June 2017
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 8, No. 6, June 2017 Issue)

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Study Links Sleep Patterns with Pain Persistence in Pediatric Surgery Patients

Jennifer A. Rabbitts, Chuan Zhou, Arthi Narayanan, Tonya M. Palermo; Departments of Anesthesiology and Pain Medicine, Pediatrics, and School of Public Health, University of Washington, Seattle, WA; Centers for Clinical and Translational Research and Health, Behavior, and Development, Seattle Children's Hospital, Seattle, WA; Departments of Neuroscience and Sociology, University of Pittsburgh, Pittsburgh, PA

About 20% of children develop persistent pain after surgery, and a new study published in The Journal of Pain showed that poorer nighttime sleep quality was significantly associated with greater next-day pain intensity.

Researchers from the University of Washington, University of Pittsburgh, and Seattle Children’s Hospital studied 66 children who had major surgery and examined the longitudinal sleep patterns over 4 months to assess the temporal relationship between daily sleep and pain. They hypothesized that poorer nighttime sleep quality would be associated with greater pain intensity.

In adults, the role of sleep disruption is considered a relevant predictor of acute as well as chronic postsurgical pain. However, perioperative daily sleep patterns have not been longitudinally assessed in children, and the role of sleep in the persistence of children’s pain after surgery has not been explored.

Results of the study showed, on average, children’s sleep duration and quality returned to baseline 4 months following surgery. But at the individual level, significant temporal relationships were found between daily sleep and pain. Poor sleep quality predicted greater pain intensity the next day and suggested that poor sleep quality may continue to influence the experience of postsurgical pain in children even 4 months after surgery.

The authors concluded that improving sleep quality could be an important variable to reduce postsurgical pain and improve surgical recovery time in children.

Acceptance and Commitment Therapy Improves Functioning for People with Chronic Pain

Lin Yu, Sam Norton, Lance M. McCracken; King's College London, Health Psychology Section, Psychology Department, Institute of Psychiatry, Psychology, and Neuroscience, London, UK; INPUT Pain Management, Guy's and St. Thomas' NHS Foundation Trust, London, UK

Acceptance and commitment therapy (ACT) is based on the psychological flexibility model, which includes a therapeutic process known as “self-as-context” (SAC). British researchers writing in The Journal of Pain examined whether ACT influences SAC and if changes in measures of SAC are associated with treatment outcomes. Four hundred twelve adults referred to a pain management center were subjects for the study.

Participants completed measures of treatment processes (SAC, pain acceptance) and outcomes (pain-related interference, work and social adjustment, depression) before treatment, upon treatment completion, and after 9 months.

Cognitive behavioral therapy (CBT) is the most frequently used psychological intervention for people with chronic pain, and new directions for improving CBT for treating chronic pain may be found in the psychological flexibility model and ACT, in particular.

Psychological flexibility is the ability to be more aware, more focused on goals, and more engaged. One aspect of psychological flexibility that is pertinent to chronic pain is committed action, which involves goal-directed, flexible persistence. For pain management, ACT is an approach based on the psychological flexibility model and focuses on building effective patterns of behavior change rather than symptom reduction.

Greater psychological flexibility has been found to be associated with less pain-related anxiety and avoidance, less depression, and less physical and psycho-social disability. Outcomes research suggests that ACT is effective for enhancing daily functioning and for decreasing psychological distress.

Results of the study showed that scores from both the process and outcomes measures significantly improved after treatment and were maintained at 9-month follow-up. The ACT-oriented treatment was associated with improved SAC as well as improved functioning. Changes in SAC were associated with changes in pain-related interference, work and social adjustment, and depression. The authors noted that the study results are consistent with an increasing number of longitudinal and mediation studies showing that ACT for chronic pain improves patient functioning, specifically through enhanced psychological flexibility.


Highlights from PAIN (Volume 158, No. 6, June 2017 Issue)

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Side Effects Can Enhance Treatment Response Through Expectancy Effects: An Experimental Analgesic Randomized Controlled Trial

Chantal Berna, Irving Kirsch, Sean R. Zion, Yvonne C. Lee, Karin B. Jensen, Pamela Sadler, Ted J. Kaptchuk, and Robert R. Edwards; Pain Center, Department of Anesthesiology, Lausanne University Hospital, Lausanne, Switzerland; Program in Placebo Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston; Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Department of Psychology, Wilfrid Laurier University, Waterloo, ON, Canada

The ability to determine whether drug and placebo effects are additive or interactive would have important implications for establishing the efficacy of various treatments. Additivity would support the implicit logic of current randomized controlled trial (RCT) methodology but also would introduce the possibility that treatment effects may be overestimated for drugs with noticeable side effects. Conversely, it has been hypothesized that large placebo responses can mask true drug effects, rendering it increasingly difficult to establish the efficacy of new drugs. In this experimental RCT, investigators evaluated whether drug and placebo effects are additive or interactive in the treatment of pain by testing the analgesic effects of diclofenac, a nonsteroidal anti-inflammatory drug, with and without an induced side effect (dry mouth) produced by the addition of atropine. They also hypothesized a mediational chain in which atropine would lead to dry mouth; dry mouth would foster the belief that a person had received the active medication, and this belief would, in turn, enhance analgesic response.

This mediation analysis confirmed the hypothesis that atropine increases the perception of side effects. The difference between diclofenac and placebo was significant only when atropine had been added.

These findings could have important implications for the design of RCTs because the double-blind nature of an RCT instills uncertainty regarding whether subjects receive the active drug or placebo. Side effects may reduce uncertainty in active drug arms, thereby enhancing drug-placebo differences. This information comes at a time when RCT methodology is being questioned in light of placebo research. These experimental findings warrant replication in clinical populations. The possibility of synergy between diclofenac and endogenous opioids in the context of a placebo effect also could be investigated further. 

HDAC6 Inhibition Effectively Reverses Chemotherapy-Induced Peripheral Neuropathy

Karen Krukowski, Jiacheng Ma, Olga Golonzhka, Geoffroy O. Laumet, Tanuja Gutti, John H. van Duzer, Ralph Mazitschek, Matthew B. Jarpe, Cobi J. Heijnen, and Annemieke Kavelaars; Department of Symptom Research, Laboratory of Neuroimmunology, The University of Texas MD Anderson Cancer Center, Houston, TX; Acetylon Pharmaceuticals Inc, Boston; Center for Systems Biology, Massachusetts General Hospital, Boston

Chemotherapy-induced peripheral neuropathy (CIPN) is among the most common and widely reported adverse side effects of cancer treatment. The overall incidence of CIPN ranges 30%–80% among patients treated for cancer, depending upon the chemotherapy regimens used and the duration of treatment. Despite the high prevalence and severity of CIPN, there are no effective U.S. Food and Drug Administration (FDA)–approved drugs to prevent or reverse CIPN. This study’s investigators tested the hypothesis that inhibition of HDAC6 prevents and treats multiple symptoms of CIPN, including mechanical allodynia, numbness, and spontaneous pain, by restoring mitochondrial function in peripheral nerve and dorsal root ganglia and reversing the loss of intraepidermal nerve fibers (IENFs) in mice treated with cisplatin.

Investigators demonstrated that pharmacological inhibition of HDAC6 with CY-1083 effectively prevents cisplatin-induced mechanical allodynia in mice. The beneficial effect of HDAC6 inhibition is not limited to the cisplatin model in mice but extends to paclitaxel-induced mechanical allodynia in rats. Prolonged treatment with either the selective HDAC6 inhibitor ACY-1083 or the less selective HDAC6 inhibitor ACY-1215 reverses established cisplatin-induced mechanical allodynia. Notably, HDAC6 inhibition also reverses cisplatin-induced spontaneous pain and numbness.

These results identify HDAC6 as a novel therapeutic target for treatment of existing cisplatin-induced peripheral neuropathy. The ability of HDAC6 inhibitors to reverse existing symptoms of CIPN is an important finding because no FDA-approved therapeutics are available for the treatment of established CIPN. In addition, the ability of the HDAC6 inhibitor ACY-1083 to prevent the primary dose-limiting toxicity of cisplatin would potentially allow oncologists to dose higher, longer, or both and achieve better clinical outcomes for patients with cancer.

CIPN represents an important challenge in cancer treatment. This study shows that HDAC6 inhibition can completely reverse multiple symptoms of CIPN. The protective effect of HDAC6 inhibition is associated with increased a-tubulin acetylation, improved axonal mitochondrial bioenergetics, and enhanced IENF density. These findings provide important evidence that HDAC6 inhibitors are promising therapeutics for the prevention and treatment of CIPN. These results also implicate IENF density as a reliable biomarker for clinical evaluation of drug efficacy in the treatment of CIPN. 

The Clinical Journal of Pain

Highlights from The Clinical Journal of Pain (Volume 33, No. 6, June 2017 Issue)


Novel Signs and Their Clinical Utility in Diagnosing Complex Regional Pain Syndrome (CRPS): A Prospective Observational Cohort Study

Anoop Kuttikat, Maliha Shaikh, Amin Oomatia, Richard Parker, and Nicholas Shenker; Department of Rheumatology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust; School of Clinical Medicine and Centre for Applied Medical Statistics, University of Cambridge, Cambridge, UK

CRPS is a chronic, debilitating pain condition of unknown etiology that usually arises after trauma to a limb. Guidelines recommend prompt diagnosis and early treatment to avoid secondary physical problems and the psychological consequences of undiagnosed chronic pain, yet patients in the United Kingdom with chronic CRPS have an average diagnostic delay of 6 months. The diagnosis of CRPS is clinical and based on the presence of disproportionate pain associated with vasomotor, sudomotor, trophic, and motor changes. Investigations such as thermography, triple-phase bone scan, and contrast-magnetic resonance imaging may aid the diagnosis but have low positive and negative predictive values. Novel clinical signs such as abnormal finger perception (FP), hand laterality identification (HL), astereognosis (AS), and body scheme report (BS) have been reported in patients with CRPS.

Although the precise pathophysiological basis of these signs remains elusive, they may have diagnostic utility in CRPS. The aims of this prospective observational cohort study were to validate these novel signs as simple bedside tests, assess their prevalence in chronic pain conditions, and prospectively assess their clinical utility in identifying CRPS in a fracture cohort.

Investigators recruited a large cohort of patients (253 patients in five different pain groups) and pain-free controls (60 healthy) and objectively defined bedside tests for FP, HL, BS, and AS. There was no relationship between the presence of a positive test and self-reported pain scores, anxiety and depression scores, or functional scores. However, the study was not powered to detect such differences, and further work is needed to explore any possible relationships. They calculated the diagnostic clinical utility (sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio) of novel signs in patients with CRPS; and BS had the highest positive predictive value (78%) and negative predictive value (91.9%). Diagnostic clinical utility was further increased by combining the two best-performing tests of FP and BS as a composite test. The absence of either abnormal FP or BS was highly predictive of the absence of persistent pain. Their presence was associated with a significant increase in the presence of persistent pain.

Novel signs of FP, HL, BS, and AS are present in patients with CRPS and have significant clinical diagnostic utility. They also are present in other chronic painful conditions. Combining FP and BS is helpful in stratifying a cohort of at-risk patients postfracture. It is a quick, simple, and reliable test that easily can be taught. The pain phenotype may be better understood by assessing for changes in BS. 

The Mediating Role of Pain Acceptance in the Relation Between Perceived Injustice and Chronic Pain Outcomes in a Community Sample

Marie-Eve Martel, Frederick Dionne, and Whitney Scott; Department of Psychology, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, QC, Canada; Health Psychology Section, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London

Perceived injustice is defined as an appraisal regarding the severity and irreparability of loss associated with pain and thoughts of blame and unfairness. Perceived injustice is a risk factor for poor pain-related recovery, as it has been associated with more pain severity, depressive symptoms, posttraumatic stress symptoms, heightened protective pain behaviors, disability, and lower probability of returning to work.

In this study, investigators explored whether pain acceptance mediates the relation between perceived injustice and pain outcomes within a community sample of individuals with chronic pain. They hypothesized that perceived injustice would be positively associated with pain intensity, distress, and disability and negatively associated with pain acceptance. They also predicted that pain acceptance would mediate the relation between perceived injustice and pain outcomes, such that lower levels of pain acceptance associated with perceived injustice would explain the positive associations between perceived injustice and pain outcomes.

In support of the first hypothesis, results showed that perceived injustice was significantly positively associated with pain intensity, disability, and psychological distress and was significantly negatively associated with pain acceptance. Low pain acceptance was associated with higher pain disability and psychological distress. Results also confirmed the second hypothesis and demonstrated that chronic pain acceptance significantly mediates the relation between perceived injustice and pain disability and the relation between perceived injustice and psychological distress. Importantly, injustice and pain acceptance explained 46% of variance in both pain disability and psychological distress. Pain acceptance did not entirely reduce the association between perceived injustice and disability or psychological distress.

Interventions aimed at increasing pain acceptance might have potential for reducing the impact of perceived injustice on distress and disability. Future research is needed to test whether interventions that foster acceptance, such as acceptance and commitment therapy, improve recovery outcomes of people who perceive pain-related injustice. Research also is needed to identify additional mediators of the relationship between perceived injustice and adverse pain outcomes.