Antipruritic effect of Neurotropin injection on moisturizer‐ and antihistamine‐resistant itch in patients with pruritus: A multicenter, open‐label, small sample study

Pruritus is a condition in which itch occurs in the absence of apparent skin lesions. It is sometimes unresponsive to treatment with topical moisturizers and often is unresponsive to antihistamines. We evaluated the antipruritic effects of Neurotropin injections in patients with moisturizer‐ and antihistamine‐resistant pruritus. We monitored these patients by itch scores recorded in symptom diaries, as well as reports of quality of life (QOL). This study investigated both the efficacy and safety of Neurotropin injections using an open‐label study design. We enrolled 40 patients from six participating study sites. Of the 40 patients that were initially enrolled, six patients were ineligible, and ultimately, 33 were included for evaluation after one patient dropped out. Neurotropin was administered by subcutaneous injection to 22 patients and intravenous injection to 11 patients at a frequency of once per week. Compared to data collected during a one‐week observation period prior to treatment, after seven injections of Neurotropin, there was a significant improvement in the Shiratori symptom severity score and the visual analog scale (VAS) scores for itch symptoms, and the Dermatology Life Quality Index (DLQI) for quality of life. No new adverse events occurred during the period of investigation. A notable benefit to Neurotropin is that it can be used in patients with renal impairment and patients receiving dialysis therapy. Our results demonstrated that Neurotropin is effective in the treatment of moisturizer‐ and antihistamine‐resistant pruritus.


| INTRODUCTION
Itch has been known to negatively affect the quality of life (QOL) in patients with a variety of dermatoses. 1 According to the International Forum for the Study of Itch, chronic itch is defined as itch lasting for six weeks or more. 2 Itch manifests on the skin, palpebral conjunctiva, and nasal mucosa, and is the major symptom experienced in a large number of skin diseases. 3,4 Pruritus is a condition in which itch occurs in the absence of apparent skin lesions, and can be caused by xerosis, drugs, and many underlying diseases such as diabetes mellitus. Xerosis is a common cause of pruritus in elderly patients. 3 Pruritus is sometimes unresponsive to treatment with topical moisturizers and often is unresponsive to antihistamines. 5 Neurotropin, a nonprotein extract isolated from the skin of rabbits inoculated with the vaccinia virus, is widely used in Japan and China to treat various chronic pain and itch conditions. 6 In Japan, Neurotropin is covered by health insurance for the treatment of pruritus associated with skin diseases, symptomatic neuralgia, lower back pain, neck-shoulder-arm syndrome, allergic rhinitis, and sequelae of subacute myelo-optico-neuropathy (SMON) such as coldness, paresthesias, and pain. A recent report of a dry-skin mouse model has shown that Neurotropin inhibits the extension of nerves from the dermis into the epidermis, thereby decreasing the itch threshold and upregulating epidermal semaphorin 3A, a nerve repulsion factor. 7 The antipruritic effects of Neurotropin have been evaluated clinically in patients with pruritus, 8 but these studies only evaluated the short-term effects using qualitative scores. In this study, we aimed to evaluate the effects of Neurotropin on itch in patients with moisturizer-and antihistamine-resistant pruritus using itch scores and QOL score recorded in an itch symptom diary.

| Inclusion and exclusion criteria
The inclusion criteria of the study were: men and women aged 20 years and over in whom pruritus was clinically diagnosed, those receiving treatment with moisturizers and/or antihistamines for pruritus more than one week before the date of study consent, those with at least one of daytime and nighttime average Shiratori severity score (Appendix 1) 9 is 2 or more during the observation period, and those meeting any of the above criteria who provided informed consent.
The exclusion criteria of the study were: those with a history of hypersensitivity to Neurotropin (injection and tablet), those with a need of continuous treatment for other diseases which affect Neurotropin itself or the evaluation, those with pregnancy, pregnancy wish and breastfeeding, those with difficulty of regular visits, those with complications such as severe heart disease, liver disease, kidney disease, and others the doctor judges that it is inappropriate.

| Drug administration protocol
One ampule of Neurotropin (Nippon Zoki Pharmaceutical Co., Ltd.) was administered once per week by subcutaneous or intravenous injection.

| Concomitant medications that were permitted or prohibited
Medications that were already being taken by the patients during the observation period for the treatment of itch and its complications were allowed to be used concomitantly. However, the dosage and method of administration of the drugs used to treat itch could not be changed during the study period, and starting new medications (including over-the-counter drugs) to treat itch during the study period was not permitted.

| Discontinuation criteria
Patient participation was discontinued if a patient requested to withdraw from the study, if an investigator judged that discontinuation was necessary due to adverse events (including worsening of itch), or if medications being used concomitantly to treat dermal pruritus were stopped, added, or changed during the study period.

| Study period
The evaluations were performed over a total of eight weeks, including the one week prior to the start of treatment (observation period), and the seven weeks during the study treatment period.

| Evaluation methods
The study patients completed an itch symptom diary based on their own assessment of itch symptoms based on Shiratori severity scores (Appendix 1) 9 , visual analogue scale (VAS) scores, and the Dermatology Life Quality Index (DLQI).

VAS
The VAS was determined by the patients based on the intensity of itch from breakfast until dinner (daytime symptoms) and from dinner until breakfast (nighttime symptoms). The VAS was represented by a line of

DLQI
The DLQI questionnaire was answered by the patients at the end of a week (ie, at the end of observation period and at the end of each treatment week). The DLQI scores were reported as: 3 points for "Very much" or "Yes," 2 points for "A lot," 1 point for "A little," and 0 points for "Not at all" or "Not relevant." Incomplete answers were counted as 0 points. The patients were asked to complete DLQI surveys as described in the previous report. 10

| Overall evaluation
One investigator evaluated the clinical effects and adverse reactions and determined at the end of the study whether Neurotropin yielded improvement using a five-level grading scale (1: Marked improvement; 2: Moderate improvement; 3: Mild improvement; 4: Unchanged; 5: Worsened). For those who did not complete the itch symptom diary (ie, those who did not write in the itch diary at week 7), the last week of data recorded in the diary was used as a substitute for treatment week 7 data.

| Adverse reactions
When adverse reactions were judged to be caused by Neurotropin, the symptoms, onset, timing, severity, treatment, and outcomes were recorded. The principal investigator provided comments regarding any suspected relationship between the adverse effect and Neurotropin. We calculated the percentage of patients with at least one adverse event related to Neurotropin.

| RESULTS
All 33 patients were administered one ampule per week of Neurotropin, with 22 patients having received subcutaneous injections and 11 having received intravenous injections. The full evaluation of the itch severity scores is shown in Table 1 and Figure 1. The VAS scores for itch are shown in Table 2 and Figure 2, and the DLQI scores are shown in Table 3 and Figure 3.
The itch severity scores were recorded each week and compared to the score recorded in the observation period. The severity score decreased each week, and a significant decrease was seen from week 3 onward in both daytime and nighttime itch based on the Wilcoxon sign test results (Table 1 and Figure 1). In addition, multi-

| DISCUSSION
This study demonstrated that Neurotropin decreases itch and improves QOL with potential placebo effects in patients with moisturizer-and antihistamine-resistant pruritus. These improvements appeared after two or three weeks with respect to itch and after four weeks based on the DLQI.
Although this study was limited by the absence of a placebo control, the administration of Neurotropin resulted in a significant In the previous investigation that evaluated intravenous, or subcutaneous Neurotropin administration to 45 patients with intractable pruritic skin disease, moderate or better improvement of daytime symptoms was found in 37.8% of patients and that for nighttime symptoms was found in 40.0% of patients after a two-week administration. 11  It is noteworthy that the patients with moisturizer-and antihistamine-resistant pruritus were enrolled in this study. Daily use of antihistamines is considered to be effective and is recommended in the guidelines for generalized skin pruritus. 5 In an open-study investigating the effects of antihistamines on generalized skin pruritus, improvement in itch was found in 52.6% of the patients with pruritic diseases. 12 In the present study, we enrolled subjects with pruritus resistant to antihistamines as well as topical steroids and moisturiz- Metabolic syndrome includes one case each of chronic kidney insufficiency, and hepatic cirrhosis and hemodialysis. Endocrine disorders include one case each of myopathy, and hemodialysis and hepatocirrhosis.
The most frequently presumed cause of itch was senile xerosis in our patients (36.3%). Metabolic syndrome, endocrine disorders, and psychogenic disease were found in 9.0% of the patients ( Table 4).
The weekly administration of Neurotropin was equally effective for each group as shown in Table 5, indicating that Neurotropin has antipruritic effects regardless of the cause of the itch.
In the present study, Neurotropin was administered to one subject who was already taking nalfurafine hydrochloride. In this patient, both the daytime and nighttime Shiratori severity scores fell from 2.6 to 1.1, and the VAS score for itch fell from 7.9 to 1.9 in the daytime observations and from 7.9 to 1.7 in the nighttime observations. This suggests that Neurotropin suppresses itch by a different mechanism than nalfurafine hydrochloride, and also shows its synergistic effect with nalfurafine hydrochloride. was not apparent in our study.
In conclusion, administering Neurotropin to patients with refractory pruritus resulted in a significant reduction in itch by all measures (Shiratori severity scale, VAS value for itch, and DLQI) over the duration of the study period. This reduction was also confirmed after the multiple comparison evaluation. These results demonstrated that Neurotropin is effective in the treatment of moisturizer-and antihistamine-resistant pruritus.

ACKNOWLEDG EMENTS
We are grateful to the doctors in the Department of Dermatology of Shimane University for their cooperation with this study.

CONFLI CT OF INTEREST
The authors declare no conflict of interest. Psychogenic disease 0 (0.0) 1 (33. Metabolic syndrome includes one case each of chronic kidney insufficiency, and hepatic cirrhosis and hemodialysis. Endocrine disorders include one case each of myopathy, and hemodialysis and hepatocirrhosis.