Deciphering Persistent Orofacial Pain - PIFP

Background and Rationale:

Persistent non-dental orofacial pain is common but poorly understood, and its underlying pathophysiology remains largely undefined. Two clinically similar entities can be distinguished. Painful post-traumatic trigeminal neuropathy (PTNP) is characterized by persistent pain accompanied by demonstrable somatosensory changes (negative signs such as hypoesthesia and hypoalgesia, and/or positive signs such as allodynia and hyperalgesia) in the painful area, typically following nerve injury. Persistent idiopathic facial pain (PIFP; formerly "atypical facial pain") is a constant, dull, poorly localized facial pain that does not follow the distribution of a single trigeminal branch, may cross the midline over time, and is not associated with a neuralgiform pain component; clinical and radiographic examinations are unremarkable. Because the two conditions are clinically nearly identical, patients frequently attribute the pain to dental causes, and unnecessary dental treatment or tooth extraction can aggravate and chronify the pain.

The absence of somatosensory deficits in PIFP suggests that altered central processing of trigeminal nociceptive input, rather than a purely peripheral mechanism, contributes to the pain. This is consistent with the concept of nociplastic pain, in which centrally altered sensory processing and pain modulation drive an augmented pain response. Prior high-resolution brainstem functional MRI (fMRI) work demonstrated that PIFP patients show stronger activation of the spinal trigeminal nucleus in response to standardized trigeminal nociceptive stimulation compared with healthy controls. However, fMRI alone cannot distinguish central sensitization (top-down) from a peripheral drive maintained by ongoing nociceptor input. This study therefore combines quantitative sensory testing (QST) with a trigemino-nociceptive fMRI paradigm that incorporates a peripheral nerve block, in order to characterize the peripheral and central contributions to PIFP.

Objectives and Hypotheses:

The overarching objective is to describe and characterize the pathophysiology of PIFP by comparing PIFP patients with age- and sex-matched healthy controls using non-invasive psychophysical and neuroimaging methods. The central hypothesis is that PIFP patients exhibit a disturbance of central trigeminal nociceptive processing at the brainstem level and in other critical trigeminal pain-processing regions, such as the thalamus and insula, that distinguishes them from healthy controls. A secondary hypothesis is that, within PIFP patients, a peripheral anesthetic nerve block will separate individuals whose pain is driven peripherally (pain abolished during the block) from those whose pain is maintained centrally/nociplastically (pain persists despite cutaneous numbness), and that these subgroups differ in their central nociceptive processing.

Study Procedure:

Participants are assigned to groups by clinical diagnosis; there is no randomization or blinding. Two components are applied to all participants: standardized psychophysical/sensory characterization and task-based fMRI with standardized electrical trigemino-nociceptive stimulation. Patients are recruited through the headache/facial pain outpatient clinic; healthy volunteers are recruited via public postings and local internet platforms. The study plans to enroll 30 patients with PIFP together with 30 age- and sex-matched healthy controls for comparison. Patients are recruited through the headache/facial pain outpatient clinic; healthy volunteers are recruited via public postings and local internet platforms.

Clinical and Psychophysical Characterization:

All participants complete standardized questionnaires for deep phenotyping, including the Patient Health Questionnaire (PHQ-9), central sensitization inventory (CSI), brief pain inventory (BPI), short form-36 health survey (SF-36), and custom instruments covering general health, medication and stimulant use, dental history, and oral hygiene, as well as detailed pain history, pain character and intensity, prior treatments, and potential triggering events. Patients undergo a standardized extraoral and intraoral dental examination, including palpation of the trigeminal exit points and masticatory apparatus and standardized oral health indices. Quantitative sensory testing is performed in all participants over the trigeminal dermatomes bilaterally, following the standardized protocol of the German Research Network on Neuropathic Pain (DFNS). Thermal thresholds are assessed with a thermal sensory analyzer, and mechanical stimuli with von Frey filaments and Pinprick stimulators.

Functional MRI Paradigm:

Task-based fMRI is acquired on a 3T scanner using a brainstem-optimized high-resolution protocol. Standardized nociceptive stimulation is delivered via an MR-compatible constant-current stimulator coupled to MR-safe electrodes positioned over the second (V2) and third (V3) branches of the trigeminal nerve bilaterally. After determination of individual electrical pain thresholds, stimulation intensity is set at 3 times the pain threshold and capped at 10 mA to remain tolerable and safe. Four stimulation sites, bilateral V2 and V3, are presented in randomized order with repeated trials across sessions, and participants rate perceived pain intensity after the first trial and for every 10 trials on each stimulation site. This paradigm probes the functional representation of trigeminal nociceptive input in the spinal trigeminal nucleus, thalamus, insula, and related brainstem structures.

PIFP patients who consent are scanned twice with this paradigm: before and after a local-anesthetic nerve block administered in the painful area by a dentist. This design distinguishes patients in whom the pain is abolished while the area is anesthetized (suggesting a predominantly peripheral, nociceptor-driven mechanism) from those in whom cutaneous numbness is achieved but the pain persists (suggesting a central, nociplastic mechanism).

Outcome Measures:

The primary outcome is the difference in the fMRI response to standardized trigemino-nociceptive stimulation within trigeminal pain-processing regions - including the spinal trigeminal nucleus, thalamus, and insula - in the following comparisons: (i) PIFP patients versus healthy controls; and (ii) within PIFP patients, the difference in activation before versus after the local-anesthetic nerve block, and between patients whose pain is completely abolished by the block versus those with persistent pain despite the block. Secondary outcome includes: (1) comparison of deep phenotyping and QST parameters between PIFP patients and healthy controls

Statistical Analysis:

The primary analysis requires 20 complete datasets per cohort. Based on previous studies with this population and sequence, approximately 25% of enrolled participants are expected to yield unusable data (dropout, excessive head motion, or incidental findings). Neuroimaging data are analyzed using a general linear model with statistical parametric mapping, contrasting the painful side versus the control side, and comparing groups and pre/post nerve-block conditions. For the fMRI data, a family-wise error-corrected threshold of PFWE \< 0.05 will be applied at the whole-brain level, except for a priori regions of interest - the spinal trigeminal nucleus, thalamus, and insula - for which small-volume-corrected PFWE \< 0.05 will be used. Psychophysical and QST parameters are compared between groups using parametric or non-parametric tests as appropriate after testing distributional assumptions, with a two-sided significance level of p \< 0.05. Analyses are performed after completion of data collection; no interim analyses are planned.