March 2016
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 17, No. 3, March 2016 Issue)

Journal of Pain cover

Some Words Hurt More Than Others

Elise R. Swannel, Christopher A. Brown, Anthony K. P. Jones, Richard J. Brown; Department of Clinical Psychology, University of Manchester, Manchester, United Kingdom; CamPain Research Group, Division of Anaesthesia, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; Human Pain Research Group, University of Manchester, Salford, United Kingdom

Memory can play an important role in pain perception, and some theories posit that memory processes can be helpful in understanding how pain occurs in the absence of painful stimulation. A new study published in The Journal of Pain showed that increasing semantic activation of pain concepts in test subjects increased their subjective ratings of pain.

A team of British researchers examined behavioral and psychological responses to painful laser stimuli after the subliminal presentation of words associated with pain. They hypothesized higher subjective pain ratings would be shown in subjects exposed to pain-associated words. Therefore, there would be a positive correlation between physical symptom reporting and priming effects caused by pain-associated words.

Twenty-seven healthy, pain-free subjects participated in the study at the University of Manchester and Cambridge University. None were taking pain medication.

Results showed there were higher subjective pain ratings after priming with words highly associated with pain and also evidence of pain anticipation after priming with the same words.

The authors concluded their findings support previous theories explaining that increasing semantic activation of pain concepts in memory also increases subjective ratings of pain. Further, activation of pain concepts often occurs without conscious awareness.

Fasting and Glucose Could Increase Neuroplasticity to Bolster Pain Treatment

Kimberly T. Sibille, Felix Bartsch, Roger B. Fillingim, Andreas Keil; Department of Aging and Geriatric Research, University of Flordia, Gainesville, FL; Pain Research and Intervention Center of Excellence, University of Flordia, Gainesville, FL; Department of Psychology, University of Florida, Gainesville, FL

University of Florida researchers reported in The Journal of Pain that alterations in the brain attributed to chronic pain, such as decreases in grey and white matter, are modifiable and reversible with effective clinical interventions. To counteract the maladaptive plasticity associated with chronic pain, treatment interventions and strategies that increase neuroplasticity could optimize the brain’s ability to learn and adapt, perhaps improving treatment outcomes.

There is emerging evidence that a wide spectrum of methods can be applied to reopen and enhance plasticity, such as transcranial direct current stimulation and transcranial magnetic stimulation. In addition, behavioral and pharmacological interventions have been investigated as well intermittent fasting and glucose administration.

The authors noted that chronic pain is a central nervous system condition maintained by maladaptive neuroplastic changes in the brain’s structure and function that have not been adequately addressed in most chronic pain treatments.

There is strong evidence that glucose administration and intermittent fasting are useful for promoting synaptic plasticity and learning, and might be applicable across a wide range of chronic pain treatment modalities, such as cognitive-behavioral, pharmacological, and physical therapy. Research is needed to determine if intermittent fasting and glucose supplements are effective in bolstering chronic pain treatments and for neuroplastic enhancement.


Highlights from PAIN (Volume 157, No. 3, March 2016 Issue)

Pain Medicine Cover

Prescription Trajectories and Effect of Total Hip Arthroplasty on the Use of Analgesics, Hypnotics, Antidepressants, and Anxiolytics: Results From a Population of Total Hip Arthroplasty Patients

Tone Blågestad, Inger H. Nordhus, Janne Grønli, Lars B. Engesæter, Sabine Ruths, Anette H. Ranhoff, Bjørn Bjorvatn, Ståle Pallesen; Department of Clinical Psychology, University of Bergen, Bergen, Norway; Department of Behavioural Sciences in Medicine, University of Oslo, Oslo, Norway; Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; Sleep and Performance Research Center, College of Medical Sciences, Washington State University, Spokane, WA; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Orthopaedics, Haukeland University Hospital, Bergen, Norway; Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Research Unit for General Practice, Uni Research Health, Bergen, Norway; Kavli Research Center for Ageing and Dementia, Haraldsplass Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway; Diakonhjemmet Hospital, Oslo, Norway; The Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway; Department of Psychosocial Science, University of Bergen, Bergen, Norway

Most patients who are waiting for total hip arthroplasty (THA) report constant pain and use of pain medications. Nocturnal pain is a key indication for THA, and 80% of all presurgical patients report awakening at night because of pain. Patients generally experience increasing levels of pain leading up to surgery, elevated postoperative pain during the 3-month recovery phase, and a pain level lower than presurgical pain at 6 to 12 months after surgery. The prevalence of anxiety and depression among these patients is between 5% and 15%.

The aim of this study was to extend previous research on THA and medication use by analyzing prescription patterns associated with three groups of analgesics and three groups of psychotropics 1 year before and 1 year after surgery. Investigators analyzed prescription trends leading up to surgery, changes in medication use during the recovery period after surgery, and long-term effects of surgery on medication use. They hypothesized that use of these medications would increase before surgery, drug use would further increase during the postoperative phase, and that THA would reduce use of medications 1 year after surgery.

Prescription trajectories revealed an increase in the use of analgesics (opioids and nonopioids) and hypnotics during the year before surgery, a peak during the postoperative recovery phase, and a decrease after THA long term, following the same pain trajectories described in the THA literature. All medication subgroups increased in user rates and drug volume during the year before surgery. Anxiety and depression related to an upcoming major surgical procedure declined rapidly after the surgery; nevertheless, an increase in use of antidepressants and anxiolytics was observed after the initial postoperative period, which might suggest that the anxiolytic and antidepressant effect of THA is not long lasting. When comparing preoperative and long-term postoperative levels, THA was associated with decreased use of analgesics, hypnotics, and anxiolytics, but not antidepressants.

The reduction in hypnotics may indicate that many patients experience improved sleep after surgery, which may be an underrecognized benefit of THA. The marked increase in analgesic and hypnotics use during the postsurgical phase, however, warrants special attention from prescribers because adverse effects (such as falls) are more likely during this phase.

Role of Extracellular Calcitonin Gene-Related Peptide in Spinal Cord Mechanisms of Cancer-Induced Bone Pain

Rikke R. Hansen, Valentina Vacca, Thomas Pitcher, Anna K. Clark, Marzia Malcangio; Wolfson Centre for Cell Biology and Neurobiology Institute, Rome, Italy; IRCCS Santa Lucia Foundation, Rome, Italy

Breast, prostate, and lung cancers are highly metastatic to bone. A frequent complication in patients with metastatic disease is cancer-induced bone pain (CIBP), which starts as intermittent pain and becomes constant with time. Furthermore, breakthrough pain, either spontaneous or attributable to weight bearing and movement, results in poor quality of life. Preclinical studies indicate that skeletal pain in primary and metastatic bone cancer includes a neuropathic component.

CIBP not only is associated with an initial tumor-induced nerve injury of distal processes of sensory fibers, but also with sprouting and formation of neuroma-like structures by sensory and sympathetic fibers innervating the tumor-bearing site. The current view is that nerve growth factor (NGF) released by endogenous stromal, immune, and inflammatory cells drives the sensory fiber ectopic sprouting, as this is significantly decreased by early anti-NGF treatment without any effect on bone destruction or tumor growth. In this study, investigators tested the hypothesis that an upregulation of calcitonin gene–related peptide (CGRP) in sensory neurons innervating the bone is mirrored by an increased release of CGRP from central terminals in the dorsal horn where CGRP can facilitate neuronal nociceptive signaling in CIBP. Also, they investigated whether astrocytes express CGRP receptors and respond to CGRP application.

Results provide evidence for increased levels of extracellular CGRP in the dorsal horn of the lumbar spinal cord in mice with CIBP. Cancer-bearing mice displayed spontaneous pain-like behavior and referred allodynia. Specifically, in dorsal horn superfusates obtained from cancer-bearing mice, overall CGRP levels were significantly higher than in slices from sham-operated mice. Accordingly, activity-evoked release of this peptide reached values that were 58% higher than in sham-operated mice. However, the respective primary afferent fiber activity-evoked release of CGRP over basal levels was not different between cancer-bearing mice and sham-operated mice. Therefore, they conclude that as a result of basal levels of CGRP being higher under CIBP conditions, overall CGRP extracellular levels are increased in the dorsal horn.

These data indicate that an increased primary afferent input into the dorsal horn is responsible for allodynia in CIBP. Glutamate drives neuronal activation at the spinal level in CIBP through activation of N-methyl-D-aspartate receptors, an effect that is potentiated by CGRP. Thus, CIBP induces a state of central sensitization in which changes in the spinal cord facilitate an increased transmission of nociceptive information. The increase in centrally available CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling, but also may act on astrocytic CGRP receptors and lead to release of adenosine 5’-triphosphate.

Clinical Journal of Pain

Highlights from Clinical Journal of Pain (Volume 32, No. 3, March 2016 Issue)


Clinical Significance of Pain at Hospital Discharge Following Traumatic Orthopedic Injury: General Health, Depression, and PTSD Outcomes at 1 Year

Kristin R. Archer, Sara E. Heins, Christine M. Abraham, William T. Obremskey, Stephen T. Wegener, and Renan C. Castillo; Departments of Orthopaedic Surgery, Physical Medicine, and Rehabilitation, School of Medicine, Vanderbilt University, Nashville, TN.; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health and Department of Physical Medicine and Rehabilitation, Johns Hopkins Medicine, Baltimore, MD

The persistence of moderate to severe pain is widespread following traumatic orthopedic injury. Elevated pain early during the recovery process can predict chronic pain. Despite the importance of persistent pain following orthopedic trauma, limited research has examined the relationship between pain during the acute postoperative period and long-term health outcomes.

The primary objective of this study was to determine whether pain at hospital discharge is associated with outcomes 1 year following traumatic orthopedic injury. Investigators hypothesized that increased early postoperative pain would be associated with decreased general health and depression and posttraumatic stress disorder (PTSD) after controlling for demographic and injury characteristics. This study prospectively enrolled 213 patients, 19–86 years of age, who were admitted to an academic level 1 trauma center for surgical treatment of atraumatic lower-extremity (87%) or upper-extremity (13%) orthopedic injury.

Results did not support the investigators’ hypothesis that pain intensity would impact long-term general physical and mental health. These results were unexpected, given that cross-sectional studies of trauma survivors have found an association between pain and general health outcomes at 12 months after injury. However, early postoperative pain was associated with depression and PTSD at 1 year. These results suggest that efforts to improve pain assessment and management in the hospital setting may have a positive impact on long-term depressive and PTSD symptoms, and these data support studies that demonstrate a pain-depression relationship longitudinally, with the severity of pain symptoms determining risk for developing psychological distress. Increased pain intensity at hospital discharge was also associated with clinically significant PTSD. These results are underscored by literature highlighting the need for interventions during the early postacute phases of recovery to address pain and patients’ psychosocial needs following traumatic injury. Studies suggest that stepped and collaborative care models may be effective for improving long-term outcomes. Self-management and brief cognitive-behavioral programs in the hospital setting also have been shown to be effective for chronic pain.

These findings highlight the importance of early screening for uncontrolled postoperative pain to identify patients at high risk for poor outcomes who could benefit from more aggressive pain treatment.

Triggering Descending Pain Inhibition by Observing Ourselves or a Loved-One in Pain

Véronique Gougeon, Isabelle Gaumond, Philippe Goffaux, Stéphane Potvin, and Serge Marchand; Département de chirurgie, Service de neurochirurgie, Equipe de recherche sur la douleur; Ecole de réadaptation, Faculté de Médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke; and Département de psychiatrie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada

Research conducted during the past decade confirms that the subjective experience of pain can be modulated by observing others in pain. These empathy-related responses are modulated by the affective relation between an observer and the individual in pain, particularly by people who are significant to us. This effect has been subsumed under the rubric of empathy-induced pain modulation.

Neuroimaging studies show that simply knowing or imagining that a loved one is currently experiencing pain is sufficient to trigger activations of pain processing regions in the brain of the observer. These regions principally include affect-processing regions of the brain (particularly the anterior cingulate and frontoinsular cortices). Affect-related pain-processing regions of the brain are also thought to play a key role in descending endogenous pain-control circuits.

This study tested the possibility that observing either ourselves or a loved one in pain would trigger descending pain inhibition without the need for a concomitantly applied painful conditioning stimulus (CS). Investigators hypothesized that the empathic modulation of subjective pain depends on the activation of descending pain inhibition. Healthy volunteers were recruited at a hospital and invited to participate in 4 experimental sessions. Descending pain inhibition was triggered by immersing the right arm of participants (15 heterosexual couples in their late 20s) in a bath of cold water. The effects of empathy on descending pain inhibition were observed by immersing participants’ right arms in a lukewarm water bath while having them watch a video of either themselves or their spouses during a previous nociceptive immersion. Immersion of the arm in a lukewarm water bath without empathic (video) observation was also included as a control condition.

Investigators found that the mere observation of one’s self or a loved one in pain can trigger a strong descending inhibition response, especially among women. These results are consistent with the literature, which demonstrates that the observation of someone in pain activates brain regions involved in the descending inhibitory system as well as in the pain experience. These results reveal a correlation between catastrophizing level and descending inhibition response: the more participants catastrophize during the CS, the better their inhibition when they observe either themselves or their spouses in pain. In this study, a higher catastrophizing score (tested at the first session) seems to have increased the conditioned inhibition. The correlation obtained was during a nonpainful condition while observing one’s self or a loved one in pain. Investigators hypothesized that the catastrophizing level of a participant would increase perceived pain, explaining why it correlates with conditioned pain modulation efficiency.

This study provides evidence of the importance of the affective component of pain, showing how pain observation can modulate physiological mechanisms. The ability to trigger endogenous pain modulation is influenced by a person’s relation with the pain of others and should be taken into account in clinical conditions.