Exadaktylos et al.
Morphine and Metastasis
Similarly Biki et al. Clearly, and as acknowledged by the authors, retrospective studies suffer from a high rate of selection and confounding biases. Furthermore, these studies were designed to test different anesthesia and analgesia regimens rather than the effect of morphine, and the existence of multiple uncontrolled variables in the two groups made it difficult to attribute the observed results to morphine administration as an independent factor.
The only prospective study with finalized and published results testing the effect of anesthesia and pain management on cancer recurrence and mortality is a multicenter randomized, controlled clinical trial performed in Australia, New Zealand, and Asia. In this study patients undergoing major abdominal surgery for cancer, mostly colon cancer, were randomly assigned to receive general anesthesia with either epidural anesthesia and analgesia, or postoperative intravenous opioid analgesia. The results showed no significant difference in cancer recurrence and mortality at 2—3 years between the two groups Myles et al.
The results of these clinical studies are summarized in Table 2. Several randomized controlled clinical trials are still in progress to assess the possible effect of anesthetic technique on the course of cancer, which might be tumor site-specific.
Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence
Whether a simple modification of the anesthetic technique and postoperative pain management can improve survival of cancer surgery patients is a highly important question awaiting the results of these prospective trials. Table 2. Considering the possibility that morphine might have direct effects on tumor growth, as opposed to centrally ablating of the stress response , the co-administration of a peripheral antagonist capable of reversing the unwanted peripheral effects of morphine without affecting its central analgesic properties is an attractive option.
This hypothesis has been tested in several experimental settings. An in vitro study showed that pre-treatment of cultured human endothelial cells with methylnaltrexone reversed the proliferation- and migration-inducing effects of morphine and other opioid agonists Singleton et al. Furthermore, in vitro and in vivo evidence were documented showing that methylnaltrexone inhibits the disruption of endothelial cell barrier and the increased vascular permeability induced by mu receptor agonists, thrombin or lipopolysaccharide Singleton et al.
As a result, methylnaltrexone was suggested to have potential therapeutic applications in controlling tumor angiogenesis.
Methylnaltrexone was further shown to have synergistic effects on the anti-angiogenic effect of the anti-cancer drugs bevacizumab, 5-fluorouracil, rapamycin, and temsirolimus Singleton et al. Results also demonstrated the involvement of mu opioid receptors in the proliferation and migration of lung cancer cells.
Naltrexone as well as MOR knockdown attenuated tumor cell growth and invasion and prevented tumor growth and invasion in vitro and metastasis in mice. Interestingly tumors did not develop in MOR knockout mice to which lung tumor cells where injected Mathew et al. Currently, a phase II clinical trial is recruiting subjects to study the possible anti-tumor effects of naltrexone tablets, on estrogen-dependent breast cancer clinicaltrials.
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However, a retrospective clinical study of patients under methadone maintenance therapy failed to show any advantage of naltrexone compared to methadone in the formation of new cancers Singleton and Moss, The potential use of opioid antagonists in the context of cancer is debatable in view of contrasting literature: naltrexone was shown to increase the proliferation of colon, pancreatic, and head and neck cancer cells in vitro. This effect was suggested to be due to antagonism of the growth inhibiting effect of endogenous opioid [Met5]enkephalin Zagon et al.
Accordingly, a study on angiogenesis during cholestasis in rats showed naltrexone to promote angiogenesis in the liver tissue Faramarzi et al. Further studies, including randomized controlled clinical trials, would shed light on whether peripheral opioid antagonists improve cancer free survival when added to opioid analgesia after cancer surgery.
Alternative pain-relieving drugs devoid of immunosuppressive effect have been proposed to replace morphine in the postoperative pain management of cancer surgery patients. These include other opioids than morphine, non-steroidal anti-inflammatory drugs NSAIDs , and adrenergic-active drugs. Fentanyl and its derivatives sufentanil and remifentanil are highly lipophilic and potent mu receptor agonists, widely used in anesthesia Forget and De Kock, While some studies show that these drugs lack the immunosuppressive effects of morphine Bilfinger et al.
Partial agonists such as buprenorphine have been suggested as a replacement for morphine and fentanyl, based on animal data showing buprenorphine is devoid of immunosuppressive effects and protects against surgery-induced increased metastasis Franchi et al. Tramadol is a low-affinity mu opioid receptor agonist with complementary central inhibition of serotonin and noradrenaline reuptake Leppert, Tramadol not only improved immune function in animals Sacerdote et al.
Non-steroidal anti-inflammatory drugs administration has different side effects and considerably lower risk of tolerance than morphine Anonymous, NSAIDs with different modes of administration have significant opioid-sparing effects and improve post-surgical pain in different types of surgery. In minor and intermediate surgical procedures they could be considered as alternatives to opioids Cashman et al.
NSAIDs further help to improve immune function and host defense against malignant cells Forget et al. It was demonstrated that adding celecoxib, a selective COX-2 inhibitor, to morphine, reduces the morphine-induced increase in prostaglandin secretion and angiogenesis, growth and metastasis of breast tumor in rodents Farooqui et al.
In a murine model of surgery-induced cellular immunosuppression, perioperative administration of the injectable NSAID ketorolac protected, while morphine decreased, the natural killer NK cell activity after laparotomy Colacchio et al. In a recent retrospective analysis of breast cancer surgery patients, preoperative administration of ketorolac was shown to be associated with lower cancer recurrence while other drugs, namely sufentanil, ketamine, and clonidine, failed to show such beneficial effect Forget et al.
Other strategies to assist in controlling postoperative pain and reduce the need for opioid analgesics include systemic administration of glucocorticoids Salerno and Hermann, ; Romundstad and Stubhaug, ; Dahl et al. Moreover, beta blockers have synergistic effects with COX-2 inhibitors, preserving the immune function after surgery, and reducing the risk of postoperative metastasis in rats Benish et al. However safety studies, particularly in patients susceptible to risks associated with hypotension, are required Yu et al. Currently a randomized clinical trial is testing the ability of intravenous esmolol to enhance postoperative pain relief and reduce the need for intraoperative opioids in patients undergoing laparoscopic prostatectomy and upper gastrointestinal surgery clinicaltrials.
The antihypertensive drug clonidine is used preoperatively to prolong regional anesthesia and reduces the need for systemic anesthetics and postoperative opioid analgesics Pyati and Gan, However due to its multiple side effects such as excessive hypotension, sedation, and bradycardia its use is limited to regional administration Buvanendran and Kroin, The anti-convulsant drug gabapentin has also been proposed to reduce acute postoperative pain and the need for opioid administration. This beneficial effect of gabapentin has been confirmed by several randomized controlled clinical trials in oncological and non-oncological surgeries Eckhardt et al.
Pregabalin, another derivative of this family has also been suggested to have opioid-sparing effects, however the results of clinical trials on its dose-dependent efficacy are inconsistent and its use in perioperative pain management still questionable Dahl et al. While these drugs are proven to alleviate pain immediately after surgery, the long-term outcome of their administration is unknown Tiippana et al. Moreover, although they significantly reduce the postoperative side effects of opioids such as nausea, vomiting, and urinary retention, they aggravate sedation to a great extent Tiippana et al.
In conclusion, laboratory data available at the moment do not draw a clear picture of morphine as a tumor-promoting or inhibiting agent. The first prospective trial testing whether regional anesthesia and analgesia improved cancer recurrence and metastasis has not confirmed the promising conclusions drawn from retrospective studies, however further prospective trials are still ongoing as the effect may be cancer type specific.
Morphine and Metastasis by Marie-Odile Parat | | Booktopia
Even if these prospective trials were to show a benefit to cancer patients in using regional analgesia and anesthesia and reduced opioid postoperative analgesia, the role of opioids per se would not be demonstrated. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Postoperative pain relief and non-opioid analgesics.
Lancet , — Pubmed Abstract Pubmed Full Text. Afsharimani, B.
Morphine and tumor growth and metastasis. Cancer Metastasis Rev. Akural, E. The effects of pre-emptive epidural sufentanil on human immune function. Acta Anaesthesiol. Balasubramanian, S. Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes.
Bar-Yosef, S. Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology 94, — Beilin, B. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Benish, M.
Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Biki, B. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology , — Bilfinger, T. Blebea, J. Opioid growth factor modulates angiogenesis. Bruzzone, A. Alpha2-adrenoceptor action on cell proliferation and mammary tumour growth in mice.
Buvanendran, A. Multimodal analgesia for controlling acute postoperative pain. Cashman, J.
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