Effectiveness of cervical spinal cord stimulation for the management of chronic pain.

INTRODUCTION: Scientific evidence supports spinal cord stimulation (SCS) as a cost-effective treatment option that, for many disease states, should be employed earlier in the treatment continuum. Reimbursement for SCS in the cervical spine has recently been challenged based on supposed lack of clinical literature. To refute this assumption, we analyzed data from an international registry to support the use of cervical SCS. MATERIALS AND METHODS: The following outcomes were collected as part of an institutional review board-approved, prospective, multicenter, international registry: pain relief, Pain Disability Index (PDI) score, quality of life (QoL), and satisfaction at 3, 6, and 12 months post-implantation. Descriptive statistics are provided for all measures. Changes from baseline in PDI scores were analyzed using Tukey's pairwise comparisons. RESULTS: Thirty-eight patients underwent implantation of SCS leads in the cervical spine at 16 study sites in the United States and 3 international study sites. Direct patient report of percentage of pain relief was 54.2%, 60.2%, and 66.8% at 3, 6, and 12 months post-implantation, respectively. Pain relief was categorized as excellent/good by 61.6% of patients at 3 months, with similar results observed at 6 and 12 months. PDI scores were significantly reduced at all time points. At 3 months post-implantation, 92.4% of patients indicated they were very satisfied/satisfied with the SCS device. No patients indicated that they were dissatisfied. Overall QoL was reported as improved/greatly improved by 73.1% of patients at 3 months. Similar results for QoL and satisfaction were reported at 6 and 12 months. CONCLUSION: The results suggest that the use of SCS in the cervical spine is a medically effective method of pain management that satisfies and improves the QoL of most patients. The use of SCS can reduce the high cost of direct medical treatment of pain, as well as increasing the productivity of patients, and therefore should be reimbursed in appropriately selected patients.

Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study.

BACKGROUND: Chronic migraine (CM) is a debilitating neurological disorder with few treatment options. Peripheral nerve stimulation (PNS) of the occipital nerves is a potentially promising therapy for CM patients. METHODS: In this randomized, controlled multicenter study, patients diagnosed with CM were implanted with a neurostimulation device near the occipital nerves and randomized 2:1 to active (n = 105) or sham (n = 52) stimulation. The primary endpoint was a difference in the percentage of responders (defined as patients that achieved a ≥50% reduction in mean daily visual analog scale scores) in each group at 12 weeks. RESULTS: There was not a significant difference in the percentage of responders in the Active compared with the Control group (95% lower confidence bound (LCB) of -0.06; p = 0.55). However, there was a significant difference in the percentage of patients that achieved a 30% reduction (p = 0.01). Importantly, compared with sham-treated patients, there were also significant differences in reduction of number of headache days (Active Group = 6.1, baseline = 22.4; Control Group = 3.0, baseline = 20.1; p = 0.008), migraine-related disability (p = 0.001) and direct reports of pain relief (p = 0.001). The most common adverse event was persistent implant site pain. CONCLUSION: Although this study failed to meet its primary endpoint, this is the first large-scale study of PNS of the occipital nerves in CM patients that showed significant reductions in pain, headache days, and migraine-related disability. Additional controlled studies using endpoints that have recently been identified and accepted as clinically meaningful are warranted in this highly disabled patient population with a large unmet medical need. TRIAL REGISTRATION: Clinical trials.gov (NCT00615342).

Delivering transcutaneous auricular neurostimulation (tAN) to improve symptoms associated with opioid withdrawal: results from a prospective clinical trial.

BACKGROUND: As pharmacological treatments are the primary option for opioid use disorder, neuromodulation has recently demonstrated efficacy in managing opioid withdrawal syndrome (OWS). This study investigated the safety and effectiveness of transcutaneous auricular neurostimulation (tAN) for managing OWS. METHODS: This prospective inpatient trial included a 30-minute randomized, sham-controlled, double-blind period followed by a 5-day open-label period. Adults with physical dependence on opioids were randomized to receive active or sham tAN following abrupt opioid discontinuation. The Clinical Opiate Withdrawal Scale (COWS) was used to determine withdrawal level, and participants were required to have a baseline COWS score ≥ 13 before enrollment. The double-blind period of the study occurred during the first 30-minutes to assess the acute effects of tAN therapy compared to a sham control. Group 1 received active tAN during both the 30-minute double-blind period and the 5-day open-label period. Group 2 received passive sham tAN (no stimulation) during the double-blind period, followed by active tAN during the 5-day open-label period. The primary outcome was change in COWS from baseline to 60-minutes of active tAN (pooled across groups, accounting for 30-minute delay). Secondary outcomes included difference in change in COWS scores between groups after 30-minutes of active or sham tAN, change in COWS scores after 120-minutes of active tAN, and change in COWS scores on Days 2-5. Non-opioid comfort medications were administered during the trial. RESULTS: Across all thirty-one participants, the mean (SD) COWS scores relative to baseline were reduced by 7.0 (4.7) points after 60-minutes of active tAN across both groups (p < 0.0001; Cohen's d = 2.0), demonstrating a significant and clinically meaningful reduction of 45.9%. After 30-minutes of active tAN (Group 1) or sham tAN (Group 2), the active tAN group demonstrated a significantly greater COWS score reduction than the sham tAN group (41.7% vs. 24.1%; p = 0.036). Participants across both groups achieved an average COWS reduction up to 74.7% on Days 2-5. CONCLUSION: Results demonstrate tAN is a safe and effective non-opioid approach for reducing symptoms of OWS. This study supported an FDA clearance. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT04075214 , Identifier: NCT04075214, Release Date: August 28, 2019.

An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury.

Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1ß 24 h later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 µg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1ß at both 30 min and 24 h after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 µg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 µg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function.

Transcutaneous Auricular Neurostimulation (tAN): A Novel Adjuvant Treatment in Neonatal Opioid Withdrawal Syndrome.

Maternal opioid use during pregnancy is a growing national problem and can lead to newborns developing neonatal opioid withdrawal syndrome (NOWS) soon after birth. Recent data demonstrates that nearly every 15 min a baby is born in the United States suffering from NOWS. The primary treatment for NOWS is opioid replacement therapy, commonly oral morphine, which has neurotoxic effects on the developing brain. There is an urgent need for non-opioid treatments for NOWS. Transcutaneous auricular neurostimulation (tAN), a novel and non-invasive form of electrostimulation, may serve as a promising alternative to morphine. tAN is delivered via a multichannel earpiece electrode worn on and around the left ear, targeting two cranial nerves-the vagus and trigeminal nerves. Prior research suggests that auricular neurostimulation exerts an anxiolytic effect on the body by releasing endogenous opioids and reduces withdrawal symptoms in adults actively withdrawing from opioids. In this first-in-human prospective, open-label trial, we investigated tAN as an adjuvant to morphine therapy in eight infants >33 weeks gestational age suffering from NOWS and receiving oral morphine treatment. Infants received tAN for 30 min 1 h before receiving a morphine dose. tAN was delivered at 0.1 mA below perception intensity at two different nerve targets on the ear: Region 1, the auricular branch of the vagus nerve; and Region 2, the auriculotemporal nerve. tAN was delivered up to four times daily for a maximum of 12 days. The primary outcome measures were safety [heart rate monitoring, Neonatal Infant Pain Scale (NIPS), and skin irritation] and morphine length of treatment (LOT). tAN was well-tolerated and resulted in no unanticipated adverse events. Comparing to the national average of 23 days, the average oral morphine LOT was 13.3 days (median 9 days) and the average LOT after tAN initiation was 7 days (median 6 days). These preliminary data suggest that tAN is safe and may serve as a promising alternative adjuvant for treating NOWS and reducing the amount of time an infant receives oral morphine.

Successful treatment of charcot-marie-tooth chronic pain with spinal cord stimulation: a case study.

OBJECTIVES: Charcot-Marie-Tooth (CMT) disease is one of the most common hereditary neuropathies affecting one in 2500 people in the United States. CMT disease is associated with moderate to severe chronic extremity pain. We present the case of a young man with chronic intractable lower extremity pain associated with CMT disease treated with spinal cord stimulation (SCS). MATERIALS AND METHODS: This was an Institutional Review Board-approved case study involving a 37-year-old man diagnosed with CMT disease with pain of more than 20 years. He was implanted with an SCS device and patient pain and quality of life was assessed one and six months later using the SF-McGill Pain Questionnaire, Visual Analog Scale, Oswestry Disability Questionnaire, Pain Disability Index, and SF-36. Baseline measures were obtained retrospectively. Qualitative data were collected from the medical record. RESULTS: SCS was effective in decreasing pain, improving quality of life and reducing medication consumption at both one and six months post-implant. In addition, the patient was satisfied with SCS treatment. CONCLUSION: SCS produced favorable results in a patient with CMT and should be considered a treatment option for pain resulting from this condition.

Exposure to intermittent nociceptive stimulation under pentobarbital anesthesia disrupts spinal cord function in rats.

RATIONALE: Spinal cord plasticity can be assessed in spinal rats using an instrumental learning paradigm in which subjects learn an instrumental response, hindlimb flexion, to minimize shock exposure. Prior exposure to uncontrollable intermittent stimulation blocks learning in spinal rats but has no effect if given before spinal transection, suggesting that supraspinal systems modulate nociceptive input to the spinal cord, rendering it less susceptible to the detrimental consequences of uncontrollable stimulation. OBJECTIVE: The present study examines whether disrupting brain function with pentobarbital blocks descending inhibitory systems that normally modulate nociceptive input, making the spinal cord more sensitive to the adverse effect of uncontrollable intermittent stimulation. MATERIALS AND METHODS: Male Sprague-Dawley rats received uncontrollable intermittent stimulation during pentobarbital anesthesia after (experiment 1) or before (experiment 2) spinal cord transection. They were then tested for instrumental learning at a later time point. Experiment 3 examined whether these manipulations affected nociceptive (thermal) thresholds. RESULTS: Experiment 1 showed that pentobarbital had no effect on the induction of the learning deficit after spinal cord transection. Experiment 2 showed that intact rats anesthetized during uncontrollable intermittent stimulation failed to learn when later transected and tested for instrumental learning. Experiment 3 found that uncontrollable intermittent stimulation induced an antinociception in intact subjects that was blocked by pentobarbital. CONCLUSIONS: The results suggest a surgical dose of pentobarbital (50 mg/kg) suppresses supraspinal (experiment 2) but not spinal (experiment 1) systems that modulate nociceptive input to the spinal cord by blocking the antinociception that is induced by this input (experiment 3).

The impact of morphine after a spinal cord injury.

Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such as pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.

Instrumental learning within the spinal cord: underlying mechanisms and implications for recovery after injury.

Using spinally transected rats, research has shown that neurons within the L4-S2 spinal cord are sensitive to response-outcome (instrumental) relations. This learning depends on a form of N-methyl-D-aspartate (NMDA)-mediated plasticity. Instrumental training enables subsequent learning, and this effect has been linked to the expression of brain-derived neurotrophic factor. Rats given uncontrollable stimulation later exhibit impaired instrumental learning, and this deficit lasts up to 48 hr. The induction of the deficit can be blocked by prior training with controllable shock, the concurrent presentation of a tonic stimulus that induces antinociception, or pretreatment with an NMDA or gamma-aminobutyric acid-A antagonist. The expression of the deficit depends on a kappa opioid. Uncontrollable stimulation enhances mechanical reactivity (allodynia), and treatments that induce allodynia (e.g., inflammation) inhibit learning. In intact animals, descending serotonergic neurons exert a protective effect that blocks the adverse consequences of uncontrollable stimulation. Uncontrollable, but not controllable, stimulation impairs the recovery of function after a contusion injury.

Uncontrollable stimulation undermines recovery after spinal cord injury.

Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome relations, a form of instrumental learning. Spinally transected rats that receive shock to one hind leg learn to maintain the leg in a flexed position that minimizes net shock exposure (controllable shock). Prior exposure to uncontrollable stimulation (intermittent shock) inhibits this spinally mediated learning. Here it is shown that uncontrollable stimulation undermines the recovery of function after a spinal contusion injury. Rats received a moderate injury (12.5 mm drop) and recovery was monitored for 6 weeks. In Experiment 1, rats received varying amounts of intermittent tailshock 1-2 days after injury. Just 6 min of intermittent shock impaired locomotor recovery. In Experiment 2, rats were shocked 1, 4, or 14 days after injury. Delaying the application of shock exposure reduced its negative effect on recovery. In Experiment 3, rats received controllable or uncontrollable shock 24 and 48 h after injury. Only uncontrollable shock disrupted recovery of locomotor function. Uncontrollably shocked rats also exhibited higher vocalization thresholds to aversive stimuli (heat and shock) applied below the injury. Across the three experiments, exposure to uncontrollable shock, (1) delayed the recovery of bladder function; (2) led to greater mortality and spasticity; and (3) increased tissue loss (white and gray matter) in the region of the injury. The results indicate that uncontrollable stimulation impairs recovery after spinal cord injury and suggest that reducing sources of uncontrolled afferent input (e.g., from peripheral tissue injury) could benefit patient recovery.

GABA(A) receptor activation is involved in noncontingent shock inhibition of instrumental conditioning in spinal rats.

Previous work has demonstrated that the spinal cord, isolated from higher neural structures, can support a simple form of instrumental learning. Furthermore, preexposure to uncontrollable (noncontingent) shock to the leg or tail inhibits this form of learning. The present study explores the role of GABA(A) receptor modulation on this inhibitory effect in spinal cord-transected rats. Intrathecal administration of the GABA(A) receptor antagonist bicuculline blocked induction and expression of the inhibition. The GABA(A) receptor agonist muscimol inhibited learning in a dose-dependent manner. However, this effect was transient and showed no additivity with shock. The findings suggest that GABA(A) receptor activation may work like a pharmacological switch that is activated by noncontingent shock to inhibit instrumental conditioning within the spinal cord.

Opioid regulation of spinal cord plasticity: evidence the kappa-2 opioid receptor agonist GR89696 inhibits learning within the rat spinal cord.

Spinal cord neurons can support a simple form of instrumental learning. In this paradigm, rats completely transected at the second thoracic vertebra learn to minimize shock exposure by maintaining a hindlimb in a flexed position. Prior exposure to uncontrollable shock (shock independent of leg position) disrupts this learning. This learning deficit lasts for at least 24h and depends on the NMDA receptor. Intrathecal application of an opioid antagonist blocks the expression, but not the induction, of the learning deficit. A comparison of selective opioid antagonists implicated the kappa-opioid receptor. The present experiments further explore how opioids affect spinal instrumental learning using selective opioid agonists. Male Sprague-Dawley rats were given an intrathecal injection (30 nmol) of a kappa-1 (U69593), a kappa-2 (GR89696), a mu (DAMGO), or a delta opioid receptor agonist (DPDPE) 10 min prior to instrumental testing. Only the kappa-2 opioid receptor agonist GR89696 inhibited acquisition (Experiment 1). GR89696 inhibited learning in a dose-dependent fashion (Experiment 2), but had no effect on instrumental performance in previously trained subjects (Experiment 3). Pretreatment with an opioid antagonist (naltrexone) blocked the GR89696-induced learning deficit (Experiment 4). Administration of GR89696 did not produce a lasting impairment (Experiment 5) and a moderate dose of GR89696 (6 nmol) reduced the adverse consequences of uncontrollable nociceptive stimulation (Experiment 6). The results suggest that a kappa-2 opioid agonist inhibits neural modifications within the spinal cord.