ORIGINAL ARTICLE
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 00, Number 00, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2015.0070
Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: A Tolerability Study David Liang,1 Joseph W. Sassani,1 Patricia J. McLaughlin,2 and Ian S. Zagon 2
Abstract
Purpose: A short-term, randomized double-masked study was conducted to test the tolerability of topical application of naltrexone to the corneal surface. Methods: Healthy human volunteers were recruited at the Penn State Hershey Medical Center between 2010 and 2013. Study groups of 4 subjects were established to receive escalating dosages of naltrexone; within each group, 1 subject received placebo. Four drops of 4 different dosages of naltrexone dissolved in commercial moxifloxacin solution were administered over a 24-h period of time; 1 group of subjects received only 1 drop. The naltrexone dosages tested were 1 · 10-6 M (1 drop), 1 · 10-6 M (4 drops), 5 · 10-6 M (4 drops), 1 · 10-5 M (4 drops), and 5 · 10-5 M (4 drops). Drops were administered over a 24-h period. Consenting subjects had complete eye examinations, including visual acuity (ETDRS), external and slit-lamp examinations, corneal sensitivity, pachymetry, corneal topography, endothelial specular microscopy, Schirmer testing with anesthetic, and fundus photography, before receiving naltrexone. Individuals were reexamined at 24 h and 7 days following naltrexone or placebo application. Results: Twenty subjects were recruited for the study; 62% were male, 90% were Caucasian; and 19 subjects completed the study. No significant differences were noted in ocular health between left (treated) and right (untreated) eyes of subjects receiving naltrexone or placebo. No significant adverse events were reported. Conclusions: Topical naltrexone was well tolerated in healthy human subjects after 1 or 4 eye drops of naltrexone at dosages up to 50 mM administered over a 24-h treatment period and observed for 1 week.
ulceration, and impaired vision.11–13 While corneal abrasions are most likely trauma induced, the underlying pathophysiology for dry eye is multifactorial. Age and gender play a role, as well as environmental factors such as temperature, humidity, and pollutants, which may increase tear film evaporation.11–13 In addition, dry eye may result from defects in tear-producing glands and other eyelid diseases. Large metropolitan areas have high levels of air pollution and increased prevalence of dry eye, with as many as 20% of the adult population seeking medical attention. Inhabitants in high altitudes have up to a 13% higher risk of dry eye syndrome.14 Reports on work-related dry eye have documented that more than 75% of female computer users (>8 h daily) had dry eye.15 Finally, more than 50% of all adults who self-medicate dry eye with nonprescription eye drops report that the drops are not effective in relieving their symptoms.14
Introduction
O
ur research over the past 25 years has identified several potential uses for topical application of the opioid antagonist naltrexone hydrochloride (NTX) eye drops.1–10 The corneal surface provides a protective barrier for the eye and lends shape to its first refracting element, the tear film. In addition, tears function to lubricate and provide nourishment to the cornea, serve in gas exchange for the eye, remove debris from the corneal surface, and contain enzymes that prevent bacterial and viral infection.11,12 Intact corneal surfaces and an adequate production of quality tears are necessary for normal vision. A deficiency in the quality or quantity of tears results in dry eye, also termed keratitis sicca. Sustained deficiencies in the production of tears lead to dry eye syndrome that may result in continuous irritation of the corneal surface, inflammation of the stroma, corneal
Departments of 1Ophthalmology and 2Neural & Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
1
2
Normal rodents display spontaneous episodic reductions in tear production.9,16,17 Examination of male rats tested between the ages of 4 and 24 weeks revealed a biphasic distribution into groups that had Schirmer scores above 8 mm and those with scores below 6 mm.9 Environmental conditions such as humidity, room temperature, or position in the animal racks were not responsible. Normal male rats with decreased tear production were administered 1 drop of 10-5 M NTX dissolved in Vigamox (moxifloxacin hydrochloride ophthalmic solution 0.5%; Alcon Laboratories, Inc, Fort Worth, TX). The tear volume was restored after 1 drop, with values equivalent to rats with normal tear fluid levels.9 The untreated eye in these rats retained the deficient Schirmer scores (e.g.,
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 00, Number 00, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2015.0070
Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: A Tolerability Study David Liang,1 Joseph W. Sassani,1 Patricia J. McLaughlin,2 and Ian S. Zagon 2
Abstract
Purpose: A short-term, randomized double-masked study was conducted to test the tolerability of topical application of naltrexone to the corneal surface. Methods: Healthy human volunteers were recruited at the Penn State Hershey Medical Center between 2010 and 2013. Study groups of 4 subjects were established to receive escalating dosages of naltrexone; within each group, 1 subject received placebo. Four drops of 4 different dosages of naltrexone dissolved in commercial moxifloxacin solution were administered over a 24-h period of time; 1 group of subjects received only 1 drop. The naltrexone dosages tested were 1 · 10-6 M (1 drop), 1 · 10-6 M (4 drops), 5 · 10-6 M (4 drops), 1 · 10-5 M (4 drops), and 5 · 10-5 M (4 drops). Drops were administered over a 24-h period. Consenting subjects had complete eye examinations, including visual acuity (ETDRS), external and slit-lamp examinations, corneal sensitivity, pachymetry, corneal topography, endothelial specular microscopy, Schirmer testing with anesthetic, and fundus photography, before receiving naltrexone. Individuals were reexamined at 24 h and 7 days following naltrexone or placebo application. Results: Twenty subjects were recruited for the study; 62% were male, 90% were Caucasian; and 19 subjects completed the study. No significant differences were noted in ocular health between left (treated) and right (untreated) eyes of subjects receiving naltrexone or placebo. No significant adverse events were reported. Conclusions: Topical naltrexone was well tolerated in healthy human subjects after 1 or 4 eye drops of naltrexone at dosages up to 50 mM administered over a 24-h treatment period and observed for 1 week.
ulceration, and impaired vision.11–13 While corneal abrasions are most likely trauma induced, the underlying pathophysiology for dry eye is multifactorial. Age and gender play a role, as well as environmental factors such as temperature, humidity, and pollutants, which may increase tear film evaporation.11–13 In addition, dry eye may result from defects in tear-producing glands and other eyelid diseases. Large metropolitan areas have high levels of air pollution and increased prevalence of dry eye, with as many as 20% of the adult population seeking medical attention. Inhabitants in high altitudes have up to a 13% higher risk of dry eye syndrome.14 Reports on work-related dry eye have documented that more than 75% of female computer users (>8 h daily) had dry eye.15 Finally, more than 50% of all adults who self-medicate dry eye with nonprescription eye drops report that the drops are not effective in relieving their symptoms.14
Introduction
O
ur research over the past 25 years has identified several potential uses for topical application of the opioid antagonist naltrexone hydrochloride (NTX) eye drops.1–10 The corneal surface provides a protective barrier for the eye and lends shape to its first refracting element, the tear film. In addition, tears function to lubricate and provide nourishment to the cornea, serve in gas exchange for the eye, remove debris from the corneal surface, and contain enzymes that prevent bacterial and viral infection.11,12 Intact corneal surfaces and an adequate production of quality tears are necessary for normal vision. A deficiency in the quality or quantity of tears results in dry eye, also termed keratitis sicca. Sustained deficiencies in the production of tears lead to dry eye syndrome that may result in continuous irritation of the corneal surface, inflammation of the stroma, corneal
Departments of 1Ophthalmology and 2Neural & Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
1
2
Normal rodents display spontaneous episodic reductions in tear production.9,16,17 Examination of male rats tested between the ages of 4 and 24 weeks revealed a biphasic distribution into groups that had Schirmer scores above 8 mm and those with scores below 6 mm.9 Environmental conditions such as humidity, room temperature, or position in the animal racks were not responsible. Normal male rats with decreased tear production were administered 1 drop of 10-5 M NTX dissolved in Vigamox (moxifloxacin hydrochloride ophthalmic solution 0.5%; Alcon Laboratories, Inc, Fort Worth, TX). The tear volume was restored after 1 drop, with values equivalent to rats with normal tear fluid levels.9 The untreated eye in these rats retained the deficient Schirmer scores (e.g.,
