Abstract
BackgroundThe International Classification of Orofacial Pain (ICOP) has defined burning mouth syndrome (BMS-ICOP) as an intraoral burning or dysaesthetic sensation that reoccurs daily for more than two hours per day and more than three months without evidence of causative lesions upon clinical examination and investigation. The burning mouth symptoms can be caused by primary and secondary BMS. Primary BMS is idiopathic BMS or true BMS, while secondary BMS, also known as burning mouth disorder (BMD), is attributed to local factors or systemic conditions. The prevalence of BMS in women was significantly higher than in men and mainly occurred at the post-menopausal age between 50 and 80 years. This intense, continuous, spontaneous pain severely affects the patient’s oral function, health, and psychology, with high reported rates of anxiety and depression. The pathophysiology of primary BMS as defined by ICOP (BMS-ICOP) remains uncertain, and with no standardised treatment protocol, treatment outcomes are further complicated. Over the years, there have been reports of altered cerebral activities in various levels of the neuraxis in patients with BMS-ICOP, which implies that BMS pain has a central nervous system component.
Aim
This thesis aimed to characterise patients’ cerebral responses associated with chronic trigeminal pain following administration of two topical peripheral-acting analgesics, clonazepam mouthwash (CMW) and dental local anaesthetic (LA), and the difference between treatment responders and non-responders. Attenuating or escalating pain in response to peripheral medications will allow in-depth phenotyping of patients with BMS-ICOP and facilitate tailored medicine. This thesis also studied and described the characteristics of patients with BMS-ICOP and the psychological impact of BMS-ICOP.
Methods
This prospective, open-label study was conducted at King’s College Dental Institute and Clinical Research Facilities, King’s College London. In the first visit, 26 participants diagnosed with BMS-ICOP were clinically screened and psychologically assessed using psychometric questionnaires. Functional magnetic resonance imaging (fMRI) and pulsed-continuous arterial spin labelling (pCASL) imaging techniques were employed to provide quantitative measurements of the resting-state functional connectivity (FC) and regional cerebral blood flow (rCBF), respectively, that related to changes in the brain activity. Participants underwent a series of fMRI and pCASL scans and rated their pain intensity using the numerical rating scale (NRS, 0-10) and visual analogue scale (VAS, 0-100) before and after the administration of CMW and LA. A subgroup of 15 BMS-ICOP patients with burning pain across the tongue was selected from the initial 26 BMS-ICOP patients to receive LA intervention. In addition to it, patients’ grey matter volume (GMV) was quantified using voxel-based morphometry (VBM) analysis. Here, we performed seed-based FC and pCASL analysis of the regions of interest (ROIs), including the left hippocampus, ventromedial prefrontal cortex (vmPFC), left amygdala, thalamus, right anterior insula (RAI), and periaqueductal grey matter (PAG); given reports of perturbed functioning changes in this region in chronic pain. Treatment responders were defined as reporting 50% or greater pain reduction from baseline following analgesic administration.
Results
Overall, the cohort of patients had daily recurring and continuously hot burning pain, with a mean NRS intensity rating of 5.15, progressively worsening during the day.
Although experiencing a high pain level, most patients had a low tendency to catastrophise the threat value of pain or pain-related thoughts and did not exhibit depression, anxiety, or somatic symptom disorders. When comparing the pain and control sites, more than 90% of patients showed no chairside qualitative sensory deficit to touch and two-point discrimination. Meanwhile, 42% and 20% of patients had pin-prick and thermal sensitivity changes, respectively. This similarity was also reflected in the quantitative mechanical detection threshold assessment, where there were no significant changes between the control and pain sites (p = 0.695, SE =0.06). We also did not observe any statistically significant correlation between behaviour changes and cerebral responses to pain (pre-intervention), such as anxiety (r=0.09, p=0.677, 95% CI= -0.31-0.46) and depression (r= -0.21, 95% CI= -0.55 – 0.2, p=0.314).
Clonazepam
Rinsing with 2mg CMW for 10 minutes significantly reduced pain intensity across the participants. An acute 2mg dose was selected to provide an immediate state of pain relief effect, keeping in mind that the suggested maximum daily prescribed clonazepam dose for pain relief is 4mg/day. Patients experienced a mean pain intensity NRS score reduction of 2.67 (p<0.001), and 15 patients responded to treatment. The study found a correlation between patients’ brain GMV and resting-state FC and pain intensity before and after rinsing with CMW. These changes were seen in the brain regions responsible for pain-related cognitive and affective processing and descending pain modulation. We also demonstrated the effect of CMW, which caused a decrease in the FC in the L hippocampus and RAI ROIs. There were alterations in the FC (∆FC) following treatment that were associated with changes in pain levels, as seen in the L hippocampus and vmPFC ROIs. In attempting to predict treatment response towards clonazepam, we tested the baseline FC with changes in pain ratings, and we did not observe any significant correlation. In addition, patients with a minimum of 50% pain reduction following CMW had a lower baseline FC than non-responders in all six ROIs. Conversely, an increased FC was noted in responders between L hippocampus-brainstem/ cerebellum and vmPFC-primary motor/somatosensory cortices. Similarly, there was a reduction in post-mouthwash rCBF compared to pre-mouthwash rCBF. No significant changes were reported upon analysis of the baseline rCBF and changes in the rCBF (∆rCBF) along with pain intensity.
Dental local anaesthesia
Following bilateral inferior alveolar nerve block, patients achieved greater pain intensity relief than CMW with a reduction of 3.73 NRS units (p<0.001, SD=1.91), with 13 patients responding to it, but two patients did not. At baseline, we also observed the FC presence between brain regions involved in cognitive and affective (emotion) pain processing and modulation, and these connectivities were associated with pain ratings and area size.
Participants with a greater reduction in their pain intensity NRS (∆NRS) and VAS (∆VAS) scores after LA had weak baseline FC strength between L hippocampus-temporal lobe (p=0.024) and PAG–L amygdala (p=0.032), respectively. However, no significant association was found between the ∆FC with pain ratings and pain area size. Contrary to CMW’s pCASL analysis, no correlation was observed between LA group patients’ baseline rCBF and pain ratings and area size. However, further exploratory pCASL analysis (uncorrected initial threshold of p=0.005) showed a reduction in rCBF after LA administration in the cognitive (dorsolateral prefrontal cortex), primary motor cortex, and primary somatosensory cortex brain regions.
When comparing the studies, differences in cerebral responses to pain are likely related to the context of expectancy effect and the differential in afferent nociceptive ascending trigeminothalamic inputs to the brain and descending pain inhibition modulation system.
Conclusion
Our cohort of patients with BMS-ICOP had a remarkable ability to engage in valued daily activities by having high pain acceptance behaviour and a low tendency to magnify the value of pain. Administration of topical peripheral analgesics during the ongoing experience of chronic pain modulated the brain’s resting state activities, such as FC and rCBF. Alterations in FC and rCBF between brain regions involved in chronic pain modulation may reflect ongoing BMS-ICOP pain symptomatology, possibly due to impaired central and/or peripheral nervous system function. Understanding the peripheral and central processes involved in BMS-ICOP pain and how analgesics alter them may provide preliminary insights into the mechanism of action of potential topical analgesics, which may be a valuable parameter in predicting treatment response and is fundamental to advancing pain medicine.
| Date of Award | 1 Jan 2024 |
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| Original language | English |
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| Supervisor | Tara Renton (Supervisor), Jan Hoffmann (Supervisor) & Elena Makovac (Supervisor) |