May 2015
David Craig, PharmD | Editor


The Journal of Pain HighlightsJournal of Pain cover

The following highlights summarize selected articles from The Journal of Pain (Volume 16, Issue 5, May 2015).

Disrupted Sleep Is Associated with Altered Pain Processing by Sex and Ethnicity in Knee Osteoarthritis

Megan E. Petrov, Burel R. Goodin, Yenisel Cruz-Almeida, Chris King, Toni L. Glover, Hailey W. Bulls, Matthew Herbert, Kimberly T. Sibille, Emily J. Bartley, Barri J. Fessler, Adriana Sotolongo, Roland Staud, David Redden, Roger B. Fillingim, and Laurence A. Bradley; Arizona State University, Phoenix, AZ; University of Alabama, Tuscaloosa, AL; and University of Florida, Gainesville, FL

The severity of sleep disruption appears to be associated with altered pain processing and central sensitization, according to research published in The Journal of Pain.

In patients with osteoarthritis (OA), more than half experience pain during the night, resulting in sleep disruption, poor sleep quality, sleep fragmentation, and frequent shifts between sleep stages. Recent studies have shown that sleep disruption can be a predictor of pain severity. Sleep disruption, therefore, could be associated with increased pain sensitivity and enhanced pain facilitation in addition to reduced pain inhibition in persons with chronic pain.

A team of researchers from Arizona State University, University of Alabama, and University of Florida analyzed the relationships of self-reported insomnia severity and maladaptive sleep behaviors with pain sensitivity in persons with knee OA. They hypothesized that reports of greater insomnia severity would be associated with lower pain thresholds and inhibition and with greater temporal summation of pain.

For the study, participants with knee pain were recruited from the community with eligibility being age 45–85, African American or non-Hispanic white, and having knee OA based on American College of Rheumatology criteria. Subjects completed sleep questionnaires and experimental pain applications.

Results showed that severity of sleep disruption were associated with altered pain processing and that sleep interventions for persons with knee OA-related pain might contribute to pain reductions. The authors noted that cognitive-behavioral therapies focused on sleep may have the most significant benefits for improving sleep in patients with insomnia and OA pain.

Defining Risk of Prescription Opioid Overdose: Pharmacy Shopping and Overlapping Prescriptions Among Long-term Opioid Users in Medicaid

Zhuo Yang, Barth Wilsey, Michele Bohm, Meghan Weyrich, Kakoli Roy, Dominique Ritley, Christopher Jones, and Joy Melnikow; Office of the Associate Director for Policy, Centers for Disease Control and Prevention, Atlanta, GA; Departments of Physical Medicine and Rehabilitation, VA Northern California Health Care System, Mather, CA; University of California Davis School of Medicine, Sacramento, CA; National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA; Center for Healthcare Policy and Research, University of California Davis School of Medicine, Sacramento, CA; Office of the Commissioner, Food and Drug Administration, Silver Spring, MD

In many states, Medicaid programs monitor the number of pharmacies visited to determine risk for misuse or abuse of opioid medications. Pharmacy shopping is a mechanism for obtaining more opioid prescription drugs than medically necessary. A study conducted in the state of Washington showed that almost half of those who died from prescription opioid overdoses were Medicaid recipients.

Despite knowing that using multiple pharmacies is linked with drug misuse, there is no consensus regarding the threshold number of pharmacies or specified length of time that define pharmacy shopping behavior. Further, there is a risk that relying on pharmacy shopping as an indicator of opioid misuse could misidentify patients who legitimately have used multiple pharmacies due to insurance coverage changes, moving, extensive traveling, and vacations.

For the study, a multicenter team of researchers examined records of more than 90,000 Medicaid enrollees who used three or more opioid prescriptions for 90 days in 2008 through 2010. The study population was limited to a cohort of Medicaid enrollees ages 18–64 who were long-term opioid users.

Results of the analysis showed that within a 90-day interval a threshold of four pharmacies had the highest diagnostic odds ratios for opioid overdose events and could be used as a definition of pharmacy shopping. Further, the overdose rate was higher within a subgroup with overlapping prescriptions.

The authors recommended that for patients whose use of overlapping prescriptions and multiple pharmacies cannot be justified medically, patient review, and restriction programs (PRRs) could restrict reimbursement for controlled prescription drugs to a single designated physician and one pharmacy.




Clinical Journal of Pain Highlights


The following highlights summarize selected articles from Clinical Journal of Pain (Volume 31, No. 5, May 2015 Issue).

Opioid Use in the Management of Diabetic Peripheral Neuropathy (DPN) in a Large Commercially Insured Population

Pravinkumar R. Patil, Jonathan Wolfe, Qayyim Said, Jeremy Thomas, and Bradley C. Martin; Division of Pharmaceutical Evaluation and Policy and Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR

Twenty percent of all patients with diabetes experience chronic neuropathic pain (NP). These investigators studied two groups: patients with diabetic peripheral neuropathy (DPN) who were prescribed pharmacologic treatments with a focus on opioid use and patients with DPN who were prescribed opioids as first-line treatment. The factors associated with any or first-line opioid uses in DPN also were studied. This study further sought to describe opioid use patterns, opioid dose patterns and durations, and average daily dose expressed in morphine equivalents.

Investigators found that 57% of patients with DPN did not receive any pharmacologic treatment that could be used for the condition. Although neuropathy treatment guidelines discourage use of opioids as first-line treatment, opioids were used by more than 50% of patients receiving a DPN medications, and opioids were the most frequently prescribed first-line agents. This finding was robust across all sensitivity analyses. Further, the mean initiation time in days for opioids was almost half that for nonopioid DPN drugs, which further demonstrates prescribers’ preferences for opioids for this condition. Approximately 50% of patients used prescribed opioids exclusively, while the remainder used opioids in conjunction with other DPN medications. With the exception of three patients, all used opioids for fewer than 90 days, indicating that physicians use opioids as an acute analgesic strategy and frequently initiate them without trying alternative guideline-recommended therapies to manage DPN at pain onset.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are not considered as drugs of choice in chronic NP conditions such as DPN. However, investigators found high NSAID use in DPN treatment. They also observed that women were more likely to receive any DPN treatment but were less likely to receive opioids as a first therapeutic agent for DPN.

Considering the availability of other agents to manage DPN that do not pose risk for tolerance and potential abuse, efforts to discourage use of opioids as first-line agents should be explored; these efforts could include clinical decision support tools, practitioner training, and incorporation of multidisciplinary practices with clinical pharmacists.

Sex Differences in Psychological Response to Pain in Patients With Fibromyalgia Syndrome

Mélanie Racine, Elena Castarlenas, Rocıo de la Vega, Catarina Tomé-Pires, Ester Solé, Jordi Miró, Mark P. Jensen, Dwight E. Moulin, and Warren R. Nielson; Lawson Health Research Institute; Beryl & Richard Ivey Rheumatology Day Programs, St Joseph’s Health Care; Department of Clinical and Neurological Sciences, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; Unit for the Study and Treatment of Pain ALGOS; Department of Psychology, Research Center for Behavior Assessment (CRAMC); Institut d’Investigacio Sanitaria Pere Virgili, Universitat Rovira i Virgili, Catalonia, Spain; and Department of Rehabilitation Medicine, University of Washington, Seattle, WA

This study’s objective was to examine whether men and women with fibromyalgia syndrome (FMS) differ in terms of their pain and functioning (depressive symptoms, pain severity, and interference), pain-related beliefs, and pain-related coping. Investigators hypothesized that they would not find significant sex differences regarding pain and functioning, instead predicting that there could be differences between men and women concerning their pain-related beliefs and pain-related coping mechanisms.

Study results revealed that men and women did not differ on any pain characteristic (including the number of pain areas), FMS-related somatic symptoms, presence of other rheumatological diseases, or sociodemographic variables. Age was the exception; men were much younger than women. There were no significant differences between men and women regarding pain and functioning, confirming the hypothesis.

This study revealed no sex difference regarding patient beliefs concerning their ability to control pain, the use of medication as a pain treatment, or the existence of a medical cure for their pain. Men were more likely than women to believe they were disabled by pain, whereas women, who stated that their emotions influence their pain, tended to believe that others should be more considerate of their pain. Men were more likely to believe that pain was an indication of bodily damage. There were no sex differences regarding any of the chronic pain-related coping strategies as measured by the Chronic Pain Coping Inventory. However, there were major differences in the pattern of pain-related activities, with men reporting more avoidance behaviors than women.

These results suggest that women and men with FMS might benefit from different types of targeted psychosocial interventions based on their beliefs and coping styles. Future clinical and experimental pain research might shed light on why clinical pain severity is not necessarily tied to pressure pain threshold or tolerance.



PAIN Highlights

Pain Medicine Cover

The following highlights summarize selected articles from PAIN (Volume 156, No. 5, May 2015 Issue)

TMPRSS2, A Novel Membrane-Anchored Mediator in Cancer Pain

David K. Lam, Dongmin Dang, Andrea N. Flynn, Markus Hardt, Brian L. Schmidt; Discipline of Oral and Maxillofacial Surgery, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto; Department of Oral and Maxillofacial Surgery, New York University, New York, NY; Bluestone Center for Clinical Research, New York University, New York, NY; Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA

Despite advances in cancer biology, mediators involved in the generation of cancer pain remain poorly understood. TMPRSS2 (transmembrane protease, serine 2) is a gene that encodes a type II transmembrane serine protease (TTSP). Members of the TTSP family have common protein structures, including a transmembrane domain at the N-terminus that anchors a canonical serine protease domain to the plasma membrane. Various TTSPs are consistently overexpressed in different cancers, suggesting their potential as biomarkers and possible targets for anticancer therapies.

This study demonstrates that TMPRSS2 is a functional serine protease that plays a critical role in cancer-induced proteolysis, spontaneous pain, and mechanical allodynia. Because human prostate cells are not known to release significant amounts of TMPRSS2 into the cancer microenvironment, the finding that TMPRSS2 is released by head and neck cancers suggests that the nociceptive effects of TMPRSS2 may be more far-reaching in head and neck cancer. TMPRSS2 contributes to cancer pain, and its effects are reversible with serine protease inhibition; consequently, the targeting of TMPRSS2 (highly localized in the cancer microenvironment) may be a novel approach to the treatment of cancer pain and may minimize treatment-related systemic side effects.

These results point to a novel role for a cell membrane–anchored mediator in cancer pain as well as pain in general.

Automated Internet-Based Pain Coping Skills Training to Manage Osteoarthritis Pain: A Randomized Controlled Trial

Christine Rini, Laura S. Porter, Tamara J. Somers, Daphne C. McKee, Robert F. DeVellis, Meredith Smith, Gary Winkel, David K. Ahern, Roberta Goldman, Jamie L. Stiller, Cara Mariani, Carol Patterson, Joanne M. Jordan, David S. Caldwell, Francis J. Keefe; Thurston Arthritis Research Center and Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC; Duke University Medical, Center, Durham, NC; Amgen, Inc., Thousand Oaks, CA; Icahn School of Medicine at Mount Sinai, New York, NY; Harvard Medical School/Brigham and Women’s Hospital, Boston, MA; Brown University, Pawtucket, RI

This pilot study was a two-arm randomized controlled trial conducted to evaluate the potential efficacy and acceptability of an 8-week automated, Internet-based version of pain-coping skills training (PCST) called PainCOACH. This program was designed to retain key therapeutic features of the in-person PCST protocol, simulating in-person PCST while presenting training in an easy-to-use format with guided instruction, individualized feedback, interactive exercises, and animated demonstrations.

Investigators hypothesized that PainCOACH would reduce pain (the primary outcome) and improve pain-related interference with functioning, pain-related anxiety, self-efficacy for pain management, and positive and negative affect and that acceptability would be high. Sex differences in responses to PainCOACH also were explored.

Study results generally supported the program’s promise among people with hip and/or knee osteoarthritis. Overall, effect sizes ranged from trivial to medium across outcomes, with the most notable effects on pain and self-efficacy for pain management. Specifically, women who used PainCOACH reported less pain than women in the control group, with an effect size in a range considered to be clinically significant. Additionally, Pain COACH users’ self-efficacy for pain management increased from baseline to postintervention, suggesting the potential for sustained benefits. These findings, along with strong evidence for the program’s acceptability, highlight the clinical promise of delivering PCST through the Internet and support continued development and evaluation of the PainCOACH program to strengthen its effects.

These findings are especially encouraging in light of the fact that participants were a racially diverse sample of older adults, some with low income and living in a rural area and/or having little experience using computers or the Internet. On average, participants had little pain-related impairment when they entered the study and little room for improvement. A more rigorous test will involve testing PainCOACH in a sample with more pronounced impairment.