Biphasic effects of cannabis and cannabinoid therapy on pain severity, anxiety, and sleep disturbance: a scoping review.

INTRODUCTION: Cannabinoids are being used by patients to help with chronic pain management and to address the 2 primary chronic pain comorbidities of anxiety and sleep disturbance. It is necessary to understand the biphasic effects of cannabinoids to improve treatment of this symptom triad. METHODS: A scoping review was conducted to identify whether biphasic effects of cannabinoids on pain severity, anxiolysis, and sleep disturbance have been reported. The search included the Embase, Biosis, and Medline databases of clinical literature published between 1970 and 2021. The inclusion criteria were (1) adults more than 18 years of age, (2) data or discussion of dose effects associated with U-shaped or linear dose responses, and (3) measurements of pain and/or anxiety and/or sleep disturbance. Data were extracted by 2 independent reviewers (with a third reviewer used as a tiebreaker) and subjected to a thematic analysis. RESULTS: After the database search and study eligibility assessment, 44 publications met the final criteria for review. Eighteen publications that specifically provided information on dose response were included in the final synthesis: 9 related to pain outcomes, 7 measuring anxiety, and 2 reporting sleep effects. CONCLUSIONS: This scoping review reports on biphasic effects of cannabinoids related to pain, sleep, and anxiety. Dose-response relationships are present, but we found gaps in the current literature with regard to biphasic effects of cannabinoids in humans. There is a lack of prospective research in humans exploring this specific relationship.

Effect of Pregabalin on the Median Effective Plasma Concentration of Intravenous Alfentanil in Capsaicin-Induced Pain.

OBJECTIVE: To apply the sequential up-down method to a human experimental pain model in order to examine the opioid-sparing effect of oral pregabalin on intravenous alfentanil. DESIGN: Double-blind, randomized, crossover. SETTING: Academic university medical center. SUBJECTS: Thirty-one healthy males. METHODS: The median effective plasma concentration of intravenous alfentanil was determined under two conditions: alfentanil alone (phase I) and alfentanil+ pregabalin (300 mg orally) (phase II). The alfentanil plasma level (after a computer-controlled infusion) producing a success criterion (at least 30% intradermal capsaicin-induced pain reduction compared with placebo) was used to determine higher or lower doses for each sequential subject. The median dose producing a success criterion and its confidence interval were determined. RESULTS: On the basis of the t test for a difference across phase and regression coefficients across groups, there was no opioid-sparing effect of pregabalin on alfentanil. Four subjects in phase I and five subjects in phase II did not complete the study. Two in phase I were technical failures, with the rest in both phases stopped because of side effects. Of the subjects who completed the study, six of 19 subjects in phase I and 11 of 12 subjects in phase II reported side effects. CONCLUSIONS: When the intradermal capsaicin-induced pain model was used in healthy volunteers, oral pregabalin had no opioid-sparing effects on intravenous alfentanil. This experimental model may be useful in studying analgesic interactions.

Responding to the Opioid Epidemic: Educational Competencies for Pain and Substance Use Disorder from the Medical Schools of the University of California.

OBJECTIVE: The University of California (UC) leadership sought to develop a robust educational response to the epidemic of opioid-related deaths. Because the contributors to this current crisis are multifactorial, a comprehensive response requires educating future physicians about safe and effective management of pain, safer opioid prescribing, and identification and treatment of substance use disorder (SUD). METHODS: The six UC medical schools appointed an opioid crisis workgroup to develop educational strategies and a coordinated response to the opioid epidemic. The workgroup had diverse specialty and disciplinary representation. This workgroup focused on developing a foundational set of educational competencies for adoption across all UC medical schools that address pain, SUD, and public health concerns related to the opioid crisis. RESULTS: The UC pain and SUD competencies were either newly created or adapted from existing competencies that addressed pain, SUD, and opioid and other prescription drug misuse. The final competencies covered three domains: pain, SUD, and public health issues related to the opioid crisis. CONCLUSIONS: The authors present a novel set of educational competencies as a response to the opioid crisis. These competencies emphasize the subject areas that are fundamental to the opioid crisis: pain management, the safe use of opioids, and understanding and treating SUD.

Consensus practice guidelines on interventions for cervical spine (facet) joint pain from a multispecialty international working group.

BACKGROUND: The past two decades have witnessed a surge in the use of cervical spine joint procedures including joint injections, nerve blocks and radiofrequency ablation to treat chronic neck pain, yet many aspects of the procedures remain controversial. METHODS: In August 2020, the American Society of Regional Anesthesia and Pain Medicine and the American Academy of Pain Medicine approved and charged the Cervical Joint Working Group to develop neck pain guidelines. Eighteen stakeholder societies were identified, and formal request-for-participation and member nomination letters were sent to those organizations. Participating entities selected panel members and an ad hoc steering committee selected preliminary questions, which were then revised by the full committee. Each question was assigned to a module composed of 4-5 members, who worked with the Subcommittee Lead and the Committee Chairs on preliminary versions, which were sent to the full committee after revisions. We used a modified Delphi method whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was reached. Before commencing, it was agreed that a recommendation would be noted with >50% agreement among committee members, but a consensus recommendation would require ≥75% agreement. RESULTS: Twenty questions were selected, with 100% consensus achieved in committee on 17 topics. Among participating organizations, 14 of 15 that voted approved or supported the guidelines en bloc, with 14 questions being approved with no dissensions or abstentions. Specific questions addressed included the value of clinical presentation and imaging in selecting patients for procedures, whether conservative treatment should be used before injections, whether imaging is necessary for blocks, diagnostic and prognostic value of medial branch blocks and intra-articular joint injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for designating a block as positive, how many blocks should be performed before radiofrequency ablation, the orientation of electrodes, whether larger lesions translate into higher success rates, whether stimulation should be used before radiofrequency ablation, how best to mitigate complication risks, if different standards should be applied to clinical practice and trials, and the indications for repeating radiofrequency ablation. CONCLUSIONS: Cervical medial branch radiofrequency ablation may provide benefit to well-selected individuals, with medial branch blocks being more predictive than intra-articular injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of false-negatives (ie, lower overall success rate). Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.

An Integrated Quantitative Index for Measuring Chronic Multisite Pain: The Multiple Areas of Pain (MAP) Study.

OBJECTIVE: Despite the high prevalence of chronic multisite pain, there is little consensus on methods to characterize it. Commonly used assessments report only one dimension of pain, that is, intensity, thus ignoring the spatial aspect of pain. We developed a novel pain quantification index, the Integrated Pain Quantification Index (IPQI), on a scale of 0 to 1 that integrates multiple distinct pain measures into a single value, thus representing multidimensional pain information with a single value. DESIGN: Single-visit, noninterventional, epidemiological study. SETTING: Fourteen outpatient multidisciplinary pain management programs. PATIENTS: Patients with chronic pain of the trunk and/or limbs for at least six months with average overall pain intensity of at least 5 on the numeric rating scale. METHODS: Development of IPQI was performed in a large population (N = 810) of chronic pain patients from the Multiple Areas of Pain (MAP) study. RESULTS: Prevalence of two or more noncontiguous painful areas was at 88.3% (95% confidence interval [CI] = 0.86-0.90), with a mean of 6.3 areas (SD = 5.57 areas). Prevalence of more than 10% body area in pain was at 52.8% (95% CI = 0.49-0.56), with a mean at 16.1% (17.16%). On average, IPQI values were near the middle of the scale, with mean and median IPQI at 0.52 (SD = 0.13) and 0.55, respectively. The IPQI was generalizable and clinically relevant across all domains recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. CONCLUSIONS: IPQI provided a single pain score for representing complex, multidimensional pain information on one scale and has implications for comparing pain populations across longitudinal clinical trials.

The Polyanalgesic Consensus Conference (PACC): Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating Risks.

INTRODUCTION: Intrathecal therapy is an important part of the pain treatment algorithm for chronic disease states. The use of this option is a viable treatment strategy, but it is inherent for pain physicians to understand risk assessment and mitigation. In this manuscript, we explore evidence and mitigating strategies to improve safety with intrathecal therapy. METHODS: A robust literature search was performed covering January 2011 to October 9, 2016, in PubMed, Embase, MEDLINE, Biomed Central, Google Scholar, Current Contents Connect, and International Pharmaceutical Abstracts. The information was cross-referenced and compiled for evidence, analysis, and consensus review, with the intent to offer weighted recommendations and consensus statements on safety for targeted intrathecal therapy delivery. RESULTS: The Polyanalgesic Consensus Conference has made several best practice recommendations to improve care and reduce morbidity and mortality associated with intrathecal therapy through all phases of management. The United States Prevention Service Task Force evidence level and consensus strength assessments are offered for each recommendation. CONCLUSION: Intrathecal therapy is a viable and relatively safe option for the treatment of cancer- and noncancer-related pain. Continued research and expert opinion are required to improve our current pharmacokinetic and pharmacodynamic model of intrathecal drug delivery, as this will undoubtedly improve safety and efficacy.

The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines.

INTRODUCTION: Pain treatment is best performed when a patient-centric, safety-based philosophy is used to determine an algorithmic process to guide care. Since 2007, the International Neuromodulation Society has organized a group of experts to evaluate evidence and create a Polyanalgesic Consensus Conference (PACC) to guide practice. METHODS: The current PACC update was designed to address the deficiencies and innovations emerging since the previous PACC publication of 2012. An extensive literature search identified publications between January 15, 2007 and November 22, 2015 and authors contributed additional relevant sources. After reviewing the literature, the panel convened to determine evidence levels and degrees of recommendations for intrathecal therapy. This meeting served as the basis for consensus development, which was ranked as strong, moderate or weak. Algorithms were developed for intrathecal medication choices to treat nociceptive and neuropathic pain for patients with cancer, terminal illness, and noncancer pain, with either localized or diffuse pain. RESULTS: The PACC has developed an algorithmic process for several aspects of intrathecal drug delivery to promote safe and efficacious evidence-based care. Consensus opinion, based on expertise, was used to fill gaps in evidence. Thirty-one consensus points emerged from the panel considerations. CONCLUSION: New algorithms and guidance have been established to improve care with the use of intrathecal drug delivery.

Post-mastectomy cancer recurrence with and without a continuous paravertebral block in the immediate postoperative period: a prospective multi-year follow-up pilot study of a randomized, triple-masked, placebo-controlled investigation.

PURPOSE: Retrospective studies have associated perioperative regional anesthesia/analgesia during mastectomy for breast cancer with a decreased incidence of cancer recurrence. However, to date, no prospective data from a randomized controlled trial have been reported. In a previous study we found that extending a single-injection paravertebral block with a multiple-day perineural local anesthetic infusion improves analgesia. This follow-up study investigates the rates of cancer recurrence for the single-injection and multiple-day infusion treatments. METHODS: Patients undergoing unilateral (n = 24) or bilateral mastectomy (n = 36) were included in the study. All patients had been diagnosed with breast cancer or tumor in situ, except for six patients who were receiving prophylactic bilateral mastectomy and were excluded from analyses. Patients received unilateral or bilateral single-injection thoracic paravertebral block(s) corresponding to their surgical site(s) with ropivacaine and perineural catheter(s). Subsequently, patients were randomized to receive either ropivacaine 0.4% (n = 30) or normal saline (n = 30) via their catheter(s) until catheter removal on postoperative day 3. Cancer recurrence from the date of surgery until at least 2 years post surgery was investigated via chart review. RESULTS: Five of the 54 (9.2%) patients experienced a cancer recurrence following mastectomy-3 of 26 (11.5%) of the patients with perineural ropivacaine and 2 of 28 (7.1%) of the patients with perineural saline. CONCLUSIONS: This pilot study found no evidence that extending a single-injection paravertebral block with a multi-day perineural local anesthetic infusion decreases the risk of post-mastectomy cancer recurrence. However, due to the small sample size of this investigation, further research is needed to draw definitive conclusions.

Comparison of Post-injection Site Pain Between Technetium Sulfur Colloid and Technetium Tilmanocept in Breast Cancer Patients Undergoing Sentinel Lymph Node Biopsy.

BACKGROUND: No prior studies have examined injection pain associated with Technetium-99m Tilmanocept (TcTM). METHODS: This was a randomized, double-blinded study comparing postinjection site pain between filtered Technetium Sulfur Colloid (fTcSC) and TcTM in breast cancer lymphoscintigraphy. Pain was evaluated with a visual analogue scale (VAS) (0-100 mm) and the short-form McGill Pain Questionnaire (SF-MPQ). The primary endpoint was mean difference in VAS scores at 1-min postinjection between fTcSC and TcTM. Secondary endpoints included a comparison of SF-MPQ scores between the groups at 5 min postinjection and construction of a linear mixed effects model to evaluate the changes in pain during the 5-min postinjection period. RESULTS: Fifty-two patients underwent injection (27-fTcSC, 25-TcTM). At 1-min postinjection, patients who received fTcSC experienced a mean change in pain of 16.8 mm (standard deviation (SD) 19.5) compared with 0.2 mm (SD 7.3) in TcTM (p = 0.0002). At 5 min postinjection, the mean total score on the SF-MPQ was 2.8 (SD 3.0) for fTcSC versus 2.1 (SD 2.5) for TcTM (p = 0.36). In the mixed effects model, injection agent (p < 0.001), time (p < 0.001) and their interaction (p < 0.001) were associated with change in pain during the 5-min postinjection period. The model found fTcSC resulted in significantly more pain of 15.2 mm (p < 0.001), 11.3 mm (p = 0.001), and 7.5 mm (p = 0.013) at 1, 2, and 3 min postinjection, respectively. CONCLUSIONS: Injection with fTcSC causes significantly more pain during the first 3 min postinjection compared with TcTM in women undergoing lymphoscintigraphy for breast cancer.

Persistent postmastectomy pain and pain-related physical and emotional functioning with and without a continuous paravertebral nerve block: a prospective 1-year follow-up assessment of a randomized, triple-masked, placebo-controlled study.

BACKGROUND: In a previous randomized, triple-masked, placebo-controlled study, the authors demonstrated that extending a single-injection paravertebral nerve block with a multiple-day perineural local anesthetic infusion improves analgesia and decreases pain-related dysfunction during the 3-day infusion but not subsequent to catheter removal within 1 month after mastectomy. This report describes a prospective follow-up study of the previously published trial to investigate the possibility that extending a single-injection paravertebral block with a multiple-day infusion may decrease persistent postsurgical pain as well as pain-induced emotional and functional dysfunction 1 year after mastectomy. METHODS: Subjects undergoing uni- or bilateral mastectomy received unilateral (n = 24) or bilateral (n = 36) single-injection thoracic paravertebral block(s) with ropivacaine and perineural catheter(s). The subjects were randomized to receive either ropivacaine 0.4 % (n = 30) or normal saline (n = 30) via their catheters until the catheters were removed on postoperative day 3. Chronic pain and pain-related physical and emotional dysfunction were measured using the Brief Pain Inventory (BPI). RESULTS: No statistically significant difference between treatments 3 months after surgery was observed with the BPI. In contrast, after 12 months, only 4 subjects (13 %) who had received a perineural ropivacaine infusion reported pain-induced dysfunction compared with 14 (47 %) who had received saline infusion (P = 0.011). At 12 months, the mean BPI was 1.6 ± 4.6 for the subjects who received ropivacaine versus 5.9 ± 11.3 for the subjects who received saline (P = 0.007). CONCLUSIONS: Adding a multiple-day, continuous ropivacaine infusion to a single-injection ropivacaine paravertebral nerve block may result in a lower incidence of pain as well as pain-related physical and emotional dysfunction 1 year after mastectomy.

A randomized, double-blind, crossover study to evaluate the depth response relationship of intradermal capsaicin-induced pain and hyperalgesia in healthy adult volunteers.

OBJECTIVE: The purpose of this study was to evaluate pain and hyperalgesia in response to different depths of intradermal (ID) capsaicin injections in healthy volunteers. DESIGN: Double-blind, cross-over study. SETTING: Clinical Research Laboratory. SUBJECTS: Fifteen healthy male subjects received ID capsaicin injections into the volar aspect of each forearm at depths of 1 mm, 3 mm, 5 mm, and 7 mm. After injection, spontaneous pain, elicited pain, flare response, heat thresholds, and area of hyperalgesia were measured at various time points. OUTCOMES MEASURE: Spontaneous pain, elicited pain (pinprick, stroking, and hot pain), hyperalgesia area, and allodynia area. RESULTS: No significant difference was found between any depths in spontaneous pain, elicited pain (pinprick, stroking, hot pain), hyperalgesia area, or allodynia area. A significant difference was found in the change in heat threshold between 5 mm and 1 mm, 7 mm and 1 mm, 5 mm and 3 mm, 7 mm and 3 mm depths. A significant difference was found in flare area between 5 mm and 3 mm depths. A significant difference was found in systolic blood pressure area under the curve (AUC) between 7 mm and 1 mm depths, and for both systolic and diastolic pressures for 5 mm and 1 mm depths, and 5 mm and 3 mm depths. A significant difference was found in pulse AUC between 5 mm and 1 mm depths and 5 mm and 3 mm depths. CONCLUSIONS: Injection of capsaicin at different depths in the skin had different effects on heart rate and blood pressure but no effect on pain. These results may have implications on the pharmacology and analgesic predictive value of the model of ID capsaicin.

Relationships Among Pain Quality, Pain Impact, and Overall Improvement in Patients with Postherpetic Neuralgia Treated with Gastroretentive Gabapentin.

OBJECTIVE: To determine the effect of gastroretentive gabapentin (G-GR) and describe relationships among pain quality, pain impact, and overall-improvement scores in patients with postherpetic neuralgia (PHN). METHODS: Analyses of integrated data from two Phase 3 studies in which PHN patients received once-daily G-GR 1,800 mg (n = 356) or placebo (n = 363). Neuropathic pain scale (NPS) and brief pain inventory (BPI) were completed at baseline and Week 10; patients' global impression of change (PGIC) at Week 10. Regression analyses described relationships among changes in the NPS, BPI, and PGIC scores. RESULTS: Compared with placebo, G-GR patients had significant reductions from baseline in individual NPS measures except cold pain (P < 0.05); composite NPS scores (P ≤ 0.003); BPI pain scores (P < 0.05); three individual (mood, sleep, and enjoyment of life) and the average of BPI interference scores (P < 0.05). Clinically significant improvements in BPI interference scores (except walking ability) were positively correlated with reductions in BPI and NPS pain (except dull and cold pain), and with improvements on the PGIC. Reductions in pain qualities at Week 2, especially in NPS pain intensity, were significant (P ≤ 0.0001) predictors of improvements in three BPI interference scores, total NPS score, and PGIC. CONCLUSIONS: For patients with PHN, G-GR provided significant improvements in multiple measures of pain quality and pain-related functional impairment. There was a positive correlation between pain relief and improvement in patient function, with reduction in pain intensity among predictors of improvements in patients' lives. Such comprehensive analyses give an insight into numerous factors that may contribute to better management of PHN.

Vaporized Cannabis versus Placebo for Acute Migraine: A Randomized Controlled Trial.

Background: Preclinical and retrospective studies suggest cannabinoids may be effective in migraine treatment. However, there have been no randomized clinical trials examining the efficacy of cannabinoids for acute migraine. Methods: In this randomized, double-blind, placebo-controlled, crossover trial, adults with migraine treated up to 4 separate migraine attacks, 1 each with vaporized 1) 6% Δ9-tetrahydrocannabinol (THC-dominant); 2) 11% cannabidiol (CBD-dominant); 3) 6% THC+11% CBD; and 4) placebo cannabis flower in a randomized order. Washout period between treated attack was ≥1 week. The primary endpoint was pain relief and secondary endpoints were pain freedom and most bothersome symptom (MBS) freedom, all assessed at 2 hours post-vaporization. Results: Ninety-two participants were enrolled and randomized, and 247 migraine attacks were treated. THC+CBD was superior to placebo at achieving pain relief (67.2% vs 46.6%, Odds Ratio [95% Confidence Interval] 2.85 [1.22, 6.65], p=0.016), pain freedom (34.5% vs. 15.5%, 3.30 [1.24, 8.80], p=0.017) and MBS freedom (60.3% vs. 34.5%, 3.32 [1.45, 7.64], p=0.005) at 2 hours, as well as sustained pain freedom at 24 hours and sustained MBS freedom at 24 and 48 hours. THC-dominant was superior to placebo for pain relief (68.9% vs. 46.6%, 3.14 [1.35, 7.30], p=0.008) but not pain freedom or MBS freedom at 2 hours. CBD-dominant was not superior to placebo for pain relief, pain freedom or MBS freedom at 2 hours. There were no serious adverse events. Conclusions: Acute migraine treatment with 6% THC+11% CBD was superior to placebo at 2 hours post-treatment with sustained benefits at 24 and 48 hours.

Cannabis and Cannabinoids in Adults With Cancer: ASCO Guideline.

PURPOSE: To guide clinicians, adults with cancer, caregivers, researchers, and oncology institutions on the medical use of cannabis and cannabinoids, including synthetic cannabinoids and herbal cannabis derivatives; single, purified cannabinoids; combinations of cannabis ingredients; and full-spectrum cannabis. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and cohort studies on the efficacy and safety of cannabis and cannabinoids when used by adults with cancer. Outcomes of interest included antineoplastic effects, cancer treatment toxicity, symptoms, and quality of life. PubMed and the Cochrane Library were searched from database inception to January 27, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: The evidence base consisted of 13 systematic reviews and five additional primary studies (four RCTs and one cohort study). The certainty of evidence for most outcomes was low or very low. RECOMMENDATIONS: Cannabis and/or cannabinoid access and use by adults with cancer has outpaced the science supporting their clinical use. This guideline provides strategies for open, nonjudgmental communication between clinicians and adults with cancer about the use of cannabis and/or cannabinoids. Clinicians should recommend against using cannabis or cannabinoids as a cancer-directed treatment unless within the context of a clinical trial. Cannabis and/or cannabinoids may improve refractory, chemotherapy-induced nausea and vomiting when added to guideline-concordant antiemetic regimens. Whether cannabis and/or cannabinoids can improve other supportive care outcomes remains uncertain. This guideline also highlights the critical need for more cannabis and/or cannabinoid research.Additional information is available at www.asco.org/supportive-care-guidelines.

Intrathecal gabapentin to treat chronic intractable noncancer pain.

BACKGROUND: Oral gabapentin is approved as an anticonvulsant medication and to treat postherpetic neuralgia. Its nonopioid properties and presumed spinal site of analgesic action made the study on intrathecal gabapentin attractive to establish the minimum effective dose for a later, pivotal trial. METHODS: The authors examined the safety and efficacy of intrathecal gabapentin in a randomized, blinded, placebo-controlled, multicenter trial in a heterogeneous cohort of candidates with chronic pain for intrathecal drug therapy. RESULTS: Patients (N = 170) were randomized to receive continuous intrathecal gabapentin (0 [placebo], 1, 6, or 30 mg/day) during 22 days of blinded treatment after implantation of a permanent drug delivery system. The highest dose, 30 mg/day, was selected to maintain a safety margin below the 100-mg/day dose that was explored in a phase 1 study. The authors found no statistically significant difference in the primary outcome measure, which was the numerical pain rating scale and response rate after 3 weeks, for any dose versus placebo. Physical functioning, quality of life, and emotional functioning also revealed no differences. Small, nonsignificant changes occurred in opioid medication use. The most frequent device-related adverse events were transient postimplant (lumbar puncture) headache, pain, and nausea. The most frequent gabapentin-related adverse events were nausea, somnolence, headache, dizziness, fatigue, and peripheral edema. CONCLUSION: Twenty-two days of intrathecal gabapentin did not demonstrate statistically significant or clinically meaningful analgesic effects. The study sponsor has no current plans for further studies. Drug-related adverse events were similar to those for oral gabapentin. Most device-related adverse events resulted from the implant surgery or anesthesia.

Treating intractable phantom limb pain with ambulatory continuous peripheral nerve blocks: a pilot study.

BACKGROUND: There is currently no reliable treatment for phantom limb pain (PLP). Chronic PLP and associated cortical abnormalities may be maintained from abnormal peripheral input, raising the possibility that a continuous peripheral nerve block (CPNB) of extended duration may permanently reorganize cortical pain mapping, thus providing lasting relief. METHODS: Three men with below-the-knee (2) or -elbow (1) amputations and intractable PLP received femoral/sciatic or infraclavicular perineural catheter(s), respectively. Subjects were randomized in a double-masked fashion to receive perineural ropivacaine (0.5%) or normal saline for over 6 days as outpatients using portable electronic infusion pumps. Four months later, subjects returned for repeated perineural catheter insertion and received an ambulatory infusion with the alternate solution ("crossover"). Subjects were followed for up to 1 year. RESULTS: By chance, all three subjects received saline during their initial infusion and reported little change in their PLP. One subject did not receive crossover treatment, but the remaining two subjects reported complete resolution of their PLP during and immediately following treatment with ropivacaine. One subject experienced no PLP recurrence through the 52-week follow-up period and the other reported mild PLP occurring once each week of just a small fraction of his original pain (pretreatment: continuous PLP rated 10/10; posttreatment: no PLP at baseline with average of one PLP episode each week rated 2/10) for 12 weeks (lost to follow-up thereafter). CONCLUSIONS: A prolonged ambulatory CPNB may be a reliable treatment for intractable PLP. The results of this pilot study suggest that a large, randomized clinical trial is warranted.

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.

NGX426, an oral AMPA-kainate antagonist, is effective in human capsaicin-induced pain and hyperalgesia.

BACKGROUND: Non-N-methyl-D-aspartate receptor subtypes modulate neurotransmitter release and mediate fast excitatory postsynaptic potentials. This study evaluated the effects of an oral prodrug to tezampanel, a selective α-amino-3-hydroxy-5-methly-4-isoxazole-proprionic acid/kainate receptor antagonist, on intradermal capsaicin-induced pain and hyperalgesia. METHODS: This was a randomized, double blind, crossover, placebo-controlled study. Eighteen subjects received 150 or 90 mg NGX426, or placebo, separated by a washout of 6 ± 2 days. In each treatment period, two intradermal injections of capsaicin were given in the volar region of alternate forearms at 30- and 120-minute drug/placebo administration. Spontaneous pain, elicited pain, and area of hyperalgesia were determined at certain time points after each injection. Subjects were asked to rate the painfulness of a 1-minute long 45°C heat stimulus (brief thermal stimulation [BTS]) applied to the anterior thigh at 4 hours and 30 minutes following drug administration, then every 30 minutes through 6 hours following drug administration. RESULTS: The 150-mg dose produced a statistically definitive reduction in spontaneous pain for all time points relative to placebo. The 90-mg dose produced a statistically significant reduction for the early time point and the entire time interval. Both doses significantly reduced elicited pain at all time points. For the BTS, the 150-mg group reached statistical significance compared with placebo at the 270-minute time point only. CONCLUSIONS: This study demonstrated that NGX426 reduces capsaicin-induced pain and hyperalgesia in human volunteers with low incidence of side effects that suggests that this class of drug may be effective in the treatment of clinical pain.

Cervical epidural depth: correlation between needle angle, cervical anatomy, and body surface area.

OBJECTIVES: Prior to performing a cervical interlaminar epidural steroid injection (CIESI), knowledge of the depth from lamina to epidural space may assist in preventing cord injury. METHODS: This is a prospective analysis of data including gender, age, weight, height, previous surgery, neck circumference, distances from tip of chin to sternal notch, occiput to C7 vertebral prominence, and ear lobe to tip of shoulder, pain score, angle from C7 vertebral prominence to the back, depth at which the Tuohy needle contacted T1 vertebral lamina and depth at which the epidural space was entered was conducted with 92 subjects, average age (± standard deviation [SD]) 41.3 ± 13.2 years underwent fluoroscopically guided C7-T1 intralaminar epidural steroid injections. RESULTS: Depth to lamina was the best individual predictor with an r value of 0.86. Weight, neck circumference, and body mass index (BMI) positively correlated with depth to epidural space with r values of 0.66, 0.62, and 0.61, respectively. A linear regression model of depth to lamina for predicting depth to epidural space was accurate to within ± 0.5 cm of the actual depth in 69% of subjects. However, when comparing predicted with actual depth to epidural space for individual subjects, the prediction was inaccurate by as much as 1.6 cm deep or 1.7 cm shallow. CONCLUSIONS: While statistically significant correlations do exist between both quantitative external body characteristics and depth to cervical epidural space and T1vertebral lamina to depth of cervical epidural space for fluoroscopically guided interlaminar epidural steroid injections at C7-T1, even the most optimal regression models do not permit clinical confidence in predicted depth to epidural space.