Publications

2008

Carroll IR, Kaplan KM, Mackey SC. Mexiletine therapy for chronic pain: survival analysis identifies factors predicting clinical success. J. Pain Symptom Manage. 2008;35(3):321-326.
Mexiletine, a sodium channel blocker, treats neuropathic pain but its clinical value has been questioned due to its significant side effects and limited efficacy. We hypothesized that ongoing therapy with mexiletine would have limited patient acceptance, but that an analgesic response to intravenous (IV) lidocaine (a pharmacologically similar drug) would identify patients most likely to choose ongoing therapy with mexiletine. We identified a cohort of 37 patients with neuropathic pain who underwent IV lidocaine infusions at our institution and were subsequently prescribed mexiletine. Time until discontinuation of mexiletine was used as the primary endpoint. Time until discontinuation is a clinically relevant, discrete, objective endpoint gaining acceptance as a metric for assessing clinical performance of drugs with significant side effects and limited efficacy. We used the techniques of survival analysis to determine factors that predicted continued therapy with mexiletine. Median time to discontinuation of mexiletine was only 43 days. A stronger analgesic response to IV lidocaine significantly predicted continued acceptance of mexiletine therapy. Decreasing age and male gender also predicted continued acceptance of mexiletine therapy. Analyzing time to mexiletine discontinuation uncovers important limitations in mexiletine s clinical performance missed by studies with conventional endpoints, such as change in pain score. Despite claims of efficacy, acceptance of mexiletine therapy is poor overall. Test infusions with lidocaine identify patients most likely to continue mexiletine therapy. Further work is needed to confirm these results and evaluate the relative acceptance of mexiletine vs. other treatments of neuropathic pain.

2007

Mackey S, Feinberg S. Pharmacologic therapies for complex regional pain syndrome. Curr. Pain Headache Rep. 2007;11(1):38-43.
Complex regional pain syndrome (CRPS) remains a challenging condition to diagnose and treat. There are few large-scale, randomized trials of pharmacologic agents, and most published studies are small, uncontrolled, or presented only in abstract form at meetings. The most commonly used agents, such as anticonvulsants, antidepressants, and opiates, have been found to be useful for other neuropathic pain conditions in large-scale trials but have not been adequately studied in CRPS. Systemic steroids delivered by multiple routes continue to be used, with some good evidence for short-term administration. N-methyl-D-aspartate antagonists have recently gained in popularity, without evidence from well-controlled trials. Bisphosphonates have been well studied and offer promise. In addition, there has been interest in thalidomide; however, we are still awaiting well-controlled trials. This article presents an overview of the available data regarding pharmacologic therapies for CRPS. These agents should be used in conjunction with a comprehensive interdisciplinary approach aimed at functional restoration and improved quality of life.
Mitra R, Zeighami A, Mackey S. Pulsed radiofrequency for the treatment of chronic ilioinguinal neuropathy. Hernia. 2007;11(4):369-371.
BACKGROUND: Ilioinguinal neuropathy is a rare but disabling condition. The condition may arise spontaneously or in the setting of pelvic surgery. To date, most therapeutic options have been limited to neuropathic pain medications, anti-inflammatory medications, nerve blocks with local anesthetics, or neurectomy. Long-term results of non-surgical interventions are fair at best. We present a case of chronic ilioinguinal neuropathy treated with pulsed radiofrequency. OBJECTIVE: To examine the efficacy of pulsed radiofrequency (PRF) lesioning on pain in ilioinguinal neuropathy. METHOD: A 58-year old man with chronic ilioinguinal neuropathy was treated with PRF and was followed for 3 months. RESULTS: The patient had significant pain relief at 3 months follow up. CONCLUSION: Pulsed radiofrequency lesioning may be a good treatment for chronic ilioinguinal neuropathy in cases refractory to conservative management.
The ability to empathize with the suffering of others is critical for maintaining relationships and engaging in prosocial behavior. Recently, a series of studies have demonstrated that while watching other people experience pain (other pain), participants engage the anterior insula (AI) and anterior cingulate cortex (ACC), brain regions involved in the direct experience of pain (self pain). Here we test the hypothesis that common activity in ACC and AI may reflect the operation of distinct but overlapping networks of regions that support perception of self or other pain. To address this possibility, we scanned participants using fMRI while they received noxious thermal stimulation (self pain) or watched short videos of other people sustaining painful injuries (other pain). We isolated overlapping regions for self and other pain in the ACC and AI and then used them as seed regions for two kinds of functional connectivity analyses. These analyses identified areas whose activity co-varied with ACC and AI activity during self or other pain either across time (intra-individual connectivity) or across participants (inter-individual connectivity). Both connectivity analyses identified clusters in the midbrain and periaqueductal gray with greater connectivity to the AI during self pain as opposed to other pain. The opposite pattern was found in the dorsal medial prefrontal cortex, that showed greater connectivity to the ACC and AI during other pain than during self pain using both types of analysis. Intra-individual connectivity analyses also revealed regions in the superior temporal sulcus, posterior cingulate, and precuneus that became more connected to ACC during other pain as compared to self pain. Together, these data demonstrated that regions showing similar activity during self and other pain may nonetheless be part of distinct functional networks. These networks could not have been detected in prior work that examined overlap between self and other pain in terms of average activity, but not connectivity.
OBJECTIVES: The proportion of chronic pain patients with suspected neuropathic pain who will have clinically meaningful pain relief with intravenous (IV) lidocaine and the clinical characteristics that identify these patients have not been described previously. METHODS: We conducted a cohort study of 99 patients who underwent IV lidocaine infusions for suspected neuropathic pain. An 11-point Numerical Rating Score (NRS) of pain intensity was recorded at the beginning and end of each infusion. A predefined literature-based criteria for “clinically meaningful” reductions in pain score was used to classify patients as responders or nonresponders. Multivariate logistic regression was used to determine clinical variables that predicted an increased likelihood of being a lidocaine responder. RESULTS: The mean reduction in NRS during lidocaine infusions was 2.34 (95% confidence interval 2.83-1.85, P\textless0.001). Forty-two percent of patients (95% confidence interval 32.5%-52.8%) had NRS reductions of 30% or greater and met the predefined criteria as lidocaine responders. Univariate and multivariate analyses indicated that advancing age and pain severity significantly increased the odds of being a lidocaine responder. Controlled for all other factors, each decade of advancing age increased the odds of being a lidocaine responder by 36%. Each 1-point increase, on an 11-point scale of baseline pain severity, increased the odds of being a lidocaine responder by 29%. DISCUSSION: IV lidocaine effectively reduces pain in a minority of patients suspected of having neuropathic pain. Pain severity and patient age can be used to target therapy to those most likely to respond.
Kornelsen J, Mackey S. Potential clinical applications for spinal functional MRI. Curr. Pain Headache Rep. 2007;11(3):165-170.
Functional MRI (fMRI) of the spinal cord is a noninvasive technique for obtaining information regarding spinal cord neuronal function. This article provides a brief overview of recent developments in spinal cord fMRI and outlines potential applications, as well as the limitations that must be overcome, for using spinal fMRI in the clinic. This technique is currently used for research purposes, but significant potential exists for spinal fMRI to become an important clinical tool.
Watcha D, Brown J, Darnauer J, Sarin R, Glover G, Mackey S. (656).; 2007.

2006

Ochsner KN, Ludlow DH, Knierim K, et al. Neural correlates of individual differences in pain-related fear and anxiety. Pain. 2006;120(1-2):69-77.
Although individual differences in fear and anxiety modulate the pain response and may even cause more suffering than the initiating physical stimulus, little is known about the neural systems mediating this relationship. The present study provided the first examination of the neural correlates of individual differences in the tendency to (1) feel anxious about the potentially negative implications of physical sensations, as measured by the anxiety sensitivity index (ASI), and (2) fear various types of physical pain, as indexed by the fear of pain questionnaire (FPQ). In separate sessions, participants completed these questionnaires and experienced alternating blocks of noxious thermal stimulation (45-50 degrees C) and neutral thermal stimulation (38 degrees C) during the collection of whole-brain fMRI data. Regression analyses demonstrated that during the experience of pain, ASI scores predicted activation of a medial prefrontal region associated with self-focused attention, whereas FPQ scores predicted activation of a ventral lateral frontal region associated with response regulation and anterior and posterior cingulate regions associated with monitoring and evaluation of affective responses. These functional relationships cannot be wholly explained by generalized anxiety (indexed by STAI-T scores), which did not significantly correlate with activation of any regions. The present findings may help clarify both the impact of individual differences in emotion on the neural correlates of pain, and the roles in anxiety, fear, and pain processing played by medial and orbitofrontal systems.