Publications

2009

Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663-672.
OBJECTIVE: Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation. In this pilot clinical trial, we tested the effectiveness of low-dose naltrexone in treating the symptoms of fibromyalgia. DESIGN: Participants completed a single-blind, crossover trial with the following time line: baseline (2 weeks), placebo (2 weeks), drug (8 weeks), and washout (2 weeks). PATIENTS: Ten women meeting criteria for fibromyalgia and not taking an opioid medication. INTERVENTIONS: Naltrexone, in addition to antagonizing opioid receptors on neurons, also inhibits microglia activity in the central nervous system. At low doses (4.5 mg), naltrexone may inhibit the activity of microglia and reverse central and peripheral inflammation. OUTCOME MEASURES: Participants completed reports of symptom severity everyday, using a handheld computer. In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity. RESULTS: Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects (including insomnia and vivid dreams) were rare, and described as minor and transient. Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response. Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone. CONCLUSIONS: We conclude that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.
Younger J, McCue R, Mackey S. Pain outcomes: a brief review of instruments and techniques. Curr. Pain Headache Rep. 2009;13(1):39-43.
Pain is a difficult outcome to measure due to its multifaceted and subjective nature. The need for selecting proper outcome measures is high because of the increasing demand for scientifically valid demonstrations of treatment efficacy. This article discusses some basic topics in the measurement of pain outcomes and addresses issues such as statistical versus clinical significance, daily home data collection, appropriate length of outcome measurement packets, and the possibility of objective pain measurements. This article also reviews some of the more commonly used tools for measuring pain and pain-related disability. By selecting the proper tools and employing them correctly, we can obtain highly reliable and valid measures of pain outcomes in research and clinical care.
Barad M, Greicius MD, Mackey S. IMAGING THE CNS CORRELATES OF NEUROPATHIC PAIN. CONTINUUM: Lifelong Learning in Neurology. 2009;15(5):30.
In recent years, there has been considerable growth in the use of imaging to understand, define, and-to a lesser extent, treat-neuropathic pain. This review seeks to summarize the newfound focus on neuroimaging and to put this research in the context of the existing definitions of neuropathic pain and the pain matrix. The research described herein is leading to an expanded definition of neuropathic pain at a time when some in the scientific community have sought to narrow the definition. The research also is helping us understand the role of central neural systems in the development, diagnosis, and treatment of chronic neuropathic pain. However, much of this early research on imaging has been based on relatively small studies and/or heterogenous patient populations, suggesting that further research needs to be done to validate them.Relationship Disclosure: Dr Barad has nothing to disclose. Dr Greicius has received personal compensation from Forest Laboratories, Inc., for serving on a patient safety monitoring panel. Dr Mackey has received personal compensation from Pfizer Inc for serving as a consultant and speaker.Unlabeled Use of Products/Investigational Use Disclosure: Drs Barad, Greicius, and Mackey have nothing to disclose.
Carroll I, Clark D, Mackey S. Sympathetic block with botulinum toxin to treat complex regional pain syndrome. Ann. Neurol. 2009;65(3):348-351.
Complex regional pain syndrome is a refractory pain condition with few tested therapies. We hypothesized that botulinum toxin A (BTA) would prolong analgesia after sympathetic blocks in patients with complex regional pain syndrome. We compared the duration of standard lumbar sympathetic block (LSB) with bupivacaine to LSB with bupivacaine and BTA in nine patients with refractory complex regional pain syndrome. Median time to analgesic failure was 71 (95% confidence interval, 12-253) days after LSB with BTA compared with fewer than 10 days (95% confidence interval, 0-12) after standard LSB (log-rank, p \textless 0.02). BTA profoundly prolonged the analgesia from sympathetic block in this preliminary study.
Neugebauer V, Galhardo V, Maione S, Mackey SC. Forebrain pain mechanisms. Brain Res. Rev. 2009;60(1):226-242.
Emotional-affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests that subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional-affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.

2008

Lawrence J, Mackey SC. Role of neuroimaging in analgesic drug development. Drugs R. D. 2008;9(5):323-334.
Rapidly developing, non-invasive, neuroimaging methods provide increasingly detailed structural and functional information about the nervous system, helping advance our understanding of pain processing, chronic pain conditions and the mechanisms of analgesia. However, effective treatment for many chronic pain conditions remains a large, unmet medical need. Neuroimaging techniques may enhance our understanding of why currently available analgesics are ineffective for so many patients and aid in identifying new neural targets for pharmacological interventions of pain. This review examines how neuroimaging has enhanced our understanding of the mechanisms of chronic pain, the neural correlates of pharmacological modulation of pain, and the role of neuroimaging in analgesic development. Rather than focusing on one method, we discuss the advantages and limitations of several techniques that may each serve a unique role in aiding drug development, and we discuss current issues that exist in the design and implementation of pharmacological neuroimaging studies. Particularly, experimental design must be carefully considered as there are limitations in terms of the pharmacokinetics of the drug of interest as well as in respect to the capabilities of the neuroimaging method in use. Finally, we identify future directions including novel approaches that may also play a role in furthering our knowledge of the neural basis of analgesia. In the future, neuroimaging will certainly impact the methodology of analgesic drug development as it may lead to quicker and more efficient methods of evaluating the neural modulation of chronic pain.
Ochsner KN, Zaki J, Hanelin J, et al. Your pain or mine? Common and distinct neural systems supporting the perception of pain in self and other. Soc. Cogn. Affect. Neurosci. 2008;3(2):144-160.
Humans possess a remarkable capacity to understand the suffering of others. Cognitive neuroscience theories of empathy suggest that this capacity is supported by shared representations of self and other. Consistent with this notion, a number of studies have found that perceiving others in pain and experiencing pain oneself recruit overlapping neural systems. Perception of pain in each of these conditions, however, may also cause unique patterns of activation, that may reveal more about the processing steps involved in each type of pain. To address this issue, we examined neural activity while participants experienced heat pain and watched videos of other individuals experiencing injuries. Results demonstrated (i) that both tasks activated anterior cingulate cortex and anterior insula, consistent with prior work; (ii) whereas self-pain activated anterior and mid insula regions implicated in interoception and nociception, other pain activated frontal, premotor, parietal and amygdala regions implicated in emotional learning and processing social cues; and (iii) that levels of trait anxiety correlated with activity in rostral lateral prefrontal cortex during perception of other pain but not during self-pain. Taken together, these data support the hypothesis that perception of pain in self and other, while sharing some neural commonalities, differ in their recruitment of systems specifically associated with decoding and learning about internal or external cues.
Younger J, Barelka P, Carroll I, et al. Reduced cold pain tolerance in chronic pain patients following opioid detoxification. Pain Med. 2008;9(8):1158-1163.
OBJECTIVE: One potential consequence of chronic opioid analgesic administration is a paradoxical increase of pain sensitivity over time. Little scientific attention has been given to how cessation of opioid medication affects the hyperalgesic state. In this study, we examined the effects of opioid tapering on pain sensitivity in chronic pain patients. DESIGN: Twelve chronic pain patients on long-term opioid analgesic treatment were observed in a 7- to 14-day inpatient pain rehabilitation program, with cold pain tolerance assessed at admission and discharge. The majority of participants were completely withdrawn from their opioids during their stay. OUTCOME MEASURES: We hypothesized that those patients with the greatest reduction in daily opioid use would show the greatest increases in pain tolerance, as assessed by a cold pressor task. RESULTS: A linear regression revealed that the amount of opioid medication withdrawn was a significant predictor of pain tolerance changes, but not in the direction hypothesized. Greater opioid reduction was associated with decreased pain tolerance. This reduction of pain tolerance was not associated with opioid withdrawal symptoms or changes in general pain. CONCLUSIONS: These findings suggest that the withdrawal of opioids in a chronic pain sample leads to an acute increase in pain sensitivity.