The journal of pain : official journal of the American Pain Society
-
Randomized Controlled Trial
Effects of Milnacipran on Clinical Pain and Hyperalgesia of Patients With Fibromyalgia: Results of a 6-Week Randomized Controlled Trial.
Milnacipran is a serotonin-norepinephrine reuptake inhibitor that was approved by the U.S. Food and Drug Administration as effective therapy for fibromyalgia (FM) symptoms. However, its analgesic mechanism of action is not well understood. We hypothesized that improvement of mechanical and heat hyperalgesia would be a critical component of overall milnacipran efficacy in FM. We used a novel quantitative sensory testing protocol for assessment of mechanical and heat pain sensitivity that can be used for testing of peripheral and central pain mechanisms and their impact on clinical pain over time. We applied tonic mechanical and heat pain stimuli to 46 patients with FM during a randomized controlled trial with either 50 mg milnacipran (n = 23) or placebo (n = 23) twice daily over 6 weeks. During this trial, mean clinical pain (standard deviation) was evaluated daily, and mechanical and heat pain sensitivity every 2 weeks. At study entry, clinical pain was 5.0 (1.8) and 5.5 (1.8) visual analog scale units for patients with FM randomized to placebo and milnacipran, respectively (P > .05). Over 6 weeks, clinical pain of patients with FM significantly declined by 15%, but this improvement was not statistically different between milnacipran and placebo. However, repeated measures of mechanical and heat pain sensitivity reliably predicted up to 80% of the variance in clinical FM pain at every time point. Clinical pain and mechanical/heat pain sensitivity of patients with FM steadily declined during this trial, but the effects of milnacipran were not found to be superior to placebo. Repeated measures of mechanical/heat hyperalgesia reliably predicted large amounts of the variance in clinical pain across all participants, indicating their relevance for FM pain. ⋯ Although clinical pain and hyperalgesia decreased during this 6-week trial, the efficacy of milnacipran was not superior to placebo. The high correlations between clinical pain and hyperalgesia ratings at every time point seem to emphasize the relevant contributions of mechanical and heat hyperalgesia to clinical FM pain.
-
Randomized Controlled Trial
A More Pessimistic Life Orientation Is Associated With Experimental Inducibility of a Neuropathy-like Pain Pattern in Healthy Individuals.
The clinical pattern of neuropathic pain, diagnosed using the quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain), could be partly mimicked in healthy volunteers after topical capsaicin application. However, similar to clinical neuropathic pain that develops in only a subgroup of patients who have a neurologic lesion, this attempt to mimick a neuropathic pain pattern succeeded only in a small fraction (18%) of healthy individuals. In the present assessment, we pursued the hypothesis that the inducible subgroup differed from the other healthy participants with respect to their psychological phenotype. Therefore, in an observational study, participants were assessed using a comprehensive set of psychological variables comprising general psychological and pain-related cognitive-emotional mechanisms. The sum scores of the questionnaires were significantly linearly correlated with each other. Principal component analysis indicated that a major source of variance (46%) could be attributed to dispositional optimism examined via the Life Orientation Test (LOT). The LOT score significantly differed between the groups of participants, either those in whom a neuropathy-like pattern of pain assessed via QST could be partly (50-60% of the 11 QST parameters) induced (n = 20) or not (n = 90; P = .0375). It emerged again as the main selection criterion in a classification and regression tree predicting a participant's group assignment (inducible neuropathy-like QST pattern versus noninducible neuropathy-like QST pattern) at a cross-validated accuracy of 95.5 ± 2.1%. Thus, the few participants in a random sample of healthy volunteers who, after topical capsaicin application, partly resemble (to a degree of about 60%) the clinical pattern of neuropathic pain in the QST test battery, are preselectable on the basis of psychological factors, with a particular emphasis on pessimistic life attitudes. ⋯ In a small fraction of 18% of healthy volunteers, topical capsaicin application resulted in a neuropathy-like pattern in 50 to 60% of the components of a clinical test battery. These individuals displayed a more pessimistic life attitude as assessed by means of the LOT.
-
The use of placebo to reduce pain is well documented; however, knowledge of the neural mechanisms underlying placebo analgesia remains incomplete. This study used functional magnetic resonance imaging data from 30 healthy individuals and dynamic causal modeling to investigate changes in effective connectivity associated with the placebo analgesic response. Before scanning, participants were conditioned to expect less thermal pain at 2 of 4 sites on their feet. Visual analog scale pain ratings revealed a significant but small difference between the baseline and placebo sites (mean difference = 6.63, t(29) = 3.91, P ≤ .001, d = .97), confirming an analgesic effect. However, no significant differences in the magnitude of brain activation between conditions were observed via traditional random effects general linear modeling. Dynamic causal modeling was then used to investigate changes in effective connectivity during placebo analgesia. The results indicate that during placebo analgesia but not baseline condition, couplings between brain regions, including those involved in cognitive processes (eg, attention, expectation, evaluation), were significantly enhanced. Specifically, a significantly consistent decrease in the dorsolateral prefrontal cortex → periaqueductal gray coupling was found. These findings highlight the differences between pain processing and modulation at the network level. Moreover, our results suggest that small placebo effects may be better characterized via changes in the temporal dynamics among pain modulatory regions than only via changes in the magnitude of blood oxygenation level dependent activation. Further application of nuanced analytical approaches that are sensitive to temporal dynamics of pain-related processes such as dynamic causal modeling are necessary to better understand the neural mechanisms underlying pain processing in patient populations. ⋯ Changes in effective connectivity among pain-related brain regions may be more sensitive detectors of the neural representation of small placebo effects than are changes in the magnitude of brain activation. Knowledge of these mechanisms highlights the importance of integrated neural networks in the understanding of pain modulation.
-
Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress. ⋯ This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain.
-
Fibromyalgia syndrome (FMS) is characterized by widespread chronic pain, fatigue, sleep disorders, and cognitive-emotional disturbance. Patients with FMS exhibit increased sensitivity to experimental pain and pain-related cues, as well as deficits in emotional regulation. The present study investigated the spatiotemporal patterns of brain activations for observed pain in 19 patients with FMS and 18 age-matched, healthy control individuals using event-related potential analysis. Patients with FMS attributed greater pain and unpleasantness to pain pictures, relative to healthy control participants. An augmented late positive potential (LPP) component (>500 milliseconds) was found in patients viewing both pain and nonpain pictures, and this amplitude difference in the LPP covaried with perceived unpleasantness of pictures. Mid-latency potentials (250-450 milliseconds) demonstrated similar amplitude increases of positive potentials in the FMS patient group. By contrast, the short-latency positive potential (140 milliseconds) was reduced in patients with FMS relative to healthy control participants. Results suggest amplitude increases to mid- to long-latency cortical activations in patients with FMS, which are known to reflect emotional control and motivational salience of stimuli. ⋯ Patients with FMS demonstrate increased activations associated with pain and nonpain pictures. The findings suggest that even innocuous, everyday visual stimuli with somatic connotations may challenge the emotional state of patients with FMS. Our study points toward the importance of cognitive-emotional therapeutic approaches for the treatment of FMS.