-->PONE-D-25-63924-->-->Efficacy of Low-Level Laser Therapy in Pain Relief During Orthodontic Treatment: Protocol for a Systematic Review-->-->PLOS One

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PLOS One

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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-->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

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Reviewer #1: This protocol outlines a planned systematic review and (conditional) meta-analysis to assess the efficacy of low-level laser therapy (LLLT; photobiomodulation) in reducing orthodontic pain across different treatment scenarios (e.g., separators, fixed appliance activation, aligner insertion). The authors will include randomized controlled trials, compare LLLT against sham/no treatment/other interventions, and evaluate primary (pain intensity/duration) and secondary outcomes (quality of life, adverse effects), using RoB 2 and GRADE to appraise risk of bias and certainty of evidence.

Technical novelty and innovation

The protocol focuses specifically on LLLT for orthodontic pain (rather than pooling heterogeneous physical modalities), aiming to stratify by orthodontic phase and laser parameters—an important refinement over prior reviews.

Explicit plan to use GRADE and RoB 2 should enhance methodological transparency and utility for clinicians.

Inclusion of gray literature and expert consultation increases comprehensiveness and mitigates publication bias.

Experimental rigor and validation

PROSPERO registration and adherence to PRISMA-P indicate prospective methodological planning and reporting.

Two-phase independent screening with calibration and duplicate processes is appropriate for minimizing selection bias.

Clarity of presentation

The clinical problem and rationale for a focused, up-to-date synthesis are well motivated; the target population, interventions, comparators, and outcomes are clearly defined at a high level.

Significance of contributions

Orthodontic pain is a common, clinically significant issue; clarifying the effectiveness and parameters of LLLT has direct implications for patient comfort, adherence, and clinical decision-making.

Technical limitations or concerns

Important statistical/analytical details are missing: prespecified timepoints for pain outcomes; choice of effect size metrics; handling of split-mouth/crossover designs; statistical model (random- vs fixed-effects); subgroup and sensitivity analyses; small-study effects assessment.

Exclusion criteria omit justification for excluding skeletal anchorage and intermaxillary elastics broadly despite their prevalence and clinical relevance; this may limit applicability.

Ambiguity about whether LED-based PBMT is included/excluded (modern PBMT often uses LEDs in addition to lasers).

Experimental gaps or methodological issues

The planned use of AI tools (LASER AI and ChatGPT) is not sufficiently detailed (versioning, tasks, safeguards, human oversight, reproducibility), raising transparency and bias concerns.

No explicit plan for data extraction items (laser parameters, dosimetry details, analgesic consumption), missing data handling, or contacting authors for outcome data.

No clear plan for dealing with multiple arms/timepoints (e.g., several wavelengths/doses or repeated measurements) and to prevent unit-of-analysis errors.

Clarity or presentation issues

Minor inconsistencies/typos (e.g., software name “LASER Al,” parameter notation “2.5 W/cm^2 and 600 J”), and PROSPERO ID formatting should be corrected; some sections are truncated (e.g., search strategy details).

Technical soundness evaluation

The PICOS framework is appropriate, but the protocol lacks essential pre-specifications:

Outcomes: Define primary timepoints (e.g., 6h, 24h, 48h, 72h, 7 days) and whether a composite (e.g., area under the pain-time curve) will be used. Predefine acceptable pain scales and how to convert heterogeneous scales; consider minimally important difference thresholds where available.

Effect measures: State the primary effect measure (MD for homogeneous scales like 0–100 mm VAS; SMD if mixed scales). Specify handling of skewed data, medians/IQR, and imputation of SD.

Design issues: For split-mouth trials, specify paired analyses and the approach to within-person correlation (use reported correlations, calculate from paired data, or impute with sensitivity analyses). For crossover trials, confirm use of first-period data only and explain how carryover will be managed.

Multiple arms/timepoints: Predefine how to select among multiple laser doses/wavelengths or multiple comparator arms (avoid double counting by appropriate arm combination or comparator splitting). For multiple post-intervention timepoints, either prespecify primary timepoint(s) or meta-analyze time windows separately.

Heterogeneity and meta-analysis model: State that a random-effects model (e.g., REML with Hartung-Knapp adjustment) will be used given expected clinical/methodological heterogeneity; report I² and τ²; plan meta-regression only if k is sufficient and covariates are prespecified (e.g., wavelength, irradiance, energy density, pulsing, number of sessions).

Subgroups/sensitivity analyses: Prespecify subgroups by treatment phase (separators vs first archwire activation vs aligners), wavelength (e.g., red vs NIR), energy density, irradiance, pulsing vs continuous-wave, application site (buccal vs buccal+palatal), number of sessions, comparator type (sham vs usual care), age group (adolescents vs adults), and risk of bias strata. Sensitivity analyses: exclude high RoB trials, imputed correlations/SDs, non-peer-reviewed sources, and outliers/influential studies.

Small-study effects/publication bias: Plan funnel plots and Egger’s regression (or Peters/Macaskill) where ≥10 studies per analysis; consider contour-enhanced plots.

Eligibility criteria:

Clarify and justify exclusions of skeletal anchorage, hybrid orthodontics, and intermaxillary elastics; these are common and clinically relevant. If the aim is to maintain homogeneity, consider including them but analyzing in prespecified subgroups—or justify exclusion with respect to differential pain mechanisms.

Clarify whether LED-based PBMT will be included (contemporary PBMT includes lasers and LEDs). Align terminology: LLLT vs PBMT.

Experimental evaluation assessment

Study selection and data extraction: Provide full details on calibration (pilot rounds and target kappa), number of reviewers for extraction, conflict resolution, and standardized extraction forms. Explicitly list data items: participant characteristics, appliance type, orthodontic procedure, comparator(s), pain measurement timing/instruments, analgesic use, LLLT parameters (device type, wavelength, power, power density, spot size/beam area, energy, energy density, pulse parameters/duty cycle, application points, time per point, sessions, contact mode), and adverse effects definitions/collection method.

Missing/incomplete data: State procedures for contacting authors (attempts, time windows) not only for full texts but also for missing outcome or parameter data; describe imputation rules where applicable.

Certainty of evidence: Identify which outcomes/timepoints will populate Summary of Findings tables; specify GRADE domains and how imprecision thresholds will be judged (e.g., optimal information size).

Comparison with related work (using the summaries provided)

Prior reviews have combined heterogeneous physical modalities or limited scope (e.g., separator pain only) and often did not grade certainty. Your plan to focus on LLLT across treatment phases and apply GRADE is appropriate. Additionally, contemporary PBMT trials in orthodontics and related dental applications exist (e.g., mini-implant peri-implant soft tissue outcomes), highlighting parameter sensitivity and the need for careful dosimetry capture—your planned parameter-level extraction/subgrouping will be valuable if explicitly prespecified.

Mechanistic reviews of LLLT/PBMT emphasize dose-response and wavelength dependence; bringing these into prespecified subgroup analyses may yield clinically actionable insights (e.g., red vs NIR wavelengths, pulsed vs continuous delivery).

Discussion of broader impact and significance

If executed with the suggested methodological refinements, this review can meaningfully guide clinical protocols (dosimetry, timing, and application points) and patient counseling about expected pain trajectories and adverse effects. The inclusion of quality-of-life and adverse event outcomes enhances translational value. Clear reporting of laser parameters will also support harmonization of future trials.

Questions for Authors

Will LED-based photobiomodulation trials (PBMT) be included, or are you restricting the review strictly to laser devices? Please clarify terminology and inclusion criteria (LLLT vs PBMT).

What are the prespecified primary timepoints for pain assessment (e.g., 24h, 48h, 72h)? Will you analyze time windows separately or use area-under-the-curve metrics?

Which effect size metrics will you use (MD vs SMD), and how will you handle heterogeneous pain scales, medians/IQR, and missing SDs?

How will you analyze split-mouth RCTs (paired analyses and correlation coefficients) and manage crossover trials (beyond first-period-only inclusion)? Please specify correlation imputation and planned sensitivity analyses.

What is your planned meta-analytic model (random-effects vs fixed) and heterogeneity metrics (I², τ²)? Will you use Hartung-Knapp adjustments?

Which subgroup and sensitivity analyses will be prespecified (e.g., wavelength, energy density, irradiance, pulsing, number of sessions, orthodontic procedure, comparator, age, RoB strata)?

How will you manage multi-arm trials (multiple doses/wavelengths) and multiple timepoints to avoid double counting and multiplicity?

Will analgesic consumption be included as a secondary outcome, given its frequent reporting and clinical relevance?

Please provide more detail on the AI tools: versions, specific tasks (screening, extraction), thresholds for human override, validation steps, data privacy safeguards, and how you will ensure reproducibility and auditability of AI-assisted decisions.

The protocol excludes studies involving skeletal anchorage and intermaxillary elastics. Could you justify these exclusions, or consider including them with planned subgroup analyses?

Reviewer #2: Manuscript title (revise to reflect content):

===========

Low‑Level Laser Therapy for Orthodontic Pain Relief: Protocol for a Systematic Review and Meta‑analysis

Small summary

==========

This manuscript describes a PRISMA‑P–based protocol (PROSPERO CRD420251033037) to systematically review randomized trials assessing low‑level laser therapy (LLLT) for pain control during orthodontic treatment. The authors plan broad database and grey‑literature searches, AI‑assisted screening/extraction (LASER AI and ChatGPT), RoB 2 risk‑of‑bias assessment, and GRADE certainty appraisal. The protocol outlines eligibility, outcomes (pain, QoL, adverse effects), and planned meta‑analyses by predefined time points.

Major points

========

(1) Title clarity: The current short title understates the planned meta‑analytic intent; change to include “systematic review and meta‑analysis” for accuracy.

(2) AI methods transparency: The protocol relies heavily on LASER AI and ChatGPT for screening/extraction but lacks sufficient detail on training, validation, reproducibility, and how AI decisions will be audited and reported. Provide explicit performance metrics and a reproducible workflow.

(3) Search timing and completeness: The full electronic search is deferred to January 2026; the protocol should clarify why submission precedes the planned search and ensure the peer‑reviewed search strategy (Appendix) is complete and reproducible.

(4) eligibility/exclusion bias risk: Excluding studies with unavailable full texts after only three contact attempts risks bias; justify this threshold and describe alternative approaches (e.g., contacting co‑authors, using interlibrary loan, or including abstracts with caution).

(5) Heterogeneity handling: Laser parameter variability is acknowledged but the statistical plan lacks detail on subgroup/meta‑regression strategies (wavelength, dose, application timing, appliance type). Predefine subgroup analyses and thresholds for pooling.

(6) Outcome measurement harmonization: Prioritize and justify the pain scales and time points; specify methods for converting different scales (e.g., VAS to standardized mean difference) and handling crossover/split‑mouth designs.

(7) Funding and competing interests: Financial disclosure fields appear incomplete and inconsistent with the competing‑interests statement; fully disclose all funding sources, grant numbers, and any role of funders.

(8) Data availability and ethics: The Data Availability statement is generic; provide a concrete plan for sharing extracted datasets, AI training annotations, and analysis code to ensure reproducibility.

Minor points

========

(1) Title punctuation and wording: Remove redundancy in the running title and ensure it matches the main title.

(2) Appendices: Ensure the full PubMed search string (PRESS‑reviewed) is included verbatim in Appendix 1 and that database‑specific adaptations are shown.

(3) LASER AI vendor details: Provide version number, date of access, and any custom settings used.

(4) Risk of bias plan: Clarify how RoB 2 judgments will be reconciled (e.g., consensus meeting, third reviewer) and how domain‑level judgments will inform sensitivity analyses.

(5) Statistical software: State the software and packages to be used for meta‑analysis (e.g., RevMan, R metafor) and thresholds for heterogeneity (I² cutoffs).

(6) Grammar/formatting: Minor typographical errors and inconsistent numbering in the Methods should be corrected for readability.

Recommended insertions of closely related work

==============================

(1) Owayda et al. — A randomized controlled trial on the effectiveness of low‑level laser therapy versus paracetamol‑caffeine for pain control during overall orthodontic treatment (Sci Rep. 2025; doi: 10.1038/s41598-025-16658-2). Place: Introduction, paragraph summarizing existing RCT evidence for LLLT. Insertion sentence: “Notably, a recent randomized trial comparing LLLT with paracetamol‑caffeine reported clinically relevant pain reductions, underscoring the need for a comprehensive synthesis of randomized evidence (Owayda et al., 2025; doi: 10.1038/s41598‑025‑16658‑2).”

(2) Al‑Hanbali et al. — The effectiveness of low‑level laser therapy and low‑intensity pulsed ultrasound in reducing pain induced by orthodontic separation: a randomized controlled trial (BMC Oral Health. 2024; doi: 10.1186/s12903-024-03926-2). Place: Introduction, when discussing separator‑related pain and prior focused reviews. Insertion sentence: “Randomized evidence addressing separator‑related pain has been produced (Al‑Hanbali et al., 2024; doi: 10.1186/s12903‑024‑03926‑2), but prior syntheses have not consistently stratified by appliance or laser parameters.”

(3) Mousa et al. — Evaluation of low‑level laser therapy and piezocision in the en‑masse retraction of upper anterior teeth (Eur J Orthod. 2025; doi: 10.1093/ejo/cjaf026). Place: Methods or Discussion, when justifying exclusion criteria and the need to isolate laser effects from adjunctive surgical interventions. Insertion sentence: “Studies combining LLLT with surgical acceleration techniques (e.g., piezocision) highlight the difficulty of isolating laser effects, supporting our exclusion of multimodal interventions where laser impact cannot be separated (Mousa et al., 2025; doi: 10.1093/ejo/cjaf026).”

(4) Alam et al. — The Effect of Low‑Level Laser Therapy on Accelerating Tooth Movement in Orthodontic Patients: A Randomized Controlled Trial (J Pharm Bioallied Sci. 2024; doi: 10.4103/jpbs.jpbs_1168_24). Place: Discussion, when addressing secondary outcomes and biological plausibility (LLLT effects on tissue/biologic response). Insertion sentence: “LLLT’s biological effects on tooth movement and tissue response have been reported in randomized trials, which informs interpretation of pain outcomes alongside potential mechanistic effects (Alam et al., 2024; doi: 10.4103/jpbs.jpbs_1168_24).”

Reviewer #3: Overall, this is a rigorous protocol for a systematic review to determine the effectiveness of low-level laser therapy in alleviating pain during orthodontic treatment. The authors provide a good rationale for conducting the study. The proposed analyses are appropriate to address the research question. The writing is clear and concise.

Major

1) The authors indicate that they will share all data generated by the study; however, there is no information about where the data will be stored and shared.

2) Although the authors indicate that they will cross check information generated by artificial intelligence tools, I recommend providing additional information and references providing evidence of the validity of using a) Laser AI to extract data from included studies and b) ChatGPT to collect data for the risk of bias assessment. These are emerging technologies without a proven track record of accurately conducting such tasks. For example, the following study examined the validity of ChatGPT’s risk of bias assessment: Taneri PE. Human versus artificial intelligence: comparing Cochrane authors' and ChatGPT's risk of bias assessments. Cochrane Evidence Synthesis and Methods. 2025 Sep;3(5):e70044.

3) The authors could include additional information about the following:

a) Why are studies with specific treatments such as hybrid orthodontics with skeletal anchorage or intermaxillary elastics being excluded?

b) Rationale for only including the first assessment from studies using cross-over or split mouth designs

Minor

4) The authors should review reference numbers to ensure that they match the study referenced. For example, on line 90, there is mention of two recent systematic reviews (20,22). It looks like 22 is not a systematic review; however, 21 is a systematic review. Also, line 209, it is unclear how references 25 and 26 relate to the information in the sentence referenced; line 214, reference 27 relates to GRADE not the Cochrane RoB 2 tool mentioned in the sentence.

5) On line, 171, the authors reference a reading platform. Consider naming the platform that will be used.

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Reviewer #1: Yes:  Ricardo Ney Cobucci

Reviewer #2: No

Reviewer #3: No

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Efficacy of Low-Level Laser Therapy in Pain Relief During Orthodontic Treatment: Protocol for a Systematic Review and Meta-analysis

PONE-D-25-63924R1

Dear Dr. Pauletto,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Spyridon N. Papageorgiou, DDS, Dr Med Dent

Academic Editor

PLOS One

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