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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 Clinical Trial Registration: NCT03689920 ( ClinicalTrials.gov ), Combining Mechanisms for Better Outcomes (COMBO)

BACKGROUND: T(1ρ) has been extensively reported as a sensitive biomarker of biochemical changes in the nucleus pulposus (NP) and annulus fibrosis of intervertebral discs (IVDs). However, no T(1ρ) study of cartilaginous endplates (CEPs) has yet been reported because the relatively long echo times (TEs) of conventional clinical T(1ρ) sequences cannot effectively capture the fast-decaying magnetic resonance signals of CEPs, which have very short T(2)/T(2)*s. This can be overcome by using ultrashort echo time (UTE) T(1ρ) acquisitions. METHODS: Seventeen subjects underwent UTE with adiabatic T(1ρ) preparation (UTE-Adiab-T(1ρ)) and T(2)-weighted fast spin echo imaging of their lumbar spines. Each IVD was manually segmented into seven regions (i.e., outer anterior annulus fibrosis, inner anterior annulus fibrosis, outer posterior annulus fibrosis, inner posterior annulus fibrosis, superior CEP, inferior CEP, and NP). T(1ρ) values of these sub-regions were correlated with IVD modified Pfirrmann grades and subjects’ ages. In addition, T(1ρ) values were compared in subjects with and without low back pain (LBP). RESULTS: Correlations of T(1ρ) values of the outer posterior annulus fibrosis, superior CEP, inferior CEP, and NP with modified Pfirrmann grades were significant (P

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.

Contributors to the ongoing epidemic of prescription opioid abuse, addiction, and death include opioid tolerance, withdrawal symptoms, and possibly opioid-induced hyperalgesia (OIH). Thirty stable chronic nonmalignant pain patients entered a 6-month long, randomized, double-blind, dose-response, 2-center trial of the potent opioid levorphanol, conducted over a decade ago during an era of permissive opioid prescribing. Eleven were taking no opioids at study entry and eleven were taking between 35 and 122 morphine equivalents. Five weeks titration preceded twenty weeks stable dosing. Tolerance and OIH were inferred individually based on chronic pain ratings, brief pain inventory scores, and results of the brief thermal sensitization model at 5 opioid dosing sessions. Seventeen patients completed. The average final daily opioid dose was 132; range 14 to 300; average addition 105 morphine equivalents. After observed dosing, the brief thermal sensitization area of hyperalgesia changed minimally but the painfulness of skin heating was reduced. Weekly 0 to 100 visual analog scale pain ratings (average 64 at study entry, 48 at end titration, 45 at end stable dosing) decreased a median 19%, but 8 completed with higher visual analog scale ratings. Three completers had evidence of both tolerance and hyperalgesia. A fully-powered trial similar to this feasibility study is ethically questionable. A large-scale pragmatic trial is more realistic. TRIAL REGISTRATION: NCT00275249 Evolution of Analgesic Tolerance With Opioids PERSPECTIVE: A double-blind, 6-month, high-dose opioid feasibility trial, completed years ago, provides critically important data for clinically defining analgesic tolerance and OIH. Overall benefit was small, and 18% of patients had evidence of both tolerance and OIH. Future work requires a different approach than a classic randomized controlled trial design.

BackgroundThe past two decades have witnessed a surge in the use of lumbar facet blocks and radiofrequency ablation (RFA) to treat low back pain (LBP), yet nearly all aspects of the procedures remain controversial.MethodsAfter approval by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine, letters were sent to a dozen pain societies, as well as representatives from the US Departments of Veterans Affairs and Defense. A steering committee was convened to select preliminary questions, which were revised by the full committee. Questions were assigned to 4–5 person modules, who worked with the Subcommittee Lead and Committee Chair on preliminary versions, which were sent to the full committee. 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 Chair, who incorporated the comments and sent out revised versions until consensus was reached.Results17 questions were selected for guideline development, with 100% consensus achieved by committee members on all topics. All societies except for one approved every recommendation, with one society dissenting on two questions (number of blocks and cut-off for a positive block before RFA), but approving the document. Specific questions that were addressed included the value of history and physical examination in selecting patients for blocks, the value of imaging in patient selection, whether conservative treatment should be used before injections, whether imaging is necessary for block performance, the diagnostic and prognostic value of medial branch blocks (MBB) and intra-articular (IA) injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for a prognostic block, how many blocks should be performed before RFA, how electrodes should be oriented, the evidence for larger lesions, whether stimulation should be used before RFA, ways to mitigate complications, if different standards should be applied to clinical practice and clinical trials and the evidence for repeating RFA (see table 12 for summary).ConclusionsLumbar medial branch RFA may provide benefit to well-selected individuals, with MBB being more predictive than IA injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of more false-negatives. Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.

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.

ObjectiveTo 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.DesignDouble-blind, randomized, crossover.SettingAcademic university medical center.SubjectsThirty-one healthy males.MethodsThe 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.ResultsOn 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.ConclusionsWhen 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.

Cannabinoids, cannabis, and cannabis-based medicines (CBMs) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We summarised efficacy and adverse events (AEs) of these types of drugs for treating pain using randomised controlled trials: in people of any age, with any type of pain, and for any treatment duration. Primary outcomes were 30% and 50% reduction in pain intensity, and AEs. We assessed risk of bias of included studies, and the overall quality of evidence using GRADE. Studies of 7 days treatment duration were analysed separately. We included 36 studies (7217 participants) delivering cannabinoids (8 studies), cannabis (6 studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Evidence of benefit was found for cannabis 7 days (risk difference 0.06, 95% confidence interval 0.01-0.12; 6 trials, 1484 patients, very low-quality evidence). No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in our primary analyses; 81% of subgroup analyses were negative. Cannabis, nabiximols, and delta-9-tetrahydrocannabinol had more AEs than control. Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.

The President of the International Association for the Study of Pain (IASP) established a Taskforce on Cannabis and Cannabinoid Analgesia, to systematically examine the evidence on (i) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain, (ii) the clinical efficacy of cannabis, cannabinoids and cannabis-based medicines (CBM) for pain, (iii) harms related to long-term use of cannabinoids, as well as (iv) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the Taskforce outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high quality clinical trials with cannabinoids are needed. Important remaining questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal and policy challenges associated with medicinal and non-medicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.

Ultrashort echo time (UTE) sequences can image tissues with transverse T(2)/T(2)* relaxations too short to be efficiently observed on routine clinical MRI sequences, such as the vertebral body cartilaginous endplate (CEP). Here, we describe a 3D adiabatic inversion recovery-prepared fat-saturated ultrashort echo time (3D IR-FS-UTE) sequence to highlight the CEP of vertebral bodies in comparison to the intervertebral disc (IVD) and bone marrow fat (BF) at 3T. The IR-FS-UTE sequence used a 3D UTE sequence combined with an adiabatic IR preparation pulse centered in the middle of the water and fat peaks, while a fat saturation module was used to suppress the signal from fat. A slab-selective half pulse was used for signal excitation, and a 3D center-out cones trajectory was used for more efficient data sampling. The 3D IR-FS-UTE sequence was applied to an ex vivo human spine sample, as well as the spines of six healthy volunteers and of three patients with back pain. Bright continue lines representing signal from CEP were found in healthy IVDs. The measured contrast-to-noise ratio (CNR) was 18.5±4.9 between the CEP and BF, and 20.3±4.15 between the CEP and IVD for the six volunteers. Abnormal IVDs showed CEP discontinuity or irregularity in the sample and patients’ studies. In conclusion, the proposed 3D IR-FS-UTE sequence is feasible for imaging of the vertebral body’s CEP in vivo with high contrast.

Opioids have been reported to increase the risk for sleep-disordered breathing (SDB) in patients with noncancer chronic pain on opioid therapy. This study aims to determine the pooled prevalence of SDB in opioid users with chronic pain and compare it with patients with pain:no opioids and no pain:no opioids.A literature search of PubMed, Medline, Embase, and Cochrane Central Register of Controlled Trials was conducted. We included all observational studies that reported the prevalence of SDB in patients with chronic pain on long-term opioid therapy (≥3 months). The primary outcome was the pooled prevalence of SDB in opioid users with chronic pain (pain:opioids group) and a comparison with pain:no opioids and no pain:no opioids groups. The meta-analysis was performed using a random-effects model.After screening 1,404 studies, 9 studies with 3,791 patients were included in the meta-analysis (pain:opioids group, n = 3181 [84%]; pain:no opioids group, n = 359 [9.4%]; no pain:no opioids group, n = 251 [6.6%]). The pooled prevalence of SDB in the pain:opioids, pain:no opioids, and no pain:no opioids groups were 91%, 83%, and 72% in sleep clinics and 63%, 10%, and 75% in pain clinics, respectively. Furthermore, in the pain: opioids group, central sleep apnea prevalence in sleep and pain clinics was 33% and 20%, respectively.The pooled prevalence of SDB in patients with chronic pain on opioid therapy is not significantly different compared with pain:no opioids and no pain:no opioids groups and varies considerably depending on the site of patient recruitment (ie, sleep vs pain clinics). The prevalence of central sleep apnea is high in sleep and pain clinics in the pain:opioids group. Clinical Trial Registration: Registry: PROSPERO: International prospective register of systematic reviews; Name: Prevalence of sleep disordered breathing, hypoxemia and hypercapnia in patients on oral opioid therapy for chronic pain management; URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018103298; Identifier: CRD42018103298.

Background: A recent meta-analysis affirmed the benefit of medicinal cannabis for chronic neuropathic pain, a disabling and difficult-to-treat condition. As medicinal cannabis use is becoming increasingly prevalent among Americans, an exploration of its economic feasibility is warranted. We present this cost-effectiveness analysis of adjunctive cannabis pharmacotherapy for chronic peripheral neuropathy. Materials and Methods: A published Markov model comparing conventional therapies for painful diabetic neuropathy was modified to include arms for augmenting first-line, second-line (if first-line failed), or third-line (if first- and second-line failed) therapies with smoked cannabis. Microsimulation of 1,000,000 patients compared the cost (2017 U.S. dollars) and effectiveness (quality-adjusted life years [QALYs]) of usual care with and without adjunctive cannabis using a composite of third-party and out-of-pocket costs. Model efficacy inputs for cannabis were adapted from clinical trial data. Adverse event rates were derived from a prospective study of cannabis for chronic noncancer pain and applied to probability inputs for conventional therapies. Cannabis cost was derived from retail market pricing. Parameter uncertainty was addressed with one-way and probabilistic sensitivity analysis. Results: Adding cannabis to first-line therapy was incrementally less effective and costlier than adding cannabis to second-line and third-line therapies. Third-line adjunctive cannabis was subject to extended dominance, that is, the second-line strategy was more effective with a more favorable incremental cost-effectiveness ratio of $48,594 per QALY gained, and therefore, third-line adjunctive cannabis was not as cost-effective. At a modest willingness-to-pay threshold of $100,000/QALY gained, second-line adjunctive cannabis was the strategy most likely to be cost-effective. Conclusion: As recently proposed willingness-to-pay thresholds for the United States health marketplace range from $110,000 to $300,000 per QALY, cannabis appears cost-effective when augmenting second-line treatment for painful neuropathy. Further research is warranted to explore the long-term benefit of smoked cannabis and standardization of its dosing for chronic neuropathic pain.

Purpose: To analyse how effective was the USA, compared to Other Western Countries (OWC) in reducing premature deaths 1989-2015. Design: This population-based study is a cost-effective model of fiscal input into health related to clinical outputs, recognising socio-economic factors influence health outcomes. Using World Bank data for total % GDP-Expenditure-on-Health, and, WHO data for Child (0-4), Adult (55-74) and Age-Standardised-Death-Rates rates per million America is compared with OWC. Cost-Effective Ratios (CEF) are calculated and Confidence Intervals (95%) tests USA against each OWC. `Excess’ deaths are calculated between the most and least expensive health systems. Setting: Twenty Other Western countries. Patients: National populations.

BACKGROUND: While conventional MRI sequences cannot visualize tissues from the osteochondral junction (OCJ) due to these tissues’ short transverse T(2)/T(2)* relaxations, ultrashort echo time (UTE) sequences can overcome this limitation. A 2D UTE sequence with a dual adiabatic inversion recovery preparation (DIR-UTE) for selective imaging of short T(2) tissues with high contrast has previously been developed, but high sensitivity to eddy currents and aliased out-of-slice excitation make it difficult to image the thin layer of the OCJ in vivo. Here, we combine the DIR scheme with a 3D UTE Cones sequence for volumetric imaging of OCJ tissues in vivo, aiming to generate higher OCJ contrast compared with a recently developed single IR-prepared UTE sequence with a fat saturation module (IR-FS-UTE). METHODS: All sequences were implemented on a 3T clinical scanner. The DIR-UTE Cones sequence combined a 3D UTE Cones sequence with two narrow-band adiabatic IR preparation pulses centered on water and fat spectrum frequencies, respectively. The 3D DIR-UTE Cones sequence was first applied to a phantom, then to the knees of four healthy volunteers and four patients diagnosed with osteoarthritis and compared to the IR-FS-UTE sequence. RESULTS: In both phantom and volunteer studies, the proposed DIR-UTE Cones sequence showed much higher contrast for OCJ imaging than the IR-FS-UTE sequence did. The 3D DIR-UTE Cones sequence showed a significantly higher contrast-to-noise ratio (CNR) between the OCJ and subchondral bone fat (BF) (mean, standard deviation (SD): 25.7 ± 2.3) and between the OCJ and superficial layers of cartilage (SC) (mean, SD: 22.2 ± 3.5) compared to the IR-FS-UTE sequence (mean, SD: 10.8 ± 2.5 and 16.3 ± 2.6, respectively). CONCLUSIONS: The 3D DIR-UTE Cones sequence is feasible for imaging of the OCJ region of the knee in vivo and produces both high resolution and high contrast.

Jan M Schilling,1 Chloe G Hughes,1 Mark S Wallace,2 Michelle Sexton,2 Miroslav Backonja,1,3 Tobias Moeller-Bertram1 1Clinical Research, Vitamed Research, Palm Desert, CA, USA; 2Department of Anesthesiology, University of California San Diego, San Diego, CA, USA; 3Department of Neurology, University of Washington, Seattle, WA, USACorrespondence: Jan M Schilling; Tobias Moeller-BertramClinical Research, Vitamed Research, LLC, 44630 Monterey Ave, Suite 100, Palm Desert, CA, 92260, USAEmail jan@vitamedresearch.com; toby@vitamedresearch.comIntroduction: Cannabis products have become easily available and accessible after decriminalization of cannabis for recreational and medicinal use in many states. Cannabidiol (CBD) has been of increasing interest to patients and is being used to self-medicate a variety of ailments. However, very limited information is available to patients and providers to form an educated opinion regarding its indicated use to treat the many conditions this substance has been implied to be helpful for. The aim of this survey was to learn about participants’ attitudes and views towards cannabis-based medicine (CBM) with a focus on perception of “CBD” and its potential role for pain management.Materials and Methods: We recruited survey participants from seven pain management clinics in Southern California to learn about their knowledge, beliefs, and personal experience with CBD products. After Institutional Review Board (IRB) review, an internet survey platform was utilized to administer the survey online.Results: A total of 253 participants answered the survey. Participants were 45.4 ± 13.8 (Mean ± SD) years of age, the majority identified as white (56.1%), had an annual household income of less than $20,000, and were primarily insured by Medicare (22.5%) or Medicaid (43.9%). Among participants, 62.0% reported trying a CBD product [including products containing delta-9-tetrahydrocannabinol (THC)]. The majority responded that these products have helped their pain (59.0%) and allowed them to reduce their pain medications (67.6%), including opioids (53.7%). They reported believing that CBD was a good treatment option (71.1%), not harmful (74.9%), and not addictive (65.3%). About half of participants (51.9%) report that they would be more comfortable with their physician prescribing CBD products. The overall attitude and experience of participants regarding CBD is reported as positive, while 91.9% of people expressed a desire to learn more about it.Summary: In summary, most participants expressed a positive attitude about CBD products as a treatment option, reported positive outcomes when used for multiple different conditions, and would prefer to obtain information about and prescription for CBD from their physicians.Keywords: survey, cannabidiol, CBD, medical marijuana, cannabis

Pain is a common and debilitating symptom of cancer. Cancer-related pain can occur at any point along the continuum from diagnosis to treatment to survivorship1. A systematic review published in 2016 estimated the prevalence of cancer pain to be 55% in those undergoing antineoplastic treatment, 66.4% in advanced cancer, and 39.3% in the post-treatment population. Thirty-eight percent of cancer patients in this pooled analysis experienced moderate to severe pain2.

Background Clinical guidelines recommend that providers risk-stratify patients with cancer before prescribing opioids. Prior research has demonstrated that a simple cancer opioid risk score might help identify to patients with cancer at the time of diagnosis with a high likelihood of long-term posttreatment opioid use. This current project validates this cancer opioid risk score in a generalizable, population-based cohort of elderly cancer survivors. Methods This study identified 44,932 Medicare beneficiaries with cancer who had received local therapy. Longitudinal opioid use was ascertained from Medicare Part D data. A risk score was calculated for each patient, and patients were categorized into low-, moderate-, and high-risk groups on the basis of the predicted probability of persistent opioid use. Model discrimination was assessed with receiver operating characteristic curves. Results In the study cohort, 5.2% of the patients were chronic opioid users 1 to 2 years after the initiation of cancer treatment. The majority of the patients (64%) were at low risk and had a 1.2% probability of long-term opioid use. Moderate-risk patients (33% of the cohort) had a 5.6% probability of long-term opioid use. High-risk patients (3.5% of the cohort) had a 75% probability of long-term opioid use. The opioid risk score had an area under the receiver operating characteristic curve of 0.869. Conclusions This study found that a cancer opioid risk score could accurately identify individuals with a high likelihood of long-term opioid use in a large, generalizable cohort of cancer survivors. Future research should focus on the implementation of these scores into clinical practice and how this could affect prescriber behavior and patient outcomes. Lay summary A novel 5-question clinical decision tool allows physicians treating patients with cancer to accurately predict which patients will persistently be using opioid medications after completing therapy.

The growing demand for improved pain treatments together with expanding legalization of, and access to, cannabinoids, cannabis, and cannabis-based medicines has intensified the focus on risk-benefit considerations in pain management. Given limited harms data from analgesic clinical trials, we conducted an overview of systematic reviews focused on all harms possibly relevant to patients receiving cannabinoids for pain management. This PROSPERO-registered, PRISMA-compliant systematic overview identified 79 reviews, encompassing over 2200 individual reports about psychiatric and psychosocial harms, cognitive/behavioral effects, motor vehicle accidents, cardiovascular, respiratory, cancer-related, maternal/fetal, and general harms. Reviews, and their included studies, were of variable quality. Available evidence suggests variable associations between cannabis exposure (ranging from monthly to daily use based largely on self-report) and psychosis, motor vehicle accidents, respiratory problems, and other harms. Most evidence comes from settings other than that of pain management (eg, nonmedicinal and experimental) but does signal a need for caution and more robust harms evaluation in future studies. Given partial overlap between patients receiving cannabinoids for pain management and individuals using cannabinoids for other reasons, lessons from the crisis of oversupply and overuse of opioids in some parts of the world emphasize the need to broadly consider harms evidence from real-world settings. The advancement of research on cannabinoid harms will serve to guide optimal approaches to the use of cannabinoids for pain management. In the meantime, this evidence should be carefully examined when making risk-benefit considerations about the use of cannabinoids, cannabis, and cannabis-based medicine for chronic pain.

Background and ObjectivesThe Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide.MethodsThe study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit.ResultsThe registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%).ConclusionsFinal study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information.

This clinical trial evaluated the independent and combined effects of a tricyclic antidepressant (desipramine) and cognitive behavioral therapy (CBT) for chronic back pain relative to an active placebo treatment. Participants (n = 142) were patients experiencing daily chronic back pain at an intensity of ≥4/10 who were randomized to a single-center, double-blind, 12-week, 4-arm, parallel groups controlled clinical trial of (1) low concentration desipramine titrated to reach a serum concentration level of 15 to 65 ng/mL; (2) CBT and active placebo medication (benztropine mesylate, 0.125 mg); (3) low concentration desipramine and CBT; and (4) active benztropine placebo medication. Participants completed the Differential Description Scale and Roland Morris Disability Questionnaires before and after treatment as validated measures of outcomes in back pain intensity and disability, respectively. Participants within each condition showed significant reductions from pre-treatment to post-treatment in pain intensity (mean changes ranged from = -2.58 to 3.87, Cohen's d's = 0.46-0.84) and improvements in pain disability (mean changes = -3.04 to 4.29, Cohen's d's = 0.54-0.88). However, intent-to-treat analyses at post-treatment showed no significant differences between any condition, with small effect sizes ranging from 0.06 to 0.27. The results from this clinical trial did not support the hypothesis that desipramine, CBT, or their combination would be statistically superior to an active medicine placebo for reducing chronic back pain intensity or disability. Key limitations included recruiting 71% of the planned sample size and use of multiple inclusion/exclusion criteria that may limit generalizability to broader populations of patients with chronic back pain.

In health and disease, the somatosensory system has been interrogated with standardized research techniques, collectively referred to as quantitative sensory testing (QST). In neuropathic pain, QST has been used to characterize multiple sensory derangements. However, the use of QST outside the lab has been limited by several factors, including a lack of standardization, variability in procedural technique, and duration of testing that would be unacceptable for clinic. To address these shortcomings, the Neuropathic Pain Research Consortium (NPRC) designed an easy and low-cost “bedside” QST procedure. To test the hypothesis that this procedure would be clinically reliable over time and across different examiners, a multi-site, blinded study was performed in subjects with postherpetic neuralgia. Generally, agreement between two examiners and over two study visits with one examiner was high. Additionally, intraclass correlation coefficients and Kappa statistics calculated showed that the battery of QST tests included were highly reliable. Interestingly, mechanical modalities (light brush, pinprick, pressure, and vibration) showed the highest reliability. The least reliable modalities were cool (room temperature) and warmth (38°C). These data demonstrate that the NPRC beside QST protocol is reliable across examiner and over time, providing a validated QST tool for use in clinical practice and clinical trials. PERSPECTIVE: This blinded, multi-center trial in 32 patients with postherpetic neuralgia demonstrates bedside quantitative sensory testing is reliable and suitable as a clinical trial outcome. The novel bedside battery could be used in clinical trials or in clinical practice over time given the reliability data presented in this article.

Background and aimsWhile the United States has been experiencing an opioid epidemic, 29 states and Washington DC have legalized cannabis for medical use. This study examined whether state-wide medical cannabis legalization was associated with reduction in opioids received by Medicaid enrollees.DesignSecondary data analysis of state-level opioid prescription records from 1993-2014 Medicaid State Drug Utilization Data. Linear time-series regressions assessed the associations between medical cannabis legalization and opioid prescriptions, controlling for state-level time-varying policy covariates (such as prescription drug monitoring programs) and socio-economic covariates (such as income).SettingUnited States.ParticipantsDrug prescription records for patients enrolled in fee-for-service Medicaid programs that primarily provide health-care coverage to low-income and disabled people.MeasurementsThe primary outcomes were population-adjusted number, dosage and Medicaid spending on opioid prescriptions. Outcomes for Schedule II opioids (e.g. hydrocodone, oxycodone) and Schedule III opioids (e.g. codeine) were analyzed separately. The primary policy variable of interest was the implementation of state-wide medical cannabis legalization.FindingsFor Schedule III opioid prescriptions, medical cannabis legalization was associated with a 29.6% (P=0.03) reduction in number of prescriptions, 29.9% (P=0.02) reduction in dosage and 28.8% (P=0.04) reduction in related Medicaid spending. No evidence was found to support the associations between medical cannabis legalization and Schedule II opioid prescriptions. Permitting medical cannabis dispensaries was not associated with Schedule II or Schedule III opioid prescriptions after controlling for medical cannabis legalization. It was estimated that, if all the states had legalized medical cannabis by 2014, Medicaid annual spending on opioid prescriptions would be reduced by 17.8 million dollars.ConclusionState-wide medical cannabis legalization appears to have been associated with reductions in both prescriptions and dosages of Schedule III (but not Schedule II) opioids received by Medicaid enrollees in the United States.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins are comprised of an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states. The receptor is located not only on inflammatory cells (meningeal and peripheral macrophages) but on neuraxial glia (microglia and astrocytes), schwann cells, fibroblasts, dorsal root ganglia and dorsal horn neurons. Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury. This review addresses the role of TLR4 as an emerging therapeutic target for the evolution of persistent pain and its role in non canonical signaling mediating anomalous proalgesic actions of opiates. Accordingly, molecules targeting inhibition of this receptor have promise as disease modifying and opioid sparing alternatives for persistent pain states.

Objective The objective of this study was to evaluate the efficacy of a telephone-delivered, home-based cognitive-behavioral intervention for chronic low back pain in comparison to a matched supportive care (SC) treatment. Methods Participants (N=66) were patients with chronic back pain that were randomized to either an 8-week Cognitive-Behavioral Therapy (CBT) or a SC condition matched for contact frequency, format, and time. Participants completed validated measures of improvement in back pain disability, pain severity, and overall improvement. Results Intent-to-treat analyses at posttreatment showed that the treatment groups not show significantly different improvements in back pain disability (mean changes, -2.4 and -2.6 for CBT and SC, respectively; Cohen d, 0.49 and 0.55, respectively) or reductions in pain severity (mean changes, -0.9 and -1.4 for CBT and SC respectively; Cohen d, 0.50, and 0.90, respectively). Participants rated their overall improvement levels at 31% (CBT) versus 18.5% (SC). Discussion Results from this clinical trial suggest that home-based, telephone-delivered CBT and SC treatments did not significantly differ in their benefits for back pain severity and disability, and may warrant further research for applications to hospital settings. Major limitations included recruitment difficulties that underpowered primary analyses, the lack of objective improvement measures, and the absence of a usual care/untreated control group for comparisons.

The Patient Assessment for Low Back Pain–Symptoms is a newly developed patient-reported outcome instrument to assess specific symptoms of chronic low back pain for use in clinical trials and practice., We describe the mixed-methods (qualitative and quantitative) development and preliminary validation of the Patient Assessment for Low Back Pain–Symptoms (PAL-S), a patient-reported outcome measure for use in chronic low back pain (cLBP) clinical trials. Qualitative methods (concept elicitation and cognitive interviews) were used to identify and refine symptom concepts and quantitative methods (classical test theory and Rasch measurement theory) were used to evaluate item- and scale-level performance of the measure using an iterative approach. Patients with cLBP participated in concept elicitation interviews (N = 43), cognitive interviews (N = 38), and interview-based assessment of paper-to-electronic mode equivalence (N = 8). A web-based sample of patients with self-reported cLBP participated in quantitative studies to evaluate preliminary (N = 598) and revised (n = 401) drafts and a physician-diagnosed cohort of patients with cLBP (N = 45) participated in preliminary validation of the measure. The PAL-S contained 14 items describing symptoms (overall pain, sharp, prickling, sensitive, tender, radiating, shocking, shooting, burning, squeezing, muscle spasms, throbbing, aching, and stiffness). Item-level performance, scale structure, and scoring seemed to be appropriate. One-week test–retest reproducibility was acceptable (intraclass correlation coefficient 0.81 [95% confidence interval, 0.61-0.91]). Convergent validity was demonstrated with total score and MOS-36 Bodily Pain (Pearson correlation −0.79), Neuropathic Pain Symptom Inventory (0.73), Roland-Morris Disability Questionnaire (0.67), and MOS-36 Physical Functioning (−0.65). Individual item scores and total score discriminated between numeric rating scale tertile groups and painDETECT categories. Respondent interpretation of paper and electronic administration modes was equivalent. The PAL-S has demonstrated content validity and is potentially useful to assess treatment benefit in cLBP clinical trials.

Objective: To assess the safety and efficacy of long-term repeated dosing of OROS® hydromorphone in chronic pain patients. Design: This multicenter, open-label extension trial enrolled patients from three short-term OROS® hydromorphone trials. Setting: Fifty-six centers in the United States and Canada. Patients: Adults with chronic cancer pain or chronic nonmalignant pain who were receiving stable doses of OROS® hydromorphone (≥8 mg/day). Three hundred and eighty-eight patients were enrolled, 106 patients completed at least 12 months of therapy. Interventions: OROS® hydromorphone (individualized doses) was administered once daily. Main outcome measures: Safety and efficacy (Brief Pain Inventory and patient and investigator global evaluations) were assessed at monthly visits. Results: The median duration of extended OROS® hydromorphone therapy was 274 days. The median daily dose of study medication was 32.0 mg at extension-study baseline, 40.0 mg at month 3, and 48.0 mg at months 6, 9, and 12, respectively. The most frequently reported adverse events were nausea (n = 93, 24.0 percent) and constipation (n = 75, 19.3 percent). The analgesic effects of OROS® hydromorphone, assessed using the Brief Pain Inventory, were maintained throughout the extension. At 12 months, 72.4 percent of patients and 75.9 percent of investigators rated overall treatment as good, very good, or excellent. Conclusions: Once-daily OROS® hydromorphone is an osmotically driven, controlled-release preparation that may be particularly well suited to long-term use, because it provides consistent plasma concentrations and sustained around-the-clock analgesia. In this study, the benefits of OROS® hydromorphone attained in short-term studies were maintained in the long-term when daily administration was continued.

Objective: To assess the long-term safety, tolerability, and consistency of effect of fentanyl pectin nasal spray (FPNS) in patients with breakthrough cancer pain (BTCP). Design: A multicenter, open-label study. Patients: Patients with chronic cancer pain treated with ≥60 mg/d oral morphine or equivalent experiencing 1-4 episodes per day of BTCP. Intervention: All patients entered into a 16-week treatment phase after undergoing a dose-titration phase with FPNS. Main outcome measures: Safety and tolerability were assessed by adverse events (AEs) and by nasal tolerability assessments. Consistency of effect was monitored through additional rescue medication use and FPNS dose change. Results: Four hundred three patients were included in the safety analyses. Of these, 356 patients entered the treatment phase and 110 patients completed the study. FPNS was self-administered for 42,227 episodes. During the treatment phase, 99 patients (24.6 percent) reported treatment-related AEs; most were mild or moderate and typical of opioids. Serious AEs were reported by 61 patients (15.1 percent), but only five were considered related to study drug. Of the 80 deaths that occurred during this study, one was assessed as possibly related to study drug. Nasal assessments revealed no significant local effects. No additional rescue medication was required after 94 percent of FPNS-treated episodes. More than 90 percent of patients required no increase in their initial dose of FPNS. Conclusions: FPNS use for BTCP was associated with AEs, typical of opioids, with no evidence of nasal toxicity. A large proportion of BTCP episodes were treated with a single dose, and doses remained stable over the 4-month period.

Background The Patient Registry of Intrathecal Ziconotide Management (PRIZM) evaluated long-term effectiveness, safety, and tolerability of intrathecal ziconotide treatment in clinical practice. Methods Patient Registry of Intrathecal Ziconotide Management was an open-label, long-term, multicenter, observational study of adult patients with severe chronic pain. This interim analysis (data through July 10, 2015) of ziconotide as the first vs. not first intrathecal agent in pump included change from baseline in the Numeric Pain Rating Scale (NPRS; primary efficacy measure) and Patient Global Impression of Change (PGIC) scores. Results Enrollment closed at 93 patients; data collection was ongoing at the time of this interim analysis. Fifty-one patients (54.8%) received ziconotide as the first agent in pump (FIP+), whereas 42 (45.2%) did not (FIP−). Mean (SD) baseline NPRS scores were 7.4 (1.9) and 7.9 (1.6) in FIP+ and FIP− patients, respectively. Mean (SEM) percentage changes in NPRS scores were −29.4% (5.5%) in FIP+ patients (n = 26) and +6.4% (7.7%) in FIP− patients (n = 17) at month 6 and −34.4% (9.1%) in FIP+ patients (n = 14) and −3.4% (10.2%) in FIP− patients (n = 9) at month 12. Improvement from baseline, measured by PGIC score, was reported in 69.2% of FIP+ (n = 26) and 35.7% of FIP− (n = 14) patients at month 6 and 85.7% of FIP+ (n = 7) and 71.4% of FIP− (n = 7) patients at month 12. The most common adverse events (≥ 10% of patients overall as of the data cut) were nausea (19.6% vs. 7.1% of FIP+ vs. FIP− patients, respectively), confusional state (9.8% vs. 11.9%), and dizziness (13.7% vs. 7.1%). Conclusions Greater improvements in efficacy outcomes were observed when ziconotide was initiated as first-line intrathecal therapy vs. not first intrathecal agent in pump. The adverse event profile was consistent with the ziconotide prescribing information.

Experimental interventions that activate specific components of clinical pain are necessary for characterization of underlying mechanisms and pharmacology. Cutaneous hyperalgesia has been described that uses nonpainful heat to induce secondary hyperalgesia. This study evaluated the effect of intravenous alfentanil on experimental cutaneous hyperalgesia created using this method. Eighteen subjects participated in a randomized, double-blinded, placebo-controlled crossover study consisting of 2 sessions, 1 with alfentanil and 1 with placebo. Using a computer-controlled infusion pump, alfentanil or matching placebo was maintained at a constant plasma level of 75 ng/mL for 1 hour followed by the application of a 40°C heat stimulus to the right thenar eminence for 15 minutes. The temperature was raised by 1°C every 15 minutes until the subject reported pain or 45°C was reached. After the end point was reached, the temperature was maintained, and repeat testing was performed. The nonpainful heat created an area of secondary cutaneous hyperalgesia and significant decrease in mechanical pain threshold on heat-treated right vs untreated left during placebo administration. Alfentanil prevented the hypersensitivity when compared to placebo (P < .05) but failed to reduce the area of secondary hyperalgesia created by nonpainful heat when compared to placebo (P = .06). Neither alfentanil nor the heat lamp treatment showed any significant effect on other neurosensory measures. This study demonstrated a reliable production of cutaneous hyperalgesia using a nonpainful stimulus that is affected by the systemic delivery of alfentanil. This model for human cutaneous experimental pain may be a useful method for scientific characterization of analgesics.

Pain remains common in the setting of malignancy, occurring as a consequence of cancer and its treatment. Several high-quality studies confirm that more than 50% of all patients with cancer experience moderate to severe pain. The prevalence of pain in cancer survivors is estimated to be 40%, while close to two-thirds of those with advanced disease live with pain. Progress has occurred in the management of cancer pain, yet undertreatment persists. Additionally, new challenges are threatening these advances. These challenges are numerous and include educational deficits, time restraints, and limited access to all types of care. New challenges to access are occurring as a result of interventions designed to combat the prescription drug abuse epidemic, with fewer clinicians willing to prescribe opioids, pharmacies reluctant to stock the medications, and payers placing strict limits on reimbursement. A related challenge is our evolving understanding of the risks of long-term adverse effects associated with opioids. And reflective of the opioid abuse epidemic affecting the general population, the potential for misuse or abuse exists in those with cancer. Guidelines have been developed to support oncologists when prescribing the long-term use of opioids for cancer survivors. The challenges surrounding the use of opioids, and the need for safe and effective alternative analgesics, are leading to intense interest in the potential benefits of cannabis for cancer-related pain. Oncologists are faced with questions regarding the types of cannabis available, differences between routes of administration, data concerning safety and efficacy, and legal and regulatory dynamics.

Objective To identify patient-reported outcome (PRO) instruments that assess chronic low back pain (cLBP) symptoms (specifically pain qualities) and/or impacts for potential use in cLBP clinical trials to demonstrate treatment benefit and support labeling claims. Design Literature review of existing PRO measures. Methods Publications detailing existing PRO measures for cLBP were identified, reviewed, and summarized. As recommended by the US Food & Drug Administration (FDA) PRO development guidance, standard measurement characteristics were reviewed, including development history, psychometric properties (validity and reliability), ability to detect change, and interpretation of observed changes. Results Thirteen instruments were selected and reviewed: Low Back Pain Bothersomeness Scale, Neuropathic Pain Symptom Inventory, PainDETECT, Pain Quality Assessment Scale Revised, Revised Short Form McGill Pain Questionnaire, Low Back Pain Impact Questionnaire, Oswestry Disability Index, Pain Disability Index, Roland-Morris Disability Questionnaire, Brief Pain Inventory and Brief Pain Inventory Short Form, Musculoskeletal Outcomes Data Evaluation and Management System Spine Module, Orebro Musculoskeletal Pain Questionnaire, and the West Haven-Yale Multidimensional Pain Inventory Interference Scale. The instruments varied in the aspects of pain and/or impacts that they assessed, and none of the instruments fulfilled all criteria for use in clinical trials to support labeling claims based on recommendations outlined in the FDA PRO guidance. Conclusions There is an unmet need for a validated PRO instrument to evaluate cLBP-related symptoms and impacts for use in clinical trials.

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.

This report examines the association between tetrahydrocannabinol (THC) plasma levels and pain response in a secondary analysis of data from a recent diabetic neuropathy study that demonstrated a dose-dependent reduction in spontaneous and elicited pain at specific time points. A randomized, double-blinded, placebo-controlled crossover study was conducted in sixteen patients with painful diabetic peripheral neuropathy. Subjects participated in four sessions, separated by 2 weeks, during each of which they were exposed to one of four conditions: placebo, or 1%, 4%, or 7% THC dose of cannabis. Baseline assessments of spontaneous and evoked pain were performed. Subjects were then administered aerosolized cannabis or placebo and pain intensity and cognitive testing at specific time points for 4 hours. A blood sample was drawn from the left antecubital vein for plasma assay of total THC at 0, 15, 30, 45, 60, 150, and 240 minutes. Associations were made between pain intensity, cognitive impairment and THC plasma levels in this secondary analysis. Results suggested a U-shaped relation whereby pain ratings are greatest at extreme (low and high) levels of THC. The therapeutic window appeared to fall between 16 ng/mL and 31 ng/mL THC plasma level. There was a significant linear effect of THC on only one out of the three cognitive tests. These findings stress the importance of measuring cannabinoid plasma levels when performing future research. Perspective: This analysis correlating plasma THC levels and pain reduction in diabetic neuropathy suggest a therapeutic window. Low and high THC levels had a negative association (no reduction) and THC levels within the window had a positive association (reduction). There was a minor negative linear effect of THC on cognitive function.

BackgroundAlthough opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse.MethodsWithin a cohort of 106 732 military veteran cancer survivors diagnosed between 2000 and 2015, we determined rates of persistent posttreatment opioid use, diagnoses of opioid abuse or dependence, and admissions for opioid toxicity. A multivariable logistic regression model was used to identify patient, cancer, and treatment risk factors associated with adverse opioid-related outcomes. Predictive risk models were developed and validated using a least absolute shrinkage and selection operator regression technique.ResultsThe rate of persistent opioid use in cancer survivors was 8.3% (95% CI = 8.1% to 8.4%); the rate of opioid abuse or dependence was 2.9% (95% CI = 2.8% to 3.0%); and the rate of opioid-related admissions was 2.1% (95% CI = 2.0% to 2.2%). On multivariable analysis, several patient, demographic, and cancer and treatment factors were associated with risk of persistent opioid use. Predictive models showed a high level of discrimination when identifying individuals at risk of adverse opioid-related outcomes including persistent opioid use (area under the curve [AUC] = 0.85), future diagnoses of opioid abuse or dependence (AUC = 0.87), and admission for opioid abuse or toxicity (AUC = 0.78).ConclusionThis study demonstrates the potential to predict adverse opioid-related outcomes among cancer survivors. With further validation, personalized risk-stratification approaches could guide management when prescribing opioids in cancer patients.

Supplemental Digital Content is Available in the Text., Introduction: With the increasing availability of cannabis and cannabinoids and their potential utility for pain treatment, there is a growing need to evaluate the risk-benefit considerations of cannabinoids for the management of pain. As part of the IASP Cannabis and Cannabinoids Task Force, this protocol describes a planned overview of systematic reviews summarizing the risks of harm with cannabinoids that are relevant to patients receiving pain treatment. Methods: This overview will involve literature searches of several databases and a defined search strategy that will target systematic reviews or meta-analyses of cannabinoids where harms are the primary focus. Data extraction will include various features of the cannabinoid(s) and the harm(s) being studied as well as other methodological features of each included systematic review. Methodological quality of each included review will be assessed using AMSTAR-2 as well as compliance with the PRISMA harms checklist. Prospero registration pending. Discussion: The broad overview of reviews defined by this protocol is expected to synthesize available good quality evidence of harms that will help inform risk-benefit considerations about the use of cannabinoids for pain management.

Objective To compare the efficacy of mental health professional versus primary care nurse-delivered telehealth cognitive-behavioral therapy (CBT) and supportive care (SC) treatments for chronic low back pain, using data from 2 separate randomized controlled trials. Both trials were completed in the same hospital and used the same study design, research team, and outcome measures. Materials and methods Participants from Study 1 (Mental Health Professional Study) (N=66; 2007 to 2011) and Study 2 (Nursing Study) (N=61; 2012 to 2016) were patients with chronic low back pain (≥4/10 intensity) randomized to either an 8-week CBT or an SC telehealth condition matched for contact frequency, format, and time. Participants completed validated measures of improvement in back pain disability (Roland Morris Disability Questionnaire [RMDQ]), pain intensity (Numeric Rating Scale [NRS]), depressive symptoms (Beck Depression Inventory 2 [BDI-2]), pain catastrophizing (Pain Catastrophizing Scale [PCS]), and overall improvement (Global Clinical Impressions [GCI]). Results Intent-to-treat analyses at posttreatment showed that scores on the RMDQ (Cohen d=0.33 to 0.55), NRS (d=0.45 to 0.90), PCS (d=0.21 to 0.41), and GCI (18.5% to 39.1%) improved significantly in both studies and in both treatments from pretreatment to posttreatment. Changes in BDI scores were inconsistent (d=-0.06 to 0.51). The analyses revealed no significant differences in treatment efficacy between the trained nurse versus the mental health professionals on the RMDQ, NRS, PCS, or GCI measures (P>0.20). Discussion Results from these clinical trials suggest that the benefits of home-based, telehealth-delivered CBT and SC treatments for chronic back pain were comparable when delivered by a primary care nurse or mental health professional.

This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

Patients with chronic pain can be challenging to manage and historically providers have relied on opiates to treat pain. Recent studies have brought into question the safety and efficacy of chronic opiate therapy in the noncancer population. There is a vast amount of literature to support the use of nonsteroidal anti-inflammatory medications, antidepressants, anticonvulsants, topical agents, cannabinoids, and botulinum toxin either in conjunction with or in lieu of opioids. Intrathecal drug delivery systems can deliver some of these medications directly to their primary site of action while minimizing the side effects seen with systemic administration.

Objectives Medical marijuana use may substitute prescription opioid use, whereas nonmedical marijuana use may be a risk factor of prescription opioid misuse. This study examined the associations between recreational marijuana legalization and prescription opioids received by Medicaid enrollees. Methods State-level quarterly prescription drug utilization records for Medicaid enrollees during 2010–2017 were obtained from Medicaid State Drug Utilization Data. The primary outcome, opioid prescriptions received, was measured in three population-adjusted variables: number of opioid prescriptions, total doses of opioid prescriptions in morphine milligram equivalents, and related Medicaid spending, per quarter per 100 enrollees. Two difference-in-difference models were used to test the associations: eight states and DC that legalized recreational marijuana during the study period were first compared among themselves, then compared to six states with medical marijuana legalized before the study period. Schedule II and III opioids were analyzed separately. Results In models comparing eight states and DC, legalization was not associated with Schedule II opioid outcomes; having recreational marijuana legalization effective in 2015 was associated with reductions in number of prescriptions, total doses, and spending of Schedule III opioids by 32% (95% CI: (−49%, −15%), p = 0.003), 30% ((−55%, −4.4%), p = 0.027), and 31% ((−59%, −3.6%), p = 0.031), respectively. In models comparing eight states and DC to six states with medical marijuana legalization, recreational marijuana legalization was not associated with any opioid outcome. Conclusions No evidence suggested that recreational marijuana legalization increased prescription opioids received by Medicaid enrollees. There was some evidence in some states for reduced Schedule III opioids following the legalization.

Purpose: To compare the UK Child (0-4) and Adult (55-74) Mortality with twenty developed countries 1989-2014 to explore whether the UK has lower priorities for children? Design: WHO data on Child and Adult mortality examined within context of World Bank %GDPExpenditure-on-Health (%GDPEH) data and Income Inequality i.e Relative poverty. Settings: 21 developed countries. Patients: National populations. Outcome Measures: Child and Adult mortality rates per million (pm) population between 1989-2014. Confi dence Intervals compares UK with other developed countries (ODC); odds ratios of average European to UK mortality calculated. Correlations explore links between mortalities, %GDPEH and Income Inequality. Important Results: Highest average 1980-2014 %GDPEH is USA 12.6%, the lowest UK 7.0%. European average 8.5% a UK to European odds ratio 1:1.21. Widest Income Inequality was USA 15.9 times, UK 13.8 was third, European average 8.5times. Child Mortality fell in every country but eleven signifi cantly better than Britain. Highest was USA 1383pm the UK fourth at 967pm. European average 728pm yielded a European to UK odds ratio of 1:1.33. Income Inequality and CRM signifi cantly correlated (RHO=+0.6188 p

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.

This study evaluated a nurse-delivered, telehealth intervention of cognitive-behavioral therapy (CBT) versus supportive psychotherapy for chronic back pain. Participants (N = 61) had chronic back pain (pain "daily" ≥6 months at an intensity of ≥4 of 10 scale) and were randomized to an 8-week, 12-session, CBT or to supportive care (SC) matched for frequency, format, and time, with each treatment delivered by a primary care nurse. The primary outcome was the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes included the numeric rating scale (NRS) and the Patient Global Impressions Scale (CGI). CBT participants (n = 30) showed significant improvements on the RMDQ (mean = 11.4 [SD = 5.9] vs 9.4 [SD = 6.1] at baseline and post-treatment, respectively, P .05; d = .33), NRS (mean = 4.9 [SD = 2.1] vs 4.0 [SD = 1.9], respectively, P .05; d = .45), and on the CGI (39.1% reporting "much improved" or "very much improved"). SC participants (n = 31) also showed significant improvements on the RMDQ (mean = 11.1 [SD = 5.4] vs 9.1 [SD = 5.2], respectively, P .05; d = .38), the NRS, (mean = 5.0 [SD = 1.9] vs 3.8 [SD = 2.1], respectively, P .05; d = .60), and 26.7% reporting "much improved" or "very much improved" on the CGI. Between groups comparisons of CBT and SC showed no differences on the study outcomes (Ps.10). The results suggest that telehealth, nurse-delivered CBT, and SC treatments for chronic back pain can offer significant and relatively comparable benefits.This article describes the benefits of training primary care nurses to deliver evidence-based behavioral therapies for low back pain. Because of the high prevalence of chronic pain and the growing emphasis on nonopioid therapies, training nurses to provide behavior therapies could be a cost-effective way to improve pain management.

Many cultures throughout history have used cannabis to treat a variety of painful ailments. Neuropathic pain is a complicated condition that is challenging to treat with our current medications. Recent scientific discovery has elucidated the intricate role of the endocannabinoid system in the pathophysiology of neuropathic pain. As societal perceptions change, and legislation on medical cannabis relaxes, there is growing interest in the use of medical cannabis for neuropathic pain. We examined current basic scientific research and data from recent randomized controlled trials (RCTs) evaluating medical cannabis for the treatment of neuropathic pain. These studies involved patients with diverse etiologies of neuropathic pain and included medical cannabis with different THC concentrations and routes of administration. Multiple RCTs demonstrated efficacy of medical cannabis for treating neuropathic pain, with number needed to treat (NNT) values similar to current pharmacotherapies. Although limited by small sample sizes and short duration of study, the evidence appears to support the safety and efficacy of short-term, low-dose cannabis vaporization and oral mucosal delivery for the treatment of neuropathic pain. The results suggest medical cannabis may be as tolerable and effective as current neuropathic agents; however, more studies are needed to determine the long-term effects of medical cannabis use. Furthermore, continued research to optimize dosing, cannabinoid ratios, and alternate routes of administration may help to refine the therapeutic role of medical cannabis for neuropathic pain.

The intrathecal space is separated by the dura and contains the spinal cord and exiting nerve roots. Since the dawn of modern anesthesia, targeted delivery of medications including opioids to the intrathecal space has been an invaluable treatment modality for managing perioperative pain, chronic intractable pain, and spasticity. Separated by the blood brain barrier, medications delivered to this space avoid the side effects of first pass metabolism. Advancement of material science and biomedical engineering has made possible computerized implantable pumps that are capable of delivering extremely accurate and small volumes to the intrathecal space. This chapter provides an in-depth overview of intrathecal drug delivery systems in treating chronic intractable pain and spasticity within the field of interventional pain management. We will explore its indications, available technology, the technical aspects of trialing and implantation, available medications, and potential complications.