Treatment of Refractory Low Back Pain Using Passive Recharge Burst in Patients Without Options for Corrective Surgery: Findings and Results From the DISTINCT Study, a Prospective Randomized Multicenter Controlled Trial.

OBJECTIVE: Spinal cord stimulation (SCS) is effective for relieving chronic intractable pain conditions. The Dorsal spInal cord STImulatioN vs mediCal management for the Treatment of low back pain study evaluates the effectiveness of SCS compared with conventional medical management (CMM) in the treatment of chronic low back pain in patients who had not undergone and were not candidates for lumbar spine surgery. METHODS AND MATERIALS: Patients were randomized to passive recharge burst therapy (n = 162) or CMM (n = 107). They reported severe pain and disability for more than a decade and had failed a multitude of therapies. Common diagnoses included degenerative disc disease, spondylosis, stenosis, and scoliosis-yet not to a degree amenable to surgery. The six-month primary end point compared responder rates, defined by a 50% reduction in pain. Hierarchical analyses of seven secondary end points were performed in the following order: composite responder rate (numerical rating scale [NRS] or Oswestry Disability Index [ODI]), NRS, ODI, Pain Catastrophizing Scale responder rate, Patient Global Impression of Change (PGIC) responder rate, and Patient-Reported Outcome Measure Information System-29 in pain interference and physical function. RESULTS: Intention-to-treat analysis showed a significant difference in pain responders on NRS between SCS (72.6%) and CMM (7.1%) arms (p < 0.0001). Of note, 85.2% of those who received six months of therapy responded on NRS compared with 6.2% of those with CMM (p < 0.0001). All secondary end points indicated the superiority of burst therapy over CMM. A composite measure on function or pain relief showed 91% of subjects with SCS improved, compared with 16% of subjects with CMM. A substantial improvement of 30 points was observed on ODI compared with a

Pain phenotypes classified by machine learning using electroencephalography features.

Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive.

Short-Term Pain Outcomes and Pain Medication Utilization Among Urine Toxicology-Identified Opioid and Marijuana Users After Elective Spine Surgery.

BACKGROUND AND OBJECTIVES: Postoperative pain outcomes may be influenced by preoperative substance use, which is often underreported due to associated stigma. This study examined the impact of urine toxicology-identified preoperative opioid and marijuana use on pain outcomes after elective spinal surgery. METHODS: Patients undergoing elective spinal surgery between September 2020 and May 2022 were recruited for this prospective cohort study. Detailed chart review was completed to collect demographic, urine toxicology, Visual Analog Scale (VAS), and pain medication data. Comparisons between self-reported and urine toxicology-identified substance use, preoperative/postoperative VAS ratings, and postoperative pain medication use were made using χ 2 tests, Student t -tests, and logistic regression, respectively. Models were adjusted for age, sex, and race. RESULTS: Among 111 participants (mean age 58 years, 59% female, 95% with ≥1 comorbidity), urine toxicology overestimated drug use (47% vs 16%, P < .001) and underestimated alcohol use (16% vs 56%, P < .001) at preoperative baseline relative to patient reports. Two weeks postoperatively, participants with preoperative opioid metabolites reported no significant improvements in pain from baseline (6.67 preoperative vs 5.92 postoperative, P = .288) unlike nonusers (6.56 preoperative vs 4.61 postoperative, P < .001). They also had worse postoperative VAS (5.92 vs 4.61, P = .030) and heavier reliance on opioid medications (odds ratio = 3.09, 95% CI = 1.21-7.89, P = .019). Conversely, participants with preoperative marijuana reported similar improvements in pain from baseline (users: 6.88 preoperative vs 4.36 postoperative, P = .001; nonusers: 6.49 preoperative vs 5.07 postoperative, P = .001), similar postoperative pain (4.36 vs 5.07, P = .238), and similar postoperative reliance on opioid medications (odds ratio = 0.96, 95% CI = 0.38-2.44, P = .928). Trends were maintained among the 83 patients who returned for the 3-month follow-up. CONCLUSION: Although urine toxicology-identified preoperative opioid use was associated with poor postoperative pain relief and reliance on postoperative opioids for pain management after elective spinal surgery, preoperative marijuana use was not. Preoperative marijuana use, hence, should not delay or be a contraindication to elective spinal surgery.

Use of Accelerometry as an Educational Tool for Spinal Cord Stimulation: A Pilot Study.

Background: Spinal cord stimulation (SCS) is an important option for patients with chronic neuropathic pain. In the United States, a successful SCS trial determines eligibility for SCS implant. Metrics to determine success are often self-reported and subjective, which may limit achievement of patient goals. This study aimed to assess whether patients undergoing SCS implant after successful trial felt that use of external accelerometry prior to implant was a useful educational tool to objectively appraise function and achievement of treatment goals. Methods: This was a single center, prospective, pilot study. Sixteen subjects with persistent spinal pain syndrome type 2 underwent a percutaneous SCS trial. Five subjects did not have a successful trial, one expired after the SCS trial, before implant, and one dropped out prior to completion of post-implant follow-up visits. Nine subjects underwent SCS implant and completed the required follow-up visits. All subjects were provided an Actigraph GT3X external accelerometer, worn 7 days prior to the trial to determine baseline physical activity and during the 7-day trial to assess for change in activity from baseline. Results were shared with subjects to individualize goals for therapy. Goal attainment was assessed at 1, 3, and 6 months after implant. Subjects wore the accelerometer again 24 hours before visits to update progress in meeting treatment goals. The primary outcome was satisfaction with using accelerometry as an educational tool to appraise function and guide treatment goals for SCS therapy. Secondary outcomes included physical activity, as captured via accelerometry, as well as validated patient-reported measures of pain severity, physical functioning, and quality-of-life. Results: Eight of nine subjects were satisfied with accelerometry as an educational tool. Secondary outcomes were not reliably assessed due to poor stewardship and study execution. Conclusion: External accelerometry may assist patients in developing individualized functional treatment goals for SCS therapy.

Transition from Compounded to Monotherapy Intrathecal Pain Medication Reduces Drug Costs: Retrospective Analysis of Patient Billing Data.

BACKGROUND: Chronic pain accounts for several hundred billion dollars in total treatment costs, and lost productivity annually. Selecting cost-effective pain treatments can reduce the financial burden on both individuals and society. Targeted drug delivery (TDD), whereby medications used to treat pain are delivered directly to the intrathecal space, remains an important treatment modality for chronic pain refractory to oral medication management. These medications can be administered alone (monotherapy), or in conjunction with other medications to give a synergistic affect (compounded therapy). While compounded therapy is often prescribed for pain refractory to both oral management and intrathecal monotherapy, compounded administration has not been approved by the United States Food and Drug Administration (FDA), and is thought to be more expensive. In this study, we hypothesized that TDD delivering monotherapy vs compounded therapy would differ significantly in cost. OBJECTIVES: In 2015, a pharmacy-led initiative resulted in an institution-wide policy requiring that all TDD patients, being treated with compounded therapy, be transitioned to FDA-approved intrathecal monotherapy. The intent of this new policy was to eliminate use of non-FDA approved, "off-label" medications. During this transition, our practice used the opportunity to retrospectively analyze and compare the costs of monotherapy vs compounded therapy. STUDY DESIGN: Billing, drug dosing, and pain data were collected from 01/2015 to 01/2019, and reviewed retrospectively for patients originally on compounded intrathecal medication therapy, and compared before and after transition to monotherapy. SETTING: A multidisciplinary hospital-based spine center within an academic tertiary care facility. METHODS: Electronic medical records from the institutional TDD program were retrospectively reviewed to identify all patients on compounded drug therapy before the transition period (2015-2016). Patients were excluded from the study if they chose to switch their care to another practice rather than transitioning from compounded therapy to monotherapy. Cost per medications refill, cost per year, and reported pain scale before and after the transition were computed, and differences were compared using unpaired t tests. Refill costs of individual drugs were also compared. RESULTS: Of 46 patients originally on compounded therapy, 26 patients met inclusion criteria. The most common pre-transition drugs administered as compounded therapy were bupivacaine (n = 17), morphine (n = 15), and clonidine (n = 14), while hydromorphone (n = 10), baclofen (n = 5), and fentanyl (n = 1) were less common. There was a 51.3% decrease in cost per refill (P = 0.135) and a 50.0% decrease in cost per year (P = 0.283) after transition. Morphine and clonidine were both significantly more expensive than hydromorphone and bupivacaine (P < 0.05). After removing cases in which hydromorphone was the baseline opiate, there was a 64.8% decrease in cost per refill (P = 0.041) and a 66.8% decrease in cost per year (P = 0.190). There was no significant difference in the average reported pain scale across the transition (P = 0.323), suggesting stable pain management efficacy. LIMITATIONS: This retrospective study is limited by its small cohort size and lack of a control group. CONCLUSIONS: Based on single-institutional billing data, transition from compounded therapy to monotherapy TDD resulted in cost savings, dependent on the specific combination of drugs initially used for therapy. A larger multi-institutional study is indicated.

Latest Evidence-Based Application for Radiofrequency Neurotomy (LEARN): Best Practice Guidelines from the American Society of Pain and Neuroscience (ASPN).

Radiofrequency neurotomy (RFN), also known as radiofrequency ablation (RFA), is a common interventional procedure used to treat pain from an innervated structure. RFN has historically been used to treat chronic facet-joint mediated pain. The use of RFN has more recently expanded beyond facet-joint mediated pain to peripherally innervated targets. In addition, there has also been the emergence of different radiofrequency modalities, including pulsed and cooled RFN. The use of RFN has been particularly important where conservative and/or surgical measures have failed to provide pain relief. With the emergence of this therapeutic option and its novel applications, the American Society of Pain and Neuroscience (ASPN) identified the need for formal evidence-based guidance. The authors formed a multidisciplinary work group tasked to examine the latest evidence-based medicine for the various applications of RFN, including cervical, thoracic, lumbar spine; posterior sacroiliac joint pain; hip and knee joints; and occipital neuralgia. Best practice guidelines, evidence and consensus grading were provided for each anatomical target.

Proclaim™ DRG Neurostimulator System for the management of chronic, intractable pain.

Chronic pain is consistently listed as one of the most costly and disabling health problems worldwide. In an effort to treat these suffering individuals, significant amounts of time and energy have been devoted to discover safe and effective pain relieving treatments. Dorsal root ganglion stimulation is the newest treatment modality to be created for chronic intractable pain. In this manuscript, we review the history and development, published research and safety profile of the Proclaim™ DRG Neurostimulator System (Abbott, TX, USA). At last, we offer our outlook on future developments with dorsal root ganglion stimulation.

Whole animal in vivo imaging after transient, nonviral gene delivery to the rat central nervous system.

We previously showed that a vector:lipid delivery system, comprised of a plasmid DNA vector and cationic lipid (lipoplex), when injected into the cerebrospinal fluid (CSF) of rats can deliver reporter genes in vivo efficiently and with widespread expression to the Central Nervous System (CNS). To further characterize this delivery system, we now present experiments that demonstrate the in vivo time-to-peak expression of the reporter gene, firefly luciferase. We infused a formulated lipoplex containing the lipid MLRI [dissymmetric myristoyl (14:0) and lauroyl (12:1) rosenthal inhibitor-substituted compound formed from the tetraalkylammonium glycerol-based DORI] and pNDluc, a luciferase vector, into CSF in the cisterna magna (CM) of the rat. Luciferase activity was followed over time by bioluminescence imaging after injection of luciferin. Our results show that luciferase activity in the CNS of rats is widespread, peaks 72 hours after injection into CM and can be detected in vivo for at least 7-10 days after peak expression. We further show that in contrast to injection into CSF, enzyme activity is not widely distributed after injection of the vector into brain parenchyma, emphasizing the importance of CSF delivery to achieve widespread vector distribution. Finally, we confirm the distribution of firefly luciferase in brain by immunohistochemical staining from an animal that was euthanized at the peak of enzyme expression.

Capnography monitoring enhances safety of postoperative patient-controlled analgesia.

BACKGROUND: Patient-controlled analgesia is associated with potentially fatal opioid-related respiratory depression. Opioids are a well-recognized cause of respiratory depression. However, in the postoperative patient, unrecognized pulmonary disease may lead to retention of carbon dioxide, which is further antagonized by opioids and may lead to life-threatening respiratory depression. Therefore, using a method that would provide earlier warnings for respiratory problems could improve patient outcomes. OBJECTIVE: To assess the efficacy of monitoring postoperative patients who were receiving patient-controlled opioid therapy with capnography modules in addition to the routine use of pulse oximetry to monitor ventilatory status and generate alerts when respiratory parameters exceed hospital-established limits. METHOD: Postoperative patients receiving patient-controlled analgesia were compared in relation to the use of pulse oximetry and capnography modules and their ability to generate alerts about abnormal respiratory parameters. A total of 634 patients receiving patient-controlled analgesia therapy were studied, of whom 239 (38%) received hydromorphone, 297 (47%) received morphine, and 98 (15%) received fentanyl. All 9 patients experiencing respiratory depression received supplemental oxygen. RESULTS: Of the 634 patients studied, 9 (1.4%) experienced respiratory depression by bradypnea (<6 breaths per minute). Six (67%) events were related to hydromorphone and 3 (33%) were related to morphine. In 7 (78%) events, there was no basal infusion rate and the saturation of peripheral oxygen was >92%. All respiratory depression events occurred within the first 24 hours of patient-controlled analgesia therapy. In all cases, capnography, but not pulse oximetry, alerted the nurse to impending respiratory depression. CONCLUSIONS: Capnography was more effective than pulse oximetry in providing early warning of respiratory depression in patients receiving supplemental oxygen. Capnographic monitoring and automatic pausing of patient-controlled analgesia improved postoperative outcomes in situations that could have otherwise been fatal. Use of capnography improved clinician confidence that opioid dosing could be safely continued in postoperative patients for more effective pain management.

A flexible method for the conjugation of aminooxy ligands to preformed complexes of nucleic acids and lipids.

Attachment of targeted ligands to nonviral DNA or RNA delivery systems is a promising strategy that seeks to overcome the poor target selectivity generally observed in systemic delivery applications. Several methods have been developed for the conjugation of ligands to lipids or polymers, however, direct conjugation of ligands onto lipid- or polymer-nucleic acid complexes is not as straightforward. Here, we examine an oximation approach to directly label a lipoplex formulation. Specifically, we report the synthesis of a cationic diketo lipid DMDK, and its use as a convenient ligation tool for attachment of aminooxy-functionalized reagents after its complexation with DNA. We demonstrate the feasibility of direct lipoplex labeling by attaching an aminooxy-functionalized fluorescent probe onto pre-formed plasmid DNA-DMDK lipoplexes (luciferase, GFP). The results reveal that DMDK protects DNA from degradation on exposure to either DNase or human cerebral spinal fluid, and that simple mixing of DMDK lipoplexes with the aminooxy probe labels the complexes without sacrificing transfection efficiency. The biocompatibility and selectivity of this method, as well as the ease of bioconjugation, make this labeling approach ideal for biological applications.