Two new studies published in the journal Anesthesiology are raising new questions about the use of opioid pain medications in cancer patients. The research papers, one an experimental study conducted in mice and the other a retrospective analysis of breast cancer patients, appear to add to a growing body of evidence that morphine and other opioids increase cancer growth and the proliferation of tumor blood vessels, a process called angiogenesis. These findings have caused concern among some in the medical community because opioids are widely used in cancer patients to control pain and for anesthesia during cancer surgery.
Opioids are among the world’s oldest drugs. The opioid category is comprised of several broad classes of psychoactive chemicals that act on opioid receptors in the central nervous system. Opioids come in naturally derived forms called opiates that include morphine and codeine, as well as an array of synthetic and semi-synthetic agents that are prescribed as pain medication and sedatives. Morphine is among the most powerful opioids and is highly addictive. Because morphine affects nerve systems throughout the body, it can cause a number of troublesome adverse effects, including severe constipation and respiratory suppression.
In 2002, researchers at the University of Minnesota Medical School first reported results from a study showing that morphine stimulates angiogenesis. [1] As in healthy tissues, blood vessels provide cancerous tumors with blood, oxygen and nutrients, so angiogenesis is an essential process for cancer development. The same research group also demonstrated that laboratory mice with implanted human breast cancers that were treated with morphine developed larger and faster growing tumors than control mice. Notably, tumors in the morphine-treated mice were packed with blood vessels, a telltale signature of angiogenesis. The researchers proposed that morphine increases angiogenesis by signaling through a specific opioid receptor called the μ-opioid receptor, or MOR.
Since that paper was published, a number of retrospective studies have suggested that cancer patients who receive localized anesthesia with opioids or who get reduced opioid doses following surgery for breast, prostate or colon cancer have lower rates of cancer recurrence than patients who received systemic opioids. [2] Other studies, however, have shown little or no association between opioid use and cancer recurrence.
In the first of the new studies published in Anesthesiology, researchers showed that mice with implanted lung cancers that highly expressed MOR had faster growing and more metastatic tumors. [3] The cancerous lung cells had 5 to 10 times more opioid receptors than non-malignant lung cells and were up to 20 times more likely to metastasize. They also demonstrated that MOR activated two enzymes (kinases), Akt and mTOR, that are involved with angiogenesis and tumor growth.
The second study, a retrospective analysis of more than 2,000 women diagnosed with breast cancer, found that women harboring a genetic mutation making them less responsive to opioids lived longer than women without the mutation. [4] The protective effect of the mutation was limited to women whose cancer had spread beyond the breast, and was most pronounced in those with advanced disease (stages III-IV). Women with two copies of the mutation appeared to have the greatest benefit, but the small number of women in this category made it difficult to draw conclusions. A drawback of the study is that it did not look at whether the women had received opioids in the past as part of their treatment, so it is not clear whether or how opioid use may have altered the disease course in any of the participants.
In addition to opioid drugs, the body produces a number of natural (endogenous) opioids, such as endorphin and endomorphins, often in response to stress. Laboratory animals with cancer have exhibited increased levels of endogenous opioids and it is likely that some human cancer patients do as well, particularly patients recovering from surgery. Whether endogenous opioids contribute to angiogenesis or tumor growth in cancer patients is not known at this time.
Despite the concerns about opioids and cancer progression, to date there have been no randomized, controlled studies in humans showing definitively that opioids promote tumor growth, nor have there been controlled studies showing that drugs that block opioid receptors suppress tumor growth, although these are both areas of ongoing research. Opioids remain an important part of pain management for cancer patients. Ongoing clinical studies using different types of opioids in cancer patients for analgesia and anesthesia should provide more information about the effects of opioids on cancer progression and angiogenesis.