Botulinum Toxin for Cramps in Diabetic Neuropathy
Condition: Muscle Cramps Aggravated; Diabetes Mellitus
MeSH terms: Muscle Cramp; Diabetic Neuropathies; Spasm
Study type: Interventional
Phase: Phase 2

Summary: 
      Objective: previous studies suggest that botulinum toxin A (BoNT/A) can reduce muscle
      hyperactivity.

      Research Design and Methods: a single-center, double-blind and placebo-controlled study
      investigating the efficacy and safety of BoNT/A intramuscular injection for treating calf or
      foot cramps refractory to common pharmacological drugs in patients with diabetic peripheral
      neuropathy. Fifty patients were subdivided in two matched groups (cases and controls) and
      BoNT/A (100 or 30 units) was injected for each side into the gastrocnemious or the small
      flexor foot muscles, respectively, according to the predominance of leg or foot cramps.
      Responders were evaluated again with a second BoNT/A administration.

      The changes of pain intensity (primary outcome) and the changes in cramp frequency, the and
      the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A
      administration.
    

Detailed description: 
      This was a single-center, randomized, double-blind, placebo-controlled prospective study.

      A consecutive series of 303 out-patients with type 2 diabetes was screened for muscle
      cramps.Patients were asked to report in a questionnaire the frequency, localization,
      intensity and time of the day of cramps. Out of these 303 diabetic patients with cramps,
      fifty patients satisfied the inclusion/exclusion criteria and entered the study.

      Cramp Evaluation

      a) Clinical evaluation All patients completed a baseline diary in the week before treatment.
      Every day the number of muscle cramp episodes was reported three times a day and the
      intensity of pain was rated on a scale 0 to 10, with 0 indicating no pain and 10 indicating
      "the worst pain imaginable" (Brief Pain Inventory-Modified Short Form, BPI-MSF, point 1).
      Daily data in this pre-treatment week were averaged and considered "basal" values. A similar
      daily diary, reporting the number of pain episodes, their intensity, time of the day and
      duration (less or more than 1 min) was kept throughout the study for the three days before
      each control visit.

      The severity of cramps interference on daily life was graded according to the functional
      scale Cramp Severity Score (CSS): 0= no cramps; 1= occasional day or night cramps not
      interfering with daily activities or with nocturnal sleep; 2= frequent muscle cramps
      triggered by muscle exercise not significantly interfering with daily activity or with
      nocturnal sleep; 3= continuous or subcontinuous muscle cramps limiting daily activities or
      nocturnal sleep; 4= continuous cramps severely interfering with daily activities and
      nocturnal sleep (4).

      Randomisation: patients were randomly assigned to either the treatment or control groups
      according to a computer-generated list. Randomization was stratified in order to match age,
      gender, duration of diabetes and the frequency and severity of cramp episodes in the two
      groups.

      At time 0 each patient received four i.m. injections, two injections for each side,
      containing either BoNT/A (100 units diluted in 1 ml saline) or saline. The total dose, for
      each side, was 100 units for the gastrocnemius muscle or 30 units for the small flexor foot
      muscles. The calf or the foot muscles were chosen according to the patient predominant leg or
      foot cramps. Patients in the control group received the same volumes of normal saline in the
      same muscles. The injections were prepared by a research nurse and both the treating
      physician and the patients were left blind.

      Ten visits were scheduled after initial evaluation: at weeks 1 and 2 after BoNT/A injection
      and, thereafter, every other week until week 16 and then at week 20. Ratings of the three
      days before each control visit were averaged to obtain values for each post-injection
      evaluation. The number of cramp episodes and cramp severity score (both self-reported in the
      daily diary) were obtained at 1, 4, 8, 12, 16 and 20 weeks after BoNT/A or placebo
      administration.

      Positive response to treatment: a 30% or greater reduction of the primary outcome score.
    

Intervention name(s): Botulinum toxin type A; Normal saline
Intervention type(s): Drug; Other
Intervention description(s): botulinum toxin type A injections
Botulinum toxin type A (100 or 30 units) was injected for each side into the gastrocnemious or the small flexor foot muscles, respectively, according to the predominance of leg or foot cramps.; Normal saline injections
The same dosage as the active group, but with normal saline alone were injected into the gastrocnemious or the small flexor foot muscles, respectively, according to the predominance of leg or foot cramps.
Other intervention name(s): Placebo
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: randomized, double-blind and placebo-controlled study
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: muscle cramps; diabetic neuropathy; botulinum toxin