Cannabinoids: Current and Future Options to Treat Chronic and Chemotherapy-Induced Neuropathic Pain

Abstract

Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient's last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN.

Fig. 1:. Current and prospective treatments for CIPN.

Current treatments for CIPN are limited, the SNRIs with duloxetine being the primary option. Numerous clinical trials investigating prospective treatments are recruiting or in progress currently. A wide variety of potential treatment options are being considered from drugs and natural products, to mechanical and electrical stimulation.

Fig. 2:. Types of cancer treated with chemotherapeutic agents.

The three classes of chemotherapeutic agents: platinum, taxane and vinca alkaloid and the different types of cancer treated.

Fig. 3:. Mechanisms of action of chemotherapeutic agents.

The three classes of chemotherapeutic agents (platinum, taxane and vinca alkaloid) all interfere with normal cell processes in order to drive cancer cells towards apoptosis.

Fig. 4:. Mechanisms of chemotherapy-induced peripheral neuropathy.

The mechanisms by which chemotherapeutics destroy cancer cells also result in damage of peripheral neurons. Inhibition of normal vital cell processes such as cell division and respiration promotes pro-inflammatory and apoptotic signaling cascades and altered excitability of peripheral neurons. Peripheral sensitization of nociceptive neurons may result in long term changes in the spinal cord and brain, resulting in chronic pain.

Fig. 5:. Cannabinoid mechanisms in pain.

Cannabinoid receptors are present throughout the brain, spinal cord, and periphery. Cannabinoid-mediated analgesia involves complicated cross-talk between various brain structures, neurotransmitter systems and receptors, and immune and glial cells.