What are the side effects of SPM active?

Design and sampling

The design of this research was a single-arm, open-label clinical trial. The protocol and all study materials were reviewed and approved by the IRB of the National University of Natural Medicine (NUNM; MetaG SPM IRB, #091515-B) and registered on ClinicalTrials.gov as Influence of an Omega-3 SPM Supplement on Quality of Life (NCT02683850). The trial aimed to assess the impact of SPM Active™ softgel supplementation on quality of life in adults with moderate to severe chronic pain symptoms (as measured by the Patient Reported Outcomes Measurement Information System (PROMIS)-43 Profile—Pain Intensity subdomain).

Participants were recruited from the greater Portland, Oregon area using community-based flyers and advertisements. Information about the study was also available through the NUNM website. In addition, a network of community physicians was established for additional recruitment. Potential participants were screened over the telephone and referred to one of five clinical sites to determine eligibility.

Eligible candidates included adults 20–70 years of age, with a Body Mass Index of 19–40 kg/m2, that had no other significant medical problems, were able to maintain stable intake of therapeutic agents for at least 30 days, and were able to refrain from adding any therapeutic agents for the duration of the study. In addition, only participants suffering from moderate to severe chronic pain (i.e. an average pain score of greater than or equal to a 4 on the PROMIS-43 Profile—Pain Intensity subdomain) for at least 3 months were included in the study. Exclusion criteria were chosen to minimize the possibility of confounding the detection of changes in pain or inflammation, such as recent initiation of, or changes to, pain medications or other pain reduction therapies. In addition, women who were lactating, pregnant, or planning pregnancy at the time of screening or would be within the 6 months subsequent to screening, were excluded from study participation.

Intervention, packaging, and labeling

Study participants received 2 bottles of the intervention: SPM Active™ softgels (Metagenics, Inc., Gig Harbor, WA). The SPM Active™ softgel is a dietary supplement Generally Recognized As Safe (GRAS), commercialized by Metagenics Inc. The SPM Active™ softgels used in this study were manufactured by Solutex (https://www.solutex.es/; Parque Empresarial Omega Edificio Gamma Avenida de Barajas 24, 3ª 28109 Madrid, Spain). These softgels met or exceeded all quality control requirements, as well as all softgel production requirements for Good Manufacturing Practices (cGMP).

Each SPM Active™ softgel contained 250 mg of a marine lipid fraction (Lipinova®), standardized to 17-HDHA and 18-HEPE (Solutex, Spain) with demonstrated pro-resolving activity covered by the patent family PCT/US2013/040313.

For the purposes of this study, the softgels were packaged in unlabeled bottles with approximately 60 softgels per bottle. A product label was provided by the Helfgott Research Institute, which included instructions on use, as well as contact information for any questions that arose.

Participants were provided with written instructions at their Baseline visit and were instructed to take 3 softgels in the morning and 3 softgels in the evening. Participants were also provided with a study supplement log to record their daily intake of the softgels and record any questions or concerns that emerged. Participants returned the study supplement log and any unused study supplement softgels at the Week 2 and Week 4 study visits.

SPM Active™ dose titration occurred during the Week 2 study visit, based on the pain ratings obtained via REDCap reported within the 2 days prior to the visit. Participants who reported PROMIS-43-measured ‘pain intensity’ levels that had decreased by 2 points or more after 2 weeks had their dose decreased to 2 softgels in the morning and 2 softgels in the evening for weeks 3 and 4 of the study (N = 16). Participants who reported PROMIS-43-measured ‘pain intensity’ levels that had not changed, had only decreased by one point, or had increased, increased their dose to 4 softgels in the morning and 4 softgels in the evening for weeks 3 and 4 of the study (N = 28). The unused supplement bottle from the first 2 weeks was relabeled with the appropriate dosing and returned to participants for the last 2 weeks of the trial.

Study visits

The study participant visits were grouped into 2 categories: screening visit and study visits. Study visit one (Baseline) occurred directly after the screening visit. Clinical re-evaluations occurred every 2 weeks, as Week 2 and Week 4 study visits.

At the screening visit, medications and supplements were reviewed, as was participant health history. Eligibility was determined by administration of a standardized ninety-one point Adverse Event Monitoring form (participants were excluded if any item was determined to be Grade 3, ‘severe or medically significant but not immediately life-threatening’, or higher); the PROMIS-43 Profile–Pain Intensity subdomain; and BMI. After an informed consent consultation, eligible participants were enrolled in the study.

The Baseline study visit and subsequent study visits included administration of the Adverse Event Monitoring form, PROMIS-43 Profile, American Chronic Pain Association’s (ACPA) Quality of Life Scale, Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder scale (GAD-7), and Brief Pain Inventory long form (BPI). In order to reduce provider interference on participant responses, the administration of all research instruments was separated from clinical care and provider interaction through the use of a centralized REDCap-based survey sent to and completed by participants on their own (but according to the study timeline). A blood sample was taken at each visit to be analyzed for the biomarkers high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR).

The Patient Global Impression of Change (PGIC) and the Patient Global Satisfaction Scale (PGSS) were administered at the Week 4 study visit only.

Outcome measures

Primary outcome measure

The primary outcome of the trial was health-related quality of life, measured by the PROMIS-43 instrument (primary measure) and the ACPA’s Quality of Life Scale (secondary measure).

PROMIS–43 Profile subdomains

The PROMIS-43 Profile consists of seven domains (Ability to Participate in Social Roles and Activities, Anxiety, Depression, Fatigue, Pain Interference, Physical Function, and Sleep Disturbance), with six questions per domain rated on a 5-point rating scale. Additionally, there is a 1-question Pain Intensity domain rated on an 11-point scale. The domains are assessed “over the past 7 days” except for the Physical Function domain, which has no specified time frame. A raw score is created from each subscale (except Pain Intensity) that makes up the Profile. Raw scores are translated into T-scores, which are reported as the final score for each participant. The PROMIS-43 Profile provides a standardized, reliable, and valid measure of Pain Interference, Pain Intensity, Physical Function, Fatigue, Sleep Disturbance, and Ability to Participate in Social Roles and Activities. The Dutch-Flemish PROMIS Pain Behavior item bank was found to have good cross-cultural validity, reliability and construct validity [17].

The subdomains used to assess quality of life as the primary outcome included Ability to Participate in Social Roles and Activities (shortened for purposes of this study to Social Function), Fatigue, and Sleep Disturbance. The subdomains of Anxiety, Depression, Pain Interference, and Physical Function, as well as Pain Intensity, were used in conjunction with additional standardized tools as exploratory outcomes, as described below.

American Chronic Pain Association’s quality of life scale

The ACPA’s Quality of Life Scale is a single item measure of function for people with chronic pain. Quality of Life is rated using an 11-point scale ranging from “Non-Functioning” to “Normal Quality of Life”. The ACPA Quality of Life scale was developed specifically as a measure of functioning for people with chronic pain. It has been used by thousands of medical professionals across the globe for many years and is used extensively by the US Department of Veterans Affairs. Wayne State University College of Nursing is currently using the scale in research of the maintenance and improvement of functional states in patients with chronic pain.

Exploratory outcome measures

Exploratory outcomes included: changes in depression and anxiety; pain relief; pain intensity; pain interference; physical function; patient satisfaction; patient impression of change in their condition; changes in inflammatory serum biomarkers; and adverse events. Changes in depression were measured by the PHQ-9 and the PROMIS-43 Profile–Depression subdomain, while changes in anxiety were measured by the GAD-7 scale and the PROMIS-43 Profile–Anxiety subdomain. Items in the BPI determined pain relief and pain quality. Pain intensity and pain interference were determined by the PROMIS-43 Profile subdomains of the same names, as well as several BPI items, as outlined below. Patient satisfaction and impression of change were determined using the PGSS and the PGIC. The biomarkers hs-CRP and ESR were used to assess changes in inflammation. A comprehensive case report form was used to determine changes in pain medication use. Adverse events were closely monitored and systematically collected. These tools are described in detail below.

Patient Health Questionnaire (PHQ-9)

The PHQ-9 is a self-administered depression scale based on the mood module from the PRIME-MD diagnostic instrument for common mental disorders. The PHQ-9 scores each of the nine DSM-IV criteria as “0” (not at all) to “3” (nearly every day), rated for the last 2 weeks—this provides a depression severity score based on a 0–21 continuous scale. The PHQ-9 is a validated instrument for detecting depression and monitoring its severity, and higher scores are associated with increasing levels of depression severity [18, 19]. The PHQ-9 final score is rated from No Depression to Severe Depression.

Generalized Anxiety Disorder scale (GAD-7)

The GAD-7 is a 7-item self-report instrument to assess generalized anxiety disorder in primary care patients. Items are rated for the last 2 weeks, using a 4-point rating scale from “1” (not at all) to “5” (nearly every day). A score of 10 or greater on the GAD-7 represents a cut point for identifying cases of generalized anxiety disorder, while cut points of 5, 10, and 15 might be interpreted as representing mild, moderate, and severe levels of anxiety on the GAD-7. There is an overall relationship between GAD-7 severity levels and disability scores, with higher mean disability values related to higher severity levels [20].

Brief Pain Inventory (BPI), long form

The BPI is a 32-item self-report questionnaire that examines pain severity/intensity and impairment caused by pain on emotional and physical functioning. The instrument consists of a series of 11-point numeric rating scales. 4 items measure pain intensity (pain now, average pain, worst pain, and least pain) using “0” (no pain) to “10” (pain as bad as you can imagine) as anchors. These scores are individually given as measures of pain. Seven items measure the level of interference with function caused by pain during the past week (general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life) with anchors of “0” (does not interfere) to “10” (completely interferes). A composite mean score of the seven items is given as a measure of pain interference.

The BPI also asks the patient to rate the quality of their pain (e.g. aching, throbbing, shooting, stabbing, etc.) and to rate the relief they feel from the current pain treatment. The BPI pain scale has been widely used and found to provide a reliable and valid measure of pain, pain interference, and improvements in pain over time across cultures and languages, and for purposes of this study, in chronic nonmalignant pain populations [21, 22].

PROMIS–43 Profile subdomains

This instrument is described in detail above (Primary Outcome Measure section). Pain Intensity and the subdomains of Anxiety, Depression, Physical Function, and Pain Interference were used as exploratory outcome measures. The Anxiety and Depression subdomains were used in conjunction with the GAD-7 and PHQ-9 to measure anxiety and depression. Pain Intensity and Pain Interference were used in conjunction with the BPI items to measure pain intensity and interference; Physical Function was used as an independent marker to determine changes in physical function.

Patient Global Impression of Change (PGIC)

The PGIC is a single-item rating of the participant’s impression of change in their condition with treatment on a 7-point scale that ranges from “very much improved” to “very much worse” with “no-change” as the midpoint. The PGIC has frequently been used as an indicator of meaningful change in response to treatments for chronic pain [23]. Consensus guidelines outline the PGIC measure as an important indicator of meaningful change in treatments for chronic pain [24, 25].

Patient Global Satisfaction Scale (PGSS)

The PGSS is a single-item rating by participants of their satisfaction with treatment on a 10-point scale that ranges from “very satisfied” to “not at all satisfied”.

High-Sensitivity C-Reactive Protein (hs-CRP)

CRP is an acute-phase protein released into the blood by the liver during inflammation and is a sensitive marker of low-grade systemic inflammation. Plasma CRP levels can increase dramatically after severe trauma, bacterial infection, inflammation, surgery, or neoplastic proliferation. Measurement of CRP has been used historically to assess activity of inflammatory disease and to monitor inflammatory processes. The hs-CRP test is a highly sensitive quantification of CRP that can be detected at a lower level than CRP [26].

Erythrocyte Sedimentation Rate (ESR)

ESR is a laboratory test for assessing inflammatory or the acute phase response. It is not diagnostic of any particular disease, but when elevated may indicate the presence of inflammation, infection, rheumatologic disease or neoplasm [27].

Multi-Systems Adverse Event Monitoring form

Adverse events were tracked and monitored using the Multi-Systems Adverse Event Monitoring form, a standardized, 91-point monitoring form that asks questions pertaining to the following organ systems: eyes/ears/nose/throat, gastrointestinal, neurological/ musculoskeletal, psychological/general, cardiopulmonary, skin, genitourinary, and whole body systems.

Data security and storage

This study used REDCap—a secure, web-based application that supports electronic data capture for research studies—for data storage and management. Data was exported from REDCap to either Excel or SPSS for analysis. All procedures conducted adhered to the Informed Consent and protocol, as approved by the MetaG SPM IRB.

Analysis

All 3 time points (Baseline, Week 2 study visit, and Week 4 study visit) for the primary and exploratory outcome measures were initially analyzed using linear mixed modeling, followed by pairwise T-tests between Baseline and Week 2, then Baseline and Week 4, for each outcome measure. For all analyses, statistical significance was set at p = 0.05. Where applicable, the raw scores from each outcome measure (primary and exploratory) were translated into T-scores at Baseline, Week 2, and Week 4. These T-scores were then reported as the final score for each patient. Results were reported as “per protocol” analyses, without imputation of missing data, due to the need to determine efficacy.

All but one of the PROMIS-43 data sets, as well as the summary BPI interference score data set, were found to have reasonably normal T-score distributions; non-parametric testing confirmed these results. However, all other questionnaire data sets exhibited non-parametric distributions—this was likely due to the relatively small scales with which these tools are scored. Thus, these data sets were retested using Wilcoxon’s Signed-Rank test or Friedman’s test.

The distribution of hs-CRP showed rightward skew, but this was largely corrected with a log-transformation. All analyses of hs-CRP therefore used T-tests of the log-transformed variable. The distribution of ESR showed a more severe skew that could not be remedied by any standard transformation; therefore, results were verified using the same non-parametric tests listed above.

The PGIC and the PGSS were asked only at one time point (study visit 3); thus, no formal comparisons were performed and only frequency data was reported.

Sample size and statistical power

This study was powered to detect clinically significant changes in the Physical Function or Fatigue subscales of the PROMIS-43 or in the ACPA QOL Scale. Earlier work on the indicated PROMIS-43 subdomains indicates that minimally significant differences between groups are generally in the range of 4–6 points on a T-scale, corresponding to a standardized effect size of d = 0.4–0.6 [28]. For within-group changes over time, which tend to show larger effects, these estimates should be conservative; and we therefore calculated power to detect an effect of d = 0.5. For the ACPA, less information is available, but we calculated power to find a change of one point; and for an 11-point scale, we reasonably estimated the standard deviation at 2 points. Assuming a correlation of r = 0.5 between pre- and post-treatment measures, this again yielded an effect size of d = 0.5. Finally, using a paired t-test design with a two-sided α = 0.05, we calculated that with 40 participants, we would have 87% power to detect an effect size of d = 0.5 in any of the primary outcome measures. With 20% attrition (32 participants for analysis), we would still retain 78% power. Note that, although the referenced effect sizes are for Physical Function and Fatigue, PROMIS-43 T-scales are scored to have equal means and standard deviations, and we would expect similar power estimates on all subdomains. All power calculations were made using G*Power v.3.1.9.2 [29].

For many years, it was assumed that inflammation is a self-limiting process, but discoveries showed the presence of an active process, that is promoted by a group of molecules called specialized-pro resolving mediators (SPM).

How SPMs help to reduce inflammation?

Let’s imagine this nice analog.
There is a pipe leaking inside your home wall.. this will damage the surrounding structures and it must be fixed early, isn’t it?
This pipe likes an injury or infection in your body, that affects the surrounding tissues and triggers the inflammation process.
You will call workers for help, to make a hall in the wall to get access to the pipe. once the damage from the leak has been contained, you will start to cut out affected structures.
This is actually what happens in case of injury, the injury sends signals to the immune system and calls the immune cells (neutrophils) to contain the damage. then the immune cells will kill the infected cells beyond repair.
Now, this mess needs to be cleared for workers to repair the pipe, then the finishing touches restore the wall as if nothing ever happened.
Here is the role of SPMs respectively

1. to tell neutrophils its role is done.
2. Then calls another immune cell (macrophages) to clear the mess from inflammation and to get rid of the dead cells.
3. then tell macrophages your job is done.
4. Finally, tell the tissue to restore its healthy position and the body to resume its normal activity. as if nothing ever happened.

What is SPM?

Specialized pro-resolving mediators are lipid mediators present in our body derived from poly-unsaturated fatty acids,
It demonstrated to have an important role in inflammation by preventing overaction of the causative organism, promoting the resolution of inflammation.
SPMs are derived from poly-unsaturated fatty acids like AA(Arachidonic acid), EPA(Eicosapentaenoic acid(, and DHA(docosahexaenoic acid).
It has a potential therapeutic role in the body. Because chronic or uncontrolled inflammation plays a key role in a variety of diseases like; cardiovascular diseases and metabolic syndrome.

Who may have reduced levels of SPMs?

1. It decreases with age.
2. Decreases due to obesity.
3. Decreases due to genetic variations.
4. Chronic stress may reduce the production of SPMs.
5. People with depression and other mental health problems.
6. For physical discomfort from everyday activities.

SPMs and chronic pain:

Chronic pain is one of the most frequent and difficult-to-manage clinical issues in medical practice, it is highly related to disorders leading to disability.
Chronic pain affects the quality of life-related to physical activities and restrictions of mobility, as well as anxiety and depression.

What causes chronic pain?

Uncontrolled inflammation, especially neuroinflammation, is the main pathophysiologic component of chronic pain.

Is SPM active can be used to manage chronic pain? How?

Recent studies have shown anti-nociceptive effects for specialized pro-resolving mediators (SPMs).
They are important regulators of the balance between pro-inflammatory and anti-inflammatory substances. They also might regulate the excessive sensitization of nociceptors after inhibiting specialized channels, therefore achieving the suppression of pain.

Evidence that supports SPM Active use for chronic pain:

There is a meta-analysis(the strongest type of clinical study) done by Goldberg et al included 17 trials that evaluate the pain-relieving effects of SPMs on patients with rheumatoid arthritis and related joint disorders of inflammatory diseases and dysmenorrhea.
The study showed that SPM supplementation reduced the patient-reported joint pain and intensity and morning stiffness.

SPMs and mental health;

SPMs may have the capacity for modulation of neuroinflammation like the pain results from the connection between immune and nervous cells. Chronic uncontrolled inflammation is associated with mental health disorders like depression, anxiety, bipolar disorders, and schizophrenia.

Role of SPM Active for mental health:

SPM production may be impaired with mental health problems like depression, and mood disorders are also associated with chronic inflammation, which is controlled by SPMs, so SPM Active can be beneficial for mental health problems such as depression and mood disorders.
Recent evidence showed that any alteration in SPMs function may cause proinflammatory and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis(MS).⁴

SPMs active and sports performance:

Athletics and sports practitioners are always susceptible to injuries and inflammation, that may reduce their performance and recovery, so it is important to support them with a compound that resolves the inflammation without compromising the immune response. This is the role of SPM Active.

Can SPMs active enhance athletic performance?

Yes, SPMs may help in sports performance. it supports natural recovery from injuries and inflammation and helps to sustain performance.
It also promotes the reduction of pain and tissue regeneration.
A study showed that fish oil supplements (DHA&EPA), the main active ingredient of SPM active, can help in muscle recovery, cognition, and cardiovascular dynamics in cyclists. It also helps in pro-inflammatory cell responses and increases lipid peroxidation and post-exercise nitric oxide.

Choosing the best SPMs supplement:

To choose the best SPM supplement you should take care of some points like, the producing company must follow the quality requirements, and the formula must have undergone clinical studies to discover the potential benefits from it. you should also read the label of the supplement to ensure it is according to your needs.

How to read supplement labels?

1. Suggested use and serving size: located at the top of the supplement’s label, and directions on how often to take the supplement.
2. Supplement facts panel: includes important details like the number of calories, fats, and macro, and micronutrients.
3. Percent of daily value: define how much the nutrient in a single serving of the dietary contributes to your daily diet.
4. Ingredients: includes anything used to make the supplement.
5. Cautions and warnings: show any allergies or drug interactions. You must contact your pharmacist to take all precautions about any medicine.

Other information included in the supplement label like pill size and storage conditions.

You can check the supplement label of our ultimate SPM supplement, SPM Active., Which is clinically studied, And The online access to quality test information for every batch assures the quality of the product,(see the product info).
In conclusion, the inflammation process must be controlled by SPMs molecules, Hence the role of SPM is active in the healing process and neuroinflammation and mental health, athletics, and sports performance.

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References:

Can SPM Active be used to improve mental health? This article examines the potential benefits of SPM Active for mental health and explores the evidence behind it.