Objective: To evaluate if spinal cord stimulation (SCS) performs better than placebo (no stimulation) in the long term to reduce persistent neuropathic leg pain refractory to medication and other conservative treatments in patients who have undergone lumbar spinal surgery.

Study design: Multicenter, double blind, randomized, sham-controlled trial.

After a positive SCS test trial, participants (18-70 years) will be implanted with a non-rechargeable SCS system providing active, subthreshold stimulation and followed for 12 months in a blinded cross-over design. The primary outcome measure is the difference in change in leg pain intensity scores using the Numeric Rating Scale (NRS) between a 3-month period with optimized subthreshold stimulation, and a 3-month period with no stimulation, as compared to baseline. Quality of life, physical functioning, sleep quality, return to work, and reduction in medication use will also be investigated.

Background: Up to 20% of patients who have undergone lumbar spinal surgery experience persistent back/leg pain leading to long-term reduction in functionality and quality of life. SCS is an established and safe, minimally invasive treatment for these patients when no further surgery is indicated and conservative therapies have been found to be ineffective. Placebo-controlled studies, comparing active and sham stimulation, were lacking until recently as traditional SCS relied on the patient feeling the stimulation (paresthesia). Technological progress with development of paresthesia-free stimulation forms now allows for the execution of placebo-controlled studies. A recent trial showing no significant difference in long-term effectiveness between active SCS and sham suffers from significant methodological shortcomings. This necessitates further sham-controlled studies to determine the effectiveness of SCS.

1. INTRODUCTION AND RATIONALE

   SCS is an established and safe, minimally invasive treatment for patients with therapy-resistant chronic neuropathic pain. The treatment is based on the development of the gate-control theory presented in the mid-1960s as a way to dampen pain impulses at the spinal cord level. SCS treatment involves the insertion of electrode(s) in the epidural space, delivering weak electrical stimulation to the dorsal columns of the spinal cord to block pain impulses traveling to the brain. In patients experiencing sufficient pain relief (usually pain reduction over 50%) during a test trial period, an implantable pulse generator (IPG) is placed under the skin and connected to the electrode(s). Patients with chronic neuropathic pain may experience pain relief with SCS when other more invasive, surgical, and conservative treatments have been attempted and appeared to be ineffective.

   The most common condition treated with SCS is enduring neuropathic back and/or leg pain after lumbar spinal surgeries, such as lumbar discectomy. Up to 20% of patients who have undergone lumbar spinal surgery for degenerative conditions exhibit new or persistent low back/leg pain, leading to impaired functionality and reduced quality of life. This condition is entitled persistent spinal pain syndrome type 2 (PSPS2, formerly known as failed back surgery syndrome). Randomized controlled trials (RCTs) with SCS have shown long-term pain reduction of up to 70-80% in this patient group. In these studies, the effectiveness of SCS is based on either comparing different forms of stimulation or comparing SCS with reoperations and medication treatments. However, placebo/sham-controlled studies, comparing active stimulation with inactive stimulation, were lacking until recently since traditional SCS relied on the patient feeling the stimulation (paresthesia), making it impossible to conduct blinded studies where the patient does not know if the stimulation is on or off. This has constituted a major disadvantage in terms of the strength of the scientific evidence for the effect of SCS treatment, as it is known that the placebo effect is significant in surgical treatments.

   New SCS treatments for pain in which the patient does no longer experience paresthesia have been developed in recent years, which allows the execution of sham-controlled studies. A recently published study showed no significant difference between SCS and sham stimulation in long-term pain relief and improving physical functioning in patients with PSPS2, raising doubts about the effectiveness and use of the treatment, which is costly due to high material costs. However, this single study has significant methodological shortcomings. This necessitates further sham-controlled studies to ascertain whether SCS is an adequate treatment for chronic pain. The aim of the current study is to compare the long-term effect of paresthesia-free SCS with a sham treatment (no stimulation) in reducing neuropathic pain in patients with PSPS2. It is hypothesized that SCS treatment will be superior compared to treatment with sham stimulation.

2. OBJECTIVES

   Primary Objective: To compare active subthreshold SCS with sham stimulation in reducing neuropathic leg pain.

   Secondary Objective(s): To compare subthreshold SCS with sham stimulation on:

   1. quality of life
   2. physical functioning
   3. sleep quality
   4. medication use
   5. return to work

3. STUDY DESIGN

This is an international, multicenter, double-blind, randomized, sham-controlled study. Patients evaluated as candidates for SCS will after a positive test trial be implanted with the non-rechargeable Boston Alpha Prime system (Boston Sci, Marlborough, MA, USA) providing active subthreshold stimulation forms that the patient does not feel (i.e., paresthesia-free) and are proven to be effective in reducing chronic neuropathic pain. According to standard clinical practice, research participants are implanted with electrode(s) during an initial surgery, which are inserted into the epidural space posterior to the spinal cord dorsal columns, with the aim of obtaining the best possible coverage of the painful area. Subsequently, patients undergo a trial phase of 2 weeks with an external IPG to determine if treatment with a subthreshold stimulation provides adequate pain relief (over 50% pain reduction). If no adequate pain relief is experienced during the trial phase, the electrode(s) are removed and the patient is excluded from further study participation. In patients responding with adequate pain relief, a permanent IPG is placed under the skin and connected to the electrode(s). Patients will then be randomized into either the active subthreshold stimulation or sham stimulation group. After randomization, patients will undergo a four-week period where stimulation settings will be optimized and patients can recover from their surgery.

After the optimization period, patients will receive either subthreshold or sham stimulation in accordance with the randomization. The subthreshold stimulation form that will be used will be based on patient response in terms of optimal pain reduction during the 2-week trial and the 4-week optimization period. Patients can use any of the subthreshold stimulation forms or combinations that are available within the Alpha Prime system. After 3 months, patients will switch to the other stimulation group according to a crossover design, where they will receive the other stimulation form until the 6-month follow-up. Subsequently, patients will receive the stimulation form they found most effective for an additional 6 months until the end of the study. Both the physician who implanted the system and the patient will be unaware of the stimulation type received (a double-blind design) during the entire study period. Patients will be aware they will receive two different stimulation forms, while being unaware of the fact that one of the stimulation forms is sham stimulation. Activation/deactivation and programming of the stimulation will be performed by a research nurse, who is the only person in the study aware of which group the patient belongs to. Subjects enrolled will be asked to complete several questionnaires prior to their procedure and at routine follow up visits at 3, 6 and 12 months. After study termination at the 12-month follow-up, blinding will be lifted and patients can receive any stimulation form available within the Boston Alpha Prime system.

Inclusion Criteria:

• History consistent with PSPS2 of at least 6 months after the last spinal surgery. The patient experienced no effect of conservative treatments and has been assessed as not eligible for further spinal surgery.
• Patients between 18-70 years of age.
• Average perceived pain intensity in one or both legs of 5 or more and average perceived pain intensity in the back of less than 3 measured with the validated 11-box NRS (0 no pain, 10 worst imaginable pain)
• The patient should have been informed verbally and in writing about the study and should have provided informed written consent to participate.
• Adequate pain relief effect (50% or more) after a two week trial with active test stimulation.

Exclusion Criteria:

• Subject is unable to understand or operate the SCS device.
• Subject currently has an active implantable device including pacemakers, spinal cord stimulator or intrathecal drug delivery system.
• Ongoing coagulation disorder.
• Ongoing abuse of alcohol, drugs, or prescription opioids.
• Active debilitating psychiatric illness.
• Active malignancy.
• Condition with increased general infection sensitivity, such as known immunodeficiency.
• Expected lifespan <1 year.
• Ongoing local infection or other skin disease where the IPG is planned to be placed.
• Pregnancy.

Individual participant data that underlie the results reported, after deidentification.

Immediately following publication. No end date.

Researchers who provide a methodologically sound proposal.

Statistician