October 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 10, October 2015).

Comorbidity of Mental Disorders and Chronic Pain: Chronology of Onset in Adolescents of a National Representative Cohort

Tegethoff, M., Belardi, A., Stalujanis, E., & Meinlschmidt, G.; Department of Psychology, Division of Clinical Psychology and Psychiatry, University of Basel, Basel, Switzerland; and Faculty of Medicine, Ruhr-University Bochum, Bochum, Germany

A team of European researchers has reported in The Journal of Pain that affective, anxiety, and behavioral disorders in adolescents are early risk factors for the eventual development of chronic pain.

For the study, data from some 6,500 study participants were accessed in the National Comorbidity Survey Replication Adolescent Supplement. Lifetime chronic pain was assessed by self-reports, and lifetime mental disorders were examined using the World Health Organization Composite International Diagnostic Interview and parent reports.

Several previous studies in adults consistently have documented increased rates of psychopathology in adults with pain conditions, including depression, anxiety, sleep disorders, substance abuse, and personality disorders. Prevalence estimates of mental disorders among persons with chronic pain range between 6% and 28%.

Little information is available about the relationship between mental disorders and chronic pain in adolescents, even though there is evidence showing a link between children and adolescents with pain and adult psychiatric symptoms and, conversely, indicating a relationship between children and adolescents with mental disorders and chronic pain in adulthood.

The main objectives of the study were to estimate the prevalence of co-occurrence of, the association between, and the temporal sequence of lifetime chronic pain and mental disorders in a sample of adolescents.

Results showed that one-fourth of the adolescents reported having chronic pain or a mental disorder in their lifetime. All types of pain were related to mental disorders, but the most substantial associations were found in cases wherein the occurrence of mental disorders preceded the onset of chronic pain. The findings indicate affective, anxiety, and behavior disorders are early risk factors for the development of chronic pain.

The authors concluded their results corroborate and advance knowledge about the link between chronic pain and mental disorders, and also show that the relationship forms in childhood and adolescence with increasing comorbidity in adulthood. The findings underscore the relevance of mental disorders in adolescence for pain research, and suggest the need for stronger collaborations between pain-care practitioners and mental health specialists.

Paradoxical Pain Perception in Posttraumatic Stress Disorder: The Unique Role of Anxiety and Dissociation

Defrin, R., Schreiber, S., & Ginzburg, K.

As much as 20% of trauma survivors experience posttraumatic stress disorder (PTSD), which is characterized by persistent re-experiencing of the traumatic event, emotional distress, and substantial functional impairments. Studies show that many persons with PTSD have chronic pain: the prevalence is estimated at 25%–93% of this population, which is two to five times the rate found in the general population.

A team of Israeli researchers hypothesized that high levels of anxiety, pain catastrophizing, and anxiety sensitivity among patients with PTSD are associated with pain hyperresponsiveness.

Thirty-two patients with combat-related PTSD were evaluated. Heat-pain threshold and pressure-pain threshold were measured, with the stimuli being gradually increased in intensity.

Results showed that the PTSD patients had higher pain thresholds and higher pain ratings than control subjects. Pain thresholds were positively associated with dissociation levels and negatively associated with anxiety sensitivity levels.

The authors concluded that the seemingly paradoxical emotional profile in PTSD—dissociation and anxiety—underlies the paradoxical pain profile in these patients, as shown by their hyposensitivity and hyperresponsiveness to pain. Clinical implications of these findings include consideration of treatments to reduce anxiety coupled with interventions to lower nociceptive excitability as early as possible. This approach could reduce the probability and/or intensity of chronic pain in individuals with PTSD.


Pain Medicine Cover

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

The Pain Course: A Randomized Controlled Trial Examining an Internet-Delivered Pain Management Program When Provided With Different Levels of Clinician Support

Blake F. Dear, Milena Gandy, Eyal Karin, Lauren G. Staples, Luke Johnston, Vincent J. Fogliati, Bethany M. Wootton, Matthew D. Terides, Rony Kayrouz, Kathryn Nicholson Perry, Louise Sharpe, Michael K. Nicholas, and Nickolai Titov; eCentreClinic, Department of Psychology, Macquarie University, Sydney, Australia; Departments of Medicine and Psychology, University of Tasmania, Hobart, Australia; Australian College of Applied Psychology, Sydney; Department of Psychology, University of Sydney, Sydney; Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney, Sydney

Internet-based delivery has potential to increase access to pain management programs. Internet-delivered programs use the same principles, content, and components as face-to-face programs but can be provided with varying levels of clinician support, ranging from regular clinician contact via e-mail or telephone to no clinician support. The majority of Internet-delivered programs for chronic pain have been based on cognitive behavior therapy, but some are now based on mindfulness and acceptance therapies. Systematic reviews and a meta-analysis have revealed evidence of small but clinically significant improvements in the primary domains targeted in pain management programs; however, as with face-to-face programs, clinical improvements have not been consistently observed in all studies, and the magnitude of improvements has varied considerably. 

The present study sought to replicate the results of the initial Pain Course trial and examine its efficacy when subjects were provided with different levels of clinical support. After a brief screening interview, participants were randomly assigned to one of four groups: a regular-contact group, an optional-contact group, a no-contact group, and a treatment-as-usual waitlist control group. It was hypothesized that participants in the three treatment groups would report significant improvements on clinical measures of disability, anxiety, depression, and pain relative to the control group, and that the regular-contact group would report greater improvements compared with the optional-contact and no-contact groups.

All three treatment groups reported significant improvements in disability, anxiety, depression, and average pain immediately posttreatment, and these improvements were found at 3-month follow-up to be sustained or further improved. No marked or consistent differences emerged between the treatment groups in clinical outcomes. Treatment completion and satisfaction rates were high and did not differ across the treatment groups.

This study also found evidence of significant reductions in medication and health service use, but these reductions were observed across the treatment and control groups. These findings suggest that good clinical outcomes can be obtained by Internet-delivered programs involving very little or no clinical contact.

More research is needed to explore the characteristics of people who do and do not benefit from Internet-delivered programs; the essential components and parameters of effective, safe, and acceptable Internet-delivered programs; and ways in which to integrate these programs into the healthcare system.

Neuropathic Pain as Part of Chronic Widepsread Pain: Environmental and Genetic Influences

Sukhleen K. Momi, Stella Maris Fabiane, Genevieve Lachance, Gregory Livshits, and Frances M. K. Williams; Department of Twin Research and Genetic Epidemiology, St. Thomas’ Hospital, King’s College London, London, United Kingdom; Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Chronic widespread pain (CWP) is a poorly understood complex condition with a prevalence that ranges between 5% and 17% in the general population. CWP is recognized as part of affective spectrum disorders and is characterized by repeated or continuous musculoskeletal pain lasting more than 3 months.

Heritability estimates show that genetic and shared environmental influences account for approximately 50% of CWP variance. It has been suggested that neuropathic features in chronic pain may be more prevalent in the general population than previously thought. Estimates for the prevalence of neuropathic pain (NP) in the population range between 6% and 8%.

In this study, investigators studied the prevalence of NP as part of CWP in TwinsUK, the largest registry of monozygotic and dizygotic twins in the United Kingdom. The registry contains extensive genotype and phenotype data obtained at clinical visits and via mailed and online questionnaires. Subjects have been shown to be similar to a singleton cohort for many traits and lifestyle factors and have been included in previous chronic pain studies. In addition to defining the prevalence of NP in CWP, the investigators estimated, using bivariate analysis, the genetic and environmental contribution shared between the traits.

The aims of this study were threefold: to determine the prevalence of neuropathic features as part of CWP, to determine the genetic and environmental influence on NP, and to determine the extent to which risk factors are shared between CWP and NP. Evidence of NP was found in 15.9% of patients with CWP. Of note, the prevalence of NP in the CWP fibromyalgia subset was substantially higher, at 24.5%. There were strong phenotypic and genetic correlations between CWP and NP, and it was this subgroup that was of particular interest.

Similar environmental factors for NP and CWP were found, with age, sex, body mass index, and smoking all implicated. These results provide insight into CWP and NP etiology and affirm the need for studies investigating the specific genetic variants underlying these pain conditions, which may further provide diagnostic tools and targets for treatment.

Pain Medicine

The following highlights summarize selected articles from Pain Medicine (Volume 16, No. 9, September 2015 Issue).

Long-Term Antihyperalgesic and Opioid Sparing Effects of 5-Day Ketamine and Morphine Infusion ("Burst Ketamine") in Diabetic Neuropathic Rats

Plato Mak, Jillian H. Broadbear, Anton Kolosov, and Colin S. Goodchild; School of Psychological Sciences, Faculty of Biomedical and Psychological Sciences, Monash University, Clayton, Victoria, Australia; Laboratory for Pain Medicine and Palliative Care, Centre for Pain Medicine and Palliative Care, Monash Institute of Medical Research, Victoria

Ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist that reliably produces antinociception in animal models of acute and neuropathic pain. Despite promising preclinical outcomes, however, the clinical investigation of ketamine as an analgesic has produced mixed results. For more than a decade, some clinics have offered long-term (5-day) continuous infusions of subanesthetic doses of ketamine in combination with an opioid to patients with neuropathic pain. This procedure, known as “burst ketamine” (BK), can produce extended periods of pain relief that are unattainable using conventional pharmacological treatment methods. However, the BK procedure has not been widely adopted because of inconsistent evidence of its effectiveness.

In this study, BK treatment was evaluated in rats that had developed diabetic neuropathy. Its long-term antinociceptive effects were assessed during a 12-week period in comparison with rats treated with ketamine or morphine alone versus a no-treatment (sham) condition. Of particular interest was whether doses of morphine that did not cause sedation could produce a significant antinociceptive response in rats with diabetic neuropathy.

The first major finding of this study was that BK treatment reversed thermal hyperalgesia in the hind paw of diabetic neuropathic rats for up to 12 weeks. The second finding was suggestive of an opioid-sparing effect: When the maximum nonsedating dose of morphine (5 mg/kg) was administered acutely, it produced no antinociceptive activity in neuropathic rats that underwent sham implant treatment. However, in rats that received BK, 5 mg/kg morphine acutely reversed thermal hyperalgesia in the hind paw for at least 6 weeks posttreatment. The finding that antihyperalgesic and opioid-sparing effects were less persistent after ketamine-only infusion demonstrates a synergistic interaction between ketamine and morphine when they are administered in combination. Paradoxically, the morphine-only infusion caused a posttreatment enhancement of hyperalgesia and loss of acute opioid analgesic efficacy, suggesting that in the absence of ketamine, morphine infusion worsens key neuropathic symptoms.

In contrast to the pronociceptive effects of the 5-day morphine infusion, the BK and ketamine-only infusion caused significant long-term reductions in paw hypersensitivity to noxious heat. These antihyperalgesic effects were likely attributable to ketamine arresting the influx of calcium at the NMDAR complex, which enabled the reversal of plastic changes in the spinal cord associated with central sensitization.

These findings complement the body of evidence supporting the effectiveness of BK for reducing chronic neuropathic pain and improving opioid response (effects that persisted for many weeks after treatment). These results have important implications for patients with severe, intractable chronic pain who do not benefit from standard analgesic treatments or who have developed tolerance to opioid analgesic effects because of prolonged use. By restoring opioid sensitivity, a low-dose analgesic regimen may be sufficient to alleviate pain after BK treatment, which would also minimize the occurrence of opioid-related side effects and toxicity.

Pharmaceutical Opioid Use and Dependence Among People Living with Chronic Pain: Associations Observed Within the Pain and Opioids in Treatment (POINT) Cohort

Gabrielle Campbell, Suzanne Nielsen, Briony Larance, Raimondo Bruno, Richard Mattick, Wayne Hall, Nicholas Lintzeris, Milton Cohen, Kimberley Smith, and Louisa Degenhardt; National Drug and Alcohol Research Centre, UNSW, Sydney, New South Wales, Australia; School of Medicine, University of Tasmania, Hobart, Tasmania, Australia; Centre for Youth Substance Abuse Research, University of Queensland, Herston, Queensland, Australia; Sydney Medical School, Sydney University, Herston, Queensland; The Langton Centre, South East Sydney Local Health District (SESLHD) Drug and Alcohol Services, Sydney, New South Wales, Australia; St. Vincent’s Clinical School, UNSW Medicine, UNSW, Sydney, New South Wales; National Addiction Centre, Kings College, London, England; School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia; Murdoch Children’s Research Institute, Australia; Department of Global Health, School of Public Health, University of Washington, Washington, USA

Short-duration randomized controlled trials have evaluated pharmaceutical opioids in the treatment of a range of chronic noncancer pain (CNCP) conditions and have demonstrated modest attenuation of pain, but few studies have run for long enough to demonstrate long-term benefit of opioids for CNCP.

Despite the limitations of the evidence, there has been a considerable increase in the long-term prescribing of opioids for CNCP in a number of countries. There has also been professional and public concern about concomitant increases in problematic opioid use and harms including dependence.

The Pain and Opioid in Treatment (POINT) cohort is designed to document patterns of pharmaceutical opioid prescribing and risk for adverse events in patients who have been prescribed opioids for CNCP. In this article, investigators sought to describe levels of current pharmaceutical opioid consumption and the correlates of different levels of consumption, examine the prevalence of lifetime dependence and past-year dependence as per ICD-10 criteria, and examine the correlates of the criteria met for pharmaceutical opioid dependence.

This detailed assessment revealed some concerning patterns of opioid consumption and clear associations between high-level consumption and a range of indicators of poorer functioning. Approximately 15% of the cohort was taking daily doses of more than 200 mg oral morphine equivalent (OME), and around 40% of the sample was consuming at least 90 mg OME daily. Those taking higher doses had the highest rates of problems with opioid medication, aberrance, and dependence. Participants receiving higher OME doses reported less pain relief from their medications than participants taking less medication. There also were no differences in rates of aberrance and dependence between these two groups.

Those consuming higher levels of opioids presented with more complex physical and mental health problems and social disadvantages. Many of the patients with chronic pain who were prescribed higher doses of long-term opioids were concurrently taking other medications (e.g., benzodiazepines) in doses that are considered high risk, and the levels of concomitant medications were higher among those taking more opioids. The association of higher opioid consumption with increasing levels of aberrant behaviors (e.g., tampering and nonmedical use) suggests that monitoring by prescribers is warranted.