Low Dose Naltrexone is a short acting, reversible opioid receptor blocker which has been found to possess immunomodulating effects when used at doses ranging from 0.5-4.5mg. Its benefit has been touted across a myriad of autoimmune and inflammatory diseases including multiple sclerosis, fibromyalgia, and psoriasis, and has also demonstrated clinical benefits in patients suffering from mood disorders, autism, HIV, and various cancers.
This drug monograph describes the use and clinical utility of LDN for PSORIASIS.
Naltrexone is also commonly compounded as a capsule in strengths ranging from 0.5-4.5mg with microcrystalline cellulose as the only filler.
For those unable to take medications in capsule form, naltrexone may be compounded as a suspension, suppository, or transdermal cream.
As an alternative to oral dosing, Harbor Compounding Pharmacy commonly compounds LDN as a Naltrexone/Ketotifen 1/0.05% Topical Cream.
Psoriasis is a chronic T-cell mediated disorder. Psoriatic patients express large amounts of CD4+ Th1, CD8+ cytotoxic T type 1 cells as well as elevated levels of the cytokines IFN-γ, tumor-necrosis factor (TNF)-α and IL-12 and has been distinguished to be a Th1 cell mediated disease.5,6,7
One of the other major triggering processes for psoriasis is the release of IL-23 from antigen-presenting dendritic cells. IL-23 promotes Treg cells to differentiate into T17 cells. T17 cells promote the inflammatory cytokine cascade which includes IL-17A, IL-17F, IL-22, IL-21 and TNF-α, which are found at increased levels in psoriatic skin and circulation.8,9.10,11
The activated T cells and resulting cytokines result in keratinocyte hyper-proliferation and abnormal differentiation. These cytokines result in chemotaxis of neutrophils and lymphocytes in skin.
1 in 5 sufferers don’t respond well to traditional therapies. Research shows that when one cytokine or inflammatory pathway is blocked, the immune system finds a work around that upregulates other inflammatory cytokines and pathways.
When used in doses of 1 to 5 mg, naltrexone acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor-4 found on microglia cells and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response.
More specifically, D-Naltrexone binds Toll Like Receptors (TLR-4) found on macrophages, mast cells, glial cells. Glial cells make up roughly 70-80% of the central nervous system and also contain microglia, where TLR-4 is predominantly expressed. These cells perform immunosurveillance. When activated, they release cytokines and enhance excitability of neighboring cells and contribute to neuroinflammation, which is the pathogenesis. By blocking TLR-4 on microglia, LDN also blocks the release of proinflammatory cytokines IL 6, IL-12, TNF alpha, NFK-B.
Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use and produces an opioid rebound effect. Naltrexone’s chemical structure is almost identical to the endogenous endorphins, Met- Enkephalin, also known as Opioid Growth Factor (OGF). L-Naltrexone is an antagonist at the OGF Receptor found on a wide range of places including the CNS, PNS, GI Tract, and lymphocytes. By blocking the OGF receptors, L-Naltrexone interferes with the endorphin feedback loop. Blockade lasts roughly 4 hours, and subsequently results in an increase of endogenous opioids (endorphins and enkephalins) as well as receptor density in subsequent 24h period - which is favorable to the immune system since endorphins regulate cell growth including immune cells, and increases in OGF receptors is associated with tissue repair and healing.
More specifically, naltrexone’s immunomodulatory effect occurs by affecting B cell production and shifting T cell production from TH1 to TH2.
The significance of this shift is obvious since psoriasis has been deemed a Th1 mediated disease.
While there is no specific research on LDN and IL23, it is known to respond to opioids through OGF, which is upregulated with LDN. This may be a potential mechanism through which LDN may decrease the triggering process for psoriasis.
Ketotifen is a mast cell stabilizer and selectively inhibits histamine receptor (H1-receptor). Ketotifen inhibits the release of mediators from mast cells involved in hypersensitivity reactions. Decreased chemotaxis and activation of eosinophils has also been demonstrated. Structurally ketotifen is suitable be applied transdermally. In fact, ketotifen has been shown in animal studies to enhance transdermal patch delivery of other drugs.
Naltrexone, a mu-opioid receptor antagonist, has been observed to help with itching in different dermatologic diseases (eczema, psoriasis and atopic dermatitis). In one small placebo-controlled pruritus study, more than 70% of the patients using the naltrexone 1% cream experienced a significant reduction of pruritus. This study showed a significant advantage of topically applied naltrexone over the placebo formulation and the findings were supported by the biopsy data from the open studies.1
Orally, LDN doses usually between 1mg and 4.5mg nightly, used as an off-label therapeutic prescribed for a variety of immune-related disorders including psoriasis, has shown to cause an intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. 3,4
Patients diagnosed with MS have reduced serum levels of opioid growth factor (OGF) (i.e. [Met5]-28 enkephalin) relative to non-MS neurologic patients, and LDN therapy restored their enkephalin levels. Enkephalins are opioid peptides that can modulate immune responses and inflammatory processes. Furthermore, they inhibit keratinocyte proliferation and differentiation in vitro.
LDN has been studied for its clinical utility in psoriasis.1,2,3,4
Naltrexone is most commonly prescribed at doses ranging from 1-4.5mg to be taken daily at bedtime.
Each patient will react to LDN at their own individual dosage.
Pediatric doses are most commonly prescribed at 0.1mg/kg/day.
Patients should be encouraged to assess the efficacy of LDN for at least 6 months before dismissing it as a clinical utility.
If clinical efficacy has not been achieved at the typical studied dosage of 4.5mg, some physicians have found benefits for their patients from doses up to 6-12mg.
If clinical efficacy has been achieved, and patients subsequently complain of a resurgence in symptoms, consider implementing drug holidays, or a complete stoppage of therapy for 2 weeks followed by a re-initiation and reassessment of an efficacious dosage.
Some patients may benefit from dosing LDN in the morning for several weeks if they experience insomnia and vivid dreams.
Many physicians report no safety concerns when dosed with short acting opioids (i.e morphine). In this population, patients should separate short acting opioid consumption to 4-6 hours before an LDN dose, or 3-4 hours after an LDN dose.
Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations and opioid analgesics, and should be separated from short acting opioid-containing medications by 4-6 hours before LDN, or 3-4 hours after LDN dosage
LDN may precipitate withdrawal symptoms with concurrent use of longer acting opioids is contraindicated.
Because naltrexone is not a substrate for CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes are unlikely to change the clearance of naltrexone.
No clinical drug interaction studies have been performed with naltrexone to evaluate drug interactions; therefore, prescribers should weigh the risks and benefits of concomitant drug use.
Naltrexone may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine.
The most commonly reported adverse effects of naltrexone taken orally include insomnia, vivid dreams, diarrhea, and headaches.
To prevent occurrence of an acute abstinence syndrome (withdrawal) in patients dependent on opioids, or exacerbation of a pre-existing subclinical abstinence syndrome, opioid-dependent patients, including those being treated for alcohol dependence, patients should be opioid-free from longer acting opioids for a minimum of 7–10 days before starting naltrexone treatment. Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge test may be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of naltrexone. Patients treated for alcohol dependence with naltrexone should be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with naltrexone. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or dependence on opioids.
To lessen the chances of acute abstinence syndrome (withdrawal) in patients taking immediate acting opioids, doses of opioids should be separated from short acting opioid-containing medications by 4-6 hours before LDN, or 3-4 hours after LDN dosage.
Patients taking LDN should be encouraged to stop their medication by at least 24hours before a scheduled or elective surgery.
Naltrexone is listed as pregnancy category C.
Safety and effectiveness have not been established in this population.
Naltrexone is almost completely absorbed (96%), but its oral bioavailability ranges between 5% and 40% due to first-pass metabolism.
In vitro data demonstrate that naltrexone plasma protein binding is low (21%).
Naltrexone’s half-life is 4 h and it is extensively metabolized (>98%) in humans—the major metabolite being 6-β-naltrexol with a half-life of 13 h and antagonist action on opioid receptors.
The cytochrome P450 system is not involved in naltrexone metabolism. Two other minor metabolites are 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. Naltrexone and its metabolites are also conjugated to form glucuronide products.
Significantly less 6β-naltrexol is generated following subcutaneous administration of naltrexone compared to administration of oral naltrexone due to a reduction in first-pass hepatic metabolism.
Glomerular filtration is the predominant mode of renal elimination for a small fraction of unmetabolized naltrexone, while 6-β-naltrexol is additionally secreted.
Naltrexone is contraindicated in:
- Patients receiving long acting opioid analgesics
- Concurrent use with short acting opioid medications
- Patients with current physiologic opioid dependence
- Patients in acute opiate withdrawal
- Any individual suspected of opioid abuse, and who has failed the naloxone challenge test or has a positive urine screen for opioids.
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Bigliardi PL, Stammer H, Jost G, Rufli T, Büchner S, Bigliardi-Qi M. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol. 2007;56(6):979-988.
- Ip K, Song G, Banov D, Bassani AS, Valdez BC. In vitro evaluation of Naltrexone HCl 1% Topical Cream in XemaTop™ for psoriasis. Arch Dermatol Res. 2020;312(2):145‐154.
- Bridgman AC, Kirchhof MG. Treatment of psoriasis vulgaris using low-dose naltrexone. JAAD Case Rep. 2018;4(8):827‐829. Published 2018 Sep 18.
- Beltran Monasterio EP. Low-dose Naltrexone: An Alternative Treatment for Erythrodermic Psoriasis. Cureus. 2019;11(1):e3943. Published 2019 Jan 23.
- Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol. 1994;102:145–149.
- Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol. 1999;113:752–759.
- Friedrich M, Krammig S, Henze M, Docke WD, Sterry W, Asadullah K. Flow cytometric characterization of lesional T cells in psoriasis: intracellular cytokine and surface antigen expression indicates an activated, memory/effector type 1 immunophenotype. Arch Dermatol Res. 2000;292:519–521.
- Boniface K, Guignouard E, Pedretti N, Garcia M, Delwail A, Bernard FX, et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol. 2007;150:407–415
- Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128:1207–1211
- 10. Caruso R, Botti E, Sarra M, Esposito M, Stolfi C, Diluvio L, et al. Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis. Nat Med. 2009;15:1013–1015.
- Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130:1373–1383.
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