Demographic characteristics
A total of 96 terminal cancer patients, all with stage IV (advanced) malignant disease and been admitted to hospice ward at National Cheng-Kung University Hospital (NCKUH) were enrolled. The eligibility criteria were 18 years of age and above, male or female, who were treated with opioids for cancer-related pain and still experiencing neuropathic cancer pain evaluated by the LANSS Pain Scale [15].There are no contraindication to topical anesthetic application. The study period was 3 days, and all participants signed informed consent forms. The symptoms of patients were evaluated by a questionnaire. The exclusion criteria were skin lesions with bacterial infection; history of allergies to para-aminobenzoic acid derivative drugs (procaine, tetracaine, benzocaine, etc.); treatment with Class IB antiarrhythmic drugs, i.e., lidocaine, tocainide, mexiletine, phenytoin; significant concomitant illness, which, in the opinion of the investigator, would interfere with the evaluation of the study medications;and treatment with topically applied medication (e.g., lidocaine/prilocaine cream, capsaicin cream, doxepin cream) 72 hours before the study. The National Cheng Kung University Hospital (NCKUH) institutional review board approved this study (BR-100-005-C).
Treatment schedule
In this study, the first visit included screening and enrollment; eligible subjects (with neuropathic cancer pain) received the study patch for three days (Fig. 1). Subsequently, the second/third visit was scheduled on the second/third day of study for endpoint evaluation. The investigator collectedinformation on concurrent diseases and symptoms as well as concomitant medication and examined skin affected by the lidocaine patch. The pain intensity, including the NRS-resting score, was assessed as baseline data before patch application. The subjects were assigned to the lidocaine group for three days. The enrolled subjects applied the patch to well-defined, intact skin to cover the most painful area. Subjects were allowed to use up to three patches simultaneously, each for 12-24 hours, once to twice daily. Any observed and spontaneously reported adverse events (AEs) are noted. Skin inspection: A brief examination of the skin under the patches was carried out at both visits to document skin redness, blanching, or irritation. In case of any ongoing adverse events, the subject was contacted for a follow-up within one week after the trial stops to evaluate the outcome of the AEs. Any new adverse events that occurred during this period were also reported.
Clinical efficacy
The primary endpoint of the analgesic effect of the experimental patch was evaluated by assessing the NRS pain intensity. The secondary endpoints of efficacy were evaluated by the pain relief score and analgesic treatment quality. Pain intensity was evaluated using a horizontal line, with a total of 11 numbers, ranging from 0 to 10, numerical rating scale (NRS) [12,13], which interprets the severity of pain on a scale ranging from 0 = no pain to 10 = the worst pain imaginable. The subject was questioned about the NRS-resting score. Furthermore, the NRS score for specific pain was recorded in parallel. The pain intensity was assessed from before the first patch was applied as the baseline (on Day 1) to after the last patch was applied (on Day 3). Pain relief score: Pain relief was assessed using a category scale consisting of 5 scores indicating the following: 0="no" pain relief, 1="slight" pain relief, 2=" moderate" pain relief, 3="much" pain relief, 4="complete" pain relief. Analgesic treatment quality: The subject rated the quality of the analgesic treatment using the following five-item scale: 1 = excellent, complete pain relief, performance status reaching 100%, no compromise of sleep and appetite; 2 = good, tolerable pain not longer than half an hour or disappearance of pain but with compromised sleep, appetite, or performance status; 3 = satisfactory, tolerable mild degree of pain, no further medication requirement; 4 = insufficient, feeling better but with pain control that was not adequate, apparent pain sensation; and 5 = poor, no improvement at all, even worse pain.
Clinical safety assessments
The safety endpoint was evaluated in terms of vital signs, skin inspections, and adverse events. The application area affected by the lidocaine patch was recorded. Vital signs consisted of systolic (SBP) and diastolic blood pressure (DBP) and theheart rate (HR),which were measured under the same conditions. A brief examination of the skin under the patches was carried out at both visits to document skin redness, blanching, or irritation. The adverse event data were listed individually by the patient and then summarized. Safety parameters such as vital signs and skin inspection were also summarized and displayed with descriptive summary statistics.
Statistical analysis
A frequency distribution was used to describe the demographic data and the distribution of each variable. The primary efficacy variable was the resting-pain intensity measurement usinga numerical rating scale (NRS). Data analyses included descriptive and inferential statistics. Descriptive statistics, including the estimated mean and standard deviation for continuous variables, as well as the percentages and frequencies for categorical variables, were tabulated. Because of violations of the normality assumption, the Wilcoxon signed-rank test and Kruskal-Wallis test were used to compare whether the median values of the two/three groups were equal. To account for the correlation among repeated measures from the same cancer patient, a generalized estimating equation (GEE) was used to estimate the effect of covariates on the mean of the response variables. All statistical tests were 2-sided, with a P-value less than 0.05 considered to indicate statistical significance. The analyses were performed using the R 4.0.2 version software package for Windows.