July 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 7, July 2015).

Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy

Mark S. Wallace, Thomas D. Marcotte, Anya Umlauf, Ben Gouaux, and Joseph H. Atkinson; Department of Anesthesiology, School of Medicine, University of California—San Diego, CA; Department of Psychiatry, School of Medicine, University of California, San Diego, CA; Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA

New research reported in The Journal of Pain shows that inhaled cannabis reduces diabetic neuropathy and the analgesic effect is dose dependent.

Researchers at the University of California—San Diego conducted a randomized double-blind study evaluating 16 subjects to assess the efficacy and tolerability of inhaled cannabis for treating pain caused by diabetic peripheral neuropathy (DPN). They studied the effects of low, medium, and high doses of inhaled cannabis on DPN pain and hyperalgesia. Subjects participated in four outpatient treatment sessions separated by 2 weeks, in which they were exposed to placebo or three different doses of aerosol 1% THC, the most abundant and psychoactive compound in cannabis.

Results showed there was a dose-dependent reduction in pain intensity from inhaled cannabis, which the authors noted is consistent with results of other trials of the drug for diverse neuropathic pain syndromes. The dose dependent analgesic effect was evident for both spontaneous and evoked pain in the trial subjects, but it was more consistent on spontaneous pain. The authors reported that all subjects experienced either euphoria or somnolence, which may limit the acceptability of cannabis as an analgesic. However in measuring the impact of inhaled cannabis impact on cognition (attention and memory), they found modest effects with no dramatic declines or impairments.DPN occurs in half of diabetes patients and 15% of diabetics with DPN have pain, especially in the feet. Many patients do not achieve satisfactory relief from two FDA-approved treatments. Animal research in models of neuropathic pain suggests that cannabinoids may be effective in reducing pain, but no studies have focused specifically on painful DPN. The authors hypothesized that that inhaled cannabis would result in a dose-dependent reduction in spontaneous and evoked pain with a concomitant effect on cognitive function.

The authors concluded their findings, along with previous studies, suggest that cannabis might have analgesic benefit in neuropathic pain syndromes, including treatment-refractory DPN.

The Mediating Role of Acceptance in Multidisciplinary Cognitive-Behavioral Therapy for Chronic Pain

Sophia Åkerblom, Sean Perrin, Marcelo Rivano Fischer, and Lance M. McCracken; Department of Pain Rehabilitation, Skåne University Hospital, Lund, Sweden; Department of Psychology, Lund University, Lund, Sweden; Department of Pain Rehabilitation, Skåne University Hospital, Lund, Sweden; and King's College London, Psychology Department, Health Psychology Section, London, United Kingdom

Cognitive-behavioral therapy (CBT) is the most widely used psychological treatment for adults with chronic pain. Many different interventions are used in the context of CBT. Researchers at Skane University Hospital in Sweden, writing in The Journal of Pain, evaluated more than 400 patients to determine if pain acceptance—a willingness to experience pain and engage in valued activities despite the pain—mediates changes over time in a CBT-based multidisciplinary pain treatment program.

The authors hypothesized that improvements on measures of pain interference, pain intensity, and depression would be observed and that pain acceptance would demonstrate significant and unique mediating effects in relation to outcome measures. Self-report data were collected at initial assessment and 2 months and 12 months after treatment. The outcomes measures were pain interference, pain intensity and depression, which were assessed with appropriate rating scales.

Consistent with previous research, the study findings showed that CBT achieved improvements in overall functioning. Pain acceptance was the strongest independent contributor to changes in outcome as measured by pain interference and depression, over and above the effects of changes in life control, affective distress, and social support during treatment. However, acceptance had weak influence related to improvements in pain intensity.

The authors concluded the results show that pain acceptance can be an important treatment process in CBT.


Pain Medicine Cover

The following highlights summarize selected articles from PAIN (Volume 156, Issue 7, July 2015).

Cerebral Analgesic Response to Nonsteroidal Anti-Inflammatory Drug Ibuprofen

Duncan J. Hodkinson, Nadine Khawaja, Owen O’Daly, Michael A. Thacker, Fernando O. Zelaya, Caroline L. Wooldridge, Tara F. Renton, Steven C. R. Williams, and Matthew A. Howard; Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Anaesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA; Department of Oral Surgery, King’s College London Dental Institute, London, United Kingdom

These authors used an established clinical pain model involving third molar extraction (TME) to assess the neural correlates of the analgesic response to ibuprofen in presurgical and postsurgical states and to assess the analgesic interaction between surgical state and treatment. The pain experienced after TME is a validated and widely used model for the clinical evaluation of analgesic efficacy. Pain intensity after TME has been shown to reach its maximum between 3 and 5 hours after surgery, supporting a strong inflammatory component. To examine the cerebral response to ibuprofen, investigators used arterial spin labeling (ASL), a magnetic resonance imaging technique that quantitatively and noninvasively measures regional cerebral blood flow (rCBF). This methodology was incorporated into a randomized double-blind placebo-controlled design with an open method of drug administration.

Findings show that independent of its antinociceptive action, ibuprofen has no effect on rCBF under normal pain-free conditions. However, in the postsurgical state, investigators observed increased activation of top-down modulatory circuits accompanied by decreases in the areas engaged because of ongoing pain. A specific network of brain regions was activated in response to ibuprofen-induced analgesia, providing evidence of a significant positive analgesic interaction involving increased regional CBF that was isolated to the rostral ventrolateral medulla periaqueductal gray, posterior cingulate cortex, amygdala, orbitofrontal cortex, and hippocampus.

These findings demonstrate that ibuprofen has a measurable analgesic response in the human brain, with the subjective effects of pain relief reflected in two distinct brain networks. The observed activation of regions involved in descending modulatory control is a unique finding that warrants further investigation because this may provide new insights into the inhibitory mechanisms of analgesia. This experimental framework is directly relevant for examining other nonopioid analgesics and novel therapeutic agents designed for the treatment of inflammatory pain.

Activation of JNK Pathway in Spinal Astrocytes Contributes to Acute Ultra-Low-Dose Morphine Thermal Hyperalgesia

Maria Domenica Sanna, Carla Ghelardini, Nicoletta Galeotti; Laboratory of Neuropsychopharmacology, Department of Neuroscience, Psychology, Drug Research, and Child Health, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

Evidence demonstrates that in addition to analgesia, opioids may enhance sensitivity to pain. This paradoxical effect is typically associated with potent mu-opioid receptor (MOR) agonists (eg, fentanyl, morphine, heroin), and hyperalgesia has been demonstrated in both clinical and laboratory studies. Enhanced pain sensitivity typically has been observed later in the time course after an immediate analgesic dose of opioid (delayed hyperalgesia) or after tolerance occurs in response to continual dosing of drugs. A series of findings released during the last decade demonstrated a role for spinal cord glial cells such as microglia and astrocytes in pain processing. Spinal cord glial cells are also activated after long-term opioid treatment, and this activation is associated with the development of antinociceptive tolerance, one of the side effects of opioid therapy.

The aim of this study was to investigate whether immediate administration of ultra-low-dose morphine might activate spinal cord glial cells and to clarify the molecular mechanisms involved. Authors focused on mitogen-activated protein kinases (MAPK), members of a superfamily of serine/threonine protein kinases, which are extensively distributed throughout the central nervous system and play a crucial role in transducing signals to the nucleus. The contribution of spinal MAPK to glial activation and their correlation with thermal hyperalgesia was studied.

Results provide evidence that supports an important role for spinal astrocytes in the induction of the paradoxical pronociceptive response to ultra-low-dose morphine. Astrocyte activation was detected after a single morphine administration. Investigators found significant increases in the astrocyte marker GFAP after morphine injection but did not detect increases in the expression of the microglial marker IBA1, suggesting that ultra-low-dose morphine selectively induces astrocyte responses. A correlation between MOR stimulation and astrocyte activation was confirmed by pharmacological and antisense treatments, ruling out the presence of an unspecific, opioid receptor-independent effect. Furthermore, astrocyte activation seemed to coincide with thermal hyperalgesia, consistent with its role in ultra-low-dose morphine hyperalgesia. There is no clinical application for extremely low-dose opioids, but the pronociceptive response detected at low doses may have clinical relevance.

The authors contend that astrocyte Jun N-terminal kinase (JNK) activation could mask morphine analgesia through neuronal-glial interactions and that targeting spinal neuronal-glial interactions may potentiate opioid analgesia and reduce opioid dosage and side effects.



Clinical Journal of Paincjop

The following highlights summarize selected articles from Clinical Journal of Pain (Volume 31, No. 7, July 2015 Issue).

Effectiveness and Safety of Transdermal Buprenorphine Versus Sustained-Release Tramadol in Patients With Moderate to Severe Musculoskeletal Pain: An 8-Week, Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled, Noninferiority Study

Xiaomei Leng, Zhanguo Li, Houshan Lv, Yi Zheng, Yi Liu, Kerong Dai, Chen Yao, Xiaoyan Yan, and Xiaofeng Zeng; Department of Rheumatology, Peking Union Medical College Hospital; Departments of Rheumatology, Orthopedics, Peking University People’s Hospital; Department of Rheumatology, Beijing Chao-Yang Hospital; Department of Medical Statistics, Peking University Clinical Research Institute, Beijing; Department of Rheumatology, Sichuan University West China Hospital, Chengdu, Sichuan Province; and Department of Orthopedics, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Buprenorphine primarily is used to manage a variety of acute and chronic pain conditions, including cancer pain and moderate to severe musculoskeletal pain (MSP) inadequately controlled with other analgesics. The buprenorphine transdermal system (BTDS), a new formulation marketed in 2001, has been shown to possess good efficacy and safety profiles, but data are lacking about its effectiveness in relation to other analgesics.

This study was a multicenter (six sites in China), randomized, double-blind, double-dummy, active-controlled, noninferiority phase III clinical trial consisting of a screening phase, treatment phase (including a 3-week titration period and a 5-week maintenance period), and follow-up phase. The study was conducted to evaluate the noninferiority of the effectiveness and safety of 7-day matrix BTDS compared with sustained-release tramadol tablets for patients with chronic moderate to severe MSP inadequately relieved by nonsteroidal anti-inflammatory drugs.

Eligible patients were adult outpatients (between 18 and 80 years of age) with a clinical diagnosis of nononcological moderate to severe MSP for 4 days per week. Patients with fibromyalgia were not eligible. After 8 weeks of receiving study medication, no statistically significant differences were observed in visual analog scale pain scores, number of nights with pain-related sleeping disturbance, improvement of sleeping quality, global impression of pain relief, dosage of paracetamol, or safety assessments between BTDS and tramadol tablets.

When compared against oral or parenteral medication delivery, transdermal products may offer some advantages to improve patients’ compliance. In this study, more than 70 percent of patients in both groups (71.57% versus 73.33%) preferred the 7-day transdermal system to tablets taken twice daily for pain relief, indicating that the patients’ choice of analgesics greatly depends on the convenience of administration. For elderly patients who need to take multiple medications to treat their comorbidities or for those with cognitive deficits, BTDS should be more convenient, especially for those with swallowing difficulties, impaired gastrointestinal function, cognitive deficits, impaired renal function, or mildly to moderately impaired liver function.

Living Life with My Child’s Pain: The Parent Pain Acceptance Questionnaire (PPAQ)

Allison M. Smith, Christine B. Sieberg, Shannon Odell, Edin Randall, and Laura E. Simons; Pain Treatment Service, Department of Anesthesiology, Perioperative and Pain Medicine, Division of Pain Medicine, Boston Children’s Hospital; Department of Psychiatry, Harvard Medical School; and P.A.I.N. (Pain & Analgesia Imaging Neuroscience) Group, Boston Children’s Hospital, Center for Pain in the Brain, Harvard Medical School, Boston, MA

Pediatric chronic pain occurs within a social context. Research demonstrates that parents’ emotional, cognitive, and behavioral responses are highly influential upon children’s pain and functional outcomes. These authors modified the items on the Chronic Pain Acceptance Questionnaire (CPAQ)-Parent Report to develop a related measure that assesses parents’ acceptance of their child’s pain. Parent pain acceptance refers to a parent’s ability to participate in his or her daily life activities in the presence of the child’s pain and permit their child’s pain to be a part of their life experience without focusing their efforts on controlling or avoiding it when these efforts conflict with parent and family values.

These investigators hypothesized that their Parent Pain Acceptance Questionnaire (PPAQ) would be a psychometrically strong measure consisting of two subscales—activity engagement and pain willingness. With regard to the measure’s construct validity, they hypothesized that creating parent acceptance of child pain would negatively correlate with parent pain catastrophizing and parent protective and minimizing responses.

Consistent with the weak correlation between child pain acceptance and child pain ratings, parent pain acceptance was not associated significantly with their child’s typical pain ratings. This suggests that what governs parents’ activity engagement in the presence of their child’s pain and acceptance of pain-related thoughts and feelings is something other than their child’s reported pain severity. Longer child pain duration was modestly associated with stronger parent pain acceptance, suggesting that parent pain acceptance may increase over time as parents shift from conceptualizing their child’s pain as needing to be eliminated to needing to be managed.

Parent pain acceptance was negatively associated with fear of pain, pain catastrophizing, and functional disability. These findings suggest that the extent to which parents engage in daily activities and accept their thoughts and feelings related to their child’s pain appears to counter characteristics associated with poor parent and child outcomes. This knowledge may inform future interventions for children with chronic pain and their parents. Additional research may further elucidate the role of parent pain acceptance as an intervention target and delineate therapeutic strategies for facilitating parent acceptance as a means to improve child outcomes.