Background: Low back pain (LBP) is the highest contributor to disability worldwide, with current intervention strategies only providing small to moderate analgesic effects. The use of vitamin D supplementation for LBP has gained interest due to its proposed anti-inflammatory and neuromodulatory properties. However, it is still unclear whether vitamin D levels differ between those with and without LBP or if vitamin D levels are associated with pain intensity. Objectives: We aim to investigate the association between vitamin D levels and LBP and to determine if vitamin D levels correlate with pain intensity in individuals with LBP. Study Design: This study was conducted in accordance with the guidelines for performing a Metaanalysis and Systematic Review Of Observational Studies in Epidemiology (MOOSE). Methods: We performed electronic database searches combined keywords relating to vitamin D and LBP in MEDLINE, CINAHL, EMBASE, AMED, WEB OF SCIENCE, and SCOPUS from the earliest record to March 2017. Studies were included if they reported any quantitative measure of vitamin D, such as serum 25-hydroxyvitamin D [25(OH)D], with adequate data in patients with and without LBP or adequate data on pain intensity in patients with LBP. No restriction on the type or duration of LBP, nor the age and gender of patients was applied. Two reviewers independently performed the selection of studies, extracted data, and assessed the methodological quality of the included studies using a modified 15-item Downs and Black checklist. Results: After the removal of duplicates and the screening of titles and abstracts, 105 full texts were evaluated. There were 29 articles included in this systemic review (22 entered into a meta-analysis), including 19 cross-sectional studies, 9 case-control studies, and one single-arm surgical trial where the pre-operative data were used in our analyses. The pooled results from 19 studies showed that individuals with LBP were more likely to have vitamin D deficiency (pooled OR = 1.60, 95% CI: 1.20 - 2.12, P = 0.001, n = 19), severe deficiency (pooled OR = 2.08, 95% CI: 1.19 - 3.64, P = 0.010, n = 7), and lower serum concentrations of 25(OH)D (weighted MD = 3.86, 95% CI: 0.20 - 7.52, P = 0.039, n = 12) compared to those without LBP (where “n” is the number of studies). The association between vitamin D deficiency (pooled OR = 1.83, 95% CI: 1.26 - 2.66, P = 0.002, n = 9) or serum 25(OH)D (weighted MD = 7.64, 95% CI: 4.02 - 11.26, P < 0.001, n = 4) and LBP was stronger for women but failed to be statistically significant for men (pooled OR = 1.06, 95% CI: 0.62 - 1.81, P = 0.213, n = 3). In addition, there were strong associations between vitamin D deficiency and LBP in patients < 60 years old (particularly women). We found minimal evidence to support an association between vitamin D levels and pain intensity in patients with LBP. Limitations: We were unable to investigate whether vitamin D deficiency increases the risk of developing LBP as there were no longitudinal studies included in this review. Conclusion: Vitamin D deficiency is associated with LBP, with stronger associations observed in younger women and those with severe levels of deficiency. The association between vitamin D levels and pain intensity is inconsistent. These results may guide the implementation of future studies on vitamin D supplementation for LBP. PROSPERO Registration No: CRD42016046874. Key words: Vitamin D, low back pain, deficiency, pain intensity, serum 25-hydroxyvitamin D, supplementation, cross-sectional study, case-control study

Background: Music is increasingly used as an adjuvant for the management of chronic pain (CP), as it is non-invasive, inexpensive, and patients usually report positive experiences with it. However, little is known about its clinical efficacy in chronic pain patients. Objectives: We aimed to determine the effect of music as an adjuvant for chronic pain, as well as to identify characteristics of music interventions associated with positive clinical outcomes. Study Design: In this systematic review and meta-analysis, we investigated randomized controlled trials (RCTs) of adult patients that reported any type of music intervention for chronic pain, chosen by the researcher or patient, lasting for any duration. Searches were performed using PsycINFO, Scopus, and PubMed for RCTs published until the end of May 2016. The primary outcome was reduction in self-reported pain using a standardized pain measurement instrument, reported post-intervention. The secondary outcomes were: quality of life measures, depression, anxiety, and related measures. Methods: The study was pre-registered with PROSPERO (CRD42016039837), and the metaanalysis was performed using RevMan 5.3 (The Nordic Cochrane Centre for The Cochrane Collaboration, Copenhagen, Denmark). We identified 768 titles and abstracts, and we included 14 RTCs that fulfilled our criteria. The sample size of the studies varied between 25 and 200 patients. Results: We found that music reduced self-reported chronic pain and depressive symptoms. We also found that music had a greater effect when the patient chose the music, compared to when the researcher chose it. Limitations: The sample size of RCTs was small and sometimes with different outcome measures. There was high heterogeneity associated with pooled estimates. Conclusions: Our analysis suggests that music may be beneficial as an adjuvant for chronic pain patients, as it reduces self-reported pain and its common comorbidities. Importantly, the analgesic effect of music appears higher with self-chosen over researcher-chosen music. Key Words: Pain, music, analgesia, music-induced analgesia, chronic pain, meta-analysis, systematic review, therapy Pain Physician 201

Background: Pain management after spinal surgery has been studied for years. Gabapentin is a third-generation antiepileptic drug that selectively affects the nociceptive process and has been used for pain relief after surgery. However, the relationship between gabapentin and postoperative pain in spinal surgery is still controversial. Objective: To assess the efficacy of the pre-emptive use of gabapentin in spinal surgery. Study Design: A meta-analysis of randomized controlled studies. Setting: The MEDLINE, EMBASE, ClinicalTrials.gov, and Web of Science databases were systematically searched. Methods: This meta-analysis of randomized controlled trials (RCTs) was performed to compare the use of gabapentin with placebo in spinal surgery regarding to the following: the mean difference (MD) of postoperative opioid requirements, the changes of visual analog scale (VAS) scores in 2 groups, and the incidence rate of adverse effects. An electronic-based search of all related literatures was conducted, and only RCTs for spinal surgery were included. The MD of postoperative opioid requirements and VAS scores and the relative risk (RR) of the incidence rate of adverse effects in the gabapentin group versus the placebo group were extracted throughout the study. Results: Ten trials, involving 827 patients, met the inclusion criteria and were included in this meta-analysis. The total morphine consumption was significantly lower over the first 24 hours postoperatively in the gabapentin group (P < 0.05). The VAS scores at 2, 4, 6, 12, and 24 hours were less in the gabapentin group (P < 0.05). The incidence rate of vomiting, pruritus, and urinary retention was significantly less in the gabapentin groups (RR = 0.53, 95% CI 0.32–0.86, P < 0.05; RR = 0.38, 95% CI 0.22–0.66, P < 0.05; RR = 0.57, 95% CI 0.34–0.98, P < 0.05, respectively). Limitations: All of the studies we screened were published online except for unpublished articles. Only 10 RCTs met our inclusion criteria, so the sample size was still relatively small. Conclusion: This meta-analysis suggests that the administration of gabapentin is effective in reducing postoperative opioid consumption, VAS scores, and some side effects after spinal surgery. Key words: Gabapentin, analgesia, spinal surgery, meta-analysis, randomized controlled trials, visual analog scale score, side effect

Background: Patients with chronic whiplash-associated disorders (CWAD) are characterized by pain of traumatic origin, cognitive deficits, and central sensitization (CS). Previous neuroimaging studies revealed altered grey matter volume (GMV) in mild traumatic brain injury patients and chronic pain conditions also characterized by CS. It can therefore be hypothesized that GMV alterations also play a role in the persistent complaints of CWAD. However, brain alterations remain poorly investigated in these patients. Objectives: This study examined regional GMV alterations in patients with CWAD compared to patients with non-traumatic chronic idiopathic neck pain (CINP), who normally do not show CS at a group level, and healthy controls. Additionally, in both patient groups, relationships between regional GMV and measures of cognition as well as pain processing were assessed. Study Design: A cross-sectional case-control study. Setting: This study was performed at the Department of Rehabilitation Sciences and Physiotherapy of Ghent University in cooperation with the Ghent Institute for Functional and Metabolic Imaging. Methods: Ninety-three women (28 healthy controls, 34 CINP patients, and 31 CWAD patients) were enrolled. First, T1-weighted magnetic resonance images (MRIs) were acquired to examine GMV alterations in the brain regions involved in processing cognition and pain. Next, cognitive performance, pain cognitions, and CS symptoms were assessed. Finally, hyperalgesia and conditioned pain modulation efficacy were examined. Results: Regional GMV of the right lateral orbitofrontal cortex, left supramarginal cortex, and left posterior cingulate cortex was decreased in CWAD patients compared to healthy controls (P = 0.023; P = 0.012; P = 0.047, respectively). Additionally, GMV of the right superior parietal cortex and left posterior cingulate cortex was decreased in CWAD patients compared to CINP patients (P = 0.008; P = 0.035, respectively). Decreased regional GMV correlated with worse cognitive performance, higher maladapted pain cognitions, CS symptoms, and hyperalgesia in CWAD patients (rs = -0.515 to -0.657; P < 0.01). In CINP patients, decreased regional GMV correlated only with worse cognitive performance (rs = -0.499 to -0.619; P < 0.01), and no GMV differences compared with the controls could be revealed. Limitations: No conclusions about the causality of the observed relationships can be drawn. Conclusions: These results provide the first evidence for reduced GMV in cortical regions involved in processing cognition and pain in patients with CWAD. Accordingly, it is recommended that therapy approaches for CWAD patients should address the brain and take into account neuroplasticity of the central nervous system (CNS). Key words: Whiplash injuries, neck pain, magnetic resonance imaging, grey matter, cognitive dysfunction, pain catastrophizing, central sensitization

Background: Over the past 2 decades, the increase in the utilization of interventional techniques has been a cause for concern. Despite multiple regulations to reduce utilization of interventional techniques, growth patterns continued through 2009. A declining trend was observed in a previous evaluation; however, a comparative analysis of utilization patterns of interventional techniques has not been performed showing utilization before and after the enactment of the Affordable Care Act (ACA). Objectives: Our aim is to assess patterns of utilization and variables of interventional techniques in chronic pain management in the fee-for-service (FFS) Medicare population, with a comparative analysis of pre- and post-ACA. Study Design: Utilization patterns and variables of interventional techniques were assessed from 2000 to 2009 and from 2009 to 2016 in the FFS Medicare population of the United States in managing chronic pain. Methods: The master data from the Centers for Medicare & Medicaid Services (CMS) physician/ supplier procedure summary from 2000 to 2016 was utilized to assess overall utilization and comparative utilization at various time periods. Results: The analysis of Medicare data from 2000 to 2016 showed an overall decrease in utilization of interventional techniques 0.6% per year from 2009 to 2016, whereas from 2000 to 2009, there was an increase of 11.8% per year per 100,000 individuals of the Medicare population. In addition, the United States experienced an increase of 0.7% per year of population growth, 3.2% of those 65 years or older and a 3% annual increase in Medicare participation from 2009 to 2016. Further analysis also showed a 1.7% annual decrease in the rate of utilization of epidural and adhesiolysis procedures per 100,000 individuals of the Medicare population, with a 2.2% decrease for disc procedures and other types of nerve blocks, whereas there was an increase of 0.8% annually for facet joint interventions and sacroiliac joint blocks from 2009 to 2016. Epidural and adhesiolysis procedures showed an 8.9% annual increase, facet joint interventions and sacroiliac joint blocks showed a 17.6% increase, and disc procedures and other types of nerve blocks showed a 7.2% increase annually per 100,000 individuals of the Medicare population from 2000 to 2009. Limitations: The limitations of this assessment include lack of analysis of individual procedures. Additional limitations include lack of inclusion of patients from Medicare Advantage plans and lack of complete and accurate data for statewide utilization. Conclusion: From 2009 to 2016, interventional techniques decreased at an annual rate of 0.6% with an overall decrease of 3.9%, compared to an overall increase of 173.6% from 2000 to 2009 with an annual increase of 11.8%. An additional analysis of data with individual procedures is essential to gain further insights into utilization patterns. Key words: Interventional pain management, chronic spinal pain, interventional techniques, epidural injections, adhesiolysis, facet joint interventions, sacroiliac joint injections, disc procedures, other types of nerve blocks

Background: Major abdominal surgeries are associated with severe pain, which can affect respiratory and cardiac functions if insufficiently treated; this increases postoperative morbidity. Objective: We aim at evaluating the efficacy of magnesium sulfate as an adjuvant to local anesthetic in an ultrasound-guided transversus abdominis plane (TAP) block for postoperative analgesia in total abdominal hysterectomy. Study Design: A prospective, randomized, double-blinded clinical trial. Setting: An academic medical center. Methods: This study is registered at https://clinicaltrials.gov (no.: NCT02930707). This randomized, double-blinded clinical trial included 60 women undergoing total abdominal hysterectomy that were divided into 2 groups (30 patients per group). Group I received a TAP block with 20 mL per side of 0.25% bupivacaine plus 2 mL magnesium sulphate 10% (200 mg). Group II received a TAP block with 20 mL per side of 0.25% bupivacaine. Visual analog scale (VAS) scores, the time of the first analgesic request, total morphine consumption, and any side effects were assessed and recorded. Results: The mean postoperative VAS score was significantly reduced in group I compared to group II in all of the time-points except after 10 hours. The mean time of the first request for rescue analgesia was significantly prolonged in group I (15.67 hrs.) compared to group II (7.33 hrs.) (P < 0.001), and the mean total morphine consumption, over the first 24 hours postoperatively, was significantly lower in group I (7.63 ± 2.93 mg) than in group II (16.20 ± 3.24 mg) (P < 0.001). No significant difference in side effects was observed. Limitations: Sample size. Conclusion: The addition of 200 mg of magnesium sulfate to bupivacaine in an ultrasound-guided TAP block significantly reduced postoperative opioid requirements, prolonged the duration of analgesia, and reduced the VAS score in patients who underwent abdominal hysterectomy, without significant side effects. Key words: Magnesium sulfate, TAP block, postoperative pain, total abdominal hysterectomy

Background: Electrical stimulation of the greater occipital nerves is performed to treat pain secondary to chronic daily headaches and occipital neuralgia. The use of fluoroscopy alone to guide the surgical placement of electrodes near the greater occipital nerves disregards the impact of tissue planes on lead stability and stimulation efficacy. Objective: We hypothesized that occipital neurostimulator (ONS) leads placed with ultrasonography combined with fluoroscopy would demonstrate increased survival rates and times when compared to ONS leads placed with fluoroscopy alone. Study Design: A 2-arm retrospective chart review. Setting: A single academic medical center. Methods: This retrospective chart review analyzed the procedure notes and demographic data of patients who underwent the permanent implant of an ONS lead between July 2012 and August 2015. Patient data included the diagnosis (reason for implant), smoking tobacco use, disability, and age. ONS lead data included the date of permanent implant, the imaging modality used during permanent implant (fluoroscopy with or without ultrasonography), and, if applicable, the date and reason for lead removal. A total of 21 patients (53 leads) were included for the review. Chi-squared tests, Fishers exact tests, 2-sample t-tests, and Wilcoxon rank-sum tests were used to compare fluoroscopy against combined fluoroscopy and ultrasonography as implant methods with respect to patient demographics. These tests were also used to evaluate the primary aim of this study, which was to compare the survival rates and times of ONS leads placed with combined ultrasonography and fluoroscopy versus those placed with fluoroscopy alone. Survival analysis was used to assess the effect of implant method, adjusted for patient demographics (age, smoking tobacco use, and disability), on the risk of lead explant. Results: Data from 21 patients were collected, including a total of 53 ONS leads. There was no statistically significant difference in the lead survival rate or time, disability, or patient age with respect to the implant method with or without ultrasonography. There was a statistically significant negative effect on the risk of explant with regards to lead removal in smoking patients compared to non-smoking patients (hazard ratio 0.36). There was also a statistically significant difference in smoking tobacco use with respect to the implant method, such that a greater number of patients whose leads were placed with combined fluoroscopy and ultrasonography had a history of smoking (P = 0.048). Limitations: This study is a retrospective chart review that had statistically significant differences in the patient groups and a small sample size. Conclusion: This study assessed the survival rates and times of ONS leads placed with ultrasonography and fluoroscopy versus fluoroscopy alone. We did not observe an effect to suggest that the incremental addition of ultrasound guidance to fluoroscopy as the intraoperative imaging modality used during the permanent implant of ONS leads yields statistically significant differences in lead survival rate or time. Medical comorbidities, including age and smoking status, may play a role in determining the risk of surgical revision and should be considered in future studies. Key words: Neuromodulation, peripheral nerve stimulation, occipital nerve stimulation, occipital neuralgia, chronic daily headaches, ultrasonograph

Background: Abuse-deterrent formulations (ADFs) represent one novel strategy for curbing the potential of opioid abuse. Objective: We aim to compare and contrast the characteristics and applications of current abusedeterrent opioid products in clinical practice. Methods: Literature searches were conducted in databases (Pubmed Medline, International Pharmaceutical Abstracts, Google Scholar) and official reports. Relevant data were screened and organized into: 1) epidemiology of opioid abuse, 2) mitigation strategies for reducing opioid abuse, 3) development of ADFs, and 4) clinical experience with these formulations. Results: Increasing trends of opioid abuse and misuse have been reported globally. There are 5 types of abuse-deterrent opioid products: physical chemical barrier, combined agonist/antagonist, sequestered aversive agent, prodrug, and novel delivery system. The advantages and disadvantages of the 5 options are discussed in this review. A total of 9 products with abuse-deterrent labels have been approved by the Food and Drug Administration (FDA). The rates of abuse, diversion, and overdose deaths of these new products are also discussed. A framework for collecting in-time data on the efficacy, benefit and risk ratio, and cost-effectiveness of these new products is suggested to facilitate their optimal use. Limitations: The present review did not utilize systematic review standards or meta-analytic techniques, given the large heterogeneity of data and outcomes reviewed. Conclusions: ADFs provide an option for inhibiting the abuse or misuse of oral opioid products by hindering extraction of the active ingredient, preventing alternative routes of administration, or causing aversion. Their relatively high costs, uncertain insurance policies, and limited data on pharmacoeconomics warrant collaborative monitoring and assessment by government agencies, pharmaceutical manufacturers, and data analysis services to define their therapeutic role in the future. Key words: Opioid abuse, abuse-deterrent formulations, ADF, post-marketing, FDA guidance, cost impact, abuse liking, physician attitude, generic abuse-deterrent formulation, clinical application

Background: Urine drug testing is used by health care providers to determine a patient’s compliance to their prescribed regimen and to detect non-prescribed medications and illicit drugs. However, the cutoff levels used by clinical labs are often arbitrarily set and may not reflect the urine drug concentrations of compliant patients. Objectives: Our aim was to test the hypothesis that commonly used cutoffs for many prescribed and illicit drugs were set too high, and methods using these cutoffs may yield a considerable number of false-negative results. The goals of this study were to outline the way to analyze patient results and estimate a more appropriate cutoff, develop and validate a high sensitivity analytical method capable of quantitating drugs and metabolites at lower than the commonly used cutoffs, and determine the number of true positive results that would have been missed when using the common cutoffs. Study Design: This was a retrospective study of urine specimens submitted for urine drug testing as part of the monitoring of prescription drug compliance described in chronic opioid therapy treatment guidelines. Setting: The study was set in a clinical toxicology laboratory, using specimens submitted for routine analysis by health care providers in the normal course of business. Methods: Lognormal distributions of test results were generated and fitted with a trendline to estimate the required cutoff level necessary to capture the normal distributions of each drug for the patient population study. A validated laboratory derived liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis capable of achieving the required cutoff levels was developed for each drug and/or metabolite. Results: The study shows that a lognormal distribution of patient urine test results fitted with a trendline is appropriate for estimating the required cutoff levels needed to assess medication adherence. The study showed a wide variation in the false-negative rate, ranging from 1.5% to 94.3% across a range of prescribed and illicit drugs. Limitations: The patient specimens were largely sourced from patients in either a long-term pain management program or in treatment for substance use disorder in the US. These specimens may not be representative of patients in other types of treatment or in countries with different approaches to these issues. Conclusions: The high-sensitivity method reduces false-negative results which could negatively impact patient care. Clinicians using less sensitive methods for detecting and quantifying drugs and metabolites in urine should exercise caution in assessing patient adherence using and changing the treatment plan based on those results. Key words: Urine drug testing, patient adherence, clinical toxicology, immunoassay, LC-MS, definitive drug testing, REMS, negative test results, false negative

Background: It is still a challenge to optimize postoperative pain management. The effects of adding dexmedetomidine (DEX) to opioid-based postoperative intravenous patient-controlled analgesia (PCA) are not fully understood. Objectives: The aim of this study is to assess the efficacy and safety of opioid-DEX combinations for postoperative PCA, and a trial sequential analysis (TSA) is utilized to evaluate the robustness of the current evidence. Study Design: A systematic review and meta-analysis. Setting: Randomized controlled trials that compared opioid-DEX combinations with opioid-only for PCA in adult surgical patients. Methods: MEDLINE, EMBASE, and CENTRAL databases were searched for relevant articles. The main outcomes analyzed were postoperative pain intensity, opioid requirement, and opioid-related adverse events. The random-effects model was used to estimate mean differences (MDs) or relative risks (RRs) with 95% confidence intervals (CIs). A TSA was performed to test whether the evidence was reliable and significant. The quality of evidence for the main outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: Eighteen studies involving 1,284 patients were included. The meta-analysis indicated that opioid-DEX combinations were associated with lower postoperative pain intensity (at rest: MD [24 hours] = -0.48, 95% CI [-0.75, -0.21], P = 0.0005), lower morphine-equivalent requirement (MD [0 – 24 hours] = -12.16 mg [-16.12, -8.21], P < 0.00001), and lower adverse events (nausea: RR = 0.66 [0.52, 0.83]; vomiting: RR = 0.65 [0.49, 0.87]; and pruritus: RR = 0.57 [0.40, 0.81]). For the above results, the TSA revealed that the cumulative Z-curve exceeded both the traditional boundary and the trial sequential monitoring boundary for benefit. DEX had no effect on the incidence of hypotension or bradycardia, which was also confirmed by the TSA. The GRADE level of evidence was high for postoperative nausea, moderate for pain intensity at rest at 24 hours postoperatively, morphine-equivalent requirement during 0 – 24 hours postoperatively, and postoperative vomiting, pruritus, and bradycardia, and low for postoperative hypotension. Limitations: The risk of introducing potentially significant heterogeneity exists, and this study did not evaluate the effects of DEX combined with opioids on long-term outcomes including chronic pain and patients’ satisfaction after hospital discharge. Conclusions: Postoperative PCA strategies with opioid-DEX combinations decreased postoperative pain, opioid requirement, and opioid-related adverse events. DEX is a useful adjuvant to opioid-based PCA. Key words: Dexmedetomidine, pain, postoperative analgesia, opioid, patient-controlled