue pequeño. Los resultados demuestran que el dispositivo FPNS proporciona un alto nivel de usabilidad independientemente del estado funcional, y que es probable que promover el uso y por lo tanto la probabilidad de éxito en el control de BTPc (AU)

Pharmacokinetics of fentanyl buccal tablet: a pooled analysis and review.

Fentanyl buccal tablet (FBT) is indicated for the treatment of breakthrough pain in patients who are already receiving and are tolerant to opioid therapy for underlying, persistent cancer pain. FBT is designed to enhance the rate and efficiency of absorption of fentanyl through the buccal mucosa. FBT was shown to be dose proportional from 100 to 1,300 µg. This analysis provides an overview of the pharmacokinetic profile of FBT based on pooled data from nine pharmacokinetic studies. In all, 365 healthy non-opioid-tolerant adults receiving naltrexone were included in the analysis. Single-dose (100 to 1,300 µg) pharmacokinetic parameters were dose normalized to 100 µg. Pharmacokinetic measures included maximum observed plasma drug concentration (C(max)), plasma drug concentration versus time curve from time zero to infinity (AUC(0-∞)), time to reach C(max) (T(max)), apparent plasma terminal elimination rate constant, and elimination half-life. After FBT administration, fentanyl was rapidly absorbed, with T(max) ranging from 20 minutes to 4 hours postdose. Mean AUC(0-∞) was 1.49 ng•hour/mL, and mean C(max) was 0.237 ng/mL. However, plasma fentanyl concentration reached 80% of C(max) within 25 minutes and was maintained through 2 hours after administration. Based on the individual studies, bioequivalence was shown for sublingual and buccal tablet placement, and no significant effect of dwell time (duration of FBT presence in the oral cavity) was observed. The pharmacokinetic profile of FBT was characterized by rapid absorption, which is consistent with the rapid-onset efficacy profile of FBT observed in clinical studies.