December 2017
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 18, No. 12, December 2017 Issue)

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Racial and Socioeconomic Disparities in Disabling Chronic Pain: Findings from a Health and Retirement Study

Mary R. Janevic, Sara J. McLaughlin, Alicia A. Heapy, Case Thacker, John D. Piette; Center for Managing Chronic Disease, University of Michigan School of Public Health, Ann Arbor, MI; Department of Health Behavior and Health Education, University of Michigan School of Public Health, Ann Arbor, MI; Department of Sociology and Gerontology and Scripps Gerontology Center, Miami University, Oxford, OH; VA Connecticut Healthcare System Pain Research, Informatics, Multimorbidities, and Education (PRIME) Health Services Research and Development Center of Innovation, Yale University School of Medicine, New Haven, CT

High-impact chronic pain affects 8 percent of the U.S. population 50 years and older, and is much more common in African Americans and lower socioeconomic strata, according to research reported in The Journal of Pain.

High-impact pain is defined not by intensity but according to protracted duration and substantial negative impact on daily life.

Researchers from the University of Michigan School of Public Health sought to gauge the population prevalence of high-impact chronic pain and assess whether its prevalence in a community setting of Americans older than age 50 varies across race, ethnicity and socioeconomic status. Data for the study came from 1,925 randomly selected individuals within a subset of respondents in the nationally representative Health and Retirement Study. The subjects were screened for the presence of pain by asking if during the past year they had experienced pain lasting a week or longer. They next answered a series of questions about pain duration, intensity and quality-of-life impact.

Results showed that high-impact pain affects 8% of the U.S. population over 50, and the analysis also revealed striking wealth disparities. The percentage of older adults living with high-impact pain is greatest in lower income groups. Education, race, ethnicity and age were not significant prevalence variables. Among older adults with any chronic pain, African-Americans and persons in the lowest wealth quartile reported the most pain-related disability.

The authors concluded their findings indicate that efforts to reduce the burden of disabling pain should prioritize socioeconomically vulnerable groups with little or no access to multimodal pain treatment to help improve function.


Highlights from PAIN (Volume 158, No. 12, December 2017 Issue)

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High Levels of Cerebrospinal Fluid Chemokines Point to the Presence of Neuroinflammation in Peripheral Neuropathic Pain: A Cross-Sectional Study of 2 Cohorts of Patients Compared with Healthy Controls

Emmanuel Bäckryd, Anne-Li Lind, Måns Thulin, Anders Larsson, Björn Gerdle, Torsten Gordh; Pain and Rehabilitation Centre and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Department of Surgical Sciences, Anesthesiology, and Intensive Care and Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden; Departments of Statistics and Medical Sciences, Uppsala University, Uppsala

Neuropathic pain (NeuP) is defined as pain caused by a lesion or disease of the somatosensory nervous system. The prevalence of chronic pain with neuropathic characteristics in the general population is estimated to be as high as 7%. Cytokines and chemokines are thought to be important mediators in the pathophysiology of NeuP, at least in preclinical models. The aim of this study was to use a multiplex panel allowing the measuring of 92 inflammation-related proteins in a single run and apply it to the cerebrospinal fluid (CSF) of patients with peripheral NeuP and healthy control subjects. The hypothesis was that investigators would be able to determine a CSF inflammatory profile of patients with NeuP and that they could mirror a postulated ongoing process of central neuroinflammation.

Investigators compared patients with NeuP (called cohort 1a) and healthy control subjects (cohort 1b) recruited at the same center in Linköping, Sweden. To test result reproducibility, another patient cohort (called cohort 2) with a similar pain condition but belonging to another center in Uppsala, Sweden, was compared with cohort 1b. For every subject in this study, intrathecal access was obtained by lumbar puncture, and a 10-mL sample of CSF was taken.

Using a panel of inflammation-related proteins, investigators determined an extensive ongoing CSF inflammatory profile of patients with severe peripheral NeuP who were candidates for (cohort 1a) or had an ongoing (cohort 2) treatment with spinal cord stimulation when compared with healthy control subjects (cohort 1b). The results from 2 cohorts of fairly comparable patients were similar (although not perfectly identical), showing that mainly a number of chemokines were upregulated in CSF from patients when compared with healthy control subjects. Investigators may have mirrored central neuroinflammation in this very debilitating chronic pain condition. However, further studies are needed to confirm these findings, and the question of causality remains difficult to answer. Because it has been suggested that prevalent comorbidities to chronic pain also are associated with neuroinflammation, it will be important to determine unique and common mediators.

Sensory Phenotype and Risk Factors for Painful Diabetic Neuropathy: A Cross-Sectional Observational Study

Jana Raputova, Iva Srotova, Eva Vlckova, Claudia Sommer, Nurcan Uceyler, Frank Birklein, Heike L. Rittner, Cora Rebhorn, Blanka Adamova, Ivana Kovalova, Eva Kralickova Nekvapilova, Lucas Forer, Jana Belobradkova, Jindrich Olsovsky, Pavel Weber, Ladislav Dusek, Jiri Jarkovsky, Josef Bednarik; Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Neurology, University Hospital Brno, Brno, Czech Republic; Department of Neurology, University of Würzburg, Würzburg, Germany; Department of Neurology, University Medical Center, Mainz, Germany; Department of Anesthesiology, Centre for Interdisciplinary Pain Medicine, University Hospital Würzburg, Würzburg; Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Diabetologic Centre, Department of Internal Medicine and Gastroenterology, University Hospital Brno; Diabetologic Centre, St. Anne University Hospital, Brno, Czech Republic; Department of Internal Medicine, Geriatrics, and Practical Medicine, University Hospital Brno; Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic

In this study, investigators sought to answer the question of why some people with distal symmetrical sensory-motor polyneuropathy (DSPN) report no pain while others with the condition report severe pain. They designed a study to characterize sensory phenotypes together with clinical and neurophysiological parameters possibly affecting the development of NeuP in a large and well-defined cohort of patients with DSPN. Several types of painful neuropathies exist for patients with diabetes, but painful diabetic DSPN (pDSPN) as a variant of a typical symmetrical length–dependent DSPN is the most common. The study’s objectives were to identify the pattern of symptoms and signs of large- and small-fiber dysfunction that distinguish pDSPN and painless DSPN.

Findings revealed detailed phenotyping using structured neurological examinations and quantitative sensory testing (QST) in a large, independent, and well-defined cohort of patients with DSPN. Key findings are that the presence and severity of NeuP were associated with more advanced diabetic neuropathy leading to higher disability and more frequent and advanced dysfunction of sensory fibers. No correlation was found between NeuP and factors related to diabetes and its control with the exception of laboratory signs of nephropathy. This study confirms key findings of a recent large-scale cohort study of DSPN subjects and adds additional information.

The deafferentation (DA) QST profile was predominant in study patients with pDSPN, and the frequency and severity of thermal loss correlated not only with the presence and severity of NeuP but also to severity of neuropathy and disability. Gain-of-function sensory abnormalities in general were rare in pDSPN in both the Pain in Neuropathy Study (PiNS) and this study.

The irritable nociceptor (IN) pattern, recently described as a “thermal hyperalgesia” sensory cluster, was only present in a minority of study patients with painful DSPN (13.6%). Patients with the IN profile had lower neuropathy disability scores, shorter duration of pain, a higher level of pain catastrophizing, and different characteristics of pain associated with lower Graded Chronic Pain Scale and Neuropathic Pain Symptom Inventory scores in comparison with most patients with pDSPN with the DA profile. Further research is needed to confirm whether the IN profile might represent a promising target for stratification of patients for analgesic treatment and future drug trials. Correlations between NeuP and hyposensitivity to small-fiber–mediated thermal perception in both this study and the PiNS study and the absence of any correlation between NeuP and NCS stresses the importance of small-fiber loss or dysfunction for the generation of pDSPN.

NeuP presence and severity are related to neuropathy severity, predominant thermal sensory loss, female sex, and nephropathy. It is also associated with levels of anxiety, depressive symptoms, and pain catastrophizing. Few people with pDSPN display gain QST abnormalities. Different sensory profiles might represent distinctive pathophysiological mechanisms of NeuP in diabetes and new target populations for future pain trials.

The Clinical Journal of Pain

Highlights from The Clinical Journal of Pain (Volume 33, No. 12, December 2017 Issue)


The Fear-Avoidance Components Scale (FACS): Responsiveness to Functional Restoration Treatment in a Chronic Musculoskeletal Pain Disorder (CMPD) Population

Randy Neblett, Tom G. Mayer, Mark J. Williams, Sali Asih, Antonio I. Cuesta-Vargas, Meredith M. Hartzell, and Robert J. Gatchel; PRIDE Research Foundation; Department of Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas; Department of Psychology, College of Science, The University of Texas at Arlington, Arlington; Department of Clinical Psychology, Faculty of Psychology, Universitas Indonesia, Depok, Jawa Barat, Indonesia; and Department of Physiotherapy of the Faculty of Health Science at the University of Malaga, Spain

Fear-avoidance (FA) is a nonadaptive style for coping with pain that involves avoidance of physical and social activities of daily living because of fear of increased pain and/or injury/reinjury. This FA pattern can result in a negative cycle of maladaptive cognitions, hypervigilance (overmonitoring of physical symptoms), overprotection of painful or injured body parts, and pain-related anxiety. FA also is prevalent in disorders related to central sensitization including chronic fatigue syndrome and fibromyalgia.

The Fear-Avoidance Components Scale (FACS) is a patient-reported measure of FA designed for patients with painful medical conditions. The purposes of this study were to assess admission-to-discharge responsiveness of FACS scores to a functional restoration program (FRP); the associations among FACS scores and other FA-related psychosocial patient-reported outcome (PRO) measures and objective lifting performance at admission and discharge; and the likelihood that discharge chronic musculoskeletal pain disorder (FACS) scores can help to predict work outcomes 1 year after completing the FRP in a cohort of patients with chronic musculoskeletal pain disorder (CMPD). All patients entered the program with severe functional limitations and either partial or total work disability. Most patients (83%) were not working at admission, and the rest were working in a limited capacity.

At FRP admission, 68% of patients scored in the severe/extreme FACS severity ranges, and only 11% scored in the subclinical/mild ranges. Patients in the severe and extreme FACS severity groups at admission were more likely to drop out of treatment than those in the lower severity groups. FACS scores improved significantly by the end of treatment, resulting in an increase in the number of patients in the subclinical, mild, and moderate FACS severity groups and a decrease in the number of patients in the severe and extreme groups. At discharge, only 23% were in the severe/extreme ranges, and 44% were in the subclinical/mild ranges.

FACS scores were highly associated with all of the same patient-reported variables (pain intensity, depressive symptoms, insomnia, perceived injustice, and perceived disability) at both admission and discharge. The association between the Tampa Scale for Kinesiophobia-13 (TSK-13) and the FACS demonstrated high construct validity of the FACS.

Use of the FACS may provide clinically relevant information that can allow health care providers to better identify and address FA-related barriers to recovery and to measure treatment responsiveness to FA-related symptoms.

Altered Functional Connectivity in Sickle Cell Disease Exists at Rest and During Acute Pain Challenge

William T. Zempsky, Michael C. Stevens, James P. Santanelli, Alexandra M. Gaynor, and Sabin Khadka; The Division of Pain and Palliative Medicine, Connecticut Children’s Medical Center; Olin Neuropsychiatry Research Center, Institute of Living, Washington Street, Hartford; Department of Pediatrics, University of Connecticut School of Medicine, Farmington Avenue, Farmington; and Department of Psychiatry, Yale University School of Medicine, New Haven, CT

During childhood and early adolescence, pain in sickle cell disease (SCD) is a consequence of discreet episodes of vascular occlusion within the microcirculation. Such “vasoocclusion” is a complex process during which abnormally shaped (so-called “sickled”) red blood cells obstruct the microcirculation, thereby causing distal ischemia and resultant pain. In SCD, there seems to be a transition from intermittently recurrent pain to chronic pain as patients age.

Alterations in functional connectivity for various clinical groups with chronic pain have been demonstrated in these well-described neural circuits. Three networks consistently linked to chronic pain are the somatosensory network (SMN), the salience network (SLN), and the default mode network (DMN). In this study, investigators sought to further evaluate if SCD is characterized by the same types of functional connectivity abnormalities seen in other chronic pain disorders and to identify which specific brain regions are involved. The primary aim was to compare a group of adolescents and young adults with SCD and non-SCD controls to localize functional connectivity abnormalities in SCD patients. The hypothesis was that the SCD group would have altered functional connectivity in SMN, SLN, and DMN networks compared with controls in regions implicated in pain sensitization in other chronic pain disorders. Another goal was to compare intrinsic connectivity profiles to connectivity during acute pain processing.

The 24 African-American participants (12 with SCD and 12 non-SCD controls) were between ages 15 and 30. Investigators found clear abnormalities in functional connectivity between those with and without SCD in the SMN, SLN, and DMN during both the resting state and the acute pain task. Within these regions of interest, there was evidence for both increased and decreased connectivity, which is consistent with findings in other chronic pain states. Weaker connectivity in chronic pain conditions reflects less coordinated activation. Also, some important functional connectivity abnormalities were more pronounced during resting states than during active pain processing. This suggests that connectivity among SCD patients’ pain-processing brain regions is more abnormal in an unstructured context instead of when patient are experiencing acute pain. This has interesting implications for models of pain sensitization, as it implies that pain sensitization reflects more neural abnormality than simple nocioception.

These results support a tentative model that SCD pain sensitization involves abnormally low functional integration of brain regions that make use of nociceptive information to plan movements and hyperconnectivity of various frontal and parietal lobe regions that direct attention to or represent higher-order abstractions within circuits involved with either nocioceptive processing or detection of abnormally salient environmental stimuli. These findings suggest that chronic pain sensitization might be related to developmentally delayed subcortical functional connectivity.

Future studies should enroll patients both at baseline and during acute pain episodes and investigate a more in-depth clinical phenotype and medical history to elucidate the impact of clinical factors such as hemoglobin genotype, age at pain onset, frequency of pain episodes, and type of chronic pain on central sensitization. A comparison group in future studies must be chosen to tease out chronicity versus maturational/developmental differences.