Special Topics in Pain: Opioids

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Does Opioid Use Cause Angiogenesis and Metastasis?

Author(s): Grandhi R K, et al.
Journal: Pain Med. 2016; Jun 26. pii: pnw132. 67 references.
Reprint: Alaa Abd-Elsayed, MD, MPH, University of Wisconsin School of Medicine and Public Health, Department of Anesthesiology B6/319 CSC, 600 Highland Ave., Madison, WI 53792-3272, USA. E-mail: alaaawny@hotmail.com
Faculty Disclosure: Abstracted by N Walea, who has nothing to disclose.
Objective: Review and evaluate the latest advances and newest information in the area of Opioids


The treatment of choice for severe cancer pain is often morphine, which can lead to tolerance and addiction. Of greater concern is the increasing number of studies examining the association of opioid use with potential increases in cancer recurrence. Several studies have indicated that morphine may have immunosuppressant properties which may cause cancer growth.

A review of PubMed and Cochrane Library was conducted. Twelve articles met the inclusion criteria for this review.

Many studies have indicated that opioids are immunosuppressive. The immune system is critical in preventing tumor formation and metastasis. Tumor cells express non-self antigens and can be destroyed via the cytotoxic action of cytokines. An intact immune system plays a key role in fighting tumor development and growth. Chronic administration of opioids, in particular morphine, inhibits immune system responses: antibody production, natural killer (NK) cell activity, cytokine expression, blood lymphocyte proliferation responses, and phagocytic activity.

Inflammation is part of a complex response to harmful stimuli, including pathogens, damaged cells, and irritants. These same risk factors that may cause inflammation were found to induce tumor development. The K-opioid receptor induces an anti-inflammatory response, while the µ-receptor produces a pro-inflammatory response. Because morphine binds the µ-receptor more tightly, the pro-inflammatory response is often favored. At the same time, morphine has been shown to prevent inflammation-induced angiogenesis in vivo. This conflicting information can make it challenging to elucidate the exact role of morphine.

Endothelial cell disruption, migration, and proliferation play a major role in angiogenesis. Morphine can influence all of these. In a non-endothelial cell system, morphine was shown to transactivate fibroblast growth factor (FGF) receptor 1, which plays a major role in angiogenesis. While some of morphine's pro-angiogenic effects are not reversed by naloxone, morphine-induced tumor growth can be reversed by the cyclooxygenase-2 inhibitor celocoxib. Morphine has been shown to down-regulate basic FGF production in human macrophages. Morphine was found to reduce blood vessel density, branching, and length when compared with placebo.

While most of the studies done in this area were done on animals, a few studies were performed on human subjects. One small study showed that patients receiving intrathecal opioids exhibited increased survival (54%) compared with systemic opioids (37%). There may be a multitude of reasons for the etiology of the difference in survival; one might be that because the tumor was not exposed to systemic opioids, cancer progression was attenuated.

Other studies have shown that certain polymorphisms of the µ-opioid receptor (MOR) may be linked to increased survival in breast cancer. The A118G polymorphism results in decreased responsiveness to µ-opioids. A study performed on 2,039 women, 5% of African American and 24% of European American women had one or two copies of the G allele. Of the women with the A/A genotype and invasive cancer, 17% died of the disease versus 8% of the women with the G allele, and the difference was statistically significant.

A retrospective analysis of 600 patients with stage IV prostate cancer showed that increased MOR expression and greater opioid requirements are associated with shorter progression-free survival and overall survival. These same findings were confirmed in non-small cell lung carcinoma.  

Important Points:
It is uncertain whether there is a clear relationship between opioid use and angiogenesis or metastasis, although the potential does exist. Pain management physicians and oncologists have questioned the use of opioids in cancer patients and must evaluate the use of appropriate alternatives. Despite retrospective analyses of alternatives to opioid analgesia and animal models, it is not clear whether altered tumor cell proliferation and invasion, inflammation, angiogenesis, and immune response will result in significant harm to the patient. Studies in animal models and in vivo cell models do not always translate into human disease. Further research is necessary to fully understand these pathways.  

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