Impact of Auditory Environments on Pain in Fibromyalgia: a 4×4 Crossover Trial

This protocol investigates the potential modulatory effects of distinct auditory environments on pain processing mechanisms in individuals with fibromyalgia syndrome. The study is grounded in emerging neuroscientific evidence suggesting that auditory stimuli can influence pain perception through direct neural pathways between the auditory cortex and pain-processing regions.

Soundscapes-defined as acoustic environments perceived, experienced, and interpreted within specific contexts-are categorized as natural or anthropogenic based on their origin for research purposes. Natural soundscapes comprise elements such as biophonies (non-human animal sounds) and geophonies (non-living natural elements), while urban soundscapes feature anthropophonies (human-generated sounds) and technophonies (mechanical sources). Recent neuroimaging research has demonstrated that these different soundscape categories elicit distinct neural signatures and may differentially shape intrinsic brain dynamics.

Fibromyalgia syndrome presents a particularly relevant clinical model for investigating auditory-pain interactions due to its characteristic heightened sensitivity to non-noxious sensory input. Preclinical evidence has identified direct neural pathways between the auditory cortex and pain-processing regions, with rodent studies showing that 20-minute broadband sound exposure significantly increases mechanical pain thresholds through mechanisms involving reduced thalamic activity. Human studies have similarly documented analgesic effects of auditory stimulation across both acute experimental pain and chronic pain conditions.

The general objective of this study is to:

GO1. Investigate the differential effects of controlled auditory environmental exposures-natural soundscapes, urban soundscapes, broadband sound, and silence-on the functioning of altered pain mechanisms in individuals with fibromyalgia syndrome, evaluated through clinical outcomes (pain intensity and perceived improvement) and experimental indices of pain processing (quantitative sensory testing measures).

The specific objectives are to:

SO1. Compare the effects of natural and urban soundscapes against broadband sound (active comparator) and silence (attention-placebo control) on the functioning of pain mechanisms.

SO2. Determine the relative efficacy of natural versus urban soundscapes in modulating the functioning of pain mechanisms in individuals with fibromyalgia syndrome.

SO3. Characterize the magnitude and direction of potential within-condition changes in the functioning of pain mechanisms following exposure to natural and urban soundscapes.

The primary hypothesis is:

PH1. Distinct auditory environmental exposures-natural soundscapes, urban soundscapes, broadband sound, and silence-will differentially modulate self-reported pain intensity in individuals with fibromyalgia syndrome, with the following specific hypothesized relationships:

PH1.1. Natural soundscape exposure will demonstrate superior analgesic efficacy compared to attention-placebo control.

PH1.2. Natural soundscape exposure will demonstrate superior analgesic efficacy compared to broadband sound exposure.

PH1.3. The analgesic effects of urban soundscape exposure will not significantly differ from attention-placebo control.

PH1.4. The analgesic effects of urban soundscape exposure will not significantly differ from broadband sound exposure.

PH1.5. Natural soundscape exposure will demonstrate superior analgesic efficacy compared to urban soundscape exposure.

The secondary hypotheses are:

SH1. Exposure to natural soundscapes will lead to significant pre-post improvements in both clinical outcomes and experimental indices of pain processing.

SH2. Exposure to urban soundscapes will demonstrate non-significant pre-post effects in both clinical outcomes and experimental indices of pain processing.

The study design optimizes statistical efficiency by allowing within-subject comparisons while controlling for period effects. The auditory exposure sessions are conducted in a controlled laboratory environment, maintaining a consistent room temperature and relative humidity.

To recruit participants, voluntary response, convenience, and snowball sampling methods will be employed. An a priori power analysis was conducted using G*Power v3.1.9.7. The sample size estimation is based on a Cohen's f effect size of 0.516, derived from the previous findings on the effect of nature sounds on pain in patients with chronic pain. A minimum of 58 participants is required to provide a power of 90% to adequately detect the determined pre-post difference at a two-tailed alpha level of .05. Allowing for an anticipated attrition rate of approximately one-third-including potential dropout, loss to follow-up, clinical reasons, and operational issues-a total of 88 participants will be recruited.

The assessment protocol follows International Association for the Study of Pain consensus guidelines and incorporates core outcome domains recommended for chronic pain trials. It covers both clinical outcomes (pain intensity and perceived improvement) and experimental indices of pain processing (quantitative sensory testing measures). These measures collectively provide a comprehensive evaluation of both subjective pain experience and biomarkers of pain processing, performed by a trained evaluator.

The primary analytical strategy will use linear mixed-effects models to examine change-from-baseline scores across conditions. Fixed effects will include treatment, period, sequence, and their interaction to detect potential carryover effects, while participants will be modeled with random intercepts. In the absence of carryover, a simplified model excluding the interaction term will be applied. Between-condition effects will be assessed via estimated marginal means with Bonferroni-adjusted pairwise comparisons. Sensitivity analyses will introduce the covariates to examine their influence on treatment effects. Within-condition (pre-post) changes will be evaluated using paired t-tests or Wilcoxon signed-rank tests, depending on data distribution.

To meet statistical assumptions, distributions of quantitative sensory testing outcomes-including mechanical pain sensitivity, temporal summation of pain, and pressure pain detection thresholds and intensity ratings-will be log-transformed, consistent with established methods. A small constant will be added to variables with potential zero values prior to transformation. For presentation purposes, transformed values will be back-converted to original units in descriptive outputs. All hypothesis testing will be two-sided with a Type I error rate of 5%, and analyses will follow the intention-to-treat principle. Multiple imputation will be considered if missingness is not at random.

This study is considered as minimal risk. No serious adverse events are expected. All participants may withdraw at any time without justification or impact on healthcare access. Discontinuation may occur at participants' request or in response to adverse events or protocol violations. Adverse events will be monitored throughout. Given the low-risk profile, oversight will be managed by the principal investigator; no independent safety board is planned. Safety monitoring will involve systematic documentation of all treatment-emergent and spontaneously reported adverse events throughout the study period.

To our knowledge, this study would represent one of the first investigations conceptualizing everyday soundscapes as environmental determinants potentially capable of modulating pain processing in chronic pain populations. The findings may contribute to several domains:

• Theoretical advancement in understanding auditory-pain interactions and their environmental influences.
• Development of novel, non-pharmacological auditory-based interventions for pain management in fibromyalgia syndrome.
• Informing environmental health policies and acoustic design strategies for healthcare settings.
• Contributing to the emerging field of environmental neuroscience by informing whether and how environmental sounds influence chronic pain processing.

Inclusion criteria

• A diagnosis of fibromyalgia syndrome, documented in the medical record provided by the participant prior to enrollment.
• Moderate or greater pain intensity during the preceding week, defined as a score higher than 3 on an 11-point Numeric Rating Scale.
• Normal hearing confirmed by a hearing test, defined as a mean threshold of ≤ 20 dB HL at 0.125, 0.25, 0.5, 1, 2, 4, 6, and 8 kHz.
• Ability to communicate in Spanish.
• Provision of signed written informed consent to participate in the research.

Exclusion criteria

• A diagnosis of misophonia or auditory processing disorders, as documented in the participant's medical record.
• Concurrent neuropathic or acute pain.
• Severe cognitive impairment, defined as a Mini-Mental State Examination score ≤ 17.
• Severe psychiatric disorders in the symptomatic phase.
• History of substance abuse in the past 12 months or current substance use disorder as reported by the participant.
• Changes in ongoing therapy during or within one month prior to study enrollment per participant self-reports.
• Central nervous system disorders.
• Any other serious or unstable medical condition that could interfere with study participation.
• Known allergies or hypersensitivity to study materials.
• Pregnancy, lactation, or being within three months postpartum at the time of study enrollment.