Spinal Cord Stimulation and Pain Relief in Painful Diabetic Peripheral Neuropathy

A Prospective Two-Center Randomized Controlled Trial

Rachel Slangen; Nicolaas C. Schaper; Catharina G. Faber; Elbert A. Joosten; Carmen D. Dirksen; Robert T. van Dongen; Alfons G. Kessels; Maarten van Kleef

Disclosures

Diabetes Care. 2014;37(11):3016-3024. 

In This Article

Research Design and Methods

Study Design

This study was designed as a prospective multicenter RCT to assess the effectiveness of SCS in combination with BMT (SCS group) compared with BMT only (BMT group) in patients with PDPN in the lower limbs on pain, HRQoL, and functional ability. Prior to inclusion, all patients were treated with BMT according to the international guidelines[5,7,15] and the treatment algorithm of Jensen et al..[6] Invasive therapy, such as intrathecal drug delivery, was not allowed. A steering committee was responsible for the design of the study and for developing the protocol (available at ClinicalTrials.gov, NCT01162993). The study was performed at the outpatient pain clinics of the Maastricht University Medical Centre (MUMC+) and Radboud University Medical Center (Radboud UMC). The study was approved by the medical ethics committee of the MUMC+and the institutional review board of the Radboud UMC. An independent data and safety monitoring board reviewed the study procedures and outcomes.

Patients

Patients with DM between 18 and 80 years of age, suffering from moderate to severe PDPN present in the lower limbs according to the Michigan Diabetic Neuropathy Score (MDNS),[16] were recruited from the outpatient pain clinics and the diabetic outpatient clinics of the two participating centers and were screened for eligibility. Inclusion criteria were as follows: insufficient pain relief and/or unacceptable side effects with drug treatment according to the guidelines and the algorithm described for PDPN by Jensen et al.,[6] including antidepressants, antiepileptic drugs, opioids, or a combination of these therapies, pain present for >12 months, with a mean pain intensity during daytime or nighttime on a numeric rating scale (NRS) of 5 or higher, and, if necessary, a psychological assessment was performed.

Exclusion criteria were as follows: neuropathic pain most prevalent in the upper limbs (NRS >3); neuropathy or chronic pain of other origin than DM; recent neuromodulation therapy (<1 month before the intake-visit); drug, medication, or alcohol (>5 units/day) abuse; insufficient cooperation from the patient (little motivation, understanding, or communication); blood clotting disorder; immune deficiency; peripheral vascular disease with no palpable foot pulses at both feet (inclusion was possible if pulses were absent, but Doppler ankle-brachial index was between 0.7 and 1.2 in both feet); active foot ulceration; life expectancy <1 year; pacemaker; local infection or other skin disorders at site of incision; psychiatric problems potentially interfering with cooperation in the study; pregnancy; severe cardiac or pulmonary failure (>NYHA classification II); unstable blood glucose control (change in hemoglobin A1c [HbA1c] >1.0% in the 3 months preceding the trial); and use of oral anticoagulation that could not be stopped for a period of 10 days around the implantation procedure.

Randomization

Prior to randomization, all patients gave written informed consent. Patients were randomized between two groups by a computerized randomization. An independent data manager designed the randomization in a 3:2 ratio to the SCS group or BMT group, with stratification according to age, sex, type of DM, and severity of the PDPN according to the MDNS.[16] This randomization ratio was chosen to facilitate the inclusion of participants. Treatment with SCS or BMT was only performed for 6 months. The surgical procedure for implantation of the SCS system was performed by four pain specialists (two at MUMC+ and two at Radboud UMC), all with extensive experience of >5 years.

Lead Placement, Trial Stimulation, and Criteria for Permanent SCS Implantation

Implantation of the SCS octapolar lead (Octad lead; Medtronic, Minneapolis, MN) was performed using local anesthesia and antibiotic prophylaxis. The patient was placed in prone position, and by using fluoroscopy, the epidural space was entered with a Tuohy needle at the lumbar level. Subsequently, the lead was advanced through the needle and connected to an external programmable stimulator (N'Vision; Medtronic). The position of the lead over the thoracic level and settings of the external stimulator were tailored for each patient in order to reach optimal paraesthesia coverage. Thereafter, the lead was anchored to the paraspinal fascia of the interspinous ligament and an extension lead was threaded through the skin, fixed, and connected to an external stimulator (External Neurostimulator Trialing System; Medtronic). After implantation, patients were admitted to the hospital for 24 h. Patients were discharged from the hospital if no change in position of the lead was seen after X-ray verification.

After a 2-week trial stimulation, the spinal cord stimulator (Synergy Versitrel or PrimeAdvanced; Medtronic) was implanted if the NRS for the intensity of pain during daytime or nighttime for the last 4 days of the trial period was at least 50% lower than the baseline score, or if there was a score of 6 or higher ("much improved" or "very much improved") on the PGIC scale for pain and sleep. After antibiotic prophylaxis, the spinal cord stimulator was placed just cranial to the greater gluteal muscle in a subcutaneous pocket or in the anterior abdominal wall and was connected by a tunneled new sterile extension lead to the stimulation lead, under local anesthesia. The first extension lead was removed. The patient remained in the hospital for 24 h while antibiotic prophylaxis was continued. If trial stimulation was unsuccessful, the stimulation lead was removed.

Outcome Measurements

Basic demographic data and PDPN history were obtained, including duration of DM, duration of painful symptoms, type of DM, length, weight, age, sex, and glycohemoglobin (HbA1c).

Outcome measures were assessed at baseline and at 3 and 6 months for all patients; SCS patients received an extra assessment to evaluate the trial stimulation at 2 weeks.

Treatment success of SCS at 6 months was predefined in the protocol as follows: ≥50% relief of pain intensity on an NRS for 4 days[17] during daytime or nighttime or a score of ≥6 on a 7-point Likert scale (1 = very much worse and 7 = very much improved) of the PGIC scale for pain and sleep.[18,19] A score of 6 or higher on the PGIC indicates a clinically important difference.

In addition, we measured pain severity, pain interference with daily life, pain characteristics, HRQoL, pain interference with sleep, sleep quality and quantity, mood, and registered medication use at all time points.

The modified Brief Pain Inventory for Diabetic Peripheral Neuropathy was used to measure pain severity and pain interference in daily life, which were averaged to form two composite scores, the Pain Severity Index (PSI) and the Pain Interference Index (PII).[18]

Neuropathic pain qualities were measured using the Neuropathic Pain Scale, which assesses two global and eight specific qualities of neuropathic pain.[19]

HRQoL was measured with the EuroQol five dimensions (EQ-5D).[20] In this instrument, a utility score can be computed for each of five health states, based on preferences from a general population in the U.K., i.e., the U.K. tariff.[21] Additionally, patients can rate their current health on a visual analog scale.[22] In addition, the Medical Outcomes Study SF-36 (MOS SF-36)[23,24] was used to evaluate patients' perceived health state, which is composed of 36 questions and standardized response choices, organized into eight multi-item scales that can be averaged to form two composite scores, the physical component score (PCS) and the mental component score (MCS).

The impact of PDPN on sleep quality and quantity was assessed using the Medical Outcomes Study Sleep Scale. A nine-item Sleep Problems Index was calculated, and quantity of sleep was scored as the average hours of sleep per night reported over the past week. Sleep was scored as optimal in cases of 7–8 h of sleep per night.[25,26]

Mood was assessed with the Beck Depression Inventory (BDI), a self-report inventory for measuring the severity of depression.[27] Finally, we documented complications and (serious) adverse events of SCS.

Medication use was registered and was scored in terms of increased, reduced, no change in medication use, switched to other medication, or completely stopped with medication.

Statistical Analysis

Data from prospective pilot studies were used to estimate the required sample size.[10–12,28] The prespecified definition of clinically relevant pain relief was a reduction of 50% on the NRS and/or improvement on the PGIC for pain and sleep. We calculated that a sample of 40 patients with PDPN was required in order to detect a difference in success of 40% between SCS and BMT compared with BMT. We assumed a proportion of success in the SCS group of 50% and in the BMT group of 10%, with a power of 80% and a two-sided type I error of 0.05, allowing for 10% lost to follow-up.

The statistical analysis was carried out according to the intent-to-treat (ITT) principle, which included all patients who were randomized, even those patients without a postbaseline measurement. Dropouts were classified as failures for SCS. The efficacy analysis was a logistic regression of the difference between the SCS group and the BMT group in the proportion of patients with a success of treatment over the course of 6 months. For the PGIC score (dichotomized as a score of <6 or ≥6), there was no pretreatment data and therefore only differences between the two groups were calculated. We performed a multivariate logistic regression to adjust for the effect of possible unbalanced distributions of the baseline characteristics (age, sex, and MDNS score) on the primary outcome measure.

Linear mixed model analysis was performed to analyze the differences in trends of the outcome measures. A random intercept regression model examined the differences in linear rate of change between the SCS group and the BMT group over the course of 6 months. This model measured each patient's deviation from the population average change over time and included a random intercept for each subject. For this model, all available data (baseline and 3 and 6 months) were used. The model estimated fixed effects for treatment. All statistical analyses were performed using SPSS Statistics for Windows, version 20.0.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....