Envolvimento de medicamentos antineoplásicos na indução de dor neuropática: bases fisiopatológicas e tratamento

Abstract

Even though neuropathic pain is the target of extensive studies, it still is a challenge for the scientific community as the causative agents are varied and anomalous pain have been shown to be the result of changes in several interconnected paths, acting as a complex mechanism. Neuropathic pain results from dysfunction or injury inflicted directly to the nerve, with different etiologies. When it comes to cancer patients, the cancer itself has the potential to induce neuropathic pain. Additionally, exposure to antineoplastic drugs can also lead to the development of chemo-induced peripheral neuropathy (CIPN). Due to the fact that a significant amount of antineoplastic drugs have been proven to be neurotoxic, CIPN is a reality that the vast majority of patients have to confront, being pain and neuronal degeneration important factors in reducing the patient's quality of life during and even after the end of treatment. Neuropathy is mainly caused by damage of sensory unmyelinated type C-fibers and the low-myelinated type Aδ fibers, which results in symptoms ranging from desensitization to touch or temperature of the affected region, to spontaneous pain or pain initiated by touch or changes in temperature. In some cases, movements may be compromised due to damage to motor myelinated Aβ fibers, which reduces the ability of movements, affecting the daily life of the patient. Although the complex mechanism of action involving numerous pathways and it is not fully understood, it was identified that changes in voltage-gated ion channels (Na +, Ca2+, K+ and Cl-) and ligand-gated channels lead to aberrant activation of nociceptive neurons deregulating pain sensitivity. Additionally, changes in the mitochondria, abnormal activities of proteases and protein kinases (mitogen activated protein kinases - MAPK and protein kinase C - PKC), as well as cytokines may also change the homeostasis of primary afferent neurons and increased excitability, causing continuous pain in situations where there should be no pain. Moreover, besides the peripheral nervous system, the central nervous system may be affected with increased activity of α-adrenergic receptors, glutamatergic NMDA and AMPA/KA receptors, serotoninergic 5-HT2A receptors, and the decrease in activity of inhibitory interneurons and receptors, such as GABAB and μ opioid receptors. The treatment of CIPN follows a standard procedure developed by the World Health Organization (WHO), involving the use of nonsteroidal anti-inflammatory drugs (NSAIDs), codeine, tramadol and morphine, according to the severity of the pain. However, it is not considered appropriate for CIPN, because there is no treatment to what causes the pain, but only to the symptoms. The challenge now is to develop drugs that can prevent and even reverse the cause, as well the development of selective antineoplastic to cancer cells with fewer side effects.