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Ophthalmic Compounding: Low-Dose Naltrexone (LDN) Eye Drops

Naltrexone is a competitive opioid receptor antagonist that provides a safe and relatively inexpensive method to treat various conditions. It is FDA-approved for treating alcohol dependence and preventing relapse to opioid dependence at doses of ≥ 50 mg, but it has also found a variety of off-label uses at much lower doses (generally ≤ 4.5 mg) (1), including autoimmune disease symptoms and dermatological conditions

Amongst the growing number of off-label indications for low-dose naltrexone (LDN) are ophthalmic conditions, such as neuropathic corneal pain and dry eye disease. In fact, LDN has shown success in treating these conditions even where other ophthalmic treatments have failed. Studies have consistently shown that LDN is generally well-tolerated with relatively minor adverse events and high patient adherence rates. Although LDN has still not received FDA approval for ophthalmic conditions due to a lack of large randomized control trials, there have been many smaller clinical studies and trials demonstrating its efficacy in this therapeutic area.

LDN eye drops for treating neuropathic corneal pain

Neuropathic corneal pain may be caused by disease or damage to the somatosensory nervous system, and patients may continue to suffer even after using topical anesthetic drops. 

Investigators at Tufts University School of Medicine used LDN eye drops to treat neuropathic corneal pain, including burning, dryness, or light sensitivity. LDN eye drops at a dose of 4.5 mg for at least four weeks were shown to be effective at reducing pain, even when previous analgesic eye drops failed. (1)

In line with previous studies, the side effects were generally mild and included vivid dreams, headaches, and stomachaches. In one patient in this study, reducing the dose from 4.5 mg to 3.0 mg was sufficient to improve their stomachache. In patients receiving the treatment for more than four weeks, only one discontinued the treatment.

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Diabetic dry eye disease

Dry eye can be either a primary disease or a secondary manifestation of another disease like diabetes (2), with more than half of diabetes patients exhibiting at least one ocular condition, such as dry eye disease, keratopathy, or retinopathy (3). Many of the currently available treatments for dry eye in patients with diabetes are expensive and don’t necessarily treat the underlying cause of dry eye. 

Murine studies

Researchers began investigating the use of LDN eye drops in type 1 diabetic mice and reversed dry eye that persisted for two to three days after treatment (4). More recently, similar results have used 20 μg/ml LDN eye drops to reverse tear film deficits and restore corneal surface sensitivity in diabetic mice, which showed no visible ocular pathology after 30 days of treatment with the LDN eye drops (5). 

Human studies

Building upon the results of these murine studies, researchers have begun administering LDN in humans. A small pilot study showed that LDN eye drops were well-tolerated in human subjects, with no significant adverse events reported during the 30-day trial. Although the primary endpoint of the study was to confirm the tolerability of LDN, the researchers noted statistically significant improvements in several symptomatic measures in LDN-treated subjects compared with those treated only with the vehicle (6). 

In December 2022, the same investigators announced the completion of a phase 2 clinical trial using 0.002% LDN ophthalmic solution for treating dry eye in diabetic patients. 

Mechanism of LDN

The results of almost three decades of research have indicated that the opioid growth factor (OGF) regulates homeostasis during corneal epithelialization and tear secretion. Because OGF is dysregulated in many diabetic patients, treatments have targeted the OGF-OGF receptor axis. LDN eye drops have been shown to block the OGF-OGFr axis and thereby reverse dry eye and restore corneal sensitivity and corneal re-epithelialization.

Potential ophthalmic indications of LDN eye drops based on research and clinical experience

The list of potential off-label uses of LDN is expanding each year and now includes Crohn’s disease, multiple sclerosis, fibromyalgia, Hailey-Hailey disease, and complex regional pain syndrome (7). However, ophthalmic indications have received comparatively less attention, especially studies conducted in human subjects.  

Corneal wound healing 

Similar to is proposed mechanism of action for treating dry eye in diabetic patients, LDN was shown to disrupt the OGF-OGFr axis and accelerated re-epithelialization in rats without showing apparent toxicity (8). 

Scleritis 

Some practitioners have suggested that LDN eye drops may be used to treat scleritis (PDF), but there is currently no peer-reviewed research specifically supporting this indication. Combined with the excellent safety profile of LDN, this may be another promising indication for LDN eye drops.

Why choose VLS Pharmacy & New Drug Loft for LDN and other ophthalmic preparations?

Although FDA-approved for other indications, naltrexone currently has not received FDA approval for ophthalmic indications, so prescribers must obtain it from a compounding pharmacy such as VLS Pharmacy & New Drug Loft. We offer a naltrexone ophthalmic solution in strengths of 0.1%, 0.2%, and 0.3%, allowing the dosage to be tailored to meet a patient’s specific needs. As shown above, fine-tuning the LDN dosage can help minimize any adverse events such as stomachaches (1).

Due to its complexity and the need for a sterile environment, ophthalmic compounding must be performed at pharmacies with appropriate facilities and equipment to ensure sterile preparations. At VLS Pharmacy & New Drug Loft, we are experts in sterile ophthalmic compounding and have the experience and facilities required by USP guidelines to create preparations in this niche area of compounding.

 

Please comment below with any thoughts or questions.

Reach out to our team to learn about best practices and to partner with our experts on custom compounded medications for your patients. All medications from VLS Pharmacy and New Drug Loft are prepared in a lab that follows safety and quality standards per our status as a 503A pharmacy.

 

References

  1. Dieckmann G, Ozmen MC, Cox SM, Engert RC, Hamrah P. Low-dose naltrexone is effective and well-tolerated for modulating symptoms in patients with neuropathic corneal pain. Ocul Surf. 2021;20:33-38. doi:10.1016/j.jtos.2020.12.003
  2. Vickers LA, Gupta PK. The Future of Dry Eye Treatment: A Glance into the Therapeutic Pipeline. Ophthalmol Ther. 2015;4(2):69-78. doi:10.1007/s40123-015-0038-y
  3. McLaughlin PJ, Sassani JW, Zagon IS. Naltrexone as a Novel Therapeutic for Diabetic Corneal Complications. J Cell Immunol. 2020;2(2):42-46. doi:10.33696/immunology.1.018
  4. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Topical Naltrexone Reverses Dry Eye and Restores Corneal Sensation in Diabetes Mellitus. Arch Ophthalmol. 2009;127(11):1468-1473. doi:10.1001/archophthalmol.2009.270
  5. McLaughlin PJ, Sassani JW, Titunick MB, Zagon IS. Efficacy and safety of a novel naltrexone treatment for dry eye in type 1 diabetes. BMC Ophthalmology. 2019;19(1):35. doi:10.1186/s12886-019-1044-y
  6. Liang D, Sassani JW, McLaughlin PJ, Zagon IS. Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: A Tolerability Study. J Ocul Pharmacol Ther. 2016;32(2):127-132. doi:10.1089/jop.2015.0070
  7. Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization. Medical Sciences. 2018;6(4):82. doi:10.3390/medsci6040082
  8. Klocek MS, Sassani JW, McLaughlin PJ, Zagon IS. Naltrexone as a Novel Treatment of Diabetic Keratopathy: Efficacy Studies. Investigative Ophthalmology & Visual Science. 2006;47(13):2761.

 

 


 

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