The journal of pain : official journal of the American Pain Society
-
Adults with irritable bowel syndrome (IBS) have been reported to have alterations in autonomic nervous system function as measured by vagal activity via heart rate variability. Whether the same is true for children is unknown. We compared young children 7 to 10 years of age with functional abdominal pain (FAP) or IBS to healthy children (HC) and explored the relationship of vagal activity and sympathovagal balance to psychological distress and stool type. Children completed questionnaires, kept a 2-week pain/stool diary, and wore a 24-hour Holter monitor to assess vagal activity. Group comparisons on vagal activity were controlled for age and body mass index. Indicators of vagal activity and sympathovagal balance did not differ between FAP/IBS children (70 girls, 30 boys) and HC (44 girls, 18 boys). Psychological distress measures were generally higher in FAP/IBS than HC, primarily in girls. Exploratory analyses suggest a potential negative correlation between vagal activity and psychological distress in FAP/IBS girls but not boys. In contrast to reports in women, no differences were found in vagal activity between FAP/IBS and HC. Preliminary findings suggest that in girls with FAP/IBS there is an inverse relationship between vagal activity and psychological distress. ⋯ The results from this study suggest a possible relationship between emotional state and vagal activity in prepubertal girls (but not boys) with FAP/IBS. Age and/or duration of symptoms may explain our contrasting findings versus adults with IBS.
-
Previous work demonstrated that both the opioid antagonist (-)-naloxone and the non-opioid (+)-naloxone inhibit toll-like receptor 4 (TLR4) signaling and reverse neuropathic pain expressed shortly after chronic constriction injury. The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2-4 months) neuropathic pain, not just to pain shortly after nerve damage. Additionally, analyses of plasma levels of (+)-naloxone after subcutaneous administration indicate that (+)-naloxone has comparable pharmacokinetics to (-)-naloxone with a relatively short half-life. This finding accounts for the rapid onset and short duration of allodynia reversal produced by subcutaneous (+)-naloxone. Given that toll-like receptor 2 (TLR2) has also recently been implicated in neuropathic pain, cell lines transfected with either TLR4 or TLR2, necessary co-signaling molecules, and a reporter gene were used to define whether (+)-naloxone effects could be accounted for by actions at TLR2 in addition to TLR4. (+)-Naloxone inhibited signaling by TLR4 but not TLR2. These studies provide evidence for broad involvement of TLR4 in neuropathic pain, both early after nerve damage and months later. Additional, they provide further support for the TLR4 inhibitor (+)-naloxone as a novel candidate for the treatment of neuropathic pain. ⋯ These studies demonstrated that (+)-naloxone, a systemically available, blood-brain barrier permeable, small molecule TLR4 inhibitor can reverse neuropathic pain in rats, even months after nerve injury. These findings suggest that (+)-naloxone, or similar compounds, be considered as a candidate novel, first-in-class treatment for neuropathic pain.
-
Randomized Controlled Trial
Effects of motor cortex modulation and descending inhibitory systems on pain thresholds in healthy subjects.
Pain modulation can be achieved using neuromodulatory tools that influence various levels of the nervous system. Transcranial direct current stimulation (tDCS), for instance, has been shown to reduce chronic pain when applied to the primary motor cortex. In contrast to this central neuromodulatory technique, diffuse noxious inhibitory controls (DNIC) refers to endogenous analgesic mechanisms that decrease pain following the introduction of heterotopic noxious stimuli. We examined whether combining top-down motor cortex modulation using anodal tDCS with a bottom-up DNIC induction paradigm synergistically increases the threshold at which pain is perceived. The pain thresholds of 15 healthy subjects were assessed before and after administration of active tDCS, sham tDCS, cold-water-induced DNIC, and combined tDCS and DNIC. We found that both tDCS and the DNIC paradigm significantly increased pain thresholds and that these approaches appeared to have additive effects. Increase in pain threshold following active tDCS was positively correlated with baseline N-acetylaspartate in the cingulate cortex and negatively correlated with baseline glutamine levels in the thalamus as measured by magnetic resonance spectroscopy. These results suggest that motor cortex modulation may have a greater analgesic effect when combined with bottom-up neuromodulatory mechanisms, presenting new avenues for modulation of pain using noninvasive neuromodulatory approaches. ⋯ This article demonstrates that both noninvasive motor cortex modulation and a descending noxious inhibitory controls paradigm significantly increase pain thresholds in healthy subjects and appear to have an additive effect when combined. These results suggest that existing pain therapies involving DNIC may be enhanced through combination with noninvasive brain stimulation.
-
Chronic neuropathic pain is one of the most prevalent and debilitating disorders. Conventional medical management, however, remains frustrating for both patients and clinicians owing to poor specificity of pharmacotherapy, delayed onset of analgesia and extensive side effects. Neuromodulation presents as a promising alternative, or at least an adjunct, as it is more specific in inducing analgesia without associated risks of pharmacotherapy. Here, we discuss common clinical and investigational methods of neuromodulation. Compared to clinical spinal cord stimulation (SCS), investigational techniques of cerebral neuromodulation, both invasive (deep brain stimulation [DBS] and motor cortical stimulation [MCS]) and noninvasive (repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]), may be more advantageous. By adaptively targeting the multidimensional experience of pain, subtended by integrative pain circuitry in the brain, including somatosensory and thalamocortical, limbic and cognitive, cerebral methods may modulate the sensory-discriminative, affective-emotional and evaluative-cognitive spheres of the pain neuromatrix. Despite promise, the current state of results alludes to the possibility that cerebral neuromodulation has thus far not been effective in producing analgesia as intended in patients with chronic pain disorders. These techniques, thus, remain investigational and off-label. We discuss issues implicated in inadequate efficacy, variability of responsiveness, and poor retention of benefit, while recommending design and conceptual refinements for future trials of cerebral neuromodulation in management of chronic neuropathic pain. ⋯ This critical review focuses on factors contributing to poor therapeutic utility of invasive and noninvasive brain stimulation in the treatment of chronic neuropathic and pain of noncancerous origin. Through key clinical trial design and conceptual refinements, retention and consistency of response may be improved, potentially facilitating the widespread clinical applicability of such approaches.
-
Intact cognitive inhibition in patients with fibromyalgia but evidence of declined processing speed.
Patients with fibromyalgia frequently report cognitive complaints. In this study we examined performance on 2 cognitive inhibition tests, the Stroop Color-Word Test (SCWT) and the Multi-Source Interference Test (MSIT), in 35 female patients with fibromyalgia and 35 age-matched healthy female controls. Experimental pressure pain thresholds (PPT) were determined, and fibromyalgia patients rated their current pain on a visual analog scale and completed the pain and fatigue subscales of the Fibromyalgia Impact Questionnaire. Further, all subjects completed questionnaires assessing symptoms of pain catastrophizing, depression, and anxiety. Significant group differences were found for SCWT and MSIT performance in both the neutral (N) and interference (I) conditions with slower reaction times in patients versus controls. However, no significant group differences were found for the difference (I-N) or proportion (I/N) scores, or on the number of errors made. For patients, pain experienced during PPT correlated significantly to several indices of cognition. Psychosocial variables were not related to cognitive test performance. Fibromyalgia patients performed worse on both tests but to a similar extent for the neutral condition and the interference condition, indicating that there is no specific problem in cognitive inhibition. Evidence of decreased mental processing and/or psychomotor speed was found in patients with fibromyalgia. ⋯ Fibromyalgia patients performed worse on interference tests, but no specific problem in cognitive inhibition was found. Decreased reaction time performance may instead point to an underlying problem of psychomotor or mental processing speed in fibromyalgia. Future studies should examine potential deficits in psychomotor function in fibromyalgia patients in more detail.