Enhanced pain relief with guanfacine as an adjuvant for trigeminal nerve blocks: insights from a PheWAS-guided randomized controlled study

Abstract

Background: Trigeminal neuralgia and painful trigeminal neuropathy are severely painful conditions which are often difficult to treat with medications. A Phenome-Wide Association Study (PheWAS) analysis identified an association between single-nucleotide variants in the alpha-2 adrenergic receptor (ADRA2) subtype B, a G protein-coupled receptor expressed on peripheral and central presynaptic terminals, and an increased risk for trigeminal nerve disorders. We hypothesized that adding the ADRA2 agonist guanfacine to routine care trigeminal nerve injections would provide enhanced pain relief in trigeminal neuralgia than routine care alone.

Methods: PheWAS analysis identified the drug target/indication pair. The trial was a single-center, prospective, randomized, controlled, double-blinded, 2-way crossover trial for patients with pain attributed to the trigeminal nerve. Injections of lidocaine alone or lidocaine + 250 µg guanfacine were delivered to the V2 and V3 branches of the trigeminal nerve by experienced clinicians. Patients reported pain using a Numeric Rating Scale (NRS) and quality of life measures (using the PROMIS Global Physical Health, Mental Health, and Pain Interference surveys).

Results: NRS pain scores over the first 8 h post-injection were significantly lower in the interventional group (guanfacine + lidocaine) compared to active control (P < .001), but not from day 1 through day 14. There was no significant difference between treatment groups in time to recovery of baseline pain intensity (primary outcome), PROMIS outcomes, or adverse events (AEs). No serious AEs were reported.

Conclusions: The addition of 250 µg guanfacine to lidocaine for a nerve block procedure enhanced analgesia compared to lidocaine alone within the first 8 h post-injection.

Clinical trial number: NCT03865940, https://clinicaltrials.gov/study/NCT03865940.

Keywords: drug repurposing; guanfacine; nerve block; neuropathic pain; trigeminal neuralgia.

Figure 1.

Study design, eligibility criteria, and participant flow. (A) Crossover study design. Participants were only eligible to receive the second nerve block injection if their NRS pain score at the scheduled time of the procedure was greater than 5. (B) Inclusion and exclusion criteria for this trial. (C). Results from the PheWAS analysis.

Figure 2.

(A) AP view of needle outside of the pterygopalatine fossa (PPF) just below the foramen rotundum. (B) Lateral view of the needle position from (A). (C) Image from (A) with arrow demonstrating needle tip and solid circle encircling the area of the foramen rotundum which is behind the needle tip. (D) Image from (B) with arrow showing the needle tip. Dashed line outlines the borders of the ipsilateral PPF.

Figure 3.

(A) AP view of the needle position for the mandibular nerve block in the area as it travels from the foramen ovale to the mandible. Contrast injections demonstrate no muscular or intravascular flow. (B) Lateral view of the image from (A). (C) Image from (A) with arrow showing needle tip and solid circle around the contrast. The dashed line demonstrates the bottom border of the maxilla (D). Image from (B) with arrow showing the needle tip and circle around the contrast spread. The dashed line outlines the mandibular notch and the top border of the mandible with the needle distal to it below this line. At this location, the needle tip is below the pterygoid muscles and the level of the pterygoid plate, and is lateral from the foramen ovale and other close structures such as the foramina spinsum and lacernum and the vascular structures which run through them.

Figure 4.

Participant flow. (A) Participant flow from consent to final dataset analysis. Analysis was performed on 64 pain intensity datasets because one participant received the second injection but did not complete the NRS pain score pain diary. In this panel, “Lost to follow up” means that participants were not able to be contacted again. (B) Infographic summary of participant crossover completion. Of the 18 participants randomized to the lidocaine alone injection first, only 10 completed the second injection of lidocaine + 250 µg guanfacine. Of the 19 participants randomized to the lidocaine +250 µg guanfacine injection first, 18 completed the second injection of lidocaine only. (C) Summary of reasons why participants did not complete the second injection arm. The majority of participants in the lidocaine alone arm did not complete the second injection because their pain level never reached the established threshold (NRS pain score 5+).

Figure 5.

Pain score outcomes and rescue medication use. (A) Average NRS pain scores over the first 8 h post injection. NRS pain scores were significantly lower in participants receiving lidocaine + 250 µg guanfacine. (B) Average NRS pain scores from baseline to day 14. (C) Proportion of participants taking rescue medication over the first 8 h post injection. (D) Proportion of participants taking rescue medication from baseline to day 14.

Figure 6.

PROMIS outcomes. (A) Average PROMIS Global Physical Health Score. (B) Average PROMIS Global Mental Health Score. (C) Average PROMIS Global Health Pain Interference Score.