Pilot Randomized Controlled Trial of Krill Oil Supplementation for Chronic Musculoskeletal Pain in Older Adults

Abstract

Background:

Chronic musculoskeletal pain is highly prevalent in older adults and the leading cause of disability. Long-chain omega-3 polyunsaturated fatty acids have anti-inflammatory and analgesic properties, yet intake and circulating levels are low in older U.S. adults. Krill oil, a phospholipid-bound source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that also contains astaxanthin and choline, may represent a feasible nutrition-based intervention for chronic musculoskeletal pain.

Objective:

To evaluate the feasibility and acceptability of krill oil supplementation in older adults with chronic musculoskeletal pain and to characterize changes in omega-3 status and exploratory pain outcomes.

Methods:

A 12-week, randomized, double-blind, placebo-controlled pilot trial in 40 community-dwelling adults aged ≥60 years with moderate chronic musculoskeletal pain. Participants were stratified by sex and randomized 1:1 to krill oil (4 g/day; 1,288 mg EPA+DHA) or placebo.

Primary outcomes were feasibility metrics (recruitment, retention, adherence, and acceptability). Secondary outcomes included biomarkers of omega-3 status and inflammation. Exploratory outcomes included pain intensity, pain interference, pain distribution, and global improvement.

Results:

Recruitment targets were met within 8 months; retention was 95%, adherence exceeded prespecified thresholds (>70%) in both groups, and overall acceptability was rated 7.7±2.3 out of 10. Krill oil supplementation increased the omega-3 index from 4.3% to 7.4%, approaching levels consistent with lower cardiometabolic risk (≥8%), whereas the placebo group showed no meaningful change. Preliminary analyses showed trends favoring krill oil for reduced pain intensity (ΔKO – ΔP = −1.05), fewer pain sites (rate ratio = 0.59; 95% CI 0.41–0.84), and global improvement (adjusted OR = 4.35, 95% CI 0.97–19.55). No serious adverse events occurred.

Conclusions:

Krill oil supplementation was feasible and acceptable among older U.S. adults with chronic musculoskeletal pain. These findings support a fully powered randomized controlled trial to evaluate krill oil as a nutritional strategy for pain management in aging populations.

Introduction

Chronic musculoskeletal (MSK) pain is disproportionately prevalent among older adults (1) and is the leading cause of disability globally (2). Pain management in this population remains particularly challenging and often ineffective, complicated by multimorbidity, age-related physiological changes, and concerns related to polypharmacy (3). Opioid analgesics used to manage moderate-to-severe pain carry the risk of adverse effects such as dependence and tolerance, cognitive impairments, and drug-drug interactions in older adults, highlighting the need for non-pharmacological approaches (3–5). Nutrition-based interventions are particularly appealing as they are non-invasive, cost-effective, highly individualized, and generally low-risk. Despite the growing burden of chronic pain in aging populations (6), safe and scalable nutrition strategies that target MSK pain remain underexplored.

Most older adults in the United States do not meet the recommended intakes of omega-3 long-chain polyunsaturated fatty acids (ω-3 LC-PUFAs), and fewer than 2% exhibit circulating levels associated with a reduced risk of cardiovascular disease and mortality (7–9). Due to their well-recognized anti-inflammatory properties (10), ω-3 LC-PUFAs, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been increasingly studied for their potential analgesic effects. Mechanistically, ω-3 LC-PUFAs may modulate pain both peripherally and centrally by promoting specialized pro-resolving mediators, dampening neuronal excitability, and supporting nerve repair and neuroimmune homeostasis (11). Additionally, ω-3 LC-PUFAs may support MSK pain specifically by attenuating catabolic processes and the progression of osteoarthritis (12, 13). Meta-analyses of ω-3 supplementation trials have found moderate, clinically meaningful reductions for inflammatory pain (11, 14, 15), whereas evidence for osteoarthritis (OA)-related pain remains limited and inconclusive (11). As suggested by Xie et al., the lack of statistically significant effects observed in some OA trials may reflect the complex and multifactorial nature of OA-related pain, including low-grade inflammation, mechanical drivers of pain, and the use of multidimensional outcome measures (11). Moreover, relatively few trials have specifically examined OA populations.

Krill oil (Ephausia superba) is a marine source of ω-3 LC-PUFAs in which EPA and DHA are predominantly bound to phospholipids rather than triglycerides or ethyl esters. This structural difference is thought to enhance bioavailability and tissue uptake (16). On the other hand, the absolute EPA and DHA content per gram in krill oil is often lower than that of concentrated fish oils (17, 18), which may offset its benefits by the need for higher volumes to achieve the desired intake of EPA and DHA, potentially compromising tolerability and acceptability, especially in older adults. Beyond ω-3 fatty acids, krill oil contains additional bioactive compounds that may be beneficial for pain. Krill is naturally rich in astaxanthin, a xanthophyll carotenoid with potent anti-inflammatory/antioxidant, geroprotective, and analgesic properties (19, 20). In addition, krill oil provides choline as phosphatidylcholine, an essential nutrient involved in neurotransmission, cell signaling, lipid metabolism, and homocysteine regulation. As a precursor to acetylcholine, choline may influence cholinergic pathways involved in pain modulation (21) and plays an important role in skeletal muscle metabolism and musculoskeletal health (22). Yet, choline is poorly consumed by older adults in the United States (23, 24). While krill oil supplementation has demonstrated favorable effects on knee OA (25), older adults have been underrepresented in these trials. As such, the feasibility, acceptability, and potential effects of krill oil on chronic MSK pain in older adults remain unknown.

The Krill Oil for Pain Elders (KOPE) pilot study was a randomized, double-blind, placebo-controlled trial designed to evaluate the feasibility of conducting a larger efficacy trial in older adults with chronic MSK pain. Consistent with the CONSORT extension for pilot and feasibility trials, the primary objectives of the KOPE pilot were to assess feasibility metrics, including recruitment, retention, adherence, acceptability, and data completeness, to inform the design of a future fully powered randomized controlled trial. Our secondary objectives were to characterize changes in ω-3 status and inflammation, and we performed preliminary analyses of pain outcomes.

Methods

Trial Design.

This pilot trial used a randomized, double-blind, placebo-controlled, parallel-group design conducted over a 12-week intervention period. Participants completed three in-person study visits: a baseline visit prior to randomization (Week 0), a mid-intervention follow-up visit (Week 6), and a final assessment at the end of the intervention period (Week 12). The trial was designed and reported in accordance with the CONSORT extension for randomized pilot and feasibility trials (see Supplementary Checklist) (26). All research was conducted at the University of Florida. The study was approved by the University of Florida Institutional Review Board (#202400581) and conducted under an active U.S. Food and Drug Administration Investigational New Drug (IND) application. All participants provided written informed consent prior to participation. The trial is registered with ClinicalTrials.gov (NCT06580912); full details are available at https://clinicaltrials.gov/study/NCT06580912.

Participants.

A total of 40 community-dwelling older adults were recruited from Gainesville, FL, and neighboring areas primarily through postcard mailings and social media ads. Participants were first screened for preliminary eligibility by telephone and subsequently invited for an in-person screening visit, during which written informed consent and eligibility assessments were completed. Eligible participants completed the baseline assessment within 30 days of the screening visit prior to randomization. If more than 30 days elapsed between screening and baseline, eligibility assessments were repeated to confirm continued eligibility.

Eligible participants were men and women aged 60 years or older who reported moderate pain (≥4 on a 0–10 scale) (27) in the hips, knees, or lower back on most days for the past 3 months and demonstrated moderate mobility limitations. Exclusion criteria were designed to minimize risks and reduce confounding. These included: bleeding or coagulation disorders; use of anticoagulants, full-dose aspirin, opioids, high-dose nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and complementary medicines/supplements that may pose a risk of food-drug interaction (e.g., St. John’s Wort) or may affect study results; omega-3 supplementation (<3 months) or >2 servings/week of fatty fish intake; seafood allergy; clinically significant or uncontrolled medical conditions; substance use history; severe mobility impairment; or planned surgery during the study period.

Randomization and Blinding.

Participants were stratified by sex and randomly assigned in a 1:1 ratio to receive either krill oil or a placebo. Randomization was performed by YCA using a computer-generated allocation sequence with block randomization using varying block sizes (2, 4, and 6) to ensure balance between groups. Allocation concealment was maintained by using identical-appearing study capsules and bottles. Except for YCA, participants, investigators, and study staff who interacted with participants were blinded to group assignment throughout the trial. YCA was not involved in patient recruitment, enrollment, or clinical assessments.

Intervention.

Participants assigned to the treatment group received 4 g/day of krill oil (Superba Boost, Aker BioMarine Antarctic US LLC; Houston, TX, USA) in the form of four 1,000 mg capsules, providing a total of 1,288 mg/d EPA+DHA, 0.45 mg astaxanthin, and 320 mg choline daily. Placebo capsules matched the krill oil capsules in appearance, odor, and taste, containing 1,000 mg of mixed vegetable oil, comprised of olive oil, corn oil, palm oil, and medium-chain triglycerides in a ratio of 4:4:3:2 (approximately 31% SFAs, 46% MUFAs, and 22% PUFAs, with no EPA or DHA). This mixture resembles the fatty acid composition of a typical Western diet (28, 29). Within the context of the whole diet, the small amount of mixed fats consumed in the placebo is not expected to have any independent effects. Participants were instructed to take the assigned capsules once daily, with a meal, for 12 weeks and to maintain their usual diet and physical activity patterns throughout the study period. Tolerance was assessed weekly for the first 3 weeks, and dosage and timing were adjusted as needed. If participants reported digestive discomfort or difficulty tolerating 4 capsules per day, they were advised to temporarily reduce intake to 1 capsule and gradually increase by 1 capsule daily as tolerated until the full daily dose was reached. If taking all capsules at once was not well tolerated, the dose could also be divided across the day (e.g., 2 capsules in the morning and 2 in the evening).

Data collection.

Study data were collected and managed using REDCap (Research Electronic Data Capture) hosted at the University of Florida (30, 31).

• Feasibility Outcomes (Primary): Feasibility was determined by meeting pre-selected criteria, which included achieving 80% or more of the recruitment goal within 12 months, maintaining less than 20% attrition, and achieving >70% adherence to the intervention. The Medication Acceptability Questionnaire (MAQ) was used to assess perceptions of convenience, taste and texture, appearance and smell, side effects, and overall acceptance (32).

• Biomarker Outcomes (Secondary): Fasted whole blood samples were obtained at each study visit. Changes in blood fatty acid profile were assessed from dried blood spots using gas chromatography (OmegaQuant Analytics, Sioux Falls, SD, USA) (33). The omega-3 index is calculated as the percentage of EPA and DHA in erythrocytes, and is considered a clinically relevant biomarker of omega-3 status that is highly responsive to dietary intake (34, 35). The circulating omega-6:omega-3 ratio was included for contextualization with prior studies, although it is no longer considered a preferred indicator of omega-3 status.

  High-sensitivity C-reactive protein (hs-CRP) was measured at every visit as an inflammatory biomarker and for safety monitoring. Hs-CRP concentrations were quantified in serum using a high-sensitivity immunoturbidimetric assay and reported in mg/L.

• Clinical Outcomes (Exploratory): Due to small sample sizes, pilot studies cannot adequately provide evidence of safety, tolerability, or effect sizes. Here, we present preliminary analyses focused on the primary endpoints planned for a future, fully powered trial: pain intensity and interference, and physical function.

  Average pain intensity was assessed using a single item from the Graded Chronic Pain Scale–Revised (GCPS-R; 0–10 scale), which includes the 3-item PEG scale (Pain, Enjoyment of life, and General activity) used as a summary measure of pain intensity and interference (36). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to measure joint pain, stiffness, and physical function; all scores were normalized to a 0–100 scale (37). The overall perceived treatment response was assessed using the Patient Global Impression of Change (PGIC) (38), dichotomized as “improved” versus “not improved.” Pain distribution was quantified as the total number of painful body sites using the Michigan Body Map (range: 0–32) (39). Self-reported physical function was assessed with the Pepper Assessment Tool for Disability (PAT-D), which evaluates mobility, transferring, upper extremity function, activities of daily living (ADL), and instrumental activities of daily living (IADL) (40, 41). Performance-based physical function was assessed using the Short Physical Performance Battery (SPPB), which includes tests of balance, gait speed, and chair stands, with a total score ranging from 0 to 12 (42, 43). Handgrip strength was measured using a handheld dynamometer as the highest value derived from the average of two trials performed on each hand (44). Functional capacity and endurance were assessed using the 6-minute walk test (6MWT) (45).

• Additional Measures: Sociodemographic characteristics (age, sex, race and ethnicity, education) were self-reported. Height and weight were measured using standardized procedures and used to calculate the body mass index (BMI). Dietary intake was assessed using the Diet History Questionnaire III (DHQ-III) to measure total energy intake, overall diet quality using the Healthy Eating Index (HEI), and dietary fat quality via the HEI Fatty Acids component. HEI scores range from 0 to 100, with higher scores indicating greater adherence to the Dietary Guidelines for Americans.

Sample Size.

This pilot study was designed to guide the design and implementation of large-scale trials. We planned to enroll 40 older adults within a 12-month period. Randomization was stratified by sex to ensure balanced representation across treatment arms (10 males and 10 females per arm). Allowing an anticipated attrition rate of approximately 20%, we expected approximately 32 participants (~16 per group) to complete the intervention. This sample size is appropriate for assessing feasibility outcomes and is consistent with methodological recommendations for pilot randomized trials, particularly when anticipated effects are small to moderate (46).

Statistical Analysis.

Analyses of feasibility outcomes were descriptive in nature and summarized using proportions and means with standard deviations. Changes in biomarkers and clinical outcomes were evaluated using mixed-effects models with fixed effects for treatment group, time (modeled as a categorical variable), and the group-by-time interaction, a random intercept for each participant, and an independent covariance structure. All models were adjusted for age, sex, and body mass index (BMI). For continuous outcomes, treatment effects are reported as adjusted between-group differences in change from baseline (ΔKO – ΔP) with 95% confidence intervals. High-sensitivity C-reactive protein (hs-CRP) was log-transformed prior to analysis due to right-skewed distributions. Total pain sites, a count outcome, were analyzed using negative binomial mixed-effects models and are reported as rate ratios with 95% confidence intervals. The Patient Global Impression of Change (PGIC) was analyzed as a binary outcome using logistic regression, with results reported as odds ratios and 95% confidence intervals. Standardized effect sizes (Cohen’s d) were also reported for continuous outcomes to aid interpretation of effect magnitude, calculated using the residual standard deviation from the mixed-effects models.

Effect sizes were interpreted using conventional thresholds, with values of approximately 0.2, 0.5, and 0.8 representing small, medium, and large effects, respectively. Model assumptions were evaluated through standard diagnostic procedures, including inspection of residual distributions and assessment of homoscedasticity. All analyses followed the intention-to-treat principle. Statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC).

Results

A participant flowchart is presented in Figure 1. Recruitment began in January 2025 and continued through September 2025. During this period, 334 individuals were phone-screened for initial eligibility. Of these, 63 participants (20.1%) met preliminary criteria and were invited to complete an in-person screening visit. A total of 23 individuals were excluded during screening. The most common reasons for exclusion were SPPB scores outside the eligible range (>10, n = 11; <4, n = 1) and a history of clinically significant conditions (n = 6). One individual declined participation during the informed consent process.

Figure 1. KOPE Pilot Participant Flowchart.

A total of 40 participants were subsequently randomized to receive either krill oil (n = 20) or placebo (n = 20) in a sex-stratified manner (10 males and 10 females per group). All randomized participants received their allocated intervention and were included in the intention-to-treat analyses.

Participant Characteristics

Baseline characteristics were generally similar between groups (Table 1). Participants had a mean age of 70.1 years (SD = 5.7), were predominantly non-Hispanic White (72.5%), and had a mean BMI of 30.8 kg/m² (SD = 6.7). The proportion of non-Hispanic White participants was slightly higher in the placebo group. Diet quality was similar between groups, although mean total energy intake was higher in the placebo group.

Table 1.

Baseline characteristics of participants in the KOPE pilot trial

Characteristic	Krill Oil (n = 20)	Placebo (n = 20)	Standardized Difference1
Age, years	69.4 ± 5.5	70.7 ± 5.9	0.23
Sex, female	10 (50)	10 (50)	0.00
Race and ethnicity			0.49
Non-Hispanic White	13 (65.0)	16 (80.0)
Non-Hispanic Black	1 (5.0)	2 (10.0)
Hispanic	4 (20.0)	2 (10.0)
Asian	2 (10.0)	0 (0)
Education			0.48
High school or less	8 (40.0)	3 (15.0)
Some college	2 (10.0)	5 (25.0)
Bachelor’s or higher	10 (50.0)	12 (60.0)
Diet
Total energy intake (kcals/day)	1326 ± 423	1652 ± 860	0.49
Healthy Eating Index (HEI)2	62.7 ± 10.4	63.8 ± 7.9	0.12
HEI Fatty Acids (0-10)3	4.6 ± 3.2	4.7 ± 3.0	0.03
Body mass index, kg/m2	29.9 ± 7.5	31.8 ± 5.9	0.28
Physical performance
SPPB total score (0–12)	9.0 ± 1.1	8.1 ± 1.6	0.66
6-minute walk distance, m	384.1 ± 63.8	352.0 ± 101.2	0.38
Handgrip strength, kg	30.2 ± 8.4	27.7 ± 10.9	0.26

Values are shown as mean ± SD or n (%).

¹Standardized differences were calculated as the difference in means or proportions divided by the pooled standard deviation. Absolute values are presented.

²HEI scores range from 0 to 100, with higher scores indicating greater adherence to the Dietary Guidelines for Americans.

³HEI Fatty Acids component reflects dietary fat quality and is calculated as the ratio of (PUFAs+MUFAs)/SFAs, expressed as a percent of total energy. Scores range from 0 to 10 points, with 0 points for a ratio ≤1.2 and 10 points assigned for a ratio ≥2.5; intermediate values are scored proprotionaly

Abbreviations: PEG, Pain, Enjoyment, General Activity; WOMAC, Western Ontario and McMaster Universities OsteoarthritisIndex; SPPB, Short Physical Performance Battery.

Participants reported a high pain burden, with a mean of 7.8 (SD = 4.2) pain sites per participant (range: 2–21). The most common pain sites were the lower back (75.0%), hips (65.0%), and knees (62.5%). The lower back was also the most frequently reported worst pain site (30.0%) and second-worst pain site (12.5%), experienced for 10 (interquartile range: 3, 16) and 5 (3, 25) years, respectively. Participants also reported moderate to high pain intensity and interference, with a mean PEG score of 5.5 (SD = 2.3) and a WOMAC score of 40.1 (SD = 13.5). Nearly half (47.5%) of participants were classified as having possible or likely neuropathic pain, with a mean PainDETECT score of 12.7 (SD = 6.8).

Performance-based physical function tests showed moderate impairments, with mean SPPB score of 8.5 (SD = 1.4), 6MWT distance of 368.0 m (SD = 85.1), and handgrip strength of 28.9 kg (SD = 9.7).

Feasibility Outcomes

Recruitment took place over approximately 8 months, with an average of 5 participants enrolled per month. Notably, enrollment differed by sex. The target enrollment for women (n = 20) was reached in approximately 5.5 months, an enrollment rate of 3.6 women per month. In contrast, men were enrolled at a rate of about 2.5 per month.

Retention throughout the study period was high, with 38 of 40 participants (95%) completing the intervention. All participants who completed the intervention also completed all scheduled assessments, resulting in complete outcome data among completers. During the 12-week intervention period, 2 participants (5.0%) in the krill oil group withdrew from the study, resulting in 38 participants who completed the final assessment. One participant withdrew within five days of intervention initiation due to a migraine flare-up, and one participant withdrew for personal reasons. No participants were discontinued during the intervention, and no withdrawals were attributed to serious adverse events.

Adherence to the study supplement was high across both groups. Based on self-reported capsule intake (n = 37), mean adherence was 95.1% (SD = 5.8) in the krill oil group and 91.7% (SD = 12.0) among controls. Using capsule counts (n = 36), mean adherence was approximately 80.8% (SD = 9.9) in the krill oil group and 77.7% (SD = 12.1) among controls. When applying the prespecified adherence criterion of ≥70% daily capsule consumption, 100% of participants in the krill oil group (n = 18) and 89.5% of controls (n = 17) met this threshold based on self-report. Similarly, 83.3% of participants in the krill oil group (n = 15) and 83.3% of controls (n = 15) met the ≥70% adherence threshold based on capsule counts.

The intervention’s acceptability, assessed with the Medicine Acceptability Questionnaire (MAQ), was generally high at the end of the study. Mean scores for convenience, taste, appearance, and tolerability ranged from approximately 71% to 85%, indicating good overall acceptability of the study products. Perceived efficacy scores were lower and more variable (mean = 46.5%, SD = 24.6). Participants also reported being generally satisfied with the side effects, with a mean of 8.1 out of 10 (SD = 2.6), and rated the overall acceptability at 7.7 out of 10 (SD = 2.3). No substantial differences were observed between study groups (all p > 0.17).

Adverse events

In total, 30 participants (75%) reported at least one adverse event during the study, with 16 (80%) in the control group and 14 (70%) in the krill oil group. A total of 92 adverse events were recorded (controls: 58; the krill oil group: 34). No serious adverse events occurred in either group. Gastrointestinal symptoms were the most frequently reported adverse events, including diarrhea, constipation, flatulence, abdominal pain, and dyspepsia. Changes in appetite were also reported: decreased appetite by 6 participants (placebo: n = 5; krill oil: n = 1) and increased appetite by 3 participants (all in the control group). Unanticipated adverse events were more frequent in the control group (11 events) than in the krill oil group (3 events). Adverse events considered related to the intervention were also more frequent among controls (placebo: 5; krill oil: 2), all of which were gastrointestinal symptoms, including diarrhea, dyspepsia, flatulence, and abdominal pain. One participant in the krill oil group discontinued the intervention due to a migraine flare-up; no participants in the control group withdrew due to adverse events.

Biomarkers

The baseline omega-3 index (adjusted mean = 4.3%, 95% CI: 3.8–4.8%) was low among participants, consistent with limited dietary intake of omega-3 fatty acids. Changes in the omega-3 index are shown in Table 2 and Figure 2. The adjusted between-group mean difference in change of 3.0% (95% CI: 1.9 to 4.0), corresponding to a very large effect (Cohen’s d = 4.40). As expected, the omega-3 index increased significantly only in the krill oil group, with a marked increase evident by 6 weeks (7.3%, 95% CI: 6.7–7.8%) and remaining stable through the final assessment (7.4%, 95% CI: 6.9–8.0%). In contrast, the placebo group showed no meaningful change over time (range: 4.5–4.7%). A similar pattern was seen with the omega-6:omega-3 ratio. No substantial changes in hs-CRP were observed.

Table 2.

Biomarker outcomes at baseline and 12 weeks, with between-group difference in change and effect size

Outcome	Krill Oil		Placebo		ΔKO - ΔP	95% CI	Cohen’s d2
	t01	t21	t01	t21
Omega-3 Index (%)	4.29	7.41	4.49	4.67	2.95	1.89, 4.00	4.40
ω-6:ω-3 ratio	9.49	5.17	9.23	9.12	−4.22	−5.75, −2.69	−4.19
log(hs-CRP)	0.79	0.68	0.74	0.84	−0.22	−1.05, 0.62	−0.48

¹Values shown are model-based adjusted least-squares means (LS-means) at baseline and 12 weeks from linear mixed-effects models, controlling for age, sex, and BMI.

²Cohen’s d was calculated using the residual standard deviation from the mixed-effects model (ΔΔ standardized mean difference). Cohen’s d interpreted as: small (≈0.2), medium (≈0.5), large (≈0.8)

Figure 2. Change in omega-3 index over 12 weeks in the KOPE pilot trial (N = 40).

Omega-3 index (% EPA + DHA in erythrocytes) measured at baseline, 6 weeks, and 12 weeks in participants randomized to krill oil or placebo. Horizontal reference lines denote omega-3 index thresholds: ≤4% indicates high cardiovascular and mortality risk, while ≥8% indicates low risk.

Clinical Pain Outcomes

Across clinical pain outcomes, changes over time favored the krill oil group (Table 3). On the GCPS-R average pain intensity item, the between-group difference in change was −1.05 points (95% CI: −2.72 to 0.62; Cohen’s d = −0.77), corresponding to greater within-group pain intensity reductions in the krill oil group compared with placebo (−1.20 vs. −0.15, respectively); shown in Figure 3A. For pain interference, assessed using the PEG scale, the between-group difference in change was small (−0.09; 95% CI: −2.00 to 1.83; Cohen’s d = −0.06), consistent with similar within-group changes in the krill oil and placebo groups (−0.76 vs. −0.68, respectively).

Table 3.

Changes in clinical pain outcomes from baseline to 12 weeks

Outcomes	Krill Oil		Placebo		ΔKO - ΔP	95% CI	Cohen’s d2
	t01	t21	t01	t21
Pain intensity (0–10)	5.52	4.32	5.19	5.04	−1.05	−2.72, 0.62	−0.77
PEG score (0–10)	5.18	4.42	5.82	5.14	−0.09	−2.00, 1.83	−0.06
WOMAC pain (0–100)	44.96	35.18	45.13	40.32	−4.96	−18.87, 8.95	−0.46
WOMAC stiffness (0–100)	48.57	39.27	56.30	55.73	−8.73	−25.58, 8.12	−0.66
WOMAC physical function (0–100)	39.00	33.01	40.91	35.84	−0.93	−13.10, 11.24	−0.13
WOMAC total score (0–100)	41.04	34.01	43.07	38.43	−2.39	−13.98, 9.20	−0.32
					Rate ratio	95% CI
Total pain sites (count)	7.91	4.46	7.54	7.19	0.59	0.41, 0.84	–

¹Values shown are model-based adjusted least-squares means (LS-means) at baseline and 12 weeks from linear mixed-effects models, controlling for age, sex, and BMI.

²Cohen’s d was calculated using the residual standard deviation from the mixed-effects model (ΔΔ standardized mean difference). Cohen’s d interpreted as: small (≈0.2), medium (≈0.5), large (≈0.8).

Abbreviations: PEG, Pain, Enjoyment, General Activity; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Figure 3. Trajectories of pain intensity and pain distribution over 12 weeks in the KOPE pilot (N = 40).

Mean pain intensity (Panel A) and count of painful body sites (Panel B) assessed at baseline, 6 weeks, and 12 weeks in the krill oil and placebo groups.

Similar patterns were observed for WOMAC outcomes. The between-group difference in change was −5.0 for pain (95% CI: −18.9 to 9.0; Cohen’s d = −0.46), −8.7 for stiffness (95% CI: −25.6 to 8.1; Cohen’s d = −0.66), and −0.9 for physical function (95% CI: −13.1 to 11.2; Cohen’s d = −0.13). For the WOMAC total score, the between-group difference in change was −2.4 (95% CI: −14.0 to 9.2; Cohen’s d = −0.32). Within-group changes are presented in Table 3.

Beyond pain intensity and interference, participants receiving krill oil demonstrated a greater reduction in pain distribution, with a mean decrease of 3.5 total pain sites compared with 0.4 sites in the placebo group (Figure 3B). This corresponded to a 41% lower rate of pain sites at follow-up (rate ratio = 0.59, 95% CI: 0.41 to 0.84).

Finally, consistent with these patterns, a greater proportion of participants in the krill oil group reported overall improvement on the Patient Global Impression of Change compared with placebo (66.7% vs. 40.0%; adjusted OR = 4.35, 95% CI: 0.97 to 19.55).

Physical Function Outcomes

No meaningful between-group differences were observed across self-reported and performance-based physical function measures (Table 4).

Table 4.

Changes in physical function outcomes from baseline to 12 weeks

Outcomes	Krill Oil		Placebo		ΔKO - ΔP	95% CI	Cohen’s d2
	t01	t21	t01	t21
PAT-D Total (0–76)	47.27	42.89	49.48	47.63	−2.53	−14.60, 9.55	−0.30
Mobility (0–28)	16.85	15.44	17.19	16.39	−0.61	−5.31, 4.10	−0.18
Basic ADLs (0–20)	14.51	13.10	15.48	14.96	−0.89	−5.21, 3.43	−0.27
Instrumental ADLs (0–28)	9.24	8.41	9.37	9.45	−0.92	−4.40, 2.57	−0.35
SPPB (0–12)	8.96	9.64	8.10	8.85	−0.072	−1.33, 1.19	−0.08
6-minute walk distance (m)	375.1	362.9	358.5	353.9	−7.61	−76.5, 61.3	−0.24
Handgrip strength (kg)	30.82	32.20	29.22	30.76	−0.18	−6.93, 6.58	−0.06

¹Values shown are model-based adjusted least-squares means (LS-means) at baseline and 12 weeks from linear mixed-effects models, controlling for age, sex, and BMI.

²Cohen’s d was calculated using the residual standard deviation from the mixed-effects model (ΔΔ standardized mean difference). Cohen’s d interpreted as: small (≈0.2), medium (≈0.5), large (≈0.8).

Abbreviations: ADL, activities of daily living; PAT-D, Pepper Assessment Tool for Disability

Discussion

This pilot randomized controlled trial shows that a 12-week protocol of 4 g/day krill oil supplementation is feasible and acceptable among older adults with moderate-to-severe chronic musculoskeletal pain. While previous studies have shown promise for the analgesic effects of krill oil, most have focused on middle-aged adults, condition- and site-specific pain (i.e., knee osteoarthritis), with mild-to-moderate symptom severity, and have been conducted outside the United States (25, 47–51). In contrast, we targeted older adults with chronic musculoskeletal pain and pain-related interference on physical function, a population with a greater burden of pain, comorbidities, and risk factors, and for whom non-pharmacological pain management strategies are particularly needed. Adherence exceeding the predetermined feasibility threshold, together with favorable acceptability, suggests that a 4 g/day dosing strategy is acceptable and implementable in this population.

The feasibility outcomes from this pilot inform and support the design of future fully powered randomized trials. Recruitment targets were met ahead of schedule, retention was high, adherence exceeded the prespecified thresholds, and overall acceptability of the intervention was favorable. We found that women were enrolled more rapidly than men, which led us to modify recruitment materials specifically for men. This suggests that diverse, targeted recruitment strategies may be needed to ensure balanced sex representation in a larger trial. Retention and adherence exceeded the prespecified criteria, supporting the feasibility of a longer intervention period and suggesting that a higher adherence threshold of ≥80% may be a reasonable benchmark.

The robust increase in the omega-3 index in the krill oil group confirms biological uptake and supports its use as an objective adherence biomarker. Mean omega-3 index values increased from approximately 4% at baseline to ~8% by follow-up, representing a clinically meaningful change from a higher-risk to a lower-risk range (52, 53). This response is consistent with dose-response predictions by Walker et al., which estimate that with a baseline omega-3 index near 4–5%, approximately 1.2–1.4 g/day of EPA+DHA (as triglycerides) would be required to reach an omega-3 index of 8% (54). While Walker’s model does not account for phospholipid-bound omega-3 sources such as krill oil, the model-based prediction closely aligns with the 1,288 mg/day provided in this trial. Additionally, the model was derived from supplementation trials with a mean treatment duration of 13.6 weeks, which is comparable to the 12-week intervention period in the present study. Interestingly, the omega-3 index increased over 6 weeks and stabilized thereafter, despite erythrocytes having an approximate 120-day lifespan. It may be that incorporation into erythrocyte membranes may reach a steady state earlier than complete red blood cell turnover. Whether longer supplementation durations would lead to further increases in the omega-3 index warrants investigation with extended follow-up. On the other hand, habitual intake of fatty fish with this supplementation protocol may achieve the desired omega-3 index threshold of 8% or higher (55).

Although the study was not designed or powered to test efficacy, preliminary analyses of clinical pain outcomes consistently favored krill oil supplementation across multiple pain measures and domains. Participants receiving krill oil demonstrated larger reductions in average pain intensity, musculoskeletal pain and stiffness, pain distribution, and a greater likelihood of reporting overall improvement compared with placebo. These trends can be expected to continue with a longer supplementation period, as a meta-analysis of ω-3 supplementation RCTs indicated that benefits are noticeable within 1 month and continue to improve by 6 months (11). These patterns suggest the potential efficacy of krill oil for more generalized, multi-site, and high-impact pain phenotypes commonly seen in older adults. Reductions in multisite pain may be particularly relevant for older adults, as widespread pain is strongly associated with mobility limitations and disability. Importantly, effect size estimates are presented to aid interpretation and considerations for future trials, and should not be interpreted as evidence of efficacy.

On the other hand, krill oil supplementation did not result in meaningful improvements in self-reported or performance-based physical function over the 12-week intervention period. As with pain interference, improvements in musculoskeletal health and physical function likely require longer intervention periods and sustained biological adaptation. Omega-3 supplementation trials have shown limited and inconsistent evidence of efficacy for muscle mass, strength, and functional outcomes in older adults, particularly in interventions under 6 months’ duration (56–59). While studies with krill oil are limited, a randomized controlled trial in generally healthy older adults showed that 4 g/day of krill oil for 6 months significantly increased knee extensor strength, handgrip strength, and vastus lateralis muscle thickness, without improvements in SPPB performance (60, 61). In addition to intervention duration, improvements in physical function may be more difficult to achieve in older adults with high-impact chronic MSK pain.

Several limitations should be considered. As a pilot feasibility study with a relatively small sample size and short duration, it cannot inform the efficacy or safety of the intervention. The participants were recruited from a single academic center and surrounding areas and were mostly non-Hispanic White, which may limit generalizability to broader, more diverse populations. On the other hand, the participants in this study exhibit diet patterns and baseline omega-3 index levels that align with those in the general older population. Baseline dietary data confirmed low consumption of oily fish, with no participant reporting more than 1 serving per week (data not shown). While adherence was high, as confirmed by self-report, capsule counts, and omega-3 index levels, long-term adherence may differ.

Conclusion

This pilot trial demonstrates that krill oil supplementation at 4 g/day is feasible and acceptable among older adults with chronic musculoskeletal pain. The feasibility and adherence data, together with consistent preliminary signals across pain outcomes, support and inform the design of a larger, fully powered randomized controlled trial. Given the burden of chronic pain in aging populations and the limitations of current pharmacologic pain management in older adults, krill oil may represent a promising, generally low-risk, first-line or adjunctive non-pharmacological strategy to support pain management in aging. The findings support the practicality of implementing a krill oil nutritional intervention in this high-risk population.

Abbreviations

GCPS-R

Graded Chronic Pain Scale–Revised

KOPE

Krill Oil for Pain in Elders

MSK

musculoskeletal

PEG

Pain, Enjoyment of life, and General activity scale

PGIC

Patient Global Impression of Change

WOMAC

Western Ontario and McMaster Universities Osteoarthritis Index

Data Sharing:

Data described in the manuscript, code book, and analytic code will be made available upon request, pending application and approval.