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Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review

  • Anesthetic Techniques in Pain Management (D Wang, Section Editor)
  • Published:
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Abstract

Purpose of Review

The purpose of this review is to evaluate and explain our current understanding of the clinical use of low-dose naltrexone in the treatment of chronic pain.

Recent Findings

Recent pre-clinical uses and clinical studies further elucidate the use of low-dose naltrexone in the treatment of chronic pain.

Summary

Low-dose naltrexone (LDN) has shown promise to reduce symptoms related to chronic pain conditions such as fibromyalgia, inflammatory bowel conditions, and multiple sclerosis. The mechanism of LDN appears to be modulation of neuro-inflammation, specifically, the modulation of the glial cells and release of inflammatory chemicals in the central nervous system. These effects appear to unique at low dosage compared to dosage for food and drug administration approved use for alcohol and opioid dependence. We review the evidence that LDN has shown more than promise and should be further investigated in clinical practice.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Vol 26. Washington, DC: The National Academies Press 2012. https://doi.org/10.3109/15360288.2012.678473

  2. • Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33(4):451–9. https://doi.org/10.1007/s10067-014-2517-2This study is small and follow-up from previous study. A well-done and rigorous study supporting use of low dose naltrexone for fibromyalgia.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Boissevain MD, McCain GA. Toward an integrated understanding of fibromyalgia syndrome. I. Medical and pathophysiological aspects. Pain. 1991. https://doi.org/10.1016/0304-3959(91)90047-2.

  4. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663–72. https://doi.org/10.1111/j.1526-4637.2009.00613.x.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hang Y, Kim J, West K. Treating chronic pain with low dose naltrexone and ultralow dose naltrexone: a review paper. History of naltrexone. J Pain Manag Ther. 2019;3:1 http://www.alliedacademies.org/pain-management-and-therapy/.

    Google Scholar 

  6. Shen KF, Crain SM. Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Brain Res. 1989;491:227–42. https://doi.org/10.1016/0006-8993(89)90059-0.

    Article  CAS  PubMed  Google Scholar 

  7. Largent-Milnes TM, Guo W, Wang HY, Burns LH, Vanderah TW. Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated μ-opioid receptor-Gscoupling. J Pain. 2008;9:700–13. https://doi.org/10.1016/j.jpain.2008.03.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang HY, Frankfurt M, Burns LH. High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence. PLoS One. 2008;3(2):1–10. https://doi.org/10.1371/journal.pone.0001554.

    Article  CAS  Google Scholar 

  9. •• Burns LH, Wang HY. Ultra-low-dose naloxone or naltrexone to improve opioid analgesia: the history, the mystery and a novel approach. Clin Med Insights Ther. 2010;2:857–68. https://doi.org/10.4137/CMT.S4870Review and update of low dose naltrexone with focus on animal studies and mechanism of analgesia.

    Article  CAS  Google Scholar 

  10. Perrot S. Fibromyalgia syndrome: a relevant recent construction of an ancient condition? Curr Opin Support Palliat Care. 2008;2:122–7. https://doi.org/10.1097/SPC.0b013e3283005479.

    Article  PubMed  Google Scholar 

  11. Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011;34:269–81. https://doi.org/10.1016/j.tins.2011.02.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Donahue RN, McLaughlin PJ, Zagon IS. The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice. Gynecol Oncol. 2011;122:382–8. https://doi.org/10.1016/j.ygyno.2011.04.009.

    Article  CAS  PubMed  Google Scholar 

  13. Lutz PE, Kieffer BL. The multiple facets of opioid receptor function: implications for addiction. Curr Opin Neurobiol. 2013;23:473–9. https://doi.org/10.1016/j.conb.2013.02.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2009;72:333–7. https://doi.org/10.1016/j.mehy.2008.06.048.

    Article  CAS  PubMed  Google Scholar 

  15. Mischoulon D, Hylek L, Yeung AS, Clain AJ, Baer L, Cusin C, et al. Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. J Affect Disord. 2017;208(October 2016):6–14. https://doi.org/10.1016/j.jad.2016.08.029.

    Article  CAS  PubMed  Google Scholar 

  16. Lin R, Karpa K, Kabbani N, Goldman-Rakic P, Levenson R. Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A. Proc Natl Acad Sci U S A. 2001;98:5258–63. https://doi.org/10.1073/pnas.011538198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007;64:327–37. https://doi.org/10.1001/archpsyc.64.3.327.

    Article  CAS  PubMed  Google Scholar 

  18. Lambert GW, Eisenhofer G, Jennings GL, Esler MD. Regional homovanillic acid production in humans. Life Sci. 1993;53:63–75. https://doi.org/10.1016/0024-3205(93)90612-7.

    Article  CAS  PubMed  Google Scholar 

  19. Klimek V, Schenck JE, Han H, Stockmeier CA, Ordway GA. Dopaminergic abnormalities in amygdaloid nuclei in major depression: a postmortem study. Biol Psychiatry. 2002;52:740–8. https://doi.org/10.1016/S0006-3223(02)01383-5.

    Article  CAS  PubMed  Google Scholar 

  20. Myers JS. Proinflammatory cytokines and sickness behavior: implications for depression and cancer-related symptoms. Oncol Nurs Forum. 2008;35(5):802–7. https://doi.org/10.1188/08.ONF.802-807.

    Article  PubMed  Google Scholar 

  21. Cleeland CS, Bennett GJ, Dantzer R, Dougherty PM, Dunn AJ, Meyers CA, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. 2003;97:2919–25. https://doi.org/10.1002/cncr.11382.

    Article  PubMed  Google Scholar 

  22. Lee BN, Dantzer R, Langley KE, Bennett GJ, Dougherty PM, Dunn AJ, et al. A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation. 2004;11:279–92. https://doi.org/10.1159/000079408.

    Article  CAS  PubMed  Google Scholar 

  23. Illman J, Corringham R, Robinson D, et al. Are inflammatory cytokines the common link between cancer-associated cachexia and depression. J Support Oncol. 2005.

  24. Cruciani RA, Lussier D, Miller-Saultz D, Arbuck DM. Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone [1]. J Pain Symptom Manag. 2003;25:491–4. https://doi.org/10.1016/S0885-3924(03)00139-8.

    Article  Google Scholar 

  25. Hamann S, Sloan P. Oral naltrexone to enhance analgesia in patients receiving continuous intraythecal morphine for chronic pain: a randomized, double-blind, prospective pilot study. J Opioid Manag. 2007.

  26. Chopra P, Cooper MS. Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN). J NeuroImmune Pharmacol. 2013;8(3):470–6. https://doi.org/10.1007/s11481-013-9451-y.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Weinstock LB, Myers TL, Walters AS, Schwartz OA, Younger JW, Chopra PJ, et al. Identification and treatment of new inflammatory triggers for complex regional pain syndrome: small intestinal bacterial overgrowth and obstructive sleep apnea. A A case reports. 2016;6:272–6. https://doi.org/10.1213/XAA.0000000000000292.

    Article  PubMed  Google Scholar 

  28. Parkitny L, Younger J. Reduced pro-inflammatory cytokines after eight weeks of low-dose naltrexone for fibromyalgia. Biomedicines. 2017;5. https://doi.org/10.3390/biomedicines5020016.

  29. Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, et al. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008;14:1076–83. https://doi.org/10.1177/1352458508095828.

    Article  CAS  PubMed  Google Scholar 

  30. Ludwig MD, Turel AP, Zagon IS, McLaughlin PJ. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Mult Scler J – Exp Transl Clin. 2016;2:205521731667224. https://doi.org/10.1177/2055217316672242.

    Article  Google Scholar 

  31. •• Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, Majdinasab N, Shalbafan B. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010. https://doi.org/10.1177/1352458510366857Recent randomized study on low dose naltrexone with multiple sclerosis and implication on quality of life. Should be compared to other randomized study with multiple sclerosis.

  32. Cree BAC, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010. https://doi.org/10.1002/ana.22006.

  33. Kariv R. Low-dose naltrexone for the treatment of irritable bowel syndrome. Am J Gastroenterol. 2003;98:S268. https://doi.org/10.1016/s0002-9270(03)01577-6.

    Article  Google Scholar 

  34. Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol. 2007;102:820–8. https://doi.org/10.1111/j.1572-0241.2007.01045.x.

    Article  CAS  PubMed  Google Scholar 

  35. Parker CE, Nguyen TM, Segal D, Macdonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2018. https://doi.org/10.1002/14651858.CD010410.pub3.

  36. Smith JP, Field D, Bingaman SI, Evans R, Mauger DT. Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn’s disease: a pilot study. J Clin Gastroenterol. 2013;47:339–45. https://doi.org/10.1097/MCG.0b013e3182702f2b.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Webster LR, Butera PG, Moran LV, Wu N, Burns LH, Friedmann N. Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain. J Pain. 2006;7(12):937–46. https://doi.org/10.1016/j.jpain.2006.05.005.

    Article  CAS  PubMed  Google Scholar 

  38. Chindalore VL, Craven RA, Yu KP, Butera PG, Burns LH, Friedmann N. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of oxytrex. J Pain. 2005;6(6):392–9. https://doi.org/10.1016/j.jpain.2005.01.356.

    Article  CAS  PubMed  Google Scholar 

  39. (CSAT) C for SA. Chapter 4- Oral Naltexone. In: Alcohol Pharmacother. Intro Med. Pract. (Treatment Improv. Protoc. Ser. No.49). Rockville, MD: Substance Abuse and Mental Health Services administration 2009:30.

  40. Torkildsen Ø, Myhr K-M, Wergeland S. Treatment-resistant immune thrombocytopenic purpura associated with LDN use in a patient with MS. Neurol - Neuroimmunol Neuroinflammation. 2014;1:e25. https://doi.org/10.1212/nxi.0000000000000025.

    Article  Google Scholar 

  41. Darrow J, Avorn J, Kesselheim S. FDA approval and regulation of pharmaceuticals, 1983-2018. Jama. 2020;323(2):164–76. https://doi.org/10.1001/jama.2019.20288.

    Article  PubMed  Google Scholar 

  42. Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Dig Dis Sci. 2011;56(7):2088–97. https://doi.org/10.1007/s10620-011-1653-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Kim, P.S., Fishman, M.A. Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review. Curr Pain Headache Rep 24, 64 (2020). https://doi.org/10.1007/s11916-020-00898-0

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