The Use of Naltrexone in Dermatology. Current Evidence and Future Directions

Author(s): Mariusz Sikora*, Adriana Rakowska, Małgorzata Olszewska, Lidia Rudnicka.

Journal Name: Current Drug Targets

Volume 20 , Issue 10 , 2019

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Graphical Abstract:


Abstract:

Naltrexone is a competitive opioid receptor antagonist approved as supportive treatment in alcohol dependence and opioid addiction. At a dose of 50-100 mg daily, naltrexone is used off-label in dermatology for the treatment of trichotillomania and different types of pruritus. At a dose as low as 1- 5 mg per day, naltrexone demonstrates immunomodulatory action i.e. modulates Toll-like receptors signaling, decreases release of proinflammatory cytokines (tumor necrosis factor, interleukin-6, interleukin- 12), inhibits T lymphocyte proliferation, down-regulates the expression of chemokine receptors and adhesion molecules. The efficacy of standard and low doses of naltrexone in a variety of dermatological disorders has been reported. These include diseases such as familial benign chronic pemphigus (Hailey-Hailey disease), dermatomyositis, systemic sclerosis, psoriasis and lichen planopilaris. Optimistic preliminary findings, low cost of therapy and good tolerance make naltrexone a promising alternative therapy or adjunct drug in dermatology.

Keywords: Alopecia, low dose naltrexone, opioid growth factor, pruritus, psoriasis, toll-like receptor.

[1]
Sudakin D. Naltrexone: Not just for opioids anymore. J Med Toxicol 2016; 12: 71-5.
[2]
Bisaga A, Mannelli P, Sullivan MA, et al. Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies. Am J Addict 2018; 27: 177-87.
[3]
Goh ET, Morgan MY. Review article: Pharmacotherapy for alcohol dependence - the why, the what and the wherefore. Aliment Pharmacol Ther 2017; 45: 865-82.
[4]
Grandone A, Di Sessa A, Umano GR, Toraldo R, Miraglia Del Giudice E. New treatment modalities for obesity. Best Pract Res Clin Endocrinol Metab 2018; 32: 535-49.
[5]
Lee NK, Jenner L, Harney A, Cameron J. Pharmacotherapy for amphetamine dependence: A systematic review. Drug Alcohol Depend 2018; 191: 309-37.
[6]
Schmitz JM, Lindsay JA, Green CE, Herin DV, Stotts AL, Moeller FG. High-dose naltrexone therapy for cocaine-alcohol dependence. Am J Addict 2009; 18: 356-62.
[7]
Mouaffak F, Leite C, Hamzaoui S, et al. Naltrexone in the treatment of broadly defined behavioral addictions: A review and meta-analysis of randomized controlled trials. Eur Addict Res 2017; 23: 204-10.
[8]
Guerdjikova AI, Walsh B, Shan K, et al. Concurrent improvement in both binge eating and depressive symptoms with Naltrexone/ Bupropion therapy in overweight or obese subjects with major depressive disorder in an open-label, uncontrolled study. Adv Ther 2017; 34: 2307-15.
[9]
Roy A, Roy M, Deb S, Unwin G, Roy A. Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. J Intellect Disabil Res 2015; 59: 293-06.
[10]
Brune A, Metze D, Luger TA, Stander S. Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133 patients. Hautarzt 2004; 55: 1130-6.
[11]
Aboujaoude E, Salame WO. Naltrexone: A pan-addiction treatment? CNS Drugs 2016; 30: 719-33.
[12]
Li Z, You Y, Griffin N, Feng J, Shan F. Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy. Int Immunopharmacol 2018; 61: 178-84.
[13]
Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)-review of therapeutic utilization. Med Sci (Basel) 2018; 6E82
[14]
Patten DK, Schultz BG, Berlau DJ. The safety and Efficacy of Low-dose Naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn’s Disease, and other chronic pain disorders. Pharmacotherapy 2018; 38: 382-9.
[15]
Turel AP, Oh KH, Zagon IS, McLaughlin PJ. Low dose Naltrexone for treatment of multiple sclerosis: A retrospective chart review of safety and tolerability. J Clin Psychopharmacol 2015; 35: 609-11.
[16]
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; 4CD010410
[17]
Metyas S, Chen CL, Yeter K, Solyman J, Arkfeld DG. Low dose Naltrexone in the treatment of fibromyalgia. Curr Rheumatol Rev 2018; 14: 177-80.
[18]
Raknes G, Smabrekke L. A sudden and unprecedented increase in low dose naltrexone (LDN) prescribing in Norway. Patient and prescriber characteristics, and dispense patterns. A drug utilization cohort study. Pharmacoepidemiol Drug Saf 2017; 26: 136-42.
[19]
Atanaskova Mesinkovska N. Emerging unconventional therapies for Alopecia Areata. J Investig Dermatol Symp Proc 2018; 19: S32-3.
[20]
Plein LM, Rittner HL. Opioids and the immune system - friend or foe. Br J Pharmacol 2018; 175: 2717-25.
[21]
Bigliardi PL, Dancik Y, Neumann C, Bigliardi-Qi M. Opioids and skin homeostasis, regeneration and ageing - What’s the evidence? Exp Dermatol 2016; 25: 586-91.
[22]
Ludwig MD, Zagon IS, McLaughlin PJ. Featured article: Serum [Met(5)]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone. Exp Biol Med (Maywood) 2017; 242: 1524-33.
[23]
Ramanathan S, Panksepp J, Johnson B. Is fibromyalgia an endocrine/endorphin deficit disorder? Is low dose naltrexone a new treatment option? Psychosomatics 2012; 53: 591-4.
[24]
Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses 2009; 72: 333-7.
[25]
Kumar K, Singh SI. Neuraxial opioid-induced pruritus: An update. J Anaesthesiol Clin Pharmacol 2013; 29: 303-7.
[26]
Phan NQ, Bernhard JD, Luger TA, Stander S. Antipruritic treatment with systemic mu-opioid receptor antagonists: a review. J Am Acad Dermatol 2010; 63: 680-8.
[27]
Barke KE, Hough LB. Opiates, mast cells and histamine release. Life Sci 1993; 53: 1391-9.
[28]
Trigo JM, Martin-Garcia E, Berrendero F, Robledo P, Maldonado R. The endogenous opioid system: a common substrate in drug addiction. Drug Alcohol Depend 2010; 108: 183-94.
[29]
Le Merrer J, Becker JA, Befort K, Kieffer BL. Reward processing by the opioid system in the brain. Physiol Rev 2009; 89: 1379-412.
[30]
Ikemoto S. Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 2010; 35: 129-50.
[31]
McLaughlin PJ, Cain JD, Titunick MB, Sassani JW, Zagon IS. Topical Naltrexone is a safe and effective alternative to standard treatment of diabetic wounds. Adv Wound Care (New Rochelle) 2017; 6: 279-88.
[32]
Albers LN, Arbiser JL, Feldman RJ. Treatment of hailey-hailey disease with Low-dose Naltrexone. JAMA Dermatol 2017; 153: 1018-20.
[33]
Neumann C, Bigliardi-Qi M, Widmann C, Bigliardi PL. The delta-opioid receptor affects epidermal homeostasis via ERK-dependent inhibition of transcription factor POU2F3. J Invest Dermatol 2015; 135: 471-80.
[34]
Bigliardi PL, Neumann C, Teo YL, Pant A, Bigliardi-Qi M. Activation of the delta-opioid receptor promotes cutaneous wound healing by affecting keratinocyte intercellular adhesion and migration. Br J Pharmacol 2015; 172: 501-14.
[35]
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: 451-9.
[36]
Cant R, Dalgleish AG, Allen RL. Naltrexone inhibits IL-6 and TNFalpha production in human immune cell subsets following stimulation with ligands for intracellular toll-like Receptors. Front Immunol 2017; 8: 809.
[37]
Parkitny L, Younger J. Reduced pro-inflammatory cytokines after eight weeks of Low-Dose Naltrexone for fibromyalgia. Biomedicines 2017; 5E16
[38]
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: 1036-50.
[39]
Cheng F, McLaughlin PJ, Verderame MF, Zagon IS. The OGF-OGFr axis utilizes the p16INK4a and p21WAF1/CIP1 pathways to restrict normal cell proliferation. Mol Biol Cell 2009; 20: 319-27.
[40]
Zagon IS, Donahue RN, Bonneau RH, McLaughlin PJ. B lymphocyte proliferation is suppressed by the opioid growth factor-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases. Immunobiology 2011; 216: 173-83.
[41]
Zagon IS, Donahue RN, Bonneau RH, McLaughlin PJ. T lymphocyte proliferation is suppressed by the opioid growth factor ([Met(5)]-enkephalin)-opioid growth factor receptor axis: implication for the treatment of autoimmune diseases. Immunobiol 2011; 216: 579-90.
[42]
McLaughlin PJ, McHugh DP, Magister MJ, Zagon IS. Endogenous opioid inhibition of proliferation of T and B cell subpopulations in response to immunization for experimental autoimmune encephalomyelitis. BMC Immunol 2015; 16: 24.
[43]
Vijay K. Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol 2018; 59: 391-412.
[44]
Toubi E, Vadasz Z. Innate immune-responses and their role in driving autoimmunity. Autoimmun Rev 2019; 18: 306-11.
[45]
Hutchinson MR, Zhang Y, Brown K, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci 2008; 28: 20-9.
[46]
Deng H, Xiao H. The role of the ATP2C1 gene in Hailey-Hailey disease. Cell Mol Life Sci 2017; 74: 3687-96.
[47]
Farahnik B, Blattner CM, Mortazie MB, et al. Interventional treatments for Hailey-Hailey disease. J Am Acad Dermatol 2017; 76: 551-8.
[48]
Ibrahim O, Hogan SR, Vij A, Fernandez AP. Low-Dose Naltrexone treatment of familial benign pemphigus (Hailey-Hailey Disease). JAMA Dermatol 2017; 153: 1015-7.
[49]
Campbell V, McGrath C, Corry A. Low-dose naltrexone: a novel treatment for Hailey-Hailey disease. Br J Dermatol 2018; 178: 1196-8.
[50]
Kollman N, Bass J. Generalized familial benign chronic pemphigus (Hailey-Hailey disease) treated successfully with low-dose naltrexone. JAAD Case Rep 2018; 4: 725-7.
[51]
Cao S, Lilly E, Chen ST. Variable response to Naltrexone in patients with Hailey-Hailey Disease. JAMA Dermatol 2018; 154: 362-3.
[52]
Tran T, Chen A, Worswick S. Successful treatment of dermatomyositis with low-dose naltrexone. Dermatol Ther 2018.e12720
[53]
Cappelletti C, Galbardi B, Kapetis D, et al. Autophagy, inflammation and innate immunity in inflammatory myopathies. PLoS One 2014; 9e111490
[54]
Kim GT, Cho ML, Park YE, et al. Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis. Clin Rheumatol 2010; 29: 273-9.
[55]
Razykov I, Levis B, Hudson M, Baron M, Thombs BD. Canadian Scleroderma research G. Prevalence and clinical correlates of pruritus in patients with systemic sclerosis: an updated analysis of 959 patients. Rheumatology (Oxford) 2013; 52: 2056-61.
[56]
Therene C, Brenaut E, Sonbol H, et al. Itch and systemic sclerosis: frequency, clinical characteristics and consequences. Br J Dermatol 2017; 176: 1392-3.
[57]
Gourier G, Therene C, Mazeas M, et al. Clinical characteristics of pruritus in systemic sclerosis vary according to the autoimmune subtype. Acta Derm Venereol 2018; 98: 735-41.
[58]
Frech T, Novak K, Revelo MP, et al. Low-dose naltrexone for pruritus in systemic sclerosis. Int J Rheumatol 2011; 2011804296
[59]
Lay J, Carbone SE, DiCello JJ, et al. Distribution and trafficking of the mu-opioid receptor in enteric neurons of the guinea pig. Am J Physiol Gastrointest Liver Physiol 2016; 311: G252-66.
[60]
Immonen JA, Zagon IS, McLaughlin PJ. Selective blockade of the OGF-OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing. Exp Biol Med (Maywood) 2014; 239: 1300-9.
[61]
Bridgman AC, Kirchhof MG. Treatment of psoriasis vulgaris using low-dose naltrexone. JAAD Case Rep 2018; 4: 827-9.
[62]
Muller G, Grieshaber R, Talley JF, Riepl M, Fellows D. Compounded low-dose Naltrexone for the treatment of Guttate Psoriasis: A case report. Int J Pharm Compd 2018; 22: 270-8.
[63]
Sikora M, Chrabaszcz M, Maciejewski C, et al. Intestinal barrier integrity in patients with plaque psoriasis. J Dermatol 2018; 45(12): 1468-70.
[64]
Lie M, van der Giessen J, Fuhler GM, et al. Low dose Naltrexone for induction of remission in inflammatory bowel disease patients. J Transl Med 2018; 16: 55.
[65]
Strazzulla LC, Avila L, Lo Sicco K, Shapiro J. Novel treatment using low-dose Naltrexone for Lichen Planopilaris. J Drugs Dermatol 2017; 16: 1140-2.
[66]
Welz-Kubiak K, Reich A. Mediators of pruritus in lichen planus. Autoimmune Dis 2013; 2013941431
[67]
Carrion VG. Naltrexone for the treatment of trichotillomania: a case report. J Clin Psychopharmacol 1995; 15: 444-5.
[68]
Oravecz R, Stuhec M. Trichotillomania successfully treated with risperidone and naltrexone: a geriatric case report. J Am Med Dir Assoc 2014; 15: 301-2.
[69]
Grant JE, Odlaug BL, Schreiber LR, Kim SW. The opiate antagonist, naltrexone, in the treatment of trichotillomania: results of a double-blind, placebo-controlled study. J Clin Psychopharmacol 2014; 34: 134-8.
[70]
De Sousa A. An open-label pilot study of naltrexone in childhood-onset trichotillomania. J Child Adolesc Psychopharmacol 2008; 18: 30-3.
[71]
Dull MM, Kremer AE. Management of chronic hepatic itch. Dermatol Clin 2018; 36: 293-300.
[72]
Carson KL, Tran TT, Cotton P, Sharara AI, Hunt CM. Pilot study of the use of naltrexone to treat the severe pruritus of cholestatic liver disease. Am J Gastroenterol 1996; 91: 1022-3.
[73]
Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterol 1997; 113: 1264-9.
[74]
Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol 2002; 37: 717-22.
[75]
Mansour-Ghanaei F, Taheri A, Froutan H, et al. Effect of oral naltrexone on pruritus in cholestatic patients. World J Gastroenterol 2006; 12: 1125-8.
[76]
Serrano L, Martinez-Escala ME, Zhou XA, Guitart J. Pruritus in cutaneous T-Cell lymphoma and its management. Dermatol Clin 2018; 36: 245-58.
[77]
Jaiswal D, Uzans D, Hayden J, Kiberd BA, Tennankore KK. Targeting the opioid pathway for uremic pruritus: A systematic review and meta-analysis. Can J Kidney Health Dis 2016; 32054358116675345
[78]
Legroux-Crespel E, Cledes J, Misery L. A comparative study on the effects of naltrexone and loratadine on uremic pruritus. Dermatology 2004; 208: 326-30.
[79]
Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348: 1552-4.
[80]
Pauli-Magnus C, Mikus G, Alscher DM, et al. Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study. J Am Soc Nephrol 2000; 11: 514-9.
[81]
Malekzad F, Arbabi M, Mohtasham N, et al. Efficacy of oral naltrexone on pruritus in atopic eczema: a double-blind, placebo-controlled study. J Eur Acad Dermatol Venereol 2009; 23: 948-50.
[82]
Lee J, Shin JU, Noh S, Park CO, Lee KH. Clinical efficacy and safety of Naltrexone combination therapy in older patients with severepruritus. Ann Dermatol 2016; 28: 159-63.
[83]
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 2019; 17: 10.


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Article Details

VOLUME: 20
ISSUE: 10
Year: 2019
Page: [1058 - 1067]
Pages: 10
DOI: 10.2174/1389450120666190318121122
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