September 2015
David Craig, PharmD | Editor


The Journal of Pain

Journal of Pain cover

The following highlights summarize selected articles from The Journal of Pain (Volume 16, Issue 9, September 2015).

Symptoms of Depression Are Associated with Opioid Use Regardless of Pain Severity and Physical Functioning Among Treatment Seeking Patients with Chronic Pain

Jenna Goesling, Matthew J. Henry, Stephanie E. Moser, Mohit Rastogi, Afton L. Hassett, Daniel J. Clauw, and Chad M. Brummett; Department of Anesthesiology, University of Michigan, Ann Arbor, MI; College of Literature, Science and Arts, University of Michigan, Ann Arbor, MI; and Department of Anesthesiology, University of Michigan, Ann Arbor, MI

Research has shown that chronic pain and depression are comorbid. Chronic pain increases the risk of depression, and depression can be a predictor for developing chronic pain. Because patients with mental health disorders usually are excluded from opioid efficacy trials, the safety and effectiveness of the medications in individuals with chronic pain and mental health disorders are difficult to ascertain. However, several studies have shown that patients with depression are more likely to receive opioid therapy across a variety of care settings and be prescribed higher doses.

Researchers from the University of Michigan examined the characteristics of patients treated at an outpatient clinic who were using opioids, and they investigated the role of depression in opioid use. They hypothesized that patients with chronic pain taking opioids would exhibit greater pain severity, worse functioning and more symptoms of depression than patients not using opioids.

The study included 2,104 new patients with chronic non-cancer pain evaluated at the University of Michigan Back and Pain Center from November 2010 to February 2014. Opioid use in the new patients was assessed via a comprehensive self-reported checklist.

Results showed that increased pain severity was associated with higher probability of taking opioids but thiseffect was moderated by depression. Among patients with symptoms of depression, the probability of taking opioids did not change based on pain severity. Also, patients with depressive symptoms were more likely to take opioids at higher levels of functioning.

The authors concludedpatients with depression may be taking opioids in part to help them manage their depressive symptoms.

Long-Term Outcome of the Management of Chronic Neuropathic Pain; A Prospective Observational Study

Dwight E. Moulin, A. John Clark, Allan Gordon, Mary Lynch, Patricia K. Morley-Forster, Howard Nathan, Cathy Smyth, Cory Toth, Elizabeth VanDenKerkhof, Ammar Gilani, and Mark A. Ware; Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada; Department of Anesthesiology, Dalhousie University, Halifax, Nova Scotia, Canada; Wasser Pain Management Centre, University of Toronto, Toronto, Ontario, Canada; Department of Anesthesiology, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Anesthesia & Perioperative Medicine, Western University, London, Ontario, Canada; Department of Anesthesiology, University of Ottawa, Ottawa, Ontario, Canada; Department of Clinical Neurological Sciences, University of Calgary, Calgary, Alberta, Canada; School of Nursing & Department of Anesthesiology & Perioperative Medicine, Queens University, Kingston, Ontario, Canada; Department of Internal Medicine, McMaster University, Hamilton, Ontario, Canada; and Department of Family Medicine, McGill University, Montreal, Quebec, Canada

Neuropathic pain affects as much as 8% of the U.S. population and accounts for one third of all chronic pain patients.

A multicenter team of Canadian researchers evaluated patient histories in the Canadian Neuropathic Pain Database to conduct a long-term observational prospective study to assess the real-world (versus clinical trial) effects of treatments for chronic neuropathic pain patients in tertiary care centers.

Nearly 800 patients with neuropathic pain were studied, and the primary outcome measure was a composite 30% reduction in pain intensity and a one-point difference in the mean Pain Interference Scale Score (0–10).

The authors noted their study is the largest to assess real-world effectiveness of the management of chronic neuropathic pain in a diverse population following established treatment guidelines.

Patients in the study were treated in accordance with standard guidelines for managing neuropathic pain. Polypharmacy was common as 28% of the patients took medications in two of the three analgesic drug classes used for treating neuropathic pain. At 12-month follow up, the percentage of patients being treated with analgesic antidepressants, anticonvulsants, and opioids did not change significantly.

Results showed that just 24% of patients treated at academic tertiary care centers for neuropathic pain achieved the primary outcome measures of a significant reduction in pain intensity and disability over 1 year. Further, at 12-month follow up, patients who had a favorable outcome were less likely to be on opioids than those with a less favorable outcome. Moreover, when those with the best outcomes were taking opioids, the doses were significatnly lower.

The authors also concluded that the study data casts doubt on the overall long-term benefit of opioid medications for most patients with chronic neuropathic pain, in consideration of the risks for opioid related adverse events.



Pain Medicine Cover

The following highlights summarize selected articles from PAIN (Volume 156, Issue 9, September 2015).

Ultrasound-Guided Intra-Atricular and Rotator Interval Corticosteroid Injections in Adhesive Capsulitis of the Shoulder: A Double-Blind, Sham Controlled Randomized Study

Tore Prestgaard, Marjon E.A. Wormgoor, Simen Haugen, and Herlof Harstad; Clinic Physical Medicine and Rehabilitation, Vestfold Hospital Trust, Tønsberg, Norway; Petter Mowinckel, Children’s Department, Oslo University Hospital, Oslo, Norway; Jens Ivar Brox, Department of Physical Medicine and Rehabilitation, Oslo University Hospital, University of Oslo, Oslo, Norway

Adhesive capsulitis or frozen shoulder is a common cause of shoulder pain and disability and is a self-limiting condition lasting up to 2–3 years. Limited evidence supports that intra-articular corticosteroid injections treat adhesive capsulitis effectively. This study compared ultrasound-guided intra-articular corticosteroid injection and combined intra-articular and rotator interval injection in a double-blind, sham-controlled randomized clinical trial. The main outcome measure was the group difference in change in shoulder pain (0-10) at 6 weeks.

A total of 122 patients were included in the study and all patients had one injection. The study found no significant differences between the intra-articular and combined interval/intraarticular injections in improving shoulder pain at any time during the follow-up period. Both corticosteroid injections were had more optimal results than a sham injection in improving shoulder pain at 6 weeks, and the effect was maintained for 12 weeks. The effectiveness was consistent for secondary outcomes, which included a combined disability and pain score, range of motion, and the use of pain medication.

Consistent with previous studies, a decrease in pain and disability was accompanied by an improvement in health-related quality of life. The low scores at baseline indicated that quality of life was hampered, but at week 26, quality of life for all groups was comparable with reference values in the normal population. However, the improvement was faster in the groups given corticosteroid injections. The improvement in health-related quality of life at 3, 6, and 12 weeks was considered to be valuable by the patients and supports the effectiveness of the corticosteroid injections.

This study did not report psychological factors and work absence, factors that are important outcomes in patients with pain and may have influenced the primary and secondary outcomes. The authors recommend the inclusion of psychological factors and work status in future studies. They also suggest that future research examine the cost-effectiveness of treatments and compare ultrasound-guided and unguided injections.

Targeting Cells of the Myeloid Lineage Attenuates Pain and Disease Progression in a Prostate Model of Bone Cancer

Michelle L. Thompson, Juan M. Jiminez-Andrade, Stephanie Chartier, James Tsai, Elizabeth A. Burton, Gaston Habets, Paul S. Lin, Brian L. West, Patrick W. Mantyh; Department of Pharmacology, Arizona Cancer Center, University of Arizona, Tuscon, AZ; Unidad Academica Multidisciplinaria Reynosa Aztlan Universidad Autonoma de Tamaulipas Reynosa, Tamaulipas, Mexico; Translational Pharmacology, Plexxikon, Inc., Berkeley, CA

Many of the treatments for cancer-induced bone pain (CIBP) that currently exist do little to improve patient survival and instead cause unwanted and severe side effects. Researchers studied the effects of PLX3397, a high-affinity small molecular antagonist, and whether it can reduce CIBP. PLX3397 is injected after formalin to treat second-stage inflammatory pain caused by the formalin injection, and it attenuates CIBP by blocking monocyte and macrophage function. PLX3397 inhibits phosphorylation of colony-stimulating factor-1 receptors (CSF1R) regulating macrophage differentiation, proliferation, and activation, which drives CIBP. 

Researchers injected rats and mice with canine ACE-1 prostate cancer cells in a hind femur. The cancer was given 14 days to propagate before treatment began. Animals were randomly divided into control groups, and a group receiving PLX3397 formulated in mouse chow. Researchers measured instance of pain in behavior and cancer prevalence in bone remodeling, tumor burden, and immunohistochemistry of the affected femurs. The behavioral queues measured were spontaneous flinching, guarding of the affected limb, and hind paw licking.

The results of the study show that PLX3397 reduces pain, as the behaviors tested as pain indicators occurred significantly less frequently in animals that were given PLX3397 than in those that were given control chow. Additionally, high resolution x-ray images of the affected femurs, immunohistochemical analysis of the hind limbs, and other methods showed that animals given PLX3397 showed fewer cancer cell colonies, a reduction in cancer-induced bone remodeling, and a smaller tumor burden area.

The authors concluded that their findings suggest that inhibiting cells in the myeloid lineage attenuates CIBP and reduces prostate tumor–induced bone remodeling and tumor growth. Additionally, the authors state that analgesics treating cancer pain can positive effects on patient survival time by decreasing stress, which can promote tumor growth. More research is needed to see if PLX3397 will have the same effects in bone cancer caused by metastasized breast, lung, and renal cancers. 

Clinical Journal of Painpainmedicine

The following highlights summarize selected articles from Clinical Journal of Pain (Volume 31, No. 9, September 2015 Issue).

Intranasal Oxytocin Administration Is Associated with Enhanced Endogenous Pain Inhibition and Reduced Negative Mood States

Burel R. Goodin, Austin J. B. Anderson, Emily L. Freeman, Hailey W. Bulls, Meredith T. Robbins, and Timothy J. Ness; Departments of Psychology and Anesthesiology, University of Alabama at Birmingham; Department of Biology, Samford University, Birmingham, AL

Although the role of oxytocin in parturition and lactation is well established, preclinical research is now indicating that this hormone may also affect somatosensory transmission, including the sensation of pain. Researchers from the University of Alabama at Birmingham and Samford University in Birmingham, AL, in a recent study published in The Clinical Journal of Pain, tested the effects of intranasal oxytocin on pain sensitivity and pain-relevant mood states in 30 pain-free young adults.

The authors hypothesized that intranasal oxytocin would be associated with less sensitivity to induced ischemic pain, greater endogenous pain inhibition, and less negative mood compared with placebo.

In the double-blind, placebo-controlled, within-subjects crossover study testing this hypothesis, participants completed three laboratory sessions on consecutive days. The first session evaluated each participant’s self-reported baseline ischemic pain sensitivity, endogenous pain inhibition via conditional pain modulation (CPM), and negative mood using the Profile of Mood States. Subsequent sessions evaluated each participant’s self-reported pain response to and mood following two tests, a modified submaximal effort tourniquet procedure and a cold pressor task, conducted after participants self-administered a placebo or 40 IU of oxytocin.

Results show that ischemic pain tolerance did not significantly differ across the three sessions. However, CPM effects following the administration of oxytocin were significantly greater than those following placebo and at baseline. The results also showed a significant decrease in anxiety and negative mood postadministration of oxytocin. Although prior evidence suggests that oxytocin can improve the effect of already positive social interactions, more study is warranted to determine whether intranasally administered oxytocin can augment endogenous pain inhibitory capacity in certain body sites and independently improve mood states, as suggested by this study. However, if substantiated, these findings may indicate oxytocin’s potential for improving clinical pain outcomes.

Genetic Polymorphisms in the Dopamine Receptor 2 Predict Acute Pain Severity After Motor Vehicle Collision

Yawar J. Qadri, Andrey V. Bortsov, Danielle C. Orrey, Robert A. Swor, David A. Peak, Jeffrey S. Jones, Niels K. Rathlev, David C. Lee, Robert M. Domeier, Phyllis L. Hendry, and Samuel A. Mclean; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC; Department of Emergency Medicine, William Beaumont Hospital, Royal Oak; Department of Emergency Medicine, Spectrum Health System, Grand Rapids; Department of Emergency Medicine, Saint Joseph Mercy Health System, Ypsilanti, MI; Department of Emergency Medicine, Massachusetts General Hospital, Boston; Department of Emergency Medicine, Bay State Medical Center, Springfield, MA; Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY; and Department of Emergency Medicine, University of Florida, Jacksonville, FL

The authors of this study studied people injured by motor vehicle collisions (MVCs), a large group with relatively homogenous injuries, to evaluate the potential impact of the dopaminergic system on acute pain. The authors hypothesized that acute pain severity after MVCs is influenced by genetic variants in the genes encoding dopamine receptor 2 (DRD2) and the dopamine active transporter. The authors also tested for sex differences in genotype effects.

After screening a total of 10,629 patients, the authors studied 948 participants aged 18–65 years who presented to emergency departments after MVC between February 2009 and October 2011. Participants had only minor injuries (99% had a maximum Abbreviated Injury Scale of 1). Blood was collected using PAXgene DNA storage tubes, DNA purification was performed using PAXgene blood DNA kits, and genotyping was performed using the Sequenom platform. All genotyped single-nucleotide polymorphisms (SNPs) were tested for Hardy-Weinberg equilibrium using a chi-squared test with Bonferroni adjustment.

The authors found that genetic variants in DRD2 were associated with acute pain severity in the hours after MVC. One DRD2 SNP showed a statistically significant main effect association with acute pain severity. One genotype that may affect acute pain may be sex-specific; another two SNPs also predicted acute pain severity in a sex-specific manner. The authors note that the functions of these SNPs are difficult to explain. They conclude that dopaminergic signaling through DRD2 is involved in nociceptive processing, that dopaminergic signaling variation is associated with acute pain severity after MVC, and that dopaminergic agents may be useful for pain control in other clinical settings.