Integrative Medicine for the InternistA Primer for 2020

UCSF Advances in Internal medicineJune 15th, 2020By Sanjay Reddy

Disclosures

• None

Roadmap of our time together

• Integrative Medicine intro• Yoga and Fascia• Acupuncture• A bit on herbs and supplements• Cannabis• Aromatherapy• MBSR and Guided imagery• Questions/Comments

What is Integrative Medicine?

Integrative Medicine (IM) is healing-oriented medicine that takes account of the whole person, including all aspects of lifestyle.

It emphasizes the therapeutic relationship between practitioner and patient, is informed by evidence, and makes use of all appropriate therapies.

From The University of Arizona

What is CAM?

CAM (Complementary and Alternative Medicine) is a group of diverse medical and health care systems, practices, and products that are not generally considered part of conventional medicine.

http://nccam.nih.gov/health/whatiscam

Fascia and Yoga

L Berrueta et al. Stretching Impacts Inflammation Resolution in Connective Tissue. J Cell Physiol. 2016 July ; 231(7): 1621–1627.

Decreased Size of Breast CA in Mice

L. Berrueta et al. Stretching Reduces Tumor Growth in a Mouse Breast Cancer Model. SCIentIFIC RepoRTS | (2018) 8:7864 |

Proposed Mechanisms

• Acupuncture points unique, Connective Tissue communication1,2:• Denser innervation, tightly packed connective tissue,

different receptor distribution

• Central opiate receptors (varying types) mediate analgesic effect3• Spinal and supraspinal neurotransmitter release; Narcan

can block effects

• Local inflammatory mediators4

1. Langevin et al. Biomechanical response to acupuncture needling in humans J Appl Physiol, 91 (2001), pp. 2471–2478

2. Abraham et al. TRPV1 expression in acupuncture points: Response to electroacupuncture stimulation(2011) Journal of Chemical Neuroanatomy, 41 (3) , pp. 129-136

3. Han, JS. Acupuncture Analgesia: Areas of consensus and controversy. Pain. 2011 Mar;152(3 Suppl):S41-8. doi: 10.1016/j.pain.2010.10.01

4. Leung, L. Neurophysiologic Basis of Acupuncture Induced Analgesia- Un Updated Review. J Acupunct Meridian Stud. 2012 Dec;5(6):261-70. doi: 10.1016/j.jams.2012.07.017. Epub 2012 Aug 22.

http://www.ncbi.nlm.nih.gov/pubmed/21078546http://www.ncbi.nlm.nih.gov/pubmed/23265077

Langevin HM et al. Mechanical signalingthrough connective tissue: a mechanism for the therapeutic effect of acupuncture. FASEB J. 2001 Oct;15(12):2275-82.

NIH ‘97 Report of Efficacy

• Myofascial Pain• Headache• Dental Pain• Fibromyalgia• Tennis Elbow• Osteoarthritis• Menstrual Cramps

• Nausea• Asthma• Stroke Rehab• Addictions• Carpal Tunnel • Lower Back Pain

WHO 2002

• “Because of the side-effects of long-term drug therapy for pain and the risks of dependence, acupuncture analgesia can be regarded as the method of choice for treating many chronically painful conditions.”

• Acupuncture: Review and Analysis of Reports on Controlled Clinical Trials

Archives of Internal Medicine 2012Acupuncture for Chronic Pain

Reviewed RCTs and performed an individual patient data meta-analyses

• Patients receiving acupuncture had significantly less pain than sham controls for back and neck pain, OA and chronic headache

Conclusion: Acupuncture is effective for the treatment of chronic pain.

Vickers AJ et al. Acupuncture for chronic pain. Individual patient data meta-analysis. Arch Intern Med. 2012; 172(19): 144401453.

Date of download: 5/14/2013 Copyright © 2012 American Medical Association. All rights reserved.

From: Prospective Investigation of Adverse Effects of Acupuncture in 97 733 Patients

Arch Intern Med. 2004;164(1):104-105. doi:10.1001/archinte.164.1.104

Nonserious Adverse Events of Acupuncture Reported in 97 733 PatientsFigure Legend:

Archives of Internal Medicine 2012Acupuncture for Chronic Pain

Reviewed RCTs and performed an individual patient data meta-analyses

• Patients receiving acupuncture had significantly less pain than sham controls for back and neck pain, OA and chronic headache

Conclusion: Acupuncture is effective for the treatment of chronic pain.

Vickers AJ et al. Acupuncture for chronic pain. Individual patient data meta-analysis. Arch Intern Med. 2012; 172(19): 144401453.

AcupunctureVs.No Control

A. OAB. HAC. MSK

AcupunctureVs.Sham

A. OAB. HAC. MSKD. Shoulder

Safety- Many studies• Sample study of German physicians:

• 140 hours of formal acupuncture training• Only 19%>350 hours of training• >95k people with >700k treatments: 6 Major Complications:

• Exacerbation of Depression • Acute HTN Crisis • Vasovagal reactionLOC• Asthma attackHTN and Angina • Pneumothorax x2

Melchart et al. Prospective investigation of adverse effects of acupuncture in 97 733 patients. Arch Intern Med.2004 Jan 12;164(1):104-5.

Date of download: 5/14/2013 Copyright © 2012 American Medical Association. All rights reserved.

From: Prospective Investigation of Adverse Effects of Acupuncture in 97 733 Patients

Arch Intern Med. 2004;164(1):104-105. doi:10.1001/archinte.164.1.104

Nonserious Adverse Events of Acupuncture Reported in 97 733 PatientsFigure Legend:

TEAS (Transcutaneous Electric AcupointStimulation)• TEAS (LI11, GB21, Ex2l)+Exercise in RCT involving 218 patients with

chronic neck pain showed a better and clinically relevaventimprovement in disability, isometric neck muscle strength, and pain compared to other arms.

• Many study protocols available for pending studies, and a fair amount of perioperative data.

A randomized clinical trial of TENS and exercise for patients with chronic neck pain. Chiu et al. Clin Rehabil. 2005;19(8):850.

TEAS in Labor• 180 Nulliparous from a Chinese Hospital:

• 37-42wks gestational age• plan vaginal delivery with singleton pregnancy• No known complications and fetal vertex• dilatation >3cm with regular contractions

• Randomized to 3 groups:• SP-6• EX-B2 T10-L3• Control

Dong C et al. Effects of electro-acupuncture on labor pain management. Arch Gynecol Obstet. 2015 Mar;291(3):531-6.

Labor and electro-stim, cont.

• VAS recorded in last contraction before intervention, then 30, 60 and 120” after

• Change of >3 considered effective

• Significant differences in pain and duration of active phase of labor

• EX-B2 more effective than SP6

Dong C et al. Effects of electro-acupuncture on labor painmanagement. Arch Gynecol Obstet. 2015 Mar;291(3):531-6.

Nausea and Vomiting Acupressure

• Cochrane review of 59 studies from 2015

• P6 acupoint stimulation vs antiemetics for PONV.

• Conclusion: “To prevent PONV, the effect of P6 acupoint stimulation is comparable to antiemetics.”

Lee A et al. Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 11 (2015 Nov 2) CD003281

Pericardium 6

Acupressure for Dysmenorrhea

• 36 women with dysmenorrhea from 4 dormitories

• Dorms divided into randomized acupressure and no acupressure, both could use ibuprofen as needed• -20min of acupressure to SP-6 intervention • 5min x2 alternating each leg: 6s on, 2s off, with thumb

• Change in pain and ibuprofen use recorded

Charandabi S et al. The effect of acupressure at the Sanyinjiao point (SP6) on primary dysmenorrhea in students resident in dormitories of Tabriz. Iran J Nurs Midwifery Res. 2011 Autumn; 16(4): 309–317.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583102/

Spleen 6 Location

Natural Products• Herbal medicines (also

known as botanicals)• Vitamins• Minerals• Other “natural

products,” such as probiotics

Botanical Medicine

• Old as people (probably)

• In the United States, the use of botanicals has increased significantly over the past two decades.

• In the USA annual total cost of more than $4 billion!

Herbal Usage

• 2012 National Health Institute Survey:• 23.6% of American adults have used herbs/dietary supplements

• A lot of our patients use them, less talk about it1• Recent study of oncologists showed less than half discuss herbs with

their patients

Lee RT et al. National survey of US oncologists' knowledge, attitudes, and practice patterns regarding herb and supplement use by patients with cancer. J Clin Oncol 2014; 32: 4095-4101

Dietary Supplement and Health Education Act ‘94Classifies vitamins, minerals, botanicals, and amino acids as supplements • Supplements can be marketed without proof of safety or efficacy

FDA must first prove that a botanical preparation unsafe!• Opposite of medications

No claims allowed to treat or cure• Manufacturers can make "structure and function" claims

• Ex. saw palmetto can be marketed to support urinary tract health but not to treat benign prostatic hyperplasia.

How to Advise Patients

• There’s a lot of adulterated products• Heavy Metals• Pesticides• Poisons• Prescription drugs

• Discuss with their providers • Review for tested products and quality• Few pregnancy studies

Herbs and Supplements Resources

• Resources for busy clinicians:• Natural Medicines Comprehensive Database

(www.naturaldatabase.com) and Natural Standard (www.naturalstandard.com).

• Third-party testing: www.consumerlab.com• 2-3$/mo, consumer products

• University of Maryland and Sloan:• https://umm.edu/health/medical/altmed/treatment/herbal-medicine• https://www.mskcc.org/cancer-care/treatments/symptom-management/integrative-

medicine/herbs/search

http://www.consumerlab.com/https://umm.edu/health/medical/altmed/treatment/herbal-medicinehttps://www.mskcc.org/cancer-care/treatments/symptom-management/integrative-medicine/herbs/search

Natural Medicines

Sloan’s site

St. John’s Wort

• St. John's wort inhibits serotonin, norepinephrine and dopamine reuptake.

• Most preparations are standardized to hypericin (0.3%) or hyperforin (5%).

• Induces Cytochrome P450 CYP3A4.

• For mild to moderate depression: 300mg orally TID

SJW Compared to Meds

• 2015 meta-analysis found St. John's wort as effective for the treatment of depression as other drug classes, with significantly fewer dropouts due to side effects.

• SJW (along with rMAO-As, SNRI, NRI, NaSSAs, SARI) with positive results, but concerns regarding limits of evidence.

Linde K et al. Efficacy and acceptability of pharmacologic treatments for depressive disorders in primary care: a systematic review and network meta-analysis. Ann Fam Med. 2015 Jan–Feb;13(1):69–79.

Resources to learn more:

• Resources at UCSF– do you have these at UCB?• Natural Medicines Comprehensive Database (www.naturaldatabase.com)

and Natural Standard (www.naturalstandard.com).

• Third-party testing: www.consumerlab.com• 2-3$/month, consumer products

• University of Maryland and Sloan:• https://umm.edu/health/medical/altmed/treatment/herbal-medicine• https://www.mskcc.org/cancer-care/treatments/symptom-management/integrative-

medicine/herbs/search

http://www.consumerlab.com/https://umm.edu/health/medical/altmed/treatment/herbal-medicinehttps://www.mskcc.org/cancer-care/treatments/symptom-management/integrative-medicine/herbs/search

CannabisCannabis sativa*, Cannabis indica, Cannabis ruderalis • Used by humans for a long time• >1000 known strains• Restricted ability to study in the United States• Medical use legal in 33 states and DC. Recreational in 12+DC• Contains over 400 chemicals (terpenes, flavonoids, alkaloids,

cannabinoid)• Changing over time, concentration of THC from 4% ‘96->12% ’12

ElSohly MA et al. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States, Biol. Psychiatry 79 (7) (2016) 613–619.

Endocannabinoids

Most known:• Anandamide [N-arachidonoyl-ethanolamine (AEA)]• 2-arachidonoylglycerol (2-AG)

• Synthesized on-demand and released immediately in intersynaptic gap-> inhibition of release of other neurotransmitters

Others:• 2-archidonoylglyceral ether (noladin ether)• O-archidonoyl ethano- lamine (virodhamine)• N-arachidonoyl dopamine

Cannabinoid Receptors

• CB1 and CB2 Receptors Identified• CB1 densely populated in the brain and throughout nervous system, present

throughout the body• CB2 largest concentration in B-Cell and NK Cells; also macrophages and

marginal zone of spleen, bone and a little in liver and nerve cells

• G-protein coupled receptors, activation-> inhibit adenylyl cyclase• Stimulates inwardly rectifying K+ channels and mitogen-activated protein

kinase cascades• Inhibits Ca2+ influx through various calcium channels• Decreases cyclic AMP and protein kinase A activity

Levinsohn EA et al. Clinical uses of cannabis and cannabinoids in the United States. Journal of the Neurological Sciences 411 (2020)

Sarzi-Puttini P et al. Medical cannabis and cannabinoids in rheumatology: where are we now? Expert Review of Clinical Immunology 2019, Vol. 15, No. 10, 1019–1032

CB1 Receptor

• Appetite• Immune Function• Muscle Control• Pain• IOP• Cognition• Emesis• Neuroexcitability• Reward • Thermoregulation

CB2 Receptor

• Immune Function• Cell Proliferation• Inflammation• Pain• In vitro effects:

• Cytokine production by RA fibroblasts and matrix metalloproteins from fibroblast-like synovial cells

• IL-1 induced proteoglycan and collagen degradation

THC and CBD

• Δ-9-tetrahydrocannabinol (THC)- Main Psychoactive Component• Analgesic, anti-inflammatory• High affinity for CB receptors• Most highly concentrated in resin of female plant• 21-carbon Terpenophenolic Cannabinoid, maybe 100s of others

• Cannabidiol (CBD)- Not psychoactive• Low affinity for CB1 (antagonist) and CB2 receptors (negative allosteric modulation)• Capsaicin analog and TRPV1 receptor agonist; 5HT1A agonist. • Antioxidant, anti-inflammatory, immunomodulatory, anticonvulsant ?mechanism• Potent Cytochrome P450 3A11 Inhibitor

Iffland K et al. An update on safety and side effects of Cannabidiol: a review of clinical data and relevant animal studies, Cannabis Cannabinoid Res. 2 (1) (2017) 139–154.

Adverse effects of THC• Psychomotor • Psychiatric• Does not depress respiration because CB1 not in midbrain• Chronic use->Depression, anxiety• Developing brain• Testicular cancer• Gynecomastia• ?Mild increased risk of MI• 10% with CUDWHO, Expert Committee on Drug Dependence, Fortieth Report, World Health Organization, 2018.

Adverse effects of CBD

• Usually none, may have:• Somnolence• Diarrhea• Fatigue• Anorexia • Medication interactions

CBD• Possible benefits:

• Anti-inflammatory• Analgesic• Anti-nausea/emetic• Anxiolytic• Anti-epileptiform

• Widely available as a wellness product• Must contain

CBD in Rat OA Model

• In rat OA model, therapeutic and prophylactic CBD effects tested. • Results End-stage OA:

• CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p 0.0001; n 58).

• Decreased acute, transient joint inflammation (p 0.0001; n 56)• Results Prophylaxis:

• Prevented the development of MIA-induced joint pain at later time points (p 0.0001; n 58) and neuroprotective (p 0.05; n 56-8).

Philpott HT et al. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017;158(12):2442-51.

“The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints.”

Philpott HT et al. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017;158(12):2442-51.

Cannabis and Opiates

• 21 pt on long acting opiates, admitted for vaporized cannabis x5d• Blood sampling was performed at 12-h intervals on days 1 and 5. The

extent of chronic pain was also assessed daily. • Pharmacokinetic investigations no sig change • Pain was significantly decreased by average 27%• Conclusion: “vaporized cannabis augments the analgesic effects of

opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.”

Abrams DI et al. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011 Dec;90(6):844-51.

Cannabis summary

• Promising for unique effects

• Science and evidence expanding rapidly

• As with all herbs, concerns about adulteration/content

• CBD is worth trying for pain management

• Cost can be prohibitive

Aromatherapy

• Utilizes essential oils (EO) for olfactory effects.

• EO are volatile liquids extracted from plant parts.

• Used with success in our pediatric hospital

• Yes, they do stuff…

Aromatherapy, Inpatient Retrospective

• >10k Patients 18yo+ from Allina Health who received aromatherapy• Pain, Anxiety and Nausea (0-10 scale) measured pre- and post- EO • 10 hospitals, 2012-2014 admissions, not ED, OBS or outpatient• Nursing delivery and data collection• 77.6% Inhaled, 19% Topical, 3.3% Combined• No side effects or complications from EO reported• Lavender, Ginger, Sweet Marjoram and Mandarin used

JR Johnson et al. The effectiveness of nurse-delivered aromatherapy in an acute care setting. Complementary Therapies in Medicine 25 (2016) 164–169.

Peppermint Oil for Post-Op Nausea (PON)

• Enrolled 123 pts, adult postop cardiac surgery patients.

• 34 had nausea and were offered peppermint oil inhaler. No control

• Avg Nausea before 3.29 (0-5 scale, 5=worst)1.44 2min after EO.• 19/34 nausea free after one use. Only 5 used it a 2nd time,

Briggs et al. Inhaled peppermint oil for postop nausea in patients undergoing cardiac surgery. Nursing2016. Volume 46, Number 7; 61-67.

Meditation Effects

• Modulation of autonomic nervous system• Different from relaxation alone

• Enhances Immune System• Reduced inflammatory cytokines• Increased antibody production with vaccines

• Brain Changes• Increased thickness and left prefrontal activity

• Endocrine and hormone changes• Reduced Cortisol and increased Melatonin

Mindfulness Meditation

• “Mindfulness means paying attention in a particular way on purpose in the present moment and non-judgementally.” -Jon Kabat-Zinn

• Focusing one’s full attention specifically

• Often starts with breath, and returning to breath

• Training of the mind

Examples of Mind-Body Forms

• Meditation and Mindfulness• Guided Imagery• Biofeedback• Hypnosis• Yoga• Tai Chi• Qi Gong

Mindfulness Based Stress Reduction

• Structured 8wk program, 28h total

• Secular, based on Buddhist traditions

• Deliberate, sustained, nonjudgmental attention • enhance self-awareness • change maladaptive thinking• increase the capacity for skillful response• reduce suffering

Who’s right for MBSR?

• Motivated to increase self-awareness• 28 hours of classroom time over 8 weeks• Important part is direct exploration of unpleasant activities as they arise

• Contraindications:• Untreated psychosis• Mania• Intoxication from active substance abuse

MBSR and Pain• 19 studies of >1200 patients, all show improved:

• Quality of life• Acceptance• Pain tolerance• Mood

• 2013 review looked at pain itself, showed 10/16 studies with significant reduction.

Reiner et al. Do mindfulness-based interventions reduce pain intensity? A critical review of the literature. Pain Med. 2013 Fen;14(2):230-42

La Cour et al. Effects of mindfulness meditation on chronic pain: a randomized controlled trial. Pain Med. 2015 Apr;16(4):641-52

Guided Imagery for Surgery• Metanalysis of 8 studies, as part of larger mind-body review• 7/8 showed improvements in psychological well-being. • 4/4 showed improvements in pain. • 3/3 decreased analgesia use.• Also decreased: time to 1st BM, cortisol, anxiety, fatigue• Conclusion: “Guided imagery was examined in eight studies, with

strong evidence for improvements in psychological well-being measures and moderate support for the efficacy of reducing analgesic intake. “

Nelson EA et al. Systematic review of the efficacy of pre-surgical mind-body based therapies on post-operative outcome measures. Complement Ther Med. 2013 Dec;21(6):697-711.

https://www.ncbi.nlm.nih.gov/pubmed/?term=Nelson%20EA%5BAuthor%5D&cauthor=true&cauthor_uid=24280480

Conclusion

• Non-pharmacologic methods can be effective for symptom management and empowering for patients

• Evaluating safety and cost are essential

• There are resources that can help

• Cannabis can be safe for select patients for symptom management

Questions/Comments?

• Thank you!

Integrative Medicine for the Internist�A Primer for 2020DisclosuresRoadmap of our time togetherWhat is Integrative Medicine?What is CAM?Slide Number 6 Fascia and YogaSlide Number 8Decreased Size of Breast CA in MiceSlide Number 10Proposed MechanismsSlide Number 12NIH ‘97 Report of Efficacy WHO 2002Archives of Internal Medicine 2012�Acupuncture for Chronic PainSlide Number 16Archives of Internal Medicine 2012�Acupuncture for Chronic PainSlide Number 18Slide Number 19Safety- Many studiesSlide Number 21TEAS (Transcutaneous Electric Acupoint Stimulation)TEAS in LaborLabor and electro-stim, cont.Nausea and Vomiting AcupressurePericardium 6Acupressure for Dysmenorrhea Spleen 6 LocationNatural ProductsBotanical MedicineHerbal UsageDietary Supplement and �Health Education Act ‘94How to Advise PatientsHerbs and Supplements ResourcesNatural MedicinesSloan’s siteSlide Number 37St. John’s WortSJW Compared to MedsResources to learn more:Slide Number 41CannabisEndocannabinoidsCannabinoid ReceptorsSlide Number 45CB1 ReceptorCB2 ReceptorTHC and CBDAdverse effects of THCAdverse effects of CBDCBDCBD in Rat OA Model Slide Number 53Cannabis and OpiatesCannabis summarySlide Number 56AromatherapyAromatherapy, Inpatient RetrospectiveSlide Number 59Peppermint Oil for Post-Op Nausea (PON)Slide Number 61Meditation Effects Mindfulness MeditationExamples of Mind-Body FormsMindfulness Based Stress ReductionWho’s right for MBSR? MBSR and PainGuided Imagery for SurgeryConclusionQuestions/Comments?