April 2016
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 17, No. 4, April 2016 Issue)

Journal of Pain cover

Study Shows Increased Risk for Depression Recurrence in Patients with Chronic Noncancer Pain After Initiation of Opioid Therapy

Jeffrey F. Scherrer, Joanne Salas, Laurel A. Copeland, Eileen M. Stock, F. David Schneider, Mark Sullivan, Kathleen K. Bucholz, Thomas Burroughs, Patrick J. Lustman; St. Louis University Medical Center, Harry S. Truman Veterans Administration Hospital Center for Applied Health Research, Baylor Scott & White Health, Central Texas Veterans Health Care System, Washington University School of Medicine, Saint Louis University Center for Outcomes Research

Several studies have shown that chronic opioid analgesic use is associated with increased risk for new-onset depression. A growing body of knowledge shows that patients with chronic noncancer pain who are prescribed opioids are more likely to develop depression. And, because pain and depression are so closely linked and pain is a predictor of depression recurrence, there is a need to evaluate the independent contribution of opioid analgesics to heightened risk for depression recurrence.

In a multicenter study, researchers sought to determine whether patients in depression remission who begin treatment with opioids for chronic noncancer pain have increased risk for depression recurrence.

For the study, patient data were obtained from the Veterans Health Administration (VHA) and Baylor Scott & White Health System (BSWH) electronic medical record files. The sample consisted of 5400 VHA patients and 842 from BSWH. All had not taken opioids for a minimum of two years, had been diagnosed with depression, and experienced a period of remission.

In both patient cohorts, the data showed that patients who were in remission for depression had a twofold greater risk of depression recurrence if they began opioid treatment compared with patients who did not take opioids. The authors noted that the study is novel because it showed that opioid therapy increased the risk of depression recurrence among patients with remitted depression. However, the researchers did not find evidence for an association between longer duration of opioid therapy or higher doses and increased risk for depression recurrence.

Opioid Compliance Checklist Helps Primary Care Physicians Screen for Aberrant Drug Behavior

Robert N. Jamison, Marc O. Martel, Chuan-Chin Huang, Dylan Jurcik, Robert R. Edwards; Brigham and Women’s Hospital

The Opioid Compliance Checklist (OCC) is a self-report measure for use in patients with chronic pain treated with long-term opioid therapy. It was designed as a brief measure to help physicians document opioid compliance. A team of Harvard researchers sought to gauge the efficacy of the tool for monitoring opioid therapy adherence among patients with chronic noncancer pain in primary care practices.

Patients were recruited for the study with flyers placed in Boston-area medical centers and were invited to participate by their primary care doctors. Eligibility was determined if patients had chronic pain for 6 months or more, averaged a score of 4 on pain intensity scales, and were eligible to be prescribed opioids by their primary care physicians. The study sample consisted of 253 patients with chronic pain from eight primary care practices. A shorted eight-item questionnaire was used instead of the original 12-item OCC.

Results of the study showed that that the simple checklist is useful clinically and preferable to asking patients if they are complying with opioid therapy. It offers a reliable method to alert doctors to ongoing risk behavior and help prevent future problems. Patients from the primary care centers had a lower incidence of drug misuse compared with patients seen in a specialty pain center.

The authors noted that the OCC items found to be the best at predicting opioid misuse at baseline asked if patients were using opioids in ways other than prescribed, if they run out of medication early, and if they miss scheduled appointments.


Highlights from PAIN (Volume 157, No. 4, April 2016 Issue)

Pain Medicine Cover

Keratinocytes as Modulators of Sensory Afferent Firing

Marsha Ritter-Jones, Sarah Najjar, and Kathryn M. Albers; Departments of Anesthesiology and Neurobiology, University of Pittsburgh, Pittsburgh, PA

Skin keratinocytes release several neuroactivator compounds such as calcitonin gene-related peptide, ATP, acetylcholine, glutamate, growth factors, and cytokines in response to various stimuli. Keratinocytes also express ligand-gated and voltage-gated ion channels and growth factor/cytokine receptors, suggesting complex autocrine and paracrine signaling occurs between epithelial cells and sensory afferents. This signaling may change in chronic diseases for which inflammation, changes in nerve innervation, paresthesias, and pain/itch are common.

An understanding of neuro-epithelial communication in cutaneous sensory transduction has been hindered because of the complexity of the skin-neural interface. It is impossible to apply natural (thermal, mechanical) stimuli in a manner that does not simultaneously affect both nerves and keratinocytes. To evaluate the contribution of each cell type to sensory transduction, optogenetic rodent models that target channelrhodopsin (ChR2), a blue light-gated cation channel, or halorhodopsin, a yellow light-stimulated chloride pump, to subsets of sensory neurons to Merkel cells or to epidermal keratinocytes were used.

Findings support a model in which neuroactivators released from activated ChR2-keratinocytes evoke action potential (AP) firing in specific subtypes of cutaneous afferents. Yellow light stimulation of keratinocytes that express the halorhodopsin chloride pump (NpHR3) blocks AP firing in response to mechanical or heat stimulation. AP firing is decreased in C fibers, A-HTMRs, and SA1 fibers.

Peripheral drivers of pain are located in both target tissues and sensory afferents. Mouse models that allow specific targeting of light-activated opsins to nonneuronal cells and specific neuronal populations will allow investigation of the extent and nature of this communication and advance understanding of sensory transduction and how it changes in pathological states.

Does Changing Pain-Related Knowledge Reduce Pain and Improve Function Through Changes in Catastrophizing?

Hopin Lee, James H. McAuley, Markus Hubscher, Steven J. Kamper, Adrian C. Traeger, and G. Lorimer Moseley; Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia; Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia; EMGO+ Institute, VU University Medical Centre, Amsterdam, the Netherlands; The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia; Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia

A systematic review of observational studies has shown that catastrophizing predicts pain intensity and functional capacity in patients with low-back pain, a finding that also has been reported in neuropathic pain; chronic temporomandibular joint pain; pain of soft-tissue injuries of the shoulder, neck, and back; and osteoarthritis. Despite compelling evidence for a predictive effect, there is only preliminary evidence for a causal effect of catastrophizing on pain and function. Although correlations between pain knowledge, catastrophizing, and pain or function have been found in previous studies, no study has formally tested the role of catastrophizing on the causal path between knowledge and pain or function. The mechanism by which improvements in pain knowledge lead to reduced pain and better function through reductions in catastrophizing can be tested using mediation analyses. Understanding this mechanism is important for the development and refinement of educational interventions that aim to reconceptualize patients’ knowledge about pain biology.

In this study, investigators hypothesized that change in catastrophizing would mediate the relationship between an initial improvement in pain biology knowledge and subsequent reduction in pain intensity and an initial improvement in pain biology knowledge and subsequent improvement in function.

Data were collected as part of a clinical audit conducted across Australia, the United States, and the United Kingdom between 2001 and 2010. Eleven clinicians (9 physiotherapists and 2 psychologists) from 7 clinics were involved in the audit in which each patient was treated by a single clinician. Subjects received an educational intervention, delivered over two to three sessions with each session ranging between 30 and 60 minutes in duration. The intervention was designed to reconceptualize patients’ understanding of pain by explaining the biological mechanisms that underpin nociception and pain.

Changes in catastrophizing did not mediate the relationship between improved pain biology knowledge and improved pain or function in the adjusted models. The adjusted models showed that an initial improvement in pain biology knowledge led to a reduction in pain, an improvement in function (total effects), and a reduction in catastrophizing. However, the reduction in catastrophizing did not lead to a reduction in pain or an improvement in function. The investigators’ first hypothesis (that changes in catastrophizing would mediate the relationship between changes in pain biology knowledge and pain) was supported by the unadjusted model but was not supported by the adjusted model. One possible explanation for the discrepancy in the results from the unadjusted and adjusted models may be attributable to the effects of confounding variables. Because consideration of confounding is critical for causal inference from observational data, investigators adjusted for selected covariates to ensure that any indirect effects identified were associated with the mediator of interest and not a confounder. The first post hoc sensitivity analysis showed that an early change in catastrophizing did not mediate the relationship between changes in pain biology knowledge and changes in pain or function.

The Clinical Journal of Pain

Highlights from The Clinical Journal of Pain (Volume 32, No. 4, April 2016 Issue)


Primary Care Physicians’ Knowledge and Attitudes Regarding Prescription Opioid Abuse and Diversion

Catherine S. Hwang, Lydia W. Turner, Stefan P. Kruszewski, Andrew Kolodny, and G. Caleb Alexander; Center for Drug Safety and Effectiveness; Departments of Epidemiology and Mental Health, Johns Hopkins Bloomberg School of Public Health; Department of Medicine, Division of General Internal Medicine, Johns Hopkins Medicine, Baltimore, MD; Stefan P. Kruszewski, MD, and Associates, Harrisburg, PA; Phoenix House Foundation; Global Institute for Public Health, New York University, New York, NY; Heller School for Social Policy and Management, Brandeis University, Waltham, MA

This study’s investigators conducted a survey of 1,000 primary care physicians in the United States to examine their knowledge, attitudes, and beliefs regarding key elements of opioid overuse. They were particularly interested in physicians’ knowledge of opioid abuse and diversion and their support for clinical and regulatory interventions that may reduce opioid-related injuries and deaths.

All surveyed physicians (100%) believed that prescription drug abuse was at least a small problem in their communities, with 37% reporting that it was “a moderate problem” and 53% reporting that it was “a big problem.” Among respondents, only 66% correctly reported that the most common route of abuse is to swallow pills intact, and nearly 46% incorrectly indicated that abuse-deterrent opioid formulations are less addictive than their nonabuse-deterrent counterparts. In addition, only 13% of physicians correctly believed that relatives and friends are the most common source for obtaining prescription opioids for nonmedical use, and 25% reported they were “not at all” or “only slightly” concerned about the potential for diversion of these medicines.

Among responding physicians, 88% reported that they “strongly supported” a requirement for patients to get opioids from a single prescriber and/or pharmacy, 66% reported similar levels of support for the use of patient agreements or contracts, and 57% strongly supported the use of urine drug testing for chronic opioid users. In addition, more than 3 in 4 physicians “often” (45%) or “sometimes” (32%) recommended the use of complementary or alternative therapies such as acupuncture, massage, and yoga for the treatment of pain. More than 75% of physicians “somewhat” or “strongly” supported each regulatory intervention examined in the survey, ranging from prohibiting pharmaceutical companies from marketing opioids for moderate pain (77%) to requiring prescribers to check a centralized patient database before prescribing opioids (88%). Further research evaluating the effectiveness of such interventions, as well as their adoption in clinical practice, is important to improve the overall risk-benefit balance of prescription opioids.

Despite the importance of preventing the inappropriate use of prescription opioids, the average medical student receives only 11 hours of pain education, and most prescribers receive little education on how to recognize patient substance abuse. Of physicians surveyed, 66% believed that clinical practice guidelines and treatment standards for pain contribute “some” or “a lot” to opioid abuse, and more than 75% believed that perceived low prescribing thresholds contribute to opioid abuse.

Characteristics of Disturbed Sleep in Patients with Fibromyalgia Compared with Insomnia or with Pain-Free Volunteers

Thomas Roth, Pritha Bhadra-Brown, Verne W. Pitman, Timothy A. Roehrs, and E. Malca Resnick; Sleep Disorders and Research Center, Henry Ford Health System, Pfizer

Primary insomnia (PI) is not associated with comorbid conditions or other sleep disorders. This distinction is made because certain medical conditions are frequently associated with disrupted, nonrestorative, or fragmented sleep. In particular, clinical studies suggest a relationship involving persistent sleep disruption and pain, chronic fatigue, and/or depression. As a result, disturbed sleep is a diagnostic criterion for the musculoskeletal pain condition fibromyalgia (FM) and for other conditions including anxiety, depression, and sleep apnea. It has long been recognized that individuals with FM have abnormal sleep characteristics on objective and subjective assessments, including delayed sleep onset, decreased sleep efficiency, more frequent arousals, and sleep-disordered breathing compared with pain-free controls. Sleep disturbances in patients with FM have been extensively studied using polysomnography (PSG).

This post hoc study of PSG data sought to evaluate the nature of sleep disturbances among patients with FM reporting difficulty with sleep, those with PI, and healthy asymptomatic volunteers. PSG data were obtained from the screening nights of these three groups of patients from separate clinical studies. Data were available for 132 patients with FM, 109 patients with PI, and 52 controls. Patients were primarily women in each cohort (86.3%, 67.9%, and 73.1%), and mean ages were 48.4, 45.4, and 30.2 years in the FM, PI, and control cohorts, respectively. Patients with FM or PI had significantly shorter total sleep time and slow-wave sleep, reduced sleep efficiency, and increased latency to persistent sleep and wake time after sleep onset (WASO) relative to controls. Patients with FM and PI had more frequent and longer wake bouts compared with controls and shorter sleep bout duration. Despite comparable WASO, patients with FM had more frequent and shorter wake bouts than those with PI. Despite comparable WASO, patients with FM can be distinguished from patients with PI and from controls without sleep difficulties on the basis of frequency and duration of wake or sleep bout episodes.

Age, but not BMI, was a significant variable in the shorter duration of wake bouts in FM versus PI. Sleep bout mean duration was similar for patients with FM or PI (9.3 versus 10.1 minutes). These characteristics may have relevance in terms of the pathophysiology of sleep disturbance and differential treatment practices for physicians evaluating and managing disrupted sleep in patients with FM or PI.

These data indicate that patients with FM have a relatively intact homeostatic sleep drive when compared to patients with PI, which causes them to quickly return to sleep after an awakening. These observations may have wider relevance to treatment practices used to manage these conditions.