Botulinum Toxin Treatment for Nocturnal Calf Cramps in Patients With Lumbar Spinal Stenosis: A Randomized Clinical Trial

Accepted Manuscript Botulinum toxin treatment for nocturnal calf cramps in patients with lumbar spinal stenosis: A randomized clinical trial Sang Jun Park, MD, Kyung Bong Yoon, MD, PhD, Duck Mi Yoon, MD, PhD, Shin Hyung Kim, MD, PhD PII:

S0003-9993(17)30082-5

DOI:

10.1016/j.apmr.2017.01.017

Reference:

YAPMR 56799

To appear in:

ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Received Date: 13 September 2016 Revised Date:

17 November 2016

Accepted Date: 12 January 2017

Please cite this article as: Park SJ, Yoon KB, Yoon DM, Kim SH, Botulinum toxin treatment for nocturnal calf cramps in patients with lumbar spinal stenosis: A randomized clinical trial, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2017), doi: 10.1016/j.apmr.2017.01.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title page

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Running title: botulinum toxin treatment and nocturnal calf cramps

Botulinum toxin treatment for nocturnal calf cramps in patients

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with lumbar spinal stenosis: A randomized clinical trial

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Sang Jun Park MD, Kyung Bong Yoon MD, PhD, Duck Mi Yoon MD, PhD, and Shin Hyung Kim MD, PhD

Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute,

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Yonsei University College of Medicine, Seoul, Republic of Korea

*Corresponding author: Shin Hyung Kim, MD, PhD. Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute,

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Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea.

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Tel: 82-2-2228-7500, Fax: 82-2-364-2951, E-mail: [email protected]

The authors declare no conflicts of interest. This study was registered at ClinicalTrials.gov (ref: NCT 02444351). This study was supported by the research grant from Yonsei University College of Medicine, Seoul, Korea (grant number 6-2015-0019).

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Abstract

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Objectives: To evaluate the clinical effectiveness of botulinum toxin (BTX) injection into the

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gastrocnemius muscles in lumbar spinal stenosis (LSS) patients with frequent nocturnal calf

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cramps (NCCs)

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Design: Prospective randomized clinical trial

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Setting: Outpatient department for interventional pain management.

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Participants: Fifty LSS patients with a frequency of NCCs ≥ once per week were enrolled.

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Intervention: Patients were randomly allocated to receive either conservative treatments plus

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gabapentin (Group GPN) or BTX injection (Group BTX).

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Main outcome measures: We assessed back/leg pain intensity, the frequency and severity of

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NCCs, insomnia severity, and functional disability at baseline and after 2 weeks, 1 month,

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and 3 months. Additionally, patient global impression of change was assessed.

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Results: Forty-five patients completed all assessments (Group GPN; n=21, Group BTX;

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n=24). Compared with Group GPN, leg pain intensity, cramp frequency and severity were

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significantly decreased in Group BTX at all follow-up visits (all, p<0.01). Also, insomnia

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significantly improved in Group BTX at 2 weeks (p=0.018) and 1 month follow-up (p=0.037).

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Functional disability significantly improved in Group BTX at 2 weeks follow-up (p=0.041).

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At the 3 month follow-up, patients in Group BTX reported higher impression of improvement

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for NCCs symptoms than those in Group GPN (p<0.001). A mean dose of 642.8 mg

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gabapentin was given daily in Group GPN, but seven patients (33.3%) reported systemic side

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effects. There were no serious complications related to BTX use.

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Conclusions: BTX treatment appears to be effective and safe for NCCs in symptomatic LSS

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patients receiving conservative care.

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Keywords: botulinum toxin; nocturnal calf cramps; spinal stenosis

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List of abbreviations: BTX, botulinum toxin; ISI, Insomnia Severity Index; LSS, lumbar

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spinal stenosis; NCCs, nocturnal calf cramps; ODI, Oswestry Disability Index; PGIC, patient

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global impression of change

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Nocturnal calf cramps (NCCs) occur as sudden and intensely painful involuntary

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contractions of the calf muscles.1,2 Cramps are generally a benign and transient problem, but

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frequent NCCs can cause prolonged pain and significant distress.1,3 Furthermore, NCCs are

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associated with substantially reduced quality of sleep and reduced physical aspects of health-

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related quality of life.4

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NCCs are more prevalent in patients with lumbar spinal stenosis (LSS) than in the general

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elderly population.5,6 The high incidence of NCCs in LSS patients could be attributed to

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disturbance in the function of the lumbar spinal nerves controlling the tonus of the affected

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muscles.7 Therefore, both spinal and peripheral mechanisms for cramp development may

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contribute to the high prevalence of NCCs in LSS patients with prolonged compression of the

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spinal nerve.7,8 Interestingly, approximately half of LSS patients consistently suffer from

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NCCs even after decompression surgery.5 Collectively, patients with LSS are vulnerable to

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NCCs, and it is difficult to treat cramps in this population.

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The use of botulinum toxin (BTX) injection is one option for the management of focal

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spasticity. The toxin affects presynaptic cholinergic nerve terminals and inhibits the release of

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acetylcholine into the neuromuscular junction, which in turn causes muscle relaxation.9 Also,

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the therapeutic effect of BTX could result from the reduction of muscle afferent input due to

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fusimotor synapse blockage.10,11 Thus, BTX could be beneficial for treating NCCs in LSS

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patients. We hypothesized that BTX injection into the gastrocnemius muscles would reduce

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leg pain and lead to better patient global impression of change following NCCs treatment in

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symptomatic LSS patients.

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The aim of this study was to evaluate the effect of BTX injection into the gastrocnemius

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muscles on leg pain in LSS patients with frequent NCCs receiving conservative treatments.

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Also, we evaluated cramp frequency and severity, insomnia severity, pain-related disability,

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and patient global impression of change during 3 months of follow-up.

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Methods

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Study population and randomization This prospective randomized clinical trial was approved by the Institutional Review Board

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(ref: 4-2015-0169) and was registered at ClinicalTrials.gov (ref: NCT 02444351). After

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written informed consent was obtained from all patients, 50 consecutive LSS patients

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(including 34 females), aged 20–80 years, who reported NCCs at least once per week were

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enrolled in this study. Patients were enrolled from our outpatient department for pain

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management between May 2015 and March 2016. We included patients with typical

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neurogenic claudication symptoms followed by leg pain with spinal stenosis confirmed by

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magnetic resonance imaging (MRI). Chronicity was established by the persistence of pain

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longer than six months. For the purpose of this study, muscle cramps were required to occur

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exclusively at night while at rest and not be preceded by physical exercise. Patients were

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excluded if they suffered from renal/endocrine diseases with electrolyte/hormonal imbalance,

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congenital musculoskeletal disease, or had frequently taken sleeping pills or sedatives for 1

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month or more. Patients also were excluded if they refused to provide consent, had other pain

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or disease requiring treatment on a preferential basis, were unable to communicate, or had

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cognitive impairment due to any psychiatric/central nervous system disturbance. Patients

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with diagnosed cancer, recent spine compression fractures, and primary insomnia were

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excluded. Before the examination, we recorded patient use of medications that can affect the

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occurrence of cramps such as diuretics, statins, and calcium channel blockers. The patients

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were requested not to change their medication during the study period. Patients were

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randomly assigned to one of two groups according to a computer-generated random-numbers

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table. Patients received routine conservative treatments plus gabapentin (Group GPN) or

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conservative treatments plus BTX injection (Group BTX). Conservative treatments for LSS

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symptoms included exercise, analgesic medication, injection therapy including epidural

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injections, and physical therapy in both groups. All enrolled patients received basic education

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for home exercise and stretching using an illustrated brochure at the first visit day. For

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treatment of NCC symptoms, gabapentin 300 mg to 1,200 mg per day was administrated in

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Group GPN, and BTX injection was performed in Group BTX. In Group GPN, the dose of

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gabapentin was titrated according to patient characteristics, comorbidities, and reported side

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effects.

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BTX injection procedure

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The same experienced pain physician performed all injections in Group BTX. The

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standardized injection sites were referenced from the clinically recommended area for BTX

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injection based on previous anatomical studies of the motor endplate zones of gastrocnemius

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muscles.12 The injection points for the gastrocnemius were marked along a reference line

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from the medial malleolus up to the proximal margin of the medial tibial condyle, at three-

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quarters for the medial head and four-fifths for the lateral head. Patients were placed in the

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prone position and prepared by placing sterile draping over the affected calves. A SonoSite

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M-Turbo ultrasound unit (SonoSite Inc, Bothell, WA, USA) with a 7.5-MHz linear probe and

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a 40-mm, 25-gauge needle were used for every patient. The probe was positioned in the

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transverse view, perpendicular to the gastrocnemius muscle surface, while the needle was

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inserted into the targeted muscle at a 30-degree angle to the probe. The BTX (Botulinum

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toxin type A, Nabota®, Daewoong Pharmaceutical Co., Ltd., Seoul, Korea) dose was 100

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units in 5 ml of 0.9% saline for the gastrocnemius medialis and lateralis. BTX was injected

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into two to three points on each medial and lateral gastrocnemius.

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Demographic and clinical data measures

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On the day of the first visit, patient data was collected including age, sex, body mass index

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(BMI), duration of pain, presence of medical comorbidities (diagnosed hypertension, diabetes

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mellitus, heart disease, or neurologic disease currently requiring medical treatment), current

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medications, spinal surgery history, presence of multilevel stenosis, severity of spinal stenosis

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based on MRI finding at the most severe level13, back/leg pain intensity using an 11-point

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numeric rating scale (NRS; 0= no pain, 10= the worst pain), and the frequency and severity

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of NCCs. We also investigated insomnia severity using the Insomnia Severity Index (ISI),14

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and the degree of disability/estimating quality of life was determined using the Oswestry

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Disability Index (ODI).15 The severity of cramps was graded from 0 to 4 according to the

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following functional criteria: 0= no cramps, 1=occasional cramps not interfering with daily

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activity or sleep, 2=frequent cramps not significantly interfering with daily activity or sleep,

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3=frequent cramps limiting daily activity or sleep, and 4=continuous cramps severely

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interfering with daily activity or sleep.11

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Patients were evaluated at baseline and 2 weeks, 1 month, and 3 months after the first

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visit. We assessed back/leg pain intensity, the frequency and severity of NCCs, ISI, and ODI

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measures at each assessment follow-up. Additionally, a seven-point patient global impression

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of change16 (PGIC; 1, very much improved; 2, much improved; 3, minimally improved; 4, no

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change; 5, minimally worse; 6, much worse; or 7, very much worse) for NCC treatment was

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assessed at the 3 month follow-up. We also compared conservative treatments for LSS during

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the study period between the two groups. In Group BTX, systemic adverse events or local

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complications associated with BTX injection were investigated. We also observed the motor

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weakness of knee/ankle joints or walking difficulty in BTX-treated patients. Another

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independent observer who was not involved in the study verified and recorded all

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measurements.

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Statistical analysis Sample size calculation was based on leg pain score as the primary endpoint. A previous

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study demonstrated that the standard deviation (SD) of the leg pain score was approximately

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2.3 in LSS patients.17 Assuming a 5% 2-tailed significance level (α=0.05) and power of 80%

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(β=0.80) to detect a mean difference of 2.0 points in NRS between the groups using an

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independent t-test, 22 patients were required in each group.16 To allow for possible dropouts,

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we calculated that 25 patients would be required for each group.

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All data are expressed as mean ± SD, median (interquartile range), or number of patients.

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The normality of distribution was assessed with the Shapiro-Wilk test. Demographic and

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clinical data were compared between the two groups using the t-test, Chi-square test, or

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Mann–Whitney U test as appropriate. Comparison of continuous variables (NRS pain scores,

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ISI, ODI) between the two groups at each assessment time point and changes between time-

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points within a group were compared using two-way repeated measure analysis of variance.

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Adjustment for multiple comparisons was made by the Bonferroni method. To compare

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nonparametric variables (frequency and severity of cramps) between the two groups at each

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assessment time point, the Friedman test with a post-hoc test using the Wilcoxon rank-sum

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test were used. PGIC score at 3 months was compared between the two groups using the

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Mann–Whitney U test. All statistical data were analyzed using the Statistical Package for the

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Social Sciences 20.0 (SPSS Inc, Chicago, IL, USA).a A p value less than 0.05 was considered

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statistically significant.

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Results A total of 366 symptomatic LSS patients were initially assessed for eligibility in this study,

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and 62 patients (16.9%) met the inclusion criteria. Finally, 50 patients consented to

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participate in the study and were randomly assigned to groups, and 45 patients (90%)

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completed all assessments during the 3 months of follow-up (Fig 1). The baseline

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characteristics and clinical data were similar between the groups (Table 1).

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Changes in patient-reported leg pain scores throughout the study period are illustrated in

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Fig 2. Baseline leg pain scores were similar between Group GPN and Group BTX (7.1 ± 1.6

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vs. 7.4 ± 1.7, Cohen’s d=-0.181, p=0.657). In Group GPN, the pain score at the 3 month

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follow-up decreased when compared with baseline (7.1 ± 1.6 vs. 6.3 ± 1.4, Cohen’s d=0.582,

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p=0.043), but the pain score at 2 weeks (7.1 ± 1.6 vs. 6.6 ± 1.2, Cohen’s d=0.353, p=0.142)

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and 1 month (7.1 ± 1.6 vs. 6.4 ± 1.5, Cohen’s d=0.451, p=0.169) were not significantly

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different from baseline (F=2.822, p=0.068). In Group BTX, leg pain scores at all follow-up

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times were lower than baseline (7.4 ± 1.7 vs. 4.4 ± 2.6, Cohen’s d=1.365, p<0.001; 7.4 ± 1.7

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vs. 4.0 ± 1.9, Cohen’s d=1.885, p<0.001; 7.4 ± 1.7 vs. 4.3 ± 1.6, Cohen’s d=1.877, p<0.001),

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indicating a significant time effect (F=19.366, p<0.001). The interaction of treatment group

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by time in leg pain scores is significant (F (3, 35.338) = 11.995, pGroup×Time < 0.001, η2 =

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0.218). Patients in Group BTX reported significantly lower leg pain intensity (mean

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difference [95% CI]) than Group GPN at 2 weeks (2.9 [1.2-4.7], Cohen’s d=1.086, p=0.003),

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1 month (3.3 [1.8-4.7], Cohen’s d=1.402, p<0.001), and 3 months (3.0 [1.8-4.2], Cohen’s

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d=1.330, p< 0.001).

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Changes in back pain scores, frequency and severity of NCCs, ISI, and ODI are presented

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in Table 2. Baseline back pain score, frequency and severity of NCCs, ISI, and ODI were

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similar between Group GPN and Group BTX. In both groups, back pain scores gradually

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decreased during the study period (F=4.444, p=0.017; F=6.525, p=0.003), but there was no

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significant difference observed between the two groups at all follow-up times (Cohen’s d=-

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0.302, p=0.325, Cohen’s d=0.342, p=0.267, Cohen’s d=0.306, p=0.289, respectively).

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Compared with baseline, frequency and severity of NCCs gradually decreased in Group GPN,

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but the change was not remarkable (χ2=3.679, p=0.298; χ2=9.102, p=0.028). In contrast,

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frequency and severity of NCCs remarkably decreased in Group BTX at all follow-up times

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(χ2=38.211, p<0.001; χ2=42.958, p<0.001). Comparing the two groups, patients in Group

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BTX reported significantly lower frequency (z=-2.701, p=0.015; z=-2.808, p=0.005; z=-2.733,

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p=0.006) and severity of NCCs (z=-3.708, p<0.001; z=-2.894, p=0.004; z=-3.378, p=0.001)

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than those in Group GPN at all follow-up times. ISI and ODI significantly decreased in

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Group BTX throughout the study period (F=27.968, p<0.001; F=14.149, p<0.001), but not in

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Group GPN (F=1.965, p=0.155; F=2.605, p=0.085). The interaction of treatment group by

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time in ISI scores is significant (F (3, 94.680) =8.413, pGroup×Time < 0.001, η2 = 0.164).

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Comparing the two groups, ISI score (mean difference [95% CI]) was significantly lower in

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Group BTX than in Group GPN at 2 weeks (4.8 [1.5-8.2], Cohen’s d=0.857, p=0.018) and 1

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month (3.7 [0.5-7.1], Cohen’s d=0.690, p=0.037). At 3 months of follow-up, the ISI of Group

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BTX tended to be lower than Group GPN, but there was no statistically significant difference

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between the two groups after adjustment for multiple comparisons (Cohen’s d=0.591,

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p=0.112). The interaction of treatment group by time in ODI scores is significant (F (3,

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86.877) = 14.087, pGroup×Time < 0.001, η2 = 0.247). ODI score (mean difference [95% CI]) was

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significantly lower in Group BTX than in Group GPN at 2 weeks (13.1 [5.0-21.1], Cohen’s

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d=0.993, p=0.041). At 1 month and 3 months of follow-up, the ODI of Group BTX tended to

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be lower than Group GPN, but there was no statistically significant difference between the

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two groups after adjustment for multiple comparisons (Cohen’s d=0.676, p=0.089; Cohen’s

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d=0.623, p=0.113, respectively).

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Treatments were given over 3 months in the two groups, as shown in Table 3. Conservative

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management for LSS symptoms was similarly performed in both groups. In Group GPN,

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gabapentin was used for treatment of NCC symptoms with titrated doses. The mean dose of

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gabapentin in Group GPN was 642.8 mg daily; however, 7 patients (33.3%) reported

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difficulty in gabapentin use due to various side effects such as dizziness, drowsiness, and

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peripheral edema.

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The distribution of PGIC score at 3 months is presented in Table 4. The median value of

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PGIC was 4 (no change) in Group GPN and 2 (much improved) in Group BTX (U=50.50,

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p<0.001).

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Among the 24 patients in Group BTX, six, three, and 15 of the right, left, and both-sides of

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the gastrocnemius muscles were injected, respectively. There were no systemic adverse

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events such as dizziness, flu-like symptoms, or respiratory difficulty after BTX injection.

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Five patients (20.8%) reported mild to moderate pain on the injection sites for a few days

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after BTX injection, but infection and hematoma formation were not observed. In addition,

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no patients reported motor weakness in the knee or ankle joints or difficulty in walking after

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BTX injection during the study period.

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Discussion In this study, we found that BTX injection into the gastrocnemius muscles significantly

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reduced leg pain intensity and the frequency and severity of NCCs in LSS patients. These

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beneficial effects appear greater than those of conservative treatments including gabapentin.

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We also found that BTX treatment improved sleep quality and consequently led to higher

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impression of improvement for NCCs symptoms in this population.

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In the present study, our main finding was significantly reduced leg pain in LSS patients

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that received an adjuvant BTX injection. The most common indications for BTX treatment

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are painful syndromes in which an increase in the tonus of the muscles generates and or

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maintains a vicious cycle of muscle contraction-pain-muscle contraction.9 Focal ischemia or

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an accumulation of metabolites following cramps may lead to pain.1,3 In this respect, the

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primary effect of BTX in this study may be a reduction in muscle tone representing decreased

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frequency and severity of NCCs, with pain reduction occurring as a secondary effect to local

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muscle flaccid paralysis. On the other hand, in vitro and in vivo data have shown that BTX

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has specific anti-nociceptive activity relating to its effect on neurogenic inflammation, axonal

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transport, ganglion inhibition, and spinal and suprasegmental level inhibition.9,18 Furthermore,

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recent studies reported that BTX relieved pain in chronic pain conditions with a neuropathic

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pain component.19,20 Therefore, the therapeutic effect of BTX, which might influence the

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noxious sensory processing in the muscle, could also contribute to relieving leg pain in this

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study.

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In the current study, we observed an improvement of sleep quality following decreased

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frequency and severity of NCCs in patients that received BTX treatment. Because insomnia

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has been shown to have negative effects on pain, mood, and physical functioning, it may also

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negatively affect the clinical outcomes of chronic pain patients.21 Recent studies highlight the

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bidirectional relationship between pain and sleep in chronic pain.22 Thus, improvement of

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insomnia may positively influence pain and treatment satisfaction in LSS patients. We also

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observed a trend in improvement of functional disability representing decreased ODI in

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patients with BTX treatment. Because ODI topics include pain and insomnia, the reduced leg

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pain and insomnia severity could have influenced the lowered ODI results. However,

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clinically meaningful improvement of disability was not observed between the groups beyond

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2 weeks follow-up. In fact, although most of the BTX-treated patients reported much less

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pain in the treated legs, they consistently complained about other painful sites such as the low

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back or buttock pain. This could be the cause of no significant change of disability such as

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claudication. We noticed that the effect of local BTX treatment did not significantly affect the

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other LSS symptoms with typical chronic pain features.

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There is no gold standard therapy for NCCs in LSS patients.1-3 Muscle stretching and an

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exercise program may be effective as a first-line therapy for NCCs;1,2 however, poor

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compliance to exercise is frequently observed in real clinical practice, especially among

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elderly patients. Various pharmacologic treatments have been studied for NCCs, including

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quinine, magnesium, calcium channel blockers, vitamin E, and anticonvulsant medications.1-3

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Among them, two studies showed that gabapentin had beneficial effects for muscle cramps

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secondary to neurologic disease.23,24 Considering the potential side effects, we chose

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gabapentin for treatment of NCCs in control subjects. However, we did not observe a

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significant improvement in NCC symptoms in control subjects. Our study population mostly

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consisted of refractory patients who failed multiple previous treatments for LSS symptoms,

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including conventional epidural injection and surgery. The NCCs in LSS patients seem to be

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a complicated symptom and are difficult to treat, and usual treatment strategies for focusing

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spinal pain do not always ensure improvement of the NCC problem in this population.5,6

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Thus, our study suggests that BTX injection may be an effective therapeutic option for NCCs

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in selected patients with poor response to conventional therapies. Also, patients tolerated

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local BTX treatment better than gabapentin in this study. In elderly patients, systemic side

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effects and potential toxicity typically caused by systemic drugs may seriously affect

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treatment outcome. Also, the effect of a single injection of BTX lasts for several months; thus,

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BTX does not require daily administration. This advantage of BTX may be beneficial in

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patients taking a lot of daily medications due to comorbidities.

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Although the optimal dosage of BTX for lower extremity muscles for NCC treatment is

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currently not determined, approximately 100 to 200 units of BTX for the gastrocnemius

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muscles are typically used in treatment for adult spasticity.25 We used a relatively lower dose

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of BTX because most of our patients were elderly. However, we did not observe any serious

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complications following BTX injection; thus, dose-dependent efficacy and safety of BTX use

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may be investigated in this population. Also, BTX injection was only performed in the

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gastrocnemius in this study. The calf is the most common area of leg cramps in LSS patients,

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but muscle cramps of mixed pattern involving the thigh, shin, calf, or foot are also observed

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in this population.5,8 Thus, BTX injection in muscles of the lower extremity according to

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cramp characteristics could be considered. We observed that the clinical benefit induced by

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BTX injection lasted about 3 months after injection, similar to other BTX clinical application

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cases.9 Many patients who received BTX treatment actually requested a repeated injection

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after study completion. However, long-term efficacy and safety of a repeated BTX injection

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and its cost-effectiveness should be analyzed in this population.

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Study limitations This study has several limitations. First, this study used a relatively small sample size,

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and the ethnic/ racial background of the participants was quite homogenous. Second,

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although we fully recognize the importance of the placebo injection in pain research, we

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could not perform this due to the ethical concerns and challenges in recruiting patients for the

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study. Thereby, the operator and patients were inevitably not blinded to the BTX injection.

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Thus, because our results may not fully exclude a placebo effect, comparative studies are

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needed between BTX and local anesthetics or peripherally acting muscle relaxants in the

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future. Third, this study also used a real-world clinical practice model in which attending

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physicians decided the treatment options for LSS; thus, we could not control for potential

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confounders such as medication type, which could affect sleep or mood. Finally, we used

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clinically relevant parameters in this study; therefore, evidence of BTX treatment for cramps

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in patients with spinal diseases using neurophysiological tests may be warranted.11

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TE D

339

EP

338

AC C

337

RI PT

325

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Conclusions In conclusion, local BTX treatment appears to be an effective and safe therapeutic

351

option for NCCs in symptomatic LSS patients receiving conservative care. Therefore, BTX

352

treatment as an adjuvant should be considered when devising pain management strategies for

353

a selected subgroup of this population, especially in refractory patients suffering from

354

frequent NCCs.

RI PT

350

SC

355

M AN U

356 357 358 359

363 364 365 366 367 368 369 370

EP

362

AC C

361

TE D

360

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371 372

Supplier a. SPSS 20.0 software; IBM corp.

RI PT

373 374 375

SC

376 377

M AN U

378 379 380

384 385 386 387 388 389 390 391

EP

383

AC C

382

TE D

381

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393 394

References 1. Monderer RS, Wu WP, Thorpy MJ. Nocturnal leg cramps. Curr Neurol Neurosci Rep 2010;10:53-9.

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2. Blyton F, Chuter V, Burns J. Unknotting night-time muscle cramp: a survey of patient

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experience, help-seeking behaviour and perceived treatment effectiveness. J Foot

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Ankle Res 2012;5:7.

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3. Butler JV, Mulkerrin EC, O'Keeffe ST. Nocturnal leg cramps in older people. Postgrad Med J 2002;78:596-8.

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4. Hawke F, Chuter V, Burns J. Impact of nocturnal calf cramping on quality of sleep and health-related quality of life. Qual Life Res 2013;22:1281-6. 5. Matsumoto M, Watanabe K, Tsuji T, et al. Nocturnal leg cramps: a common

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complaint in patients with lumbar spinal canal stenosis. Spine (Phila Pa 1976)

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2009;34:E189-94.

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6. Rish BL. Nerve root compression and night cramps. JAMA 1985;254:361.

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7. Jansen PH, Joosten EM, Vingerhoets HM. Muscle cramp: main theories as to

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aetiology. Eur Arch Psychiatry Neurol Sci 1990;239(5):337-42.

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8. Nishant, Chhabra HS, Kapoor KS. Nocturnal cramps in patients with lumbar spinal canal stenosis treated conservatively: a prospective study. Asian Spine J 2014;8:62431.

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9. Casale R, Tugnoli V. Botulinum toxin for pain. Drugs R D 2008;9:11-27.

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10. Priori A, Berardelli A, Mercuri B, Manfredi M. Physiological effects produced by

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botulinum toxin treatment of upper limb dystonia. Changes in reciprocal inhibition

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between forearm muscles. Brain 1995;118:801-7.

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11. Bertolasi L, Priori A, Tomelleri G, et al. Botulinum toxin treatment of muscle cramps:

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a clinical and neurophysiological study. Ann Neurol 1997;41:181-6.

12. Van Campenhout A, Molenaers G. Localization of the motor endplate zone in human

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skeletal muscles of the lower limb: anatomical guidelines for injection with

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botulinum toxin. Dev Med Child Neurol 2011;53:108-19.

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13. Lee GY, Lee JW, Choi HS, Oh KJ, Kang HS. A new grading system of lumbar central

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canal stenosis on MRI: An easy and reliable method. Skeletal Radiol 2011;40:1033-9.

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14. Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an

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outcome measure for insomnia research. Sleep Med 2001;2:297-307. 15. Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine (Phila Pa 1976)

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2000 ;25:2940-52.

16. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of

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changes in chronic pain intensity measured on an 11-point numerical pain rating scale.

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Pain 2001;94:149-58.

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17. Ohtori S, Yamashita M, Murata Y, et al. Incidence of nocturnal leg cramps in patients with lumbar spinal stenosis before and after conservative and surgical treatment. Yonsei Med J 2014;55:779-84.

18. Pavone F, Luvisetto S. Botulinum neurotoxin for pain management: insights from animal models. Toxins (Basel) 2010;2:2890-913. 19. Fabregat G, De Andrés J, Villanueva-Pérez VL, Asensio-Samper JM. Subcutaneous

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and perineural botulinum toxin type A for neuropathic pain: a descriptive review. Clin

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J Pain 2013;29:1006-12. 20. Mustafa G, Anderson EM, Bokrand-Donatelli Y, Neubert JK, Caudle RM. Anti-

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nociceptive effect of a conjugate of substance P and light chain of botulinum

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neurotoxin type A. Pain 2013;154:2547-53.

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21. Gore M, Sadosky A, Stacey BR, Tai KS, Leslie D. The burden of chronic low back

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pain: clinical comorbidities, treatment patterns, and health care costs in usual care

442

settings. Spine (Phila Pa 1976) 2012;37:E668-77.

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22. Alsaadi SM, McAuley JH, Hush JM, et al. The bidirectional relationship between

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pain intensity and sleep disturbance/quality in patients with low back pain. Clin J

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Pain 2014;30:755-65.

23. Mueller ME, Gruenthal M, Olson WL, Olson WH. Gabapentin for relief of upper

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motor neuron symptoms in multiple sclerosis. Arch Phys Med Rehabil 1997;78:521-4.

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24. Serrao M, Rossi P, Cardinali P, Valente G, Parisi L, Pierelli F. Gabapentin treatment

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for muscle cramps: an open-label trial. Clin Neuropharmacol 2000;23:45-9. 25. Pathak MS, Nguyen HT, Graham HK, Moore AP. Management of spasticity in adults:

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practical application of botulinum toxin. Eur J Neurol 2006;13:42-50.

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Figure legends

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Figure 1. The CONSORT flow diagram. Group GPN, gabapentin treatment group; Group

460

BTX, botulinum toxin treatment group; LSS, lumbar spinal stenosis; NCCs, nocturnal calf

461

cramps; BTX, botulinum toxin.

RI PT

458

462

Figure 2. Changes in leg pain scores during the study period. Values are expressed as the

464

mean ± SD. Group GPN (□), gabapentin treatment group; Group BTX (■), botulinum toxin

465

treatment group; NRS, numeric rating scale.

466

*p<0.05 vs. baseline in each group, †p<0.01 vs. Group GPN.

M AN U

SC

463

467

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468

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Table 1. Patient characteristics and baseline clinical data.

Group BTX (n=24)

p-value

17 (80.9%)

15 (62.5%)

0.173

66.1 ± 10.5

66.2 ± 8.2

0.971

BMI, kg/m

24.8 ± 3.1

24.7 ± 3.2

0.944

Pain duration, months

35.2 ± 43.1

34.3 ± 42.5

Comorbidities, n

16 (76.1%)

18 (75.0%)

Prior spinal surgery, n

6 (28.5%)

7 (29.1%)

Multilevel stenosis, n

11 (52.3%)

15 (62.5%)

Female, n Age, years 2

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Stenosis severity, n

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Group GPN (n=21)

0.784

0.538

0.965

0.807

0.453

2 (9.5%)

1 (4.1%)

grade 2 (moderate)

16 (76.1%)

17 (70.8%)

grade 3 (severe)

3 (14.2%)

6 (25.0%)

medications

20 (95.2%)

22 (91.6%)

0.632

physical therapy

16 (76.1%)

15 (62.5%)

0.322

epidural injection

14 (66.6%)

18 (75.0%)

0.538

acupuncture

4 (19.0%)

7 (29.1%)

0.431

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grade 1 (mild)

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Previous treatments, n

Values are expressed as the mean ± SD or number of patients (%). Group GPN, gabapentin treatment group; Group BTX, botulinum toxin treatment group. Stenosis grades were based on the axial T2-

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weighted magnetic resonance images at the most severe level.17

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Table 2. Changes in back pain score, frequency and severity of cramps, ISI, and ODI during the study period.

Group GPN

2 week follow-up Group BTX

Group GPN

1 month follow-up

Group BTX

Group GPN

*

Back pain, 0 to 10 NRS

7.3±1.7

7.2±1.6

6.7±1.7

6.2±1.6

Cramp frequency, number per week

3.0 (2.0-5.5)

3.0(2.0-6.5)

2.0 (2.0-3.5)

1.0 (0.0-2.75)

Cramp severity, 0 to 4 criteria

3.0 (3.0-4.0)

4.0 (3.0-4.0)

3.0 (3.0-3.0)

1.0 (0.0-2.0)

ISI, 0 to 28 score

14.6±3.5

15.3±6.3

12.1±5.7

7.3±5.5

ODI, %

42.9±13.7

44.5±16.0

41.6±12.1

28.5±14.2

6.3±1.6 *†

*

2.0 (2.0-3.0)*

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*†

Group BTX

5.8±1.3

Group GPN

*

1.0 (0.0-1.75)

3.0 (2.0-3.0)

1.0 (0.0-1.75)

11.9±5.5

8.1±5.5

39.5±12.7

30.1±15.0

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*†

3 month follow-up

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Baseline

SC

Assessment time

*†

*

6.0±1.4

*

Group BTX 5.6±1.2

*

*†

2.0 (2.0-3.5)

1.0 (1.0-1.0)

*†

3.0 (2.0-3.0)

1.0 (1.0-2.0)

12.3±4.8

9.2±5.9

40.3±11.1

32.0±15.2

*†

*†

*

*

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Values are expressed as mean ± SD or median (interquartile range), Group GPN, gabapentin treatment group; Group BTX, botulinum toxin treatment group; NRS, numeric rating scale; ISI, Insomnia Severity Index; ODI, Oswestry Disability Index.

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* p<0.05 vs. baseline in each group, †p< 0.05 vs. Group GPN.

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Table 3. Conservative treatments performed during the study period.

Group BTX (n=24)

p-value

Home exercise

5 (23.8%)

6 (25.0%)

0.926

Physical therapy

9 (42.8%)

7 (29.1%)

0.338

Epidural injection

16 (76.1%)

15 (62.5%)

0.322

acetaminophen

1 (4.7%)

2 (8.3%)

NSAIDs

14 (66.6%)

16 (66.6%)

muscle relaxants

13 (61.9%)

12 (50.0%)

opioids/tramadol

8 (38.0%)

5 (20.8%)

0.202

antidepressants

3 (14.2%)

3 (12.5%)

0.860

prostaglandin E1

18 (85.7%)

17 (70.8%)

0.231

0.632

1.000

0.423

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Medications

RI PT

Group GPN (n=21)

Values are expressed as number of patients (%). Group GPN, gabapentin treatment group; Group

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BTX, botulinum toxin treatment group; NSAIDs, non-steroidal anti-inflammatory drugs.

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Table 4. Patient global impression of change in nocturnal calf cramps at 3 months follow-up. PGIC ratings

Group GPN (n=21)

Group BTX (n=24)

0 (0%)

4 (16.6%)

2. Much improved

0 (0%)

14 (58.4%)

3. Minimally improved

4 (19.1%)

3 (12.5%)

4. No change

16 (76.1%)

2 (8.3%)

5. Minimally worse

1 (4.8%)

1 (4.2%)

6. Much worse

0 (0%)

0 (0%)

7. Very much worse

0 (0%)

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RI PT

1. Very much improved

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0 (0%)

Values are expressed as number of patients (%). Group GPN, gabapentin treatment group; Group BTX, botulinum toxin treatment group; PGIC, patient global impression of change. Mann–Whitney U

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test showed a significant difference in PGIC ratings between the two groups at p<0.001.

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Patients with LSS assessed for eligibility (n=366)

Excluded: - refused to recruit (n=1) - cancer (n=3) - psychiatric/neurologic diseases (n=2) - uncontrolled endocrine diseases (n=2) - severe scoliosis (n=1) - recent compression fracture (n= 1) - primary insomnia (n=2)

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Patients with frequency of NCCs ≥ once per week (n=62)

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Excluded: - not meeting inclusion criteria (n=304)

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Lost to follow up - Patients who underwent spine surgery (n=4)

EP

Group GPN Conservative treatments + gabapentin (n=25)

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Randomization (n=50)

Analyzed (n=21)

Group BTX Conservative treatments + BTX injection (n=25)

Lost to follow up - Patients who underwent spine surgery (n=1)

Analyzed (n=24)

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