## 4 Discussion  
In our pilot study, we found that perioperative pregabalin did not reduce the presence of DE symptoms six months after LASIK. This included overall symptoms of DE, assessed using standardized questionnaires like the DEQ5 and OSDI, and symptoms related to pain, assessed via standardized pain questionnaires applied to eye pain e.g., NRS, NPSI-Eye, and sf-MPQ. There are several explanations for our findings. First, it is possible that \(\alpha 28\) ligands are not the optimal agents to prevent mechanisms that lead to ocular symptoms. Other agents, such as anti-depressants (tricyclics and serotonin and norepinephrine reuptake inhibitors) have been used as preventative agents in PPOP, and may be better suited for controlling eye pain. Furthermore, combination therapies, such as using an \(\alpha 28\) ligand and an analgesic antidepressant (e.g., nortriptyline), might have been more beneficial via targeting of multiple mechanisms contributing to the transition from acute to chronic ocular pain. Combined therapy with gabapentin and nortriptyline, for example, has been shown to suppress neuropathic pain wherein individual components may be ineffective [41]. Second, it is possible that our dosing strategy was not optimal. In the literature, dosing strategies vary tremendously and range from exclusively high dose preoperative administration, to a low preoperative dose followed by an extended taper [14; 42]. Third, it is possible that our study population was not optimal. Additionally, the overall severity of DE symptoms and ocular pain in our population at six months were low, and second, despite randomization, our groups were not matched at baseline with respect to gender. However, noted baseline differences, specifically female gender, did not predict ocular symptoms at six months, although female gender has been identified as a risk factor for PPOP in other studies [42; 43; 44]. Given that baseline ocular symptoms and mental health indices (e.g., depression, anxiety) were most influential in predicting symptoms at six months, restricting our population to those with these risk factors may have been a more optimal strategy in testing our hypothesis. Finally, it is likely that a single systemically administered analgesic agent, such as pregabalin, although adequate to reduce symptoms of established neuropathic pain, may not be adequate to suppress the entire afferent barrage of nociceptive signals or chemical mediators originating from the cornea and affecting the central nervous system leading to sensitization and chronicity of pain [45]. Although the concept of preemptive analgesia, as originally introduced by [PERSON] and [PERSON], promoted the preemptive use of analgesics to prevent central sensitization, subsequent studies produced contradictory results [46]. Therefore, what might be necessary to more effectively suppress peripheral and central sensitization and reduce the transition to chronicity is combined preventive application of multiple classes of analgesics from different routes, such as local anesthetics and multimodal systemic agents of different classes, extending from the preoperative phase to the postoperative period [46; 47]. In fact, this is already utilized in LASIK in the form of topical anesthetics during surgery and topical corticosteroids in the postoperative period. According to existing PPOP literature, the frequency of mild DE symptoms in this study (45% at six months) is higher than PPOP rates after dental implant surgery (8.5-36%) [48], as well as inguinal hernia repair (5-30%) [49], and is similar to PPOP rates post-thoracotomy (5-65%) [49] and breast surgery (20-50%) [49]. Fortunately, most individuals had mild symptoms, with only 12% of subjects reporting severe symptoms. In a similar manner, of the 14 subjects who reported eye pain over a one week recall, 12 patients rated it as mild (1-3) [50]. None of our patients had debilitating symptoms that necessitated escalation of therapy beyond that typically used to address DE (artificial tears, punctal plugs).