Association of Alterations in Gray Matter Volume With Reduced Evoked‐Pain Connectivity Following Short‐Term Administration of Pregabalin in Patients With Fibromyalgia

Abstract

Objective; Pregabalin (PGB) is an α2β calcium channel subunit ligand that has previously been shown to reduce chronic pain in multiple conditions. Preclinical studies indicate that PGB may down-regulate brain glutamate release while also inhibiting astrocyte induction of glutamatergic synapse formation. Recent clinical research supports PGB modulating glutamatergic activity and functional brain connectivity in order to produce analgesia. However, no studies have examined concurrent changes in brain gray matter volume (GMV) or evoked-pain connectivity in humans receiving PGB. Methods Sixteen female fibromyalgia patients completed a randomized double-blind two-period cross-over study of PGB versus placebo (PBO). Before and after each period, patients had high-resolution structural and evoked pressure-pain functional brain imaging. GMV was analyzed using voxel-based morphometry, and functional connectivity during evoked pressure-pain was also assessed. Results PGB administration significantly reduced GMV within the posterior insula bilaterally, whereas there were no significant changes in insular GMV following PBO treatment. GMV reductions were also observed when comparing PGB versus PBO treatment in the medial frontal gyrus, which were associated with reduced clinical pain. These reductions in insular GMV were associated with concomitant reductions in connectivity to the default mode network (DMN), which was also associated with reduced clinical pain. Conclusion Short-term PGB treatment alters brain structure and evoked-pain connectivity, and these decreases were associated with reduced clinical pain. We speculate that these fairly rapid changes in GMV may be related to brain neuroplasticity. It is unknown if these effects are generalizable to other chronic pain states.

Modulation of NMDA Receptor Activity in Fibromyalgia

“…A number of drugs used in the management of fibromyalgia, such as different antidepressants, likely have an indirect effect on NMDAR function through reduction of the NMDAR ligands glutamate and aspartate [ 50 , 51 ]. Glutamate reduction in relevant pain-related brain regions in fibromyalgia patients is seen with pregabalin [ 9 , 52 ], with beneficial clinical effects likely to involve changes in NMDAR function in brain and spinal cord due to less synaptic glutamate being available to facilitate receptor activation. Pregabalin also decreases synaptic substance P and noradrenaline, and has other central effects relevant to fibromyalgia management, including improvement in sleep quality and anxiety [ 53 ].…”

Functional and neurochemical disruptions of brain hub topology in chronic pain

“…The data from 31 FM and 46 HCs were previously published in manuscripts focusing on functional connectivity, 1 H-MRS, and treatment outcomes. 22 , 23 , 25 , 28 , 42 , 43 , 49 , 51 Data from the remaining 9 FM patients have not been published. The University of Michigan Institutional Review Board approved the studies, and written informed consent was obtained from all participants in accordance with the Declaration of Helsinki.…”

Opioids and Alternatives in Female Chronic Pelvic Pain

“…Medications in this class act on both peripheral and central neuropathic pain and have been shown to produce functional and neurochemical alterations in the brain, seen on neuroimaging. 52,53 Data also support the use of gabapentin in patients with CPP, and has been shown to decrease pain levels in patients with pain refractory to nonopioid pain medications. 47,54 A small randomized pilot study evaluated efficacy of gabapentin compared to placebo for treatment of CPP of unknown etiology.…”