Conditional Recommendations for Specific Dietary Ingredients as an Approach to Chronic Musculoskeletal Pain: Evidence-Based Decision Aid for Health Care Providers, Participants, and Policy Makers

Objective. Approximately 55-76% of Service members use dietary supplements for various reasons; although such use has become popular for a wide range of pain conditions, decisions to use supplements are often driven by information that is not evidence-based. This work evaluates whether the current research on dietary ingredients for chronic musculoskeletal pain provides sufficient evidence to inform decisions for practice and self-care, specifically for Special Operations Forces personnel. Methods. A steering committee convened to develop research questions and factors required for decision-making. Key databases were searched through August 2016. Eligible systematic reviews and randomized controlled trials were assessed for methodological quality. Meta-analysis was applied where feasible. GRADE was used to determine confidence in the effect estimates. A decision table was constructed to make evidence-informed judgments across factors required for decision-making, and recommendations were made for practice and self-care use. Results. Nineteen dietary ingredients were included. Conditional evidence-based recommendations were made for the use of avocado soybean unsaponifiables, capsaicin, curcuma, ginger, glucosamine, melatonin, polyunsaturated fatty acids, and vitamin D. In these cases, desirable effects outweighed undesirable effects, but there was uncertainty about the trade-offs, either because the evidence was low quality or because benefits and downsides were closely balanced. Conclusions. The evidence showed that certain dietary ingredients, when taken as part of a balanced diet and/or as a supplement (e.g., pill, tablet, capsule, cream), may alleviate musculoskeletal pain with no to minimal risk of harm. This finding emphasizes and reinforces the critical importance of shared decision-making between Operators and their health care providers.

# Introduction
Musculoskeletal (MSK) injuries are a leading cause of pain, medical encounters, lost duty time, and disability within the military due to the extreme demands of physical training and combat missions [bib_ref] Prevention of physical training-related injuries recommendations for the military and other active..., Bullock [/bib_ref] [bib_ref] Musculoskeletal injuries description of an under-recognized injury problem among military personnel, Hauret [/bib_ref]. Although MSK pain is typically treated with medications (e.g., nonsteroidal anti-inflammatories , injections, physical therapy, acupuncture, and other modalities, alternative approaches are needed. Dietary ingredients may be one such option. Dietary supplement use for a wide range of conditions, including pain, has become increasingly popular, with about 70-74% of the general adult population and 55-76% of Service members using dietary supplements for various reasons [bib_ref] A systematic review and meta-analysis on the prevalence of dietary supplement use..., Knapik [/bib_ref]. Despite their popularity, evidence for their use is unclear [bib_ref] Are active self-care complementary and integrative therapies effective for management of chronic..., Buckenmaier [/bib_ref] [bib_ref] Evidence for the efficacy of complementary and alternative medicines in the management..., Silva [/bib_ref] , and decisions to use these supplements may be driven by information that is not evidence-based (e.g., advice from peers, family members, and other sources). It is imperative that evidence-based research be used to inform decisions regarding such use to ensure safe and effective management of MSK pain.
As part of the US Special Operations Command's Preservation of the Force and Family Behavioral Health Program, this project sought to determine whether current research on dietary ingredients for chronic MSK pain could provide sufficient evidence to inform decisions for both practice and self-care use. To achieve this, stateof-the-science evidence methodologies were applied to provide clear, comprehensive, and unbiased information to the Special Operations community and enable key stakeholders and subject matter experts to make evidence-based recommendations to inform policy decisions regarding dietary ingredients for improving pain and pain-related (e.g., psychological health, quality of life) outcomes.
The aim of this article is to describe the resulting evidence-based recommendations made for the use of dietary supplements. This paper is the second in a series of articles [bib_ref] How Evidence-Based Recommendations May Direct Policy Decisions Regarding Appropriate Selection and Use..., Cota [/bib_ref] [bib_ref] Dietary Ingredients Requiring Further Research before Evidence-Based Recommendations Can be Made for..., Crawford [/bib_ref] [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref] that detail the methodological approach and relevance of this work to Special Operators, specific evidence-based recommendations, and implications for policy decisions. It is important to note that although formal processes were followed and recommendations made, this is not intended to serve as a formal clinical practice guideline.

# Methods
The project's full methodological approach is detailed within the first of this series of three articles (Supplementary Data: Detailed Methodology) [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref]. Briefly, 1) the authors followed the Institute of Medicine guidelines to ensure transparent processes were followed and mitigate any conflicts of interest to carefully select and recruit an unbiased group of key stakeholders and subject matter experts. The committee, named the Holistic Evidence Review Board (HERB), was convened to develop the criteria to inform the clinical question(s), definitions [bib_ref] Report of the Task Force on Research Standards for chronic low-back pain, Deyo [/bib_ref] , and factors required for decision-making (Supplementary Data: GRADE Grid); 2) a review team, independent of the HERB, then conducted a series of systematic reviews to assess the current state of the evidence and to explore the safety and efficacy of various dietary ingredients for treating pain and related outcomes (Supplementary Data: Summary Report); 3) the gathered evidence was integrated with the expertise of those subject matter experts; and 4) modified Delphi methods were used to develop evidence-based recommendations for the use of dietary ingredients and priority areas in need of future research following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref] [bib_ref] Consensus methods, clinical guidelines, and the RAND study of chiropractic, Coulter [/bib_ref] [bib_ref] Use of GRADE grid to reach decisions on clinical practice guidelines when..., Jaeschke [/bib_ref]. The series of systematic reviews used to inform recommendations are reported in the Supplementary Data: Summary Report.
Conditional recommendations were made when the desirable anticipated effects outweighed the undesirable effects but there was uncertainty about the trade-offs, either because the key evidence was of low quality or because the benefits and downsides were closely balanced. No recommendations were made either because the quality of the evidence was too low or trade-offs were so closely balanced that any recommendation would be too speculative. Recommendations against the current use of an ingredient, based on available evidence, were made when undesirable anticipated effects outweighed the desirable effects or the downsides clearly outweighed the benefits overall.

# Results
Nineteen dietary ingredients were identified and evaluated using systematic review methods (Supplementary Data: Detailed Methodology and Summary Report) [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref]. Integrating the evidence with the HERB clinical acumen across the factors required for decision-making, three types of recommendations were ultimately made for these dietary ingredients [fig_ref] Figure 1: Recommendations. [/fig_ref]. This article details dietary ingredients for which conditional, evidence-based recommendations were ultimately made; recommended ingredients include avocado soybean unsaponifiables (ASU) [bib_ref] Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis..., Blotman [/bib_ref] [bib_ref] Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double..., Appelboom [/bib_ref] [bib_ref] Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in..., Maheu [/bib_ref] [bib_ref] Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the..., Maheu [/bib_ref] [bib_ref] Efficacy and safety of piascledine 300 versus chondroitin sulfate in a 6..., Pavelka [/bib_ref] [bib_ref] Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of..., Lequesne [/bib_ref] , capsaicin [bib_ref] Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients, Casanueva [/bib_ref] [bib_ref] Efficacy of a 0.1% capsaicin hydrogel patch for myofascial neck pain: A..., Cho [/bib_ref] [bib_ref] Effectiveness and safety of topical capsaicin cream in the treatment of chronic..., Chrubasik [/bib_ref] [bib_ref] Topical treatment of chronic low back pain with a capsicum plaster, Frerick [/bib_ref] [bib_ref] Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus..., Kosuwon [/bib_ref] [bib_ref] High strength capsaicin cream for osteoarthritis pain: Rapid onset of action and..., Schnitzer [/bib_ref] [bib_ref] Capsicum pain plaster in chronic non-specific low back pain, Keitel [/bib_ref] [bib_ref] Capsaicin cream 0.025% as monotherapy for osteoarthritis: A double-blind study, Altman [/bib_ref] [bib_ref] Treatment of arthritis with topical capsaicin: A double-blind trial, Deal [/bib_ref] [bib_ref] Topical application of capsaicin for the treatment of localized pain in the..., Winocur [/bib_ref] [bib_ref] Systematic review of topical capsaicin for the treatment of chronic pain, Mason [/bib_ref] , curcuma [bib_ref] A randomized, pilot study to assess the efficacy and safety of curcumin..., Chandran [/bib_ref] [bib_ref] Curcuminoid treatment for knee osteoarthritis: A randomized double-blind placebo-controlled trial, Panahi [/bib_ref] [bib_ref] Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: A randomized, double-blind,..., Nakagawa [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts in patients with knee osteoarthritis, Kuptniratsaikul [/bib_ref] [bib_ref] Safety and efficacy of curcuma longa extract in the treatment of painful..., Madhu [/bib_ref] [bib_ref] The efficacy of Curcuma longa L. extract as an adjuvant therapy in..., Pinsornsak [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts compared with ibuprofen in patients..., Kuptniratsaikul [/bib_ref] [bib_ref] Treatment of osteoarthritis with a herbomineral formulation: A double-blind, placebocontrolled, cross-over study, Kulkarni [/bib_ref] [bib_ref] Clinical evaluation of a formulation containing curcuma longa and boswellia serrata extracts..., Kizhakkedath [/bib_ref] [bib_ref] Boswellia-curcumin preparation for treating knee osteoarthritis: A clinical evaluation, Badria [/bib_ref] , ginger [bib_ref] Evaluating the effects of ginger extract on knee pain, stiffness and difficulty..., Zakeri [/bib_ref] [bib_ref] Effects of a ginger extract on knee pain in patients with osteoarthritis, Altman [/bib_ref] [bib_ref] The efficacy of powdered ginger in osteoarthritis of the knee, Niempoog [/bib_ref] [bib_ref] The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis, Wigler [/bib_ref] [bib_ref] Comparing analgesic effects of a topical herbal mixed medicine with salicylate in..., Zahmatkash [/bib_ref] [bib_ref] A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis, Bliddal [/bib_ref] [bib_ref] Comparing the effects of ginger (Zingiber officinale) extract and ibuprofen on patients..., Haghighi [/bib_ref] [bib_ref] Influence of a specific ginger combination on gastropathy conditions in patients with..., Drozdov [/bib_ref] [bib_ref] Comparable efficacy of standardized ayurveda formulation and hydroxychloroquine sulfate (HCQS) in the..., Chopra [/bib_ref] [bib_ref] A commercialized dietary supplement alleviates joint pain in community adults: A double-blind,..., Nieman [/bib_ref] [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref] , glucosamine [bib_ref] Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: Results of..., Bruyere [/bib_ref] [bib_ref] Risk of bias and brand explain the observed inconsistency in trials on..., Eriksen [/bib_ref] [bib_ref] Efficacy and safety of glucosamine, diacerein, and NSAIDs in osteoarthritis knee: A..., Kongtharvonskul [/bib_ref] [bib_ref] Glucosamine therapy for treating osteoarthritis, Towheed [/bib_ref] [bib_ref] Effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib..., Zeng [/bib_ref] [bib_ref] OARSI recommendations for the management of hip and knee osteoarthritis: Part III:..., Zhang [/bib_ref] , melatonin [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] [bib_ref] Adjuvant use of melatonin for treatment of fibromyalgia, Hussain [/bib_ref] [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref] , polyunsaturated fatty acids (PUFA) [bib_ref] Polyunsaturated fatty acids and chronic pain: A systematic review and meta-analysis, Prego-Dominguez [/bib_ref] , and vitamin D [bib_ref] Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate..., Salesi [/bib_ref] [bib_ref] An evaluation of high-dose vitamin D for rheumatoid arthritis, Hansen [/bib_ref] [bib_ref] The effect of vitamin D on nonspecific low back pain, Sandoughi [/bib_ref] [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] [bib_ref] Diffuse musculoskeletal pain is not associated with low vitamin D levels or..., Warner [/bib_ref] [bib_ref] A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic..., Gendelman [/bib_ref] [bib_ref] Effect of vitamin D supplementation on progression of knee pain and cartilage..., Mcalindon [/bib_ref] [bib_ref] Effect of vitamin D supplementation on tibial cartilage volume and knee pain..., Jin [/bib_ref] [bib_ref] Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot..., Sanghi [/bib_ref] [bib_ref] Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind,..., Knutsen [/bib_ref] [bib_ref] Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: A randomized..., Schreuder [/bib_ref] [bib_ref] The effect of oral and parenteral vitamin D supplementation in the elderly:..., Sakalli [/bib_ref] [bib_ref] Effect of vitamin D supplementation on pain: A systematic review and meta-analysis, Wu [/bib_ref].
Although uncertainties remain, thereby precluding any strong recommendations for immediate use, these dietary ingredients, when taken as part of a balanced diet, applied as a cream, or administered as a supplement, may help alleviate pain from chronic MSK conditions and are suggested for use. In these cases, health care providers should be prepared to help individuals make decisions consistent with their own values, and Special Operators should be aware of the potential benefits and discuss the use of these ingredients with a provider. Because no strong recommendations were made to endorse an ingredient for immediate use without any caveats, there is a need to encourage discussion and debate among stakeholders before policy decisions are made. [fig_ref] Table 2: Summary of findings [/fig_ref] displays the ingredients where conditional recommendations were made, the graded evidence for efficacy as well as safety and other considerations examined when making recommendations. [fig_ref] Table 3: Judgments across factors for decision-making [/fig_ref] details the summary of judgments across factors and resulting recommendations.

## Conditional evidence-based recommendations

## Avocado soybean unsaponifiables
Avocado soybean unsaponifiables are a natural vegetable extract made from one-third avocado oil and two-thirds soybean oil. ASU are commonly used for osteoarthritis symptoms, as it is believed that they slow down disease progression [bib_ref] Management of osteoarthritis with avocado/soybean unsaponifiables, Christiansen [/bib_ref].
Six studies meeting the review's criteria compared ASU with placebo or chondroitin sulfate in knee and/or hip osteoarthritis populations [bib_ref] Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis..., Blotman [/bib_ref] [bib_ref] Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double..., Appelboom [/bib_ref] [bib_ref] Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in..., Maheu [/bib_ref] [bib_ref] Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the..., Maheu [/bib_ref] [bib_ref] Efficacy and safety of piascledine 300 versus chondroitin sulfate in a 6..., Pavelka [/bib_ref] [bib_ref] Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of..., Lequesne [/bib_ref]. Studies administered 300 or 600 mg/d of ASU for anywhere from three months to three years [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (75% weak, in favor; 12.5% none; 12.5% weak, against) for the use of PiascledineV R 300 (300-600 mg/d), a commercialized brand of ASU, as a dietary supplement for pain and related symptoms.
The low to moderate quality and certainty of the evidence suggests that Piascledine 300 or 600 mg/d is associated with a statistically significant reduction in pain (standardized mean difference [SMD] 14 -0.60) and improvement in function (SMD 14 -0.64) as compared with placebo at time points of three to six months' duration. (Supplementary Data: Summary Report). These desirable anticipated effects appeared to be moderate, whereas any undesirable effects, primarily gastrointestinal complaints noted across all treatment groups, were small to trivial. There was a high degree of statistically significant heterogeneity detected from the pooled studies, as well as risk of bias associated with some studies. Additionally, the small sample sizes reduced the certainty of the evidence evaluated.
Research trials to date appear to consistently report on the use of Piascledine 300, the majority of which are funded by the same entity that supplied the intervention. Although ASU appear to be available over the counter (OTC) and in combination with other "joint health" supplements, evidence to support their use in these formularies is unknown. Resources required for the use of ASU are highly dependent on the type of formulary. For . Focused PICOS used to define the narrowed research question: Are there dietary supplements/ingredients that can safely mitigate chronic pain in adults (18 years old) with musculoskeletal disorders?

## Population
- Adults (18 years) with chronic pain due to musculoskeletal disorders. - Chronic pain was defined as ongoing or recurrent pain, lasting beyond the usual course of acute illness or injury (i.e., >3 months and occurring at least half of the days over the past 6 months), and which adversely affects the individual's well-being [bib_ref] Report of the Task Force on Research Standards for chronic low-back pain, Deyo [/bib_ref]. - Musculoskeletal pain was defined as pain affecting the bones, muscles, ligaments, or disorders of the muscles, nerves, tendons, joints, and cartilage, and disorders of the nerves, tendons, muscles, and supporting structures of the upper and lower limbs, neck, and lower back that are caused, precipitated, or exacerbated by sudden exertion or prolonged exposure to physical factors such as repetition, force, vibration, or awkward posture. Note that headaches/ migraines and musculoskeletal pain conditions resulting from another disease or injury (e.g., fracture, contusion, abrasion, laceration) were excluded. Intervention
Any single or multiple (e.g., combination of ingredients) dietary ingredient(s)- Indicated for neuropathic pain as secondline treatment; may also be effective for musculoskeletal pain.
- Be aware of possible burning sensation upon application, especially at higher doses (0.25%).
- Invest in resources in dose response study to understand dose response curve.
vs other

## 2/194
Fibromyalgia, osteoarthritis Only one study compared capsaicin with another comparator (i.e., usual care). Both high (i.e., 0.25% capsaicin) and low (i.e., 0.025% capsaicin) doses were effective. Although a higher dose may produce more burning sensation, the application of the product may be required less frequently, and preliminary evidence suggests that pain relief occurs quicker at this higher dose.
(continued) - Already available in tea/food; no additional risk in obtaining ginger via food sources.

## Conditionally recommended dietary ingredients for pain
- Divergent opinions regarding feasibility, acceptability, and suitability.
- Invest more in research, specifically in larger trials.
vs other 

## 2/187
Osteoarthritis Two studies compared ginger with ibuprofen and reported mixed results. The higher the dose (e.g., 1,000 mg), the more likely a positive benefit for ginger only.
*Studies combining ginger (N 14 4) with other ingredients were heterogeneous. Overall, combination products showed positive benefit for reducing pain and possibly overall health/quality of life but not for improving function.
(continued) - Moderate-quality evidence supports the use of glucosamine in the form of pCGS at 1,500 mg/d and suggests that it has similar effects to ibuprofen but takes longer to obtain a response.
- Effects of pCGS combined with prescription chondroitin are still unknown.
- pCGS implementation requires obtaining a supplement with the same purity levels of the pCGS ingredients.
- OTC appears safe, but types and effects of formulations are unknown. Fibromyalgia Two studies showed that melatonin was effective, and in some cases more effective, than other comparators in improving pain, sleep, health-related quality of life, mood, and physical function.

## - 
(continued) *Eight voting members judged factors to consider together to develop recommendations. A summary weight is provided for each ingredient ranking the desirable consequences to the unknown or undesirable consequences across factors, which was done anonymously. The quality was not assigned a weight, as this was used to determine the weight of the certainty of the evidence across all outcomes assessed, and as supplied by the evidence review independently (Supplementary Data: Summary Report). Although the accumulated judgments of all factors were used to inform the recommendations ultimately made and displayed using the GRADE Grid (Supplementary Data: GRADE Grid) visually, they were not assigned a weighted summary score.  Conditionally recommend use as a food source, not as a dietary supplement, at this time.
example, Piascledine 300 is made in France, and therefore the required resources are perhaps higher than other dietary ingredients. Because it is unknown what formularies might be beneficial beyond Piascledine 300, members had divergent opinions regarding ASU's required resources, acceptability to stakeholders, and feasibility of implementation.
Given that the desirable effects outweigh the undesirable, research should focus on understanding OTC formulations and conducting third-party evaluations before strong recommendations can be made. The purity of ASU ingredients should also be confirmed via United States Pharmacopeia (USP)-verified or NSF-certified products.

## Capsaicin
Capsaicin, one of the primary constituents of the Capsicum species, is an active component of chili peppers. Capsicum is grown worldwide and adds color, pungency (i.e., heat), and aroma to food. Capsaicin is used orally, topically, and intranasally for a variety of conditions. It is most commonly used topically for MSK conditions such as osteoarthritis, rheumatoid arthritis, neuralgias/neuropathies, back pain, fibromyalgia, and muscle spasms. In fact, both low-concentration OTC and Food and Drug Administration (FDA)-approved, high-concentration (i.e., Qutenza TM ) topical formulations are available.
Ten randomized controlled trials (RCTs) [bib_ref] Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients, Casanueva [/bib_ref] [bib_ref] Efficacy of a 0.1% capsaicin hydrogel patch for myofascial neck pain: A..., Cho [/bib_ref] [bib_ref] Effectiveness and safety of topical capsaicin cream in the treatment of chronic..., Chrubasik [/bib_ref] [bib_ref] Topical treatment of chronic low back pain with a capsicum plaster, Frerick [/bib_ref] [bib_ref] Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus..., Kosuwon [/bib_ref] [bib_ref] High strength capsaicin cream for osteoarthritis pain: Rapid onset of action and..., Schnitzer [/bib_ref] [bib_ref] Capsicum pain plaster in chronic non-specific low back pain, Keitel [/bib_ref] [bib_ref] Capsaicin cream 0.025% as monotherapy for osteoarthritis: A double-blind study, Altman [/bib_ref] [bib_ref] Treatment of arthritis with topical capsaicin: A double-blind trial, Deal [/bib_ref] [bib_ref] Topical application of capsaicin for the treatment of localized pain in the..., Winocur [/bib_ref] compared the effect of capsaicin with placebo, usual treatment, or other capsaicin products within a variety of populations, including those with osteoarthritis, rheumatoid arthritis, and other MSK conditions. Capsaicin was delivered topically either as a patch or gel/cream; capsaicin gels/creams were labeled as Capsika gelV R , ZostrixV R , Dolarac TM , FinalgonV R , or SensedolV R . Daily dosages of patches containing either 0.1% or 22-37.4 ug/cm 2 of capsaicin were applied at times ranging from four to 12 hours over three to four weeks, whereas dosages of creams containing 0.0125-0.25% capsaicin were applied at times ranging from twice to four times daily for three to 12 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (37.5% weak, in favor; 62.5% strong, in favor) for the use of capsaicin as a cream or patch for pain and related symptoms.
Current research shows high-quality evidence and certainty that capsaicin will produce a statistically significant reduction in pain (SMD 14 -0.56) and the patient's global assessment of improvement (risk difference [RD] 14 -0.21) compared with placebo at time points closest to four weeks (Supplementary Data: Summary Report). These desirable anticipated effects were judged to be moderate overall, and the undesirable anticipated effects, primarily associated with burning, itching, and irritation, were judged to be small to trivial. Most OTC creams contain 0.025-0.075% capsaicin and can be applied three to four times a day to the affected area. The application of higher OTC doses (i.e., 0.25%) is only recommended if the patient can tolerate the increased undesirable effects, an approach that can potentially provide quicker pain relief with less frequent applications.
Because the cost of capsaicin is highly dependent upon its dose and delivery system, it was challenging for members to judge the required resources based on the current evidence. Given the desirable vs undesirable anticipated effects, however, its use likely justifies the resource requirements and out-of-pocket expenses. Members agreed that capsaicin would likely be acceptable to stakeholders and feasible/suitable to implement for use as a cream or patch.

## Curcuma
Turmeric, commonly referred to by its Latin name, curcuma, is a plant related to ginger and is grown throughout India, parts of Asia, and Central America [89]. Curcuma is formulated into capsules, tablets, teas, extracts, and/or pastes and is used for inflammation, arthritis, stomach, skin, liver and gallbladder problems, cancer, and other conditions. Turmeric root and powder are available as grocery items for cooking.
The authors identified 10 RCTs [bib_ref] A randomized, pilot study to assess the efficacy and safety of curcumin..., Chandran [/bib_ref] [bib_ref] Curcuminoid treatment for knee osteoarthritis: A randomized double-blind placebo-controlled trial, Panahi [/bib_ref] [bib_ref] Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: A randomized, double-blind,..., Nakagawa [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts in patients with knee osteoarthritis, Kuptniratsaikul [/bib_ref] [bib_ref] Safety and efficacy of curcuma longa extract in the treatment of painful..., Madhu [/bib_ref] [bib_ref] The efficacy of Curcuma longa L. extract as an adjuvant therapy in..., Pinsornsak [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts compared with ibuprofen in patients..., Kuptniratsaikul [/bib_ref] [bib_ref] Treatment of osteoarthritis with a herbomineral formulation: A double-blind, placebocontrolled, cross-over study, Kulkarni [/bib_ref] [bib_ref] Clinical evaluation of a formulation containing curcuma longa and boswellia serrata extracts..., Kizhakkedath [/bib_ref] [bib_ref] Boswellia-curcumin preparation for treating knee osteoarthritis: A clinical evaluation, Badria [/bib_ref] meeting the review's inclusion criteria. Studies compared curcuma, either alone (N 14 7) or combined with other ingredients , with other dietary ingredients, NSAIDs, or placebo in samples with osteoarthritis and/or rheumatoid arthritis. Doses ranged from 700 to 2,000 mg/d over 42 days to 12 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (75% weak in favor; 12.5% none; 12.5% weak, against) for the use of curcuma as a food source in daily diets at dose equivalents of 500 mg two to three times per day for pain and related symptoms. The HERB did not recommend curcuma as a dietary supplement at this time.
A large (SMD 14 -1.05) and statistically significant desirable anticipated effect was noted for pain reduction, enhanced global function (SMD 14 -0.87), and reduced medication use (RD 14 -0.50), as compared with placebo at the time point closest to two months. The quality and certainty of the evidence are very low to low. Potential risk of bias across the pooled studies, small sample size, and statistically significant heterogeneity were reasons for downgrading (Supplementary Data: Summary Report).
Curcuma was rated as a high priority research area given that its potential desirable effects outweigh the minimal undesirable effects (e.g., minor gastrointestinal complaints). Until further research is conducted, curcuma is suggested as a useful dietary source but should not be used as a dietary supplement. Costs were rated as negligible to even moderate savings. There was some disagreement as to whether curcuma would be acceptable to stakeholders or feasible to implement. Once further research emerges, additional stakeholder debate would be required [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref].

## Ginger
Ginger is a tropical plant widely used as a flavoring or fragrance in foods, beverages, soaps, and cosmetics. Common forms include the fresh or dried root, tablets, capsules, liquid extracts, and teas. Ginger is currently used as a dietary ingredient for nausea, rheumatoid arthritis, and osteoarthritis.
Ten RCTs [bib_ref] Evaluating the effects of ginger extract on knee pain, stiffness and difficulty..., Zakeri [/bib_ref] [bib_ref] Effects of a ginger extract on knee pain in patients with osteoarthritis, Altman [/bib_ref] [bib_ref] The efficacy of powdered ginger in osteoarthritis of the knee, Niempoog [/bib_ref] [bib_ref] The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis, Wigler [/bib_ref] [bib_ref] Comparing analgesic effects of a topical herbal mixed medicine with salicylate in..., Zahmatkash [/bib_ref] [bib_ref] A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis, Bliddal [/bib_ref] [bib_ref] Comparing the effects of ginger (Zingiber officinale) extract and ibuprofen on patients..., Haghighi [/bib_ref] [bib_ref] Influence of a specific ginger combination on gastropathy conditions in patients with..., Drozdov [/bib_ref] [bib_ref] Comparable efficacy of standardized ayurveda formulation and hydroxychloroquine sulfate (HCQS) in the..., Chopra [/bib_ref] [bib_ref] A commercialized dietary supplement alleviates joint pain in community adults: A double-blind,..., Nieman [/bib_ref] met the review's eligibility criteria, five of which were also included in Bartels et al.'s 2015 systematic review and meta-analysis [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref] on ginger for osteoarthritis. Studies compared ginger, either alone or combined with other ingredients, with herbal, pharmacologic, and placebo comparators in osteoarthritis, rheumatoid arthritis, and chronic joint pain populations. Dosages ranged from 250 to 1,000 mg/d (delivered as a capsule) and 6 g/d (delivered as an ointment) over anywhere from three to 12 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Whereas no recommendation was provided (37.5% weak, in favor; 37.5% none; 25% weak, against) for the use of ginger as a dietary supplement, members agreed that minimal adverse events have been noted and that the certainty and quality of the evidence for a small yet statistically significant reduction in pain (SMD 14 -0.30) and disability (SMD 14 -0.22) were moderate (Supplementary Data: Summary Report) [bib_ref] Dietary Ingredients Requiring Further Research before Evidence-Based Recommendations Can be Made for..., Crawford [/bib_ref] [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref]. The desirable anticipated effect was not as substantial as the other ingredients reported here; however, members agreed that it is already available in tea and food and, if readily available, could be suggested for use.
Although the critical threshold for a clinically relevant effect is debatable, the effect size of ginger does fall within the range of some other nutraceuticals/herbal medicines, and NSAIDs and may be beneficial to some individuals [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref]. The exact dose is not well established, but plausible dose responses associated with ginger in higher doses (i.e., 1,000 mg) appear to produce a larger effect than lower doses (i.e., 250 mg) [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref]. Risk of bias was detected across some studies evaluated. The cost appears negligible or even a moderate savings compared with other active pain medications, but members did not agree as to whether this would justify its use or out-ofpocket costs. Members mostly agreed that there are concerns over feasibility and suitability with ginger in mission planning and that it would likely not be acceptable to stakeholders for use.

## Glucosamine, prescription/over-the-counter
Glucosamine is an amino sugar naturally produced in the human body. It is required for the synthesis of glucoproteins, glyocolipids, and glucosaminoglycans found in the tendons, ligaments, cartilage, synovial fluid, mucous membranes, eye structures, blood vessels, and heart valves. It can also be derived from marine exoskeletons or produced synthetically [bib_ref] Glucosamine hydrochloride for the treatment of osteoarthritis symptoms, Fox [/bib_ref]. Glucosamine sulfate and glucosamine hydrochloride are delivered orally for many MSK conditions such as temporomandibular disorder, joint pain, osteoarthritis, knee pain, and back pain. Both are also commonly combined with each other or other products (e.g., chondroitin sulfate, N-acetyl glucosamine).
Controversy surrounds the reported effectiveness of glucosamine [bib_ref] Efficacy and safety of glucosamine sulfate in the management of osteoarthritis: Evidence..., Bruyere [/bib_ref] ; however, a Cochrane review recently confirmed that a particular glucosamine sulfate product (Dona, Rotta Pharmaceuticals), as opposed to other formulations, was effective in reducing osteoarthritic pain [bib_ref] Glucosamine therapy for treating osteoarthritis, Towheed [/bib_ref].
Conditional recommendations were made (62.5% weak; 37.5% strong, in favor) for the use of prescription patented Crystalized Glucosamine Sulfate (pCGS) at daily doses of 1,500 mg for pain and related symptoms. It is important to note that the controversy concerning the use of glucosamine sulfate and combination products containing glucosamine largely reflects the differing regulatory status, labeling, and availability of medications in separate countries and regions of the world. Hence, to date it appears that pCGS, as supplied by RottaPharm, is the only product with a well-documented pharmacological effect [bib_ref] Risk of bias and brand explain the observed inconsistency in trials on..., Eriksen [/bib_ref] [bib_ref] Glucosamine therapy for treating osteoarthritis, Towheed [/bib_ref].
There is moderate overall quality and certainty that this product will produce a statistically significant effect in reducing pain (SMD 14 -0.27) compared with placebo [bib_ref] Risk of bias and brand explain the observed inconsistency in trials on..., Eriksen [/bib_ref] [bib_ref] OARSI recommendations for the management of hip and knee osteoarthritis: Part III:..., Zhang [/bib_ref]. pCGS appears to be well-tolerated, as associated undesirable effects (e.g., mild gastrointestinal complaints) are small to trivial. Although pCGS shows similar effects to ibuprofen, it does take longer to obtain a response. Members mostly agreed that the cost would be negligible to even a moderate savings compared with other active ingredients for pain relief. Moreover, they concurred that it would likely justify out-of-pocket expenses and be both acceptable to stakeholders and feasible/suitable to implement, provided that any implemented supplement had the same purity levels as the pCGS ingredients, as in the RottaPharm product.
Effects of pCGS combined with chondroitin remain unknown. OTC glucosamine is available, and although the certainty of the evidence was very low to low and the desirable effects likely small, the members believed that the undesirable effects would be small to trivial. Conditional recommendations were provided for OTC glucosamine (62.5% weak, in favor; 37.5% none), should pCGS not be available to a Special Operator.

## Melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone naturally produced by the pineal gland in the brain. This hormone plays a role in sleep, with production and release related to time of day (i.e., rising in the evening, falling in the morning) [bib_ref] Melatonin in humans, Brzezinski [/bib_ref]. Melatonin is commonly administered orally via capsule for sleep disorders but may be also used to manage neuropathies, headaches, cancers, or osteoporosis.
Three RCTs meeting the review's inclusion criteria compared the effect of melatonin with either a placebo [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref] or a pharmacological drug (i.e., fluoxetine [bib_ref] Adjuvant use of melatonin for treatment of fibromyalgia, Hussain [/bib_ref] or amitriptyline [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] in fibromyalgia [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] [bib_ref] Adjuvant use of melatonin for treatment of fibromyalgia, Hussain [/bib_ref] and myofascial temporomandibular disorder (TMJ) populations [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref]. Melatonin doses ranged from 3 to 10 mg/d across four to eight weeks [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref]. Baseline levels of melatonin were not reported by any study [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (75% weak, in favor; 12.5% none; 12.5% weak, against) for short-term use of low-dose (i.e., 3-5 mg/d) USP-verified or NSF-certified melatonin products as a dietary supplement for pain and related symptoms.
Preliminary evidence demonstrates that melatonin is superior to placebo [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref] , and perhaps to amitryptline [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] , in reducing pain and reliance on other medications while improving sleep patterns. Little is known about how large these desirable anticipated effects may be or the potential adverse events that might be associated with long-term use. Nonrandomized trials have reported that drowsiness, headache, dizziness, and nausea are uncommon. The HERB agreed that higher doses of melatonin should be avoided until further long-term studies are conducted. Melatonin is a dietary ingredient already broadly used, acceptable to many stakeholders, and available as a sleep aid, so it is likely feasible to implement for pain and sleep improvement. Associated costs are viewed as negligible or even a moderate savings compared with other pain-relieving medications. The quality and certainty of the evidence were judged to be very low to low, with insufficient studies to conduct a meta-analysis.

## Polyunsaturated fatty acids
Fish oil comes from various species, including mackerel, herring, tuna, halibut, salmon, cod liver, and whale and seal blubber. Thus, these types of fish are dietary sources of omega-3 fatty acids, also known as n-3 fatty acids [bib_ref] Beyond the Mediterranean diet: The role of omega-3 fatty acids in the..., Harper [/bib_ref]. Omega-3 fatty acids are essential dietary ingredients and include alpha-linolenic acid (ALA), longchain omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Fish oil supplements contain varying amounts of EPA and DHA (18-51% and 12-32%, respectively). Although ALA is mainly found in green vegetables, canola oil, and soybeans, EPA and DHA almost exclusively come from fish oil and other seafood. ALA, EPA, and DHA are types of omega-3 fatty acids but may serve different functional roles and should subsequently not be considered interchangeable. Although proprietary prescription fish oil is FDAapproved to lower levels of triglycerides, nonprescription formulations of fish oil are also used for other conditions including chronic fatigue syndrome, cognitive function/ impairment, and MSK (e.g., rheumatoid arthritis, muscle strength, muscle soreness, osteoporosis, osteoarthritis, migraines) issues .
The authors relied upon evidence on PUFA for chronic pain presented in Prego-Dominguez et al.'s 2016 systematic review and meta-analysis [bib_ref] Polyunsaturated fatty acids and chronic pain: A systematic review and meta-analysis, Prego-Dominguez [/bib_ref]. The majority of examined studies compared various combinations of PUFA with placebo or other comparators for pain reduction in rheumatoid arthritis patients, with doses ranging from 300 to 9,600 mg for anywhere from four to 48 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (50% weak; 50% strong, in favor) for the use of PUFA supplementation for pain and related symptoms, incorporated into the daily diet at 1,200 mg/d, and not to exceed 2 g/d. Whereas the undesirable effects appear to be small to trivial at low doses, >3 g/d is likely to increase the potential for adverse events (e.g., inhibition of platelet aggregation, risk of bleeding, and potentially hemorrhagic stroke at very high doses) (Supplementary Data: Summary Report).
Moderate-quality evidence suggests that the desirable anticipated effects for pain reduction (SMD 14 -0.40 range) are statistically significant as compared with placebo [bib_ref] Polyunsaturated fatty acids and chronic pain: A systematic review and meta-analysis, Prego-Dominguez [/bib_ref]. Heterogeneity is noted across the assessed studies and is likely due to varying blends of omega-3/6 used. Although research points to the association between omega-3, rather than omega-6, and pain reduction, the exact ratio, dose, and duration of PUFA use are yet to be determined; most studies, however, report benefit between 1 and 2 g/d.
PUFA do have preventive benefits, are available in food, and should be considered as a dietary source. Nutrition education is critical, moreover, to ensure that the proper amounts are being obtained via food or supplementation to avoid excessive intake. Members mostly agreed that the certainty of the evidence is moderate and that cost is negligible, with even moderate savings compared with currently used pain medications. Subsequently, PUFA are likely acceptable, feasible, and suitable to implement as a dietary food source or supplement, preferably from a USP-verified or NSF-certified product.
Vitamin D Vitamin D is a fat-soluble vitamin obtained from sun exposure, food, and/or dietary supplements. Vitamin D promotes calcium absorption, is necessary for bone growth, and appears to also affect skeletal muscle, immune regulation, cardiovascular health, and metabolic activities [bib_ref] Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis..., Razzaque [/bib_ref]. Vitamin D deficiencies can result in thin, brittle, or misshapen bones, bone pain, muscle weakness, rickets, and osteomalacia [bib_ref] Vitamin D: Importance in the prevention of cancers, type 1 diabetes, heart..., Holick [/bib_ref]. Vitamin D is most commonly used for osteoporosis, osteomalacia, and falls and fractures in individuals at risk for osteoporosis.
The authors relied on the systematic review published by Wu et al. [bib_ref] Effect of vitamin D supplementation on pain: A systematic review and meta-analysis, Wu [/bib_ref] and individual RCTs examining populations with rheumatoid arthritis, chronic low back, fibromyalgia, chronic nonspecific MSK pain, and knee osteoarthritis [bib_ref] Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate..., Salesi [/bib_ref] [bib_ref] An evaluation of high-dose vitamin D for rheumatoid arthritis, Hansen [/bib_ref] [bib_ref] The effect of vitamin D on nonspecific low back pain, Sandoughi [/bib_ref] [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] [bib_ref] Diffuse musculoskeletal pain is not associated with low vitamin D levels or..., Warner [/bib_ref] [bib_ref] A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic..., Gendelman [/bib_ref] [bib_ref] Effect of vitamin D supplementation on progression of knee pain and cartilage..., Mcalindon [/bib_ref] [bib_ref] Effect of vitamin D supplementation on tibial cartilage volume and knee pain..., Jin [/bib_ref] [bib_ref] Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot..., Sanghi [/bib_ref] [bib_ref] Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind,..., Knutsen [/bib_ref] [bib_ref] Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: A randomized..., Schreuder [/bib_ref] [bib_ref] The effect of oral and parenteral vitamin D supplementation in the elderly:..., Sakalli [/bib_ref] to evaluate and present the evidence on vitamin D for chronic MSK pain. Ingredients were labeled calcifediol [bib_ref] Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate..., Salesi [/bib_ref] [bib_ref] The effect of vitamin D on nonspecific low back pain, Sandoughi [/bib_ref] , vitamin D 2 [bib_ref] An evaluation of high-dose vitamin D for rheumatoid arthritis, Hansen [/bib_ref] [bib_ref] Diffuse musculoskeletal pain is not associated with low vitamin D levels or..., Warner [/bib_ref] , vitamin D 3 [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] [bib_ref] A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic..., Gendelman [/bib_ref] [bib_ref] Effect of vitamin D supplementation on progression of knee pain and cartilage..., Mcalindon [/bib_ref] [bib_ref] Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot..., Sanghi [/bib_ref] [bib_ref] Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind,..., Knutsen [/bib_ref] [bib_ref] Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: A randomized..., Schreuder [/bib_ref] , and vitamin D [bib_ref] The effect of oral and parenteral vitamin D supplementation in the elderly:..., Sakalli [/bib_ref]. Baseline vitamin D levels ranged from 12.8 6 8.7 to 42.9 6 11.3 ng/mL in the vitamin D group and 15.0 6 3.0 to 37.3 6 13.2 ng/mL in the comparator arm. Dosages ranged from 400 IU to 300,000 IU/d for anywhere from a single dose to a course of two years. All studies except one [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] that included a triglyceride solution compared vitamin D with placebo [fig_ref] Table 2: Summary of findings [/fig_ref] Supplementary Data: Summary Report).
Following a strict methodological approach and using evidence to guide judgments [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref] , conditional recommendations (100% weak, in favor) were made for the use of vitamin D supplementation for pain and related symptoms at doses of 2,000 IU/d, not to exceed 4000 IU/d. Higher doses should only be used for short-term treatment of vitamin D deficiency and when instructed by a health care provider. Recent evidence suggests that individuals who consume high doses of vitamin D could be at risk of vitamin D intoxication, dysregulation of calcium and phosphorous metabolism, hypercalcemia, hypercalciuria, and hyperphosphatemia. Current approaches to assessing serum levels of 25 hydroxyvitamin D do not necessarily reflect current intake or stores of vitamin D [bib_ref] Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis..., Razzaque [/bib_ref] [bib_ref] Association between calium or vitamin D supplementation and fracture incidence in community-dwelling..., Zhao [/bib_ref].
Based on the evidence, the HERB judged the desirable anticipated effects for pain reduction to be moderate in size (SMD 14 -0.55) at final follow-up, and results were statistically significant compared with placebo when used at low doses [bib_ref] Effect of vitamin D supplementation on pain: A systematic review and meta-analysis, Wu [/bib_ref]. Undesirable effects were judged to be small to trivial. This research is of low quality, primarily due to concerns over heterogeneity, varying populations with potentially different baseline vitamin D levels, and varying doses and durations of intake, which make interpretation challenging (Supplementary Data: Summary Report). Members judged the certainty of the evidence to be low and agreed that cost was negligible compared with ibuprofen 2400 mg/d.
Because the desirable effects likely outweigh the undesirable, resource requirements may justify vitamin D use. Members agreed that vitamin D up to 2,000 IU per day would probably be feasible and acceptable to stakeholders when the product was produced by reputable manufacturers and sold by trusted vendors. Only some vitamin D products sold are on the United States Pharmacopeia National Formulary (USP-NF) verified product list. Although vitamin D can be obtained via food and sun exposure, the HERB members agreed that Special Operators may not receive adequate exposure to sunlight due to wearing long-sleeved clothing/tactical gear and being outside during nighttime operations.

# Discussion
Evidence-based conditional recommendations have been made for various dietary ingredients, which suggests that they could be used in support of managing chronic MSK pain, specifically for Special Operations Forces (SOF). Nineteen dietary ingredients [fig_ref] Figure 1: Recommendations. [/fig_ref] had sufficient scientific evidence available to evaluate the state-of-the-science and evidence for any desirable and undesirable anticipated effects on chronic MSK pain, function, and related outcomes through systematic review and meta-analysis techniques. The GRADE approach was used to determine the quality of that evidence by examining the risk of bias, inconsistency, imprecision, and indirectness from the pooled studies. Subject matter experts and key stakeholders evaluated the certainty of the overall evidence, weighed the desirable to undesirable anticipated effects, and considered resource requirements, acceptability, and feasibility/suitability to determine the strength and direction of evidence-based recommendations that could be practical/useful to SOF [fig_ref] Table 3: Judgments across factors for decision-making [/fig_ref].
ASU, capsaicin, curcuma, ginger, glucosamine, melatonin, PUFA, and vitamin D are recommended and may help alleviate chronic MSK pain. They are suggested for use when taken either as part of a balanced diet and/or as a supplement or applied as a cream. Individuals should discuss options with a health care provider before initiating use of any dietary ingredient. Individuals should also select USP-verified products when possible as they 1) contain the ingredients listed on the label in the declared potency and amounts, 2) contain no harmful levels of specified contaminants, 3) break down and release into the body within a specified amount of time, and 4) have been made according to FDA current Good Manufacturing Practices by using sanitary and wellcontrolled procedures. Operators can also consider NSF Certified for Sportproducts and refer to Operation Supplement Safety, a Department of Defense dietary supplement resource [bib_ref] Usefulness of a risk assessment tool to risk stratify dietary supplements, Attipoe [/bib_ref] , to verify safety.
Because recommendations were only conditional and did not strongly endorse an ingredient for immediate use, discussion and debate among stakeholders before policy decisions are made surrounding these dietary ingredients and future efforts worthy of further investigation are encouraged.

## Weighing the desirable and undesirable effects
The HERB members weighed desirable and undesirable anticipated effects based on the evidence supplied through systematic review and meta-analysis. Each conditionally recommended ingredient showed an improvement in pain over time compared with placebo or other active comparators. The quality of that evidence varied among the dietary ingredients evaluated. For example, evidence for pain reduction via capsaicin and PUFA is high and moderate, respectively; conversely, the evidence that vitamin D will produce a statistically significant reduction in pain associated with chronic MSK pain is of low quality. Further, although curcuma shows the largest estimated effect for decreasing pain and improving global function, and perhaps decreasing medication use, the quality of the evidence is very low to low. Some ingredients showed improvement in other pain-related outcomes, but how these ingredients affect such outcomes overall and whether they influence outcomes beyond those in [fig_ref] Table 2: Summary of findings [/fig_ref] are unknown.
In addition, how substantial these reported desirable effects might be for any one individual may vary significantly. What is considered a clinically meaningful improvement in pain, as well as other outcomes, is under considerable debate and is a point of discussion by the HERB members. , compared the SMD from their meta-analysis with other SMDs noted from other interventions, stating,
The SMD of 0.30 for ginger compared with placebo corresponds to an effect size for pain which is only slightly above the critical threshold limit for a relevant SMD in osteoarthritis, and it is comparable, although a little higher, to the SMD of 0.21 seen with intake of acetaminophen [bib_ref] Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised..., Zhang [/bib_ref]. The observed pain reducing effect for ginger is in the same range as SMD previously reported for other nutraceuticals/herbal medicines like diacerein with an SMD of 0.24 [bib_ref] Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: A..., Bartels [/bib_ref] , ASU with an SMD of 0.39 [bib_ref] Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: A..., Bartels [/bib_ref] , and rose hip powder of 0.37 [bib_ref] Does the rose hip powder of rosa canina (rosehip) reduce pain in..., Christensen [/bib_ref] , all in comparison with placebo. Compared to the effect of NSAIDs, the SMD for ginger has an effect size in the middle of the NSAID range of 0.17 to 0.66, all when compared to placebo [bib_ref] Efficacy of etoricoxib, celecoxib, lumiracoxib, non-selective NSAIDs, and acetaminophen in osteoarthritis: A..., Stam [/bib_ref] [bib_ref] Influence of flare design on symptomatic efficacy of non-steroidal anti-inflammatory drugs in..., Trijau [/bib_ref] [bib_ref] Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: Meta-analysis of..., Bjordal [/bib_ref].
The HERB used the effect of high-dose ibuprofen, 2,400 mg/d, reported as SMD 14 -0.41 compared with placebo [bib_ref] Efficacy of etoricoxib, celecoxib, lumiracoxib, non-selective NSAIDs, and acetaminophen in osteoarthritis: A..., Stam [/bib_ref] , as a reference point. To date, comparative effectiveness trials across dietary ingredients are heterogeneous and challenging to pool in meta-analysis in any meaningful way. Further research is needed for comparing ingredients with placebo and other standards of care.
Undesirable anticipated effects, as reported in the evaluated studies, primarily consisted of minor gastrointestinal complaints. Given their nonserious and infrequent nature, members judged that the desirable effects outweighed the undesired across all dietary ingredients. Currently data from published studies showing how these ingredients directly compare with other active comparators in terms of varying adverse events are insufficient. There is concern that when used at higher doses, more and additional adverse events, beyond gastrointestinal issues, may occur. For example, extremely high doses of PUFA may increase the risk of both ischemic and hemorrhagic stroke [bib_ref] Fish consumption and stroke: A community case-control study in Asturias, Spain, Caicoya [/bib_ref] , and extremely high doses of vitamin D could lead to intoxication [bib_ref] Vitamin D intoxication associated with an over-the-counter supplement, Koutkia [/bib_ref]. Other adverse events, though relatively mild (e.g., "bad taste" associated with ginger and PUFA) can cause some individuals to discontinue use [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref] [bib_ref] Effects of new fish oil derivative on fatty acid phospholipidmembrane pattern in..., Belluzzi [/bib_ref] [bib_ref] Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease, Kris-Etherton [/bib_ref].

## Certainty of the evidence
Although the quality of the evidence was determined using the GRADE approach and was specific to each outcome evaluated, the certainty of the evidence was judged based on reviewing the evidence of effects across all outcomes where it was feasible to pool results into a metaanalysis [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report.) Members judged the certainty of the overall evidence for PUFA and ginger as moderate and for curcuma and vitamin D as very low to low. Further research is needed to address gaps of ingredients with low-quality studies and uncertain evidence. In some circumstances, the use of ingredients with some evidence suggesting desirable effect can be suggested when the risk of using the ingredient is minimal. In all cases, discussions with a health care provider are recommended to consider ingredient use and an approach to shared decision-making.

## Justification of resource requirements/cost
Cost is an essential factor required for decision-making that affects all individuals at some level. On average, given the doses reported in the studies, the cost associated with any of these ingredients was considered negligible to moderate savings compared with commonly used pain relievers (e.g., ibuprofen 2,400 mg, estimated at approximately $1/d to serve as a reference point for comparison). As such, most members agreed that resource requirements and out-of-pocket costs were justified.

## Other considerations: feasibility, acceptability, suitability
The HERB members agreed that capsaicin, pCGS, melatonin, PUFA, and vitamin D would probably be acceptable to stakeholders and feasible/suitable to implement as a policy of practice, whereas there was more debate concerning ginger, curcuma, and ASU. Although ginger and curcuma should both be considered a dietary food (e.g., teas, cooking ingredient) and may have the potential to pre-emptively mitigate pain, there was insufficient strong research for recommending their use as a supplement. The overall effect of ginger was relatively small, and although curcuma produced a large effect, the authors were less confident in that effect estimate. It is possible that these ingredients could be inserted into a mission planning process and added to a nutrition checklist by mission dietitians. Whether it would be feasible for Special Operators to obtain ginger and curcuma during specific operational missions is unknown.
Research on ASU evaluated by the authors was confined to the commercialized French product Piascledine. The quality of the evidence for its effects on pain reduction is moderate, diminished by potential bias of being funded by the manufacturer. Third-party evaluations of Piascledine are needed. In addition, Piascledine 300 costs more than the other dietary ingredients and other products that claim to be made with ASU. HERB member opinions regarding Piascledine or other ASU products' (that lack rigorous clinical evidence) acceptability and feasibility were diverse.

## Remarks on the methodological approach
Systematic reviews provide essential information to lay the foundation for evidence-based practice but are often insufficient for making well-informed decisions. Stakeholders can easily judge the appropriateness of an intervention or treatment when high-quality evidence supports substantial desirable anticipated effects and there are minimal to no undesirable anticipated effects. In these cases, treatments are recommended with little need for further debate. Little debate is needed when treatments are judged to be inappropriate and risks clearly outweigh benefits. In between these two judgments is a massive gray area where the evidence is of low, indeterminate, or equivocal quality. Importantly, dietary ingredients are not intended to treat any particular health condition. If a particular ingredient or combination of ingredients were identified as potentially useful for mitigating or treating MSK pain, then the ingredient would be classified as a drug and required to go through the FDA Investigational New Drug Applications process. Despite this, many dietary supplements are marketed for pain relief. A casual search of the National Institutes of Health's Office of Dietary Supplement's Dietary Supplement Label Database (https://www.dsld. nlm.nih.gov/dsld/index.jsp) yielded a total of 272 products when the terms "pain" and "muscle" were used to search for label statements or health claims. Thus, caution is urged, and obtaining ingredients through food is always preferred, unless the evidence of safety and efficacy is clear and manufactures' production processes are verified or certified by trusted third parties.
A framework for decision-making is essential. The authors involved diverse subject matter experts and key stakeholders proactively to develop key questions and to drive the direction of evidence evaluation that illuminated critical outcomes and factors important to them. This evaluation, conducted by a third party, used processes and procedures designed to minimize bias. Factors required for decision-making for this project were adapted from the GRADE framework and specific to the Special Operations environment. The integration of systematic review results into the GRADE Evidence to Decision Framework and the use of a modified Delphi voting process seeking points of convergence and divergence enable all voices to be heard. Subsequently, recommendations about practice, policy, and next steps for research that are useful to the diversity of end users can be developed. A limitation in all research is wide generalizability, and the framework used here can be adapted to different contexts, settings, and stakeholders to consider other essential factors important for decisionmaking.

# Conclusions
Conditional, evidence-based recommendations were made for the use of vitamin D (2,000 mg/d), PUFA (1,200 mg/d), curcuma and ginger (as food sources), melatonin (3-5 mg/d), a proprietary brand of ASU (300-600 mg/d), capsaicin (as a cream, 0.025-0.075% applied 3-4/d), and prescription glucosamine (pCGS, 1,500 mg/d) as alternative or supplemental approaches for mitigating pain and related symptoms associated with chronic MSK pain. These recommendations were based upon rigorous evidence evaluation and integrated with expert clinical acumen by using strict methodological criteria and processes designed and practiced to minimize bias. The process allowed for all voices to be heard with regard to reaching the greatest spread of end user impact. Caveats exist, and in some cases the quality and/or certainty of the evidence remains low; however, the resulting recommendations can serve as a decision aid for practitioners and participants to make shared decisions.
[fig] Figure 1: Recommendations. [/fig]
[fig] 14: no; NS no included studies; PN probably no; PUFA polyunsaturated fatty acids; PY probably yes; RX prescription; VL very low; Y yes. [/fig]
[table] Table 2: Summary of findings [/table]
[table] Table 3: Judgments across factors for decision-making [/table]