RESUMO
Chronic pain in multiple sclerosis is common and difficult to treat. Its mechanisms remain incompletely understood. Dysfunction of the descending pain modulatory system is known to contribute to human chronic pain conditions. However, it is not clear how alterations in executive function influence this network, despite healthy volunteer studies linking function of the descending pain modulatory system, to cognition. In adults with multiple sclerosis-associated chronic neuropathic limb pain, compared to those without pain, we hypothesized altered functional connectivity of the descending pain modulatory system, coupled to executive dysfunction. Specifically we hypothesized reduced mental flexibility, because of potential importance in stimulus reappraisal. To investigate these hypotheses, we conducted a case-control cross-sectional study of 47 adults with relapsing remitting multiple sclerosis (31 with chronic neuropathic limb pain, 16 without pain), employing clinical, neuropsychological, structural, and functional MRI measures. We measured brain lesions and atrophy affecting descending pain modulatory system structures. Both cognitive and affective dysfunctions were confirmed in the chronic neuropathic limb pain group, including reduced mental flexibility (Delis Kaplan Executive Function System card sorting tests P < 0.001). Functional connectivity of rostral anterior cingulate and ventrolateral periaqueductal gray, key structures of the descending pain modulatory system, was significantly lower in the group experiencing chronic neuropathic pain. There was no significant between-group difference in whole-brain grey matter or lesion volumes, nor lesion volume affecting white matter tracts between rostral anterior cingulate and periaqueductal gray. Brainstem-specific lesion volume was higher in the chronic neuropathic limb pain group (P = 0.0017). Differential functional connectivity remained after correction for brainstem-specific lesion volume. Gabapentinoid medications were more frequently used in the chronic pain group. We describe executive dysfunction in people with multiple sclerosis affected by chronic neuropathic pain, along with functional and structural MRI evidence compatible with dysfunction of the descending pain modulatory system. These findings extend understanding of close inter-relationships between cognition, function of the descending pain modulatory system, and chronic pain, both in multiple sclerosis and more generally in human chronic pain conditions. These findings could support application of pharmacological and cognitive interventions in chronic neuropathic pain associated with multiple sclerosis.
RESUMO
OBJECTIVE: To inform feasibility and design of a future randomised controlled trial (RCT) using brain functional MRI (fMRI) to determine the mechanism of action of gabapentin in managing chronic pelvic pain (CPP) in women. DESIGN: Mechanistic study embedded in pilot RCT. SETTING: University Hospital. PARTICIPANTS: Twelve women (18-50 years) with CPP and no pelvic pathology (follow-up completed March 2014). INTERVENTION: Oral gabapentin (300-2700 mg) or matched placebo. OUTCOME MEASURES: After 12 weeks of treatment, participants underwent fMRI of the brain (Verio Siemens 3T MRI) during which noxious heat and punctate stimuli were delivered to the pelvis and arm. Outcome measures included pain (visual analogue scale), blood oxygen level dependent signal change and a semi-structured acceptability questionnaire at study completion prior to unblinding. RESULTS: Full datasets were obtained for 11 participants. Following noxious heat to the abdomen, the gabapentin group (GG) had lower pain scores (Mean: 3.8 [SD 2.2]) than the placebo group (PG) (Mean: 5.8 [SD 0.9]). This was also the case for noxious heat to the arm with the GG having lower pain scores (Mean: 2.6 [SD 2.5]) than the PG (Mean: 6.2 [SD 1.1]). Seven out of 12 participants completed the acceptability questionnaire. 71% (five out of seven) described their participation in the fMRI study as positive; the remaining two rated it as a negative experience. CONCLUSIONS: Incorporating brain fMRI in a future RCT to determine the mechanism of action of gabapentin in managing CPP in women was feasible and acceptable to most women. TRIAL REGISTRATION NUMBER: ISRCTN70960777.
