More than 500,000 individuals undergo laser vision correction surgery each year in the United States, including laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). These procedures damage the nerves in the corneal epithelium causing intense acute pain that most patients rate as greater than 6 on a 0-10 scale; many report the pain to be âunbearableâ, even after analgesic treatment. While virtually all patients will experience acute pain, up to 40% will also experience chronic dry eye after corrective surgery. This is likely because damage to corneal sensory nerves disrupts afferent signaling that causes tear production in response to the sensation of dryness at the ocular surface. The patients who develop chronic dry eye disease are also at risk for developing chronic pain. Current approaches to managing pain after PRK include systemic and topical nonsteroidal anti-inflammatory drugs and opioids, but these medications have potentially severe side effects including gastric distress with NSAIDs and addiction with opioids. Thus, better analgesics for ocular surgical procedures represents a large unmet clinical need. Resveratrol is a natural polyphenol found in red grapes and other plant sources and has been shown in preclinical models to attenuate both acute and chronic incision pain as well as prevent the transition to a chronic pain state. Resveratrol is thought to reduce pain by activating AMP-activated protein kinase (AMPK) and engaging its downstream mechanisms. It possesses appropriate chemical properties for topical dosing and tissue permeation (i.e. it is highly lipophilic), is already viewed as safe for human consumption by the FDA, and is approved as an active antioxidant ingredient for topical formulas (non-corneal). The Aicher laboratory has developed a preclinical model of PRK that uses heptanol to remove the corneal epithelium and produce an abrasion that shears terminal nerve endings in the epithelium. This preclinical model mimics the epithelial/neuronal damage produced by PRK in humans and causes key post-operative symptoms, including acute pain and chronic dry eye, making it an ideal model to test novel therapeutics to attenuate PRK pain. Our proposed studies will test the hypothesis that resveratrol-containing eye drops can be used as a novel therapeutic for corneal pain using this preclinical model of PRK. We will first test whether resveratrol has efficacy for corneal hyperalgesia (Aim 1) and dry eye symptoms (Aim 2) after abrasion injury in the rat. These studies will then assess whether resveratrol interferes will epithelial repair after injury (Aim 3). Together these experiments will generate preclinical rationale for the development of resveratrol for the treatment of PRK pain, and potentially for use in other ocular surgical procedures.
Public Health Relevance Statement: More than 500,000 individuals undergo laser vision correction surgery each year in the United States, which damages the nerves in the corneal epithelium causing intense acute pain and chronic dry eye. Current approaches to managing pain after vision correction surgery include systemic and topical nonsteroidal anti-inflammatory drugs and opioids, but these medications do not have adequate efficacy and they also have the potential for addiction with opioids. Our proposed studies will use a preclinical model of photorefractive keratectomy (PRK) that mimics the epithelial/neuronal damage produced by PRK in humans and causes key post-operative symptoms including pain and dry eye, to test the hypothesis that resveratrol-containing eye drops can be used as a novel therapeutic for corneal pain.
Project Terms: 5'-AMP-activated protein kinase; Acute; Acute Pain; addiction; afferent nerve; Analgesics; Antioxidants; aqueous; Attenuated; chemical property; Chronic; chronic pain; Clinical; Clinical assessments; Consumption; Cornea; Corneal Abrasion; corneal epithelium; Corneal pain; Development; Disease; Distress; Dose; Dryness; Epithelial; Epithelium; Esthesia; experience; experimental study; Eye; Eye diseases; eye dryness; Eyedrops; Failure; Future; Grapes; healing; Heptanol; Hour; Human; Hyperalgesia; Impairment; In Situ; Individual; Injury; keratomileusis; Laboratories; Lasers; lipophilicity; Measures; Menthol; Modeling; Nerve; Nerve Endings; Neurons; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; novel; novel therapeutics; ocular surface; Operative Surgical Procedures; Opioid; Pain; Pain management; pain model; pain reduction; Patients; Persistent pain; Pharmaceutical Preparations; Phosphotransferases; Photorefractive Keratectomy; Plant Sources; polyphenol; Postoperative Period; pre-clinical; Pre-Clinical Model; prescription opioid; prevent; Procedures; Production; Proteins; Rattus; repaired; Reporting; response; restoration; Resveratrol; Risk; side effect; Signal Transduction; Skin; Stomach; Surgical incisions; Symptoms; Testing; Therapeutic; therapeutic development; Tissues; Translations; United States; virtual; Vision; W
