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The effect of subcutaneous injection of methylprednisolone acetate and lidocaine for refractory postherpetic neuralgia: a prospective, observational study

Abstract Background Postherpetic neuralgia (PHN) is the most common and bearable complication of herpes zoster (HZ). This pain may have negative impact on the patient's all aspects of daily life and health‐related quality of life (HRQOL). Despite numerous advances in treatment, many patients remain resistant to the current therapy options. It is the first time subcutaneous injection of methylprednisolone acetate and lidocaine has been used to treat refractory PHN. We report the results of this treatment evaluating pain relief and HRQOL improvement in this disorder. Methods A total of 43 patients with refractory PHN was enrolled in the observational study. All patients received daily subcutaneous injection of methylprednisolone acetate and lidocaine for 10 consecutive days. The severity of pain was assessed by using Visual Analog Scale (VAS), and 36‐Item Short Form Survey (SF‐36) was applied to evaluate HRQOL. Assessment of the pain and HRQOL was carried out at baseline and posttreatment at 4 weeks as well as 6 and 12 months. Results At baseline, all patients experienced severe PHN with average VAS scores of 8.44 ± 0.85 (minimum 7; maximum 10). At 4 weeks, 6 months, and 12 months after treatment, the pain had significantly decreased (P < .001), and all subjects showed significant improvement in all eight domains of HRQOL. No major adverse events associated with the subcutaneous injection were observed. Conclusions Our results indicate that subcutaneous injection of methylprednisolone acetate and lidocaine can be an effective and safe treatment for PHN.


| INTRODUCTION
Postherpetic neuralgia (PHN), a feared complication of herpes zoster (shingles), is commonly defined when herpes-associated pain persists 3 months or longer following herpes zoster outbreak. 1,2 The typical characteristic of this chronic neuropathic pain is various including constant aching or intense burning pain, a paroxysmal, lancinating pain. It is also frequently accompanied by allodynia (pain from usually nonnoxious stimuli) and/or hyperalgesia (increased response caused by stimuli that normally provoke pain). 3,4 The negative impacts on patients' activities of daily living and health-related quality of life (HRQOL) may be devastating. 5 It affects not only physical but also functional and psychological health of the patients and even spouses and relatives. [6][7][8] Additionally, PHN has a negative effect on healthcare system as well as a whole society. 5 Despite numerous advanced treatments, PHN can be prolonged for many months or even years and refractory to currently available therapy options. 5,9 Subcutaneous injection of corticosteroids and local anesthetics has been administered to prevent and treat PHN 10,11 , but not yet to be used to treat refractory PHN. We carried out this study to assess the effectiveness of subcutaneous injection of methylprednisolone acetate and lidocaine on this condition. We defined refractory PHN as constant aching or intense burning pain, a paroxysmal and lancinating pain with allodynia and/or hyperalgesia that was in the restriction of dermatome involved to original herpes zoster, 12 and did not respond to conventional treatment including anticonvulsants (gabapentin and pregabalin), tricyclic antidepressants (amitriptyline and nortriptyline), topical agents (5% lidocaine patch), tramadol (in combination with acetaminophen), or patients had contraindications to or intolerance of the drugs. The patients were to be included only if the pain duration was longer than 3 months after the resolution of the HZ-associated skin rash.
We excluded the cases with one or more of the following conditions: coagulation disorders due to any origin; bacterial or fungal infection in the involved dermatome; polyneuropathy; neuropathic pain due to other causes, known allergy to methylprednisolone acetate or lidocaine; serious immunodeficiency diseases (eg, HIV and cancer).

| Protocol
All eligible patients received a combination of methylprednisolone acetate (5-10 mg) and lidocaine 2% (6-12 mL), depending on the severity and area of pain. The affected site was divided into a chessboard form with 0.3 to 1.0 mL subcutaneously injected at each point to cover the entire pain area ( Figure S1).
The injection was once daily administered with a 25 G needle for 10 consecutive days. The injection points can be changed if pain at the previous injected point increases or a large hemorrhage occurred.
The severity of pain was assessed by using VAS. It consists of a straight horizontal line of 100 mm length. The ends are defined as the extreme limits of the pain "no pain at all" on the left end (0 cm) and "as bad as it could be" on the right end of the scale (100 mm).
The VAS was frequently used for measurement of pain in recent years. 13 The severity of pain was categorized as severe (VAS score:

| Statistics
The data were entered into Excel spreadsheet and then transferred to SPSS software for analysis and processing. The data are expressed as mean, standard deviation, maximum value, minimum value, number, and percentage. Numeric data were expressed as mean ± SD, and non-numeric data were presented as percentage. The difference between the averages is assessed by the Wilcoxon signed rank sum test. The continuous line graphs were used to present the change of pain severity (VAS score) and improvement of HRQOL (SF-36 score) over time. P < .05 was considered statistically significant. The data were analyzed on SPSS software (version 22.0) for Windows operating system (SPSS Inc. IBM Company) ( Figure 1).

| RESULTS
During the 18-month enrollment period, a total of 46 PHN patients were screened and 43 patients recruited in the study. Three of them were excluded for declining to participate in the study, and 43 subjects completed the 12-month follow-up. The clinical and demographic characteristics of the subjects before the start of the research are presented in Table 1.  The HRQOL, as measured by SF-36, showed statistically significant improvement in all eight domains from baseline at any follow-up evaluation ( Figure 3 and Table S1).

| DISCUSSION AND CONCLUSION
PHN is the most common and troublesome chronic complication associated with HZ. 17,18 Managing PHN, so far, can be still a challenging process due to the lack of the therapeutic approach with both efficacy and tolerability. 3  In terms of pain-relieving effect, we found that within initial 2 to Only one 74-year-old female patient with HZ at lower thoracic (D9-D12) area, 12 months after intervention, reported intermittent mild intra-abdominal pain with VAS-score of 3 (before treatment VAS-score of 9), but the cutaneous symptoms cleared completely with this treatment. Therefore, the patient did not require any further intervention.
It has been known that neural and perineural inflammation, peripheral sensitization of primary afferent sensory nerve fibers, and central sensitization are thought to be responsible for PHN. [22][23][24] Lidocaine is proposed to block voltage-gated sodium channels of dysfunctional small myelinated Aδ-and unmyelinated C-fibers resulting in reduction in ectopic impulses and decreased spontaneous pain, allodynia, and hyperalgesia. 25,26 Corticosteroids act as an antiinflammatory agent, which has been suggested to minimize nerve damage and stabilize neural-cell membranes and suppress ectopic neural discharges of C-fibers, and thereby relieve HZ-associated pain. 27,28 Additionally, among available corticosteroids, methylprednisolone acetate has been found to be the least neurotoxic agent in humans. 29 Therefore, this drug was used in our study. An intervention course of 10 consecutive days was applied because a pain-relieving permanent effect can be obtained with a series of 8 to 12 infiltrations on consecutive days. 28 Moreover, little additional benefit can be expected after the initial 12 to 14 intervention days, 30   result after treating with a single-level T10 thoracic transforaminal epidural steroid injection. 34 In 2018, Oh also reported a 82-year-old male patient with a treatment-resistant thoracic PHN who was successfully treated using ultrasound-guided pectoral II block. 35 In a more recent research, Hu and coworkers treated 13 severe PHN patients who had VAS-score of 9 or 10 with subcutaneous Botulinum F I G U R E 3 Health-related quality of life before treatment and 12-month follow-up Toxin-A injection. The results suggested that this drug was an effective approach for reducing pain in patients with PHN. However, the authors did not mention whether prior to enrollment the patients were refractory to conventional treatments or not. 36 In general, to date, the effective treatments for refractory PHN are still lacking, and seeking new methods are always necessary.

| Complications
The subcutaneous injection of methylprednisolone in combination with lidocaine is an invasive intervention, thereby technique and medication-associated complications can occur during or after procedure. Local complications such as abscesses, cutaneous atrophy, and scarring have been reported in previous investigations, 10,30 but they were not observed in our study. In our opinion, that was because we used only a small dose of methylprednisolone acetate (5-10 mg) diluted in lidocaine (6-12 mL), so these complications were minimized.
In the present study, subcutaneous hemorrhage was commonly seen, and it was noted predominantly in older female patients. However, this bleeding was self-limited and completely absorbed over time.
Another frequent minor complication was pain at the injection points.
We found that this pain only persisted for one to two initial intervention days, and all patients showed a good tolerance. Systemic complications: vertigo due to lidocaine intoxication, and weight gain caused by fluid retention effect of corticosteroid were also complained by a few patients, but they were minimal, transient, and rapidly reversible. Despite the appearance of the abovementioned adverse effects, they were generally mild and did not disrupt the course or success of the treatment.

| Limitations
A major limitation in this research was the lack of a control group for comparison. However, as earlier described, prior to enrolling, all available conventional medications for PHN management had been prescribed for the patients, but they all showed no response or tolerance. Therefore, we did not establish control groups as patients were treated with the above drugs. Ideally, the standard control group in our study should have been treated with subcutaneous injection of saline solution alone (placebo), but it would have been impossible because of different reasons as mentioned in previous studies. 10,11,30 An additional drawback was the small sample size. From May 2016 to October 2018, we screened a total of 43 refractory PHN patients, but they all agreed to participate in the research and none of them dropped out during the 12-month follow-up.

| Advantages
Despite the abovementioned limitations, the method described in our study offers many advantages. Firstly, it is highly effective and safe.
The excellent results reach 100% and exceed the initial expectations while the major complications are not seen, and all side effects are mild and reversible. Secondly, the intervention presents as a simple procedure because it only requires a syringe and a needle as an equipment that is easily available at any hospital or clinic. Additionally, any physician can implement this treatment method. Lastly, this treatment can be applied to the treatment of HZ at any site of the body. This point is superior to other interventions such as intrathecal or epidural injection; paravertebral block, which cannot be applied for PHN involving the trigeminal nerve.
In conclusion, the results indicate that subcutaneous injection of methylprednisolone acetate and lidocaine can be an effective and safe treatment for refractory PHN.
and that any discrepancies from the study as planned have been explained.

FINANCIAL STATEMENT
In our study, there are no funding sources or financial supports.
Therefore, there is no conflict of interest.

DATA AVAILABILITY STATEMENT
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.