The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain

Jarred Younger, Luke Parkitny, David McLain, Jarred Younger, Luke Parkitny, David McLain

Abstract

Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

Figures

Fig. 1
Fig. 1
Fibromyalgia participants’ (N = 29) self-reported improvement in symptoms after daily LDN treatment. The figure uses data from an earlier clinical trial [9] and has not been previously published
Fig. 2
Fig. 2
Relationship between baseline erythrocyte sedimentation rate (ESR) and change in pain during administration of LDN (left pane) and placebo (right pane). The figure uses data from earlier clinical trials [9, 15] and has not been previously published

References

    1. Greeley JD, Lê AD, Poulos CX, Cappell H. "Paradoxical" analgesia induced by naloxone and naltrexone. Psychopharmacology (Berlin) 1988;96(1):36–39. doi: 10.1007/BF02431530.
    1. Burns LH, Wang HY (2010) Ultra-low-dose naloxone or naltrexone to improve opioid analgesia: the history, the mystery and a novel approach clinical medicine insights
    1. Davis M, Goforth HW, Gamier P. Oxycodone combined with opioid receptor antagonists: efficacy and safety. Expert Opin Drug Saf. 2013;12(3):389–402. doi: 10.1517/14740338.2013.783564.
    1. Resnick RB, Volavka J, Freedman AM, Thomas M. Studies of EN-1639A (naltrexone): a new narcotic antagonist. Am J Psychiatry. 1974;131(6):646–650.
    1. Verebey K, Mulé SJ. Naltrexone pharmacology, pharmacokinetics, and metabolism: current status. Am J Drug Alcohol Abuse. 1975;2(3–4):357–363. doi: 10.3109/00952997509005661.
    1. Gold MS, Dackis CA, Pottash AL, Sternbach HH, Annitto WJ, Martin D, Dackis MP. Naltrexone, opiate addiction, and endorphins. Med Res Rev. 1982;2(3):211–246. doi: 10.1002/med.2610020302.
    1. Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, Zagon IS. 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):2088–2097. doi: 10.1007/s10620-011-1653-7.
    1. Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010;68(2):145–150.
    1. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65(2):529–538. doi: 10.1002/art.37734.
    1. Bihari B. Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function. Altern Ther Health Med. 2013;19(2):56–65.
    1. Zagon IS, McLaughlin PJ. Opioid antagonist modulation of murine neuroblastoma: a profile of cell proliferation and opioid peptides and receptors. Brain Res. 1989;480(1–2):16–28. doi: 10.1016/0006-8993(89)91562-X.
    1. 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(4):820–828. doi: 10.1111/j.1572-0241.2007.01045.x.
    1. Clauw DJ, Arnold LM, McCarberg BH, FibroCollaborative The science of fibromyalgia. Mayo Clin Proc. 2011;86(9):907–911. doi: 10.4065/mcp.2011.0206.
    1. Wallace DJ. Is there a role for cytokine based therapies in fibromyalgia. Curr Pharm Des. 2006;12(1):17–22. doi: 10.2174/138161206775193208.
    1. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663–672. doi: 10.1111/j.1526-4637.2009.00613.x.
    1. Wang D, Sun X, Sadee W. Different effects of opioid antagonists on mu-, delta-, and kappa-opioid receptors with and without agonist pretreatment. J Pharmacol Exp Ther. 2007;321(2):544–552. doi: 10.1124/jpet.106.118810.
    1. Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF. Norman cousins lecture. Glia as the "bad guys": implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun. 2007;21(2):131–146. doi: 10.1016/j.bbi.2006.10.011.
    1. McCusker RH, Kelley KW. Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol. 2013;216(Pt 1):84–98. doi: 10.1242/jeb.073411.
    1. Dantzer R (2007) Twenty years of research on cytokine-induced sickness behavior Brain, behavior, and immunity
    1. Kelley KW, Bluthé RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, Broussard SR. Cytokine-induced sickness behavior. Brain Behav Immun. 2003;17(Suppl 1):S112–S118. doi: 10.1016/S0889-1591(02)00077-6.
    1. Wieseler-Frank J, Maier SF, Watkins LR. Immune-to-brain communication dynamically modulates pain: physiological and pathological consequences. Brain Behav Immun. 2005;19(2):104–111. doi: 10.1016/j.bbi.2004.08.004.
    1. Hutchinson MR, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4) Eur J Neurosci. 2008;28(1):20–29. doi: 10.1111/j.1460-9568.2008.06321.x.
    1. Liu B, Du L, Hong JS. Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther. 2000;293(2):607–617.
    1. Chang RC, Rota C, Glover RE, Mason RP, Hong JS. A novel effect of an opioid receptor antagonist, naloxone, on the production of reactive oxygen species by microglia: a study by electron paramagnetic resonance spectroscopy. Brain Res. 2000;854(1–2):224–229. doi: 10.1016/S0006-8993(99)02267-2.
    1. Liu SL, Li YH, Shi GY, Chen YH, Huang CW, Hong JS, Wu HL. A novel inhibitory effect of naloxone on macrophage activation and atherosclerosis formation in mice. J Am Coll Cardiol. 2006;48(9):1871–1879. doi: 10.1016/j.jacc.2006.07.036.
    1. Valentino RJ, Katz JL, Medzihradsky F, Woods JH. Receptor binding, antagonist, and withdrawal precipitating properties of opiate antagonists. Life Sci. 1983;32(25):2887–2896. doi: 10.1016/0024-3205(83)90325-9.
    1. Lewis SS, Loram LC, Hutchinson MR, Li CM, Zhang Y, Maier SF, Huang Y, Rice KC, Watkins LR. (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain. 2012;13(5):498–506. doi: 10.1016/j.jpain.2012.02.005.
    1. Stevens CW, Aravind S, Das S, Davis RL. Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4. Br J Pharmacol. 2013;168(6):1421–1429. doi: 10.1111/bph.12028.
    1. Fukagawa H, Koyama T, Kakuyama M, Fukuda K. Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4. J Anesth. 2013;27(1):93–97. doi: 10.1007/s00540-012-1469-4.
    1. Block L, Björklund U, Westerlund A, Jörneberg P, Biber B, Hansson E. A new concept affecting restoration of inflammation-reactive astrocytes. Neuroscience. 2013;250:536–545. doi: 10.1016/j.neuroscience.2013.07.033.
    1. Wang Q, Zhou H, Gao H, Chen SH, Chu CH, Wilson B, Hong JS. Naloxone inhibits immune cell function by suppressing superoxide production through a direct interaction with gp91phox subunit of NADPH oxidase. J Neuroinflammation. 2012;9:32. doi: 10.1186/1742-2094-9-32.
    1. Zagon IS, Verderame MF, McLaughlin PJ. The biology of the opioid growth factor receptor (OGFr) Brain Res Brain Res Rev. 2002;38(3):351–376. doi: 10.1016/S0165-0173(01)00160-6.
    1. Sharma R, Rauchhaus M, Ponikowski PP, Varney S, Poole-Wilson PA, Mann DL, Coats AJ, Anker SD. The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2000;36(2):523–528. doi: 10.1016/S0735-1097(00)00745-2.
    1. García JJ, Cidoncha A, Bote ME, Hinchado MD, Ortega E. Altered profile of chemokines in fibromyalgia patients. Ann Clin Biochem. 2013;6(7):425–435.
    1. Xiao Y, Haynes WL, Michalek JE, Russell IJ. Elevated serum high-sensitivity C-reactive protein levels in fibromyalgia syndrome patients correlate with body mass index, interleukin-6, interleukin-8, erythrocyte sedimentation rate. Rheumatol Int. 2013;33(5):1259–1264. doi: 10.1007/s00296-012-2538-6.
    1. 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(4):339–345. doi: 10.1097/MCG.0b013e3182702f2b.
    1. 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;16(8):964–969. doi: 10.1177/1352458510366857.
    1. Chopra P, Cooper MS. Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN) J Neuroimmune Pharm. 2013;8(3):470–476. doi: 10.1007/s11481-013-9451-y.
    1. Parkitny L, McAuley JH, Di Pietro F, Stanton TR, O’Connell NE, Marinus J, van Hilten JJ, Moseley GL. Inflammation in complex regional pain syndrome: a systematic review and meta-analysis. Neurology. 2013;80(1):106–117. doi: 10.1212/WNL.0b013e31827b1aa1.
    1. Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2009;72(3):333–337. doi: 10.1016/j.mehy.2008.06.048.
    1. Tempel A, Gardner EL, Zukin RS. Neurochemical and functional correlates of naltrexone-induced opiate receptor up-regulation. J Pharmacol Exp Ther. 1985;232(2):439–444.
    1. Zagon IS, McLaughlin PJ. Gene-peptide relationships in the developing rat brain: the response of preproenkephalin mRNA and [Met5]-enkephalin to acute opioid antagonist (naltrexone) exposure. Brain Res Mol Brain Res. 1995;33(1):111–120. doi: 10.1016/0169-328X(95)00119-D.
    1. Donahue RN, McLaughlin PJ, Zagon IS. 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 (Maywood) 2011;236(9):1036–1050. doi: 10.1258/ebm.2011.011121.
    1. Kayser V, Besson JM, Guilbaud G. Paradoxical hyperalgesic effect of exceedingly low doses of systemic morphine in an animal model of persistent pain (Freund’s adjuvant-induced arthritic rats) Brain Res. 1987;414(1):155–157. doi: 10.1016/0006-8993(87)91338-2.
    1. Galeotti N, Stefano GB, Guarna M, Bianchi E, Ghelardini C. Signaling pathway of morphine induced acute thermal hyperalgesia in mice. Pain. 2006;123(3):294–305. doi: 10.1016/j.pain.2006.03.008.
    1. Physicians’ Desk Reference 2013 (67th ed) Montvale, NJ: PDR
    1. Pini LA, Ferretti C, Trenti T, Ferrari A, Sternieri E. Effects of long-term treatment with naltrexone on hepatic enzyme activity. Drug Metabol Drug Interact. 1991;9(2):161–174. doi: 10.1515/DMDI.1991.9.2.161.
    1. Zagon IS, Donahue R, McLaughlin PJ. Targeting the opioid growth factor: opioid growth factor receptor axis for treatment of human ovarian cancer. Exp Biol Med (Maywood) 2013;238(5):579–587. doi: 10.1177/1535370213488483.
    1. Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain. 2012;135(Pt 4):1224–1236. doi: 10.1093/brain/aws072.
    1. Zhou Q, Price DD, Callam CS, Woodruff MA, Verne GN. Effects of the N-methyl-D-aspartate receptor on temporal summation of second pain (wind-up) in irritable bowel syndrome. J Pain. 2011;12(2):297–303. doi: 10.1016/j.jpain.2010.09.002.
    1. Swift RM. Naltrexone and nalmefene: any meaningful difference? Biol Psychiatry. 2013;73(8):700–701. doi: 10.1016/j.biopsych.2013.03.002.
    1. Tang C, Godfrey T, Stawell R, Nikpour M. Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects. Int Med J. 2012;42(9):968–978.
    1. Steere AC, Angelis SM. Therapy for Lyme arthritis: strategies for the treatment of antibiotic-refractory arthritis. Arthritis Rheum. 2006;54(10):3079–3086. doi: 10.1002/art.22131.
    1. Choi DK, Koppula S, Suk K. Inhibitors of microglial neurotoxicity: focus on natural products. Molecules. 2011;16(2):1021–1043. doi: 10.3390/molecules16021021.
    1. Moore A, Wilkinson S. The promise of low dose naltrexone. North Carolina: McFarland; 2009.

Source: PubMed

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