Opiates/Opioids

[Rich66]

http://www.scientificamerican.com/ar...r-surgery-pain
June 25, 2010

Morphine and Other Pain Relief Drugs Used in Cancer Surgery May Spur Return of Malignancy

Cancer seems to thrive on exposure to opioids, particularly morphine, the most widely used narcotic for relief of surgical pain. In the presence of these drugs tumors grow faster and develop more extensive networks of the blood vessels they rely on to feed their expansion—a process called angiogenesis, says Jonathan Moss, an anesthesiologist at the University of Chicago (U. of C.) Medical Center.

The key actors here likely are mu-opioid receptors, molecules on cell membranes that allow opioids to bind to them and interact with the cell itself, he says. Moss has shown that animals lacking these receptors do not develop lung cancer when injected with cancer cells. "If they don't have the receptor they don't get the tumor," adds Moss, whose group presented its findings at a cancer meeting last November and is now submitting them for publication. "That implies that the mu-opioid receptor is somehow involved in tumor progression.

And a team led by Moss and U. of C. Medical Center assistant professor of medicine Patrick Singleton as well as other groups, have also given drugs that block opioid receptors to mice with cancer. The result is a sharp reduction in the growth and spread of tumors, according to Moss and Singleton's findings."

A similar link to a risk for returning cancer is cropping up in studies of the form of anesthesia provided during cancer surgeries. Patients who undergo general anesthesia typically require more opioid painkillers after surgery than those who receive general anesthetics—which keep patients asleep but do not deaden nerves—plus injections of local anesthetic to block the nerves at or near the site of surgery.

On top of that, the latter approach—called regional anesthesia, or a nerve block—is thought to reduce the stress of surgery on the body's immune system. Scientists think weakened immunity in the aftermath of cancer surgery might promote recurrence later. Here's why: when surgeons remove a tumor, they inevitably leave behind a few straggler cancer cells. Cells that slough into the bloodstream can take hold at distant sites—and a metastasis is born.

Drifting cancer cells are not unlike invading bacteria, says Edward Nemergut, an anesthesiologist at the University of Virginia (U.V.A.) Health System in Charlottesville: "They spread when cancer is resected [removed], and you need a functioning immune system to take care of them. When the immune system is suppressed, it's less effective at doing that."

Results from a 2006 study in Ireland and the U.S. suggest that patients who undergo surgery to remove breast or prostate cancer might be less prone to recurrence if they are administered regional anesthesia during their procedures, rather than general anesthesia alone. And this approach may be more effective at preventing the disease from returning and spreading than treatment with chemotherapy after the operation, says Marcel Durieux, an anesthesiologist at the U.V.A. Health System .

http://www.reuters.com/article/healt...5AH5GN20091118

Pain drug morphine may accelerate cancer growth

Wed, Nov 18 2009
By Julie Steenhuysen
CHICAGO (Reuters) - Evidence is mounting that morphine, commonly used to manage pain, may accelerate cancer growth, but a newly-approved drug that blocks its side effects

Prior lab studies by Singleton and colleague Jonathan Moss have shown that morphine can boost tumor cell growth and inhibit the immune response.
They also found that opiates promote the growth of new blood vessels, a process called angiogenesis, and can make blood vessels leaky, which could increase the chances that tumor cells in the blood can spread in the body.
In the latest studies, the team looked specifically at the effects of blocking opiate receptors or molecular doorways on cancer cells with the drug Relistor, or methylnaltrexone.

"And the drug methylnaltrexone (Relistor) seems to inhibit cancer growth and invasion."
Singleton said the drug does not alter the effect of the anesthesia, but it does alter some of the side effects of opiates. "One of the side effects may turn out to be very important in terms of cancer progression," he said.

Research

Cancer Res. 2002 Aug 1;62(15):4491-8.
Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth.

FULL TEXT and PDF: http://cancerres.aacrjournals.org/cg...ull/62/15/4491

Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP.
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. gupta014@umn.edu
Morphine is used to treat pain in several medical conditions including cancer. Here we show that morphine, in a concentration typical of that observed in patients' blood, stimulates human microvascular endothelial cell proliferation and angiogenesis in vitro and in vivo. It does so by activating mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation via Gi/Go-coupled G protein receptors and nitric oxide in these microvascular endothelial cells. Other contributing effects of morphine include activation of the survival signal PKB/Akt, inhibition of apoptosis, and promotion of cell cycle progression by increasing cyclin D1. Consistent with these effects, morphine in clinically relevant doses promotes tumor neovascularization in a human breast tumor xenograft model in mice leading to increased tumor progression. These results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers.

PMID: 12154060 [PubMed - indexed for MEDLINE]

We show that morphine at medically relevant concentrations stimulates endothelial proliferation, survival, and cell cycle progression, and angiogenesis in both in vitro and in vivo assays. Because of the potential limitations of in vitro angiogenesis assays (37) , we also demonstrate that these effects of morphine translate into enhanced tumor neovascularization in vivo in a breast tumor model. One previous study showed that high concentrations of morphine [1.65, 3.3, and 16.5 mM morphine (5, 10, or 50 µg/4 µl)] inhibited angiogenesis in the chick chorioallantoic membrane assay (38) . We found that morphine is cytotoxic to endothelial cells at high concentrations. Therefore, the inhibition of angiogenesis by mM concentration of morphine, observed by others (38) , could be because of its cytotoxic effect at such concentrations. However, as serum/plasma concentrations of morphine in patients reach levels of only between 2 nM and 3.5 µM (32 , 33) , the proangiogenic activity of 1 µM morphine observed by us in the present study is more likely to be the clinically relevant effect.

Because angiogenesis actively participates in tumor progression (2) , we also examined the effect of morphine in a breast tumor model. We observed that morphine induced tumor neovascularization and increased tumor progression. Other studies have shown that morphine inhibits the proliferation of MCF-7 breast cancer cells (50) used in the tumor model in this study. Therefore, the morphine-induced tumor progression we observed appears to be primarily dependent on morphine-induced tumor angiogenesis. This is also supported by our observation that morphine did not influence the initial growth of the tumors, which is less likely to be influenced by angiogenesis. Most of the clinically used opioid analgesics are MOR agonists, and we have shown here that MOR agonist DAMGO had the same effect as morphine on endothelial signaling as well as function. Nevertheless, the effect of other opioid analgesics on angiogenesis needs to be specifically studied. Similar to the observations made by others (51) , we also observed that naloxone by itself inhibited breast tumor growth. Because of the therapeutic potential of inhibition of tumor growth by naloxone, we are currently investigating its mechanism of action. Previously, little was known about the effect of morphine on the vascular endothelium and angiogenesis. The proangiogenic activity of morphine shown here might have implications for its therapeutic application in cardiovascular medicine and wound healing. In contrast, opioid administration to patients with cancer or retinopathy might inadvertently increase angiogenesis, raising concerns about the widespread use of these analgesics in patients with cancer.

Does AnestheticManagement Affect Cancer Outcome?
http://www.apsf.org/assets/Documents/winter2009.pdf

The immune system has developed to protect us not only from infection but also from cancer. The perioperative stress response affects our immune system. Therefore, it might be expected that in patients undergoing cancer surgery (often associated with release of cancerous cells through the body) their defenses againstmetastasis are suppressed just at a time when they need them the most.

..many animal studies have shown that the choice of anesthetic drugs and techniques profoundly influences the immune response and, as a result, cancer metastasis.

Postoperative pain therapy may play a very important role in metastasis after cancer surgery. Page and colleagues demonstrated in rats that the provision of pain relief attenuates the surgery induced increase in metastatic susceptibility, likely because of the reduction in the stress response. They demonstrated that preoperative intrathecal administration of bupivacaine plus morphine and the perioperative systemic administration of fentanyl significantly enhanced the host resistance to surgery induced increases in lung metastasis. They suggested that the pain-alleviating effect of these drugs attenuated the surgery-induced promotion of metastasis rather than having direct effects on immunity, tumor cells, or other mechanisms.
On the other hand, opioids likely play a profoundly negative role. Morphine has been repeatedly shown to promote angiogenesis, and it promotes breast tumor growth in rodents.12 It is well established that opioids inhibit cellular and humoral immune function in humans.

If reducing volatile anesthetic requirements or opiates is the main factor, it might be possible to obtain similar benefits using drugs like dexmedetomidine or intravenous lidocaine.

Effects of Anesthetics on Cancer Recurrence (To the editor) 8/3/09

Robert J. Israel
Medical Affairs, Progenics Pharmaceuticals, Tarrytown, NY

We read with great interest the recent article by Weckermann et al on the perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. The authors postulate “unknown perioperatively acting triggers that stimulate outgrowth of DTCs” (disseminated tumor cells). Recent clinical and laboratory data suggest that anesthetic technique may play a role in tumor dissemination and recurrence.

In a retrospective study of prostate cancer, there was a significant difference in the rate of tumor recurrence contingent on the type of anesthesia used. A small retrospective study in breast cancer had similar findings. A large, multicenter,
prospective, randomized trial investigating the influence of type of anesthesia on breast cancer recurrence is currently underway.
In addition to the clinical studies, there is also an evolving basic science literature suggesting that opiates affect tumor growth. Both we and Gupta et al have shown that clinically relevant concentrations of opiates can cause endothelial cell proliferation and migration in vitro. The proangiogenic effect of mu opioid agonists seems to be the result of reciprocal transactivation of the vascular endothelial growth factor receptor. We have also demonstrated that mu opioids induce a defect in barrier function, potentially allowing penetration of tumor cells. The effects of mu agonists on both angiogenesis and barrier function are reversed by tertiary opiate antagonists or by methylnaltrexone, a peripherally acting mu opioid receptor antagonist approved
in the United States to treat opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxatives has not been sufficient.
If these laboratory studies are confirmed clinically, then the selection of anesthetic technique used during the operative procedure and the possible use of peripheral mu opioid receptor antagonists in the perioperative period may be of potential importance.

Mayo Clin Proc. 2008 Oct;83(10):1116-30.
Development of peripheral opioid antagonists: new insights into opioid effects.

FULL TEXT and PDF http://www.mayoclinicproceedings.com...3/10/1116.full

Moss J, Rosow CE.
Department of Anesthesia and Critical Care, University of Chicago, 5841 S Maryland Ave, MC 4028, Chicago, IL 60637, USA. jm47@midway.uchicago.edu
Comment in:

• Mayo Clin Proc. 2008 Oct;83(10):1083-6.

The recent approval by the US Food and Drug Administration of 2 medications--methylnaltrexone and alvimopan--introduces a new class of therapeutic entities to clinicians. These peripherally acting mu-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence.

PMID: 18828971 [PubMed - indexed for MEDLINE]

One reason to postulate an effect of opioids on tumor growth is the ability of these drugs to promote tumor angiogenesis in cellular models. Gupta et al⁸⁷ showed that clinically relevant concentrations of morphine induced new blood vessel growth in human breast tissue xenografts in mice. We initiated laboratory studies of the effects of opioids and MNTX in angiogenesis because a few of our patients with cancer who had received MNTX under a compassionate use protocol appeared to have slower disease progression.

Opioid growth factor regulates the cell cycle of human neoplasias.
Zagon IS, Roesener CD, Verderame MF, Ohlsson-Wilhelm BM, Levin RJ, McLaughlin PJ.
Int J Oncol. 2000 Nov;17(5):1053-61.PMID: 11029512 [PubMed - indexed for MEDLINE

Opioid growth factor modulates angiogenesis.
Blebea J, Mazo JE, Kihara TK, Vu JH, McLaughlin PJ, Atnip RG, Zagon IS.
J Vasc Surg. 2000 Aug;32(2):364-73.PMID: 10917997 [PubMed - indexed for MEDLINE]



Studies Suggest Link Between Opioids and Cancer Progression
ISSUE: MARCH, 2010 | VOLUME: 8:03
http://www.painmedicinenews.com/inde...ticle_id=14878

“This experimental evidence concurs with others, which suggests that opioids, the mainstay treatment of acute postoperative pain after cancer surgery, might inadvertently facilitate cancer cell survival and progression,” said Donal J. Buggy, MD, clinician investigator with the Mater-University College of Dublin Clinical Research Centre & Conway Institute for Biomedical Science at University College Dublin in Ireland.

Dr. Buggy is leading a large, international, prospective trial that will attempt to answer some of the questions raised by recent research into the peripheral effects of pain therapy in cancer patients. The study is being done in collaboration with the Outcomes Research Consortium, directed by Daniel Sessler, MD, chair of the Department of Outcomes Research at the Cleveland Clinic in Ohio.

ALTERNATIVES:

Br J Cancer. 2007 Dec 3;97(11):1523-31. Epub 2007 Oct 30.
COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia.

Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, Song CW, Gupta K.
1Division of Hematology, Oncology and Transplantation, the Vascular Biology Center, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
Morphine and its congener opioids are the main therapy for severe pain in cancer. However, chronic morphine treatment stimulates angiogenesis and tumour growth in mice. We examined if celecoxib (a cyclooxygenase-2 (COX-2) inhibitor) prevents morphine-induced tumour growth without compromising analgesia. The effect of chronic treatment with celecoxib (by gavage) and/or morphine (subcutaneously), or PBS on tumour prostaglandin E(2) (PGE(2)), COX-2, angiogenesis, tumour growth, metastasis, pain behaviour and survival was determined in a highly invasive SCK breast cancer model in A/J mice. Two weeks of chronic morphine treatment at clinically relevant doses stimulates COX-2 and PGE(2) (4.5-fold compared to vehicle alone) and angiogenesis in breast tumours in mice. This is accompanied by increased tumour weight ( approximately 35%) and increased metastasis and reduced survival. Co-administration of celecoxib prevents these morphine-induced effects. In addition, morphine and celecoxib together provided better analgesia than either agent alone. Celecoxib prevents morphine-induced stimulation of COX-2, PGE(2), angiogenesis, tumour growth, metastasis and mortality without compromising analgesia in a murine breast cancer model. In fact, the combination provided significantly better analgesia than with morphine or celecoxib alone. Clinical trials of this combination for analgesia in chronic and severe pain in cancer are warranted.

PMID: 17971769 [PubMed - indexed for MEDLINE]




Microvasc Res. 2006 Jul-Sep;72(1-2):3-11. Epub 2006 Jul 3.
Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation.

Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J.
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, agents that inhibit angiogenesis have important therapeutic implications in numerous malignancies. We examined the effects of methylnaltrexone (MNTX), a peripheral mu opioid receptor antagonist, on agonist-induced human EC proliferation and migration, two key components in angiogenesis. Using human dermal microvascular EC, we observed that morphine sulfate (MS), the active metabolite, morphine-6-glucuronide (M6G), DAMGO ([d-Ala(2), N-Me-Phe(4), Gly(5)-ol]enkaphalin) and VEGF induced migration which were inhibited by pretreatment with MNTX at therapeutically relevant concentration (0.1 microM). The biologically inactive metabolite morphine-3-glucuronide (M3G) did not affect EC migration. We next examined the mechanism(s) by which MNTX inhibits opioid and VEGF-induced angiogenesis using human pulmonary microvascular EC. MS and DAMGO induced Src activation which was required for VEGF receptor transactivation and opioid-induced EC proliferation and migration. MNTX inhibited MS, DAMGO and VEGF induced tyrosine phosphorylation (transactivation) of VEGF receptors 1 and 2. Furthermore, MS, DAMGO and VEGF induced RhoA activation which was inhibited by MNTX or VEGF receptor tyrosine kinase inhibition. Finally, MNTX or silencing RhoA expression (siRNA) blocked MS, DAMGO and VEGF-induced EC proliferation and migration. Taken together, these results indicate that MNTX inhibits opioid-induced EC proliferation and migration via inhibition of VEGF receptor phosphorylation/transactivation with subsequent inhibition of RhoA activation. These results suggest that MNTX inhibition of angiogenesis can be a useful therapeutic intervention for cancer treatment.

PMID: 16820176 [PubMed - indexed for MEDLINE]




Am J Respir Cell Mol Biol. 2007 Aug;37(2):222-31. Epub 2007 Mar 29.
Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation.

Singleton PA, Moreno-Vinasco L, Sammani S, Wanderling SL, Moss J, Garcia JG.
Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Avenue, W604, Chicago, IL 60637, USA.
Endothelial cell (EC) barrier dysfunction (i.e., increased vascular permeability) is observed in inflammatory states, tumor angiogenesis, atherosclerosis, and both sepsis and acute lung injury. Therefore, agents that preserve vascular integrity have important clinical therapeutic implications. We examined the effects of methylnaltrexone (MNTX), a mu opioid receptor (mOP-R) antagonist, on human pulmonary EC barrier disruption produced by edemagenic agents including morphine, the endogenous mOP-R agonist DAMGO, thrombin, and LPS. Pretreatment of EC with MNTX (0.1 muM, 1 h) or the uncharged mOP-R antagonist naloxone attenuated morphine- and DAMGO-induced barrier disruption in vitro. However, MNTX, but not naloxone, pretreatment of EC inhibited thrombin- and LPS-induced barrier disruption, indicating potential mOP-R-independent effects of MNTX. In addition, intravenously delivered MNTX attenuated LPS-induced vascular hyperpermeability in the murine lung. We next examined the mechanistic basis for this MNTX barrier protection and observed that silencing of mOP-R attenuated the morphine- and DAMGO-induced EC barrier disruption, but not the permeability response to either thrombin or LPS. Because activation of the sphingosine 1-phosphate receptor, S1P(3), is key to a number of barrier-disruptive responses, we examined the role of this receptor in the permeability response to mOP-R ligation. Morphine, DAMGO, thrombin, and LPS induced RhoA/ROCK-mediated threonine phosphorylation of S1P(3), which was blocked by MNTX, suggesting S1P(3) transactivation. In addition, silencing of S1P(3) receptor expression (siRNA) abolished the permeability response to each edemagenic agonist. These results indicate that MNTX provides barrier protection against edemagenic agonists via inhibition of S1P(3) receptor activation and represents a potentially useful therapeutic agent for syndromes of increased vascular permeability.

PMID: 17395891 [PubMed - indexed for MEDLINE]



Mol Cancer Ther. 2008 Jun;7(6):1669-79.
Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor-induced angiogenesis.

Singleton PA, Garcia JG, Moss J.
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Many patients with cancer receive combinations of drug treatments that include 5-fluorouracil (5-FU) and bevacizumab. Therapeutic doses of 5-FU are often associated with unwanted side effects, and bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that methylnaltrexone (MNTX), a peripheral antagonist of the mu-opioid receptor, exerts a synergistic effect with 5-FU and bevacizumab on inhibition of vascular endothelial growth factor (VEGF)-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC(50) of approximately 100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC(50) of 5-FU from approximately 5 micromol/L to approximately 7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC(50) of bevacizumab on inhibition of EC migration from approximately 25 to approximately 6 ng/mL. 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 receptor protein tyrosine phosphatase mu activity, which was independent of mu-opioid receptor expression. Silencing receptor protein tyrosine phosphatase mu expression (small interfering RNA) in human EC inhibited both synergy between MNTX and bevacizumab or 5-FU and increased VEGF-induced tyrosine phosphorylation of Src and p190 RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory protein, RhoA, whereas silencing Src, Akt, or RhoA blocked VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of 5-FU and bevacizumab, which could improve index.

PMID: 18566238 [PubMed - indexed for MEDLINE]

Dose Dependent:

Anesth Analg. 2008 Aug;107(2):686-92.
Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice.

Lam CF, Chang PJ, Huang YS, Sung YH, Huang CC, Lin MW, Liu YC, Tsai YC.
Department of Anesthesiology, National Cheng Kung University, Medical College and Hospital, Tainan City, Taiwan.
BACKGROUND: Morphine is one of the most commonly prescribed analgesics for treating wound pain. Using a mouse model of excisional wound injury, we determined the effects of high-dose morphine on angiogenesis and mobilization of endothelial progenitor cells. METHODS: An excisional wound was created on mice treated with placebo or morphine (20 mg/kg, i.p. injection for 14 days). Wound healing was compared by measuring the final-to-initial wound area ratio. Generation of superoxide anions in the wound was determined by luminol-enhanced chemiluminescence. Circulating mononuclear cells were isolated and measured for endothelial progenitor cell (defined as CD34+/CD133+ cell) counts. In vivo and in vitro measurements of angiogenesis after morphine treatment were performed using the Matrigel assay. RESULTS: Mice treated with morphine had reduced wound closure and higher wound superoxide ions concentrations than control mice. Morphine reduced the number of postwound circulating endothelial progenitor cells. Matrigel assay showed impaired angiogenesis in animals and reduced capillary tube formation in cultured endothelial cells treated with morphine. CONCLUSION: High-dose morphine impaired angiogenesis, increased systemic oxidative stress, and impaired mobilization of endothelial progenitor cells. This study emphasizes the potential detrimental effect of high-dose morphine on angiogenesis after systemic administration.

PMID: 18633053 [PubMed - indexed for MEDLINE]