Reviewing the Evidence for Opioids and Cancer Growth

Eric Widera recently posted about the media’s irresponsible headlines implying that opioids cause cancer growth. This is our most read post to date (over 1000 direct visits plus email subscribers).

Why was this post so widely read? Because this issue touches on a critically important therapy and the media were clearly irresponsible in their treatment of this story. The media took a story about an opioid antagonist (methylnaltrexone) potentially inhibiting cancer growth in mice, and converted this into a story about morphine causing cancer growth.

As a follow up to Eric’s post I emailed the authors of the study, asking them if they would like to comment or post a response. One of the authors called me to give his opinion. He said they have avoided talking to the media, declined multiple interviews with the press, and would not post a reply on our blog. However, he did state that he believed there is strong reason to suspect that opioids may promote cancer growth, and he wanted me to read the evidence. To that end, he sent me 7 articles to review. I’d like to go over them briefly here.

1. Singelton, J. et al. Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis. Mol Cancer Ther 2008;7(6):1669–79. The authors found that methylnaltrexone reduces the concentration of two chemotherapeutic agents necessary to inhibit cancer cell growth in vitro.
2. Moss, J. From Bench to Clinic: Our Story with 21st Century Drug Development. Association of University Anesthesiologists Update, Spring 2009. This is a newsletter story discussing the development and testing of methylnaltrexone for treatment of constipation and potential other uses.
3. Durieux, M. Does Anesthetic Management Affect Cancer Outcome? Anesthesia Patient Safety Foundation newsletter, Winter 2009. A newsletter reviewing the evidence for anesthetic technique influencing cancer surgery outcomes. Regarding opioids, the author notes that one the one hand, opioids have been shown to promote angiogenesis (formation of new blood vessels necessary for tumor growth). On the other hand, opioids have been shown to decrease metastases around the time of surgery in rats, likely due to a decrease in the pain-related stress response (stress can promote cancer spread).
4. Moss, J, and Israel, R. Effects of Anesthetics on Cancer Recurrence. Letter to the editor. Journal of Clinical Oncology 2009. This letter is a review of prior studies.
5. Moss, J, and Rosow, C. Development of Peripheral Opioid Antagonists: New Insights Into Opioid Effects. Mayo Clinic Procedings 2008. This is another review.
6. Singelton, J. et al. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis:Role of receptor transactivation. This was a laboratory study where the authors found that morphine promotes endothelial cell migration.
7. Mathew, B. et al. The Mu Receptor Regulates Lewis Lung Carcinoma Tumor Growth and Metastasis. This is the abstract that garnered so much press. In lung cancer cell lines and mice, the authors found that methylnaltrexone inhibited lung cancer growth by blocking the opioid receptor.

So 2 published studies, 1 abstract, 2 newsletters, 1 letter to the editor, and 1 review. Note that Eric discussed the two articles from Anesthesia on regional versus general anesthetic technique in the previous post. The author of one of those studies, in a letter to the editor, acknowledged that “Under no circumstances should a small retrospective study be the basis for practice.”

So what is the take home message? (and I want to hear yours). I think there is evidence that the opioid receptor shows some potential promise as a target for reducing tumor growth. Is there sufficient evidence to state that opioids promote cancer growth? Absolutely not. Opioids have not been tested as potentiating tumor growth in humans. Pathophysiologically, opioids might promote cancer growth (via angiogenesis) or they might reduce cancer growth (via a reduction in the stress response).

Why is it important to not leap to the conclusionthat opioids cause cancer growth? Two recent examples come to mind: hormone replacement therapy for post-menopausal women and vitamin E. Early retrospective studies (in humans, not mice) seemed to demonstrate that hormone replacement therapy led to reduced mortality. Unfortunately, large prospective cohort studies showed the opposite to be true! When researchers went back to re-examine the earlier studies, they found those earlier studies failed to account for important baseline differences in women: those who were healthier were more likely to take hormone replacement therapy, and therefore had better health outcomes that were attributed to the drug. Similarly, there was a great deal of excitement about vitamin E, including bizillions of laboratory studies that showed plausible mechanisms by which vitamin E could reduce heart attacks (antioxidant properties, etc). Again, large studies showed the opposite: people who do not take vitamin E live longer and have fewer heart attacks than people who do take vitamin E. In both the case of hormone replacement therapy and vitamin E, patients were taking the drug and health care providers were recommending treatment based on early evidence. And people died.

Some are already leaping to conclusions.  Here’s a quote from a physician on the blog Medpie:

For patients due to undergo surgery for cancer, it is probably worthwhile for them to have a frank discussion with their surgeon and anesthesiologist about whether regional anesthesia is feasable (sic) and safe in their case, and whether opiate analgesia can be minimized. patients should “discuss avoiding general anesthesia and minimizing opioid medications).

As Christian Sinclair (of Pallimed) noticed, if you Google search “morphine cancer” the fourth hit is “Pain drug morphine may accelerate cancer growth | Reuters.” Think of all of our patients and caregivers who, seeking information, are clicking on that link.

Let’s set the record straight.