Dysesthesia

For each individual, demographic information (age, sex, race, ethnicity), past ocular and medical history, and medication information were collected. Medications were categorized into anxiolytics, antidepressants, analgesics, antihistamines, and the gabapentinoids.
Patients filled out standardized questionnaires regarding dry eye symptoms, including the Dry Eye Questionnaire 5 (DEQ5)^{22 (link)} and the Ocular Surface Disease Index (OSDI).^{23 (link)} The DEQ5 is a validated, five-item questionnaire that combines patient responses regarding “eye discomfort” (frequency and intensity), “eye dryness” (frequency and intensity), and “watery eyes” (frequency) during the past month. Scores on the DEQ5 can range from 0 to 22, with higher scores indicating greater severity of symptoms. The OSDI is a 12-item questionnaire that assesses the frequency of dry eye symptoms and their impact on function on a 0 to 100 scale, with higher scores indicating greater severity of disease.^{23 (link)} It has good psychometric properties^{23 (link)} and has been used in a number of studies of dry eye and quality of life.^{24 (link),25 (link)}Pain questionnaires were used to assess for the presence and quality of ocular pain. A numerical rating scale (NRS; score 0–10) was used to assess the “average intensity of eye pain during the past week.” The Neuropathic Pain Symptom Inventory (NPSI),^{26 (link)} modified for the eye, was used to quantify the severity of clinically relevant dimensions of neuropathic pain. This questionnaire was chosen as it has been validated and used in a number of patient populations with various neuropathic pain conditions,^{26 (link)–30 (link, link, link, link)} though it has not been specifically validated for eye pain. The NPSI consists of 10 scored items that help identify and assess the severity of spontaneous and paroxysmal pain, paresthesias, allodynia, and hyperalgesia. In order to modify the NPSI so that it was relevant to neuropathic ocular pain (NOP), we replaced three of the original questions regarding the severity of allodynia or hyperalgesia caused by (1) light touch, (2) pressure, or (3) contact with something cold on the skin, with questions specific to ocular allodynia or hyperalgesia (eye pain caused or increased by [1] wind, [2] light, and [3] heat or cold). A total NPSI eye score was calculated, along with five subscores (burning spontaneous pain, pressing spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia), as an indication of the severity of neuropathic-like ocular pain.
Regarding mental health indices, symptoms of PTSD were assessed via the PTSD Checklist–Military Version (PCL-M) (score 17–85)^{31 (link),32 (link)} and symptoms of depression via the Patient Health Questionnaire 9 (PHQ9) (score 0–27).^{33 (link)}

The proportion of patients in each arm who achieved optimal therapeutic effect (OTE) was assessed. OTE was defined as: no change in background chronic pain medication (assessed by an Independent Data Review Board); no discontinuation of the study drug due to lack of efficacy or tolerability prior to Week 8; ≥30% reduction in the NPRS score over at least 4 consecutive days from baseline to Week 8; and no moderate or severe adverse drug reactions (ADRs) during the stable treatment period. For the capsaicin patch, the stable treatment period equated to weeks 1–8 of the treatment period. It excluded the first week of treatment to avoid confounding factors associated with the use of short‐acting oral analgesics during this period, and to allow for the onset of action of the capsaicin patch. For pregabalin the stable treatment period equated to the period over which the subject was dosed at the optimal maintenance dose, and was different for each subject.
Time‐to‐onset of pain relief (in days) as assessed by ≥30% reduction in the NPRS score. The median time‐to‐onset of pain relief was the first of 3 consecutive days where 50% of patients had a ≥30% reduction in NPRS score versus baseline.
Change from baseline NPRS for the past 24 h was assessed by the proportion of patients who achieved ≥30% and ≥50% decrease in the NPRS score from baseline to the mean of all scores recorded between Week 2 and Week 8, respectively; as well as the absolute and per cent change.
Pre‐specified analyses of the primary endpoint were performed according to patient subgroups based on patient age (<65, ≥65, <75 years), gender, time since diagnosis (<6 months, ≥6 months to ≤1 year, >1 year to ≤2 years, >2 years to ≤10 years, >10 years), maximum Neuropathic Pain Symptom Inventory (NPSI) subscales [burning (superficial) spontaneous pain, pressing (deep) spontaneous pain, paroxymal pain, evoked pain, paraesthesia/dysaesthesia], type of pain (PHN, PNI, non‐diabetic painful peripheral polyneuropathy), pain grading (probable neuropathic pain, definite neuropathic pain), baseline pain score (<7, ≥7) and previous use of pregabalin/gabapentin.
Treatment satisfaction, as assessed by the proportion of patients who discontinued study drug or withdrew from the study due to either a lack of efficacy or tolerability; willingness to continue treatment at Week 8; and the Treatment Satisfaction Questionnaire for Medication (TSQM) questionnaire at Week 4 and Week 8, with statistical comparisons of TSQM scores adjusted for country group and gender.
Other patient rated outcomes were assessed (EQ‐5D‐5L, Patient Global Impression of Change, Medical Outcomes Study 6‐Item Cognitive Functioning and Sleep) and will be reported separately.
Safety analyses were conducted on all patients who received study drug. A treatment‐emergent adverse event (TEAE) was defined as an AE that started or increased in severity after intake/application of the study drug. An ADR was defined as an AE with probable or possible relationship with the study drug.