Analgesic Effect of a 5% Lidocaine Patch in Patients With Opioid Treatment-Resistant Neuropathic Cancer Pain

Purpose Limited ecacy has been observed when using morphine to treat neuropathic pain. Lidocaine patches reduce neuropathic pain in post-herpetic neuralgia, but their benets for cancer-related neuropathic pain remain unclear. This study aimed to demonstrate a useful treatment for cancer-related neuropathic pain. The primary endpoint was pain intensity evaluated by the visual analog scale (VAS). The secondary endpoints were the pain relief score and the quality of analgesic treatment. Methods We assessed the ecacy and safety of lidocaine patches in patients experiencing neuropathic cancer pain. Terminal cancer patients with opioid treatment resistance participated in the 3-day study. The results showed a statistically signicant difference in the median VAS over three days (Kruskal-Wallis test, P<0.0001). The median VAS pain intensity from Day 1 to Day 3 was 4.0 with 95% C.I. (3.3, 5.0), 3.0 (2.5, 3.5) and 2.5 (2.0, 3.0), respectively. The difference between the median VAS pain intensities of any two days was statistically signicant (Wilcoxon signed-rank test, P < 0.0001). There was no statistically signicant difference in the pain relief score or the quality of analgesic treatment.


Background
According to the World Health Organization (WHO) guidelines, cancer pain treatment is effective and safe [1]. Neuropathic pain (NP) is a common problem encountered in 40% of cancer patients [2,3]. NP that results from neoplastic insults to the peripheral or central nervous system is characterized by continuous or intermittent spontaneous pain and abnormal sensitivity of the painful site to a variety of noxious (hyperalgesic) or innocuous (allodynic) stimuli [4,5]. Evoked pain that results from light touch by garments, running water or even cold air can be too bothersome for many of these patients. However, neuropathic pain is often described as 'intractable' and 'opioid resistant,' and the e cacy of opioids, nonsteroidal anti-in ammatory drugs, and other adjuvants remains controversial [6].
Several classes of drugs are moderately effective, but complete or near-complete relief is unlikely.
Antidepressants and anticonvulsants are most commonly used. Opioid analgesics can provide some relief but are less effective for NP than for nociceptive pain; adverse effects may prevent adequate analgesia. Topical drugs and a lidocaine-containing patch may be useful for peripheral syndromes [7].
Sympathetic blockade is usually ineffective, except for some complex regional pain syndromes [8]. A lidocaine patch may be useful in relieving numbness, tingling, and other symptoms of neuropathy [9]. It is unknown whether a lidocaine patch is effective in treating neuropathy in cancer patients whose pain is refractory to morphine.
Lidocaine is an aminoethylamide local anesthetic that blocks voltage-gated sodium channels on excitable membranes, thereby preventing the generation and conduction of nerve impulses and providing analgesic relief [10,11]. The systemic absorption of lidocaine from the patch is minimal. The amount absorbed is directly related to the skin surface area covered and the lidocaine patch application duration.
A 5% lidocaine patch was approved by the FDA for relief of pain associated with post-herpetic neuralgia and was marketed in March 1999 in the United States. The patch helps provide relief at the site of pain caused by damaged nerves. This new formulation of topical lidocaine is applied to intact painful skin and has been shown to produce signi cant pain relief without clinically signi cant serum levels [10,11].
The present study aimed to evaluate the analgesic effect of a 5% lidocaine patch in patients with neuropathic cancer pain exhibiting opioid treatment resistance, and neuropathic pain was assessed by pain intensity via the visual analog scale (VAS), pain relief score, and analgesic treatment quality [12][13][14].
We evaluated the e cacy and safety of lidocaine patches in patients experiencing cancer-related neuropathic pain.

Patients And Methods
Demographic characteristics A total of 96 terminal cancer patients, all with stage IV 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; and experiencing neuropathic cancer pain evaluated by the LANSS Pain Scale [15] with opioid treatment resistance and without 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; signi cant 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 rst 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 collected information on concurrent diseases and symptoms as well as concomitant medication and examined skin affected by the lidocaine patch. The pain intensity, including the VAS-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-de ned, 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 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 e cacy
The primary endpoint of the analgesic effect of the experimental patch was evaluated by assessing the VAS pain intensity. The secondary endpoints of e cacy were evaluated by the pain relief score and analgesic treatment quality. Pain intensity was evaluated using a horizontal 100 mm visual analog scale (VAS), 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 VAS-resting score. Furthermore, the VAS score for speci c pain was recorded in parallel. The pain intensity was assessed from before the rst 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 ve-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 = insu cient, 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 the heart 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 e cacy variable was the resting-pain intensity measurement using a horizontal 100 mm visual analog scale (VAS). 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 signi cance. The analyses were performed using the R 4.0.2 version software package for Windows.

Patient characteristics
A total of 96 terminal cancer patients in hospice wards were referred to our studies. The median age was 58 Y/O, and 50/46 patients were male/female. The most common types of cancer were head and neck  Table 1. All patients were morphine resistant, and the combination of analgesic regimens included nonsteroidal anti-in ammatory drugs (NSAIDs), acetaminophen, corticosteroids, and antidepressants.

Clinical symptom relief on pain intensity
The patients recorded their results for the three-day VAS pain intensity, pain relief score, and analgesic treatment quality. The Kruskal-Wallis test was used for pain assessment. We assessed the difference in inferring the patch's analgesic effect in patients experiencing cancer-related neuralgia under the patch. In this analysis, inferences are made with con dence levels below 95%. The results showed a statistically signi cant difference in the median VAS pain intensity over three days (Fig. 2a, Kruskal-Wallis test, Pvalue <0.0001). The median VAS pain intensity from Day 1 to Day 3 was 4.0 with 95% CI (3.3, 5.0), 3.0 (2.5, 3.5) and 2.5 (2.0, 3.0), respectively. The median VAS pain intensity of any two days was statistically signi cant (Wilcoxon signed-rank test, P-value < 0.0001). The paired VAS pain intensity data for any two days are presented in Fig. 2b. We reported changes in the number of patients with different VAS pain intensities on any two days (Table 2). On Day 1 and Day 2, 51 patients had decreased VAS pain intensity. A total of 8.3% and 44.8% of patients had a reduction of more than 4 points and 0.5-3.5 points, respectively. Sixteen patients had increased VAS pain intensity. A total of 14.6% and 2.1% of patients reported that their pain intensity increased by 0.5-4 points and 5 points, respectively. There were similar results for any two days. The data are shown in Table 2.
We also used the generalized estimating equation (GEE) model for the same patient with a three-day series assessed by VAS pain intensity. The GEE estimation model shows that the VAS pain intensity on the second day decreased by approximately 0.8 points compared with the rst day and that the VAS pain intensity on the third day decreased by approximately 1.4 points compared with the rst day. The test results showed statistically signi cant differences between the VAS pain intensities on any two days (Table 3). Based on the above results, the patch's effect on pain assessed by the VAS pain intensity score was statistically signi cant.

Effect on pain relief score
The results showed no statistically signi cant difference in the median of the three-day pain relief score.
Supplementary Material 1 shows that the average and median pain relief scores did not change signi cantly (Kruskal-Wallis test, P-value = 0.79). There were no statistically signi cant differences in the median pain relief score for any two days as assessed by the Wilcoxon signed-rank test (P-value = 0.24, 0.36, 0.9).

Effect on the quality of analgesic treatment
The results showed no statistically signi cant difference in the median of the three-day quality of analgesic treatment. Supplementary Material 1 shows that the average and median analgesic treatment quality did not change signi cantly (Kruskal-Wallis test, P-value = 0.77). There were no statistically signi cant differences in the median analgesic treatment quality for any two days as assessed by the Wilcoxon signed-rank test (P-value = 0.21, 0.7, 0.029).

Discussion
From the box-and-whisker plot of VAS pain intensity, we can see that the number of days of lidocaine patch use decreased the average and median VAS pain intensity. There was a statistically signi cant difference in the median three-day VAS pain intensity. According to the GEE estimation results, the patch's pain relief effect was statistically signi cant as assessed by the VAS pain intensity in the time series. The results of this study showed that the addition of 5% lidocaine patches could be useful in the short term for treating neuropathic cancer pain by decreasing the VAS pain intensity. However, the underlying mechanisms responsible for topical lidocaine symptom relief in patients with allodynia are not fully understood. Hans G et al [16] reported a prospective study including 40 patients with severe neuropathic pain due to surgical or nonsurgical trauma. Approximately 52.5% of the patients bene ted from treatment with lidocaine, with the severity of their pain on a VAS diminishing at the end of the study. These results are similar to those obtained for super cial neuropathic pain following surgery.
In a placebo-controlled, crossover study, a 5% lidocaine medicated plaster effectively relieved ongoing pain and allodynia within the rst eight hours, with effects lasting up to one week [17]. As in our study, we emphasized the precise selection of the patients in whom, in addition to the presence of neuropathic pain, the pain had to be well localized, super cial, and involve positive symptoms such as allodynia, raised pinprick threshold, and hyperalgesia. The severity of the pain was analyzed using a VAS, thus measuring Day 1 to Day 3. Neuropathic cancer pain cannot be treated according to the World Health Organization (WHO) recommendations because there is no evidence that such pain responds to drugs that are recommended for mild or moderate cancer pain (steps 1 and 2 of the WHO's pain relief ladder) [1]. The majority of our patients who were treated with lidocaine patches often found them practical for reducing mild and moderate neuropathic pain assessed by VAS pain intensity.
There was no statistically signi cant difference in the median of the three-day pain relief score or analgesic treatment quality from the box-and-whisker diagram (Supplementary Material 1). According to GEE estimates, the patch's pain relief effect was not statistically signi cant in terms of the pain relief score and the quality of analgesic treatment. We concluded that the patch could not be statistically supported for pain relief scores and analgesic treatment quality. Derry et al. also reviewed topical lidocaine for neuropathic pain in adults [18]. This review found no evidence from good quality randomized controlled studies to support topical lidocaine as a treatment for neuropathic pain. We did not assess the emotional dimension, quality of life, or sleep. This may constitute a limitation since the present study failed to demonstrate improvements in pain relief and quality with the lidocaine patch. We also did not nd that the extent of pain interfered with daily activities.
The concept of a topical, local anesthetic patch as a therapy for allodynia has a great appeal to clinicians and patients due to a topical formulation's simplicity. The reasons for this appeal are the bene ts of the patch formulation as a barrier protecting hypersensitive skin from external stimuli and the lack of clinically signi cant systemic absorption, drug interactions, and other serious adverse effects [10,11]. The present sample was not very large but included different cancer types. The results of this study showed that the investigated treatment carries no risk; nurses can apply the skin patch.
There are certain limitations to extrapolating our results; this was a non-controlled, open-label study for pain control. It is subject to a signi cant risk of the placebo effect and of recall bias. Unless the patients' neuropathic pain were cutaneous or super cial, a lidocaine patch was not likely to penetrate deep enough to have a pharmacological effect. Despite the restrictions in prescribing lidocaine patches, there were several good reasons for trying this treatment in our cancer patients: (i) the intractable nature of neuropathic pain, which is incredibly resistant to morphine, (ii) the potential bene ts of the treatment in reducing VAS pain intensity, and (iii) the lack of systemic adverse side effects. These reasons led us to use this topical formulation to treat our cancer patients with neuropathic pain resistant to morphine.

Conclusion
In this study, a 5% lidocaine skin patch reduced the VAS pain intensity in patients experiencing morphineresistant neuropathic cancer pain. Such topical medication is generally useful and well tolerated. Ethics approval: This study was approved by the institutional review board of NCKUH (BR-100-005-C) and conducted in accordance with the Declaration of Helsinki.

Declarations
Consent to participate All participants provided written informed consent.
Consent for publication All authors agree for publication.   Figure 1 Treatment schedule. The rst visit included screening and enrollment; eligible subjects received the study patch for three days. Subsequently, the second visit was scheduled on the second and third days of the study, and the third visit was scheduled for endpoint evaluation. Figure 2 a and b. Effect on pain intensity assessed by the visual analog scale Pain intensity was assessed using a horizontal 100 mm visual analog scale (VAS), which interprets the severity of pain on a scale ranging from 0 = no pain to 10 = worst pain imaginable. The pain intensity was assessed before the rst patch was applied as the baseline (on Day 1) and after the last patch was used on (Day 3).