By Nat Jones, RPh, FAPC, PCCA Clinical Compounding Pharmacist

If there were such an award, naltrexone would certainly be nominated as the drug of the last decade. It has been over fifty years since its discovery in 1963, and we are still uncovering uses for this versatile substance at various dosages. As our knowledge of its pharmacology and corresponding mechanistic physiology improves over time, we continue to uncover more data as to how it works on a plethora of disease states. As has been discussed in medical literature for decades, naltrexone is an oral opioid receptor antagonist primarily used to help maintain an opiate-free state in patients with opiate addiction.¹ However, in the past 30 years, it has become a novel treatment for over 100 different diseases in doses far lower than the standard 50 mg manufactured tablets, which is why we often talk about low-dose naltrexone (LDN). While there are no large, randomized clinical trials for each disease state for which LDN has been tried, there are a number of smaller studies, and the evidence is starting to mount.

What Is LDN Therapy?

LDN therapy, defined by some as dosages between 0.5 mg and 5 mg daily, was developed in 1985 by a physician from New York: Bernard Bihari, MD, a doctor of internal medicine, psychiatry and neurology. Dr. Bihari changed his research interest from addiction to AIDs in the early 1980s when the AIDS epidemic began. He discovered that AIDS patients had 20% of the normal endorphin levels of healthy patients. His key discovery was that 1% of the normal 50 mg dose of naltrexone caused an unusual effect of a 300% increase in endorphin levels.² It is estimated that by his time of death in 2010, there were over 30,000 patients on LDN worldwide. Dr. Bihari’s standard dosing protocol titrates patients with weekly increases starting at 1.5 mg orally at bedtime, next up to 3 mg and then to a maintenance dose of 4.5 mg, pending assessment of patient tolerance and clinical progress.

In addition to this increase in endorphin levels following the short blockade of opioid receptors, LDN exhibits anti-inflammatory effects by inhibiting nonopioid receptors. Naltrexone blocks toll-like receptor 4 (TLR4), which is found on keratinocytes and also on macrophages such as microglia.³ These macrophages also contain inflammatory compounds such as tumor necrosis factor α and interleukin 6. Low-dose naltrexone can suppress levels of these inflammatory markers. It is important to note that these anti-inflammatory effects have not been observed at the standard higher doses of naltrexone.⁴

LDN and Dermatology

Doctors have more widely prescribed LDN in recent years, and patients have begun reporting improvements in their health to others with similar conditions, including autoimmune inflammatory dermatologic conditions. The list of those maladies includes Hailey-Hailey disease, lichen planopilaris, psoriasis and various types of pruritus.^5,6,7 Journals have published multiple case studies (see table below). Two case reports in particular describe significant improvement of patients with Hailey-Hailey disease after LDN had been used as a single-agent treatment. The disease was intractable in all four patients within these reports. In the first case, the patient drastically improved in clinical status, and the severity of the disease fell on the dermatology quality-of-life index scale from 29 to 4 in just seven months.⁸ The second case report describes three patients who experienced at least an 80% reduction in the extent of their disease within three months of starting LDN as their only treatment. Also, the frequency of recurrence was reduced, and no drug-induced side effects were reported.⁹ A common thread in all of these case reports was that the patients requested LDN as a treatment, indicating that this therapy is largely patient-driven. More LDN research in the future would be useful to improve the level of evidence and provide a more robust understanding of the broader effects on larger numbers of patients.

Dermatologists are seeing increasing rates of autoimmune disease manifesting in primary skin conditions that are often difficult to manage without a risk of immunosuppressive therapies. LDN influences a variety of systemic pathways, including the immune system, and this phenomenon has piqued the interest of researchers and practitioners regarding its potential in the treatment of several autoimmune conditions without suppressing the immune system’s functionality. Specifically, researchers have noted that LDN has the potential for the treatment of chronic inflammatory skin conditions.⁴

In addition to oral LDN therapy for dermatologic conditions, topical naltrexone has also shown promise. In one case study, a 1% naltrexone cream was compared to a vehicle alone for the treatment of pruritus, commonly known as itchy skin. Patients using this topical cream reported a 30% decrease in scores on the visual analog scale for acute and chronic pain, and it took effect 30 minutes faster than the vehicle. Patients with chronic episodes of pruritus responded better than those with acute episodes.¹⁰

Naltrexone has potential utility in various topical formulas for a number of situations where there is a need for anti-inflammatory and immune enhancement functions. In addition to permeation-enhanced topical pain formulas, topical naltrexone combinations for dermatological applications are often prescribed with one or more other active ingredients, such as antihistamines, mast cell stabilizers, corticosteroids, calcineurin inhibitors and/or sodium channel blockers for myriad conditions. These formulations create great opportunities for pharmacy compounding to fit the individualized needs of your dermatology patients.

PCCA members with Clinical Services support can find a list of commonly requested LDN formulas related to dermatology in our formula database. If they have any questions about compounding LDN for dermatology, please contact our Clinical Services department at 800.331.2498.

Nat Jones, RPh, FAPC, graduated from the Virginia Commonwealth University, Medical College of Virginia’s School of Pharmacy in 1979. In 2014, after 20 years of owning a compounding pharmacy, he joined PCCA’s staff. Nat has given continuing education lectures at medical professional seminars and webinars on numerous topics, including general compounding, wound care, pain management, nutrition, otolaryngology, women’s health, sexual dysfunction, insulin resistance, hormone replacement therapy, neurotransmitter imbalance and dermatology. He has published many articles and case studies in magazines and professional journals along with an open-access ebook titled Advances in Psoriasis with Avid Science. Since 2016, Nat has served on the Texas State Palliative Care Interdisciplinary Advisory Council.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

1. Toljan, K., & Vrooman, B. (2018). Low-dose naltrexone (LDN) — Review of therapeutic utilization. Medical Sciences, 6(4). https://doi.org/10.3390/medsci6040082

2. Schopick, J., (2013). Bernard Bihari, MD: Low-dose naltrexone for normalizing immune system function. Alternative Therapies in Health and Medicine, 19(2), 56–65. Retrieved September 14, 2020, from https://todayspractitioner.com/wp-content/uploads/2013/10/Bernard-Bihari-MD-Low-dose-Naltrexone-for-Normalizing-Immune-System-Function-athm_19_2_bihari_56_65.pdf

3. Lee, B., & Elston, D. M. (2019). The uses of naltrexone in dermatologic conditions. Journal of the American Academy of Dermatology, 80 (6), 1746–1752. https://doi.org/10.1016/j.jaad.2018.12.031

4. Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33(4), 451–459. https://doi.org/10.1007/s10067-014-2517-2

5. Ekelem, C., Juhasz, M., Khera, P., & Mesinkovska, N. A. (2019). Utility of naltrexone treatment for chronic inflammatory dermatologic conditions: A systematic review. JAMA Dermatology, 155 (2), 229–236. https://doi.org/10.1001/jamadermatol.2018.4093

6. Bridgman, A. C., & Kirchhof, M. G. (2018). Treatment of psoriasis vulgaris using low-dose naltrexone. JAAD Case Reports, 4 (8), 827–829. https://dx.doi.org/10.1016%2Fj.jdcr.2018.06.001

7. Strazzulla, L. C., Avila, L., Lo Sicco, K., & Shapiro, J. (2017). Novel treatment using low-dose naltrexone for lichen planopilaris. Journal of Drugs in Dermatology, 16(11), 1140–1142. Retrieved September 14, 2020, from https://jddonline.com/articles/dermatology/S1545961617P1140X

8. Campbell, V., McGrath, C., & Corry, A. (2018). Low-dose naltrexone: A novel treatment for Hailey-Hailey disease. British Journal of Dermatology, 178(5), 1196–1198. https://doi.org/10.1111/bjd.16045

9. Ibrahim O., Hogan, S. R., Vij, A., & Fernandez, A. P. (2017). Low-dose naltrexone treatment of familial benign pemphigus (Hailey-Hailey disease). JAMA Dermatology, 153(10), 1015–1017. https://doi.org/10.1001/jamadermatol.2017.2445

10. Bigliardi P. L., Stammer, H., Jost, G., Rufli, T., Büchner, S., & Bigliardi-Qi, M. (2007). Treatment of pruritus with topically applied opiate receptor antagonist. Journal of the American Academy of Dermatology, 56(6), 979–988. https://doi.org/10.1016/j.jaad.2007.01.007

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.