Combination therapy with simultaneous delivery of spinal cord stimulation modalities: COMBO randomized controlled trial.

Aim: The Combining Mechanisms for Better Outcomes randomized controlled trial assessed the effectiveness of various spinal cord stimulation (SCS) modalities for chronic pain. Specifically, combination therapy (simultaneous use of customized sub-perception field and paresthesia-based SCS) versus monotherapy (paresthesia-based SCS) was evaluated. Methods: Participants were prospectively enrolled (key inclusion criterion: chronic pain for ≥6 months). Primary end point was the proportion with ≥50% pain reduction without increased opioids at the 3 month follow-up. Patients were followed for 2 years. Results: The primary end point was met (n = 89; p < 0.0001) in 88% of patients in the combination-therapy arm (n = 36/41) and 71% in the monotherapy arm (n = 34/48). Responder rates at 1 and 2 years (with available SCS modalities) were 84% and 85%, respectively. Sustained functional outcomes improvement was observed out to 2 years. Conclusion: SCS-based combination therapy can improve outcomes in patients with chronic pain. Clinical Trial Registration: NCT03689920 (ClinicalTrials.gov), Combining Mechanisms for Better Outcomes (COMBO).

Spinal cord stimulation (SCS) is a device-based therapy for chronic pain that delivers electrical impulses to the spinal cord, disrupting pain signals to the brain. Pain relief can be achieved using different SCS techniques that use or do not use paresthesia (stimulation that produces a tingling sensation). These approaches affect patients in different ways, suggesting that different biological processes are involved in enabling pain relief. Research also suggests that better long-term results occur when patients can choose the therapy that is best for their own needs. This clinical study compared pain relief and other functional activities in those receiving combination therapy (simultaneous use of SCS that does and does not produce tingling sensation) against those receiving monotherapy (only SCS therapy producing tingling sensation) for 3 months. In the study, 88% of those receiving combination therapy and 71% with monotherapy alone reported a 50% (or greater) decrease in overall pain (the 'responder rate') without an increased dose of opioid drugs at 3 months after the start of therapy. This responder rate was found to be 84% at 1 year and 85% at 2 years (with all SCS therapy options available). Analysis of functional activities or disability showed that patients improved from 'severely disabled' at study start to 'moderately disabled' after 2 years, indicating that effective long-term (2 year) improvement can be achieved using SCS-based combination therapy for chronic pain.

Onset, Maintenance, and Cessation of Effect of Galcanezumab for Prevention of Migraine: A Narrative Review of Three Randomized Placebo-Controlled Trials.

INTRODUCTION: Galcanezumab, a humanized monoclonal antibody that binds to calcitonin gene-related peptide, is approved for the preventive treatment of migraine in adults. It is self-administered once monthly as a subcutaneous injection. This paper describes the time course of effect of galcanezumab in patients with episodic and chronic migraine. METHODS: Data were based on three double-blind, placebo-controlled, phase 3 studies. Patients (1773 episodic and 1113 chronic) were randomized (2:1:1) to monthly doses of placebo, galcanezumab 120 mg with a 240 mg loading dose, or galcanezumab 240 mg (January 2016-March 2017). Onset of effect was determined using a sequential analysis approach based on earliest time point at which galcanezumab achieved and subsequently maintained statistical superiority to placebo. Maintenance of effect was a comparison of the percentages of galcanezumab- and placebo-treated patients with maintenance of at least 50% response at the individual patient level. Cessation of effect was determined during a 4-month post-treatment period on the basis of change from baseline in monthly migraine headache days. RESULTS: Galcanezumab led to a lower percentage of patients who had a migraine headache on the first day after injection, provided maintenance of effect throughout the duration of the double-blind treatment period, and gradually lost effect without signs of rebound headache throughout the post-treatment period in most patients with episodic and chronic migraine. CONCLUSION: Galcanezumab is a novel preventive therapeutic option for adult patients with migraine that has early onset of action, maintenance of effect, and gradual reduction of effect upon treatment cessation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02614183 (EVOLVE-1); NCT02614196 (EVOLVE-2); NCT02614261 (REGAIN).

Pain relief outcomes using an SCS device capable of delivering combination therapy with advanced waveforms and field shapes.

BACKGROUND: Given the range of subjective experiences reported by patients with chronic pain, Spinal Cord Stimulation (SCS) systems designed for tailored delivery of analgesic therapy may help improve treatment effectiveness and satisfaction. RESEARCH DESIGN AND METHODS: This case-series evaluated 420 patients with chronic back and/or leg pain implanted with an SCS device capable of sequential or simultaneous delivery of neurostimulation (i.e. combination therapy) as well as multiple waveforms and/or field shapes. Following implantation, an array of standard programs (e.g. paresthesia-based SCS), and a custom set of sub-perception programs were provided per patient feedback. Pain scores (Numeric Rating Scale, NRS) were collected at baseline and during follow-up. RESULTS: In this multicenter, observational series (n = 420, 53.1% female; Age: 64.2 ± 13.4 years), a mean overall pain score of 7.2 ± 1.8 (SD) was reported pre-trial (Baseline). At a mean follow-up duration of 208 ± 200 (SD) days, the mean overall pain score reduced to 2.4 (p < 0.0001). Overall pain was reduced by 5.1 ± 2.4 and 4.5 ± 2.4 points (NRS) at 3-months (N = 256) and at 12-months post-implant (N = 122) respectively (p < 0.0001). CONCLUSIONS: These results suggest that highly 'customizable' SCS approaches may allow for highly effective pain relief within the real-world clinical setting.

Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Pain Following Amputation.

INTRODUCTION: Chronic pain and reduced function are significant problems for Military Service members and Veterans following amputation. Peripheral nerve stimulation (PNS) is a promising therapy, but PNS systems have traditionally been limited by invasiveness and complications. Recently, a novel percutaneous PNS system was developed to reduce the risk of complications and enable delivery of stimulation without surgery. MATERIALS AND METHODS: Percutaneous PNS was evaluated to determine if stimulation provides relief from residual and phantom limb pain following lower-extremity amputation. PNS leads were implanted percutaneously to deliver stimulation to the femoral and/or sciatic nerves. Patients received stimulation for up to 60 days followed by withdrawal of the leads. RESULTS: A review of recent studies and clinical reports found that a majority of patients (18/24, 75%) reported substantial (≥50%) clinically relevant relief of chronic post-amputation pain following up to 60 days of percutaneous PNS. Reductions in pain were frequently associated with reductions in disability and pain interference. CONCLUSIONS: Percutaneous PNS can durably reduce pain, thereby enabling improvements in quality of life, function, and rehabilitation in individuals with residual or phantom limb pain following amputation. Percutaneous PNS may have additional benefit for Military Service members and Veterans with post-surgical or post-traumatic pain.

Clinical Outcomes of 1 kHz Subperception Spinal Cord Stimulation in Implanted Patients With Failed Paresthesia-Based Stimulation: Results of a Prospective Randomized Controlled Trial.

BACKGROUND: Pain relief via spinal cord stimulation (SCS) has historically revolved around producing paresthesia to replace pain, with success measured by the extent of paresthesia-pain overlap. In a recent murine study, by Shechter et al., showed the superior efficacy of high frequency SCS (1 kHz and 10 kHz) at inhibiting the effects of mechanical hypersensitivity compared to sham or 50 Hz stimulation. In the same study, authors report there were no differences in efficacy between 1 kHz and 10 kHz delivered at subperception stimulation strength (80% of motor threshold). Therefore, we designed a randomized, 2 × 2 crossover study of low frequency supra-perception SCS vs. subperception SCS at 1 kHz frequency in order to test whether subperception stimulation at 1 kHz was sufficient to provide effective pain relief in human subjects. METHODS: Twenty-two subjects with SCS, and inadequate pain relief based on numeric pain rating scale (NPRS) scores (>5) were enrolled, and observed for total of seven weeks (three weeks of treatment, one week wash off, and another three weeks of treatment). Subjects were asked to rate their pain on NPRS as a primary efficacy variable, and complete the Oswestry Disability Index (ODI) and Patient's Global Impression of Change (PGIC) as secondary outcome measures. RESULTS: Out of 22 subjects that completed the study, 21 subjects (95%) reported improvements in average, best, and worst pain NPRS scores. All NPRS scores were significantly lower with subperception stimulation compared to paresthesia-based stimulation (p < 0.01, p < 0.05, and p < 0.05, respectively). As with NPRS scores, the treatment effect of subperception stimulation was significantly greater than that of paresthesia based stimulation on ODI scores (p = 3.9737 × 10-5 ) and PGIC scores (p = 3.0396 × 10-5 ).

The Effect of a Novel form of Extended-Release Gabapentin on Pain and Sleep in Fibromyalgia Subjects: An Open-Label Pilot Study.

INTRODUCTION: We assessed the efficacy and safety of extended-release gabapentin in a 15-week, open-label, single-arm, single-center study in patients with fibromyalgia (FM). METHODS: Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended-release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS). RESULTS: A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P < 0.0001) on NPRS. Subjects also reported similar magnitude of improvements in FM and its impact on daily life by end of 4 weeks on FIQ (P < 0.0001). Survey of MOS showed our subjects reporting improved sleep quantity (on average, 1.2 hours over baseline) with gradual and statistically significant improvement in quality. Improvements in primary and secondary measurements were reflected in PGIC, with significant improvement in patient's impression of FM by week 8. LIMITATIONS: Small sample size, geographical bias, relatively short duration of treatment, and single-arm study without control group. CONCLUSIONS: Extended-release gabapentin relieved FM pain symptoms and improved quality-of-life for the FM subjects studied. Subjects reported improvements in both quantity and quality of sleep.

Intrathecal Clonidine via Lumbar Puncture Decreases Blood Pressure in Patients With Poorly Controlled Hypertension.

OBJECTIVES: Oral clonidine is used to treat hypertension but often produces sedation and severe dry mouth; intrathecal clonidine is used to treat chronic pain but may produce hypotension. This clinical feasibility study was conducted to determine if intrathecal clonidine decreases blood pressure in patients with poorly controlled hypertension. MATERIALS AND METHODS: This prospective, single-arm, open-label study was conducted in ten subjects who were taking at least three antihypertensive medications including a diuretic and had an in-office systolic blood pressure between 140 and 190 mm Hg. On the day of treatment, blood pressure was measured before and after a single lumbar intrathecal dose (150 mcg) of clonidine using an automatic oscillometric device every 10-15 min for four hours. Student's paired t-test was used for statistical comparisons. RESULTS: Maximal reductions in systolic and diastolic blood pressures averaging 63 ± 20/29 ± 13 mm Hg were observed approximately two hours after clonidine administration. Decreases in systolic pressure were strongly correlated with baseline systolic pressure. Clonidine produced a significant decrease in heart rate of 11 ± 7 beats/min. No subject required intravenous fluids or vasopressor rescue therapy, or reported spinal headache. CONCLUSIONS: This is the first clinical study in subjects with hypertension that demonstrates significant and profound acute reductions in blood pressure after a single dose of intrathecal clonidine. Future placebo-controlled, dose-escalating studies are warranted to assess the long-term effects of intrathecal clonidine infusion via an implantable drug pump in patients with treatment-resistant hypertension at risk of stroke or myocardial infarction.

Treatment of post-amputation pain with peripheral nerve stimulation.

BACKGROUND: Present treatment methods are often unsatisfactory in reducing post-amputation pain. Peripheral nerve stimulation (PNS) could reduce the pain, but it is rarely used because present methods require invasive surgical access and precise placement of the leads in close proximity (≤ 2 mm) with the nerve. METHODS: The present study investigated the feasibility of delivering PNS to patients with moderate-to-severe post-amputation pain in the lower extremity using a fine-wire lead placed percutaneously under ultrasound guidance a remote distance (0.5-3.0 cm) away from the sciatic and/or femoral nerves. RESULTS: Fourteen of the 16 subjects who completed in-clinic testing responded to stimulation, reported ≥ 75% paresthesia coverage, obtained clinically significant pain relief, and proceeded to a two-week home trial with a percutaneous PNS system. Two of the 14 responders had their leads removed early because of accidental dislodgement (N = 2), two had temporary discomfort near the lead (N = 2), and one had return of post-amputation pain despite stimulation (N = 1) and did not complete the home trial. The nine responders who completed the home trial reported reductions in their mean daily worst post-amputation pain (56 ± 26%, 56 ± 26%, N = 9), average residual limb pain (72 ± 28%, 42 ± 27%, N = 7), average phantom limb pain (81 ± 28%, 47 ± 48%, N = 7), residual limb pain interference (81 ± 27%, 53 ± 17%, N = 6), phantom limb pain interference (83 ± 31%, 56 ± 46%, N = 7), and Pain Disability Index (70 ± 38%, 55 ± 32%, N = 9) during the second week of stimulation and four weeks after the end of stimulation, respectively. All nine responders rated their change in quality of life as improved at the end of stimulation and at the end of the four-week follow-up period. Subjects reported minor decreases in the Beck Depression Inventory scores (43 ± 51%, 32 ± 57%, N = 9). Most subjects had no substantial changes other than minor decreases (N = 3) in pain medication. CONCLUSION: Achievement of significant pain relief and improvements in quality of life with a minimally invasive method of PNS holds promise for providing relief of post-amputation pain.

Peripheral nerve stimulation for the treatment of postamputation pain--a case report.

Many amputees suffer from postamputation pain, which can be extremely debilitating, decrease quality of life, increase the risk of depression, and negatively affect interpersonal relationships and the ability to work. Present methods of treatment, including medications, are often unsatisfactory in reducing postamputation pain. Electrical stimulation of the nerve innervating the painful area could reduce the pain, but peripheral nerve stimulation is rarely used to treat postamputation pain because present methods require invasive surgical access and precise placement of the leads in close proximity (≤ 2 mm) with the nerve. The present study investigated a novel approach to peripheral nerve stimulation in which a lead was placed percutaneously a remote distance (> 1 cm) away from the femoral nerve in a patient with severe residual limb pain (RLP) 33 years following a below-knee amputation. Electrical stimulation generated ≥ 75% paresthesia coverage, reduced RLP by > 60%, and improved quality of life outcomes as measured by the pain interference scale of the Brief Pain Inventory-Short Form (100% reduction in pain interference), Pain Disability Index (74% reduction in disability), and the Patient Global Impression of Change (very much improved) during a 2-week home trial. There were no adverse events. The ability to generate significant paresthesia coverage and pain relief with a single lead inserted percutaneously and remotely from the target nerve holds promise for providing relief of postamputation pain.

Intrathecal ziconotide for neuropathic pain: a review.

Neuropathic pain is a considerable burden that affects activities of daily living. The management of neuropathic pain can be challenging because of multiple etiologies and complex manifestations. Ziconotide is a nonopioid intrathecal (IT) analgesic option for patients with neuropathic pain refractory to conventional treatments. The objective of this article is to review the published literature on ziconotide for the treatment of neuropathic pain. Relevant publications were identified through searches of all years of 6 databases, which included PubMed, EMBASE, and CINAHL. Search terms used were ziconotide, SNX-111, MVIIA, Prialt, and neuropathic pain. Publications were included if ziconotide was intrathecally administered (either alone or in combination with other IT agents) to treat neuropathic pain of any etiology and if pain assessment was an outcome measure. Data extracted included study design, IT drug doses, pain outcome measures, and adverse events (AEs). Twenty-eight articles met the inclusion criteria: 5 were preclinical studies and 23 were clinical studies. In the preclinical studies, ziconotide demonstrated antiallodynic effects on neuropathic pain. Data from double-blind, placebo-controlled (DBPC) trials indicated that patients with neuropathic pain reported a mean percent improvement in pain score with ziconotide monotherapy that ranged from 15.7% to 31.6%. A low starting dose and slow titration of ziconotide resulted in an improved safety profile in the aforementioned trials. Common AEs associated with ziconotide include nausea and/or vomiting, dizziness, confusion, urinary retention, and somnolence. Evidence from DBPC trials, open-label studies, case series, and case studies suggests that ziconotide, as either monotherapy or in combination with other IT drugs, is a potential therapeutic option for patients with refractory neuropathic pain. Additional studies are needed to establish the long-term efficacy and safety of ziconotide for neuropathic pain.