Prospective of low dose naltrexone use in treatment of autoimmune pathology and endometriosis

Authors

DOI:

https://doi.org/10.18370/2309-4117.2020.55.53-57

Keywords:

naltrexone, autoimmune pathology, pregnancy, endometriosis

Abstract

There are still many complex issues in the management of autoimmune pathologies in gynecology and reproductology, endometriosis in particular. Naltrexone, a competitive antagonist of opiate receptors in the central and peripheral nervous systems, reveals new qualities such as effects on autoimmune processes. Naltrexone in low doses of 1.7–5 mg (Low Dose Naltrexone, LDN) revealed the opposite effect on opiate receptors in the form of a rebound effect and, as a consequence, a strong increase in endogenous endorphins and enkephalins. Studies of elevated levels of these neurotransmitters have provided evidence of a multidisciplinary beneficial effect on the immune system of people with endorphin and enkephalin deficiency, an association between the endogenous opiate system and cells and tissue growth in general and healthy immune function was confirmed. The most explored effects of them are such as blocking the synthesis of

pro inflammatory cytokines IL-6, IL-12, tumor necrosis factor, the effect on neuroglia through toll-like receptors, the effect on the cycle cells growth, especially malignant tumor cells, through interaction with opiate growth factor, modulation synthesis of T- and B-lymphocytes. Growing evidence of LDN efficacy is becoming a potentially effective clinical practice in autoimmune pathologies, but still off-label used.

Some data of clinical trials is presented. Four studies with Crohn's disease with results of relief of symptoms and remission, including experience in pediatrics. Three clinical trials with LDN results in multiple sclerosis with improved quality of life and improved symptoms. The scientific hypothesis suggests the success of LDN due to the reduction of induced nitric oxide synthase activity. The success of management of patients with malignant tumors is also presented. The article contains the latest data from clinical trials on reported serious and non-serious side effects of naltrexone at various doses, including data confirming the safety of taking mid-therapeutic naltrexone doses throughout pregnancy. These effects of LDN may prove to be effective in management patients with endometriosis.

Author Biographies

O. V. Golianovskyi, P.L. Shupik NMAPE, Kyiv

MD, professor, head of the Obstetrics and Gynecology Department № 1

O. O. Andrienko, P.L. Shupik NMAPE, Kyiv

Graduate student, Department of Obstetrics and Gynecology №1

O. V. Furman, Vinnytsia National Pirogov Memorial Medical University, Vinnytsia

PhD, associate professor at the Obstetrics and Gynecology Department No. 2

Phil Boyle, International Institute for Restorative Reproductive Medicine; Neo Fertility, Dublin

President of the International Institute for Restorative Reproductive Medicine;

Founder of Neo Fertility

References

  1. Sudakin, D. “Naltrexone: Not Just for Opioids Anymore.” J Med Toxicol 12.1 (2016): 71–5. DOI: 10.1007/s13181-015-0512-x
  2. Bihari, B. “Bernard Bihari, MD: low-dose naltrexone for normalizing imune system function.” Altern Ther Health Med 19.2 (2013): 56–6.
  3. Tahamtan, A., et al. “Opioids and Viral Infections: A Double-Edged Sword.” Front Microbiol (2016). DOI: 10.3389/fmicb.2016.00970
  4. Pasternak, G.W., Pan, Y.-X. “Mu Opioids and Their Receptors: Evolution of a Concept.” Pharmacological Reviews 65.4 (2013): 1257–1317. DOI: 10.1124/pr.112.007138
  5. Anderson, G. “Pathoetiology and pathophysiology of borderline personality: Role of prenatal factors, gut microbiome, mu- and kappa-opioid receptors in amygdala-PFC interactions.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 98 (2020): 109782. DOI: 10.1016/j.pnpbp.2019.109782
  6. Yakovleva, A.A. “Formation of fetal opioid system.” Journal of Obstetrics and Women's Diseases 2.65 (2016): 64–9. DOI: 10.17816/JOWD65264-69
  7. Spetz Holm, A.-C., et al. “Acupuncture as Treatment of Hot Flashes and the Possible Role of Calcitonin Gene-Related Peptide.” Evidence-Based Complementary and Alternative Medicine. Special Issues (2012). DOI: 10.1155/2012/579321
  8. Hilgers, T.W. The Medical&Surgical Practice of NaProTechnology (2004): 567 p.
  9. Torres-Reverón, A., et al. “Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray.” Reprod Sci 23.9 (2016): 1158–67. DOI: 10.1177/1933719116630410
  10. Wang, X., Zhang, Y., Peng, Y., et al. “Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4.” Br J Pharmacol 173 (2016): 856–69. DOI: 10.1111/bph.13394
  11. Neili Xu, et al. “Naltrexone (NTX) relieves inflammation in the collagen-induced arthritis (CIA) rat models through regulating TLR4/NFκB signaling pathway.” International Immunopharmacology 79 (2020): 106056. DOI: 10.1016/j. intimp.2019.106056
  12. Jablon, O.S., Vlasenko, D.Y. “Toll like receptors: the role of innate immunity in the pathogenesis of preterm birth and in mechanisms of central nervous system damage in preterm infants.” Modern pediatry 5 (2015): 119–23.
  13. Selfridge, B.R., Wang, X., Zhang, Y., et al. “Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists.” J Med Chem 58 (2015): 5038–52. DOI: 10.1021/acs. jmedchem.5b00426
  14. Rahn, K.A., McLaughlin, P.J., Zagon, I.S. “Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis.” Brain Res 1381 (2011): 243–53. DOI: 10.1016/j.brainres.2011.01.036
  15. Zagon, I.S., Donahue, R., McLaughlin, P.J. “Targeting the opioid growth factor: Opioid growth factor receptor axis for treatment of human ovarian cancer.” Exp Biol Med (Maywood) 238 (2013): 579–87. DOI: 10.1177/1535370213488483
  16. Rogosnitzky, M., Finegold, M.J., McLaughlin, P.J., Zagon, I.S. “Opioid growth factor (OGF) for hepatoblastoma: A novel non-toxic treatment.” Investig New Drugs 31 (2013): 1066–70. DOI: 10.1007/s10637-012-9918-3
  17. Donahue, R.N., McLaughlin, P.J., Zagon, I.S. “Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation: Mechanistic evidence from a tissue culture model.” Exp Biol Med 236 (2011): 1036–50. DOI: 10.1258/ebm.2011.011121
  18. Wang, R., et al. “Interaction of opioid growth factor (OGF) and opioid antagonist and their significance in cancer therapy.” Int Immunopharmacol 75 (2019): 105785. DOI: 10.1016/j.intimp.2019.105785
  19. McLaughlin, P.J., Zagon, I.S. “Duration of opioid receptor blockade determines biotherapeutic response.” Biochem Pharmacol 97.3 (2015): 236–46. DOI: 10.1016/j.bcp.2015.06.016
  20. Zagon, I.S., McLaughlin, P.J. “Intermittent blockade of OGFr and treatment of autoimmune disorders.” Exp Biol Med (Maywood) 243.17-18 (2018): 1323–30. DOI: 10.1177/1535370218817746
  21. Zagon, I.S., et al. “B lymphocyte proliferation is suppressed by the opioid growth factor–opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases.” Immunobiology 216.1–2 (2011): 173–83. DOI: 10.1016/j.imbio.2010.06.001
  22. Zagon, I.S., et al. “T lymphocyte proliferation is suppressed by the opioid growth factor ([Met5]-enkephalin)-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases.” Immunobiology 216.5 (2011): 579–90. DOI: 10.1016/j.imbio.2010.09.014
  23. McLaughlin, P., McHugh, D.P., Magister, M.J., Zagon, I.S. “Endogenous opioid inhibition of proliferation of T and B cell subpopulations in response to immunization for experimental autoimmune encephalomyelitis.” BMC Immunol 16 (2015): 24. DOI: 10.1186/s12865-015-0093-0
  24. Parkitny, L., Younger, J. “Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia.” Biomedicines 5.2 (2017). DOI: 10.3390/biomedicines5020016
  25. Cant, R., et al. “Naltrexone Inhibits IL-6 and TNFα Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors.” Frontiers in Immunology 8 (2017). DOI: 10.3389/fimmu.2017.00809
  26. Okun, E., Griffioen, K.J., Mattson, M.P. “Toll-like receptor signaling in neural plasticity and disease.” Trends Neurosci 34 (2011): 269–81. DOI: 10.1016/j.tins.2011.02.005
  27. Chopra, P. Mechanism of action of Low Dose Naltrexone (LDN). Available from: [https://ldnresearchtrust.org/sites/default/files/LDN_Mechanism_Of_Action_ Pradeep_Chopra_MD.pdf], last accessed Aug 18, 2020.
  28. Shannon, A., Alkhouri, N., Mayacy, S., et al. “Low-dose naltrexone for treatment of duodenal Crohn’s disease in a pediatric patient.” Inflamm Bowel Dis 16 (2010): 1457. DOI: 10.1002/ibd.21185
  29. Smith, J.P., Bingaman, S.I., Ruggiero, F., et al. “Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's disease: a randomized placebo-controlled trial.” Dig Dis Sci 56.7 (2011): 2088–97. DOI: 10.1007/s10620-011-1653-7
  30. Lie, M.R.K.L., van der Giessen, J., Fuhler, G.M., et al. “Low dose Naltrexone for induction of remission in inflammatory bowel disease patients.” J Transl Med 55 (2018): 16. DOI: 10.1186/s12967-018-1427-5
  31. Wu, G.F., Alvarez, E. “The immuno-pathophysiology of multiple sclerosis.” Neurol Clin 29.2 (2011): 257–78. DOI: 10.1016/j.ncl.2010.12.009
  32. Agrawal, Y.P. “Low dose naltrexone therapy in multiple sclerosis.” Med Hypotheses 64 (2005): 721–4. DOI: 10.1016/j.mehy.2004.09.024
  33. Gironi, M., Martinelli-Boneschi, F., Sacerdote, P., et al. “A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.” Mult Scler 14 (2008): 1076–83. DOI: 10.1177/1352458508095828
  34. Cree, B.A.C., Kornyeyeva, E., Goodin, D.S. “Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis.” Ann Neurol (2010). DOI: 10.1002/ana.22006
  35. Turel, A.P., Oh, K.H., Zagon, I.S., McLaughlin, P.J. “Low Dose Naltrexone for Treatment of Multiple Sclerosis: A Retrospective Chart Review of Safety and Tolerability.” J Clin Psychopharmacol 35 (2015): 609–11. DOI: 10.1097/JCP.0000000000000373
  36. Berkson, B.M., Rubin, D.M., Berkson, A.J. “The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous α-lipoic acid/low-dose naltrexone protocol.” Integr Cancer Ther 5 (2006): 83–9. DOI: 10.1177/1534735405285901
  37. Berkson, B.M., Rubin, D.M., Berkson, A.J. “Revisiting the ALA/N (α-Lipoic Acid/Low-Dose Naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: A report of 3 new cases.” Integr Cancer Ther 8 (2009): 416–22. DOI: 10.1177/1534735409352082
  38. Berkson, B.M., Rubin, D.M., Berkson, A.J. “Reversal of signs and symptoms of a B-cell lymphoma in a patient using only low-dose naltrexone.” Integr Cancer Ther 6 (2007): 293–6. DOI: 10.1177/1534735407306358
  39. Bolton, M., Hodkinson, A., Boda, S., et al. “Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis.” BMC Med 17.10 (2019). DOI: 10.1186/s12916-018-1242-0
  40. Towers, C.V., et al. “Use of Naltrexone in treating pregnant women with opioid use disorder (OUD).” American Journal of Obstetrics and Gynecology 220.1 (2019): S109. DOI: 10.1016/j.ajog.2018.11.162
  41. Wachman, E.M., et al. “Naltrexone Treatment for Pregnant Women With Opioid Use Disorder Compared With Matched Buprenorphine Control Subjects.” Clinical Therapeutics 41.9 (2019). DOI: 10.1016/j.clinthera.2019.07.003

Published

2020-11-30

How to Cite

Golianovskyi, O. V., Andrienko, O. O., Furman, O. V., & Boyle, P. (2020). Prospective of low dose naltrexone use in treatment of autoimmune pathology and endometriosis. REPRODUCTIVE ENDOCRINOLOGY, (55), 53–57. https://doi.org/10.18370/2309-4117.2020.55.53-57

Issue

Section

Gynecology