New Approaches to Pain Management after PRK

Both oral and topical options show early promise

BY ELLA FAKTOROVICH, MD

Since its FDA approval nearly 15 years ago, photorefractive keratectomy has remained an excellent procedure for many patients interested in better vision. With improvement in techniques, bandage contact lenses, topical and oral medications, patient comfort has improved as well. Nevertheless, some patients still experience varying degrees of discomfort after PRK and some may not tolerate current methods of analgesia well. This article discusses opportunities to develop novel methods of corneal analgesia that would be effective and safe.

Current Methods Of Analgesia: Effects And Limitations

PRK results in a complex series of events that trigger the activity of most of the corneal nerve fibers. Pain relief strategies after PRK are, therefore, aimed at reducing stimulation of these various nociceptors.

To relieve the foreign body sensation caused by mechanoreceptor stimulation due to lid movement over the epithelial defect, a bandage contact lens is placed on the cornea after PRK. Diluted topical anesthetics are used as well. These are non-specific analgesics that block sodium potassium channels on all types of nerve cells and reduce impulse propagation.

Cold BSS provides cryoanalgesia by blocking impulse conduction along the nerve fibers similar to topical anesthetics. Merocel sponges with frozen BSS applied at the conclusion of PRK provide cryoanalgesia; so do the cold artificial tears during the postoperative period. NSAIDs and steroids, both topical and systemic, reduce the amount and activity of inflammatory mediators. This, in turn, reduces stimulation of the polymodal nociceptors. Oral narcotics, including opiates, reduce pain by interacting with receptors in the central nervous system.

All these methods provide a measure of pain relief, but breakthrough pain still occurs and patients may experience varying amounts of discomfort despite various treatment modalities. In addition, each method has potential side effects. Bandage contact lens may be too tight, resulting in a tight lens syndrome.¹ The lens may be too loose, causing irritation and foreign body sensation.¹ Bacterial keratitis and subepithelial infiltrates have been reported in patients fitted with therapeutic soft contact lens after PRK.²

At our practice, we tried different contact lenses over the years and found Acuvue Oasys to be tolerated best by most patients. The lens has 38% water content and Dk of 174; Focus Night and Day, by comparison, has 24% water content and Dk of 140. We typically use a base curve of 8.4 in most patients. The lens also comes in an 8.8 base curve, but we found it too loose even on patients with steep corneas. In corneas 47.0 D and greater, we use Focus Night and Day with a base curve of 8.6.

Topical NSAIDs are commonly used after PRK. When applied outside of prescribed parameters, they have been associated with corneal toxicity.^3-5 Corneal subepithelial infiltrates have been described when patients are treated with topical NSAIDs without adequate use of topical steroid concomitantly.⁶ Topical anesthetics, including tetracaine, proparacaine, lidocaine, and bupivicaine, can disrupt corneal epithelial cell motility by altering cytoskeletal elements.⁷ They may also be toxic to keratocytes.⁸

Repeated or prolonged use of topical anesthetics has been associated with poorly or non-healing epithelium and increased corneal permeability, resulting in corneal swelling. Although diluted anesthetics reduce pain after PRK, toxic keratopathy associated with low-dose topical anesthetic after PRK has been reported.^9,10 Finally, oral analgesics, including NSAIDs and opiates, can have gastrointestinal, respiratory, cardiovascular and central nervous system side effects.¹¹

New Oral Analgesics

Recently, new oral analgesics have been considered for pain management after PRK. Neurontin (gabapentin) and Lyrica (pregabalin) are FDA approved to treat neuropathic pain (they are also indicated for epilepsy). Although their mechanism of action is not yet fully understood, it is thought that these medications raise levels of the inhibitory neurotransmitter GABA in the central nervous system. GABA acts as the brains natural “calming agent” for overstimulated neurons. By raising GABA levels, these medications reduce neuronal activity in the brain. Common side effects in higher doses include drowsiness and problems with balance. Though they can be used in addition to oral opiates, an additive effect on central nervous system depression may occur. Abuse potential exists with Lyrica, especially when taken in higher doses or for longer periods of time. The effect is described similar to that of diazepam (Valium).

The analgesic efficacy of Lyrica and Neurontin for post-PRK pain has been anecdotal so far. The use of oral sumatriptan (Imitrex) to relieve after PRK, however, has been published.¹² Imitrex is a medication FDA approved for the treatment of migraine headaches. In a small study published in 2002, 100 mg of Imitrex was given orally to patients who underwent PRK. Thirteen out of 15 patients reported pain relief. Nine patients required a second dose five hours later to treat recurrent pain.

New Topical Analgesics

We have been studying new methods of topical analgesia after PRK. An ideal analgesic is effective in relieving pain, doesn't interfere with corneal healing, has no adverse effects and is applied topically without systemic penetration and systemic side effects. Topical opiates and other types of analgesics targeting specific receptors on nerve cells have the potential to be the ideal analgesics.

The presence of opioid receptors on the peripheral nerves of inflamed or injured tissue has been identified.¹³ This gave rise to the studies of analgesic efficacy of locally applied exogenous opioids using small, systemically inactive doses. Most of the published data comes from the intraarticular application of morphine after arthroscopic knee surgery.^14,15 The analgesic effect of this treatment on postoperative pain has been well documented. The effect is more pronounced in the presence of higher inflammatory response, consistent with the hypothesis that opioid receptors are upregulated in response to inflammatory mediators.

The cornea mounts an inflammatory response after PRK that includes stromal infiltration by inflammatory cells and release of cytokines and pro-inflammatory mediators such as NGF.¹⁶ These inflammatory mediators reach the trigeminal ganglion and stimulate the cell bodies of the primary afferent corneal nociceptors to synthesize opioid receptors. The receptors are then transported to the peripheral terminals of these nociceptors. The receptors are targeted by endogenous opioids called enkephalins released by the immune cells at the site of injury or inflammation.¹⁷ This is the body's own attempt to relieve pain in the inflamed tissue. The endogenous opiates, however, do not provide sufficient pain relief. Rather, the opioid receptors on the peripheral nerves are available and can be targeted by the exogenously applied opiates to achieve analgesia.

We conducted a prospective randomized placebo-controlled study of the effect of topical 0.5% morphine on pain control after PRK. Twenty patients were randomized to topical morphine and another 20 to a vehicle-only control group. All patients administered the drops four times per day for the first four days — until the epithelial defect healed and the bandage contact lens was removed.

Using pain assessment questionnaires, average and maximum pain scores were recorded during the four days. Patients in the topical morphine group experienced up to 50% less pain on average compared to the patients in the vehicle control (Figure 1). They needed to take less supplemental oral analgesic. Moreover, there was no delay in re-epithelialization and no adverse reactions observed in the topical morphine group (Figure 2).

We are now studying safety and efficacy of higher concentrations of topical opiates. In addition, we've conducted a pilot study of the safety and efficacy of another type of analgesic — topical sumatriptan (Imitrex). Trip tan (5HT1D) receptors have been identified on the cornea.¹⁸ We used a 1.2% formulation that was compounded from Imitrex nasal spray and found this concentration to be safe without delaying re-epithelialization or resulting in any adverse effects. Further studies have been initiated with higher doses to assess the analgesic efficacy.

PRK will remain a strong presence in refractive surgery and will continue to be an excellent option for many patients. With the development of new methods of analgesia targeting specific receptors on the corneal nerves, patient comfort may be achieved with greater safety. OM

References

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Ella G. Faktorovich, MD, is director of the Pacific Vision Institute in San Francisco and the founder of the Annual San Francisco Cornea, Cataract, and Refractive Symposium. She can be reached at ella@pacificvision.org. The author has no financial or proprietary interest in any material or method presented herein.