Although progress in cancer treatment and awareness for cancer pain has significantly increased over the last years, the prevalence of cancer pain is still high.

The data shows that 1/3 of patients during their treatment and more than half with advanced disease experience moderate to severe pain.¹

Cancer pain can be characterized as Visceral, Somatic, Neuropathic, and may result from various reasons, including tumor spread in contiguous tissues, metastasis ( bone), cancer treatment ( chemotherapy, radiation, surgery)

Chemotherapy is along with surgery the first line of treatment for malignant neoplasms.

Chemotherapeutic agents have cytotoxic properties and are used to stop the growth and division of cancer cells but at the same time affect healthy cells causing significant side effects.

In relation to pain the most significant side effect, is Chemotherapy Induced Peripheral Neuropathy (CIPN).

To understand how chemotherapy treatment influences the pain therapeutic modalities we have to evaluate the mechanisms that cause CIPN and develop mechanistic approaches for its treatment.

There are peripheral mechanisms that contribute to the development of CIPN with alterations in the DRG involving activation of protein kinases A and C, PI3/AKT pathway, as well as increased expression of various pro-inflammatory cytokines such as IL1, IL 1-a, IL1-b, IL6, TNF a, CXCL1.

Preclinical studies demonstrated that there is an increased expression of the Transient Receptor Potential (TRP) channels TRPV1 and TRPV4 in the DRG eluding in their possible role in CIPN.

Voltage gated sodium channels such as Nav1.7 and Nav1.8 play a significant role in the transmission of pain-related signals. Chemotherapy causes activation and increased expression of the Nav1.7 and Nav 1.8 channels in the peripheral nerve terminals and the DRG, contributing to chemotherapy induced pain. It has been demonstrated in preclinical studies that chemotherapy also causes depolarization of potassium channels in peripheral sensory neurons increasing their excitation, as well as increased expression of d-1calcium channels leading to exacerbation of pain.²

Mitochondrial damage, oxidative stress, inhibition of transcription factors are additional peripheral mechanisms contributing to the development of CIPN.

Spinal mechanisms of CIPN include similarly activation of ion channels, transcription factors, inflammatory mediators, immune regulation on nociceptive signal transmission.²

Supraspinal regions such as the amygdala, anterior cingulate cortex and prefrontal cortex NMDA receptors, are involved in chemotherapy induced pain.^{3 4}

Pharmacological treatment recommended based on the above mechanisms for the development of CIPN include nerve-protective therapy with Erythropoietin,

N-acetylcysteine, ion channel targeted therapies, with medications such as Lidocaine, Mexiletine, Gabapentin, Pregabalin, Magnesium, Anti-inflammatory therapy with Metformin, minocycline, Neurotransmitter-based therapy with medications such as Venlafaxine, Duloxetine, and Tricyclic Antidepressants and Antioxidants.⁵

Immunotherapy is based in the appreciation of the whole tumor microenvironment, and it is a rapidly advancing field in cancer therapeutics. The discovery of tumor biomarkers derived from the tumor microenvironment can lead to a shift from the pre-existing immune response to a therapy induced individualized immune response.⁶

Immunotherapy may cause sometimes significant inflammation and immune related adverse events are mostly induced by agents known as immune check point inhibitors (ICI). Occasionally there is a need for an immunosuppressant such as a steroid to attenuate the inflammation at a safer level. Tapering of the steroid course must be quick to avoid risk of infection. The adverse events from immunotherapy when severe may cause pain. The Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group has developed recommendations for managing toxicities associated with ICI.⁷

Most common ones are hepatobiliary adverse events such as liver, pancreatic toxicities and gallbladder injury. Additionally endocrine adverse events such as hypophysitis and thyrotoxicosis, and pulmonary as well as rheumatologic/musculoskeletal adverse events may be developed. Pain in the above circumstances is treated by applying the WHO algorithm limiting the use of acetaminophen and NSAIDS when appropriate. Also it is important to be mindful of their antipyretic effect that could be masking an underlying infection in the immunosuppressed cancer patients.

During chemotherapy/immunotherapy cancer pain is treated mostly with medications and non-drug treatment options. Interventional therapies are limited due to the risk of infection and bleeding due to chemotherapy induced immunosuppression and thrombocytopenia.

While pharmacotherapy is effective for the treatment of mild to moderate and even severe pain when opioids are used the development of tolerance overtime may render it ineffective.

It is important to mention that several interventional procedures such as intrathecal drug delivery, or spinal cord and peripheral nerve stimulation amongst others can improve pain control.

Although the application of the intrathecal drug delivery systems (IDDS) remains underutilized in patients with cancer pain its effectiveness has been established for significantly improving cancer pain as well as decreasing the risks of adverse events from chronic opioid use.⁸ More studies are currently conducted to improve the evidence of the efficacy, the cost effectiveness, risk mitigation, and to establish a common approach for the use of IDDS to improve cancer pain.⁹

References

1. Marieke HJ van den Beuken-van Everdingen, et al. Treatment of pain in cancer: towards personalized medicine. Cancers (Basel) 2018 Dec;10(12):502.

2. Yuhao Xu, et al. Mechanisms underlying paclitaxel-induced neuropathic pain: channels, inflammation and immune regulations. European Journal of Pharmacology 2022;933:1752888.

3. Liu J, et al. Glutaminergic neurons in the amygdala are involved in Paclitaxel -induced pain and anxiety, Front Psychiatr;13:869544.

4. Liang L, et al. Paclitaxel induces sex-biased behavioral deficits and changes in gene expression in mouse prefrontal cortex. Neuroscience 2020;426:168-178.

5. Lang-Yue Hu, et al. Prevention and treatment for chemotherapy-induced peripheral neuropathy: therapies based on CIPN mechanisms. Current Neuropharmacology 2019;17:184-196.

6. Wolf H Fridman, et al. The immune contexture in cancer prognosis and treatment. Nature Reviews, Clinical Oncology, December 2017;14:717.

7. Puzanov I, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal of ImmunoTherapy of Cancer 2017;5:95.

8. Rui Duarte, et al. Effectiveness and safety of intrathecal drug delivery systems for the management of cancer pain: a systematic review and meta-analysis. Neuromodulation 2023;26:11-26-1141.

9. Shane E Brogan, et al. Controversies in intrathecal drug delivery for cancer pain. Reg Anesth Pain Med 2023;48:319-325.