Background: Chronic neuropathic pain (NP) is a complex disease that results from damage or presumed damage to the somatosensory nervous system. Current treatment regimens are often ineffective. The major impediment in developing effective treatments is our limited understanding of the underlying mechanisms. Preclinical evidence suggests that glial changes are crucial for the development of NP and a recent study reported oscillatory activity differences within the ascending pain pathway at frequencies similar to that of cyclic gliotransmission in NP. Furthermore, there is evidence that glial modifying medications may be effective in treating NP. The aim of this Phase I open-label clinical trial is to determine whether glial modifying medication palmitoylethanolamide (PEA) will reduce NP and whether this is associated with reductions in oscillatory activity within the pain pathway. Methods: We investigated whether 6 weeks of PEA treatment would reduce pain and infra-slow oscillatory activity within the ascending trigeminal pathway in 22 individuals (17 females) with chronic orofacial NP. Results: PEA reduced pain in 16 (73%) of the 22 subjects, 11 subjects showed pain reduction of over 20%. Whilst both the responders and non-responders showed reductions in infra-slow oscillatory activity where orofacial nociceptor afferents terminate in the brainstem, only responders displayed reductions in the thalamus. Furthermore, functional connections between the brainstem and thalamus were altered only in responders. Conclusion: PEA is effective at relieving NP. This reduction is coupled to a reduction in resting oscillations along the ascending pain pathway that are likely driven by rhythmic astrocytic gliotransmission.

Background

Chronic pain, particularly that following nerve injury, can occur in the absence of external stimuli. Although the ongoing pain is sometimes continuous, in many individuals the intensity of their pain fluctuates. Experimental animal studies have shown that the brainstem contains circuits that modulate nociceptive information at the primary afferent synapse and these circuits are involved in maintaining ongoing continuous neuropathic pain. However, it remains unknown if these circuits are involved in regulating fluctuations of ongoing neuropathic pain in humans.

Methods

We used functional magnetic resonance imaging to determine whether in 19 subjects with painful trigeminal neuropathy, brainstem pain-modulation circuitry function changes according to moment-to-moment fluctuations in spontaneous pain intensity as rated online over a 12-minute period.

Results

We found that when pain intensity was spontaneously high, connectivity strengths between regions of the brainstem endogenous pain-modulating circuitry-the midbrain periaqueductal gray, rostral ventromedial medulla (RVM), and the spinal trigeminal nucleus (SpV)-were high, and vice-versa (when pain was low, connectivity was low). Additionally, sliding-window connectivity analysis using 50-second windows revealed a significant positive relationship between ongoing pain intensity and RVM-SpV connectivity over the duration of the 12-minute scan.

Conclusion

These data reveal that moment-to-moment changes in brainstem pain-modulation circuitry functioning likely contribute to fluctuations in spontaneous pain intensity in individuals with chronic neuropathic pain.