August 2017
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 18, No. 8, August 2017 Issue)

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Pain Severity Leading Predictor of Prolonged Opioid Use After Surgery

Brittany N. Rosenbloom, Colin J.L. McCartney, Sonya Canzian, Hans J. Kreder, Joel Katz; Institute of Medical Science, Department of Anesthesia, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Psychology, Faculty of Health, York University, Toronto, Ontario, Canada; Trauma and Neurosurgery Program, St. Michael's Hospital, Toronto, Ontario, Canada; Division of Orthopedics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Canadian researchers writing in The Journal of Pain reported that the strongest predictive factors for prolonged opioid use after a traumatic musculoskeletal injury and surgery are pain severity and a poor sense of control over pain.

Previous studies have shown that people who sustain traumatic injuries are at higher risk than the general population for using and abusing opioids. Many studies have identified risk factors for persistent opioid use, such as a history of drug or alcohol abuse and taking medications for depression and anxiety. However, the extent that acute post-surgical pain and chronic pain influence persistent opioid use is not clear.

Using secondary data analysis, the researchers hypothesized that pain severity measured in the hospital within two weeks of injury would predict use of prescription opioids four months after discharge. They also explored whether psychological distress would predict opioid use as much or more than pain severity.

Results showed that 35 percent of patients in the study reported using a prescription opioid for pain relief four months following a traumatic musculoskeletal injury requiring surgery. These patients had significantly greater pain severity and pain interference scores than patients who were not using opioids. This supports the hypothesis that initial in-hospital pain severity would predict use of prescription opioids four months after surgery. The data strongly suggest that pain severity and poor sense of pain control, not psychological distress, are the main factors associated with prolonged opioid use following musculoskeletal trauma and surgery.

Study Shows Optical Nerve Stimulation Could Treat Migraine

Yinglu Liu, Zhao Dong, Rongfei Wang, Ran Ao, Xun Han, Wenjing Tang, Shengyuan Yu; Department of Neurology, Chinese PLA General Hospital, Beijing, China

Chinese researchers writing in The Journal of Pain reported findings of a randomized, controlled trial showing that transcutaneous occipital nerve stimulation (tONS) can reduce headache intensity in migraine patients and could be considered a promising treatment for patients who prefer non-pharmacological therapy.

The aim of the study was to evaluate the efficacy and tolerability of iONS in migraine patients, and explore whether different iONS frequencies influenced treatment effectiveness. Patients were randomized in five therapeutic groups for one month of treatment. Three received iONS at different frequencies, one group had a sham intervention, and the fifth was given an oral medication, topiramate. One hundred ten patients completed the study.

Results showed the primary outcome was a 50 percent response rate for the three iONS groups and the topiramate group. From baseline to the one-month treatment period, the tONS 100 Hz frequency group and the topiramate group exhibited significant decreases in headache duration. The authors concluded that iONS therapy is a promising approach for migraine treatment and prevention.



Highlights from PAIN (Volume 158, No. 8, August 2017 Issue)

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Stratifying Patients With Peripheral Neuropathic Pain Based on Sensory Profiles: Algorithm and Sample Size Recommendations

Jan Vollert, Christoph Maier, Nadine Attal, David L. H. Bennett, Didier Bouhassira, Elena K. Enax-Krumova, Nanna B. Finnerup, Rainer Freynhagen, Janne Gierthmuhlen, Maija Haanpaa, Per Hansson, Philipp Hullemanno, Troels S. Jensen, Walter Magerl, Juan D. Ramirez, Andrew S. C. Riceo, Sigrid Schuh-Hofer, Marta Segerdahl, Jordi Serra, Pallai R. Shillo, Soeren Sindrup, Solomon Tesfaye, Andreas C. Themistocleous, Thomas R. Tolle, Rolf-Detlef Treede, Ralf Baron; Department of Pain Medicine, BG University Hospital Bergmannsheil GmbH, Ruhr-University Bochum, Bochum, Germany; Center of Biomedicine and Medical Technology Mannheim CBTM, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; INSERM U-987, Centre d’Evaluation et de Traitement de la Douleur, CHU Ambroise Pare, Boulogne-Billancourt, France; Universite´ Versailles-Saint-Quentin, Versailles, France; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom; Department of Neurology, BG University Hospital Bergmannsheil GmbH; Ruhr-University Bochum, Bochum, Germany; Department of Neurology, Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark; Department of Anaesthesiology, Critical Care Medicine, Pain Therapy and Palliative Care, Pain Center Lake Starnberg, Benedictus Hospital Tutzing, Tutzing, Germany; Anaesthesiological Clinic, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany; Division of Neurological Pain Research and Therapy, Department of Neurology, Universitatsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany; Departments of Helsinki University Central Hospital, Helsinki, Finland; Etera Mutual Pension Insurance Company, Helsinki, Finland; Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Pain Research, Department of Surgery and Cancer, Imperial College, London, United Kingdom; H. Lundbeck A/S, Copenhagen, Denmark; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; Neuroscience Technologies, Ltd, Barcelona, Spain; Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom; Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Neurology, Odense University Hospital, Odense, Denmark; Department of Neurology, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany

Although all neuropathic pain states result from a lesion or disease of the somatosensory nervous system, the pathogenesis and subsequent pathophysiological mechanisms in damaged, and surviving afferent nerve fibers such as conduction block, ectopic impulse generation, and peripheral and central sensitization may differ between patients. A comprehensive method with which to assess the sensory profile of a patient is quantitative sensory testing (QST) in accordance with the protocol of the German Research Network on Neuropathic Pain. This article provides an algorithm based on the results of the investigators’ previous work that can be used to estimate probabilities for patients to be allocated to each of three named phenotypes.

The investigators developed an algorithm that enables individual allocation of patients to 1 or more sensory phenotypes and can separate patients from healthy subjects with a very high specificity of 94% and a sensitivity of 78%. All phenotypes are present in diabetic polyneuropathy, peripheral nerve injury, and postherpetic neuralgia in reasonable frequencies, resulting in acceptable estimated sample sizes for phenotype-stratified trials, especially if crossover-designed studies are planned.

The European Medicines Agency’s (EMA) committee for medicinal products for human use recommends this phenotype stratification to determine eligible sensory phenotypes of patients in exploratory trials on neuropathic pain and also incorporated it into the new EMA guideline for clinical development of new treatments for pain. The investigators encourage validation of this concept by applying it in prospectively phenotype-stratified trials on peripheral neuropathic pain.

Genetic Predictors of Recovery in Low Back and Lumbar Radicular Pain

Siri Bjorland, Cecilie Røe, Aurora Moen, Elina Schista, Aqsa Mahmood, Johannes Gjerstad; Institute of Medicine, University of Oslo, Oslo, Norway, Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Ulleval, Oslo; Department of Psychology and Physiology, National Institute of Occupational Health, Oslo; Department of Molecular Bioscience, University of Oslo

Studies show that low back pain (LBP) has a lifetime prevalence of 70%. Lumbar radicular pain (LRP), also referred to as “sciatica,” accounts for only 5% to 10% of these LBP conditions. Although most back disorders are benign, many are associated with a slow recovery. LBP may have a muscular etiology. However, back disorders also can be related to degenerative changes in the intervertebral disks or in the spine. If such changes cause mechanical compression of the nerve roots, this may lead to LRP. In addition, biochemical mediators released after disk herniation may influence neuronal excitability and promote pain. For example, genetic variants in genes encoding proteins such as vitamin D receptor, collagens, and matrix metalloproteinases (MMPs) may affect degeneration of the intervertebral disks. The aim of this study was to test a panel of genetic variants, namely VDR rs731236, COL11 rs1676486,MMP1 rs1792750,MMP9 rs17576, IL-1a rs1800587, IL-1RN rs2234677, OPRM1 rs1799971, and the COMT rs6269/ rs4633/rs4818/rs4680 haplotype, to assess their role in pain recovery for outpatients with LRP and LBP.

Investigators did not check for psychosocial covariates, although psychosocial factors such as anxiety, depression, and somatization may contribute to chronic LBP and LRP. Therefore, indirect effects of MMP9 rs17576 and OPRM1 rs1799971 on pain could not be excluded. Still, together with individual factors such as sex, age, smoking status, obesity, and education level, genetic predisposition may be a prognostic factor for patients with LBP and LRP. Thus, development of persistent pain may be multifactorial. In contrast to earlier studies with shorter follow-up, these patients with LBP reported more pain than patients with LRP at 5-year follow-up. This emphasizes that the maintenance of persistent pain is probably a dynamic process.

These data demonstrate that the rare allele of MMP9 rs17576 is associated with poor pain recovery, whereas the rare allele of OPRM1 rs1799971 is associated with better pain recovery in patients with LBP and LRP. Although the causal relationship between these single nucleotide polymorphisms (SNPs) and pain remains to be investigated, these results support the hypothesis that genetic factors involved in tissue degeneration and pain perception may predict long-term recovery for patients. However, each SNP explains only about 2% to 5% of the variance, emphasizing the multifactorial nature of LBP and LRP.

The Clinical Journal of Pain

Highlights from The Clinical Journal of Pain (Volume 33, No. 8, August 2017 Issue)


Ethnicity, Cortisol, and Experimental Pain Responses Among Persons With Symptomatic Knee Osteoarthritis

Matthew S. Herbert, Burel R. Goodin, Hailey W. Bulls, Adriana Sotolongo, Megan E. Petrov, Jeffrey C. Edberg, Laurence A. Bradley, and Roger B. Fillingim; Center of Excellence for Stress and Mental Health; San Diego Healthcare System, University of California, San Diego; Department of Psychology, University of Alabama at Birmingham; Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham; College of Nursing and Health Innovation, Arizona State University, Phoenix; Department of Community Dentistry and Behavioral Science, University of Florida; and Pain Research and Intervention Center of Excellence, University of Florida, Gainesville

Research has consistently reported significant differences in pain experiences between African American (AA) and non-Hispanic white (NHW) people. Among healthy adults, AAs demonstrate more pain sensitivity in response to several experimental pain stimuli (through quantitative sensory testing) than NHWs. Among individuals with knee osteoarthritis (OA), AAs report more clinical and experimental pain severity and more physical and psychological disability than NHWs.

The aim of this study was to determine if the relationship between cortisol and pain responses during a coldpressor task (CPT) differs as a function of ethnicity among those with knee OA. Investigators hypothesized that (1) AA participants, relative to NHW participants, would produce greater pain intensity and unpleasantness ratings during the CPT and (2) cortisol concentrations obtained before the CPT would be negatively associated with pain intensity and unpleasantness ratings among NHW participants but not AA participants. A second aim was to assess the relationship between perceived racial discrimination and cortisol concentrations among AA participants. Investigators hypothesized that perceived racial discrimination would be negatively associated with cortisol concentrations and positively associated with pain intensity and unpleasantness ratings during the CPT.

Patients were recruited via posted fliers, radio and print media advertisements, orthopedic clinic recruitment, and word-of-mouth referral. Contrary to predictions, investigators did not find ethnic differences in pain intensity or unpleasantness ratings during the CPT, nor did they find ethnic differences in cortisol concentrations. However, cortisol concentrations obtained before the CPT were inversely associated with pain intensity ratings during the CPT for NHW participants, but not for AA participants. Contrary to predictions, perceived racial discrimination was not related to cortisol variables or pain ratings. In exploratory analyses, cortisol reactivity positively correlated with pain ratings during the CPT across ethnic group. There were no ethnic differences in cortisol reactivity, nor was perceived racial discrimination related to cortisol reactivity among AA participants.

This study reveals that older AAs with knee OA exhibit an absence of a relationship between cortisol concentrations and CPT pain responses. Mixed findings in the literature and findings in the present study do not necessarily suggest a lack of relationship between perceived racial discrimination and cortisol, but rather that the frequency of perceived discriminatory events may be less important than other aspects of racial discrimination, such as the degree that racism is internalized. Future research should be designed to capture different aspects of perceived racial discrimination in addition to the frequency of discriminatory events to better delineate the relationship between perceived racial discrimination and cortisol responses to pain.

Cold Pain Threshold Identifies a Subgroup of Individuals With Knee Osteoarthritis That Present With Multimodality Hyperalgesia and Elevated Pain Levels

Anthony Wright, Heather A. E. Benson, Rob Will, and Penny Moss; School of Physiotherapy and Exercise Science; School of Pharmacy, CHIRI Bioscience, Curtin University; and School of Medicine and Pharmacology, University of Western Australia, Perth

Some patients with knee osteoarthritis (OA) exhibit features of neuropathic pain, which may be associated with sensory deficits and widespread multimodality hyperalgesia. Although there is considerable evidence that local and widespread pressure hyperalgesia is a common feature in people with painful knee OA, the potential importance of heat and cold hyperalgesia has yet to be fully established. This study investigated the extent to which widespread cold, pressure, and heat hyperalgesia is experienced by participants with knee OA, compared with pain-free controls (PFC). The study also tested sensory detection thresholds to determine whether sensory deficits were present. Z-score analysis was used to identify a subcohort of knee OA participants who exhibited widespread cold hyperalgesia. This subcohort was compared with the remaining OA participants to determine differences in levels of pain, pain characteristics, and perceived function.

When compared to PFCs, a cohort of 80 individuals with knee OA exhibited signs of widespread cold hyperalgesia, pressure hyperalgesia at the index knee, and no evidence of heat hyperalgesia. When individuals with OA were divided into high and low cold pain threshold (CPT) groups according to normalized Z-scores, there was clear differentiation, with the high CPT (cold hyperalgesic) subgroup showing widespread hyperalgesia to pressure and to thermal modalities when compared with the remaining OA cohort. Importantly, the cold hyperalgesic group also reported higher pain levels, more reduced function, and increased features of neuropathic-type pain, as compared with the low CPT group for which pain appeared to be more limited and nociceptive in quality. Interestingly, there was no difference in scores for the mental health subscale of the SF-36 between any of the groups, suggesting that while the high CPT group experienced more pain and functional limitation, they did not appear to experience significantly elevated psychological distress.

Further research is required to determine the extent to which widespread pressure hyperalgesia might vary in a total OA cohort. There were, however, clear differences in CPT at all sites, indicating widespread cold hyperalgesia in the OA cohort. Considering the importance of elevated CPT as an indicator of pain severity and chronicity in other conditions, this is an important finding that has potential clinical implications for prognosis and warrants further investigation.

The study found a significantly increased heat pain threshold in the cold hyperalgesic subgroup compared with both the remaining OA cohort and the PFC group, suggesting there is a substantial subgroup of people with knee OA that experiences widespread heat hyperalgesia. Overall, there were differences between the OA CPT subgroups in multimodality hyperalgesia, pain report, neuropathic pain features, and perceived physical function, suggesting that the presence of cold hyperalgesia indicates a group with a more severe pain presentation.

Study Highlights Inconsistencies in Fibromyalgia Treatment Guidelines