Efficacy and Safety of Low-dose Codeine Containing Combination Analgesics for Pain: Systematic Review and Meta-analysis, Objective: To investigate the efficacy and safety of combination analgesic products containing low-dose codeine (up to 30▒mg per dose) for pain. Methods: We used electronic databases to identify eligible placebo-controlled RCTs. Two authors extracted data and assessed risk of bias. Data were pooled using a random effects model with strength of evidence assessed using GRADE. The primary outcome was immediate pain relief (3-hours post-administration) on a 0-100 pain scale. Results: Ten RCTs were eligible. There is low quality evidence (4 RCTs, n=211 participants) that a single dose of a combination analgesic product (with an NSAID) containing low-dose codeine (15▒mg to 30▒mg) provides small pain relief for acute dental pain; mean difference (MD) [95% CI] −12.7 [−18.5, −6.9] and moderate quality evidence (1 RCT, n=93) of small pain relief for post-episiotomy pain and orthopaedic surgery pain; MD [95% CI] −10.0 [−19.0, −1.0] and −11.0 [−20.7, −1.3] respectively. There is low quality evidence (1 RCT, n=80) that a multiple dose regimen provides small pain relief for acute pain following photorefractive keratectomy; MD [95% CI] −16.0 [−24.5, −7.5] and moderate quality evidence of moderate pain relief for certain chronic pain conditions; −19.0 [−31.2, −6.8] for hip osteoarthritis and −26.0 [−44.5, −7.5] for temporomandibular joint pain. Two studies reported a higher incidence of drowsiness in the treatment group compared with the placebo group; RR [95%CI] 8.50 [1.96, 36.8] to 19.3 [1.2, 306.5]. Discussion: There is low to moderate level evidence that combination analgesic products containing low-dose codeine provide small to moderate pain relief for acute nociceptive and chronic pain conditions in the immediate short term with limited trial data on use beyond 24-hours. Further research examining regular use of these medicines is needed with more emphasis on measuring potential harmful effects. Funding: This research was funded by the Therapeutic Goods Administration, Australia. Funding/Support: This research was supported by the Therapeutic Goods Administration, Australia. The authors declare no conflict of interest. Reprints: Christina Abdel Shaheed, PhD, Faculty of Medicine and Health, Sydney School of Public Health, University of Sydney, Sydney, Australia, Level 10 North, King George V Building, Royal Prince Alfred Hospital (C39) PO Box 179, MISSENDEN ROAD NSW 2050 (e-mail: Christina.Abdelshaheed@sydney.edu.au). Received August 31, 2018 Received in revised form June 23, 2019 Accepted June 30, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Brief Cognitive Behavioral Therapy for Chronic Pain: Results from a Clinical Demonstration Project in Primary Care Behavioral Health Objectives: Although cognitive behavioral therapy is an effective intervention for chronic pain, it is a lengthy treatment typically applied only in specialty care settings. The aim of this project was to collect preliminary effectiveness data for Brief Cognitive Behavioral Therapy for Chronic Pain (Brief CBT-CP), an abbreviated, modular form of treatment designed for use in primary care. Methods: A clinical demonstration project was conducted in which Brief CBT-CP was delivered to primary care patients by 22 integrated care providers practicing in the Primary Care Behavioral Health model of Veterans Health Administration primary care clinics. Brief measures were used at each appointment to collect patient reported clinical outcomes. Results: One hundred eighteen patients provided sufficient data for analysis (male, 75%; mean age, 51.4▒y). Multi-level modeling suggested that a composite measure of pain intensity and functional limitations showed statistically significant improvements by the third appointment (Cohen’s D=0.65). Pain-related self-efficacy outcomes showed a similar pattern of results but of smaller effect size (Cohen’s D=0.22). Exploratory analysis identified that Brief CBT-CP modules addressing psychoeducation and goal setting, pacing, and relaxation training were associated with the most significant gains in treatment outcomes. Discussion: These findings provide early support for the effectiveness of Brief CBT-CP when delivered by providers in every day Primary Care Behavioral Health settings. Results are discussed in relation to the need for additional research regarding the potential value of employing safe, population-based, non-pharmacologic approaches to pain management in primary care. This material is the result of work supported with resources and the use of facilities at the VA Center for Integrated Healthcare at the VA Western New York Healthcare System. The information provided in this study does not represent the views of the Department of Veterans Affairs or the United States Government. Disclosure and Acknowledgements: There are no known conflicts of interest for reasons financial or otherwise, no known competing interests, and no companies or products are being featured in this research. Reprints: Gregory P. Beehler, PhD, MA, VA Center for Integrated Healthcare (116N), VA WNY Healthcare System, 3495 Bailey Ave, Buffalo, NY 14215 (e-mail: gregory.beehler@va.gov). Received January 22, 2019 Received in revised form June 26, 2019 Accepted July 2, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Letter to the Editor for Article Titled Dexmedetomidine as an Adjuvant to Local Anesthetics in Transversus Abdominis Plane Block: A Systematic Review and Meta-analysis No abstract available

Non-specific Low Back Pain: Inflammatory Profiles of Patients with Acute and Chronic Pain Background: The pathogenesis of low back pain (LBP) remains unclear. However, recent studies suggest that the inflammatory response may be inherent in spinal pain. Purpose: To discern inflammatory profiles in patients with non-specific acute and chronic low back pain (LBP) in relation to those in asymptomatic subjects. Methods: Peripheral blood samples were obtained from asymptomatic subjects and patients with non-specific acute and chronic LBP reporting a minimum pain score of 3 on a 10-point visual analogue scale (VAS). The levels of in vitro production of pro-inflammatory (TNFα, IL-1β, IL-6, IL-2, IFN[Latin Small Letter Gamma]) and anti-inflammatory (IL-1 RA, sTNFR2 and IL-10) mediators were determined by specific immunoassays. Results: The mean VAS scores were comparable between the acute and chronic LBP patient groups. Compared to asymptomatic subjects, the production of TNFα, IL-1β, IL-6 and their ratios to IL-10 levels were significantly elevated in both patient groups (P=0.0001-0.003). In acute LBP group, the ratio of IL-2: IL-10 was also significantly increased (P=0.02). In contrast, the production of IFN[Latin Small Letter Gamma] was significantly reduced compared with the other study groups (P=0.005-0.01), nevertheless, it was positively correlated (P=0.006) with pain scores. In chronic LBP patients, the production of TNFα, IL-1RA and sTNFR2 was significantly increased (P=0.001-0.03) in comparison with the control and acute LBP groups, and TNFα and IL-1β levels were positively correlated (P<0.001) with VAS scores. Conclusion: The inflammatory profiles of patients with acute and chronic LBP are distinct. Nonetheless, in both patient groups, an imbalance between pro- and anti-inflammatory mediator levels favors the production of pro-inflammatory components. ACKNOWLEDGMENTS: We wish to express our appreciation and gratitude to Dr. A. Teitelbaum for performing phlebotomy. The excellent technical assistance of Ms. A. Corless is deeply appreciated. Conflict of Interest and Source of Funding: All authors declare that they have no conflict of interest to disclose regarding this manuscript. The study was supported by funds from Canadian Memorial Chiropractic College. Reprints: H. Stephen Injeyan, PhD, DC, Canadian Memorial Chiropractic College, 6100 Leslie Street, Toronto, Ontario, M2H 3J1, Canada (e-mail: sinjeyan@cmcc.ca). Received December 27, 2018 Received in revised form May 15, 2019 Accepted June 14, 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Validity of the Budapest Criteria for Post-stroke Complex Regional Pain Syndrome Objectives: Complex regional pain syndrome-1 (CRPS-1) is a chronic neuropathic disorder, and post-stroke CRPS (PS-CRPS) is not a rare complication. There is a lack of study implementing the Budapest criteria for PS-CRPS diagnosis. Thus, the present study investigated the validity of the Budapest criteria for PS-CRPS diagnosis and assessed the PS-CRPS-related factors in stroke patients with an affected upper extremity. Methods: The study included 72 patients with first-ever stroke resulting in hemiplegia. The prevalence of PS-CRPS and diagnostic validity were compared among the Budapest clinical criteria, Budapest research criteria, modified Budapest criteria (removal of the motor factor from the motor/trophic category), and International Association for the Study of Pain (IASP) criteria in patients diagnosed with PS-CRPS according to the Budapest clinical criteria. Results: PS-CRPS was diagnosed in 6 (8.3%), 1 (1.4%), 6 (8.3%), and 11 patients (15.3%) according to the Budapest clinical criteria, Budapest research criteria, modified Budapest criteria, and IASP criteria, respectively. The Budapest criteria and IASP criteria had sensitivities of 0.99 and 1.00, respectively, and specificities of 0.68 and 0.41, respectively, for PS-CRPS diagnosis. There were no differences in risk factors between PS-CRPS patients and non-PS-CRPS patients when the diagnosis was based on the Budapest clinical criteria. However, there were differences in muscle strength and Brunnstrom stage between PS-CRPS patients and non-PS-CRPS patients when the diagnosis was based on the IASP criteria. Discussion: Our findings indicate that the diagnostic validity of the current Budapest clinical criteria for PS-CRPS is low. Thus, the current Budapest criteria might not be appropriate for PS-CRPS diagnosis. Acknowledgments: We would like to thank Editage (http://www.editage.co.kr) for English language editing. There are no conflicts of interest. Conflicts of Interest and Source of Funding: We would like to thank Editage (http://www.editage.co.kr) for English language editing. Reprints: Joon-Ho Shin, MD, MS, Department of Rehabilitation Medicine, National Rehabilitation Center, 58, Samgaksan-ro, Gangbuk-gu, Seoul, 01022, Republic of Korea (e-mail: asfreelyas@gmail.com). Received January 17, 2019 Accepted June 17, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Mandatory Pain Assessment in a Pediatric Emergency Department: Failure or Success? A Retrospective Study Objective: Pain control is a priority in patient evaluation. Despite the proliferation of guidelines, pain is still under assessed and undertreated, especially in children. To improve efficiency and to adhere to best medical practice, our triage software was upgraded; it included mandatory pain scoring for the admission of a child to the pediatric emergency service, thereby limiting the chances of overlooking a child experiencing pain. We conducted this study to verify the effect of routine versus mandatory pain scoring on pain management under the hypothesis that mandatory pain assessment would improve re-evaluation and pain treatment. Methods: This retrospective case-control study was conducted in our Pediatric Emergency Department. We collected data regarding pain assessment and reassessment at triage and during the entire stay in the ED, as well as the drugs eventually administered. We reviewed the charts of 1274 patients admitted with the older triage software and of 1262 patients admitted with the newer triage software (intervention group). Results: Pain was evaluated significantly more frequently in the intervention group at triage, during medical evaluation, and at discharge. In the intervention group, a smaller percentage of patients were treated for pain at both triage and during their stay in the ED (P=0.078 and P=0.048). Pain re-assessment resulted worse in the intervention group (P<<0.001). Discussion: Mandatory pain assessment improved the pain evaluation rate. This did not, however, translate into better treatment and management of pain in the pediatric emergency setting. No funding sources were provided for this study. DISCLOSURE: The authors declare no conflict of interest. Reprints: Federico Marzona, MD, University of Udine, Department of Medicine (DAME), “S. Maria della Misericordia” Academic Hospital, 33100, Udine, Italy (e-mail: federico.marzona@asuiud.sanita.fvg.it). Received December 11, 2018 Received in revised form June 4, 2019 Accepted June 24, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Patient and Disease Characteristics Associates With Sensory Testing Results in Chronic Pancreatitis Background: Abdominal pain is the most common symptom in chronic pancreatitis and has extensive impact on patients’ lives. Quantitative sensory testing (QST) provides information on sensitivity to pain and mechanisms which can help quantify pain and guide treatment. The aims of this study were (1) to explore sensitivity to pain in patients with chronic pancreatitis using QST, and (2) to associate patient- and disease characteristics with QST results. Methods: Ninety-one patients with painful chronic pancreatitis and 28 healthy control subjects completed a QST paradigm using static tests (muscle pressure stimulation and electrical skin stimulations) to unravel segmental and widespread hyperalgesia as a consequence of visceral pain. A dynamic conditioned pain modulation (CPM) paradigm was used as proxy of pain modulation from brainstem to inhibit incoming nociceptive barrage, and questionnaires were used to gather information on pain experience and quality of life. Results: Patients had impaired conditioned pain modulation compared to controls (18.0±29.3% vs. 30.9±29.3%, P=0.04) and were hypersensitive to pressure stimulation, specifically in the pancreatic (Th10) dermatome (P<0.001). The capacity of CPM was associated with clinical pain intensity (P=0.01) and (in univariate analysis only) the use of opioids was associated with hyperalgesia to pressure stimulation (P<0.05). Conclusion: Sensitivity to pain in chronic pancreatitis patients can be characterized by a simple bedside QST. Severe clinical pain in chronic pancreatitis was associated with reduced CPM function and should be targeted in management. Funding sources: None declared. Disclosures: The authors have nothing to disclose. Conflict of interest: None declared. Reprints: Asbjørn Mohr Drewes, MD, PhD, DMSc, Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark (e-mail: amd@rn.dk). Received January 23, 2019 Received in revised form June 4, 2019 Accepted June 14, 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Insomnia Increases Symptom Severity and Health Care Utilization in Patients with Fibromyalgia: A Population-based Study Objective: This study aimed to determine whether comorbid insomnia is associated with increased use of fibromyalgia-related medications and health resources in fibromyalgia patients. Methods: We analyzed data retrieved from the Longitudinal Health Insurance Database 2010, which contains claims data of 1 million beneficiaries randomly selected from Taiwan’s National Health Insurance program. Patients treated for fibromyalgia (n=17, 920) on two separate visits between 2000 and 2001 were selected and subsequently divided into two groups: patients with and without comorbid insomnia (n=5466 and 12, 454, respectively). Insomnia was identified through diagnosis on two separate visits after the index fibromyalgia date. Fibromyalgia-related pharmacotherapies and ambulatory care visits were tracked from the index date to the end of 2013. Results: Insomnia was associated with increased likelihood of future use of antidepressants (adjusted odds ratio (OR)=3.84, P<0.001), gabapentin (adjusted OR=1.67, P<0.001), pregabalin (adjusted OR=1.79, P=0.046), muscle relaxants (adjusted OR=3.05, P<0.001), and opioids and tramadol (adjusted OR=1.59, P<0.001) among fibromyalgia patients compared with fibromyalgia patients without insomnia. In addition, a diagnosis of insomnia was associated with an increased frequency of visits to ambulatory care services for both fibromyalgia (β=1.79, 95% CI=1.57–2.02, P<0.001) and other conditions (β=108.51, 95% CI=103.14–113.89, P<0.001). Discussion: This study demonstrates the substantial burden of comorbid insomnia in patients with fibromyalgia. CJ Huang and CL Huang contributed equally to the paper. Author contribution: Pei-Shan Tsai contributed to the conception of the idea, the study design, and to acquisition, analysis and interpretation of data; drafted and revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Chun-Jen Huang and Chin-Liang Huang contributed to the conception of the idea, analysis and interpretation of results; drafted and revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Yen-Chun Fan and Ting-Yu Chen were involved in the analysis and interpretation of data, drafting and revising the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Conflicts of interest and source of funding: Chun-Jen Huang, Chin-Liang Huang; Yen-Chun Fan, Ting-Yu Chen and Pei-Shan Tsai declare that there is no conflict of interest regarding the publication of this paper. This study was supported by grants from Taiwan Ministry of Science and Technology (MOST #105-2314-B038-052-MY3 & MOST #107-2314-B038-023-MY3). Reprints: Pei-Shan Tsai, PhD, Taipei Medical University, 250 Wuxing St. Taipei 11031, Taiwan (e-mail: ptsai@tmu.edu.tw). Received January 29, 2019 Received in revised form April 28, 2019 Accepted June 4, 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Effects of Conditioned Pain Modulation on the Nociceptive Flexion Reflex in Healthy People: A Systematic Review Objectives: The nociceptive flexion reflex (NFR) is a spinal reflex induced by painful stimuli resulting in a withdrawal response. Research has shown that the NFR is inhibited through endogenous pain inhibitory mechanisms, which can be assessed by conditioned pain modulation (CPM) paradigms. Although accumulating research suggests that the NFR can be affected by CPM, no clear overview of the current evidence exists. Therefore, the present review aimed at providing such a synthesis of the literature. In addition, the influence of personal factors on the CPM of the NFR was investigated. Materials and Methods: A systematic review was performed and reported following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Five electronic databases were searched to identify relevant articles. Retrieved articles were screened on eligibility using predefined inclusion criteria. Risk of bias was investigated according to the modified Newcastle-Ottawa Scale. Levels of evidence and strength of conclusion were assigned following the guidelines of the Dutch Institute for Healthcare Improvement. Results: Forty articles were included. There is some evidence that CPM produced by thermal or mechanical stimuli induces inhibitory effects on the NFR. However, inconclusive evidence exists with regard to the effect of electrical conditioning stimuli. While several personal factors do not affect CPM of the NFR, increased cognitive interference is associated with reduced NFR inhibition. Discussion: The present review demonstrates that certain types of nociceptive conditioning stimuli have the potential to depress, at the spinal level, nociceptive stimuli elicited from distant body regions. Although CPM of the NFR seems to be robust to the influence of several personal factors, it can be affected by cognitive influences. J.V.O. is a postdoctoral research fellow funded by the Research Foundation—Flanders (FWO) (12L5616N) Brussels, Belgium. S.V.O. is a PhD researcher supported by a research project grant from the Research Foundation—Flanders (FWO) received by L.D. and J.V.O. (G0B3718N). I.C. is a postdoctoral researcher funded by the Research Foundation—Flanders (FWO) (G007217N) and the Agency for Innovation by Science and Technology (IWT)—Applied Biomedical Research Program (TBM) (150180), Brussels, Belgium. The remaining author declare no conflict of interest. Reprints: Jessica Van Oosterwijck, PhD, Department of Rehabilitation Sciences, SPINE Research Unit Ghent, Ghent University, Campus UZ Ghent, Corneel Heymanslaan 10, B3, Ghent 9000, Belgium (e-mail: jessica.vanoosterwijck@ugent.be). Received February 4, 2019 Received in revised form March 22, 2019 Accepted April 8, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Effect of Adding Dexmedetomidine to Local Anesthetic Agents for Transversus Abdominis Plane Block: A Meta-analysis Background: Dexmedetomidine (Dex) has been used adjuvant in Transversus abdominis plane (TAP) blocks. This meta-analysis was aimed at evaluating the effect of Dex in TAP blocks. Objectives: Outcome measures were total opiate consumption in 24-hours after surgery, time to systemic rescue analgesia, pain scores after surgery, and adverse events. Materials and methods: Randomized controlled trials (RCTs) comparing Dex with local anesthetics (LAs) to LAs alone for analgesia after abdominal surgeries were searched included. Standardized mean difference (SMD) and mean difference (MD) were used for continuous variables, and odds ratio for frequency data. Results: Analysis of data from 9 RCTs (598 patients) showed that addition of Dex to LAs decreased opiate use in 24 hours after surgery (SMD −3.07, 95% CI: −4.78, −1.35), increased time to rescue analgesia (171.8▒min, 95% CI: 112.34, 231.26), and decreased pain scores (scale of 0-10) at 4 hours (MD −0.36, 95% CI: −0.65, −0.07) and 8 hours (MD −0.17, 95% CI: −0.29, −0.04) after surgery. Frequency of adverse events was similar between the two groups (OR 1, 95% CI: 0.61-1.63). The estimates for pain scores were prone to sensitivity analysis. The estimates for post-op opiate use, time to rescue analgesia and pain scores at 8 hours had significant heterogeneity. Conclusions: Addition of Dex to LAs in TAP block for analgesia after abdominal surgeries decreased 24 hour opiate use and increased the overall time to rescue analgesia including certain subgroups without increasing adverse events. Its effect on post-op pain scores was not as definitive. Disclosures: None. Source of funding: None. Conflicts of Interest: None. Reprints: Prannal Bansal, MD, 4301 W. Markham St., Little Rock, AR-72205 (e-mail: pbansal@uams.edu). Received September 14, 2018 Received in revised form June 12, 2019 Accepted June 18, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.