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Percutaneous Neuromodulation of the Brachial Plexus and Sciatic Nerve for the Treatment of Acute Pain Following Surgery: Secondary Outcomes From a Multicenter, Randomized, Controlled Pilot Study
Address correspondence to: Brian M. Ilfeld, MD, MS, Department of Anesthesiology, University California San Diego, 9500 Gilman Drive, MC 0898, La Jolla, CA 92093-0898, USA.
Outcomes Research Consortium, Cleveland, OH, USADepartments of Quantitative Health Sciences and Outcomes Research, Cleveland Clinic, Cleveland, OH, USA
Outcomes Research Consortium, Cleveland, OH, USADepartments of Quantitative Health Sciences and Outcomes Research, Cleveland Clinic, Cleveland, OH, USA
We recently reported that percutaneous peripheral nerve stimulation (PNS or “neuromodulation”) decreased pain and opioid consumption within the first two weeks following ambulatory surgery. However, the anatomic lead locations were combined for the analysis, and benefits for each location remain unknown. We therefore now report the effects of percutaneous PNS for brachial plexus and sciatic nerve leads separately.
Materials and Methods
Before surgery, leads were implanted percutaneously to target the brachial plexus (N = 21) for rotator cuff repair or sciatic nerve (N = 40) for foot/ankle surgery, followed by a single injection of local anesthetic. Postoperatively, subjects were randomized in a double masked fashion to 14 days of electrical stimulation (N = 30) or sham/placebo (N = 31) using an external pulse generator. The primary outcome of interest was opioid consumption and pain scores evaluated jointly. Thus, stimulation was deemed effective if superior on either outcome and at least noninferior on the other.
Results
For brachial plexus leads, during the first seven postoperative days pain measured with the numeric rating scale in participants given active stimulation was a median [interquartile range] of 0.8 [0.5, 1.6] versus 3.2 [2.7, 3.5] in patients given sham (p < 0.001). For this same group, opioid consumption in participants given active stimulation was 10 mg [5, 20] versus 71 mg [35, 125] in patients given sham (p = 0.043). For sciatic nerve leads, pain scores for the active treatment group were 0.7 [0, 1.4] versus 2.8 [1.6, 4.6] in patients given sham (p < 0.001). During this same period, participants given active stimulation consumed 5 mg [0, 30] of opioids versus 40 mg [20, 105] in patients given sham (p = 0.004). Treatment effects did not differ statistically between the two locations.
Conclusions
Ambulatory percutaneous PNS of both the brachial plexus and sciatic nerve is an effective treatment for acute pain free of systemic side effects following painful orthopedic surgery.
Neuromodulation appropriateness consensus C: the appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.
However, its application to acute postoperative pain was impractical until the advent of percutaneous leads that could temporarily target peripheral nerves. Ultrasound-guided percutaneous peripheral nerve stimulation (PNS) was first reported in situ by Huntoon and Burgher in 2009 using an epidural neurostimulation electrode for the treatment of neuropathic pain.
Ultrasound-guided permanent implantation of peripheral nerve stimulation (PNS) system for neuropathic pain of the extremities: original cases and outcomes.
Subsequently, the first percutaneous PNS lead and pulse generator system to treat both acute and chronic pain was cleared by the U.S. Food and Drug Administration.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the suprascapular nerve and brachial plexus for postoperative analgesia following ambulatory rotator cuff repair. A proof-of-concept study.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the femoral nerve for postoperative analgesia following ambulatory anterior cruciate ligament reconstruction: a proof of concept study.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the sciatic nerve for postoperative analgesia following ambulatory foot surgery, a proof-of-concept study.
These uncontrolled feasibility studies suggested that percutaneous PNS might both improve analgesia and decrease—or even obviate—opioid requirements, all without any demonstrated risk of adverse systemic side effects or opioid dependence.
Consequently, we performed a multicenter, randomized, double-masked, sham-controlled pilot study which produced strong evidence that PNS of the brachial plexus, femoral nerve, and sciatic nerve results in dramatic decreases in both pain scores and opioid consumption following rotator cuff repair, anterior cruciate ligament reconstruction, and painful foot/ankle surgery (eg, hallux valgus correction).
Percutaneous peripheral nerve stimulation (neuromodulation) for the treatment of postoperative pain: evidence from a multicenter, randomized, double-masked, sham-controlled pilot study.
Additionally, the analgesic profile following these surgical procedures beyond just a few days remains relatively unknown, and therefore the analgesic requirements also remain unelucidated.
We therefore have conducted a secondary analysis and now report both the two-week analgesic trajectories following these procedures (derived from the control group), along with the effects of ultrasound-guided percutaneous PNS for brachial plexus and sciatic leads (femoral leads were excluded due to limited enrollment). Because all comparisons are post hoc analyses, statistical correction for multiple comparisons was not applied (with the exception of the one-week pain score and opioid consumption comparisons) and all statistically significant differences between treatments must be viewed as exploratory, requiring confirmation in a subsequent definitive trial.
Materials and Methods
This trial followed good clinical practice and was conducted within the ethical guidelines outlined in the Declaration of Helsinki. The trial was prospectively registered at ClinicalTrials.gov (NCT03481725, PI: Ilfeld, March 29, 2018). The protocol was approved by the institutional review board at each of the seven enrolling centers (Table 1) as well as the United States Army Medical Research and Development Command Human Research Protection Office. An independent data safety monitoring board was responsible for the conduct and oversight of all aspects of the investigation from the planning phase through data analysis (Appendix A). Written informed consent was obtained from all participants.
Table 1Enrolling Centers and Local Principal Investigators.
Enrollment was offered to adult patients scheduled for ambulatory orthopedic surgery with a planned single-injection peripheral nerve block for postoperative analgesia. The surgical procedures included rotator cuff repair, hallux valgus correction, anterior cruciate ligament repair with a patellar autograft, and ankle arthrodesis or arthroplasty. Patients were excluded if they had any of the following: 1) chronic analgesic use including opioids (daily use within the two weeks prior to surgery and duration of use greater than four weeks); 2) neuromuscular deficit of the target nerve(s); 3) compromised immune system based on medical history (eg, immunosuppressive therapies such as chemotherapy, radiation, sepsis, infection), or other condition that placed the subject at increased infection risk; 4) implanted spinal cord stimulator, cardiac pacemaker/defibrillator, deep brain stimulator, or other implantable neurostimulator whose stimulus current pathway may overlap; 5) history of bleeding disorder; 6) antiplatelet or anticoagulation therapies other than aspirin; 7) allergy to skin-contact materials (occlusive dressings, bandages, tape, etc.); 8) incarceration; 9) pregnancy; 10) chronic pain for more than three months of any severity in an anatomic location other than the surgical site; 11) anxiety disorder; 12) history of substance abuse; or 13) inability to contact the investigators during the treatment period and vice versa (eg, lack of telephone access).
Details of the lead implantation protocol have been published previously.
Percutaneous peripheral nerve stimulation (neuromodulation) for the treatment of postoperative pain: evidence from a multicenter, randomized, double-masked, sham-controlled pilot study.
In brief, the surgical site dictated the anatomic lead implantation site: brachial plexus for shoulder surgery, femoral nerve for knee procedures, and sciatic nerve for foot or ankle surgery. Preoperatively and without sedation, participants had a percutaneous lead (MicroLead™, SPR Therapeutics, Inc, Cleveland, OH; Fig. 1) implanted under ultrasound guidance using an in-plane technique. Electric current was delivered at 100 Hz with the intensity slowly increased from zero. The pulse generator intensity setting spans a range of 0 (no current) to 100 (maximum), indicating a combination of amplitude (0–30 mA) and pulse duration (10–133 μsec), the specific combination of which at each intensity setting is proprietary and therefore unavailable for publication. The optimal sensory changes targeted the surgical area, and if sensory changes occurred in a different location or if muscle contractions were induced, the stimulator was switched off, and then the probe/introducer was advanced or withdrawn and readvanced with a slightly different trajectory. This process was repeated until sensory changes (often described as a “pleasant massage”) were perceived in the surgical area.
Figure 1A percutaneous peripheral nerve stimulation system cleared by the U.S. Food and Drug Administration to treat acute and chronic pain (SPRINT® PNS System, SPR Therapeutics, Inc). The insulated lead (MicroLead™, SPR Therapeutics, Inc) is <0.3 mm in diameter wrapped into a helical coil 0.6 mm in diameter (top panel) which is percutaneously implanted using a preloaded introducer (middle panel). The rechargeable battery snaps into the pulse generator (SPRINT® PNS System®, SPR Therapeutics, Inc) that is controlled with a handheld remote (bottom panels). The pulse generators have a mass (30 g) and footprint (6.2 × 3.7 × 1.4 cm) small enough to allow the unit to be adhered directly to the patient. Used with permission from Brian M. Ilfeld, MD, MS.
Participants subsequently received an ultrasound-guided single-injection interscalene (shoulder), adductor canal (knee), or popliteal-sciatic (foot/ankle) nerve block with 20 mL of ropivacaine 0.5% (with epinephrine) immediately prior to surgery.
Treatment Group Assignment
After confirmation of successful lead implantation, participants were randomly allocated to one of two possible treatments: receiving either electric current (experimental group) or not (sham/placebo/control group). The pulse generators (SPRINT® PNS System®, SPR Therapeutics, Inc) are capable of being programmed to either 1) pass electrical current or 2) not pass electrical current. Importantly, these two modes (active and sham) are indistinguishable in appearance, and therefore investigators, participants, and all clinical staff were masked to treatment group assignment, with the only exception being the unmasked individual who programmed the stimulator and was not involved in subsequent patient assessments.
Following surgery, the pulse generator was attached to the lead and activated within the recovery room. Patients and their caretakers were educated on lead/stimulator care and functioning. While the frequency (100 Hz) was fixed, the intensity was controlled by participants with a small Bluetooth-connected remote (Fig. 1). Patients were provided with two rechargeable batteries, instructed to keep one in the wall charger and the other attached to the pulse generator (Fig. 1), and exchange these two batteries at the same time daily. Participants were discharged home with their leads in situ and with a prescription for immediate release oral opioid tablets. Lead removal occurred on postoperative day 14 (±2 days) by healthcare providers. Similar to perineural catheters, this procedure encompasses simply removing the occlusive dressing and slowly withdrawing the lead with gentle traction. If resistance was encountered during lead removal, static tension was maintained until resistance decreased.
Outcome Measurements (End Points)
Outcomes were evaluated at baseline (prior to lead implantation), during the intervention (postoperative days 1–4, 7, and 11), and following lead removal (postoperative day 15, months 1 and 4). Baseline measurements were collected in person which included the Post-Traumatic Stress Disorder Checklist (PCL-C), a 20-item self-report measure validated in military,
All subsequent outcomes were collected by investigators at the University of California San Diego by telephone regardless of enrolling center.
The primary instrument was the Brief Pain Inventory (short form) which assesses pain and its interference with physical and emotional functioning on days 3, 7, and 15 as well as months 1 and 4.
The instrument includes three domains: 1) pain, with four questions using a numeric rating scale (NRS) to evaluate four pain levels: current, least, worst, and average; 2) percentage of relief provided by pain treatments with one question; and 3) interference with physical and emotional functioning using a 0–10 scale (0 = no interference; 10 = complete interference). The seven interference questions involve general activity, mood, walking ability, normal work activities (both inside and outside of the home), relationships, sleep, and enjoyment of life.
These seven functioning questions can be combined to produce an interference subscale (0–70). The use of both single items (eg, mood) and the composite score is supported by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus recommendations for assessing pain in clinical trials.
The randomized groups were compared for balance on baseline characteristics using descriptive statistics and the standardized difference (ie, difference in means or proportions divided by pooled standard deviation [SD]). In these exploratory analyses, no adjustment was made for variables that appeared clinically imbalanced at baseline. Primary analyses were modified intent-to-treat, such that all randomized patients who received at least some of the study intervention were included in the analyses, and with the group to which they were randomized.
We established a priori that we would assess the treatment effect on opioid consumption and pain score jointly, so that stimulation would be deemed effective if found superior on either or both outcomes and not worse on either (ie, at least noninferior).
We first assessed noninferiority of PNS to usual care (sham/control group) on each of the two outcomes using one-tailed noninferiority tests. The a priori-defined noninferiority deltas were 1 point (worse) in pain score and 20% higher in opioid consumption. Noninferiority was assessed at the overall 0.025 significance level with no adjustment to the significance criterion for testing two outcomes since noninferiority is required on both outcomes—that is, an intersection union test. A noninferiority delta of 1 point in pain score is conservative since receiver operating characteristic curve analysis has demonstrated that changes from baseline of at least 1.7 along a 10-point NRS accurately identified patients who rated improvements as “much improved” or more, compared with those who perceived no change or worsening following analgesic interventions.
We tested for noninferiority on pain score with a one-tailed t-test in which the numerator was the estimated treatment effect from the model minus the noninferiority delta (1 point), and the denominator was the standard error of the estimated treatment effect. The estimated treatment effect for pain score was derived from a linear mixed effects model with the outcome of patient “average” pain score for each day, including fixed effects for intervention (PNS vs usual care) and time (days 1 through 7), assuming an autoregressive correlation structure among and measurements on the same patient overtime, and adjusting for baseline pain score.
Cumulative opioid consumption was not normally distributed, but approximately log-normal. We therefore assessed the treatment effect of PNS versus usual care on log-transformed cumulative opioid consumption from recovery room discharge through postoperative day 7 using a simple linear regression model. The estimated treatment effect (ie, difference between groups) was then used in a noninferiority test with null and alternative hypotheses as: H0: μ1 − μ2 ≥ log(1.2) = 0.263 versus HA: μ1 − μ2 < log(1.2) = 0.263, where μ1 and μ2 are the means of log-transformed opioid consumption for PNS and usual care, respectively, and μ1 − μ2 is estimated by the coefficient (ie, β) for PNS versus usual care in the regression model. The estimated treatment effect β is also an estimate of the ratio of geometric means for PNS versus usual care, assuming data are log-normal with similar coefficient of variation between groups.
In this planning phase, we placed focus on the estimated confidence interval (CI) for the treatment effects and the variability of the outcomes (SD for pain score and coefficient of variation for opioid consumption).
Superiority Testing
Since noninferiority was found on both pain and opioid consumption, we next tested for superiority on each outcome using one-tailed tests in the same direction. For superiority testing, since superiority on either outcome was sufficient to reject the joint null hypothesis (ie, a union-intersection test), we controlled the type I error at 0.025 across the two outcomes by using a Bonferroni correction and using 0.025/2 = 0.0125 as the significance criterion for each outcome. We thus reported 97.5% CIs for superiority for the primary outcomes (cumulative opioid consumption and patient “average” pain over days 1–7).
Secondary Outcomes
We used a linear mixed effects model to assess the treatment effect over time for additional outcomes measured at postoperative days 1–7,
Neuromodulation appropriateness consensus C: the appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.
Ultrasound-guided permanent implantation of peripheral nerve stimulation (PNS) system for neuropathic pain of the extremities: original cases and outcomes.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the suprascapular nerve and brachial plexus for postoperative analgesia following ambulatory rotator cuff repair. A proof-of-concept study.
as in the primary analysis, including worst pain and the Defense and Veterans Pain Rating Scale; we similarly assessed the treatment effect on total severity score and total interference score at days 3 and 7. For Brief Pain Inventory components and other outcomes analyzed at a single time point (days 11 and 15, months 1 and 4), we used linear regression or Wilcoxon rank sum test for ordinal outcomes, as appropriate, and chi-square analyses for binary outcomes (eg, incidence of chronic pain). We used Wilcoxon rank sum test for quality of life measured by the World Health Organization Quality of Life-BREF Instrument.
Treatment Effect Heterogeneity
For all outcome variables, we further assessed whether the effect of active stimulation versus sham differed between the brachial plexus and sciatic nerve patients using the relevant regression model (i.e., the same analytic method used for analyzing each subgroup, but combining the subgroups and assessing the treatment-by-location interaction).
Missing outcomes data were summarized along with a known etiology of the absence. All analyses were intention to treat, and missing data were largely assumed to be missing at random. We therefore did not impute missing data for outcomes measured once or for repeated measures analyses.
Results
Between January 2019 and September 2020, a total of 66 patients were enrolled (Table 2), had a lead successfully implanted, and randomized to either stimulation (N = 32) or sham/placebo (N = 34). The surgery for one participant randomized to active stimulation was canceled and he was therefore not included in the analysis since he received no portion of the intervention (Fig. 2). Only four participants underwent knee surgery, and of these only one received active treatment. Therefore, subjects who received femoral leads are excluded from this report. One patient receiving brachial plexus stimulation withdrew from the study on postoperative day 3 and was included in all analyses per the intent-to-treat protocol.
Table 2Anthropometric, Demographic, Baseline, Lead Insertion, and Surgical Data.
The pulse generator intensity setting spans a range of 0 (no current) to 100 (maximum), indicating a combination of amplitude (0–30 mA) and pulse duration (10–133 μsec), the specific combination of which at each intensity setting is proprietary and therefore unavailable for publication.
The pulse generator intensity setting spans a range of 0 (no current) to 100 (maximum), indicating a combination of amplitude (0–30 mA) and pulse duration (10–133 μsec), the specific combination of which at each intensity setting is proprietary and therefore unavailable for publication.
The pulse generator intensity setting spans a range of 0 (no current) to 100 (maximum), indicating a combination of amplitude (0–30 mA) and pulse duration (10–133 μsec), the specific combination of which at each intensity setting is proprietary and therefore unavailable for publication.
The pulse generator intensity setting spans a range of 0 (no current) to 100 (maximum), indicating a combination of amplitude (0–30 mA) and pulse duration (10–133 μsec), the specific combination of which at each intensity setting is proprietary and therefore unavailable for publication.
Data reported as mean ± SD, median [quartiles] or N (%).
∗ Totals not equal to 100% due to rounding error.
† The pulse generator intensity setting spans a range of 0 (no current) to 100 (maximum), indicating a combination of amplitude (0–30 mA) and pulse duration (10–133 μsec), the specific combination of which at each intensity setting is proprietary and therefore unavailable for publication.
‡ One missing data point in each group in sciatic nerve subgroup.
§ One missing data point in active group in sciatic nerve subgroup.
During the first seven postoperative days, opioid consumption in participants given active stimulation was a median [interquartile range (IQR)] of 10 mg [5, 20] versus 71 mg [35, 125] in patients given sham treatment: ratio of geometric means (97.5% CI) of 0.17 (0.03, 1.2), p = 0.043 (Fig. 3; Supplementary Data Table 1a). Similarly, in the first postoperative week average pain scores on the NRS for those receiving active treatment was a median [IQR] of 0.8 [0.5, 1.6] versus 3.2 [2.7, 3.5] in patients given sham: difference in means (95% CI) of −2.1 (−3.4, −0.8), p < 0.001 (Fig. 4, Supplementary Data Table 2a). During this same week, the worst (maximum) NRS for active treatment was 3.2 [2.0, 5.3] vs 5.8 [4.8, 7.2] for sham: difference in means (95% CI) of −2.0 (−3.9, −0.1), p = 0.040 (Fig. 5). For nearly all individual days, opioid consumption as well as average and worst pain scores were lower for the stimulation group until lead removal on day 14 (Figure 3, Figure 4, Figure 5, Supplementary Data Tables 1a–3a). Pain score results were quite consistent whether comparing groups on the mean using the repeated measures models (main analyses) or using nonparametric testing (sensitivity analyses; Supplementary Data Tables 3a and 4a). Importantly, participants who received active treatment had dramatically less physical and emotional interference due to pain during the treatment phase as well as the day following lead removal (Fig. 6).
Figure 3Effects of 14 days of percutaneous peripheral nerve stimulation on opioid consumption (oral morphine equivalents). For the opioid consumption within 24 hours at each time point, p values were estimated from Wilcoxon rank test (skewed data) stratified by surgical location. Data expressed as median (dark horizontal bars) with 25th–75th (box), 10th–90th (whiskers), mean (diamonds), and outliers (circles).
Figure 4Effects of 14 days of percutaneous peripheral nerve stimulation on average pain over the previous 24 hours. Pain severity is indicated using a numeric rating scale with 0 equal to no pain and 10 being the worst imaginable pain. For scores during the initial seven postoperative days, p values were estimated from repeated measures linear mixed effects model with an autoregressive correlation structure, adjusting for baseline scores and imbalanced surgical location; for postoperative days 11 and 15, p values were estimated from Wilcoxon rank sum test stratified by surgical location; for month 1, p values were estimated from multivariable linear regression models adjusting for baseline scores and surgical location. Data expressed as median (dark horizontal bars) with 25th–75th (box), 10th–90th (whiskers), mean (diamonds), and outliers (circles).
Figure 5Effects of 14 days of percutaneous peripheral nerve stimulation on the worst (maximum) pain over the previous 24 hours. Pain severity is indicated using a numeric rating scale with 0 equal to no pain and 10 being the worst imaginable pain. For scores during the initial seven postoperative days, p values were estimated from repeated measures linear mixed effects model with an autoregressive correlation structure, adjusting for baseline scores and imbalanced surgical location; for postoperative days 11 and 15, p values were estimated from Wilcoxon rank sum test stratified by surgical location; for month 1, p values were estimated from multivariable linear regression models adjusting for baseline scores and surgical location. Data expressed as median (dark horizontal bars) with 25th–75th (box), 10th–90th (whiskers), mean (diamonds), and outliers (circles).
Figure 6Effects of 14 days of percutaneous peripheral nerve stimulation on the Brief Pain Inventory interference domain. Pain interference indicated using a numeric rating scale of 0–70, with 0 and 70 equal to no and maximal interference, respectively. During postoperative days 3 and 7, p values were estimated from repeated measures linear mixed model with an autoregressive correlation structure, adjusting for baseline values and imbalanced surgical location; for postoperative day 15, p values were estimated from Wilcoxon rank test (skewed data) stratified by surgical location; for 1 month, p values were estimated from multivariable linear regression models adjusting for baseline values and surgical location. Data expressed as pain's interference on either the total or of each of the seven components (higher scores = more interference) demarked as median (dark horizontal bars) with 25th–75th (box), 10th–90th (whiskers), mean (diamonds), and outliers (circles).
During the first seven postoperative days, opioid consumption in participants given active stimulation was a median [IQR] of 5 mg [0, 30] versus 40 mg [20, 105] in patients given sham treatment: ratio of geometric means (97.5% CI) of 0.2 (0.05, 0.7), p = 0.004 (Fig. 3, Supplementary Data Table 1b). Similarly, in the first postoperative week average pain scores on the NRS for those receiving active treatment was a median [IQR] of 0.7 [0, 1.4] versus 2.8 [1.6, 4.6] in patients given sham: difference in means (95% CI) of −1.9 (−3.1, −0.8), p < 0.001 (Fig. 4, Supplementary Data Table 1b). During this same week, the worst (maximum) NRS for active treatment was 1.8 [1.1, 3.5] versus 5.2 [3.6, 6.5] for sham: difference in means of −2.6 (−3.9, −1.4), p < 0.001 (Fig. 5). For nearly all individual days, opioid consumption as well as average and worst pain scores were lower for the stimulation group until lead removal on day 14 (Figure 3, Figure 4, Figure 5, Supplementary Data Tables 1b–3b). Pain score results were quite consistent whether comparing groups on the mean using the repeated measures models (main analyses) or using nonparametric testing (sensitivity analyses; Supplementary Data Tables 3b and 4b). Similar to the participants with brachial plexus leads, participants with sciatic leads who received active treatment had dramatically less physical and emotional interference due to pain during the treatment phase as well as the day following lead removal (Fig. 6).
Treatment Effect Heterogeneity
There was no evidence that the treatment effect differed significantly between the two procedure locations for any of the outcome variables assessed (Supplementary Data Tables 3a and 3b, 4a and 4b). While these tests are rather underpowered for this study, most are quite nonsignificant, suggesting that in general the treatment effects are consistent.
Discussion
Ambulatory percutaneous PNS of the brachial plexus and sciatic nerve provides analgesia following painful orthopedic surgery. In the first postoperative week, neuromodulation decreased opioid consumption 88% for shoulder and the same percentage for foot/ankle surgery, although the absolute decrease was greater for the brachial plexus leads due to patients of the control group undergoing rotator cuff repair consuming nearly twice the opioid dose (72 mg) as participants having foot/ankle procedures (40 mg).
Neuromodulation similarly diminished average and worst/maximum pain scores to a clinically relevant and statistically significant degree through the first postoperative week.
For participants who received the active treatment, pain was similar for both shoulder and foot/ankle procedures through day 4, but thereafter diverged with participants having rotator cuff repair demonstrating higher levels of pain through day 30. The lead and pulse generator system used in this study are cleared for use up to 60 days,
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the suprascapular nerve and brachial plexus for postoperative analgesia following ambulatory rotator cuff repair. A proof-of-concept study.
It is clear that for a majority of patients, a 3–4 day continuous interscalene nerve block provides an inadequate duration of pain control following rotator cuff repair, and alternative analgesic methods are required.
Ambulatory continuous interscalene nerve blocks decrease the time to discharge readiness after total shoulder arthroplasty: a randomized, triple-masked, placebo-controlled study.
We anticipated that improving analgesia would decrease pain's interference with physical and emotional functioning; but the degree of improvement with neuromodulation for both lead locations was unexpected. With higher values indicating greater (undesirable) interference, shoulder and foot/ankle participants receiving standard-of-care reported interference subscale median of 8–33 on postoperative days 3 and 7. In contrast, patients provided neuromodulation had a median of zero at both time points: a majority of patients experienced no interference to physical and emotional functioning due to pain. To provide a general idea of the clinical relevance of these differences, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) concluded that a difference of a single point on the Interference Scale “would be a reasonable benchmark for future studies designed to identify to minimally clinically important changes.”
Therefore, the data of the current study suggest not only decreases in opioid and pain scores, but also a profound improvement in the overall postoperative experience of patients undergoing some of the most painful orthopedic surgical procedures performed on an ambulatory basis.
These benefits did not come at the expense of safety or undesirable side effects vis-à-vis local anesthetic-based regional analgesics in the relatively small cohort of postoperative patients followed to date. While a thorough discussion of the relative risks and benefits of percutaneous PNS and continuous peripheral nerve blocks is outside the scope of the present article and can be found elsewhere,
a few items bear mentioning. The risk of infection for helically coiled leads is significantly lower than for perineural catheters: fewer than one per 32,000 indwelling days with an average indwelling time for each lead over one year.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the suprascapular nerve and brachial plexus for postoperative analgesia following ambulatory rotator cuff repair. A proof-of-concept study.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the sciatic nerve for postoperative analgesia following ambulatory foot surgery, a proof-of-concept study.
Similarly, unlike for peripheral nerve block and perineural catheter administration, the leads and introducers are positioned 1–2 cm from the target nerve, thus reducing the risk of needle-to-nerve contact and possible neurologic injury. Patient burden is greatly decreased with small pulse generators and rechargeable batteries which allow treatment without carrying an infusion pump and local anesthetic reservoir as with continuous peripheral nerve blocks. These attributes support prolonged application. For example, the leads used in this trial are cleared by the food and drug administration for up to 60 days—thus providing analgesia, which substantially outlasts the duration of acute pain following most surgical procedures.
Major limitations of percutaneous PNS include a lack of surgical block, increased time for lead implantation, and cost.
there were only two fractures (3%) found in the current study, neither with any clinical consequences. However, given the relatively small cohort of patients studied to date, definitive conclusions will require far larger clinical trials and systematic evaluation of adverse events in large clinical practice.
In summary, percutaneous PNS of both the brachial plexus and sciatic nerve is highly effective for treatment of acute pain free of systemic side effects following shoulder and foot/ankle surgery, respectively.
Acknowledgements
The authors appreciate the invaluable assistance of Jeffrey Mills, BA (Clinical Translational Research Center, University California San Diego, La Jolla, CA). This manuscript is a product of the NIH-DoD-VA Pain Management Collaboratory. For more information about the Collaboratory, go to www.painmanagementcollaboratory.org.
Authorship Statements
Brian M. Ilfeld substantially contributed to the study conception, design, funding, execution, acquisition of data, analysis, and interpretation of data, drafting and critically reviewing the manuscript for intellectual content, and final approval of the version to be submitted. Anthony Plunkett, Alice M. Vijjeswarapu, Robert Hackworth, and Harold Gelfand substantially contributed to the study design, execution, and critically reviewing the manuscript for intellectual content, and final approval of the version to be submitted. Sandeep Dhanjal and Alparslan Turan substantially contributed to the study design and critically reviewing the manuscript for intellectual content, and final approval of the version to be submitted. Steven P. Cohen, James C. Eisenach, Scott Griffith, Steven Hanling, and Daniel I. Sessler substantially contributed to the study design, funding, interpretation of data, and critically reviewing the manuscript for intellectual content, and final approval of the version to be submitted. Edward J. Mascha and Yanyan Han substantially contributed to study design, analysis, drafting and critically reviewing the manuscript for intellectual content, and final approval of the version to be submitted. Joseph W. Boggs and Amorn Wongsarnpigoon substantially contributed to study design and critically reviewing the manuscript for intellectual content, and final approval of the version to be submitted. All authors approved the final version of the manuscript.
Appendix A. Data Safety Monitoring Board (Uncompensated)
Steven Shafer, MD (Chair and Medical Monitor)
Stanford University, Stanford, California
Pamela Flood, MD
Stanford University, Stanford, California
Jarrod Dalton, PhD (statistician)
Cleveland Clinic, Cleveland, Ohio
Appendix B. Enrolling Center Investigators (PAINfRE Investigators)
No conflicts to report unless otherwise noted.
Brooke Army Medical Center, Fort Sam Houston, Texas
Elizabeth Salazar, BS
Cedars-Sinai Medical Center, Los Angeles, California
Daniel Chien, MD
Katherine Kobayashi, BS
Christopher Massey, MD, MPH
Tiffany Pouldar, MD
Michael A. Stone, MD
David Blake Thordarson, MD
Tina Vajdi, MD
Wendy Weissberg, BS, BA, CCRP
Cleveland Clinic, Cleveland, Ohio
Andrew Lucic, MD.
Naval Medical Center San Diego, San Diego, California
Richard Fisher, MD
Ian Fowler, MD
Lucas S. McDonald, MD
Anthony Scherschel, MD
Marisa Kinnally, BS
Palo Alto Veterans Affairs, Palo Alto, California
Edward R. Mariano, MD, MAS
University of California, San Diego, San Diego, California
Baharin Abdullah, MD (National Program Manager)
David J. Dalstrom, MD
John J. Finneran IV, MD
COI: Epimed (Farmers Branch, Texas, research funding), Infutronics (Natick, Massachusetts, research funding), and SPR Therapeutics (Cleveland, Ohio, research funding) for other projects
Rodney A. Gabriel, MD, MAS
COI: Epimed (Farmers Branch, Texas, research funding), Infutronics (Natick, Massachusetts, research funding), and SPR Therapeutics (Cleveland, Ohio, research funding) for other projects
Matthew J. Meunier, MD
Catherine M. Robertson, MD
Engy T. Said, MD
COI: Epimed (Farmers Branch, Texas, research funding), Infutronics (Natick, Massachusetts, research funding), and SPR Therapeutics (Cleveland, Ohio, research funding) for other projects
Matthew W. Swisher, MD, MS
COI: Epimed (Farmers Branch, Texas, research funding), Infutronics (Natick, Massachusetts, research funding), and SPR Therapeutics (Cleveland, Ohio, research funding) for other projects
Walter Reed National Military Medical Center, Bethesda, Maryland
Robert Burch, MD
Kyle Cyr, MD
Jeremy Dublon, DPM
Morgan Hunt, BS
Dylan V. Scarton, MS
Megan Tsui, BS
Womack Army Medical Center, Fort Bragg, North Carolina
Brachial Plexus Primary Outcomes: Joint Hypothesis Testing Noninferiority and superiority tests of Stimulation compared to Sham (placebo)
Table 1b. Sciatic Nerve Primary Outcomes: Joint Hypothesis Testing Noninferiority and superiority tests of Stimulation compared to Sham (placebo).
Table 2a. Brachial Plexus: Opioid consumption within 24 hours by postoperative day 1 to 30
Table 2b. Sciatic Nerve: Opioid consumption within 24 hours by postoperative day 1 to 30
Table 3a. Brachial Plexus: Treatment effect on secondary outcomes within 7-days postoperatively
Table 3b. Sciatic Nerve: Treatment effect on secondary outcomes within 7-days postoperatively
Table 4a. Brachial Plexus: Treatment effect on secondary outcomes after postoperative day 7
Table 4b. Sciatic Nerve: Treatment effect on secondary outcomes after postoperative day 7
References
Deer T.R.
Mekhail N.
Provenzano D.
et al.
Neuromodulation appropriateness consensus C: the appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee.
Ultrasound-guided permanent implantation of peripheral nerve stimulation (PNS) system for neuropathic pain of the extremities: original cases and outcomes.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the suprascapular nerve and brachial plexus for postoperative analgesia following ambulatory rotator cuff repair. A proof-of-concept study.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the femoral nerve for postoperative analgesia following ambulatory anterior cruciate ligament reconstruction: a proof of concept study.
Ultrasound-guided percutaneous peripheral nerve stimulation: neuromodulation of the sciatic nerve for postoperative analgesia following ambulatory foot surgery, a proof-of-concept study.
Percutaneous peripheral nerve stimulation (neuromodulation) for the treatment of postoperative pain: evidence from a multicenter, randomized, double-masked, sham-controlled pilot study.
Ambulatory continuous interscalene nerve blocks decrease the time to discharge readiness after total shoulder arthroplasty: a randomized, triple-masked, placebo-controlled study.
Complete list of PAINfRE Investigators is provided in Appendix B.
Source(s) of financial support: The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Pain Management Collaboratory—Pragmatic Clinical Trials Demonstration Projects under Awards No. W81XWH-18-2-0003, W81XWH-18-2-0007, W81XWH-18-2-0008, and W81XWH-18-2-0009. Research reported in this publication was made possible by Grant Number U24 AT009769 from the National Center for Complementary and Integrative Health (NCCIH), and the Office of Behavioral and Social Sciences Research (OBSSR). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the funding agencies. This manuscript is a product of the NIH-DoD-VA Pain Management Collaboratory. For more information about the Collaboratory, visit https://painmanagementcollaboratory.org.
Conflict of Interest: Harold Gelfand is participating in Henry Jackson Foundation (Bethesda, MD) funded research through a grant from Pacira Pharmaceuticals (Parsippany, NJ). Brian M. Ilfeld's institution has received funding for other research from Infutronix (Natick, MA), Epimed International (Farmers Branch, TX), and SPR Therapeutics (Cleveland, OH). Daniel I. Sessler serves as a consultant for Pacira Pharmaceuticals (Parsippany, NJ). The author's institution receives funding from Pacira Pharmaceuticals (Parsippany, NJ) and Heron Therapeutics (San Diego, CA). Alparslan Turan's institution receives funding from Pacira Pharmaceuticals (Parsippany, NJ) and Heron Therapeutics (San Diego, CA). Joseph W. Boggs and Amorn Wongsarnpigoon are employees of SPR Therapeutics, the manufacturer of the electrical leads and pulse generators under investigation in this study. Both authors own stock options in this company. Of note, this was an investigator-initiated project fully funded by the U.S. Department of Defense, and the first author retained complete control of the grant proposal, study protocol, data collection, analysis, and interpretation, and the resulting manuscript. Drs Boggs and Wongsarnpigoon were provided the initial protocol on which to comment, with some suggested revisions incorporated into the protocol while others were not. The remaining authors report no conflicts.
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