The SPIDOL (SPInal cord injury pain DOLor) trial is underway to assess the efficacy of intrathecal ziconotide (ITZ) in patients with severe refractory pain, particularly those with spinal cord injuries. This randomized, double-blind, placebo-controlled, crossover study aims to provide robust evidence on the analgesic effects of ITZ.
Study Design and Setting
The SPIDOL trial is designed as a 45-month study involving multiple centers. Patients eligible for the study must have already demonstrated a positive response to ITZ during a test period, aligning with recommendations from the Haute Autorité de Santé (HAS). The trial includes a screening phase, a pre-inclusion visit, pump implantation, and two six-month treatment phases separated by a one-month washout period.
Patient Selection and Randomization
Patients are tested for ITZ efficacy using either a lumbar puncture (LP) test or a continuous infusion test. Responders, defined as those achieving a VAS reduction of ≥40% or reporting ≥40% satisfaction, are considered eligible. Those with psychiatric disorders, as identified by the Mini International Neuropsychiatric Interview (MINI) questionnaire, are excluded. Eligible patients undergo centralized randomization, balanced across participating centers, to receive either ITZ or placebo during the first phase, followed by crossover to the alternate treatment in the second phase.
Treatment Protocol
Ziconotide is administered intrathecally via a continuous infusion pump at a concentration of 10 μg/mL. The initial dosage is determined based on the patient's response during the pre-test phase, typically starting around 3 μg per day. Dosage adjustments are permitted at monthly refill visits, with increases generally limited to 1 μg per month, up to a maximum of 20 μg per day. The placebo consists of a standard saline solution, indistinguishable from the active treatment. Physicians remain blinded to the treatment assignment throughout the study.
Outcome Measures
The primary outcome measure is the intra-individual comparison of average pain measured under placebo and under ziconotide using a numeric scale. Secondary outcomes include assessments of quality of life (SF12), memory complaints (McNair scale), depression and anxiety (HADS scale), executive functions (BRIEF-A questionnaire), and pain-related distress (PCS). Pain is evaluated daily using an electronic diary, and comprehensive assessments are conducted at the end of each treatment phase and the washout period.
Statistical Analysis
The primary analysis will involve a paired t-test or Wilcoxon signed-rank test to compare pain scores under ITZ and placebo. A mixed-effect linear model will also be used to account for repeated measures and assess treatment effects on pain over time. Carryover effects will be evaluated, and analyses may be restricted to the first phase if necessary. The statistical significance level is set at p < 0.05.
Safety and Blinding
Blinding is maintained through the use of indistinguishable active and placebo treatments, prepared and packaged by local pharmacies. Unblinding is reserved for clinical conditions where knowledge of the treatment is essential for patient management and can be performed by contacting the Centre Anti Poison de Lyon (CAP). Patients are provided with a participation card containing the CAP contact information.
Expected Impact
The SPIDOL trial is expected to provide high-quality evidence regarding the efficacy and safety of intrathecal ziconotide for severe refractory pain. The results will inform clinical practice and contribute to optimizing pain management strategies for patients with spinal cord injuries and other chronic pain conditions.
