June 2015
David Craig, PharmD | Editor


The Journal of Pain Highlights

Journal of Pain cover

The following highlights summarize selected articles from The Journal of Pain (Volume 16, Issue 6, June 2015).

The Effect of Sleep Continuity on Pain in Adults with Sickle Cell Disease

Gyasi Moscou-Jackson, Patrick H. Finan, Claudia M. Campbell, Joshua M. Smyth, Jennifer A. Haythornthwaite; Department of Acute and Chronic Care, Department of Psychiatry and Behavioral Sciences, Department of Biobehavioral Health, Johns Hopkins University School of Nursing, Baltimore, MD

Published evidence shows that poor sleep can predict increases in pain, and some studies have reported the significance of sleep fragmentation or disruption as a contributor to pain vulnerability. However, is it not known if disrupted sleep interacts with other variables of sleep quality to predict pain.

Researchers at Johns Hopkins University sought to determine the impact of sleep continuity on next-day pain experienced by individuals with sickle cell disease, for which pain is the most commonly reported symptom. Investigators hypothesized that decreased sleep duration and sleep fragmentation would be associated with increased next-day pain severity.

Study participants were recruited from sickle cell clinics and with posters and ads. After screening 246 subjects by telephone, 84 were found eligible for the study. The subjects completed electronic pain diaries in the morning and evening for three months. The data reported was used to examine the effects of sleep quality on pain and assess the synergistic effects of sleep fragmentation and sleep duration on pain.

Results showed that nights in which subjects experienced shorter sleep duration, more sleep fragmentation, and less efficient sleep were followed by days of higher than normal pain intensity. The study also showed that the effect of sleep duration is different on days with fragmented sleep. As sleep duration increases, its impact on next-day pain severity occurs only if sleep fragmentation is low. The researchers concluded that daily changes in sleep fragmentation and total sleep time can predict variation in next-day pain severity from sickle cell disease. In addition, sleep duration should not be considered by itself because its impact on sickle cell pain may be influenced by degrees of sleep fragmentation.

Based on the findings of this study, clinicians treating sickle cell disease should discuss sleep habits with their patients, especially those whose pain is poorly controlled.

The Interaction of Patient Race, Provider Bias, and Clinical Ambiguity on Pain Management Decisions

Adam T. Hirsh, Nicole A. Hollingshead, Leslie Ashburn-Nardo, Kurt Kroenke; Department of Psychology, Indiana University–Purdue University Indianapolis, Indianapolis, IN; VA Health Services Research and Development Center of Excellence on Implementing Evidence-Based Practice, Roudebush VA Medical Center, Indianapolis, IN

A unique study conducted by Indiana-Purdue University and the VA Medical Center in Indianapolis used computer-simulated patients to examine the influence of patient race, provider bias, and clinical ambiguity on pain treatment decisions.

It has been widely reported that suboptimal pain care disproportionately affects African Americans, which has been attributed to differences in pain sensitivity, patient preferences, access to healthcare services, and provider biases.

The study used virtual human technology to examine the role of provider bias and ambiguity regarding pain elements, such as severity and duration, in the care of white and black pain patients. The researchers hypothesized that providers would be less likely to prescribe opioids to blacks than whites, and the impact of patient race on provider opioid decisions would be greater in cases with high versus low clinical ambiguity.

Investigators recruited 129 study participants from medical residency and fellowship programs throughout the United States. They asked participants to make pain intensity and treatment assessments for 12 virtual patients with acute pain. The research team used a process that allowed for manipulation of race and clinical ambiguity while holding other pain care variables constant.

Results of the study showed that provider racial bias did not account for variability in pain-management decisions, and providers were not hesitant to prescribe opioids for black patients. The authors concluded that variations in pain care recommended for black and white patients often are attributable to differences in their individual clinical situations.

The researchers also noted that given the prevalence and cost of pain care and the high number of pain patients seen by physicians in their careers, there is a public health need for interventions that reduce disparities to help improve pain care.



Pain Medicine Highlights

Pain Medicine Cover

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

Opioid-Related Adverse Effects in Children Undergoing Surgery: Unequal Burden on Younger Girls with Higher Doses of Opioids

Senthilkumar Sadhasivam, Vidya Chidambaran, Vanessa A. Olbrecht, Andrew Costandi, Smokey Clay, Cynthia A. Prows, Xue Zhang, and Lisa J. Martin; Department of Anesthesia, Divisions of Human Genetics, Patient Services, and Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Clinical trials investigating postoperative pain and sex differences have produced inconsistent results, and data on sex differences related to opioid analgesics from adult human trials are not sufficient to reliably guide pediatric clinical practice. However, the study of sex differences regarding morphine effects in children is important because mechanisms underlying these effects are likely influenced by physiological, developmental, and hormonal factors, which may vary between prepubertal children, adolescents, and adults.

This study's investigators hypothesized that gender affects postoperative analgesic and adverse outcomes with the use of opioids, and the aim of their study was to ascertain the role of gender in determining the analgesic property and adverse effects of morphine use in children undergoing tonsillectomy. Results of this prospective clinical observational study demonstrate that white girls are more sensitive to opioid adverse effects as total morphine doses increase. White girls have differential responses to higher total morphine doses, leading to an unequal burden of higher incidence of opioid-related adverse effects and prolonged hospital stays after outpatient surgery. Specifically, increasing doses of morphine in girls was associated with increased respiratory depression (RD), postoperative nausea and vomiting (PONV), and prolonged stays in the recovery room because of opioid-related RD and PONV. When not stratified by total morphine to low, medium, and high doses, the safety and analgesic outcomes with the perioperative use of morphine in children did not differ by gender. These findings were not associated with age, body mass index, and surgical technique, and they conflict with findings from other human adult studies that suggest that women experience better pain control with opioids.

It is important to note that this analysis was restricted to a single self-reported white population. When treating pain in children, practitioners should bear in mind that although they experience analgesia in ways similar to boys, white girls are relatively more sensitive to higher doses of opioids, have more opioid-related adverse events, and stay longer in the postanesthesia care unit than boys. As a result, the use of opioid-sparing techniques, including nonsteroidal analgesics, dexmedetomidine, regional techniques when applicable, and opioid agonist-antagonists such as nalbuphine, may help to decrease the incidence of opioid-related adverse effects in girls. Awareness and effective monitoring for opioid adverse effects may be especially relevant for girls younger than 13 years of age, and practitioners should consider restricting morphine doses to less than 0.3 mg/kg for girls undergoing tonsillectomy.

Increased Pain Sensitivity in Chronic Pain Subjects on Opioid Therapy: A Cross-Sectional Study Using Quantitative Sensory Testing

Yi Zhang, Shihab Ahmed, Trang Vo, Kristin St. Hilaire, Mary Houghton, Abigail S. Cohen, Jianren Mao, and Lucy Chen; MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

With a goal to more effectively identify the characteristic changes in thermal pain sensitivity associated with opioid therapy, this group examined a variety of responses to innocuous or noxious heat and cold stimulation using office-based quantitative sensory testing (QST) in a large cohort including subjects with chronic pain who were and were not receiving opioid therapy and healthy controls.

Investigators studied thermal pain threshold, tolerance, and temporal summation in 172 subjects with chronic pain who were receiving opioid therapy, 121 subjects with chronic pain receiving nonopioid therapy, and 129 healthy subjects.

In a subgroup of subjects with chronic pain receiving opioid therapy who had increased heat pain sensitivity, their average opioid medication dosage was significantly higher than the dosage among those who had an above-average heat pain threshold. Moreover, a subset of subjects with chronic pain taking opioid therapy exhibited a significant decrease in diffuse noxious inhibitory control (DNIC) when compared with subjects with chronic pain taking nonopioid therapy. These findings suggest that a subset of QST parameters can reflect opioid-associated thermal pain sensitivity alteration, including decreased heat pain threshold, decreased cold and heat pain tolerance, diminished DNIC, or exacerbated temporal summation.

PAIN Highlights

Pain Medicine Cover

The following highlights summarize selected articles from PAIN (Volume 156, Issue 6, June 2015).

Transplant-Mediated Enhancement of Spinal Cord GABAergic Inhibition Reverses Paclitaxel-Induced Mechanical and Heat Hypersensitivity

João M. Bráz,, Xidao Wang, Zhonghui Guan, John L. Rubenstein, Allan I. Basbaum; Departments of Anatomy, Anesthesia and Critical Care, and Psychiatry, The Nina Ireland Laboratory of Developmental Neurobiology, University of California–San Francisco

These authors previously reported that medial ganglionic eminence (MGE) cells can completely reverse the mechanical hypersensitivity produced in a mouse model of peripheral nerve injury–induced neuropathic pain (they also demonstrated that MGE cells have antipruritic effects in a Bhlhb5 mutant mouse model of neuropathic chronic itch). In this study, they provide further evidence of the broad therapeutic potential of MGE cell transplantation. In addition to counteracting the neuropathic pain phenotype after traumatic nerve damage, these transplants are effective against both mechanical and heat hyperalgesia in a chemotherapy-induced model of neuropathic pain. This study also demonstrates that the utility of these transplants is not limited to conditions in which there is profound loss of GABAergic inhibitory controls. Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury.

This study demonstrates that MGE cell transplantation is effective in neuropathic pain conditions in which levels of glutamic acid decarboxylase (GAD), the enzyme required for GABA synthesis, are not reduced. Specifically, an MGE cell transplant reversed both the mechanical and heat hypersensitivity produced in a chemotherapy (paclitaxel)-induced model of neuropathic pain. Authors also studied the utility of transplanting MGE cells from mice with a deletion of VGAT, the vesicular GABA transporter. Transplants from these mice, in which GABA is synthesized but cannot be stored or released, had no effect on the mechanical hypersensitivity or heat hyperalgesia in the paclitaxel model. Investigators concluded that the antihyperalgesic effect of MGE transplants is GABA mediated.

The MGE transplant approach has beneficial effects even in pathological conditions in which a major indicator of GABAergic functionality, namely the level of GAD enzyme, is intact, according to this study. These results suggest that transplant-mediated enhancement of GABAergic tone may be a promising therapeutic approach with which to treat a wide variety of neuropathic pain and itch conditions of varying etiologies.

Self-Reports of Medication Side Effects and Pain-Related Activity Interference in Patients with Chronic Pain: A Longitudinal Cohort Study

Marc O. Martel, Patrick H. Finan, Andrew J. Dolman, Subu Subramanian, Robert R. Edwards, Ajay D. Wasan, and Robert N. Jamison; Department of Anesthesiology, Harvard Medical School, Brigham and Women's Hospital Pain Management Center, Chestnut Hill, MA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, MA; UPMC Pain Medicine, Departments of Anesthesiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA

Most research that has been conducted on medication side effects has focused on the determinants of various side-effect profiles, but little research has addressed the association between medication side effects and pain-related activity interference (e.g., reductions in daily life activities because of pain). In this study, 111 patients with chronic musculoskeletal pain were asked to provide, once a month for 6 months, self-reports of medication use and the presence of any side effects associated with their medications. The primary purpose of the study was to examine the unique association between self-reports of medication side effects and pain-related activity interference.

Patients used a personal digital assistant to report whether they were experiencing any of the following medication side effects: nausea, constipation, headache, dry mouth, itching, sneezing, sweating, weakness, dizziness, confusion, memory problems, or visual problems. They were then asked to rate the intensity of each perceived medication side effect on a 0-to-10 visual analog scale (VAS). They also rated their current level of anxiety and depression on a 0-to-10 VAS and rated the degree to which pain interfered with their daily routine activities, outdoor activities, and social activities.

On average, across assessment time points, men and women did not differ significantly in pain intensity, negative affect, or pain-related activity interference. However, self-reports of medication side effects were more common among women and month-to-month increases in pain intensity were associated with higher ratings of pain-related activity interference. Increases in negative affect were associated with higher ratings of pain-related activity interference. Of particular importance is the finding that increases in perceived medication side effects were associated with higher ratings of pain-related activity interference even after controlling for month-to-month changes in patients' levels of pain and negative affect. This association between perceived medication side effects and pain-related activity interference suggests that side effects have the potential to interfere with activities independent of patients' pain and affective states.

These findings suggest that greater efforts should be placed on the assessment and treatment of medication side effects. If side effects emerge as a result of medication use, they should be targeted directly and treated using interventions to prevent their potentially deleterious influence on patients' activity engagement. Additional studies that use a more frequent data collection schedule to better capture the dynamic relationships between side effects and pain-related activity interference are needed.