IAHPC BOARD MEMBERS’ REPORTS
Do opioids influence cancer growth? The IAHPC perspective
Lukas Radbruch, M.R. Rajagopal, Liliana De Lima, Eduardo Bruera, David Currow, Roberto Wenk, Jim Cleary, Carla Ripamonti and Michael I. Bennett, members of the IAHPC research and scientific committee.
Two new studies (1,2) and a commentary (3) published in the April edition of the journal Anesthesiology report a link between opioid drugs used to relieve pain in postoperative and chronic cancer patients and cancer growth and spread. A press release from the University of Chicago (4) argues that this adds to the growing body of evidence that opioids can stimulate the growth and spread of cancer cells.
Patients who are taking opioids for legitimate reasons, care givers and professionals who are prescribing opioids for patients in need, may find these publications upsetting and confusing, and this may add to the already existing fears of using opioids. Several members of the IAHPC research and scientific committee of the board of directors feel that this evidence needs to be put into perspective so that patients, care givers and professionals are able to understand the clinical implications of the findings and be guided in the use of opioids for pain relief. For this reason, the IAHPC members of scientific and research committee decided to offer this position statement.
The discussion on the effect of opioids (either endogenous = produced in the body, or exogenous = administered as a medicine) on cancer growth as well as on immune suppression has been discussed for some years now. However, the evidence from research is far from clear. Much of the evidence has been sought in experimental studies with cell lines or in animals, and it is to be questioned if this is true also in humans. Opioids interact with a multitude of pathways and receptors, not all interactions are produced via opioid receptors and the effects seem to differ between in vitro (experimental) and in vivo (in animals and humans).
Two recent reviews have compiled the available evidence: Afsharimani et al. 2011 (5) and Gach et al. 2011 (6). These reviews both conclude that the effect of opioids on cancer growth is still under discussion, as both growth-promoting and growth-inhibiting effects have been observed.
More specifically, Gach et al. state that:
- morphine has a pro-apoptotic effect (stimulates cell death) in human cancer cell lines at clinical concentrations,
- some studies show morphine inhibited the secretion of VEGF (the vascular endothelial growth factor produced by hypoxic tumour cells) and this significantly reduced cancer-induced angiogenesis (growth of new blood vessels) and cancer growth,
- morphine reduced spread of colon cancer cells by inhibiting adhesion and migration of these cells to the extracellular matrix (ECM),
- there seems to be a dual concentration-dependent effect, with high concentrations of morphine reducing the growth of tumors,
- chronic high doses of morphine suppress cancer growth, while tumor-enhancing effects with morphine occur after a single dose or low daily doses.
The controversy over the published research data indicates that the effect of opioids on cancer growth and spread is rather small – a borderline effect. The available evidence might also be used as a plea to use opioids regularly during the treatment of cancer pain, not only for short periods of time, but in effective (high) dosages.
Even if future studies demonstrate that opioids promote cancer growth and spread, this negative effect is far outweighed by the positive effects of adequate relief of suffering. Unalleviated pain, with its stress response and its adverse effects on energy, appetite and on general well-being would be a far more significant problem, and may also lead to significant co-morbidity and shorter survival.
There are an increasing number of published papers describing the effectiveness of palliative care teams: While in most cases, the interventions of palliative care teams result in an increase in the opioid dosage, studies also indicate that increased opioid dosages do not decrease the length of survival. Indeed, a publication by Temel et al. (7) that has received much attention showed that early intervention of palliative care considerably increased patient quality of life, mood and survival.
Throughout the world, patients are suffering from unrelieved pain, and IAHPC as well as other organizations have advocated for adequate pain management with opioids to relieve this suffering. IAHPC welcomes discussions and proposals based on scientific evidence, leading to the improvement in the quality of life of patients and the quality of care provided.
Note: This position statement is also published in the EAPC blog in http://eapcnet.wordpress.com/
References
- Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA. Over expression of the μ-Opioid Receptor in Human Non-Small Cell Lung Cancer Promotes Akt and mTOR Activation, Tumor Growth, and Metastasis. Anesthesiology. 2012 Apr; 116(4):857-867.
- Bortsov AV, Millikan RC, Belfer I, Boortz-Marx RL, Arora H, McLean SA. μ-Opioid Receptor Gene A118G Polymorphism Predicts Survival in Patients with Breast Cancer. Anesthesiology. 2012 Apr; 116(4):896-902.
- Lennon FE, Moss J, Singleton PA. The μ-Opioid Receptor in Cancer Progression: Is There a Direct Effect? Anesthesiology. 2012 Apr; 116(4):940-5.
- University of Chicago. Evidence mounts for link between opioids and cancer growth. Press release - March 12, 2012 http://www.uchospitals.edu/news/2012/20120321-opioid.html
- Afsharimani B, Cabot P, Parat MO. Morphine and tumor growth and metastasis. Cancer Metastasis Rev. 2011 Jun; 30(2):225-38. Retrieved March 25 from the Internet: http://www.ncbi.nlm.nih.gov/pubmed/21267766
- Gach K, Wyrębska A, Fichna J, Janecka A. The role of morphine in regulation of cancer cell growth. Naunyn Schmiedebergs Arch Pharmacol. 2011 Sep; 384(3):221-30. doi: 10.1007/s00210-011-0672-4. Epub 2011 Jul 29. Retrieved March 25 from the Internet: http://www.ncbi.nlm.nih.gov/pubmed/21800094
- Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19; 363(8):733-42.
Designation of WHO Collaborating Centre in Trivandrum, Kerala, India
By Dr M.R. Rajagopal
Trivandrum Institute of Palliative Sciences (TIPS), the flagship program of Pallium India (www.palliumindia.org), a registered charitable trust headquartered in Trivandrum, Kerala, India has been declared a World Health Organization Collaborating Center (WHOCC). Dr Samlee Plianbangchang, Regional Director of World Health Organization, informed the organization in a message delivered on February 28, 2012 that the designation is for a period of four years and is for collaboration in the areas of “Training and Policy on Access to Pain Relief”.
Today in India, more than 99% of the needy — people with cancer, HIV/AIDS, and other diseases causing prolonged pain — have no access to pain relief. Twenty-five years after the World Health Organization (WHO) came out with a viable protocol for pain relief, oral morphine is still not available in the majority of hospitals in India; also modern principles of pain management are not taught to medical students except in a handful of the medical colleges in the country. Through this recent announcement, the WHO is showing its commitment to turning this situation around for India and the rest of the developing world.
In his message to Pallium India, Mr Willem Scholten who leads the “Access to Controlled Medicines” program in World Health Organization’s headquarters at Geneva said, “Trivandrum Institute of Palliative Medicine is an example for other pain centres and policy makers around the world. Unfortunately, very restricted access to pain medicines is rather the rule than the exception, like it used to be all over India in the past, but Kerala shows that it is possible to improve."
Pioneering work by the Indian palliative care community in association with the WHO Collaborating Center at Madison-Wisconsin has resulted in simplification of narcotic regulations in 14 Indian states. Kerala, where TIPS is headquartered, has particularly been far ahead of the rest of the country in this aspect. There, about 100 institutions stock and dispense oral morphine to the needy for use in the home setting. At least three medical colleges in the state impart education in pain management and palliative care. Kerala remains the only state in India to declare a palliative care policy.
TIPS has its office in Pattom, Trivandrum, Kerala and its patient services based at the S.U.T Royal Hospital, in Government Medical College Hospital, Trivandrum and in some rural Government Hospitals. It provides outpatient and home visit facilities from these bases of operation. The Institute works with volunteer-led community based organizations to provide weekly home visits to bed-bound patients. TIPS is also a training centre, conducting six week certificate courses for doctors, nurses and other professionals six times a year, as well as a ten-day foundation course for doctors.
The newly designated WHO collaborating center at TIPS will work with organs of WHO, with Central and State Governments, with the Indian Association of Palliative Care and with other national and international agencies to improve access to pain relief for those in need in the country. Through these efforts, we will continue our goal of ensuring that all Indians are treated with respect, and that those with serious illness can live with the dignity they deserve.
Dr M.R. Rajagopal is the director of the Palliative Sciences, WHO Collaborating Centre for Training and Policy on Access to Pain, in Trivandrum, Kerala, India.
Dr M.R. Rajagopal is a Lifetime Adviser of the IAHPC Board. His bio may be found at: http://www.hospicecare.com/Bio/mr_rajagopal.htm
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