A diretoria da International Association of Hospice and Palliative Care (IAHCP), juntamente com a European Association for Paliative Care (EAPC), divulgou no início de abril um documento em que se posiciona sobre os artigos polêmicos [referências 1,2, 3], publicados na edição de abril do jornal da American Society of Anesthesiologists (ASA). Esses artigos, juntamente com um comunicado à imprensa da Universidade de Chicago [referência 4], sugerem que medicação opioide pode induzir ao câncer.

Com este documento, a IAHPC vem à público esclarecer e posicionar-se em relação a esse assunto e solicita a todos – médicos, profissionais de saúde, pacientes e cuidadores – que evitem qualquer julgamento precipitado visto que, como será demonstrado a seguir, as evidências não são conclusivas e os benefícios dos opioides ainda superam em muito seus prováveis efeitos negativos.

A diretoria da Academia Nacional de Cuidados Paliativos (ANCP) concorda com os argumentos da IAHPC e também pede a todos – médicos, profissionais de saúde, pacientes e cuidadores brasileiros – que mantenham seus procedimentos enquanto estudos mais conclusivos não sejam publicados.

Leia, a seguir, o Esclarecimento Público da IAHPC traduzido para o português e, na sequência, o original em inglês.

Esclarecimento Público

Lukas Radbruch, M.R. Rajagopal, Liliana De Lima, Eduardo Bruera, David Currow, Roberto Wenk, Jim Cleary, Carla Ripamonti and Michael I. Bennett, membros do comietê científico da International Association for Hospice and Palliative Care

Apesar da discussão – sobre se opioides induzem ao câncer -acontecer há muito tempo, os estudos, até agora, não são conclusivos. Muitas resultados foram conseguidos através de pesquisas com células germinais ou de animais, sem aplicação em seres humanos. Opioides interagem com uma vasta gama de receptores e seus efeitos parecem ser diferentes em estudos in vitro (experimentais) e in vivo (com animais ou seres humanos).

Além disso, duas revisões recentes, Afsharimaniet al. 2011[5] and Gach et al 2011[6], concluem que a ação dos opioides nos tumores ainda necessita de mais dados, visto que foram observados igualmente dois tipos de efeitos: de crescimento e de inibição.

Gach et al.  descrevem que:

a) a morfina – em concentrações clínicas – tem um efeito pró-apoptótico (estimula a morte de células cancerígenas germinais);

b) a morfina inibe a secreção de VEGF (fator de crescimento endotelial vascular produzido por tumores hipóxicos), reduzindo a angiogênese induzida por câncer (crescimento de novos vasos sanguíneos) e o desenvolvimento da doença;

c) em câncer de cólon, a morfina reduz a propagação das células malignas pela inibição da aderência e da migração dessas células da matriz extracelular (ECM);

d) parece haver um efeito dosagem-dependente: altas doses contínuas de morfina reduzem o crescimento de tumores, enquanto dose única ou baixas doses diárias podem promover seu aparecimento.

Mais importante: os dados científicos publicados até agora indicam que a indução do câncer por opioides é efeito colateral menor e raro. Esses dados apontam para a manutenção dos protocolos de uso não somente em altas doses, mas também por períodos curtos.

Mesmo que estudos futuros demonstrem que opioides induzem ao câncer, este efeito negativo é muito menor se comparado aos efeitos positivos que essas drogas trazem para pacientes que sofrem de dor crônica e extrema. Dor não tratada causa estresse,  perda de energia, de apetite e piora no estado geral do paciente.  Estes sinais podem significar aumento da co-morbidade e diminuição de sobrevida.

Implicações para os Cuidados Paliativos

Os benefícios dos Cuidados Paliativos estão mais do que comprovados. Estudos indicam que a intervenção das equipes multiprofissionais geralmente aumenta o uso de opioides, contudo há também aumento da sobrevida dos pacientes. Um artigo de Temel et al[7] mostrou que Cuidados Paliativos melhoram a vitalidade e o estado geral dos pacientes.

No mundo todo, pessoas estão sofrendo por causa de dor não tratada ou mal tratada. A IAHCP, como também outras organizações, defende o adequado manejo da dor com opioides.

Por fim, a IAHPC é a favor de novos debates e propostas baseados em evidências científicas que levem à melhoria da qualidade de vida dos pacientes e do cuidado oferecido.

Nota: Esta declaração também está publicada no blog da EAPC: http://eapcnet.wordpress.com/.

Referências:

[1] 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.

[2] 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.

[3] 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.

[4] 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

[5] 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

[6] 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://www.ncbi.nlm.nih.gov/pubmed/21800094

[7] 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.

Versão em inglês

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 research and scientific committee of the International Association for Hospice and Palliative Care.

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 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: Afsharimaniet 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. 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 tumors, 
e) 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 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 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 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 relief 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

[1] 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.

[2] 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.

[3] 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.

[4] 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

[5] 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

[6] 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://www.ncbi.nlm.nih.gov/pubmed/21800094

[7] 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.