Surgeons/anaesthesiologists should avoidgiving opiates (morphine) to cancer patients

[Lani]

(unless with MNTX)

Opiates it turns out are angiogenic and increase tumor growth--part of a presentation at AACR meeting now going on in Boston

Common pain relief medication may encourage cancer growth

Although morphine has been the gold-standard treatment for postoperative and chronic cancer pain for two centuries, a growing body of evidence is showing that opiate-based painkillers can stimulate the growth and spread of cancer cells. Two new studies advance that argument and demonstrate how shielding lung cancer cells from opiates reduces cell proliferation, invasion and migration in both cell-culture and mouse models.

The reports--to be presented November 18, 2009, at "Molecular Targets and Cancer Therapeutics," a joint meeting in Boston of the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer--highlight the mu opiate receptor, where morphine works, as a potential therapeutic target.

"If confirmed clinically, this could change how we do surgical anesthesia for our cancer patients," said Patrick A. Singleton, PhD, assistant professor of medicine at the University of Chicago Medical Center and principal author of both studies. "It also suggests potential new applications for this novel class of drugs which should be explored."

The proposition that opiates influence cancer recurrence, prompted by several unrelated clinical and laboratory studies, has gradually gained support. It started with a 2002 palliative-care trial in which patients who received spinal rather than systemic pain relief survived longer. Soon after that, Singleton's colleague, anesthesiologist Jonathan Moss, noticed that several cancer patients receiving a selective opiate blocker in a compassionate-use protocol lived longer than expected. Two recent retrospective studies found that breast and prostate cancer patients who received regional rather than general anesthesia had fewer recurrences. In February, 2009, the Anesthesia Patient Safety Foundation highlighted the issue.

Moss's palliative-care patients were taking methylnaltrexone (MNTX), developed in the 1980s for opiate-induced constipation by the late University of Chicago pharmacologist Leon Goldberg. Goldberg modified an established drug that blocks morphine so that it could no longer cross the protective barrier that surrounds the brain. So MNTX blocks morphine's peripheral side effects but does not interfere with its effect on pain, which is centered in the brain. It won FDA approval in 2008.

"These were patients with advanced cancer and a life expectancy of one to two months," Moss recalled, "yet several lived for another five or six. It made us wonder whether this was just a consequence of better GI function or could there possibly be an effect on the tumors."

So Singleton, Moss and colleagues, including Joe G.N. Garcia, MD, professor of medicine at the University of Chicago, began a series of studies looking at the many peripheral effects of opiates and the potential benefits of blocking those effects.

In laboratory studies, morphine can directly boost tumor-cell proliferation and inhibit the immune response. The researchers found that opiates also promote angiogenesis, the growth of new blood vessels, and decrease barrier function--effects that may exacerbate diseases involving vascular leakiness including acute lung injury in experimental models. In a surgical setting, decreased barrier function may make it easier for tumors to invade tissue and spread to distant sites. Increased angiogenesis helps cancers thrive in a new site.

In the studies to be presented Nov. 18, Singleton and colleagues focus on the mu opiate receptor as a regulator of tumor growth and metastasis and examine the ability of methylnaltrexone to attenuate these effects.

Using two different models of non-small cell lung cancer, the research teams showed that MNTX inhibited the tumor-promoting effects of opiates. In one study, using bronchioloalveolar carcinoma cells, MNTX blocked oncogenic signaling and prevented tumor-cell proliferation and migration.

In the other study, using Lewis lung carcinoma cells, mice without the mu opiate receptor did not develop the tumors that normal mice did when injected with cancer cells. The researchers further showed that MNTX reduced proliferation of cancer cells by 90 percent in normal mice. It also prevented invasion in cell culture and tumor growth and metastasis in mice.

The opioid receptor promotes Lewis lung cancer tumor growth, angiogenesis and metastasis, the authors conclude in a summary of the second study. "Methylnaltrexone attenuates these oncogenic effects."

"In conjunction with previous studies on opiate-induced angiogenesis by our laboratory and others, these experimental data suggest a plausible explanation for the epidemiologic observations," notes Moss, professor of anesthesiology and critical care at the University of Chicago. "If these laboratory studies are confirmed clinically, the selection of anesthetic technique used during the operative procedure and the possible use of opiate antagonists in the perioperative period may be important."

#

[Rich66]

Hmmm.
Oxycodone, commonly prescribed to cancer patients is an opioid. Could it be a "bad opioid"? Is it all about the mu receptor?

A similar but apparently different "low dose naltrexone" thread here:
http://her2support.org/vbulletin/showthread.php?t=40502&highlight=Naltrexone

[Rich66]

Ok...no idea if this makes it ok, but..looks like Oxycodone works on a different receptor(not mu) than morphine:

The intrinsic antinociceptive effects of oxycodone appear to be kappa-opioid receptor mediated Journal name Pain Publication date 1997 Volume number 73 Start page 151 End page 157 Abstract Our previous studies in the Sprague-Dawley rat showed that the intrinsic antinociceptive effects of oxycodone are naloxone reversible in a manner analogous to morphine but that in contrast to morphine, oxycodone's antinociceptive effects have a rapid onset of maximum effect (approximate to 5-7 min compared to 30-45 min for morphine), comprise one antinociceptive phase (compared to two phases) and are of relatively short duration (approximate to 90 min compared to approximate to 180 min). In the present study, administration of a range of selective opioid receptor antagonists has shown that the intrinsic antinociceptive effects of oxycodone (171 nmol) are not attenuated by i.c.v. administration of (i) naloxonazine, a mu(1)-selective opioid receptor antagonist, or (ii) naltrindole, a delta-selective opioid receptor antagonist, in doses that completely attenuated the intrinsic antinociceptive effects of equipotent doses of the respective mu- and delta-opioid agonists, morphine and enkephalin-[D-Pen(2,5)] (DPDPE). Although beta-funaltrexamine (beta-FNA) attenuated the antinociceptive effects of oxycodone (171 nmol i.c.v.), it also attenuated the antinociceptive effects of morphine and bremazocine (kappa-opioid agonist) indicative of non-selective antagonism. Importantly, the antinociceptive effects of oxycodone (171 nmol i.c.v.) were markedly attenuated by the prior i.c.v. administration of the selective kappa-opioid receptor antagonist, norbinaltorphimine (nor-BNI), in a dose (0.3 nmol) that did not attenuate the antinociceptive effects of an equipotent dose of i.c.v. morphine (78 nmol). Taken together, these data strongly suggest that the intrinsic antinociceptive effects of oxycodone are mediated by K-opioid receptors, in contrast to morphine which interacts primarily with mu-opioid receptors. (C) 1997 International Association for the Study of Pain. Published by Elsevier Science B.V.

But...a subset of mu?
Preclinical Studies of the Combination of Morphine Plus Oxycodone

Pharmacology

Different opioids appear to interact differently with various opioid receptor subtypes (mu, delta, kappa), and some opioids have mixed agonist/antagonist effects. Recent studies have shown that there are at least 10 mu receptor subtypes in humans, and that individual patients differ in the extent to which a drug such as morphine binds to a subset of these mu receptors. Based on results of molecular pharmacology studies, a research team headed by Maree Smith (Univ. Queensland, AUS) and others have demonstrated morphine binds to multiple mu receptors with varying potencies, whereas oxycodone binds to kappa-2 receptors, as well as a subset of mu-receptors (Nielsen et al, Pain, 2007, 132: 289-300).
This work supports the concept of opioid potentiation (see Fig 1). Isobologram analysis (Fig 2) in rodent pain models demonstrated that the concurrent administration of morphine and oxycodone in ratios of 3:1, 1:1 or 1:3, produced marked analgesic synergy in response to painful stimuli (Ross et al, Pain, 2000, 84: 421-428). Interestingly, Smith’s group observed no potentiation of side effects.
Specifically, sedation and respiratory depression were not enhanced by dual opioids. Other studies in rodents suggest that a kappa agonist (eg, oxycodone) and a mu agonist (morphine) are antagonistic in respect to respiratory depression (Dosaka-Akita, J. Pharm. Exptl. Ther., 1993, 264: 631-637). Subsequently, Pasternak’s group in U.S. similarly demonstrated in rodents that combinations of other opioid agonists commonly produced analgesic synergy compared to the doses needed of either opioid given alone (Bolan et al, J. Pharmacol. Exptl. Ther., 2002, 303: 557-562).

[Rich66]

Looks like the researchers filed for a related patent last year.

Patrick A. Singleton

CHICAGO, IL US

1. 20080274119 Use of Opioid Antagonists to Attenuate Endothelial Cell Proliferation and Migration 11-06-2008 (http://www.faqs.org/patents/app/20080274119)

[0056]The present invention provides methods of attenuating abnormal or undesirable migration and/or proliferation of endothelial cells. As such, the invention provides methods for attenuating angiogenesis in a tissue or an organ of a subject by the use of opioid antagonists, and a novel approach for treating angiogenic related diseases and other hyperproliferative diseases in mammals. For example, as described above, solid tumors rely on the generation of new blood vessels for nutrients to reach the cells within the tumor. The growth factors required for angiogenesis can be produced by the tumor cells or alternatively, exogenous factors, such as opioids can stimulate new blood vessel growth. The present invention by the use of opioid antagonists provides a novel therapeutic approach to the treatment of such tumors, wherein the generation of new blood vessels within the tumor, rather than the tumor cells themselves, is the target. This treatment is not likely to lead to the development of resistant tumor cells.

[0057]Described herein are opioid antagonists inhibit proliferation and migration induced by opioids, endogenous or exogenous, and growth factors, such as VEGF, PDGF, S1P etc. Peripheral opioid antagonists, in particular, showed a substantial efficacy in inhibiting opioid and growth factor induced proliferation and migration of endothelial cells. The peripheral opioid antagonist methylnaltrexone (MNTX) inhibited both opioid and growth factor induced proliferation and migration in a concentration dependent manner. In addition, naloxone also inhibited opioid-induced endothelial migration. It should be noted, however, that the naloxone inhibition of DAMGO induced migration of endothelial cells occurred at a relatively high, micromolar, concentration of naloxone. Furthermore, it has now been discovered that opioid antagonists, and the peripheral opioid antagonist MNTX in particular, inhibit agonist induced endothelial cell (EC) proliferation and migration via inhibition of receptor phosphorylation and/or transactivation and subsequent inhibition of RhoA activation. The agonists can be opioids, exogenous and/or endogenous, angiogenic factors (VEGF), and other proliferation and/or migration stimulating factors (PDGF, S1P, S1P3 receptor, RhoA, etc). These results suggest that inhibition of angiogenesis by opioid antagonists can be a useful therapeutic intervention for, among other disorders, cancer.


Ok..MNTX is different than regular ole naltrexone
Abstract

Methylnaltrexone potentiates the antiangiogenic effects of the mTOR inhibitor, temsirolimus

P. A. Singleton, J. Moss and J. G. Garcia University of Chicago, Chicago, IL
e14636
Background: Angiogenesis is important in cancer growth and metastasis. Recent therapeutic interventions cancer, include drugs such as temsirolimus that target both tumor growth and angiogenesis including the mammalian target of rapamycin (mTOR) inhibitor. Previously, we have demonstrated that the peripheral opioid antagonist methylnaltrexone (MNTX) potentiates the effects of bevacizumab and 5FU on endothelial cell (EC) migration and proliferation. Since mTOR inhibitor therapy is also associated with significant side effects, we examined potential adjunctive agents that could reduce the therapeutic dose and improve the therapeutic window for this approach. Methods: We determined the effect(s) of MNTX, naloxone and/or temsirolimus on VEGF-induced human pulmonary microvascular EC proliferation and migration assays. We used siRNA and specific inhibitors to analyze Src, Akt and mTOR regulation. Results: MNTX inhibited EC VEGF-induced proliferation and migration with an IC50 of http://meeting.ascopubs.org/math/sim.gif100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation from http://meeting.ascopubs.org/math/sim.gif10 nM to http://meeting.ascopubs.org/math/sim.gif1 nM. Further, adding 10 nM MNTX shifted the IC50 of temsirolimus on inhibition of EC migration from http://meeting.ascopubs.org/math/sim.gif50 nM to http://meeting.ascopubs.org/math/sim.gif10 nM. These synergistic effects were not observed with naltrexone, a tertiary mu opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased protein tyrosine phosphatase (PTP) activity which was independent of mu opioid receptor expression. Treatment of human EC with the PTP inhibitor, 3,4-Dephostatin, inhibited both the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR complex 1 (temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events. Conclusions: Synergy of MNTX with mTOR inhibitors may have therapeutic implications which await clinical proof-of-concept.


Anticancer Res. (javascript:AL_get(this,%20'jour',%20'Anticancer%2 0Res.');) 2009 Aug;29(8):2927-32.
Methylnaltrexone, a peripherally acting opioid receptor antagonist, enhances tumoricidal effects of 5-Fu on human carcinoma cells.

Wang CZ (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wang%20CZ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Li XL (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Li%20XL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Sun S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sun%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Xie JT (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Xie%20JT%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Aung HH (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Aung%20HH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tong R (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tong%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), McEntee E (http://www.ncbi.nlm.nih.gov/pubmed?term=%22McEntee%20E%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Yuan CS (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yuan%20CS%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA.
BACKGROUND: Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities of chemotherapeutic agents, however, have not been evaluated. In this study, the effect of methylnaltrexone on the action of 5-fluorouracil (5-FU) was tested in three human cancer cell lines. MATERIALS AND METHODS: Treatment was for 72 h and the effects on cell proliferation were measured in human SW-480 colorectal cancer cells, MCF-7 breast cancer cells and non-small cell lung cancer cells in vitro. The apoptotic effect was analyzed by using flow cytometry. The cell cycle and expression of cyclin A were assayed after staining with propidium iodide and cyclin A-fluorescein isothiocyanate. RESULTS: 5-FU decreased the cancer cell growth significantly in all three cancer cell lines in a concentration-dependent manner and methylnaltrexone enhanced the actions of 5-FU. Compared to 5-FU 10 muM alone on SW-480 cells (63.5+/-1.1%), on MCF-7 cells (58.3+/-3.1%), or on non-small cell lung cancer cells (81.3+/-1.6%), 5-FU 10 muM plus methylnaltrexone 1.0 muM reduced cancer cell growth in all three cell lines to 50.2+/-2.9% for SW-480 cells (p<0.05), 50.0+/-1.7% for MCF-7 cells (p<0.05) and 68.7+/-2.2% for lung cancer cells (p<0.01). Methylnaltrexone alone also showed anti-proliferative activity in the three cell lines. Methylnaltrexone at 1.0 muM, reduced SW-480 cell growth to 81.9+/-3.7% (p<0.01), MCF-7 cell growth to 85.9+/-2.4% (p<0.01) and lung cancer cell growth to 85.5+/-2.2% (p<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 muM methylnaltrexone for 48 h. However, methylnaltrexone increased the number of cells in the G(1)-phase and decreased the expression of cyclin A. CONCLUSION: At its therapeutic concentrations for opioid-induced constipation, methylnaltrexone does not attenuate and in fact may enhance the tumoricidal activity of 5-FU. Enhanced 5-FU activity may be attributed to the distinct pathways of 5-FU and methylnaltrexone, an effect that could give methylnaltrexone a complementary role in the treatment of cancer with chemotherapeutic agents.

PMID: 19661297 [PubMed - indexed for MEDLINE]

[Rich66]

You folks actively taking opiate pain meds. Talked to yer docs?

[Rich66]

Ok..slow going poking around on the web so...
Called a pharmacist and he said all the typical 'codones etc are opiates involved with the mu receptor. He said a prescription NSAID with similar strength would be Toradol/Ketorac (http://www.webmd.com/drugs/drug-57954-Toradol+Oral.aspx?drugid=57954&drugname=Toradol+Oral):

http://www.webmd.com/drugs/drug-57954-Toradol+Oral.aspx?drugid=57954&drugname=Toradol+Oral


Maybe not too friendly:
Toradol, a nonsteroidal anti-inflammatory drug (http://www.drugs.com/pdr/toradol.html#), is used to relieve moderately severe, acute pain. It is prescribed for a limited amount of time (no more than 5 days for adults and as a single dose for children), not for long-term therapy.
Most important fact about Toradol

Toradol can cause serious side effects, including ulcers (http://www.drugs.com/pdr/toradol.html#) and internal bleeding. Never take it for more than 5 days.

[Rich66]

Found at livestrong

Pain signals that something is wrong in your body, whether it be an injury or illness. Regardless of where pain originates, the pain message is processed in the brain. Nerve endings at the site of the injury or illness transmit the pain messages to the brain. Pain medications do not fix the problem that is causing the pain, but they diminish the pain messages until the body has time to heal.
Opiates

The opiate family of pain medications includes drugs like morphine, codeine, hydrocodone, fentanyl and oxycodone. These drugs stimulate the mu receptors on nerve endings. Stimulation of the mu receptors lessens the ability of the body to feel pain. Since opiates work all along the central nervous system, they can decrease the cascading affect of the pain message as it travels along the nerves and spinal cord.

The mu receptors have many other functions other than the transmission of pain, which result in side effects such as repressed respiration, drowsiness and constipation. Opiates also cause feelings of euphoria, which makes them likely to be abused.
Tramadol

Tramadol weakly stimulates the mu receptor, but it also increases the amount of the neurotransmitters serotonin and norepinephrine in the central nervous system. These neurotransmitters suppress pain signals in the central nervous system.
NSAIDs

Prostaglandins are substances that have many jobs in the human body, from forming a barrier that protects the stomach from digestive acids to sending pain signals. Prostaglandins are also responsible for stimulating inflammation in the tissues and causing fever. NSAIDS, or non-steroidal anti-inflammatory drugs, block the synthesis of prostaglandins.

NSAIDS often cause stomach upset; the family of NSAIDS known as COX-2 selective inhibitors, like Celebrex and Mobic, do not affect prostaglandins in the stomach. The COX-2 selective inhibitors cause much less stomach upset, but in some patients stomach upset still occurs.
Acetaminophen

Acetaminophen, commonly known by the brand name Tylenol, also affects prostaglandin synthesis, but only in the central nervous system. New information shows that acetaminophen might block prostaglandin synthesis in an enzyme known as COX-3, which is only found in the central nervous system.
Antidepressants

Antidepressants relieve depression by increasing the levels of neurotransmitters like serotonin and norepinephrine in the central nervous system. Higher levels of these neurotransmitters decrease the transmission of the pain signals. Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are all used for pain management, but they are reserved for chronic pain conditions, such as fibromyalgia or diabetic neuropathy.
Anticonvulsants

Anticonvulsants reduce seizures by decreasing the excitability of the nervous system. They also decrease the transmission of pain signals. Like the antidepressants, anticonvulsants are used for chronic pain conditions.

[Chelee]

I haven't felt up to using the computer much or researching anything since my hip surgery last week. Too much pain. But today I wasn't happy to see the title of this thread. :(

I've been given far to many opiates since my femur surgery and came home with morphine. In cancerland you just can't win. This concerns me more so since I've been told I have had a recurrence, and I'm still not on any chemo. I'm on all kind of opiates & can't imagine not taking them right now...far too much pain. I haven't even had time to read all this yet but I will.

Thanks for sharing this...we just can't win.

Chelee

[Rich66]

Chelee,
I expanded this over in artcles and there are some potentail solutions with existing opiate companions:
http://her2support.org/vbulletin/showthread.php?t=42074

Another option is diclophenac. M y mom needed pain relief and after a negotiation wit the NP, came to came to this. It is an antinflammatory she said is used by ortho docs. Tramadol is a weak opiate but m=might be better than a prmary opiate, especially in combination wit hone of teh supplemental reversers below.
Anyway..the two opiate companions that may avoid the cancer issue are methylnaltrexone and cox inhibitors. Methylnaltrexone is available as Relistor and is sometimes prescribed to address opiate induced constipation. Maybe you need some Relistor anyway ;)

[Rich66]

Umm..if you like your liver, maybe skip the Diclofenac:

http://www.medscape.com/viewarticle/713451

['lizbeth]

Rich,

You are turning into a medical encyclopedia. It is amazing. I don't think you've left one stone unturned in digging up cancer information.