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Thread: Heroin and the Immune-System Modulating Properties of Opioids

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    Default Heroin and the Immune-System Modulating Properties of Opioids

    Heroin and the Immune-System Modulating Properties of Opioids

    by Steven J Baumrucker, MD
    (This essay appeared in slightly different form in The American Journal of Hospice and Palliative Care.)
    In the '80s, a debate raged over the use of heroin in cancer pain. Sides were drawn, studies performed, and in the end the conclusion seemed to be "the relative efficacy of heroin and morphine in the relief of chronic cancer pain remains unknown." Since then, very few studies on heroin versus other opioids have been published. In fact, a Medline search using the terms "heroin AND neoplasms AND pain [MeSH Terms]" generated only two hits in the last five years. Reaching back ten years yielded eight citations, but twenty years generated 37. One argument against the use of heroin (diacetylmorphine) is that it offers nothing over the opioids that we have already at our disposal, and introducing yet another potentially troublesome drug to the marketplace would be therefore a mistake.
    Interestingly, there is mounting evidence that opioids have immune and tumor growth rate modulating activities. A study from Ohio State University showed that the opioid antagonist naltrexone reduced the overall size of mammary tumors in rats over a 25 day period. Tumor regression occurred in 75% of rats who were given naltrexone orally, and those tumors were primarily estrogen and progesterone receptor positive. Human breast cancer cells have been shown to have opioid peptide immunoreactivity, and in one study from Denmark, 56% of the invasive ductal carcinomas from 61 premenopausal women were found to have cells expressing opioid reactivity. The endogenous opiate dynorphin has been shown to increase the growth of a prostatic carcinoma cell line, an effect blocked by naloxone and felt to be due to stimulation of the kappa opioid receptor.
    Naloxone had a starring role in a Japanese study involving human ovarian carcinoma cells. Nude mice were inoculated with growth culture cells derived from a human ovarian cancer cell line. The mice were either pre-treated or post-treated with naloxone. The study showed that "in comparison to a median survival time of 38 days for untreated controls, the naloxone pre- and post-treated groups showed increases of 26-71% in median survival."
    Morphine was actually shown to increase metastatic tumor growth of a certain carcinosarcoma cell line in a 1986 study. Rats were inoculated with the tumor cells, then morphine administered. There was a significant increase in subpulmonic metastases in the morphine group, with blockade of this effect by pre-treatment with naloxone. Contrary to expectation, naloxone alone did not influence the number of metastases. Coadministration of pentazocine (an agonist to kappa receptors, but imperfectly antagonistic of mu receptors) partially blocked the enhancing effects of morphine.
    The mechanism of morphine's enhancement of the growth of certain tumors is suggested in another Japanese study from 1993. Morphine treated mice showed decreased T and B-cell responses to standard stimuli, while growth of certain cancer cell lines was enhanced. It was felt that there was an overall immunosuppressive effect of morphine administration responsible for these findings. Once again, the effect was blocked by naloxone. Immunosuppression with morphine tolerance is also seen in a study from Walter Reed Army Institute of Research, where splenic and thymic atrophy were found in mice treated with chronic opioids. However, morphine suppressed the growth of a specific B-lymphoma cell line while activating a T-lymphoma line, in another study. Additionally, morphine metabolites have been shown to inhibit cytotoxic T lymphocyte induction.
    The reader should not become too pessimistic about the use of morphine in cancer pain, however. The beneficial effects of morphine on the growth of metastatic colon cancer in vivo was demonstrated in a 1991 study from Dartmouth-Hitchcock Medical Center. This paper demonstrated that intermittent opioid injections may decrease the growth of tumor cells that gain access to the circulation during surgery. In other words, rats that were given the equivalent of excellent pain control with morphine showed a significant decrease in post-operative tumor burden.
    If these studies could be duplicated in humans, the results could have far-reaching effects on the way we treat cancer pain. If we knew that, for example, certain tumor types slowed their growth when specific opioids were given, a new list of "drugs of first choice" would certainly be the result. Tumor growth can result in increasing pain and malaise, as well as decreased life expectancy.
    All of us have seen patients who seem to stabilize once admitted to hospice care, some to the point of having to be discharged from hospice until such time as they begin to deteriorate again. Explanations of this effect have tended toward chance, increased exposure to caregivers, and the beneficial effects of "TLC". It is certainly possible that some of these patients received a beneficial effect secondary to the administration of an opioid, however. If excellent pain control can result in an increased life expectancy, the "six month rule" will have to be reevaluated.
    This editorial began by discussing the lack of recent clinical research into the uses of heroin, especially in cancer pain. It is suggested by the literature that morphine may have a negative effect on certain neoplasms. Heroin, however was shown to inhibit tumor growth and prolong life span in mice with neuroblastoma in a 1991 study. This effect was not dose related. Mean survival time was prolonged by 32-39%, and this effect was also blocked by naloxone. It was felt that in addition to heroin's analgesic properties, it may have a greater significance as a modulator of neoplasia.
    As always, further research is needed to determine whether hospice and palliative caregivers should be selecting opioids not only for their pain effects but for their effect on specific tumors. If we are ever to get to that point, however, the studies must actually get done. And if the studies get done and confirm that different opioids have different effects on different neoplasms, then the more flexible and specific a response we can muster will depend on the availability of different opioid preparations. In the end, if the Zagon study proves relevant to humankind, the only morally proper course will be to legalize heroin for use in cancer pain. Even if efficacy studies in pain control showed no significant difference between morphine and heroin, the possibility of affecting survival through medications used for pain control will change the practice of palliative care forever.
    Levine, MN, et al. Heroin vs morphine for cancer pain? Arch Intern Med 1986; 146(2): 353-6.
    Abou-Issa H, Tejwani GA. Antitumor activity of naltrexone and correlation with steroid hormone receptors. Biochem Biophys Res Commun 1991; 175(2): 625-30.
    Scopsi L, et al. Immunoreactive opioid peptides in human breast cancer. Am J Pathol 1989; 134(2): 473-9.
    Moon TD. The effect of opiates upon prostatic carcinoma cell growth. Biochem Biophys Res Commun 1988; 153(2): 722-7.
    Kikuchi Y, et al. Effects of naloxone on human ovarian cancer cell growth in vitro and in vivo. Jpn J Cancer Res 1987; 78(5): 519-25.
    Simon RH, Arbo TE. Morphine increases metastatic tumor growth. Brain Res Bull 1986; 16(3): 363-7.
    Ishikawa M, et al. Enhancement of tumor growth by morphine and its possible mechanism in mice. Biol Pharm Bull 1993; 16(8): 762-6.
    Bryant HU, et al. Immunosuppressive effects of chronic morphine treatment in mice. Life Sci 1987; 41(14): 1731-8.
    Sergeeva MG, et al. Morphine effect on proliferation of normal and tumor cells of immune origin. Immunol Lett 1993; 36(2): 215-8.
    Thomas PT, et al. Immunomodulatory effects of in vitro exposure to morphine and its metabolites. Pharmacology 1995; 50(1): 51-62.
    Yeager MP, Colacchio TA. Effect of morphine on growth of metastatic colon cancer in vivo. Arch Surg 1991; 126(4): 454-6.
    Zagon IS, McLaughlin PJ. Heroin prolongs survival time and retards tumor growth in mice with neuroblastoma. Brain Res Bull 1981; 7: 25-32.












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    sabra
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    Thanks dr.Ahmed

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