A randomized controlled trial of botulinum toxin A for treating neuropathic pain in patients with spinal cord injury.

BACKGROUND: To assess the effect of botulinum toxin A (BTA) for treating neuropathic pain in patients with spinal cord injury (SCI).
METHODS: A total of 44 patients with SCI with neuropathic pain were randomly divided into the intervention group and the placebo group, each group 21 patients. The subjects in the intervention group received BTA (200 U subcutaneous injection, once daily) at the painful area, whereas those in the placebo group were administered a saline placebo. This study was conducted from December 2014 to November 2016. The primary outcome was measured using the visual analog scale (VAS). The secondary outcomes were measured using the short-form McGill Pain Questionnaire (SF-MPQ), and World Health Organization quality of life (WHOQOL-BREF) questionnaire. All outcome measurements were performed before and after 4 and 8 weeks of intervention.
RESULTS: Forty-one participants completed the study. The intervention with BTA showed greater efficacy than placebo in decreasing the VAS score after week 4 and week 8 of treatment. Significant differences in the SF-MPQ and WHOQOL-BREF were also found between the 2 groups.
CONCLUSION: The results of this study demonstrated that BTA might decrease intractable neuropathic pain for patients with SCI.

RCT Entities:   Population Interventions Outcomes

Introduction

Neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory system.”[ It is one of the most common complications of spinal cord injury (SCI), with prevalence ranging between 75% and 81%.[ This type of pain often leads to poor quality of life and interferes with cognitive, emotional, and physical functioning following SCI.[ Moreover, the pain is usually severe, refractory to treatment, and persistent for a long time.[

Botulinum toxin type A (BTA) is a potent neurotoxin and is usually used for treating focal muscle dystonia and spasticity.[ Previous studies have reported that BTA had promising effect for treating chronic neuropathic pain syndromes associated with muscle disorders.[ Its mechanism involves the preventing neurogenic inflammation and also reducing the peripheral sensitization of nociceptive fibers.[ Moreover, its central mechanism involves the antinociceptive effect by the axonal transport on the spinal cord.[

In this study, we tested the hypothesis that BTA could reduce neuropathic pain in patients with SCI.

Methods

Design

This study was designed as a randomized double-blind placebo-controlled trial. This study was approved by the Medical Ethical Committee of Hongqi Hospital of Mudanjiang Medical School and was conducted at this hospital. Forty-four SCI patients with neuropathic pain were recruited in this study from December 2014 to November 2016. All patients were identified and selected based on the inclusion and exclusion criteria. All included subjects were randomly divided into the intervention group or the placebo group in a 1:1 ratio.

Inclusion and exclusion criteria

The inclusion criteria were patients with SCI with neuropathic pain aged from 18 to 65 years, levels of SCI from A to D (American Spinal Injury Association [ASIA] impairment scale), more than 1 year after SCI, daily neuropathic pain lasting more than 3 months, and visual analog scale (VAS) score ≥40 (VAS, 0–100 mm). The subjects were excluded if they had a contraindication, hypersensitivity, history of BTA, any other reasons that led to neuropathic pain except SCI, coagulation disorders, pregnancy, or declined to participate. However, the other concomitant analgesic medication with stable dose was allowed in this study.

Randomization and blinding

Block randomization schedule was performed using a computerized number generator by SAS Software (version 8.3; SAS Institute Inc, Cary, NC). The randomization assignments were concealed in opaque sequentially numbered sealed envelopes. Then, 44 eligible patients were assigned at a 1:1 ratio to the intervention group or placebo group. The patients, clinicians, outcome assessors, as well as data analysts were blinded to the treatment allocation.

Intervention

All participants were administered a subcutaneous injection of 200 U BTA (Research Biological Institute of Lanzhou HengLi Botox, Lanzhou, Gansu, China) in 4 mL saline solution at the painful area in the intervention group. Patients in the placebo group received 4 mL saline solution at the painful area. Subjects in both groups were treated once daily for 8 weeks.

Outcome measurements

The primary outcome was measured using VAS scale (0 = no pain, 100 = worst pain imaginable). The secondary outcome measurements consisted of the short-form McGill Pain Questionnaire (SF-MPQ) and World Health Organization quality of life (WHOQOL-BREF) questionnaire.[ All the primary and secondary outcomes were measured and evaluated after 4 weeks and 8 weeks of treatment. In addition, all the adverse events (AEs) of BTA were recorded in this study.

Statistical analysis

The estimated sample size was 22 patients in each group with the VAS of 20 mm, and the difference of standard deviation of 2 mm at week 4 (change from baseline), α = 0.05 (2-sided) and β = 0.20.[ Assuming a 15% dropout rate, at least 44 patients with 22 in each group were required to be recruited in this study. All outcome data were analyzed by an intention-to-treat (ITT) approach. t test or Wilcoxon rank sum test was used to analyze the data with relative risks and 95% confidence intervals.

Results

Sixty-seven patients initially entered the study (Fig. 1). Of these 67, 20 individuals did not meet the inclusion criteria, and 3 declined to participate. Therefore, 44 patients were randomized into the study. All included participants received the study medication and all the data of primary and secondary outcomes were analyzed by an ITT approach. Three patients withdrew from the study. The major reasons for withdrawal were the withdrawal of consent and patients who were lost to follow-up (Fig. 1). In addition, the characteristics of all included patients at baseline are shown in Table 1.

Figure 1

Flow of patients through the trial.

Table 1

Patients characteristics at baseline.

We examined the mean change from the baseline by intervention and the difference between BTA and placebo groups to evaluate the efficacy of BTA. The results for the efficacy endpoints at the end of week-4 and week-8 are summarized in Table 2. BTA treatment improved all primary and secondary outcomes compared with placebo at the end of week 4 and week 8. At the end of week 4 of treatment, the BTA group exhibited significant improvements in VAS, SF-MPQ, and WHOQOL-BREF scores compared with the placebo group (Table 2). These improvements were maintained throughout the end of week 8 (Table 2).

Table 2

Outcome measurements at the end of 4-week, and 8-week treatment (change from baseline).

No allergic reactions occurred in both groups. In addition, no other local or systemic side effects were recorded and reported in this study, except 4 patients in the BTA group and 3 participants in the placebo group reported that the injections were painful but with no significant difference. In addition, no treatment-related deaths were found in both groups.

Discussion

Neuropathic pain manifests as burning, electric, or shooting with accompanying sensory changes of allodynia or hyperalgesia. It often consists of 2 subtypes with at-level and below-level neuropathic pain according to the pain pathology. The first involves a segmental pattern and occurs at the associated level of neurological injury or within 3 dermatomes below this level.[ The latter subtype occurs more than 3 dermatomes below the neurological level of injury and is commonly associated with spinal cord trauma and ischemia.[ In this study, BTA injection was used to treat below-level neuropathic pain after SCI according to the pathological differences underlying the 2 different pain types.

BTA has been previously used to treat neuropathic pain.[ Its pain relief effect might be mediated through the sensory system.[The dosage of BTA previously used for treating neuropathic pain was between 2.5 and 7.5 U/cm2 at each painful surface area with the maximum total dosage from 100 to 200 U.[ In this study, the painful surface area in patients with SCI was larger than that in patients with other diseases. Therefore, we used the dose of BTA at 200 U at the painful area, and the maximal injection area was <20% of the total body surface.

Although several clinical studies have reported the positive effect of BTA for neuropathic pain relief, its mechanism is still far from clarity. The previous study found that BTA may reduce the neuropathic pain of SCI by regulating the receptors and ion channels from the reorganization of the nervous system and its functional changes.[ Some other studies found that neuropeptides played a very pivotal role in the process of the peripheral sensitization in nociception.[ Therefore, the possible mechanisms of BTA injection for treating neuropathic pain in patients with SCI may be by preventing neuropeptides in the periphery and the spinal cord. In addition, BTA might induce neuropathic pain relief by decreasing calcium-mediated neurotransmitter release.[

In this study, our results demonstrated that 200 U BTA injection at each painful area is safe and effective in reducing the VAS and SF-MPQ scores in patients with SCI with neuropathic pain. BTA also significantly improved the WHOQOL-BREF score than placebo.

This study has several limitations. First, this study was conducted only at the Hongqi Hospital of Mudanjiang medical school, and all the participants were Han Chinese, which might have influenced the generalizability of our findings to patients in other hospitals and other ethnicities. Second, pain relief was evaluated using the VAS, which is a relatively subjective tool and may be affected by multiple unknown factors. Finally, it was impossible for patients to interrupt their standard medication regimens; hence, most patients continued to take their daily medications. Although the baseline medication was similar between the 2 treatment groups, the observed effect might have been the result of the synergistic effect of BTA and medication and not BTA alone.

The results of this study showed that the administration of BTA injections in patients with SCI induced a significant neuropathic pain relief and was safe. Future clinical trials are still needed to further explore its mechanism and optimal administration, such as dose, duration, and onset time.