Publications

2010

Younger J, Aron A, Parke S, Chatterjee N, Mackey S. Viewing pictures of a romantic partner reduces experimental pain: involvement of neural reward systems. PLoS One. 2010;5(10):e13309.
The early stages of a new romantic relationship are characterized by intense feelings of euphoria, well-being, and preoccupation with the romantic partner. Neuroimaging research has linked those feelings to activation of reward systems in the human brain. The results of those studies may be relevant to pain management in humans, as basic animal research has shown that pharmacologic activation of reward systems can substantially reduce pain. Indeed, viewing pictures of a romantic partner was recently demonstrated to reduce experimental thermal pain. We hypothesized that pain relief evoked by viewing pictures of a romantic partner would be associated with neural activations in reward-processing centers. In this functional magnetic resonance imaging (fMRI) study, we examined fifteen individuals in the first nine months of a new, romantic relationship. Participants completed three tasks under periods of moderate and high thermal pain: 1) viewing pictures of their romantic partner, 2) viewing pictures of an equally attractive and familiar acquaintance, and 3) a word-association distraction task previously demonstrated to reduce pain. The partner and distraction tasks both significantly reduced self-reported pain, although only the partner task was associated with activation of reward systems. Greater analgesia while viewing pictures of a romantic partner was associated with increased activity in several reward-processing regions, including the caudate head, nucleus accumbens, lateral orbitofrontal cortex, amygdala, and dorsolateral prefrontal cortex–regions not associated with distraction-induced analgesia. The results suggest that the activation of neural reward systems via non-pharmacologic means can reduce the experience of pain.
Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D. Subcutaneous injection of botulinum toxin a is beneficial in postherpetic neuralgia. Pain Med. 2010;11(12):1827-1833.
OBJECTIVE: To assess the benefits of subcutaneous injection of botulinum toxin A (BTX-A) for the treatment of postherpetic neuralgia (PHN). DESIGN: We investigated the therapeutic benefits of BTX-A in subjects with PHN in a randomized, double-blind, placebo-controlled study. Sixty subjects with PHN were randomly and evenly distributed into BTX-A, lidocaine, and placebo groups. MEASURES: After randomization, one of the following solutions was injected subcutaneously in the affected dermatome: 5u/mL BTX-A, 0.5% lidocaine, or 0.9% saline (placebo). Visual analog scale (VAS) pain and sleeping time (hours) were evaluated at the time of pretreatment, day 1, day 7, and 3 months posttreatment. Opioid usage was calculated at day 7 and 3 months posttreatment. RESULTS: Compared with pretreatment, VAS pain scores decreased at day 7 and 3 months posttreatment in all three groups (P\textless0.01). However, the VAS pain scores of the BTX-A group decreased more significantly compared with lidocaine and placebo groups at day 7 and 3 months posttreatment (P\textless0.01). Sleep time (hours) had improved at day 7 and at 3 months compared with pretreatment in all three groups, but the BTX-A group improved more significantly compared with lidocaine and placebo groups (P\textless0.01). The percent of subjects using opioids posttreatment in the BTX-A group was the lowest (21.1%) compared with the lidocaine (52.6%) and placebo (66.7%) groups (P\textless0.01). CONCLUSIONS: Subcutaneous administration of BTX-A significantly decreased pain in PHN and reduced opioid use compared with lidocaine and placebo at day 7 and 3 months post-treatment. It also increased subjects sleep times.
Myofascial pain of the temporomandibular region (M-TMD) is a common, but poorly understood chronic disorder. It is unknown whether the condition is a peripheral problem, or a disorder of the central nervous system (CNS). To investigate possible CNS substrates of M-TMD, we compared the brain morphology of 15 women with M-TMD to that of 15 age- and gender-matched healthy controls. High-resolution structural brain and brainstem scans were carried out using magnetic resonance imaging (MRI), and data were analyzed using a voxel-based morphometry approach. The M-TMD group evidenced decreased or increased gray matter volume compared to controls in several areas of the trigeminothalamocortical pathway, including brainstem trigeminal sensory nuclei, the thalamus, and the primary somatosensory cortex. In addition, M-TMD individuals showed increased gray matter volume compared to controls in limbic regions such as the posterior putamen, globus pallidus, and anterior insula. Within the M-TMD group, jaw pain, pain tolerance, and pain duration were differentially associated with brain and brainstem gray matter volume. Self-reported pain severity was associated with increased gray matter in the rostral anterior cingulate cortex and posterior cingulate. Sensitivity to pressure algometry was associated with decreased gray matter in the pons, corresponding to the trigeminal sensory nuclei. Longer pain duration was associated with greater gray matter in the posterior cingulate, hippocampus, midbrain, and cerebellum. The pattern of gray matter abnormality found in M-TMD individuals suggests the involvement of trigeminal and limbic system dysregulation, as well as potential somatotopic reorganization in the putamen, thalamus, and somatosensory cortex.
Carroll IR, Younger JW, Mackey SC. Pain quality predicts lidocaine analgesia among patients with suspected neuropathic pain. Pain Med. 2010;11(4):617-621.
OBJECTIVE: Oral sodium channel blockers have shown mixed results in randomized controlled trials despite the known importance of sodium channels in generating pain. We hypothesized that differing baseline pain qualities (e.g. “stabbing” vs “dull”) might define specific subgroups responsive to intravenous (IV) lidocaine-a potent sodium channel blocker. DESIGN: A prospective cohort study of 71 patient with chronic pain suspected of being neuropathic were recruited between January 2003 and July 2007 and underwent lidocaine infusions at Stanford University Hospital in a single-blind nonrandomized fashion. Baseline sensory pain qualities were measured with the Short-Form McGill Pain Questionnaire (SF-MPQ). Pain intensity was measured with a visual analog scale (VAS). RESULTS: Factor analysis demonstrated two underlying pain quality factors among SF-MPQ sensory items: a heavy pain and a stabbing pain. Baseline heavy pain quality, but not stabbing quality predicted subsequent relief of pain intensity in response to lidocaine. In contrast, these factors did not predict divergent analgesic responses to placebo infusions. In response to each 1 mcg/mL increase in lidocaine plasma level, patients with high heavy pain quality drop their VAS 0.24 (95% CI 0.05-0.43) more points than those with low heavy pain quality (P \textless 0.013). CONCLUSIONS: “Heavy” pain quality may indentify patients with enhanced lidocaine responsiveness. Pain quality may identify subgroups among patients with suspected neuropathic pain responsive to IV lidocaine. Further investigation is warranted to validate and extend these findings.
The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.
Harden NR, Bruehl S, Perez RSGM, et al. Development of a severity score for CRPS. Pain. 2010;151(3):870-876.
The clinical diagnosis of Complex Regional Pain Syndrome (CRPS) is a dichotomous (yes/no) categorization necessary for clinical decision-making. However, such dichotomous diagnostic categories do not convey an individual s subtle and temporal gradations in severity of the condition, and have poor statistical power when used as an outcome measure in research. This study evaluated the validity and potential utility of a continuous type score to index severity of CRPS. Psychometric and medical evaluations were conducted in 114 CRPS patients and 41 non-CRPS neuropathic pain patients. Based on the presence/absence of 17 clinically-assessed signs and symptoms of CRPS, an overall CRPS Severity Score (CSS) was derived. The CSS discriminated well between CRPS and non-CRPS patients (p\textless.001), and displayed strong associations with dichotomous CRPS diagnoses using both IASP diagnostic criteria (Eta=0.69) and proposed revised criteria (Eta=0.77-0.88). Higher CSS was associated with significantly higher clinical pain intensity, distress, and functional impairments, as well as greater bilateral temperature asymmetry and thermal perception abnormalities (p s\textless.05). In an archival prospective dataset, increases in anxiety and depression from pre-surgical baseline to 4 weeks post-knee arthroplasty were found to predict significantly higher CSS at 6- and 12-month follow-up (p s\textless.05). Results indicate the CSS corresponds with and complements currently accepted dichotomous diagnostic criteria for CRPS, and support its validity as an index of CRPS severity. Its utility as an outcome measure in research studies is also suggested, with potential statistical advantages over dichotomous diagnostic criteria.
Current IASP diagnostic criteria for CRPS have low specificity, potentially leading to overdiagnosis. This validation study compared current IASP diagnostic criteria for CRPS to proposed new diagnostic criteria (the “Budapest Criteria”) regarding diagnostic accuracy. Structured evaluations of CRPS-related signs and symptoms were conducted in 113 CRPS-I and 47 non-CRPS neuropathic pain patients. Discriminating between diagnostic groups based on presence of signs or symptoms meeting IASP criteria showed high diagnostic sensitivity (1.00), but poor specificity (0.41), replicating prior work. In comparison, the Budapest clinical criteria retained the exceptional sensitivity of the IASP criteria (0.99), but greatly improved upon the specificity (0.68). As designed, the Budapest research criteria resulted in the highest specificity (0.79), again replicating prior work. Analyses indicated that inclusion of four distinct CRPS components in the Budapest Criteria contributed to enhanced specificity. Overall, results corroborate the validity of the Budapest Criteria and suggest they improve upon existing IASP diagnostic criteria for CRPS.
Dworkin RH, Connor ABO, Audette J, et al. Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update. Mayo Clin. Proc. 2010;85(3, Supplement):S3—S14.
The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel α2-δ ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

2009

Shen YF, Younger J, Goddard G, Mackey S. Randomized clinical trial of acupuncture for myofascial pain of the jaw muscles. J. Orofac. Pain. 2009;23(4):353-359.
AIMS: To evaluate the effectiveness of acupuncture in treating symptoms associated with myofascial pain of the jaw muscles. METHODS: Twenty-eight subjects over the age of 18 and diagnosed with chronic myofascial pain of the jaw muscles were randomized to receive real (n = 16) or sham (n = 12) acupuncture. Prior to treatment, each subject clenched his or her teeth for 2 minutes. Acupuncture or sham acupuncture was then administered at the Hegu large intestine 4 (LI4) acupoint for 15 minutes. Real acupuncture was given by penetrating the needle through a sticky foam pad at the acupoint. Sham acupuncture was conducted by pricking the skin, without penetration, with a shortened, blunted acupuncture needle through a foam pad placed away from the acupoint. General head and neck pain ratings were obtained before and after treatment on a numerical rating scale. A mechanical pain stimulus on the masseter muscle was given before and after treatment and rated on a visual analog scale to measure pain tolerance level. Paired t tests were performed to detect significant changes in pain levels. RESULTS: Subjects receiving real acupuncture experienced a significant reduction in jaw pain (P = .04), jaw/face tightness (P = .04), and neck pain (P = .04), and a significant increase in pain tolerance of the masseter muscle (P = .001). Subjects were not able to determine whether they received real or sham acupuncture (P = .69). No significant pain reductions were observed in the sham acupuncture group. CONCLUSION: A single acupuncture session using one acupoint at Hegu large intestine 4 significantly reduced most myofascial pain endpoints when compared to sham acupuncture.
Wang CK, Gowda A, Barad M, Mackey SC, Carroll IR. Serratus muscle stimulation effectively treats notalgia paresthetica caused by long thoracic nerve dysfunction: a case series. J. Brachial Plex. Peripher. Nerve Inj. 2009;4(1):17.
Currently, notalgia paresthetica (NP) is a poorly-understood condition diagnosed on the basis of pruritus, pain, or both, in the area medial to the scapula and lateral to the thoracic spine. It has been proposed that NP is caused by degenerative changes to the T2-T6 vertebrae, genetic disposition, or nerve entrapment of the posterior rami of spinal nerves arising at T2-T6. Despite considerable research, the etiology of NP remains unclear, and a multitude of different treatment modalities have correspondingly met with varying degrees of success. Here we demonstrate that NP can be caused by long thoracic nerve injury leading to serratus anterior dysfunction, and that electrical muscle stimulation (EMS) of the serratus anterior can successfully and conservatively treat NP. In four cases of NP with known injury to the long thoracic nerve we performed transcutaneous EMS to the serratus anterior in an area far lateral to the site of pain and pruritus, resulting in significant and rapid pain relief. These findings are the first to identify long thoracic nerve injury as a cause for notalgia paresthetica and electrical muscle stimulation of the serratus anterior as a possible treatment, and we discuss the implications of these findings on better diagnosing and treating notalgia paresthetica.