Integrative Medicine: Evidence and Pearls

Annual Review in Family Medicine

2016

Kevin Barrows, MD Osher Center for Integrative Medicine

UCSF

Taxonomy

1. Whole Systems 2. Biological Therapies 3. Mind-Body Medicine 4. Manual Medicine 5. Energy Medicine

Taxonomy

1. Whole Systems - Chinese Medicine (acupuncture)

2. Biological Therapies - fish oil, SJW, probiotics

3. Mind-Body Medicine - mindfulness, Tai chi

4. Manual Medicine

5. Energy Medicine

Outline

Evidence & Pearls for:

• Acupuncture • Fish Oil • St. John’s Wort • Probiotics • Mindfulness Meditation • Tai chi

Acupuncture

Acupuncture Evidence: Post-op Pain • 15 RCT’s, n = 1166 • Total opioid use, postoperative pain decreased • Decreased opioid-related side-effects (nausea

dizziness, sedation, pruritus, urinary retention) • “Perioperative acupuncture may be a useful

adjunct for acute postoperative pain management.”

Sun Y et al. Acupuncture and related techniques for postoperative pain: a systematic review of randomized controlled trials. Br J Anesth. 2008 Aug;101(2):151–60.

Acupuncture Evidence: Osteoarthritis • 16 RCT’s, n = 3,498 • clinically relevant short-term improvements in pain

and function vs. wait-list controls • acupuncture was superior or equal to active control

groups in head-on comparison trials • in comparison with sham control, acupuncture

showed short-term improvements in pain and function, however did not meet predefined thresholds for clinical relevance

Acupuncture for peripheral joint osteoarthritis. Manheimer E, Cheng K, Linde K, Lao L, Yoo J, Wieland S, van der Windt DA, Berman BM, Bouter LM. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001977.

Acupuncture

Evidence: Osteoarthritis

2010 OARSI (Osteoarthritis Research Society International) guidelines • “This non-pharmacological modality does have

some efficacy for relief of pain.”

OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Zhang W, et al Osteoarthritis Cartilage. 2010 Apr;18(4):476-99.

Acupuncture Evidence: Chronic Neck Pain • 10 RCT’s, n = 661 • better than sham treatments and wait list controls

(moderate evidence) • more effective than inactive treatments and this is

maintained at short-term follow-up (moderate evidence) • for chronic neck pain with radicular symptoms,

acupuncture was more effective than a wait-list control at short-term follow-up (moderate evidence)

Acupuncture for neck disorders. Trinh KV, Graham N, Gross AR, Goldsmith CH, Wang E, Cameron ID, Kay T; Cervical Overview Group. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004870.

Acupuncture Evidence: Migraine Prophylaxis • 22 RCT’s, n = 4,419 • “there is consistent evidence that acupuncture provides

benefit to treatment of migraine ” • “acupuncture is at least as effective as, or possibly more

effective than, prophylactic drug treatment, and has fewer adverse effects”

• “There is no evidence for an effect of 'true' acupuncture over sham interventions”

• “Acupuncture should be considered a treatment option for patients willing to undergo this treatment.”

Acupuncture for migraine prophylaxis. Linde K, et al Cochrane Database Syst Rev. 2009 Jan 21;(1):CD001218

Acupuncture Evidence: Tension-type Headache

• 11 RCT’s, n = 2,317 • frequency and severity, short term (<3 months) • Conclusion: “Acupuncture is a valuable non-

pharmacological tool in patients with frequent episodic or chronic tension-type headaches.”

Acupuncture for tension-type headache. Linde K, et al Cochrane Database Syst Rev. 2009 Jan 21;(1):CD007587

Acupuncture Evidence: Overview for pain conditions

• “Several Cochrane reviews of acupuncture for a wide range of pain conditions have recently been published.

• All of these reviews were of high quality. • Their results suggest that acupuncture is

effective for some but not all types of pain.”

Acupuncture for pain: an overview of Cochrane reviews. Lee MS, Ernst E. Chin J Integr Med. 2011 Mar;17(3):187-9.

Acupuncture Evidence: Nausea & Vomiting (post-op) • 59 trials, n = 7,667 • reduced the incidence of nausea, vomiting and

the need for rescue antiemetics • compared to six different types of antiemetic

drugs (metoclopramide, cyclizine, prochlorperazine, droperidol, ondansetron and dexamethasone), there was no difference

Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting. Lee A, Chan SK, Fan LT. Cochrane Database Syst Rev. 2015 Nov 2;(11):CD003281

Acupuncture Evidence: Nausea & Vomiting (chemotherapy) • 11 trials, n = 1,247 • reduced incidence of acute vomiting (RR = 0.82; 95%

confidence interval 0.69 to 0.99) but not nausea severity • Acupressure reduced mean acute nausea severity but

not acute vomiting or delayed symptoms • “Self-administered acupressure appears to have a

protective effect for acute nausea and can readily be taught to patients.”

Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Ezzo JM et al Cochrane Database Syst Rev. 2006 Apr 19;(2):CD002285.

Acupuncture

Pearls: 1) Any type of pain

2) Fatigue

3) Systemic Illness

Acupuncture Evidence: Other Pain • TMJ • other orofacial pain • chronic neck pain • chronic shoulder pain • dysmenorrhea • peripheral neuropathy • acute zoster pain • arthralgias from aromatase inhibitors in women

with breast cancer

Fish Oil

Fish Oil Evidence: Hypertriglyceridemia • dozens of trials • unanimous benefit (20-50% lowering) • 2-4 g/d of ω-3 • AHA recommended • FDA-approved Lovaza® Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. Eslick GD, Howe PR, Smith C, Priest R, Bensoussan A. Int J Cardiol. 2009 Jul 24;136(1):4-16.

Fish Oil Evidence: Hypertension • 3 meta-analyses (largest n=36 RCT’s)

• “fish oil supplementation, especially at higher doses, significantly lowers blood pressure”

• SBP 3-6 mm Hg and DBP 2-4 mm Hg

Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. Geleijnse JM; Giltay EJ; Grobbee DE; Donders AR; Kok FJ J Hypertens 2002 Aug;20(8):1493-9

Fish Oil Evidence: 2° prevention CHD • Dozens of RCT’s, including 10,000’s

patients • 1999 GISSI-Prevenzione (n=11,000) Shows large reduction: 1) in sudden cardiac death 2) total cardiovascular mortality 3) overall mortality

Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999 Aug 7;354(9177):447-55.

Fish Oil Evidence: 2° prevention CHD

• negative studies • two RCT’s add-on to modern full usual care OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline- adjusted therapy after myocaridal infarction. Rauch B, et al, OMEGA Study Group. Circulation. 2010 Nov 23;122(21):2152-9. n-3 fatty acids and cardiovascular events after myocardial infarction. Kromhout D, et al Alpha Omega Trial Group. N Engl J Med. 2010 Nov 18;363(21):2015-26

Fish Oil

Evidence: 2° prevention CHD • negative meta-analyses Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.,Kwak SM, et al, Korean Meta-analysis Study Group. Arch Intern Med. 2012 May 14;172(9):686-94

Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. JAMA. 2012 Sep 12;308(10):1024-33.

Fish Oil Evidence: 2° prevention CHD • 11 trials, n = 15,348 • protective effects were observed for

cardiac death (RR, 0.68; 95% CI, 0.56 to 0.83) sudden death (RR, 0.67; 95% CI, 0.52 to 0.87) and MI (RR, 0.75; 95% CI, 0.63 to 0.88)

Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, placebo controlled trials. Casula M, et al Atheroscler Suppl. 2013 Aug;14(2):243-51.

Fish Oil

Evidence: 2° prevention CHD • 19 studies, 16 countries, n = 45,637 • biomarker concentrations of ω-3 fatty

acids are associated with a modestly lower incidence of fatal CHD [RR of 0.91 (95% CI, 0.84-0.98)]

Effects of Polyunsaturated Fatty Acid Treatment on Postdischarge Outcomes After Acute Myocardial Infarction. Greene SJ et al Am J Cardiol. 2016 Feb 1;117(3):340-6

Fish Oil

Pearls: 1) Rheumatoid Arthritis

2) dry eyes

3) ADHD, BAD, subthreshold psychosis

Fish Oil

Side Effects: – “fishy burp”, halitosis, heartburn, dyspepsia,

nausea, loose stools – Increase LDL but larger more buoyant

particles – Small increase HDL – Cod liver oil risk of hypervitaminosis A – Risk of bleeding with anticoagulants

overstated (no problem up to 3g/d)

Fish Oil Side Effects:

- Contamination? (Mercury, PCB’s) - Most brands meet govt. standards for safety - ? Prostate CA

Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. Brasky TM, et al J Natl Cancer Inst. 2013 Aug 7;105(15):1132-41 Fatty acid patterns and risk of prostate cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. Dahm CC, et al Am J Clin Nutr. 2012 Dec;96(6):1354-61.

Fish Oil Recommendations: 1) Dose by EPA + DHA a) Hypertriglyceridemia = 2-4 g/d

b) HTN = 3 g/d c) 2° prevention CHD = 1 g/d

2) <1g/d dose then cheaper, less concentrated product OK.

If >1g/d choose more concentrated.

Fish Oil

3) Palatability: capsules vs. oil, brand, flavor, before meal, freeze the capsules 4) Vegetarian options - flax seed, etc. but ALA conversion problem - algae (DHA predominant)

St. John’s Wort Hypericum perforatum

St. John’s Wort Evidence: Major Depression • >60 RCT’s • 2008 Cochrane Review 1) more effective than placebo 2) equal efficacy to pharmaceutical antidepressants 3) fewer side effects than pharmaceuticals

St. John’s wort for depression, Linde K, et al, Cochrane Database Syst Rev. 2008;(4):CD000448

St. John’s Wort Evidence: Major Depression Head-to-head Trials vs. SSRI’s

1) SJW vs. citalopram (RCT, n=388) >>> equal efficacy

2) SJW vs. paroxetine “non-inferiority”(RCT, n=251) >>> SJW (57%) and paroxetine (45%)

3) SJW vs. fluoxetine (DBRCT, n=240) >>> SJW greater efficacy, fewer side effects

4) SJW vs. sertraline (DBRCT, n= 340) >>> neither SJW nor sertraline more effective than placebo

St. John’s Wort • Compartive efficacy and safety of a once-daily dosage of hypericum extract

STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study. Gastpar M, Singer A, Zeller K., Pharmacopsychiatry. 2006 Mar;39(2):66-75.

• Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonic reuptake inhibitors: a meta-analysis. Rahimi R, Nikfar S, Abdollahi M., Prog Neuropsychopharmacol Biol Psychiatry. 2009 Feb 1;33(1):118-27.

• Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. Szegedi A, Kohnen R, Dienel A, Kieser M., BMJ. 2005 Mar 5;330(7490):503.

• Effect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomized controlled trial. Hypericum Depression Trial Study Group., JAMA. 2002 Apr 10;287(14):1807-14.

St. John’s Wort Pearl: Somatoform Disorders Evidence: • 2 DBPC RCT’s (n=151, n= 184) • both show large benefit over placebo with high statistical significance

Treatment of somatoform disorders with St. John’s wort: a randomized, double-blind and placebo-controlled trial. Müller T, Mannel M, Murck H, Rahlfs VW. Psychosom Med. 2004 Jul-Aug;66(4):538-47.

St. John’s wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial. Volz HP, Murck H, Kasper S, Möller HJ. Psychopharmacology (Berl). 2002 Nov;164(3):294-300.

St. John’s Wort

Side Effects: i. well-tolerated ii. photodermatitis iii. headache iv. restlessness v. case reports of withdrawal sxs vi. Herb-drug interactions

St. John’s Wort Herb-drug interactions

- SJW is potent inducer of cytochrome P450 system (isozyme CYP3A4)

- May lower the blood levels of medications that are metabolized by this system (eg, alprazolam, estradiol, warfarin, cyclosporine, statins, indinavir)

- Wean off 5 days before surgery (due to risk of interactions with peri-operative meds)

- Do not combine with pharmaceutical SSRI’s due to risk of serotonin syndrome

St. John’s Wort Pregnancy & Lactation

• Insufficient data • Pregnancy

– No clear evidence of risk in animals or humans

• Lactation – Very little excreted into breast milk

St. John’s Wort

Recommendations: 1) Good choice for depression (and

somatoform d/o’s) 2) Dose 300 mg tid of preparation

standardized 0.3% hypericin or 2-3% hyperforin content (made from flowers and stems)

3) Check for herb-drug interactions

Probiotics

Probiotics Evidence: prevention of antibiotic-associated diarrhea (AAD)

• 63 RCT’s, n = 11,811 • reduction in AAD (RR = 0.58; 95% CI, 0.50 to 0.68)

Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Goldenberg JZ, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC. Cochrane Database Syst Rev. 2015 Dec 22;(12):CD004827 Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. Hempel S, et al JAMA. 2012 May 9;307(18):1959-69.

Probiotics Evidence: treating acute infectious diarrhea • 63 RCT’s, n= 8,014 • “probiotics appear to be safe and have clear

beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhoea”

Probiotics for treating acute infectious diarrhoea. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD003048

Systematic review with meta-analysis: Lactobacillus reuteri DSM 17938 for diarrhoeal diseases in children. Urbańska M, Gieruszczak-Białek D, Szajewska H. Aliment Pharmacol Ther. 2016 May;43(10):1025-34.

Probiotics Evidence: prevention of C. diff • 23 RCT’s, n = 4,213 • “moderate quality evidence probiotics are both

safe and effective for preventing Clostridium difficile-associated diarrhea.”

• “probiotics significantly reduce this risk by 64%”

Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Goldenberg JZ, et al Cochrane Database Syst Rev. 2013 May 31;(5):CD006095.

Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Johnston BC, et al Ann Intern Med. 2012 Dec 18;157(12):878-88.

Probiotics Evidence: treatment of IBS • 15 RCT’s, n = 1,793 • “Probiotics reduce pain and symptom severity

scores” (RR’s 1.96 to 2.43) Effectiveness of probiotics in irritable bowel syndrome: Updated systematic review with meta-analysis. Didari T, Mozaffari S, Nikfar S, Abdollahi M. World J Gastroenterol. 2015 Mar 14;21(10):3072-84

Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Ford AC, et al Am J Gastroenterol. 2014 Oct;109(10):1547-61

Probiotics

Pearls: • chemotherapy induced diarrhea • pouchitis • prevention of Traveler’s Diarrhea

Probiotics Side Effects: - Flatulence (diminishes with time), change in bowel frequency - Sepsis (4 case reports, Saccharomyces boulardii or Lactobacillus spp. in immunocompromised pts.) No serious adverse events in RCT’s. - Contraindicated in pancreatitis - Safe in children, likely safe in pregnancy/lactation

Probiotics Recommendations: 1) choose products that contain both

Lactobacillus and Bifidobacterium genera. (species less important)

2) Consider Saccharomyces boulardii if bacterial probiotics not effective. Also use S. boulardii as first line if recurrent CDAD

3) dose in billions (e.g. initial 3-5 billion/d, goal at least 10 billion/d)

Mindfulness Meditation

Mindfulness Meditation

Evidence: • over 200 experimental trials • depression, anxiety, chronic pain,

cancer-related • consistent mental health benefit

Mindfulness Meditation Mindfulness-based stress reduction for integrative cancer care: a summary of evidence. Musial F, Büssing A, Heusser P, Choi KE, Ostermann T. Forsch Komplementmed. 2011;18(4):192-202. The efficacy of mindfulness-based stress reduction on mental health of breast cancer patients: a meta-analysis. Zainal NZ, Booth S, Huppert FA Psychooncology. 2013 Jul;22(7):1457-65. Mindfulness-based stress reduction and cancer: a meta-analysis. Ledesma D, Kumano H. Psychooncology. 2009 Jun;18(6):571-9.

Mindfulness Meditation Do mindfulness-based interventions reduce pain intensity? A critical review of the literature. Reiner K, Tibi L, Lipsitz JD. Pain Med. 2013 Feb;14(2):230-42. Mindfulness-based therapy: a comprehensive meta-analysis. Khoury B, Lecomte T, Fortin G, Masse M, Therien P, Bouchard V, Chapleau MA, Paquin K, Hofmann SG. Clin Psychol Rev. 2013 Aug;33(6):763-71. Mindfulness- and acceptance-based interventions for anxiety disorders: a systematic review and meta-analysis. Vøllestad J, Nielsen MB, Nielsen GH. Br J Clin Psychol. 2012 Sep;51(3):239-60.

Mindfulness Meditation

Pearls: • any suffering • energy budgeting with CFS (SEID) or

FM or other fatigue

Tai Chi

Tai Chi

Evidence: • balance • fall prevention in elderly • Parkinson’s Disease

Tai Chi Tai chi as an intervention to improve balance and reduce falls in older adults: A systematic and meta-analytical review. Leung DP, Chan CK, Tsang HW, Tsang WW, Jones AY. Altern Ther Health Med. 2011 Jan-Feb;17(1):40-8.

Tai Chi for improvement of motor function, balance and gait in Parkinson's disease: a systematic review and meta-analysis. Yang Y, Li XY, Gong L, Zhu YL, Hao YL. PLoS One. 2014 Jul 21;9(7)

Tai Chi

Pearls: • cognitive fx in elders • heart failure • think of Tai Chi as gentle

rehab/exercise

Drug Interactions

1) www.naturalmedicines.com Natural Medicines Comprehensive Database (Prescriber’s Letter) 2) www.naturalstandard.com Natural Standard

Product Quality Three methods to assess product quality:

1) Independent third-party testing - ConsumerLab.com

2) Choose product used in clinical trial - Naturalstandard.com - PubMed

3) Assess product yourself - seals - label analysis

Product Quality

1) USP (United States Pharmacopoeia) Seal - verifies ingredients listed on label - verifies the declared strengths and amounts - examines for contaminants - confirms product will break down and release

ingredients in the body within a specified amount of time

- checks for Good Manufacturing Practices (GMPs) compliance

Product Quality

2) NSF (National Sanitation Foundation) - verifies ingredients on the label - verifies the amounts listed - examines for contaminants - checks for GMP compliance

Product Quality Label Analysis - name of product - name and place of business - lot number - expiration date - net quantity - directions for use - serving size - scientific name (if plant or probiotic) - which part of plant (e.g. root, leaf, etc.) - strength (e.g. of tincture) - non-dietary ingredients (e.g. fillers,

sweeteners)