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Topic: Effects of opioids on cancer progression

Forum: Clinical Trials, Research News, Podcasts, Study Results —

Share your research articles, interpretations and experiences here. Let us know how these studies affect you and your decisions.

Posted on: Sep 26, 2015 05:04AM - edited Nov 2, 2015 07:18AM by Fallleaves

Fallleaves wrote:

The studies about opioids and recurrence are mixed. There are actually some that show anti-cancer effects, or that opioid use has no impact on recurrence. But there have been enough animal studies showing direct effects of opioids on cancer growth and spread to cause some concern. I don't want to alarm anyone who has gotten morphine or other opioids, because they are of value in pain management, and in that respect may inhibit cancer progression. Personally, I find some of this conflicting and confusing, but I thought this information deserves discussion.



This large, prospective cohort study provided no clinically relevant evidence of an association between opioid prescriptions and breast cancer recurrence.
http://www.ncbi.nlm.nih.gov/pubmed/26207518
(Cronin-Fenton, 2015)


The results presented in this study indicate that morphine may attenuate the invasion-promoting effects of IL-4 or the paracrine interaction between macrophages and cancer in the context of a tumour microenvironment.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468425/
(Khabbazi, 2015)


This study covers the positive and negative effects of morphine on cancer progression.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158334/
(Gach, 2011)


"Morphine and tumor growth and metastasis"
http://www.ncbi.nlm.nih.gov/pubmed/21267766
(Afsharimani, 2011)



"The role of morphine in animal models of cancer: does morphine promote or inhibit the tumor growth?"
http://www.ncbi.nlm.nih.gov/pubmed/24069592
(Bimonte, 2013)


"Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer."
http://www.ncbi.nlm.nih.gov/pubmed/?term=morphine+promotes+tumor+angiogensis
(Nguyen, 2014)

"Effect of Opiates, Anesthetic techniques, and other Perioperative Factors in Surgical Cancer Patients"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052589/#i1524-5012-14-2-216-b32
(Kaye, 2014)


"Morphine promotes tumor angiogensis and increases breast cancer progression."
www.ncbi.nlm.nih.gov/pubmed/?t...+and+increases+breast+cancer+progression
(Bimonte, 2015)


"The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats."
http://www.ncbi.nlm.nih.gov/pubmed/12161016
(Gaspani, 2002)




This study seems to have drawn a lot of attention, getting people looking at the connection between opioid receptors and cancer growth.
http://anesthesiology.pubs.asahq.org/article.aspx?...
(Lennon, 2012)


Article about above study:
"Opiates already in body may encourage cancer growth, certain medications could slow it."
http://www.sciencedaily.com/releases/2012/12/121212092102.htm
(Science Daily, 2012)


"The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and epithelial Mesenchymal Transition (EMT) in human lung cancer."
http://www.ncbi.nlm.nih.gov/pubmed/24662916
(Lennon, 2014)


"The mu opioid receptor: a new target for cancer therapy?"
http://www.ncbi.nlm.nih.gov/pubmed/26043235
(Singleton, 2015)


Here's an interesting study about women with different genotypes of mu opioid receptors having different survival rates:
"Mu opioid receptor gene A 118G polymorphism predicts survival in patients with breast cancer."
http://www.ncbi.nlm.nih.gov/pubmed/?term=mu+opioid+receptor+gene+A+118G+polymorphism+predicts+survival+in+patients+with+breast+cancer
(Bortsov, 2012)


"Drug for digestive problems can extend life for many advanced cancer patients" http://medicalxpress.com/news/2015-10-drug-digesti...



Links to BCO threads that are related to this topic:

Topic: Paravertebral Nerve Block and Propofol Sept. 2015, by Falleaves

https://community.breastcancer.org/forum/73/topic/834546?page=1#idx_15

topic: Toradol (ketorolac) linked to Recurrence Prevention July. 2015, by sas-schatzi

https://community.breastcancer.org/forum/73/topic/...

Topic: ketorolac to reduce recurrence Mar. 2014, by Falleaves

https://community.breastcancer.org/forum/91/topic/818961?page=1#post_3936891

Topic: Anesthesia and recurrence of cancer Sept. 2015, by Fallleaves

https://community.breastcancer.org/forum/73/topic/835244

Topic: NSAIDS and Breast Cancer Sept. 2015, by 123JustMe

https://community.breastcancer.org/forum/73/topic/835343









Dx 7/5/2013, IDC, 2cm, Stage I, Grade 2, 0/2 nodes, ER+/PR+, HER2- Surgery 8/20/2013 Lumpectomy: Right
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Sep 26, 2015 05:29AM dlb823 wrote:

Looks like you've done some extensive research on the subject. Thanks for sharing. Deanna

Deanna "The soul would have no rainbow if the eyes had no tears" Native American proverb Dx 2/1/2008, 1cm, Stage IIA, Grade 3, 1/16 nodes, ER+/PR+, HER2- Dx 1/3/2014, Stage IV
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Nov 2, 2015 07:21AM - edited Nov 2, 2015 07:21AM by Fallleaves

Added 10/27/15 Medical Xpress article about methylnaltrexone on 11/2/15. The article was previously posted by dlb823 on a separate thread.

Dx 7/5/2013, IDC, 2cm, Stage I, Grade 2, 0/2 nodes, ER+/PR+, HER2- Surgery 8/20/2013 Lumpectomy: Right
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Dec 28, 2015 05:16AM sas-schatzi wrote:

Bump

Life's journey is not to arrive at the grave safely in a well preserved body, but rather to skid in sideways, totally worn out shouting "holy crap....what a ride".
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Dec 28, 2015 06:08AM dlb823 wrote:

Thanks for bumping this, sas. I think it's a really important topic, and I was actually thinking about it again in the past few days, mulling over some of our very sad recent losses here on BCO, and thinking about all the possible contributing factors. I still kick myself for not knowing this before I had a few days of heavy, self-administered morphine after my mx+Diep recon back in 2008. I didn't react well to that drug back then, and have since noted that I'm "allergic" to it in my med file, and this just reinforces that. I think the above is information everyone should read and know about. Deanna

Deanna "The soul would have no rainbow if the eyes had no tears" Native American proverb Dx 2/1/2008, 1cm, Stage IIA, Grade 3, 1/16 nodes, ER+/PR+, HER2- Dx 1/3/2014, Stage IV
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Dec 28, 2015 12:47PM gentianviolet wrote:

In April of 2009 I had exploratory surgery for a burst appendix and subsequently received IV morphine for 10 days......this was before breast cancer. By August of 2009 I found a lump and after a biopsy and lumpectomy I was diagnosed with IDC stage II. Coincidence? Perhaps. I asked my breast surgeon if she thought I had DCIS that went malignant after the morphine, and she said, "Could be, maybe not, but you will never know." For what ever surgeries I may have in the future I will request that no opioids be involved, just in case.

Barbara Dx 8/13/2009, IDC: Cribriform, Right, 2cm, Stage IIA, Grade 1, 1/14 nodes, ER+/PR+, HER2- (FISH) Surgery 8/31/2009 Lumpectomy: Right; Lymph node removal: Right, Sentinel, Underarm/Axillary Radiation Therapy 10/14/2009 Whole-breast: Breast Hormonal Therapy 12/31/2009 Arimidex (anastrozole), Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone)
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Dec 30, 2015 06:55AM - edited Dec 30, 2015 07:02AM by sas-schatzi

Falls, thought I'd bring the doc letters here too :), but difficulty cutting and pasting. I'll bring the link.

Dbl, thanks

https://community.breastcancer.org/forum/73/topics/833612?page=7#post_4496841





Life's journey is not to arrive at the grave safely in a well preserved body, but rather to skid in sideways, totally worn out shouting "holy crap....what a ride".
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Dec 31, 2015 05:29PM grandma3X wrote:

Here's a paper showing no effect of morphine on cancer progression in mice models:

http://dx.doi.org.udel.idm.oclc.org/10.1097/j.pain...

The discussion section nicely outlines some of the limitations of other studies. Just something to be aware of.

Oncotype score 10. Married 35 years, 2 kids, 3 grands. Marine biologist/biochemist. No BC in my family tree. First diagnosed with multi focal ILC with 2 small tumors seen on MRI. Final pathology showed 1 large tumor measuring 5 cm! Dx 1/13/2016, ILC, Left, 5cm, Stage IIA, Grade 2, 0/1 nodes, ER+/PR+, HER2- Surgery 1/13/2016 Lymph node removal: Sentinel; Mastectomy: Left; Reconstruction (left): Tissue expander placement Surgery 5/18/2016 Prophylactic mastectomy: Right; Reconstruction (right): Tissue expander placement Surgery 10/26/2016 Reconstruction (left): Silicone implant; Reconstruction (right): Silicone implant Surgery 10/11/2017 Reconstruction (left): Fat grafting; Reconstruction (right): Fat grafting Surgery 10/11/2017 Prophylactic ovary removal Hormonal Therapy Femara (letrozole)
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Jan 1, 2016 05:33AM - edited Jan 1, 2016 05:51AM by Fallleaves

Hi Grandma3x, I wasn't able to see the study (the link asks for a password and log-in), but I would really like to. I would definitely like to add it to the above studies. The science on morphine's cancer effects is certainly not settled. Since morphine and other opioids are still the mainstays of anesthesia, it would be helpful to figure out whether the negative effects can be diminished by lowering dosage or by combining it with other drugs that counter the immunosuppressive and cancer promoting aspects of opioids seen in some studies. And studies that show neutral or positive effects may provide clues on situations in which morphine and other opioids are actually beneficial. I think some people are just shying away from opioids based on the precautionary principle.

Dx 7/5/2013, IDC, 2cm, Stage I, Grade 2, 0/2 nodes, ER+/PR+, HER2- Surgery 8/20/2013 Lumpectomy: Right
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Jan 1, 2016 06:40AM - edited Jan 1, 2016 06:41AM by grandma3X

Falls - sorry about that! Here's the abstract:

Author: Doornebal, Chris W. a,b; Vrijland, Kim a; Hau, Cheei-Sing a; Coffelt, Seth B. a; Ciampricotti, Metamia a; Jonkers, Jos c; de Visser, Karin E. a,*; Hollmann, Markus W. b

Institution: (a)Division of Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands

(b)Department of Anesthesiology, Academic Medical Center, Amsterdam, the Netherlands

(c)Division of Molecular Pathology and Cancer Genomics Center, Netherlands Cancer Institute, Amsterdam, the Netherlands

Title:

Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2+ breast cancer.[Article]

Source: Pain. 156(8):1424-1432, August 2015.

Abstract: Morphine and other opioid analgesics are potent pain-relieving agents routinely used for pain management in patients with cancer. However, these drugs have recently been associated with a worse relapse-free survival in patients with surgical cancer, thus suggesting that morphine adversely affects cancer progression and relapse. In this study, we evaluated the impact of morphine on breast cancer progression, metastatic dissemination, and outgrowth of minimal residual disease. Using preclinical mouse models for metastatic invasive lobular and HER2+ breast cancer, we show that analgesic doses of morphine do not affect mammary tumor growth, angiogenesis, and the composition of tumor-infiltrating immune cells. Our studies further demonstrate that morphine, administered in the presence or absence of surgery-induced tissue damage, neither facilitates de novo metastatic dissemination nor promotes outgrowth of minimal residual disease after surgery. Together, these findings indicate that opioid analgesics can be used safely for perioperative pain management in patients with cancer and emphasize that current standards of "good clinical practice" should be maintained.

(My notes here): The difference between this study and others (so they say - I have not looked at the other studies) is that they implanted cancer into the mammary glands of the mice rather than inject into the blood stream as other studies have done. They then surgically removed the cancer with or without morphine, and compared cancer progression to animals that did not go through surgery, with and without morphine. In the end, the use of morphine had no negative effect on the outcome but seemed to have positive effect on the number of lung mets for one mouse model (addition of morphine resulted in lower number of mets). They used two mouse cancer cell lines - lobular and Her2+, so that they could also test to see if the outcome was at all influenced by cancer type, which the was not.

In the discussion, they also mention that mice metabolize morphine differently, and the products of metabolism do not have an analgesic effect, whereas in humans, metabolism produces another compound that is also analgesic - meaning that humans need a smaller dose relative to mice to achieve the same effect. In other studies, the investigators were giving mice the same dose (relative to weight) that humans would get, so did not achieve the same level of pain control in their mice. The authors here hypothesize that the higher level of pain experienced by mice in other studies may have contributed to worse outcome for the mice in these other studies (that is, progression of the disease), and not due to the use of morphine per se.

Of course, all these studies on mice may have no relationship to cancer progression in humans. I understand that there are some clinical trials in progress so we may have an answer soon.

I am going to go back and re-read the paper again to be sure I've summarized everything correctly, so this post may be edited. I also ran across a review paper with a table of all the studies that have been done and how they differed. I'll see if I can find it again and post a link here.

Oncotype score 10. Married 35 years, 2 kids, 3 grands. Marine biologist/biochemist. No BC in my family tree. First diagnosed with multi focal ILC with 2 small tumors seen on MRI. Final pathology showed 1 large tumor measuring 5 cm! Dx 1/13/2016, ILC, Left, 5cm, Stage IIA, Grade 2, 0/1 nodes, ER+/PR+, HER2- Surgery 1/13/2016 Lymph node removal: Sentinel; Mastectomy: Left; Reconstruction (left): Tissue expander placement Surgery 5/18/2016 Prophylactic mastectomy: Right; Reconstruction (right): Tissue expander placement Surgery 10/26/2016 Reconstruction (left): Silicone implant; Reconstruction (right): Silicone implant Surgery 10/11/2017 Reconstruction (left): Fat grafting; Reconstruction (right): Fat grafting Surgery 10/11/2017 Prophylactic ovary removal Hormonal Therapy Femara (letrozole)
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Jan 1, 2016 07:53AM Fallleaves wrote:

Thanks, Grandma3x! I will look back at some of the other rat/mouse studies and see how they were done. That would be wonderful if you could post the review paper too.

Dx 7/5/2013, IDC, 2cm, Stage I, Grade 2, 0/2 nodes, ER+/PR+, HER2- Surgery 8/20/2013 Lumpectomy: Right
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Jan 2, 2016 05:04AM - edited Jan 2, 2016 07:49AM by grandma3X

here is a link to the journal with the review article I referenced above. It is open source so should be accessible to anyone:

http://www.ncbi.nlm.nih.gov/pubmed/24467261

the title of the paper is "Comparison and analysis of the animal models used to study the effect of morphine on tumour growth and metastasis" on page 251.

Abstract: The effect of opioids on tumour growth and metastasis has been debated for many years, with recent emphasis on the

possibility that they might influence the rate of disease-free survival after tumour resection when used in the perioperative

pain management of cancer surgery patients. The literature presents conflicting and inconclusive in vitro and in vivo data

about the potential effect of opioids, especially morphine, on tumour growth and metastasis. To inform clinical practice,

appropriate animal models are needed to test whether opioids alter the course of tumour growth and metastasis. Here, we

review the literature on animal-based studies testing the effect of morphine on cancer so far, and analyse differences between

the models used that may explain the discrepancies in published results. Such analysis should elucidate the role of opioids in

cancer and help define ideal pre-clinical models to provide definitive answers.

Oncotype score 10. Married 35 years, 2 kids, 3 grands. Marine biologist/biochemist. No BC in my family tree. First diagnosed with multi focal ILC with 2 small tumors seen on MRI. Final pathology showed 1 large tumor measuring 5 cm! Dx 1/13/2016, ILC, Left, 5cm, Stage IIA, Grade 2, 0/1 nodes, ER+/PR+, HER2- Surgery 1/13/2016 Lymph node removal: Sentinel; Mastectomy: Left; Reconstruction (left): Tissue expander placement Surgery 5/18/2016 Prophylactic mastectomy: Right; Reconstruction (right): Tissue expander placement Surgery 10/26/2016 Reconstruction (left): Silicone implant; Reconstruction (right): Silicone implant Surgery 10/11/2017 Reconstruction (left): Fat grafting; Reconstruction (right): Fat grafting Surgery 10/11/2017 Prophylactic ovary removal Hormonal Therapy Femara (letrozole)
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Jan 2, 2016 06:32AM Fallleaves wrote:

Hi Grandma3x, I don't know why, but I keep running into the user/password page at U of Delaware. But I was able to access the article on pubmed (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC429294...) I just skimmed it, and it looks like a really good one, too. Thanks for sharing it! Afsharimani seems to be doing a lot of the research in this area.

Dx 7/5/2013, IDC, 2cm, Stage I, Grade 2, 0/2 nodes, ER+/PR+, HER2- Surgery 8/20/2013 Lumpectomy: Right
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Jan 2, 2016 07:49AM grandma3X wrote:

OK, I just fixed the link in the previous post :)

Oncotype score 10. Married 35 years, 2 kids, 3 grands. Marine biologist/biochemist. No BC in my family tree. First diagnosed with multi focal ILC with 2 small tumors seen on MRI. Final pathology showed 1 large tumor measuring 5 cm! Dx 1/13/2016, ILC, Left, 5cm, Stage IIA, Grade 2, 0/1 nodes, ER+/PR+, HER2- Surgery 1/13/2016 Lymph node removal: Sentinel; Mastectomy: Left; Reconstruction (left): Tissue expander placement Surgery 5/18/2016 Prophylactic mastectomy: Right; Reconstruction (right): Tissue expander placement Surgery 10/26/2016 Reconstruction (left): Silicone implant; Reconstruction (right): Silicone implant Surgery 10/11/2017 Reconstruction (left): Fat grafting; Reconstruction (right): Fat grafting Surgery 10/11/2017 Prophylactic ovary removal Hormonal Therapy Femara (letrozole)
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Mar 30, 2016 02:47AM sas-schatzi wrote:

Bump

Life's journey is not to arrive at the grave safely in a well preserved body, but rather to skid in sideways, totally worn out shouting "holy crap....what a ride".
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May 30, 2016 07:25AM sas-schatzi wrote:

Bump

Life's journey is not to arrive at the grave safely in a well preserved body, but rather to skid in sideways, totally worn out shouting "holy crap....what a ride".

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