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]

[Rich66]

Diclofenac Linked to Liver Failure, Death


12/5/09
http://www.medscape.com/viewarticle/713451
Damn..a non-opiate turns out to have it's own red flag:

Treatment with all products containing diclofenac sodium, including Voltaren Gel, may increase liver dysfunction, resulting in severe hepatic reactions and liver transplantation or death, the US Food and Drug Administration (FDA), Endo, and Novartis announced late last night. Cases of drug-induced hepatotoxicity have been reported within the first month of treatment with diclofenac but can occur at any time during treatment.

[Rich66]

Effects of Anesthetics on Cancer Recurrence

Jonathan Moss Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL

Robert J. Israel
Medical Affairs, Progenics Pharmaceuticals, Tarrytown, NY
To the Editor:
We read with great interest the recent article by Weckermann et al¹ 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. This issue has been highlighted in the anesthesia literature in a recent article of the Anesthesia Patient Safety Foundation Newsletter, which reviews the clinical and laboratory data for such an effect.² In a retrospective study of prostate cancer,³ 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.⁴ A large, multicenter, prospective, randomized trial investigating the influence of type of anesthesia on breast cancer recurrence is currently underway.⁵
In addition to the clinical studies, there is also an evolving basic science literature suggesting that opiates affect tumor growth. Both we⁶ and Gupta et al⁷ 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.⁸ 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.^9,10
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. It would be particularly interesting if the authors were able to review the perioperative records of their patients to see which drugs were administered and what anesthetic techniques were used.
We commend the authors for their diligent work and believe that their observations deserve additional investigation.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Robert J. Israel, Progenics Pharmaceuticals (C) Consultant or Advisory Role: Jonathan Moss, Progenics Pharmaceuticals (C) Stock Ownership: Jonathan Moss, Progenics Pharmaceuticals; Robert J. Israel, Progenics Pharmaceuticals Honoraria: Jonathan Moss, Progenics Pharmaceuticals Research Funding: None Expert Testimony: None Other Remuneration: Jonathan Moss, patent holder, methylnaltrexone
REFERENCES
1. Weckermann D, Polzer B, Ragg T, et al: Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J Clin Oncol 27:1549–1556, 2009.[Abstract/Free Full Text]
2. Durieux ME. Does anesthetic management affect cancer outcome? http://www.apsf.org/assets/Documents/winter2009.pdf.
3. Biki B, Mascha E, Moriarty DC, et al: Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. Anesthesiology 109:180–187, 2008.[CrossRef][Medline]
4. Exadaktylos AK, Bugy DJ, Moriarty DC, et al: Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105:660–664, 2006.[CrossRef][Medline]
5. Sessler DI, Ben-Eliyahu S, Mascha EJ, et al: Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemp Clin Trials 29:517–526, 2008.[CrossRef][Medline]
6. Gupta K, Kshirsagar S, Chang L, et al: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 62:4491–4498, 2002.[Abstract/Free Full Text]
7. Singleton PA, Lingen MW, Fekete MJ, et al: Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: Role of receptor transactivation. Microvasc Res 72:3–11, 2006.[CrossRef][Medline]
8. Singleton PA, Moreno-Vinasco L, Sammani S, et al: Attenuation of vascular permeability by methylnaltrexone: Role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 37:222–231, 2007.[Abstract/Free Full Text]
9. Methylnaltrexone (Relistor) for opioid-induced constipation. Med Lett Drugs Ther 50:63–64, 2008.[Medline] 10. Moss J, Rosow CE: Development of peripheral opioid antagonists: New insights into opioid effects. Mayo Clin Proc 83:1116–1130, 2008.[Abstract/Free Full Text]

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http://www.joacp.org/index.php?optio...&id=60&catid=1

Anesthesia May Affect Metastasis Risk After Cancer Surgery

Does the type of anesthesia administered to a woman during surgery to remove breast cancer affect the odds that her disease will return or spread? Does the type of anesthesia administered to a woman during surgery to remove breast cancer affect the odds that her disease will return or spread? As tenuous as that link might first appear, a new study by U.S. and European researchers suggests just that: Women who undergo regional and general anesthesia during their tumor operations face one-quarter the risk for local or metastatic recurrence of women given only general anesthesia during the procedure and opioids afterwards. The researchers stress that their study, reported in the journal Anesthesiology (2006;105:660-664), is retrospective and preliminary and must be confirmed in a prospective trial. However, the results echo animal studies that support the hypothesis that general anesthesia and opioid drugs to prevent post-surgery pain create an environment that, albeit short-lived, encourages the growth and spread of cancer cells. Daniel Sessler, MD, Chair of Outcomes Research at the Cleveland Clinic in Ohio, and senior author of the study, was cautious about exaggerating the importance of his group’s findings. “Retrospective studies are highly suspect, and that’s why I’m not going around saying this is true,” Dr. Sessler said. “However, it is nice preliminary data that supports the need for a major outcome trial.” He and his colleagues are now organizing such a study, which will require “thousands” of patients at multiple sites. Dr. Sessler and other experts believe the results—“strange as they might seem,” he added—are well rooted in experimental and anecdotal evidence. Studies conducted in animals and humans suggest that the type of anesthesia used during surgery, the operation itself and opioid analgesia all sap the immune system. “What determines whether cancer surgery is successful is largely a function of host defense—that is, whether the patient’s immune system can deal with the little bit of tumor that’s left and kill it off,” Dr. Sessler said. “If we do things that impair immune function exactly at that time, it seems likely to diminish the chances of cleaning up the residual tumor.” Stunned Defenses Give Tumor Cells A Second Chance Breast cancer is the most common form of cancer among women and the second leading cause of cancer-related death, next to lung cancer, in the United States. The vast majority of women with the disease undergo surgery to remove their tumor or tumors, as well as part or all of the affected breast. But surgeons cannot cut away every trace of cancer, so small numbers of tumor cells remain in the operating site that eventually can seed either local or distant recurrences. These cells are called micrometastases or minimal residual disease (MRD). Ideally, the body’s cellular and humeral immune system will detect and destroy residual disease before it can erupt. As a stopgap, though, women also frequently receive chemotherapy and radiation after tumor surgery. At the heart of the new study is a connection, supported by a growing body of evidence, between anesthesia, opioid pain relief and the immune system’s response to cancer surgery. “Cancer surgery as done normally is bad for the immune system because the surgery itself, the anesthesia itself and the opioids used to control pain all impair natural killer cell function,” Dr. Sessler said. Although ranking the insults is difficult, surgery may deliver the single biggest blow to the immune system. The body responds to the stress of the procedure by impeding the performance of natural killer cells. It also suppresses chemicals that deprive tumors of their blood supply and boosts the production of molecules, including vascular endothelial growth factor (VEGF), that stimulate their growth. Animal studies also have suggested that anesthesia weakens the activity of natural killer cells, which lead the attack against cancerous cells and pathogens. Compared to general anesthesia, regional techniques may allow more killer cells to proliferate, raising the chances that these cells will be able to catch any leftover cancer cells. Similarly, morphine and other opioids have been shown to suppress the immune system and, in particular, natural killer cells. Regional anesthesia during surgery can reduce the need for postoperative opioids, which may in turn leave the immune system stronger. Much of the research in this area has come from the laboratory of Shamgar Ben-Eliyahu, PhD, Professor of Physiology and Psychology at Tel Aviv University, in Israel. Over the past decade, Dr. Ben-Eliyahu, an expert in neuroimmunomodulation, has published a series of studies, many funded by the U.S. National Institutes of Health, illuminating the effects of surgery, anesthesia and analgesia on human and animal tissues. In what he called a “crucial” article (Anesthesiology 2001;94:1066-1073), Dr. Ben-Eliyahu and colleagues showed that rats given a spinal blockade—which reduces the neuroendocrine stress response to surgery—in addition to general anesthesia developed 70% fewer lung metastases after laparotomy than animals that received general anesthesia alone. Then, in a study published in Neuroimmunomodulation (2004;11:255-260), Dr. Ben-Eliyahu and fellow investigators demonstrated that the opioid fentanyl inhibited the activity of natural killer cells in rats inoculated with tumor cells and increased the rodents’ risk for metastatic cancer. The tumor burden rose with the dose of fentanyl the animals received. Dr. Ben-Eliyahu said the newest research adds an important clinical piece to the puzzle he has been completing. Led by Aristomenis K. Exadaktylos, MD, an anesthesia research fellow at Mater Misericordiae University Hospital in Dublin, Ireland, the researchers compared rates of recurrence and metastasis in 129 women who had undergone breast cancer surgery at that institution between September 2001 and December 2002. Of those, 50 received paraverterbral anesthesia—consisting of a 0.2-mL/kg bolus of 0.25% levobupivicaine—before induction of general anesthesia. For the general regimen, anesthesia was induced with 0.5 mcg/kg of fentanyl and 1.5-3.0 mg/kg of propofol (Diprivan, AstraZeneca), after which the women were given a laryngeal mask airway through which was administered 2% to 3% sevoflurane in nitrous oxide and oxygen. Every woman also was given a 100-mg suppository of diclofenac after induction but before surgery, along with 0.05-mg/kg boluses of morphine during the operation at the discretion of the anesthetist. Over the next three years, three women (6%) who received paravertebral anesthesia developed recurrent or metastatic tumors, compared with 19 of the 79 (24%) who received general anesthesia alone. At 36 months after surgery, 94% of women in the first group remained free of disease, compared with 77% of the others (P=0.007). Paravertebral anesthesia also seemed to delay the return of breast cancer (P =0.013) in the women who went on to suffer recurrences. The researchers found no statistically significant differences in tumor grade, disease progression, adjuvant treatment, age and other factors among women in the two study groups. However, they noted, women who received general anesthesia alone tended to have slightly larger tumors, smaller tumor margins and higher rates of receiving chemotherapy than the other women—which could have influenced the outcome of the study. Study Method Faulted Critics of the research pointed to its retrospective nature and the inability to control for factors that might have biased the results. “It’s very unclear whether the groups of patients receiving the blockade were equivalent to the patients who didn’t,” said E. Andrew Ochroch, MD, Director of Thoracic Anesthesiology at the University of Pennsylvania Health System in Philadelphia and co-author of an editorial accompanying the Anesthesiology article. The study “seems to be pushing us in the direction that the blockade is very, very good, but I believe that’s a false assumption. There’s not enough data to show that.” Still, Jonathan Moss, MD, Professor of Anesthesiology and Critical Care at the University of Chicago Hospitals, called Dr. Sessler’s study “intriguing” and said it could have far-reaching implications for the care of patients with cancer if confirmed. “What happens during the course of your hospital surgery and anesthesia can really affect your well-being two years out,” Dr. Moss said. Support for a direct connection between analgesia and tumor growth has come from recent studies demonstrating that opioids in clinical doses potentiate endothelial cell migration and proliferation, two components of angiogenesis that improve gastrointestinal recovery from the effects of surgery. In an article recently published in the journal Microvascular Research, Dr. Moss and colleagues showed that methylnaltrexone, a peripheral opioid receptor antagonist being developed by Wyeth and Progenics for postoperative ileus and constipation from opioid use, blocks opiate- and VEGF-induced angiogenesis in human lung and skin cells. “An effect of opioids on tumor proliferation could also explain the findings in [Dr. Sessler’s] study,” Dr. Moss said. “In addition to the opiates we routinely give, endogenous opioids go up quite substantially during surgery, and maybe even into the postoperative period.” To be sure, the new research raises a host of questions. One of them is the relative impact on immune function of anesthesia, analgesia and the physical act of surgery. Another, the optimal time frame for quashing MRD and minimizing the odds of recurrence. Although Dr. Ben-Eliyahu cannot be certain, he believes this window is extremely small. “I cannot tell you whether it is a week or a month—nobody can,” he said. “My gut feeling is that it’s a matter of days. All our animal studies show that it is a very short period of opportunity.” Whatever the case, Dr. Moss predicted, the study is certain to trigger additional interest in the intersection between anesthesia, surgery, pain relief and cancer. “I think people are going to be scurrying around to look at the data.” Vol. 11, No. 4, 2004 Free Abstract Article (References) Article (PDF 125 KB) Original Paper Effects of Fentanyl on Natural Killer Cell Activity and on Resistance to Tumor Metastasis in Rats Dose and Timing Study Yehuda Shavita, Shamgar Ben-Eliyahub, Alexander Zeidelc, Benzion Beilinc aDepartment of Psychology, Hebrew University, Jerusalem, bDepartment of Psychology, Neuroimmunology Research Unit, Tel Aviv University, Tel Aviv, and cDepartment of Anesthesiology, Rabin Medical Center, Golda-Hasharon Campus, Petah Tiqva, Israel Address of Corresponding Author Neuroimmunomodulation 2004;11:255-260 (DOI: 10.1159/000078444) Key Words Opiates Natural killer cells Lung tumor retention and metastasis Abstract Objectives: Opiates, which serve an integral role in anesthesia, suppress immune function, particularly natural killer cell cytotoxicity (NKCC). NK cells play an important role in tumor and metastasis surveillance. We reported that large-dose fentanyl anesthesia induced prolonged suppression of NKCC in patients undergoing abdominal surgery. The immune modulatory effects of opiates may depend on the interaction between dose and time of administration. The present study examined the effects of different doses of fentanyl, administered at different time points relative to tumor inoculation, on NKCC and on experimental tumor metastasis in rats. Methods: Fischer 344 rats were injected with low or high doses of fentanyl, 6 or 2 h before, simultaneously with or 1 h after being inoculated intravenously with MADB106 tumor cells. Lung tumor retention (LTR) was assessed 4 h after, and lung tumor metastases were counted 3 weeks after tumor inoculation. NKCC was assessed 1 h after the fentanyl injection. Results: At all time points, except 6 h before tumor inoculation, fentanyl (0.1-0.3 mg/kg) induced a dose-dependent increase in MADB106 LTR (2.3- to 74-fold). An intermediate dose of fentanyl (0.15 mg/kg) doubled the number of lung metastasis, and, within animal, suppressed NKCC and increased MADB106 LTR in a correlated manner. Conclusion: These findings indicate that fentanyl suppresses NKCC and increases the risk of tumor metastasis. Suppression of NK cells at a time when surgery may induce tumor dissemination can prove to be critical to the spread of metastases. It is suggested that the acute administration of a moderate dose of opiates during surgery should be applied cautiously, particularly in cancer patients. Copyright © 2004 S. Karger AG, Basel

[Rich66]

Relistor (Methylnaltrexone)

http://www.wyeth.com/hcp/relistor/home

[Rich66]

12.28.2009
Pain Medication May Increase the Symptoms of Chronic Pain
LINK
By Dr. Stephen F. Grinstead, LMFT, ACRPS, CADC-II
Over the past twenty seven years I have worked with many people taking opiate medications who develop a condition known as opioid-induced hyperalgesia. For those of you unfamiliar with this phenomenon here is the definition of opiate-induced hyperalgesia from Wikipedia. Opioid-induced hyperalgesia or opioid-induced abnormal pain sensitivity is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, Oxycodone, and methadone. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.
If an individual is taking opioids for a chronic non-cancer pain condition, and cannot achieve effective pain relief despite increases in dose, they may be experiencing opioid-induced hyperalgesia. In this case, they may benefit from complete withdrawal from opioid therapy. Many individuals report reduced pain levels when opioids are withdrawn.
When people are undergoing chronic pain management they want help stopping or relieving their pain symptoms. What they may not realize is that some pain medications can actually cause or increase the pain that they are using the medication to manage. That is why it is crucial for people undergoing chronic pain management to educate themselves and learn as much as possible about their chronic pain condition as well as the most effective treatment options.
For example many people experiencing frequent headaches, especially migraines, do not realize that the medication they are using can actually be increasing the frequency and even severity of their pain. The use of opiates to treat migraines can lead to an increased risk for what is called transformed migraines. Transformed migraines are chronic, daily headaches with a vascular quality — meaning that they are throbbing in nature.
As anyone who ever experienced a migraine headache knows it can be extremely debilitating. Unless a migraine sufferer goes to a treatment provider who understands appropriate treatment interventions for this condition, they can run the risk of unnecessary pain and suffering including transformed migraines or even potential prescription drug addiction. Many people are prescribed opiates even though they are not an FDA approved medication for migraine treatment.
Long-term use of opioids to manage other chronic pain conditions also increases patients’ sensitivity to certain types of pain, and similar hyperalgesia develops with methadone-maintained drug abusers as researchers from the University of Adelaide, in Australia, report. This observational study by Justin L. Hay, MD, and colleagues was posted is in the March 2009 issue of the Journal of Pain.
David Clark, MD, from the Palo Alto VA Health Care System, in California, has also studied opioid-induced hyperalgesia and adds his comments regarding this study. According to Dr. Clark, "An important finding in this study was that not only addicts have this type of sensitization. Chronic-pain patients have it as well, so this problem goes beyond the boundaries of what is unique to drug abusers."
Dr. Clark said the finding that long-term use of opioids seems to sensitize patients to pain itself suggests factors that could both limit the clinical utility of opioids used to control chronic pain and add to pain problems in those being treated for addiction. “The emerging experience regarding the long-term use of opioids for chronic pain is not terribly encouraging, and opioid-induced hyperalgesia is one explanation for why this therapy might have limited success,” he said.
The evolving need of people undergoing chronic pain management for safe, effective pain relief is driving research into new therapeutic modalities and fresh approaches to familiar treatments. New innovations involving both opioid and nonopioid pain modalities as well as nonpharmacological approaches are vital because some patients fail to achieve a good outcome with opioid therapy alone.
That is why nonopioid medications and non-medication type interventions are receiving greater research attention. Opioids are also the subject of new exploration, most of this directed toward separating desired analgesia from unwanted side effects such as euphoria, tolerance, abuse risk, addiction and constipation.
To learn more about effective chronic pain management please check out our Addiction-Free.Com Website. Be sure to review the Articles and the News and Research pages for free information and patient education.

[Rich66]

Br J Anaesth. 2009 Nov;103(5):685-90. Epub 2009 Sep 22.
Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro.

Deegan CA, Murray D, Doran P, Ecimovic P, Moriarty DC, Buggy DJ.




Source

Department of Anaesthesia and Intensive Care Medicine, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.

Erratum in

• Br J Anaesth. 2010 Apr;104(4):516.

Abstract

BACKGROUND:

Metastatic recurrence is the main cause of breast cancer-related deaths. Tumour cell proliferation and migration are crucial steps in the metastatic process. Several perioperative factors, including general anaesthesia and opioid analgesia, adversely affect immune function, potentially increasing metastatic recurrence. Regional anaesthesia-analgesia has been consistently shown to attenuate the stress response to surgery, and also reduce opioid and general anaesthesia requirements, thereby attenuating this perioperative immunosuppression. We investigated the effect of serum from breast cancer surgery patients who received different anaesthetic techniques on breast cancer cell function in vitro.
METHODS:

Patients were randomized to receive propofol/paravertebral anaesthesia-analgesia (propofol/paravertebral, n=11) or sevoflurane general anaesthesia with opioid analgesia (sevoflurane/opioid, n=11). The ER-negative MDA-MB-231 cell line was treated with patient serum from both groups. The effects on proliferation and migration were measured.
RESULTS:

Treatment groups were well balanced for age, weight, surgical procedure, and cancer pathology. Pain scores were lower at 1 and 2 h in the propofol/paravertebral analgesia group. Compared with preoperative values, proliferation of MDA-MB-231 cells treated with postoperative patient serum at 10% concentration from the propofol/paravertebral group was significantly reduced compared with the sevoflurane/opioid group (-24% vs 73%, P=0.01). There was no significant change in MDA-MB-231 cell migration after treatment with patient serum between the two groups.

CONCLUSIONS:

Serum from patients receiving propofol/paravertebral anaesthesia for breast cancer surgery inhibited proliferation, but not migration, of ER-MDA-MB-231 cells in vitro, to a greater extent than that from patients receiving sevoflurane/opioid anaesthesia-analgesia. This implies that anaesthetic technique alters the serum molecular milieu in ways that may affect breast cancer cell function, possibly by altering anaesthetic and opioid drug administration and resultant pain scores.

PMID:

19776028

[PubMed - indexed for MEDLINE]

Free full text

Br J Anaesth. 2010 Aug;105(2):106-15.
Effect of anaesthetic technique and other perioperative factors on cancer recurrence.

Snyder GL, Greenberg S.




Source

Department of Anesthesia and Perioperative Medicine, University of California San Francisco, 505 Parnassus Ave., San Francisco, CA 94143, USA. gabrielsnyder@hotmail.com

Abstract

Surgical excision is the mainstay of treatment for potentially curable solid tumours. Metastatic disease is the most important cause of cancer-related death in these patients. The likelihood of tumour metastases depends on the balance between the metastatic potential of the tumour and the anti-metastatic host defences, of which cell-mediated immunity, and natural killer cell function in particular, is a critical component. It is increasingly recognized that anaesthetic technique and other perioperative factors have the potential to effect long-term outcome after cancer surgery. Surgery can inhibit important host defences and promote the development of metastases. Anaesthetic technique and drug choice can interact with the cellular immune system and effect long-term outcome. The potential effect of i.v. anaesthetics, volatile agents, local anaesthetic drugs, opiates, and non-steroidal anti-inflammatory drugs are reviewed here. There is particular interest at present in the effect of regional anaesthesia, which appears to be beneficial. Retrospective analyses have shown an outcome benefit for paravertebral analgesia for breast cancer surgery and epidural analgesia for prostatectomy. Blood transfusion, pain, stress, and hypothermia are other potentially important perioperative factors to consider.

PMID:

20627881

[PubMed - indexed for MEDLINE]

Anesth Analg. 2011 Oct 14. [Epub ahead of print]
Morphine-Induced Epidermal Growth Factor Pathway Activation in Non-Small Cell Lung Cancer.

Fujioka N, Nguyen J, Chen C, Li Y, Pasrija T, Niehans G, Johnson KN, Gupta V, Kratzke RA, Gupta K.
Source

From the *Department of Medicine, Division of Hematology, Oncology, Transplantation, University of Minnesota, Minneapolis;

Abstract

Background: Epidermal growth factor receptor (EGFR) is coactivated by the μ-opioid receptor (MOR), expressed on non-small cell lung cancer (NSCLC) cells and human lung cancer. We hypothesized that clinically used opioid analgesics that are MOR agonists coactivate EGFR, resulting in growth- and survival-promoting signaling.



Methods:We used H2009, a human adenocarcinoma NSCLC cell line, with constitutive EGFR phosphorylation, which showed increased expression of MOR and the δ-opioid receptor by reverse transcriptase polymerase chain reaction. We used Western immunoblotting, magnetic bead-based Bio-Plex cytokine assay, immunofluorescent staining, BrdU incorporation enzyme-linked immunosorbent assay, and BioCoat™ Matrigel™ invasion assay to examine cell signaling, cytokine expression, colocalization of MOR and EGFR in human lung cancer, and cell proliferation and invasion, respectively.



Results: Similar to epidermal growth factor (EGF), morphine stimulated phosphorylation of EGFR, Akt/protein kinase B (Akt), and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling in H2009 cells. Opioid receptor (OR) antagonist, naloxone, EGFR tyrosine kinase inhibitor, erlotinib, and silencing of MOR and δ-opioid receptor abrogated morphine- and EGF-induced phosphorylation of signaling, suggestive of OR-mediated coactivation of EGFR. H2009 cells secreted significantly higher levels of cytokines compared with control Beas2B epithelial cells. H2009-conditioned medium stimulated MOR expression in Beas2B cells, suggesting that cytokines secreted by H2009 may be associated with increased OR expression in H2009. We observed colocalization of EGFR and MOR, in human NSCLC tissue. Functionally, morphine- and EGF-induced proliferation and invasion of H2009 cells was ameliorated by naloxone as well as erlotinib.


Conclusion: Morphine-induced phosphorylation of EGFR occurs via ORs, leading to downstream MAPK/ERK, Akt phosphorylation, cell proliferation, and increased invasion. Notably, ORs are also associated with EGF-induced phosphorylation of EGFR. Increased coexpression of MOR and EGFR in human lung cancer suggests that morphine may have a growth-promoting effect in lung cancer.

PMID:

22003224

[PubMed - as supplied by publisher]