Cancer pain: Overview

Abstract
The aim of this qualitative study was to characterize opioid stigma in cancer remission using the Opioid Stigma Framework as a grounding theoretical framework. We conducted in-depth qualitative interviews with cancer survivors in remission who are currently or were previously prescribed opioids for moderate-to-severe pain related to their cancer diagnosis (n=17) and clinicians who routinely treat chronic cancer-related pain (n=20). Interviews occurred at a single institution from 05/2021-12/2021. The primary focus of this analysis was to describe perceived stigma from a patient perspective, as relayed by either survivors or treating clinicians. Survivors and clinicians perceived externalized stigma in a variety of healthcare settings, sometimes influenced by survivors' sociodemographic characteristics (e.g., race). Survivors and clinicians also reported stigmatizing behaviors from a variety of personal relationships, including family and community members, which then impacted decisions around prescription opioid use. Finally, survivors and clinicians described a pervasive sense of internalized stigma related to prescription opioid use in survivorship, including shame, embarrassment, and fear of addiction. Survivors and clinicians also reflected on known disparities in pain management, which in turn may have influenced experiences with opioid stigma. This research extends the Opioid Stigma Framework's concepts - previously described in patients with active cancer - to opioid stigma in cancer survivors. Given the frequency of opioid prescribing across the cancer continuum, it is crucial to develop targeted and tailored interventions to de-stigmatize clinical care and improve safe, effective chronic cancer pain management. PERSPECTIVE: Cancer survivors endorsed experiences with opioid stigma, including stigmatizing experiences with healthcare systems and personal relationships alongside negative internalized attitudes. Since opioid prescribing is common across the cancer continuum and into survivorship, it is necessary to develop tailored interventions to provide safe, effective, and de-stigmatized care to patients.

Abstract
Background: Opioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minority of patients do not benefit from therapy. Genetics might play a role in predisposing patients to a good or poor response to opioids. Here, we investigated this issue by conducting a genome-wide association study (GWAS).

Methods: We genotyped 2057 European advanced cancer patients treated with morphine, buprenorphine, fentanyl and oxycodone. We carried out a whole-genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring patient pain intensity.

Results: The GWAS identified five non-coding variants on chromosome 20 with a p-value <5.0 × 10-8. For all of them, the minor allele was associated with lower pain intensity. These variants were intronic to the PCMTD2 gene and were 200 kbp downstream of OPRL1, the opioid related nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions.

Conclusions: Our results support the role of genetics in the opioid response in advanced cancer patients. Further functional analyses are needed to understand the biological mechanism underlying the observed association and lead to the development of individualized pain treatment plans, ultimately improving the quality of life for cancer patients.

Significance statement: This genome-wide association study on European advanced cancer patients treated with opioids identifies novel regulatory variants on chromosome 20 (near PCMTD2 and OPRL1 genes) associated with pain intensity. These findings enhance our understanding of the genetic basis of opioid response, suggesting new potential markers for opioid efficacy. The study is a significant advancement in pharmacogenomics, providing a robust dataset and new insights into the genetic factors influencing pain intensity, which could lead to personalized cancer pain management.

Abstract
In September 2023, the Japanese Society for Palliative Medicine (JSPM) issued this consensus statement on chronic pain treatment in cancer survivors. With recent advances in the early diagnosis and treatment of cancer, its prognosis has improved, so prolonged pain in cancer survivors is considered to represent chronic pain and should be addressed. In this statement, we emphasize that not all cancer survivor pain is cancer pain. Pain that is not cancer pain should be managed with analgesics other than opioids and nerve blocks, and pain that persists despite this approach should be treated as non-cancer chronic pain so as to prevent opioid overuse. In addition, cancer survivors at any stage of disease have a potentially life-threatening condition and constantly carry the fear of cancer recurrence. Therefore, even non-cancer pain should not be treated in the same way as general chronic pain, but should be managed with consideration of emotional distress. In the future, we plan to create educational tools for healthcare professionals and to conduct online seminars, both with the goal of providing cancer survivors with appropriate assessment and treatment of chronic pain.