2018 Sports Concussion Update Supplements in Concussion Tx

2018 Sports Concussion Update Supplements in Concussion Tx EBM Andrew Gregory, MD, FAAP, FACSM Associate Professor, Orthopedics, Neurosurgery & Pediatrics Pediatric Sports Medicine, Vanderbilt University Vanderbilt Sports Medicine

Disclosures • I do not have any financial relationships that are relevant to this topic. • I serve on the Medical Advisor Board for USA Football, Board of Directors for PRISM, Clinical Leadership Committee for ACSM, Editor for Up. To. Date, Reviewer for multiple journals • I do intend to discuss unapproved/investigative use of commercial products/devices in my presentation. Vanderbilt Sports Medicine

Supplements • Natural remedies to supplement the normal diet • If it is natural it must be safe, right? - supplements are drugs! • FDA does not monitor supplement production/ purity unless significant SE’s are reported as they claim no “drug effect” • You may not be getting what you think! • By aware of supplement/ drug interactions Vanderbilt Sports Medicine

People At Risk for interactions • Multiple medications • Chronic Illness – Kidney disease – Liver disease Vanderbilt Sports Medicine

Potential Interactions • Reduced drug efficacy – increased clearance, decreased absorption • Increased drug efficacy – decreased clearance, increased absorption • Increase side effects – same as above • Combinations of changed efficacy and side effects Vanderbilt Sports Medicine

Common Class Interactions • • • Anticoagulants (Blood thinners) Antihistamines (Allergy medications) Antidepressants (MAOI’s, SSRI’s) Oral Contraceptives (Birth Control) Antihypertensives Anticonvulsants Immunosuppressants Diabetes Medications Cholesterol Lowering Vanderbilt Sports Medicine

Who should we look out for? • Life/ Organ threatening: – Transplant recipients – kidney* – People on blood thinners – blood clots, arrythmias, artificial valves • Common/ Non-life threatening – – – – Seasonal Allergies/ Asthma Epilepsy Depression Birth Control Diabeties Hypertension High Cholesterol Vanderbilt Sports Medicine

Evidence Based Medicine • The conscientious, explicit, judicious and reasonable use of modern, best evidence in making decisions about the care of individual patients • Integrates clinical experience and patient values with the best available research information • Better evidence! Vanderbilt Sports Medicine

Strength of Evidence Vanderbilt Sports Medicine

How to search for best evidence • Sumsearch 2 – separates articles into original, systematic reviews & guidelines • University of Kansas School of Medicine • Pubmed, Medline, Cochrane, DARE, National Guidelines Clearinghouse Vanderbilt Sports Medicine

How to read an article (Worksheet) • Hypothesis, Study Type & Design? • Methods – control group, prospective or retrospective, bias? • Statistics – appropriate? • Results – Statistical vs. clinical significance? • Level of Evidence? • If no bias, a clinically significant difference and representative of your patients, you should consider changing your practice! Spindler et al. Reading and Reviewing the Orthopaedic Literature: A Systematic, EBM Approach. JAAOS. 2005 Vanderbilt Sports Medicine

Burke et al. In search of evidence-based treatment for concussion: characteristics of current clinical trials. Brain Inj. 2015; 29(3): 300 -5. . EBM and Concussion Treatment • Systematic review, 71 studies • Treatments: – cognitive/behavioral therapies (28%), medications (28%), devices (11%), dietary supplements (9%), return-to-activity/rest (1%) and others (22%) • Outcomes: – Symptom-based questionnaires (39%) and neuropsychological tests (28%) • Paucity of trials addressing return-to-play Vanderbilt Sports Medicine • small sample size and trial heterogeneity

Supplements and Concussion EBM • • • DHA Melatonin Resveratrol N-acetyl cysteine Branched Chain AA MLC 901 Vanderbilt Sports Medicine

Fish Oil • Fish oil can be obtained by eating fish or taking supplements • Fish that are especially rich in omega-3 fatty acids include mackerel, herring, tuna, salmon, cod liver, whale and seal blubber not catfish or fish fingers • Important omega-3 fatty acids - eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) • Used to treat depression, bipolar disorder, psychosis, attention deficit-hyperactivity disorder (ADHD), Alzheimer's disease, developmental coordination disorder, migraine headache, epilepsy, schizophrenia, post-traumatic stress disorder, and mental impairment Vanderbilt Sports Medicine • estimated human intake of 387 mg/d DHA

Barrett et al. ω-3 fatty acid supplementation as a potential therapeutic aid for the recovery from mild traumatic brain injury/concussion. Adv Nutr. 2014 May 14; 5(3): 268 -77. DHA and Concussion • Systematic Review • The current science is based on animal models that have limitations that preclude their ability to be generalized to humans • Compelling nature of animal trials data resulted in a 2011 recommendation from IOM to conduct human clinical trials • First human clinical trials are currently Vanderbilt Sports Medicine underway

Oliver et al. Effect of Docosahexaenoic Acid on a Biomarker of Head Trauma in American Football. MSSE 2016 Jun; 48(6): 974 -82. Effect of DHA on a Biomarker of Head Trauma in Football • RCT - 81 NCAA DI football athletes were assigned to ingest either 2, 4, 6 g·d of DHA or placebo • DHA supplementation increased plasma DHA in a dosedependent manner – (2 g·d: mean difference from baseline; ± 90% CL; 2 g·d: 1. 3; ± 0. 6; 4 g·d: 1. 6; ± 0. 7%; 6 g·d: 2. 8; ± 1. 2%) • Serum NFL (neurofilament light ) increased to a greater extent in starters (area under the curve, 1995 ± 1383 pg·m. L) vs. nonstarters (1398 ± 581 pg·m. L; P = 0. 024) • Supplemental DHA likely attenuated serum NFL coincident with increases in serum NFL by likely small and moderate Vanderbilt Sports Medicine magnitude (effect size = 0. 4 -0. 7)

Auld F. Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med Rev. 2017 Aug; 34: 10 -22. Melatonin & Sleep • Meta-analyses • 12 studies included for review based on the inclusion criteria of being: double or single-blind, randomized and controlled • Most in patients aged 55 -80 • Results showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia (p = 0. 002), delayed sleep phase syndrome (p < 0. 0001), and regulating the sleep-wake patterns • No RCTs or long term studies showing evidence for therapeutic use in pediatric age patients • The development of large-scale RCTs is recommended Vanderbilt Sports Medicine

Bramley et al. Sleep Disturbance Following Concussion Is a Risk Factor for a Prolonged Recovery. Clin Pediatr (Phila). 2017 Dec; 56(14): 1280 -1285. Melatonin, Sleep & Concussion • 417 patients included - 123(34%) reported disturbance in sleep • No difference in sleep disturbance based on age, gender, or past number of concussions • Sleep disturbance was associated with a 3 - to 4 -fold increase in recovery time • Non-sport-related concussions were more likely to be associated with sleep disturbance compared to sport-related concussions (45% vs 29%, P =. 01) • Melatonin improved sleep disturbance in 67% of the patients Vanderbilt Sports Medicine

Resveratrol • Stilbenoi, a type of natural phenol, and a phytoalein produced by some plants in response to injury or, when the plant is under attack by pathogens such as bacteria or fungi • Sources in food include the skin of grapes, blueberries, raspberries and mulberries. • Some evidence of protection from m. TBI in rats • SE’s: nausea, diarrhea, and weight loss Vanderbilt Sports Medicine

N-Acetylcysteine • Comes from the amino acid L-cysteine • Antioxidant • Used to counteract acetaminophen (Tylenol) and carbon monoxide poisoning, preventing alcoholic liver damage, chest pain, ALS • SE’s: nausea, vomiting, diarrhea or constipation, rashes, fever, headache, drowsiness, and low blood pressure Vanderbilt Sports Medicine • Source: Web. MD

Branched Chained AA • m. TBI decreases circulating BCAA and their metabolite levels • May contribute to decreased energy production and neurotransmitter synthesis and contribute to TBI pathophysiology • Supplementation of BCAAs and/or their metabolites may reduce TBI pathology and improve outcome. Vanderbilt Sports Medicine • J Neurotrauma 2013; 30: 8

MLC 901 - Neuro. Aid • Traditional Chinese Medicine • Treatment for stroke sold by Moleac Pte Ltd, a biopharmaceutical company in Singapore • 14 ingredients - 9 derived from plants and 5 from animals • Induces neuroprotective and neuroregenerative benefits after m. TBI in rats • Source: Nature Vanderbilt Sports Medicine

Theadom et al. MLC 901 (Neuro. Ai. D II™) for cognition after traumatic brain injury: a pilot randomized clinical trial. Eur J Neurol. 2018 Apr 3. MLC 901 (Neuro. Aid) • RCT, adults after mild to moderate TBI • 78 participants [mean age 38 ± 15 years, 39 (50%) female] • Baseline variables were similar between groups (treatment group, n = 36; control group, n = 42) • Significant improvements in complex attention (P = 0. 04, d = 0. 6) and executive functioning (P = 0. 04, d = 0. 4) at 6 months in the MLC 901 group compared with controls • There were no significant differences between the groups for neurobehavioral sequelae, mood, fatigue, physical disability or overall quality of life at 6 months • No serious adverse events were reported Vanderbilt Sports Medicine

von Luckner A, Riederer F. Magnesium in Migraine Prophylaxis-Is There an Evidence-Based Rationale? A Systematic Review. Headache. 2018 Feb; 58(2): 199 -209. Magnesium • 5 RCTs fulfilling the selection criteria • 1/2 Class I evidence trials showed a significant reduction of the number of migraine attacks compared with placebo • 2/3 Class III trials evinced a statistically significant reduction of the primary efficacy parameters compared with placebo • Grade C (possibly effective) evidence for prevention of migraine with magnesium • Magnesium dicitrate (600 mg) seems to be safe and cost effective for prevention of migraine Vanderbilt Sports Medicine

Feverfew • Grows naturally in Europe and North/ South America • Leaves are normally dried for use in medicine • Some research suggests it may help to prevent migraine headaches, but results are mixed • EBM guidelines from the AAN and AHS suggest that it may be effective and should be considered for migraine prevention • Tanacetum parthenium Active ingredient : parthenolide • 100– 300 mg, up to 4 times daily • SE: nausea, digestive problems, and bloating; if the fresh leaves are chewed, sores and irritation of the mouth Vanderbilt Sports Medicine • Source – Web MD, NCCIH

Riboflavin • Also known as vitamin B 2, a coenzyme • Active forms flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) • Found in milk, cheese, eggs, leaf vegetables, liver, kidney, legumes, mushrooms and almonds • Used to prevent and treat riboflavin deficiency and prevent migraines • RDA 1 mg per day • A 2017 review found it may be useful to prevent migraines in adults, but that clinical trials in adolescents and children had produced mixed outcomes Vanderbilt Sports Medicine

Skoromets et al. Efficacy of the cytoflavin in the treatment of consequences of mild brain injury. Zh Nevrol Psikhiatr Im S S Korsakova 2010; 110(3): 31 -6. Cytoflavin • Inosinum, Nicotinamidum, Riboflavinum, Acidum succinicum, Inosine, Nicotinamide, Riboflavin, Acid Succinic • 60 patients, aged 18 -50 years, with mild TBI 21 -180 days prior • Tx group received cytoflavin 425 mg, 2 tablets twice a day for 4 weeks, patients of the control group received aminalon (GABA) 500 mg, 2 tablets 3 times a day for 4 weeks • Positive changes on scales of pain, anxiety, depression, asthenia, sleep quality, autonomic dysfunctions, & performance on neurocognitive tests in Tx group • Use of analgesics and sedatives was reduced significantly • SE’s: HTN, insomnia and abdominal pain Vanderbilt Sports Medicine

Brenner et al. Growing literature but limited evidence: A systematic review regarding prebiotic and probiotic interventions for those with traumatic brain injury and/or posttraumatic stress disorder. Brain Behav Immune. 2017 Oct; 65: 57 -67. Pre/Probiotics for TBI & PTSD • Systematic Review • Inflammation may be an underlying mechanism of both conditions • Anti-inflammatory/immunoregulatory agents, including probiotics, may represent a novel strategy to treat TBI & PTSD • Only 4 studies were identified (3 severe TBI, 1 PTSD, 0 cooccurring TBI and PTSD) • Although findings suggested some promise, work in this area is nascent and results to date do not support claims of efficacy of probiotics Vanderbilt Sports Medicine

Summary • Several supplements that have some supportive evidence for treatment of migraine • No supplements have conclusive evidence for treatment of concussion • Use supplements that subject themselves to voluntary testing for purity/ contamination • Rec: obtain plants from the Solomon’s garden Vanderbilt Sports Medicine

Voluntary Testing • US Pharmacopeia • Consumer. Lab. com • NSF International – Certified for Sport Vanderbilt Sports Medicine

Resources – Web Sites • FDA: http//vm. cfsan. fda. gov/~dms/aems. html • NIH Office of Dietary Supplements: www. nccam. org, http: //ods. od. nih. gov/databases/ibids. html • U. S. Pharmacopeia: www. usp. org/did/mgraphs/botanica/index. htm • Dietary Supplements Reference: http: //dietary-supplements. info. nih. gov • US Olympic Committee: www. usoc. org • IOC: www. olympics. org • NCAA: www. ncaa. org • www. consumerlabs. com • Natural Medicine Database: www. naturaldatabase. com • Micromedex-Alt. Med. Dex: www. micromedex. com Vanderbilt Sports Medicine

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Thank You! Vanderbilt Sports Medicine