Outpatient Oral Neuropathic Pain Management with Photobiomodulation Therapy: A Prospective Analgesic Pharmacotherapy-Paralleled Feasibility Trial

Abstract

Neuropathic pain (NP) can be challenging to treat effectively as analgesic pharmacotherapy (MED) can reduce pain, but the majority of patients do not experience complete pain relief. Our pilot approach is to assess the feasibility and efficacy of an evidence-based photobiomodulation (PBM) intervention protocol. This would be as an alternative to paralleled standard analgesic MED for modulating NP intensity-related physical function and quality of life (QoL) prospectively in a mixed neurological primary burning mouth syndrome and oral iatrogenic neuropathy study population (n = 28). The study group assignments and outcome evaluation strategy/location depended on the individual patient preferences and convenience rather than on randomisation. Our prospective parallel study aimed to evaluate the possible pre/post-benefit of PBM and to allow for a first qualitative comparison with MED, various patient-reported outcome measures (PROMs) based on Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT-II) were used for up to a nine-month follow-up period in both intervention groups (PBM and MED). The PBM protocol applied to the PBM group was as follows: λ810 nm, 200 mW, 0.088 cm², 30 s/point, 9 trigger and affected points, twice a week for five consecutive weeks, whereas the MED protocol followed the National Institute of Clinical Excellence (NICE) guidelines. Our results showed that despite the severe and persistent nature of the symptoms of 57.50 ± 47.93 months at baseline in the PBM group, a notably rapid reduction in PIS_max on VAS from 7.6 at baseline (T0) to 3.9 at one-month post-treatment (T3) could be achieved. On the other hand, mean PIS_max was only reduced from 8.2 at baseline to 6.8 at T3 in the MED group. Our positive PBM findings furthermore support more patients' benefits in improving QoL and functional activities, which were considerably impaired by NP such as: eating, drinking and tasting, whereas the analgesic medication regimens did not. No adverse events were observed in both groups. To the best knowledge of the authors, our study is the first to investigate PBM efficacy as a monotherapy compared to the gold standard analgesic pharmacotherapy. Our positive data proves statistically significant improvements in patient self-reported NP, functionality, psychological profile and QoL at mid- and end-treatment, as well as throughout the follow-up time points (one, three, six and nine months) and sustained up to nine months in the PBM group, compared to the MED group. Our study, for the first time, proves the efficacy and safety of PBM as a potent analgesic in oral NP and as a valid alternative to the gold standard pharmacotherapy approach. Furthermore, we observed long-term pain relief and functional benefits that indicate that PBM modulates NP pathology in a pro-regenerative manner, presumably via antioxidant mechanisms.

Keywords: EQ-5D-5L; IMMPACT; PROMs; burning mouth syndrome; functional problems; neuropathic pain; oral iatrogenic neuropathy; pharmacotherapy; photobiomodulation therapy; psychological dysfunction; standard analgesic.

Figure 1

Schematic description of the PBM effects on injured peripheral neurons via its primary, secondary and tertiary activities. Several signaling pathways are induced by PBM irradiation, in reducing neuropathic pain and pro-inflammatory cytokines and neurotransmitter mediators. Abbreviations: PBM: photobiomodulation; TRPV1: transient receptor potential cation channel subfamily V member 1; Ca⁺²: calcium ion; K⁺¹: potassium ion; Na⁺¹: sodium ion; cyt c oxidase: cytostome c oxidase; CAMP: cyclic adenosine monophosphate, ROS: reactive oxygen species; ATP: adenosine triphosphate; NO: nitric oxide; AP1: activation protein1; NF-kB: nuclear factor-kappa (Supplementary File S2).

Figure 2

Shows the visual analogue scale (VAS) utilised throughout the treatment and follow-up time points [59].

Figure 3

Shows the European Quality of life (EuroQol) Group, 5 dimension 5 levels (EQ 5D-5L) questionnaires. Based on combining supplementary measures that all capture aspects related to the QoL. The EQ-5D-5L questionnaires are based on qualitative and quantitative measures. (A) The variables’ questions and associated levels. (B) Overall general health percentage [61].

Figure 4

(A–F) Illustrates the position of the 810 nm laser intraoral single prob applied at 90° (perpendicular) with <1 mm distance from the target tissue as well the allocation and number irradiated points on the trigger and affected points, using “spot technique”. The blue circles illustrate the number and allocation of the points irradiating the affected areas. Clinical photos (A–C) shows the following 3 points on the anterior two-thirds of dorsal tongue: anterior (A), middle (B) and posterior (C) of right side of the dorsal tongue; clinical photo (D) shows the distribution of 3 points on the affected areas along the distribution of the inferior alveolar nerve and lingual nerve along chorda tympani nerve (sensory branch of the facial nerve); photos (E,F) illustrate the application of the PBM irradiation on the affected areas on the ventral surface of the tongue where the lingual and chorda tympani nerves are distributed). Clinical photo (F) shows the application of single laser probe at 90° to the ventral surface of the tongue, irradiating the middle point, whereas assembled photo (E) shows the allocation of the 3 irradiated points: anterior, middle and posterior of right ventral surface of the tongue.

Figure 5

Illustrates the CONSORT diagram flow of subjects’ enrolment, allocation, follow-up and analysis for both groups: PBM and MED, including the treatments and follow-up protocols. Abbreviations: T0: baseline (Pre-treatment); T1: mid-treatment; T2: end-treatment; T3: one-month; T4: three-months; T5: six-months; T6: nine-months; VAS: visual analogue scale; EQ-5D-5L: European-QoL-5 dimensions 5 levels; mW: milliwatt; CW: continuous emission mode; n: number (Supplementary File S2).

Figure 6

Shows types of self-reported previous or ongoing and medical conditions representing a confounder risk in both test (PBM) and comparison (MED) groups. Abbreviations: PBM: photobiomodulation; MED: pharmacotherapy; #: number of patients; IDDM: insulin-dependent diabetic mellites.

Figure 7

(A–C) Shows self-reported highest pain intensity score (PIS_max). (A) shows PIS_max (mean ± SD) over time in the PBM group (circles) and (B) shows PIS_max (mean ± SD) over time for the parallel MED group (squares) on a visual analogue scale from zero to ten cm. (C) shows mean differences in PIS_max between both interventions and the 95%-confidence intervals as the result of a full mixed-effects two-way ANOVA analysis, demonstrating analgesic efficacy in favour of the PBM-treatment throughout the study period. Bonferroni’s multiple comparison statistics: p-value indications: n.s. = not significant; ** < 0.01; *** < 0.001; # < 0.0001. In (A,B) (means ± SD): p-value indications show the significance level of pairwise differences between means of the respective time points with T0. Abbreviations: PIS_max: self-reported highest pain intensity score; T0: baseline; T1: mid-treatment; T2: end-treatment; T3: one-month; T4: 3 months; T5: 6 months; T6: 9 months.

Figure 8

(A,B) Shows the results of EQ-5D-5L indices for PBM and MED groups for the different assessment time points. (A) Shows the self-reported EQ-5D-5L indices as mean (± SD) and aligned for paralleled intervention groups PBM (circles) and MED (squares). (B) Depicts mean differences between the interventions (±95%-confidence intervals) at different time points of selected EQ-5D-5L indices, for which a main-effects analysis revealed a significant group and time dependency, along with p-value indications for Bonferroni’s multiple comparison statistics of the full mixed-effects model: n.s.: not significant; * < 0.05; ** < 0.01; # < 0.0001. Abbreviations: T0: baseline; T1: mid-treatment; T2: end-treatment; T3: one-month; T4: three-months; T5: six months; T6: nine-months.

Figure 9

Pain interference with 14 functional indices as experienced and self-reported by the study participants on a scale from zero (=no interference) to ten (total interference or complete loss of functionality), allocated to either PBM (circles) or MED (squares) intervention groups. The functional parameters assessed, relating to QoL, are depicted above in each graph, as well as the significance level of the main effects by ANOVA analysis (Group-effect = intervention dependency, Time-effect = time-point dependency) for the respective functional parameter in the study (n.s. = not significant; * < 0.05; ** < 0.01; *** < 0.001; # < 0.0001). Abbreviations: T0: baseline; T1: mid-treatment; T2: end-treatment; T3: one-month; T4: three-months; T5: six-months; T6: nine-months.