October 2016
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 17, No. 10, October 2016 Issue)

Journal of Pain cover

The Association Between Clinical Characteristics of Migraine and Brain GABA Level: An Exploratory Study

Maria-Eliza R. Aguila, Trudy Rebbeck, Andrew M. Leaver, Jim Lagopoulos, Patrick C. Brennan, Markus Hubscher, Kathryn M. Refshauge; The University of Sydney Faculty of Health Sciences, Lidcombe, New South Wales, Australia; University of the Philippines College of Allied Medical Professions, Manila, Philippines; Brain and Mind Centre, Sydney Medical School, Camperdown, New South Wales, Australia; Sunshine Coast Mind and Neuroscience – Thompson Institute, University of the Sunshine Coast, Birtinya, Queensland, Australia; Neuroscience Research Australia and The University of New South Wales, Randwick, New South Wales, Australia

According to research reported in The Journal of Pain gamma aminobutyric (GABA) is a neurotransmitter found at higher levels in people with migraine and could become a reliable biomarker for improved diagnosis of the headache disorder.

A team of Australian researchers sought to validate GABA as a migraine biomarker by identifying whether specific characteristics of migraine—pain, central nervous system sensitization, impaired emotional state, and headache-related disability—are associated with brain GABA levels.

Despite the burden that migraine imposes on individuals and society, its underlying mechanisms are poorly understood. The authors noted that better understanding of migraine and improved diagnosis and treatment may be achieved through deeper investigation of clinical symptoms and features and their relationship to potential biomarkers such as GABA.

For this study, 20 adults with migraine and 20 age and gender–matched control subjects completed a questionnaire measuring migraine characteristics. Their GABA levels were measured by proton magnetic resonance spectroscopy.

Results showed that pain and central sensitization scores had a positive correlation with GABA levels in participants with migraine. The authors believe the association between increased GABA levels and migraine symptoms indicates a change in brain chemistry specific to migraine. They concluded that the relationship between migraine clinical features and GABA levels support the role of GABA as a potential biomarker for migraine.

Empathy Predicts an Experimental Pain Reduction During Touch

Pavel Goldstein, Simone G. Shamay-Tsoory, Shahar Yellinek, Irit Weissman-Fogel; Departments of Psychology and Statistics, University of Haifa, Haifa, Israel; Physical Therapy Department, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel

An Israeli study published in The Journal of Pain reports that social touching can produce an analgesic effect.

The goal of the study was to examine the analgesic impact of social touch and partner empathy. The authors hypothesized that social touch would diminish levels of experimental pain compared with no touch, and that a life partner’s touch would have a stronger analgesic effect compared to a stranger.

Twenty-three couples participated in the study. Tonic heart stimuli was administered to the women. Concurrently, the partners touched the women’s hands, a stranger touched their hands, and no one interacted with them.

The results showed diminished levels of pain in the partner-touch scenario versus no touch and stranger touch. The authors concluded that their findings support the powerful analgesic effect of social touch and suggest that empathy between romantic partners may explain the pain alleviating action of social touch. Further, the synergistic analgesic effect of touch and empathy has implications for some acute pain conditions, such as in-labor pain management.


Highlights from PAIN (Volume 157, No. 10, October 2016 Issue)

Pain Medicine Cover

Does Association of Opioid Use with Pain and Function Differ by Fibromyalgia or Widespread Pain Status?

Judith A. Turner, Susan M. Shortreed, Kathleen W. Saunders, Linda LeResche, Stephen Thielke, Michael Von Korff; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; Group Health Research Institute, Seattle; Departments of Biostatistics and Oral Medicine, University of Washington, Seattle; Geriatric Research, Education, and Clinical Center, Puget Sound VA Medical Center, Seattle

Patients with fibromyalgia often are treated with chronic opioid therapy (COT). Although they often report COT as being helpful, this intervention is viewed by many experts as inappropriate for fibromyalgia treatment. For this study, investigators hypothesized that the difference in 12-month outcomes for those with continued opioid use versus minimal/no opioid use would be more pronounced for patients with fibromyalgia. In the subgroup of patients taking COT, investigators explored whether self-reported helpfulness of opioids differed by fibromyalgia status. In the subgroup of patients who discontinued opioids, differences in reasons given for discontinuation were explored. Data on diagnoses, opioid prescriptions, and self-reports, including pain and activity interference measures at baseline, 4 months, and 12 months, were obtained.

As expected, in light of previous findings from the middle-aged/seniors chronic opioid therapy longitudinal study of patients initiating COT for chronic pain, outcomes were worse for patients who used opioids long-term than for those with minimal/no opioid use at 12 months. However, the hypothesis regarding worse outcomes associated with opioid use for patients with fibromyalgia was not confirmed. Among patients who continued to use opioids at the 12-month follow-up, pain and activity interference outcomes were similar for those with and without fibromyalgia.

Patients with fibromyalgia did not differ from those without fibromyalgia when citing concerns about dependency or addiction, or concerns that they were having trouble controlling how much medication they took, as reasons for stopping. Only a minority of patients with fibromyalgia (21%) discontinued opioid use by the 12-month follow-up. Patients with fibromyalgia were less likely to discontinue opioids because of pain improvement and more likely to discontinue because of side effects. This may help to explain why, among patients with minimal or no opioid use at 12 months, those with fibromyalgia had worse pain and function outcomes.

Among patients who initiated COT for chronic pain, many had discontinued opioid use or used opioids only minimally 12 months later. In this group, those with fibromyalgia had the worst outcomes. Among the patients who continued to use opioids long-term, either on an intermittent/lower dose or regular/higher dose basis, those with fibromyalgia or widespread pain had no worse and no better pain outcomes than patients with other chronic pain problems. Regardless of baseline fibromyalgia status or scores on a measure of widespread pain, long-term pain and activity interference outcomes were worse for those who continued to use opioids long-term than for those who discontinued opioids or used them minimally by 12 months.

Endogenous Opioidergic Dysregulation of Pain in Fibromyalgia: A PET and fMRI Study

Andrew Schrepf, Daniel Elliott Harper, Steven E. Harte, Heng Wang, Eric Ichesco, Johnson P. Hampson, Jon-Kar Zubieta, Daniel J. Clauw, Richard E. Harris; Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor; Department of Psychiatry, University of Utah, Salt Lake City

The role that endogenous opioids play in promoting core symptoms of fibromyalgia (FM), including widespread clinical pain and hyperalgesia to experimental stimuli, is yet to be characterized. This knowledge deficit is striking, considering the continued use of opioids in the treatment of FM and despite poor evidence supporting opioid efficacy for this condition and solid evidence showing that long-term opioid administration can lead to opioid-induced hyperalgesia. To better characterize the relationship between endogenous opioids and neural correlates of pain processing in FM, investigators measured tonic, resting µ-opioid receptor (MOR) availability using [11C]-carfentanil positron emission tomography and the blood oxygenation level-dependent (BOLD) effect during evoked pain assessed by functional magnetic resonance imaging (fMRI). This allowed investigators to explore the relationship between MOR availability and dynamic pain responses in patients with deficient MOR availability. This relationship was explored using whole-brain voxel-to-voxel comparisons of BOLD and MOR binding potential (BP) and a targeted approach using regions of interest exhibiting lower BP in patients with FM relative to controls. To explore the clinical relevance of these findings, the authors investigated whether opioid availability and pain-evoked activity in FM were associated with self-reported clinical pain.

Investigators observed strong within-patient associations between neural activity in response to experimental pressure pain and MOR BP. In whole-brain analyses, eight regions showed significant associations between fMRI BOLD and MOR BP, all in a positive direction. Some correlations were detected in regions considered to inhibit pain when activated, including the dorsolateral prefrontal cortex and multiple regions within the cingulate cortex. All correlations, including those that did not reach significance, were in a negative direction. No imaging outcome was associated with overall depression, suggesting that the above associations are specific to pain.

This study’s authors contend that for the first time, robust associations can be made between evoked pain brain activity and MOR availability within the same brain regions and the same individuals with chronic pain who have already been shown to display MOR availability deficiencies in pain-processing brain regions. These findings suggest that the dysregulation of the endogenous opioid system previously reported in these patients is strongly related to an objective neural marker of their pain sensitivity. These findings may contribute to the mechanistic understanding of experimental pain sensitivity and clinical pain report in FM and demonstrate a direct association between the endogenous opioid system and antinociceptive brain responses. These results strengthen the authors’ contention that opioids are unlikely to be efficacious in FM because of the already reduced numbers of MORs or receptor affinity, and instead support a plausible mechanism by which long-term opioid use could worsen pain outcomes by exacerbating an existing vulnerability in the endogenous opioid system.

The Clinical Journal of Pain

Highlights from The Clinical Journal of Pain (Volume 32, No. 10, October 2016 Issue)


Somatosensory and Biomechanical Abnormalities in Females with Patellofemoral Pain

Brian Noehren, Logan Shuping, Aron Jones, David A. Akers, Heather Bush, Kathleen Sluka; Department of Biostatistics, College of Public Health, Lexington; Graduate Program in Physical Therapy and Rehabilitation Science, University of Iowa, College of Medicine, Iowa City

Patellofemoral pain (PFP) is a common orthopedic condition; 25%–40% of all PFP becomes chronic, with as many as 91% of patients reporting continued pain at 4- to 18-year follow-ups. Women are two times more likely than men to develop PFP, with pain commonly first reported in adolescence. Although PFP is typically associated with younger patients, evidence suggests that having PFP earlier in life is linked to the later development of patellofemoral osteoarthritis. Despite the high incidence, chronicity, and cost of treating PFP, little is understood about the pain physiology associated with the condition. This study’s authors hypothesized that individuals with PFP would have lower pressure pain threshold (PPT) measurements at both the knee and elbow and that their threshold to detect light touch would be increased when compared to pain-free participants. They also hypothesized that frontal plane knee angles during a single-leg step down task would be correlated with PPT and self-reported greater pain in the PFP group but not the control group.

This study was designed to define the differences in localized and generalized hyperalgesia, degree of hypoesthesia, and relationship of hyperalgesia and pain to knee frontal plane angle in females with PFP. Investigators assessed pain, PPT, detection to light touch, and the relationship of pain and PPTs to knee abduction angle during a stair step-down task among females with and without PFP. They found that compared with the control group, women with PFP had lower PPTs both locally at the patellofemoral joint and at a remote location (elbow). They also had a significantly impaired ability to detect light touch over the center of the patella. A smaller knee adduction angle during a single-leg step down in the PFP group was related to a lower PPT at the knee and more self-reported pain intensity. These results suggest that the pain response in PFP extends beyond a localized increase in pain, and that a relationship exists between altered movement mechanics and increased nociceptive input. Women with PFP in this study had lower PPT values at the knee. Findings also demonstrated a significant relationship between lower PPT values and frontal plane knee angles during a step-down task in the PFP group (which was not observed in the control participants). However, there was no relationship between PPT at the elbow and the frontal plane knee angle during a squat. This would suggest that alterations in knee mechanics most likely were not significant contributors to generalized hyperalgesia.

These results provide evidence that alterations in biomechanics directly relate to hyperalgesia and pain and suggest that women with PFP may have greater centralization of their pain sensitivity. There is a need for additional larger prospective observational studies to define the time course for these changes and delineate which alterations are occurring first.

Risk of Opioid Abuse and Biopsychosocial Characteristics Associated with this Risk Among Chronic Pain Patients Attending a Multidisciplinary Pain Treatment Facility

M. Gabrielle Pagé, Hichem Saïdi, Mark A. Ware, Manon Choiniere; Centre de recherche du Centre hospitalier de l’Universite de Montreal (CRCHUM); Departments of Biomedical Sciences

The objectives of this observational prospective design study were to determine the proportion of new patients attending a multidisciplinary pain treatment facility (MPTF) who were at risk for opioid abuse; examine biopsychosocial correlates associated with this risk; and compare outcomes among patients at low, moderate, and severe risk for opioid abuse based on their type of treatment (taking opioids or not) over a 6-month period.

Study findings revealed that patients at low risk for opioid abuse were more likely to be opioid naïve, whereas patients at moderate or severe risk for abuse were more likely to be on opioid treatment for their pain. These results suggest that a significant proportion of patients with chronic noncancer pain at moderate or severe risk for opioid abuse are on a long-term opioid therapy.

Several variables measured at baseline were associated with risk for opioid abuse. These included being separated or divorced, having pain for more than 10 years, reporting lower mental health–related quality of life (QOL), and being a current cigarette smoker. The average pain duration was more than 6 years, most patients had already tried many therapeutic approaches, and the vast majority were receiving ongoing pain treatments when they arrived at the MPTF. This heterogeneity in treatment status at the onset of the study might account for the lack of association between initial pain intensity and risk for opioid abuse. Many studies have shown that psychiatric comorbidities including depression are risk factors for opioid abuse. The results of this study go a step further in suggesting that the impact of medical condition on mental health–related QOL makes patients more vulnerable to opioid abuse.

Taking opioids, regardless of patients’ potential for abuse, seems to be a risk factor for worse outcomes at follow-up, whereas being at low risk for opioid abuse is associated with better outcomes at follow-up whether or not patients are taking opioid treatment. Opioid risk profile, combined with type of treatment, significantly helped to predict treatment outcomes at 6-month follow-up. These results point to the importance of assessing risk for opioid abuse in patients with chronic pain and considering how this risk can influence treatment outcomes.