Multicenter, Double-Blinded, Randomized, Active-Sham Controlled Clinical Study Design to Assess the Safety and Effectiveness of a Novel High Frequency Electric Nerve Block System in the Treatment of Post-Amputation Pain (The QUEST Study).

Background: Chronic pain that follows amputation of a limb is reported as "one of the most severe pains in the human experience," due to the magnitude of tissue injury and the multiple potential of pain generators at the local peripheral, spinal, and cortical levels. The Altius® System was developed to deliver high-frequency nerve block (HFNB) therapy via a cuff electrode applied to the peripheral nerve(s) and an implantable pulse generator. We report a novel clinical trial design for the first study of an active-implantable medical device in subjects with lower-limb post-amputation pain utilizing a multicenter, double-blinded, randomized, active-sham controlled clinical study protocol called QUEST, which is an ongoing investigational device exemption study to support United States Food and Drug Administration approval. Methods: The study enrollment of 180 subjects was completed in September 2021. Subjects were randomized 1:1 to the treatment group or the active-sham control group for the 3-month primary effectiveness and safety endpoints. After month 3, the active-sham control program group crossed over to the treatment program group and all subjects continued to the 12-month study endpoint. Study effectiveness success is determined by a superiority test between responder rates in the treatment and control groups at 3 months. A responder is defined as someone who experiences a 50% or greater reduction in pain scores - after a 30-minute treatment session - for more than 50% of all pain episodes in which the treatment was used. Discussion: The QUEST study design employs an active-sham control group to objectively assess the effectiveness of HFNB therapy. Additionally, the electronic diary repeated measures data collection in QUEST is expected to reduce the intra-subject variation typically observed in pain treatment studies. Finally, the longitudinal measurement of health-related quality of life and use of pain medication may, for example, show effectiveness in reducing opioid use over time.

Peripheral Neuromodulation to Treat Postamputation Pain.

Some of the more common peripherally mediated pain disorders are postamputation stump pain and phantom pain. These disabling conditions have proven difficult to treat. Here we aim to illustrate an option to treat postamputation pain using peripheral neurostimulation techniques. Traditional peripheral neuromodulation techniques use standard stimulation parameters and work by stimulation of nerve tissues which are then felt by the patient as a tingling sensation or paresthesia. Recently introduced high-frequency (10 kHz) electrical nerve block [HFAC (high-frequency alternating current) block] via a surgically implanted peripheral nerve cuff electrode results in true conduction block which actually blocks action potentials emanating from the painful neuroma and thus suppresses pain without tingling or paresthesia felt by the patient. In a recently completed 10-patient pilot study, the average pain level decreased from a score of 5.7 to 1.4 (out of 10) after HFAC block therapy with 85% of all testing sessions yielding a >50% pain reduction; a very significant reduction in the use of opioid and other analgesics was also noted, with all tested patients either stopping or decreasing their analgesic intake significantly. Patients achieved meaningful and significant pain reduction throughout the study, and patients who had phantom pain (in addition to stump pain) that responded to local anesthetic injections also responded favorably with HFAC block, presumably because in these particular patients, the phantom symptoms were peripherally generated. Each of the tested patients reported that HFAC block provided the most significant amount of pain reduction they had ever experienced when compared to other pain modalities tried since their amputations. The high-frequency electric nerve block technique is currently investigational pending FDA clearance. The next step for this modality is a pivotal trial, with the goal of having this therapy available to the mass market upon FDA clearance.

High-frequency electrical nerve block for postamputation pain: a pilot study.

OBJECTIVES: This study aimed to assess the analgesic effect of kilohertz alternating current applied to the severed nerves in amputees afflicted by intractable limb pain. METHODS: Ten lower-limb amputees with chronic and severe residual limb pain or phantom limb pain who attained significant pain reduction after local nerve block injection were enrolled. A cuff electrode was wrapped around the sciatic or tibial nerve. An external waveform generator was used for the main part of the study, while an implantable generator was developed and implanted in the responders after 9 to 12 months. Sinusoidal waveforms of 10 kHz and up to 10 V were applied for 30 min during each subject-initiated treatment session. A diary was used to record pain intensities before and after each session. RESULTS: Among the seven subjects who received treatment, the average pain reduction was 75% at the three-month primary end point. These subjects were responders per predefined criterion of achieving ≥50% pain reduction in ≥50% of treatment sessions for the three-month end point. Pain medication use and interference of pain on functions was significantly reduced. The treatment efficacy was sustained through the follow-up period of up to 12 months. Besides dislodgement and loss of function for one electrode in one subject, all other devices functioned as intended. No changes of residual motor and sensory function were observed. CONCLUSION: This pilot study generated preliminary evidence on the efficacy and safety of kilohertz electrical nerve block for postamputation pain, justifying a pivotal study for regulatory approval.

Intramuscular electrical stimulation for upper limb recovery in chronic hemiparesis: an exploratory randomized clinical trial.

BACKGROUND: Surface electrical stimulation (ES) has been shown to improve the motor impairment of stroke survivors. However, surface ES can be painful and motor activation can be inconsistent from session to session. Percutaneous intramuscular ES may be an effective alternative. OBJECTIVE: Evaluate the effectiveness of percutaneous intramuscular ES in facilitating the recovery of the hemiparetic upper limb of chronic stroke survivors. METHODS: A total of 26 chronic stroke survivors were randomly assigned to percutaneous intramuscular ES for hand opening (n = 13) or percutaneous ES for sensory stimulation only (n = 13). The intramuscular ES group received cyclic, electromyography (EMG)-triggered or EMG-controlled ES depending on baseline motor status. All participants received 1 hour of stimulation per day for 6 weeks. After completion of ES, participants received 18 hours of task-specific functional training. The primary outcome measure was the Fugl-Meyer Motor Assessment. Secondary measures included the Arm Motor Ability Test and delay and termination of EMG activity. Outcomes were assessed in a blinded manner at baseline, at the end of ES, at the end of functional training, and at 1, 3, and 6 months follow-up. RESULTS: Repeated measure analysis of variance did not yield any significant treatment, or time by treatment interaction effects for any of the outcome measures. CONCLUSION: Percutaneous intramuscular ES does not appear to be any more effective than sensory ES in enhancing the recovery of the hemiparetic upper limb among chronic stroke survivors. However, because of the exploratory nature of the study and its inherent limitations, conclusions must be drawn with caution.

MRI findings in the painful poststroke shoulder.

BACKGROUND AND PURPOSE: We describe the structural abnormalities in the painful shoulder of stroke survivors and their relationships to clinical characteristics. Method- Eighty-nine chronic stroke survivors with poststroke shoulder pain underwent T1- and T2-weighted multiplanar, multisequence MRI of the painful paretic shoulder. All scans were reviewed by one radiologist for the following abnormalities: rotator cuff, biceps and deltoid tears, tendinopathies and atrophy, subacromial bursa fluid, labral ligamentous complex abnormalities, and acromioclavicular capsular hypertrophy. Clinical variables included subject demographics, stroke characteristics, and the Brief Pain Inventory Questions 12. The relationship between MRI findings and clinical characteristics was assessed through logistic regression. RESULTS: Thirty-five percent of subjects exhibited a tear of at least one rotator cuff, biceps or deltoid muscle. Fifty-three percent of subjects exhibited tendinopathy of at least one rotator cuff, bicep or deltoid muscle. The prevalence of rotator cuff tears increased with age. However, rotator cuff tears and rotator cuff and deltoid tendinopathies were not related to severity of poststroke shoulder pain. In approximately 20% of cases, rotator cuff and deltoid muscles exhibited evidence of atrophy. Atrophy was associated with reduced motor strength and reduced severity of shoulder pain. CONCLUSIONS: Rotator cuff tears and rotator cuff and deltoid tendinopathies are highly prevalent in poststroke shoulder pain. However, their relationship to shoulder pain is uncertain. Atrophy is less common but is associated with less severe shoulder pain.

Intramuscular electrical stimulation for shoulder pain in hemiplegia: does time from stroke onset predict treatment success?

BACKGROUND: A randomized clinical has shown the effectiveness of intramuscular electrical stimulation for the treatment of poststroke shoulder pain. OBJECTIVE: Identify predictors of treatment success and assess the impact of the strongest predictor on outcomes. METHOD: This is a secondary analysis of a multisite randomized clinical trial of intramuscular electrical stimulation for poststroke shoulder pain. The study included 61 chronic stroke survivors with shoulder pain randomized to a 6-week course of intramuscular electrical stimulation (n = 32) versus a hemisling (n = 29). The primary outcome measure was Brief Pain Inventory Question 12. Treatment success was defined as > or = 2-point reduction in this measure at end of treatment and at 3, 6, and 12 months posttreatment. Forward stepwise regression was used to identify factors predictive of treatment success among participants assigned to the electrical stimulation group. The factor most predictive of treatment success was used as an explanatory variable, and the clinical trials data were reanalyzed. RESULTS: Time from stroke onset was most predictive of treatment success. Subjects were divided according to the median value of stroke onset: early (<77 weeks) versus late (> 77 weeks). Electrical stimulation was effective in reducing poststroke shoulder pain for the early group (94% vs 7%, P < .001) but not for the late group (31% vs 33%). Repeated-measure analysis of variance revealed significant treatment (P < .001), time from stroke onset (P = .032), and treatment by time from stroke onset interaction (P < .001) effects. CONCLUSIONS: Stroke survivors who are treated early after stroke onset may experience greater benefit from intramuscular electrical stimulation for poststroke shoulder pain. However, the relative importance of time from stroke onset versus duration of pain is not known.

Poststroke shoulder pain: its relationship to motor impairment, activity limitation, and quality of life.

OBJECTIVE: To assess the relationship between poststroke shoulder pain, upper-limb motor impairment, activity limitation, and pain-related quality of life (QOL). DESIGN: Cross-sectional, secondary analysis of baseline data from a multisite clinical trial. SETTING: Outpatient rehabilitation clinics of 7 academic medical centers. PARTICIPANTS: Volunteer sample of 61 chronic stroke survivors with poststroke shoulder pain and glenohumeral subluxation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We measured poststroke shoulder pain with the Brief Pain Inventory question 12 (BPI 12), a self-reported 11-point numeric rating scale (NRS) that assesses "worst pain" in the last 7 days. Motor impairment was measured with the Fugl-Meyer Assessment (FMA). Activity limitation was measured with the Arm Motor Ability Test (AMAT) and the FIM instrument. Pain-related QOL was measured with BPI question 23, a self-reported 11-point NRS that assesses pain interference with general activity, mood, walking ability, normal work, interpersonal relationships, sleep, and enjoyment of life. RESULTS: Stepwise regression analyses indicated that poststroke shoulder pain is associated with the BPI 23, but not with the FMA, FIM, or AMAT scores. CONCLUSIONS: Poststroke shoulder pain is associated with reduced QOL, but not with motor impairment or activity limitation.

Intramuscular electrical stimulation for hemiplegic shoulder pain: a 12-month follow-up of a multiple-center, randomized clinical trial.

OBJECTIVE: Assess the effectiveness of intramuscular electrical stimulation in reducing hemiplegic shoulder pain at 12 mos posttreatment. DESIGN: A total of 61 chronic stroke survivors with shoulder pain and subluxation participated in this multiple-center, single-blinded, randomized clinical trial. Treatment subjects received intramuscular electrical stimulation to the supraspinatus, posterior deltoid, middle deltoid, and upper trapezius for 6 hrs/day for 6 wks. Control subjects were treated with a cuff-type sling for 6 wks. Brief Pain Inventory question 12, an 11-point numeric rating scale was administered in a blinded manner at baseline, end of treatment, and at 3, 6, and 12 mos posttreatment. Treatment success was defined as a minimum 2-point reduction in Brief Pain Inventory question 12 at all posttreatment assessments. Secondary measures included pain-related quality of life (Brief Pain Inventory question 23), subluxation, motor impairment, range of motion, spasticity, and activity limitation. RESULTS: The electrical stimulation group exhibited a significantly higher success rate than controls (63% vs. 21%, P = 0.001). Repeated-measure analysis of variance revealed significant treatment effects on posttreatment Brief Pain Inventory question 12 (F = 21.2, P < 0.001) and Brief Pain Inventory question 23 (F = 8.3, P < 0.001). Treatment effects on other secondary measures were not significant. CONCLUSIONS: Intramuscular electrical stimulation reduces hemiplegic shoulder pain, and the effect is maintained for > or =12 mos posttreatment.

Intramuscular neuromuscular electric stimulation for poststroke shoulder pain: a multicenter randomized clinical trial.

OBJECTIVE: To assess the effectiveness of intramuscular neuromuscular electric stimulation (NMES) in reducing poststroke shoulder pain. DESIGN: Multicenter, single-blinded, randomized clinical trial. SETTING: Ambulatory centers of 7 academic rehabilitation centers in the United States. PARTICIPANTS: Volunteer sample of 61 chronic stroke survivors with shoulder pain and subluxation. INTERVENTION: Treatment subjects received intramuscular NMES to the supraspinatus, posterior deltoid, middle deltoid, and trapezius for 6 hours a day for 6 weeks. Control subjects were treated with a cuff-type sling for 6 weeks. Main outcome measure Brief Pain Inventory question 12 (BPI 12), an 11-point numeric rating scale administered in a blinded manner at the end of treatment, and at 3 and 6 months posttreatment. RESULTS: The NMES group exhibited significantly higher proportions of success based on the 3-point or more reduction in BPI 12 success criterion at the end of treatment (65.6% vs 24.1%, P<.01), at 3 months (59.4% vs 20.7%, P<.01), and at 6 months (59.4% vs 27.6%, P<.05). By using the most stringent "no pain" criterion, the NMES group also exhibited significantly higher proportions of success at the end of treatment (34.4% vs 3.4%, P<.01), at 3 months (34.4% vs 0.0%, P<.001), and at 6 months (34.4% vs 10.3%, P<.05). CONCLUSIONS: Intramuscular NMES reduces poststroke shoulder pain among those with shoulder subluxation and the effect is maintained for at least 6 months posttreatment.