"Opioids appear to have a significant and direct proliferative effect on cancer cells.”
The suspicion that opioid drugs for pain could encourage cancer growth began with a laboratory report from the University of Minnesota in 2002. Then at the University of Chicago, cancer patients in clinical trials of the opioid-blocker methylnaltrexone - a form of naltrexone(1) developed to reverse opioid side effects such as itching & constipation without affecting pain relief - began living longer than expected.
Something important was going on, and research teams at Chicago and the University of North Carolina pursued it to the conclusion that opioid drugs used to relieve pain in postoperative and chronic cancer patients may indeed stimulate the growth and spread of tumors. (While opioid antagonists may suppress it.)
As reported in a suite of free-access articles published in the April issue of Anesthesiology,(2,3,4) "Epidemiologic findings suggest that the type of anesthesia we do for cancer surgery influences recurrence rate, and laboratory studies demonstrate that opioids influence tumor progression and metastasis," says U Chicago co-author Jonathan Moss, MD, PhD.
"These studies have caused anesthesiologists to re-evaluate how best to do anesthesia and pain control for cancer patients."
New Studies Provide New Clues
Opioid-based painkillers, such as morphine, have been the gold standard for treatment of postoperative and chronic cancer pain for 200 years. Several studies published since 2002, however, suggest that opioids can stimulate the growth and spread of cancer cells.
Laboratory research from the University of Chicago Medicine and a genetic study from the University of North Carolina Medical Center both argue that the mu-opioid receptor (mu refers to morphine) plays an important role in tumor progression, and support a therapeutic role for opioid antagonists.
Cancer Cells Have 5 to 10 Times More Opioid Receptors than Normal Cells
A study led at Chicago by Prof Patrick Singleton, PhD,(4) shows how opioids already present in the body can enhance the malignant tendencies of human lung cancer cells transplanted into mice, even without the addition of morphine.
Dr. Singleton’s team found that cells from various types of human lung cancers have 5 to 10 times as many opioid receptors as non-cancerous lung cells.
• They mapped out two of the biochemical pathways - Akt and mTOR, both targets for current chemotherapeutics - that are triggered by contact between the body's endogenous opioids and the receptors.
• They also show how this interaction can increase proliferation, migration and invasion of tumor cells, three hallmarks of cancer growth and spread.
• And they found that human lung cancer cells with additional copies of the opioid receptor grew more than twice as fast as tumor cells that lacked extra receptors when transplanted into mice.
More troubling, the cancer cells were 20 times more likely to spread to distant sites.
Medications that block the opioid receptors, such as naloxone or methylnaltrexone, reduced tumor growth and spread. "Our findings," they conclude, "suggest the mu opioid receptor may be a therapeutic target."
Genetic Mutation for Poor Opioid Sensitivity is Protective
The retrospective study by Andrey Bortsov, MD, PhD, and colleagues at the University of North Carolina(2) used human data to bolster the opioid-cancer link. Dr. Bortsov's team looked at survival rates from an earlier study of more than 2,000 breast cancer patients.
Women being treated for invasive breast cancer who had a tiny genetic mutation that made them less sensitive to opioids were much more likely to be alive 10 years after cancer treatment.
• Women with one copy of the protective mutation were nearly twice as likely to have survived;
• Those with two copies were four times as likely to have survived 10 years.
"The results of this study," the authors wrote, "provide support for the hypothesis that endogenous and/or exogenous opioids, acting via the mu opioid receptor, may influence cancer outcomes."
Higher Cancer Risk if Opioid Medication is Systemic
The suspicion that opioids might encourage cancer growth arose with a 2002 laboratory report from the University of Minnesota.
• Later, a randomized palliative-care trial from Virginia Commonwealth University found that patients who received spinal opiates (OK) rather than systemic pain relief survived longer.
• Then two retrospective studies showed that breast or prostate cancer patients who received local or regional anesthesia rather than systemic morphine had improved survival after surgery.
• More recent epidemiologic studies in colon cancer, however, failed to confirm the relationship.
Methylnaltrexone Trials Took It to the Next Level
Dr. Moss and colleagues at Chicago approached the issue from a similar angle. They were involved in clinical trials of methylnaltrexone, a drug developed at Chicago and approved by the FDA in 2008.(3)
This drug, marketed as Relistor™, was designed to block the peripheral side effects of opioids, such as nausea and constipation, without disrupting pain relief, which occurs in the brain. (By comparison the opioid-blocking drug naltrexone crosses the blood-brain barrier.) Following an early clinical study, Dr. Moss and colleagues noted that cancer patients receiving this peripheral opioid blocker in a compassionate-use protocol lived longer than expected.
"These were patients with advanced cancer and a life expectancy of one to two months," Dr. Moss recalls, "yet several lived for another five or six months. It made us wonder whether this was just a consequence of better GI function, or could there possibly be an effect on the tumors?"
They began a series of studies looking at the many peripheral effects of opioids and the potential benefits of blocking those effects.
• They found that those opioids enhanced tumor growth, angiogenesis, vascular permeability and metastasis.
• Drugs that blocked the opioid receptor reduced cancer growth and helped prevent invasion and metastasis.
• Tumors did not grow in mice that lacked the mu opioid receptor.
In commenting on their findings, Dr. Moss, Dr. Singleton and Dr. Frances Lennon, PhD,(4) summarize results from multiple studies to argue that opioids - drugs like morphine or the body's own opioids, such as endorphins - appear to have a significant and direct proliferative effect on cancer cells, aside from their effect suppressing immunity.
They suggest a possible therapeutic role for mu opioid receptor antagonists on cancer growth and metastasis, but caution that "there are no clinical trials in humans demonstrating a direct effect."
Funding and Investigator Interests
Funding for the studies was provided by the National Cancer Institute, the University of North Carolina and the University of Chicago. Dr. Moss, one of the developers of methylnaltrexone, receives royalties from its sale and is a paid consultant for its distributor, Salix Pharmaceuticals Inc.
Source: Based on University of Chicago Medical Center news release, Mar 20, 2012 and American Society of Anesthesiologists news release, Mar 21, 2012
1. Unlike naltrexone, which crosses the blood-brain barrier, methylnaltrexone does not, so its activity does not affect pain processing in the brain and is confined to blocking opioid activity peripherally; e.g., in the GI tract. For more information on trials involving low-dose naltrexone therapy for fibromyalgia, chronic fatigue syndrome, and autoimmune diseases generally, see “Low-Dose Naltrexone for Autoimmune Diseases and Fibromyalgia?” by Dr. Joseph Mercola.
2. Full text: “Mu-Opioid Receptor Gene A118G Polymorphism Predicts Survival in Patients with Breast Cancer,” Bortsov AV, McLean S, et al.
3. Full text: “Overexpression of the mu-Opioid Receptor in Human Non-Small Lung Cancer Promotes Akt and mTOR Activation, Tumor Growth, and Metastasis,” Lennon FE, Moss J, et al.
4. Full text: “The mu-Opioid Receptor in Cancer Progression: Is There a Direct Effect?” Lennon FE, Moss J, Singleton PA.