We conducted a prospective, open-label, single-arm study for pain control. A total of 96 terminal cancer patients with stage IV (advanced) malignant disease who were admitted to the 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 [14]. In addition to neuropathic pain, the pain had to be well localized, superficial, and involve positive symptoms such as allodynia, raised pin-prick threshold, and hyperalgesia. Regardless of the intensity, all patients with such neuropathic pain were included. There was no contraindication to topical anesthetic application. The study period was 3 days, and all participants signed informed consent forms. Patient symptoms were evaluated by questionnaires, including an 11-point pain intensity scale, a 5-item pain relief score, and 5-item analgesic treatment quality. The exclusion criteria included the following: (1) skin lesions with bacterial infection and allergies to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.); (2) a significant concomitant illness that the investigator believed would interfere with the evaluation of the study medications, including lidocaine, tocainide, mexiletine, and phenytoin; and (3) the patient received treatment with topically applied medication (e.g., lidocaine/prilocaine cream, capsaicin cream, and doxepin cream) 72 hours before the study. The National Cheng Kung University Hospital institutional review board approved this study (BR-100-005-C).

In this study, the first visit included screening and enrollment, and eligible subjects (with neuropathic cancer pain) received the study patch for 3 days (Fig. 1). Subsequently, the second/third visit was scheduled on the second or third day of the study for endpoint evaluation. All subjects were assigned to the lidocaine group for 3 days. Pain intensity, including the numerical rating scale (NRS)-resting score, was also assessed as baseline data before patch application. 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) were recorded. In addition to collecting information on concurrent diseases and medications, the investigator evaluated clinical efficacy and safety at each visit. To assess the outcome of ongoing adverse events, the subject was contacted within 1 week after the trial ended for a follow-up. We also reported any new adverse events that occurred during this period.

Treatment schedule. The first visit included screening and enrollment; eligible subjects received the study patch for 3 days. Subsequently, the second visit was scheduled on the second and third days of the study, and the third visit was the end of the evaluation

The primary endpoint of the analgesic effect of the experimental patch was evaluated by the 11-point NRS pain intensity on Day 2 and Day 3. The secondary endpoints of efficacy were evaluated by the five-item pain relief score and analgesic treatment quality on Day 2 and Day 3. Pain intensity was evaluated using a horizontal line, with a total of 11 points, ranging from 0 to 10, on a numerical rating scale (NRS) [11, 12], 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 on Day 1. Furthermore, the NRS score for neuropathic 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 2 and Day 3). The 5-item pain relief score was determined as follows. Pain relief was assessed using a category scale consisting of the following 5 scores: 0 = “no” pain relief; one = “slight” pain relief; two = “moderate” pain relief; three = “much” pain relief; and four = “complete” pain relief [1]. A modified version of the Brief Pain Inventory (BPI) [15] was used as an assessment tool for analgesic treatment quality. The subject rated the 5-item 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.

We evaluated the safety of the lidocaine patches using vital signs, skin inspections, and skin examinations. The application area affected by the lidocaine patch was recorded. Under the same conditions, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured. A brief examination of the skin under the patches was carried out at each visit to document skin redness, blanching, or irritation. Detailed adverse event data were recorded by the patient and summarized.

The demographic data and the distribution of each variable were described using frequency distributions. Data analyses included descriptive and inferential statistics. A descriptive analysis was conducted, including the estimated mean and standard deviation for continuous variables and the percentages and frequencies for categorical variables. Because of violations of the normality assumption, the Wilcoxon signed-rank test and the 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. Safety parameters such as vital signs and skin inspection were also summarized and displayed with descriptive summary statistics. The analyses were performed using the R 4.0.2 version software package for Windows.