Lukas Radbruch, MR Rajagopal, Liliana De Lima, Eduardo Bruera, David Currow, Roberto Wenk, Jim Cleary, Carla Ripamonti and Michael I Bennett, members of the research and scientific committee of the International Association for Palliative Care (IAHPC)
Two new studies and a commentary 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 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 fear of taking 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 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 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 whether 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 in Cancer and Metastasis Review and Gach et al 2011 in Naunyn Schmiedebergs Arch Pharmacol.) 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. describe that:
a) Morphine has a pro-apoptotic effect (stimulates cell death) in human cancer cell lines at clinical concentrations.
b) 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.
c) Morphine reduced spread of colon cancer cells by inhibiting adhesion and migration of these cells to the extracellular matrix (ECM).
d) There seems to be a dual concentration-dependent effect, with high concentrations of morphine reducing the growth of tumours.
e) Chronic high doses of morphine suppress cancer growth, while tumour-enhancing effects with morphine occur after a single dose or low daily doses.
The controversy on 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, not only for short periods of time, and 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 might also lead to significant comorbidity 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. that 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 organisations 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.