The Clinical Journal of Pain

Development of a Measure of Nociception for Patients with Severe Brain Injury Objectives: Severe brain injury is often accompanied by painful comorbidities, and by concurrent limitations in the ability to report pain. Assessment of nociception aids diagnosis and helps balance reduction in suffering with avoidance of sedating medications. Existing assessment methods confound patients’ level of consciousness with the intensity of nociception, complicating pain assessment as consciousness evolves. We sought to develop a measure of nociception that is independent of level of consciousness. Methods We identified 15 behavioral and physiological items likely to be sensitive to nociception. We rated non-communicative patients with traumatic brain injury (TBI) in 4 different activities predicted to modulate nociception, on each of 2 days, one randomly chosen for acetaminophen administration. Level of consciousness and level of agitation were also measured. Rasch Analysis: Was used to assess item fit to an underlying dimension of nociception. Results: Five items which demonstrated poor fit to the dimension were removed. The 10 remaining items demonstrated acceptable fit. Scores were significantly influenced by activity and analgesic treatment, and were largely independent of measures of consciousness and agitation. Accurate scores could be obtained in about 10 minutes and were robust to missing data. Discussion: The results provide evidence that the Brain Injury Nociception Assessment Measure (BINAM) is reliable and feasible to administer. It can assess intensity of nociception largely independent of level of consciousness. Further research is warranted on the impact of BINAM use on care of patients with severe TBI. John Whyte and Ingrid Poulsen share first authorship. Acknowledgments: Funding for this study was provided by the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR; Grant # 90DP0037-02, T. Hart, PI). Author Contributions: John Whyte contributed to the literature search, study design, data management, data analysis, data interpretation, and writing. Ingrid Poulsen contributed to the literature search, study design, data management, data interpretation, and writing. Rikke Guldager contributed to the literature search, study design, data collection, data interpretation, and writing. Marianne Eskildsen contributed to the data collection, data interpretation, and writing. Pengsheng Ni contributed to data analysis, data interpretation, and writing. The authors declare no conflict of interest. Reprints: John Whyte, MD, PhD, Moss Rehabilitation Research Institute, 50 Township Line Rd., Elkins Park PA 19027 (e-mail: jwhyte@einstein.edu). Received April 25, 2019 Received in revised form September 16, 2019 Accepted December 9, 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 © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Association between Inflammatory Biomarkers and Non-specific Low Back Pain: A Systematic Review Objective: Chronic inflammation increases the production of cytokines and activates pro-inflammatory pathways which may lead to non-specific low back pain (LBP). We systematically reviewed the literature to investigate whether inflammatory biomarkers are associated with non-specific LBP. Methods: CINAHL, Medline and EMBASE were searched between January 1946 and May 2018. MeSH terms and key words were used to identify studies examining the association between inflammatory biomarkers and LBP. Two reviewers performed the risk of bias assessment and three reviewers extracted data independently. Qualitative evidence synthesis was performed. Results: Thirteen studies, ranging from fair to low quality, were included. Five studies examined the association between C-reactive protein (CRP)/high-sensitivity CRP and LBP; six studies assessed tumour necrosis factors (TNFs); eight studies assessed interleukins (IL) and two studies assessed fibrinogen. There was evidence for an association of elevated levels of CRP, TNFs, and IL-6 with LBP. There was conflicting evidence for an association between IL-1β, fibrinogen and LBP. Discussion: Our findings support the notion of a positive association between inflammatory biomarkers and non-specific LBP, specifically for CRP, TNFs and IL-6. Although further high quality longitudinal studies are needed to confirm these findings and evaluate the magnitude of these associations, our findings suggest a role of inflammation in the pathogenesis of non-specific LBP. Y Z Lim and Y Wang equally contributed to this study. Funding: The work was not funded by any funding agency. YZL received National Health and Medical Research Council (NHMRC) Clinical Postgraduate Scholarship [#1133903]; Royal Australasian College of Physicians Woolcock Scholarship; Australian Rheumatology Association Top-Up Scholarship; Monash University Postgraduate Excellence Award. YW is the recipient of NHMRC Translating Research into Practice Fellowship (#1168185). LC received Australian Postgraduate Award and Arthritis Foundation Scholarship. SMH is the recipient of NHMRC Early Career Fellowship (#1142198). Funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflict of interest: No conflict of interest has been declared by the authors. Reprints: Sultana Monira Hussain, PhD, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, 553 St Kilda Road, Melbourne, VIC 3004, Australia (e-mail: monira.hussain@monash.edu). Received August 18, 2019 Received in revised form December 6, 2019 Accepted January 7, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Efficacy and Safety of Tapentadol Immediate Release for Acute Pain: A Systematic Review and Meta-analysis Objective: Tapentadol immediate release (IR) is a newer opioid option for acute pain. The aim of this systematic review is to examine the efficacy and safety of tapentadol IR compared to other opioids for acute pain. Methods: A systematic literature search as conducted using the Cochrane Library, Embase, International Pharmaceutical Abstracts, Medline, PubMed and Web of Science. The search included all randomized controlled trials (RCTs) and observational studies examining tapentadol IR versus other orally administered IR opioids for acute pain. The protocol for this study was registered on PROSPERO (CRD42018110267). Results: Thirteen studies and one abstract were included in the systematic review (n=12,814 patients). Of these, five studies and one abstract were included in the qualitative review (n=9108 patients). Eight RCTs (n=3,706 patients) comparing 50-100▒mg tapentadol IR versus 5-15▒mg oxycodone IR were included in the meta-analysis. The lowest dose of tapentadol IR (i.e. 50▒mg) was associated with less pain control compared to oxycodone IR (standardized mean difference 0.25, 95% CI 0.06 to 0.44, P<0.01). However, there were no significant differences at higher doses (i.e. 75▒mg, 100▒mg or when a titration strategy was used). In the qualitative analysis, pain control with tapentadol IR was also similar to morphine IR and tramadol IR. Tapentadol IR was less likely to have gastrointestinal adverse effects such as nausea and constipation compared to other opioids. Discussion: Tapentadol IR is as effective as other opioids at higher doses for acute pain and is associated with fewer gastrointestinal adverse effects. Based on these findings, tapentadol IR can be considered as a first line opioid for acute pain. Conflicts of interest and source of funding: None declared. Reprints: Asad E. Patanwala, PharmD, MPH, Pharmacy and Bank Building (A15), Camperdown Campus, University of Sydney, Sydney, New South Wales 2006, Australia (e-mail: asad.patanwala@sydney.edu.au). Received July 21, 2019 Received in revised form September 27, 2019 Accepted December 3, 2019 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Clinical Scenarios for which Cervical Mobilization and Manipulation Are Considered by an Expert Panel to be Appropriate (and Inappropriate) for Patients with Chronic Neck Pain Objectives: Cervical mobilization and manipulation are two therapies commonly used for chronic neck pain (CNP). However, the safety, especially of cervical manipulation, is controversial. This study identifies the clinical scenarios for which an expert panel rated cervical mobilization and manipulation as appropriate and inappropriate. Methods: An expert panel, following a well-validated modified-Delphi approach, used an evidence synthesis and clinical acumen to develop and then rate the appropriateness of cervical mobilization and manipulation for each of an exhaustive list of clinical scenarios for CNP. Key patient characteristics were identified using decision tree analysis (DTA). Results: Three hundred seventy-two clinical scenarios were defined and rated by an 11-member expert panel as to the appropriateness of cervical mobilization and manipulation. Across clinical scenarios more were rated inappropriate than appropriate for both therapies, and more scenarios were rated inappropriate for manipulation than mobilization. However, the number of patients presenting with each scenario is not yet known. Nevertheless, DTA indicates that all clinical scenarios that included red flags (e.g., fever, cancer, inflammatory arthritides or vasculitides), and some others involving major neurologic findings, especially if previous manual therapy was unfavorable, were rated as inappropriate for both cervical mobilization and manipulation. DTA also identified the absence of cervical disc herniation, stenosis, or foraminal osteophytosis on additional testing as the most important patient characteristic in predicting ratings of appropriate. Conclusions: Clinical guidelines for CNP should include information on the clinical scenarios for which cervical mobilization and manipulation were found inappropriate, including those with red flags, and others involving major neurologic findings if previous manual therapy was unfavorable. Funding: The work has been funded by a cooperative agreement (U19) from the National Center for Complementary and Integrative Health (NCCIH). Grant No. 1U19AT007912-01. The authors declare no conflict of interest. Reprints: Patricia M. Herman, ND, PhD, RAND Corporation, 1776 Main Street, PO Box 2138, Santa Monica, CA 90403 (e-mail: pherman@rand.org). Received April 1, 2019 Received in revised form December 4, 2019 Accepted December 27, 2019 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Factors Associated with Minimum Effective Volume of Lidocaine 1.5% for Sciatic Nerve Blocks Objectives: The objectives of this study were to investigate the correlations between the minimum effective volume (MEV) of lidocaine 1.5% for an ultrasound-guided popliteal sciatic nerve block (PSNB) and individual factors including the cross-sectional nerve area, sex, age, body mass index (BMI) and the depth of the sciatic nerve and to evaluate the safety of combined femoral and sciatic nerve blocks by monitoring the plasma concentration of local anesthetics (LAs). Methods: Forty patients received combined single-shot femoral and continuous sciatic nerve blocks. The femoral nerve block was performed with an in-plane technique and 15▒mL of lidocaine 1.5%. A continuous peripheral nerve block annular tube was positioned between the tibial and peroneal nerves inside the paraneural sheath. Thirty minutes after the femoral nerve block, a loading dose of 5▒mL of lidocaine 1.5% was given to block the sciatic nerve after obtaining the maximum compound muscle action potential (CMAP) amplitude using nerve conduction studies (NCSs). Additional lidocaine 1.5% was pumped at a rate of 30▒mL/h through the indwelling annular tube if after 8 minutes, the CMAP amplitude was still present. The CMAP amplitude monitored by the NCSs and pinprick tests were recorded every 2 minutes after the administration of lidocaine 1.5%. When the CMAP amplitude decreased to nearly 0▒mV, this MEV was recorded. The influences of the cross-sectional area of the sciatic nerve, sex, age, BMI and the depth of the sciatic nerve on the MEV were analyzed using stepwise multiple linear regression. Blood samples were collected from ten patients to evaluate the safety of combined femoral and sciatic nerve blocks by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Blood was drawn at 0 minutes before femoral nerve injection, 0 minutes before sciatic nerve injection, 8 minutes after sciatic nerve injection and 0, 10, 20, 30, 45, 60, 75, 90, and 120 minutes after the pumping of lidocaine 1.5% stopped. Results: A significant correlation was found between the MEV of lidocaine 1.5% and the cross-sectional area of the sciatic nerve (r=0.459), with a regression equation of the MEV (mL)=5.969 + 0.095× (the cross-sectional area of the sciatic nerve). The coefficient of determination was 0.211 (P<0.05). The MEV of lidocaine 1.5% for complete sciatic nerve blocks ranged from 7 to 15▒mL. The maximum concentrations of lidocaine, monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were 1672.9 (227.6), 265.7 (32.7) and 42.2 (22.4) ng/mL, respectively. Conclusions: There is a positive correlation between the cross-sectional area of the sciatic nerve and the MEV. The regression equation can help to predict the MEV of lidocaine 1.5% for PSNBs. The maximum concentrations of lidocaine and its metabolites did not approach toxic threshold limits in this study. Funding: Science Plan Program of Science and Technology Commission of Shanghai (18441905700). Application Research Project on Key Technologies of the People’s Livelihood and Technology of Suzhou (ss201637). Funding: Science Plan Program of Science and Technology Commission of Shanghai (18441905700) and Application Research Project on Key Technologies of People’s Livelihood and Technology of Suzhou (ss201637). Conflicts of Interest: The authors have declared no conflicts of interest. Conflicts of Interest: The authors declare no conflicts of interest. Reprints: Bin Yu, PhD, Department of Anesthesiology, Tongji Hospital affiliated with Tongji University, School of Medicine, Tongji University Shanghai, China. No.389, Xincun Road, Putuo District, Shanghai, P.R. China, 200065 (e-mail: yubin@tongji.edu.cn). Received March 20, 2019 Received in revised form December 9, 2019 Accepted December 31, 2019 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Investigating the Effect of Perioperative Chlorzoxazone On Acute Postoperative Pain After Total Hip and Knee Replacement Surgery Background and Aims: Severe pre- and acute postoperative pain have been associated with development of chronic postoperative pain. Chlorzoxazone (a muscle relaxant) has been suggested to enhance acute postoperative pain recovery but the lack of larger randomized controlled trials have however questioned the continued use. Despite this, chlorzoxazone is still used for acute postoperative pain management following total knee or hip replacement (TKR or THR). The currentrandomized, double blinded, placebo-controlled, parallel group, clinical trial aimed to assess the effect of chlorzoxazone for postoperative pain management following TKR or THR. Methods: 393 patients scheduled for TKR or THR were included in the trial. Patients were assigned to 250▒mg chlorzoxazone three times daily for the first seven days postoperative or placebo. The primary outcome was pain after 5 meter walk assessed 24-hours postoperative. Secondary outcomes included, changes in preoperative pain at rest, worst pain in the last 24 hours, and Oxford Knee or Hip Score compared with 12 months follow-up. In addition, adverse events were assessed in the perioperative period. Results: No significant differences were found for any of the outcome parameters after TKR or THR. For neither TKR or THR no effects were demonstrated for pain after 5 meters walk 24-hours after surgery (P>0.313), or for any of the secondary outcomes (P>0.288) or adverse event (P>0.112) in the group receiving chlorzoxazone compared with placebo. Conclusions: The current study demonstrated no analgesic effects of postoperative chlorzoxazone administration compared with placebo on acute or chronic postoperative pain 12 months following TKR and THR. Original paper for: Clinical Journal of Pain Article Type: Original Research Conflicts of Interest and Source of Funding: The authors declare no conflict of interest. Reprints: Peter Skrejborg, MSc, PhD-fellow, SMI, Department of Health Science and Technology, School of Medicine, Aalborg University, Fredrik Bajers Vej 7 D3, DK-9220 Aalborg, Denmark (e-mail: PESK@HST.AAU.DK). Received July 10, 2019 Received in revised form January 3, 2020 Accepted January 8, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Efficacy of Nalbuphine as an Adjuvant to Ropivacaine in Ultrasound Guided Supraclavicular Brachial Block – A Prospective Randomized Controlled Study Background: A brachial plexus block provides anesthesia and analgesia with limited duration. Various opioids have been used as adjuvants of local anesthetics to improve the effects. Objective: To evaluate the safety and effectiveness of nalbuphine used as an adjuvant to local anesthetic during the supraclavicular brachial plexus block. Methods: In this prospective, double-blinded, randomized controlled study, ninety ASA Physical Status I and II patients (aged 20 to 65▒y) of either gender undergoing upper limb orthopedic surgeries under ultrasound guided supraclavicular brachial plexus block were randomly allocated into three groups: Group C (n=30), Group NL (n=30) and Group NH (n=30) for analyses. Each patient received 18▒mL of 100▒mg ropivacaine solution combined with 2▒mL normal saline, 2▒mL of 10▒mg nalbuphine, or 2▒mL of 20▒mg nalbuphine. The time of onset and block duration of sensory and motor blocks, duration of analgesia, hemodynamic variables, and any adverse effects were assessed. Results: Compared with Group C, onset time of both sensory and motor blocks were significantly shortened. The sensory block and motor block duration were significantly prolonged in group NL and group NH. There was no significant difference between the duration of analgesia in group NL and NH although the analgesia duration of both of groups was longer than group C. But incidence of side effects in group NH such as vomiting was significantly higher than group NL. Conclusion: Nalbuphine is an effective adjuvant to 0.5% ropivacaine in US-guided supraclavicular brachial plexus block. The dosage of 10▒mg improves quality of the anesthesia with less incidence of side effects. Trial registration: chictr.org.cn identifier: NO.ChiCTR1800016112. Prakash Kalika, Ran Ran, and Rui Xue contributed equally to this work. The authors declare no conflict of interest. Reprints: Ran Ran, PhD, Department of Anesthesiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China (e-mail: ranran1146@163.com). Received June 14, 2019 Received in revised form December 19, 2019 Accepted December 31, 2019 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

A Systematic Review of Clinical Practice Guidelines for Acute Procedural Pain on Neonates Objectives: During hospitalization in neonatal intensive care units (NICU), neonates are exposed to many painful procedures within a stressful environment. To date, many evidence-based guidelines are available. However, the quality of these guidelines and their clinical application remain unclear. This systematic review aims at determining the quality of existing guidelines on the management of procedural pain in neonates and to summarize the recommendations provided by these guidelines. Methods: A structured search was conducted in Embase, PubMed, CINAHL, JBI database and in grey literature resources in November 2018 to identify relevant guidelines published from 2007 onwards. Published guidelines and guidelines from complementary searches were included treating assessment or management of procedural pain in neonates. The methodological quality was analyzed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument. Results: A total of 1154 records were identified. After screening for eligibility, 17 guidelines were included in this review. Among these, 11 were identified to be high quality guidelines. Besides the usual recommendations for pharmacological and non-pharmacological treatments, inclusion of parents, improving interprofessional collaboration and considering the setting were identified as important elements. Discussion: The results of this review show that there is a need to improve the methodological quality of guidelines for procedural pain in newborns. The set of recommendations for procedural pain prevention needs to involve not only pharmacological and non-pharmacological pain treatment but also parents and interprofessional collaboration. It is also essential to take into account facilitators, barriers and context to improve pain management. Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. Funding Source: No funding was secured for this study. Conflict of Interest: The authors have no potential conflicts of interest to disclose. Reprints: Colette Balice-Bourgois, RN, MSc, PhD candidate, Ente Ospedaliero Cantonale, Nursing Research Center, Viale Officina 3, 6500 Bellinzona, Switzerland (e-mail: colette.balice@eoc.ch). Received September 3, 2019 Received in revised form December 10, 2019 Accepted January 6, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The Relationship between Clinical and Quantitative Measures of Pain Sensitization in Knee Osteoarthritis Objectives: Pain sensitization in knee osteoarthritis is associated with greater symptom severity and poorer clinical outcomes. Measures which identify pain sensitization and are accessible to use in clinical practice have been suggested to enable more targeted treatments. This merits further investigation. This study examines the relationship between Quantitative Sensory Testing (QST) and clinical measures of pain sensitization in people with knee osteoarthritis. Methods: A secondary analysis of data from 134 participants with knee osteoarthritis was performed. Clinical measures included: manual tender point count (MTPC), the Central Sensitization Inventory (CSI) to capture centrally mediated co-morbidities, number of painful sites on a body chart, and neuropathic pain-like symptoms assessed using the modified PainDetect Questionnaire (mPD-Q). Relationships between clinical measures and QST measures of pressure pain thresholds (PPTs), temporal summation (TS) and conditioned pain modulation (CPM) were investigated using correlation and multivariable regression analyses. Results: Fair to moderate correlations, ranging from −0.331 to −0.577 (P<0.05), were identified between MTPC, the CSI, number of painful sites, and PPTs. Fair correlations, ranging from 0.28 to 0.30 (P<0.01), were identified between MTPC, the CSI, number of painful sites, and CPM. Correlations between the clinical and self-reported measures and TS were weak and inconsistent (0.09 to 0.25.). In adjusted regression models, MTPC was the only clinical measure consistently associated with QST and accounted for 11-12% of variance in PPTs. Discussion: MTPC demonstrated the strongest associations with QST measures and may be the most promising proxy measure to detect pain sensitization clinically. Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. The Health Research Board of Ireland supported the primary research in this study. H. O’Leary received a Research Fellowship for Healthcare Professionals to perform the research in the primary study. Grant number: HPF/2013/449. Reprints: Amanda M. Clifford, PhD, School of Allied Health, Faculty of Education and Health Sciences, Health Sciences Building, University of Limerick, Limerick, V94 T9PX, Ireland (e-mail: Amanda.Clifford@ul.ie). Received May 20, 2019 Received in revised form December 13, 2019 Accepted January 7, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The Interplay of Parent and Child Coping Responses in Understanding Child Functioning in the Context of Living with a Parent with or Without Chronic Pain Objectives: Pain problems tend to run in families and children of individuals with chronic pain (ICPs) have been found to report lower functioning. Drawing upon a social learning perspective, the current study examined how diverse maternal pain coping responses (i.e., pain catastrophizing and distraction) may, via corresponding child pain coping responses, act as a vulnerability or protective factor for child functioning in the context of parental chronic pain (CP). Methods: A cross-sectional study was conducted in mothers with CP and their pain-free child (N=100) and mothers without CP and their pain-free child (N=74). Moderated mediation analyses were performed to test whether associations between maternal coping responses and child functioning (i.e., somatic symptoms, physical functioning and psychosocial health) were mediated by corresponding child coping responses and whether these associations were moderated by the presence or absence of maternal CP. Results: Maternal pain catastrophizing was indirectly related to more somatic symptoms, lower physical functioning and lower psychosocial health in their child via child pain catastrophizing. Relationships were moderated by the presence or absence of maternal CP, such that mediated relationships were only found in mothers without CP and their child. No (in)direct relationships between maternal distraction, child distraction and child functioning were observed. Discussion: The current findings demonstrated that child functioning was associated with maternal and child pain catastrophizing, but only in children of mothers without CP. No evidence was found in support of maternal pain coping responses as vulnerability or protective factors in the context of parental CP. Disclosures: This work was supported by Research Foundation–Flanders (FWO Vlaanderen, Grant number 11ZY917N). The authors declare no conflict of interest. Reprints: Elke Van Lierde, Department of Experimental-Clinical and Health Psychology, Ghent University, Henri Dunantlaan 2, B-9000 Gent, Belgium (e-mail: elke.vanlierde@ugent.be). Received April 19, 2019 Received in revised form December 29, 2019 Accepted January 6, 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.