March 2017
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 18, No. 3, March 2017 Issue)

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Severe Pain More Common in Veterans than General Population

Richard L. Nahin; National Center for Contemporary and Integrative Health, National Institutes of Health

The prevalence of severe pain is strikingly more common in U.S. military veterans than in the general population, especially in veterans who served in recent conflicts, according to research published in The Journal of Pain.

Richard L. Nahin from the National Center for Complimentary and Integrative Health conducted the first study to examine the severity of pain in a nationally representative population of veterans vs. nonveterans. The objectives of the study were:

  • compare the 3-month prevalence of any pain as well as severe pain
  • examine the relationship of age and sex with pain prevalence and severity
  • compare the prevalence of severe pain associated with specific pain-related conditions.

For the study, researchers applied data from the National Health Interview Survey (NHIS) Sample Adult Core and the NHIS Adult Functioning and Disability (AFD) Supplement. The AFD collected information on the persistence and intensity of self-reported pain in the previous 3 months. Respondents were first asked if they had pain in the previous 3 months, and how often (i.e., never, some days, most days, or every day). Severe pain was defined as that which occurs most days or every day and bothers the individual “a lot.” The data enabled comparison of pain prevalence in a sample of 6,647 veterans and 61,049 nonveterans.

Results showed 65% of veterans reported pain vs. 54% of nonveterans. The rate of severe pain in veterans was 40% higher than nonveterans. The difference was more pronounced in younger veterans (18-39 years of age), who are overrepresented by those who served in the wars in Iraq and Afghanistan.

Regarding sex differences, male veterans were more likely to report severe pain than nonveterans, but there was no difference between the two female groups. Also, the prevalence of severe pain was significantly higher in veterans with back pain, jaw pain, severe headache or migraine, and neck pain than among nonveterans.

Nahin concluded that increased pain in veterans suggest that more attention should be paid to helping veterans cope with pain. Some veterans may benefit from a revised pain management plan that addresses the full range of biological, psychological, and social effects of pain on the individual.

Study Explores Relationship Between Chronic Fatigue Syndrome and Chronic Widespread Pain in Adolescents

Tom Norris, Kevin Deere, Jon H. Tobias, Esther Crawley; Centre for Child and Adolescent Health, School of Social and Community Medicine, Bristol, United Kingdom; Musculoskeletal Research Unit, School of Clinical Sciences, Bristol, United Kingdom

A team of British researchers examined the prevalence and co-occurrence of chronic fatigue syndrome (CFS) and chronic widespread pain (CWP) in adolescents. They hypothesized that CFS and CWP would share common associations on the basis of findings from separate studies that have revealed other covariates with CFS (i.e., depression, obesity, and anxiety). Another objective was to investigate the relationship of CFS and CWP and a range of covariates after taking into account the overlap between the two conditions.

Data for the study was acquired from responses to a pain questionnaire from individuals participating in the Avon Longitudinal Study of Parents and Children. The total sample was 5,217 adolescents. Subjects were asked to shade the site of their pain on a mannequin and indicate if the pain had started within the past 3 months or earlier. Similar to fibromyalgia, CWP was defined as pain lasting longer than 3 months, axial pain, and upper right quadrant pain plus lower left quadrant pain or upper left quadrant pain plus lower right quadrant pain. The questionnaire also assessed pain severity on a 1 to 10 scale, with 1 representing no pain.

Participants were classified with CFS if they indicated being tired or lacking in energy during the past month. Participants were excluded from CFS if the tiredness or lack of energy had lasted less than 6 months, if the adolescent believed the condition was due to exercise or medication, and if daily activities were not impaired.

Covariates assessed in the study were depression and anxiety, which are known to be associated with CFS or CWP. The subjects were assessed using the CIS-R, a self-administered computerized interview, which allows researchers to assess psychiatric morbidity for a range of common mental disorders.

Results showed that 3% of the adolescents have CFS and 5% have CWP. In this cohort, 15% of adolescents with CFS have comorbid CWP. Higher levels of depression and anxiety were associated with exclusive CFS, and anxiety without depression appeared to be related to exclusive CWP. Further, increasing levels of anxiety and depression were more strongly associated with the presence of CFS and CWP together than the two conditions independently.

This is the first population-based study to show the prevalence of overlap between CFS and CWP in adolescents. The researchers noted that future studies should investigate whether depression and anxiety are causal or secondary to CFS and whether anxiety is causal for CWP.


Highlights from PAIN (Volume 158, No. 3, March 2017 Issue)

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A Prospective Study of Predictors of Long-Term Opioid Use Among Patients with Chronic Noncancer Pain

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

The objective of this study was to test a sample of patients who had initiated a new episode of opioid therapy for chronic noncancer pain (CNCP) and who had a moderate likelihood of continuing opioid use long term to determine if predictors of unfavorable pain and problem opioid use outcomes also predicted opioid use and higher-dose use 1 year later. Investigators hypothesized that increased risk for an unfavorable pain outcome (as defined by a chronic pain prognostic risk score), increased risk for problem opioid use (as defined by a problem opioid use risk score), and greater depressive symptom severity each would predict opioid use 1 year later.

In a large sample of middle-age and older adults who had a moderate likelihood of receiving long-term opioid therapy for CNCP, 46% continued to use opioids 1 year later. Fewer than 5% were using opioids at higher doses (a 50-mg morphine-equivalent dose/day or higher) at 1 year. A pain prognostic risk score calculated from baseline measures of pain intensity, pain-related interference with activities, number of days with pain in the prior 6 months, and widespread pain did not predict continued opioid use 1 year later in adjusted models.

In contrast, a problem opioid use risk score (calculated based on history of diagnosis during the past 2 years of opioid or nonopioid abuse/dependence, a mental health disorder, hepatitis C, or alcohol abuse/dependence; self-report as a current smoker; and age younger than 65) was a significant predictor for sustained opioid use in adjusted models. Among all variables examined, the patient’s rating of the likelihood of using opioids at 1 year was the strongest predictor of 1-year opioid use in univariate and multivariate analyses. These findings indicate that patient expectations regarding future opioid use may be independent of other patient-level or medication-level characteristics in determining whether a patient continues opioid therapy long term. Baseline depression and chronic pain prognostic risk score did not predict opioid use 1 year later after adjusting for the problem opioid use risk score and relevant covariates.

Future research should assess whether patient expectations regarding sustained opioid use can be influenced through brief counseling and whether altering patient expectations regarding duration of opioid use (such as by prespecifying a time limit for opioid therapy) could lower the likelihood of opioid use continuing for longer periods of time than clinically indicated.

Effects of Cognitive Behavioral Therapy (CBT) on Brain Connectivity Supporting Catastrophizing in Fibromyalgia

Asimina Lazaridou, Jieun Kim, Christine M. Cahalan, Marco L. Loggia, Olivia Franceschelli, Chantal Berna, Peter Schur, Vitaly Napadow, and Robert R. Edwards; Departments of Anesthesiology and Medicine and Division of Rheumatology, Harvard Medical School, Brigham & Women’s Hospital, Chestnut Hill; MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA; and Clinical Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea

Fibromyalgia (FM) is a chronic musculoskeletal pain condition that affects 2% to 4% of the population and is characterized by anatomically widespread pain symptoms accompanied by fatigue and disturbed sleep and mood. FM pain is experienced predominantly in the muscles and soft tissue; however, the diverse and widespread symptoms also may extend to nearly any anatomic region. Recent meta-analyses and reviews suggest that cognitive behavioral therapy (CBT), compared with other active treatments, reduces pain intensity, disability, and emotional distress among individuals with FM.

Although the mechanisms supporting CBT’s benefits have not been fully elucidated, CBT acts to reduce negative affective responses to pain such as those characterized by pain-related catastrophizing. The aim in this randomized controlled trial was to assess CBT’s effects on brain circuitry underlying clinical pain and hyperalgesia and to evaluate the association between treatment-related changes in catastrophizing and treatment-related changes in pain-related brain circuitry. After the baseline visit, patients with FM were randomly assigned into either a month-long, four-session individual CBT treatment program or a month-long, four-session FM education treatment program. Among the 16 completers, all participants completed all four treatment visits. Cuff pain algometry was used to produce tonic deep-tissue pain.

Results support prior findings that individual CBT for patients with FM produces long-term improvements in pain, and reductions in catastrophizing may serve as an important factor in shaping these outcomes. Treatment-related changes in catastrophizing in this study were much larger than changes in a more general affective factor such as depressive symptomatology. A substantial portion of CBT’s effectiveness for pain management likely is attributable to its emphasis on cognitive skills (e.g., cognitive restructuring, distraction) that can be honed through practice and deployed to manage daily pain symptoms. This trial enrolled only high-catastrophizing patients, and recent evidence suggests that patients who catastrophize most frequently may benefit most from these cognitive coping skills.

These results add to a growing body of literature suggesting important links between clinical outcomes in FM and the degree of connectivity between the anterior/middle insula cortex and brain regions not typically connected to the insula in a resting state (i.e., primary somatosensory and default mode network areas). These pilot findings suggest that CBT reduces potentially dysfunctional brain states and improves clinical outcomes such as pain-related disability in part by reducing catastrophizing. Future longitudinal studies using fMRI-derived variables as biomarkers and including substantially larger sample sizes will be needed to identify the clinical potential of these preliminary findings.

The Clinical Journal of Pain

Highlights from The Clinical Journal of Pain (Volume 33, No. 3, March 2017 Issue)


Intraoperative Ketamine Reduces Immediate Postoperative Opioid Consumption After Spinal Fusion Surgery in Chronic Pain Patients with Opioid Dependency: A Randomized, Blinded Trial

Rikke Vibeke Nielsen, Jonna Storm Fomsgaard, Hanna Siegel, Robertas Martusevicius, Lone Nikolajsen, Jørgen Berg Dahl, Ole Mathiesen; Department of Neuroanesthesiology, Rigshospitalet—Glostrup, Copenhagen University Hospital, Glostrup, Denmark; Department of Anesthesiology, Nykoebing Falster Hospital, Nykoebing Falster, Denmark, Copenhagen University Hospital; Department of Anesthesiology, Aarhus University Hospital, Aarhus, Denmark; Department of Anesthesiology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Department of Anesthesiology, Zealand University Hospital Koege, Copenhagen University Hospital, Koege, Denmark

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist blocking NMDA receptors in the central and peripheral nervous systems. Experimental studies suggest that ketamine attenuates central sensitization and hyperalgesia and thereby reduces postoperative opioid tolerance. The primary aim of this trial was to examine if intraoperative low-dose ketamine would reduce postoperative opioid consumption and acute pain when compared with placebo in opioid-dependent patients. The primary outcome was 24-hour postoperative morphine consumption. Secondary outcomes were acute pain at rest and during mobilization 2 to 24 hours after surgery, adverse effects, and persistent pain 6 months postoperatively.

This study demonstrated that intraoperative low-dose intravenous (IV) ketamine significantly reduced supplemental IV patient-controlled morphine consumption during the first 24 hours after lumbar fusion surgery in opioid-dependent patients. Sedation was significantly reduced in the ketamine group. Six months after surgery, patients in the ketamine group reported significantly more improvement of their back pain than those in the placebo group; further, walking distance was improved versus findings in the placebo group. The Oswestry index score demonstrated significantly less disability in the ketamine group. There were no differences between groups regarding nausea and vomiting. Significantly lower sedation scores were demonstrated in the ketamine group 6 and 24 hours after surgery, possibly as a result of the higher opioid consumption in the placebo group.

Regarding ketamine side effects (hallucinations and nightmares), there were no significant differences between groups. Six months after surgery, patients in the ketamine group reported significantly more improvement of their back pain than those in the placebo group. Patients in the ketamine group also reported a longer walking distance and had less disability on the Oswestry index.

Reasons for Discontinuation of Long-Term Opioid Therapy in Patients With and Without Substance Use Disorders

Travis I. Lovejoy, Benjamin J. Morasco, Michael I. Demidenko, Thomas H. A. Meath, Joseph W. Frank, Steven K. Dobscha; Center to Improve Veteran Involvement in Care, VA Portland Health Care System, Portland, OR; Department of Psychiatry, Oregon Health & Science University, Portland; School of Public Health, Oregon Health & Science University, Portland; Center for Health Systems Effectiveness, Oregon Health & Science University, Portland, OR; Center of Innovation for Veteran-Centered and Value-Driven Care, VA Eastern Colorado Health Care System, Denver, CO; Division of General Internal Medicine, University of Colorado School of Medicine, Aurora, CO

A substantial body of empirical evidence indicates that patients with substance use disorder (SUD) histories who are prescribed opioid therapy for chronic pain are at increased risk for engaging in opioid-related hazardous behaviors such as opioid misuse and abuse, diversion, and concurrent use and abuse of alcohol and other illicit substances. Patients with SUD also are at increased risk for opioid-related adverse events such as overdose and death. However, patients with SUD are more likely to be prescribed long-term and high-dose opioid therapy—a phenomenon scholars have termed “adverse selection.”

The aim of this study was to compare reasons for discontinuation of long-term opioid therapy (LTOT) between patients with and without SUD who received care within a major U.S. healthcare system in the years after release of the 2009 and 2010 opioid therapy clinical practice guidelines. Investigators hypothesized that patients with SUD would be more likely to discontinue LTOT because of aberrant behaviors, including illicit substance use, aberrant urine drug tests results, opioid misuse, and diversion.

The study sample involved 300 patients with an SUD diagnosis during the year before opioid therapy discontinuation and 300 propensity score–matched patients without an SUD diagnosis. Nearly all patients (86%) had been diagnosed with musculoskeletal pain, with smaller proportions having been diagnosed with headaches (including migraine, 11%) or neuropathic pain (6%). Hydrocodone, oxycodone, methadone, and morphine were the most commonly prescribed opioid medications during the year before discontinuation, with 57%, 38%, 29%, and 26% of patients being prescribed these medications, respectively.

In most scenarios (85%), clinicians, not patients, initiated LTOT discontinuation. Clinicians face challenges when discontinuing LTOT for patients who engage in behaviors that heighten risk for opioid-related adverse events. Conversely, discontinuing LTOT when aberrant behaviors are identified, even when these actions represent good clinical practice, may erode the patient-provider relationship. The ways in which clinicians communicate with patients before, during, and after discontinuation of LTOT are paramount to ensure patients continue to receive pain care and other needed services rather than disengaging from a clinic or healthcare system entirely. If mishandled, patients may be at increased risk for engaging in illicit behaviors to obtain opioids, attempting to obtain opioids from other clinics or an emergency room, or resorting to street drugs such as heroin.

Treating chronic pain in patients with SUD is further complicated by high rates of medical and psychiatric comorbidities. The complexity of this patient population points to the need for comprehensive, multidisciplinary care that, at a minimum, concurrently addresses substance use and pain as well as other psychiatric and medical conditions that exacerbate pain and SUD symptoms. Additional research is needed to determine if such models will prove efficacious for patients who discontinue LTOT.