WEEDS AND SEEDS IN INFLAMMATION AND PAIN MANAGEMENT

BY SAHAR SWIDAN, PHARM.D., BCPS, ABAAHP, FAARFM, FACA

AUTOIMMUNE DISEASE

There are varying symptoms depending on the disease

• Common symptoms include low grade fever, pain in joints, and fatigue

These diseases result in a person’s body attacking it’s own tissues

• In a normal immune system, the antibodies attack antigens

CAUSES OF AUTOIMMUNE DISEASE

Main issue with autoimmune disease is the immune system attacks healthy tissues that it thinks are harmful antigens

1

Caused by the adaptive immune response

2

The underlying cause of autoimmune disorder is multifactorial

• Genetics

• Environmental triggers

• Infection

• Certain foods (Ex. Gluten)

• Chemical exposures

• Pharmaceutical drugs

• Extreme stress or physical trauma

3

AUTOIMMUNE DISEASES: RISK FACTORS

Women of child-bearing

age

Women > men

Family history Some races and ethnicities have

higher risk

SLE African

Americans

Type 1 DM Whites

Genetics Environmental

factors

FIBROMYALGIA

A common neurological health condition that

causes widespread pain and tenderness (sensitive

to touch)

Many people who have this are very fatigued and

have sleep issues

Causes are unclear

Diagnosis made based on symptoms

PAIN PROCESSING IN FIBROMYALGIA

Nociceptors transmit pain from the body

to the brain

Via releasing chemicals like substance P

Descending pain is modulated by

chemical like NE, serotonin, and GABA

These two pathways in fibromyalgia are

NOT balanced

Increased in ascending and decreased activity in descending

• This is due to the pain volume being turned up

PAIN PROCESSING IN FIBROMYALGIA

Brain activity in response to experimental pain is heightened in these patients

• Attributed to the increased pain sensitivity seen

Higher levels of substance P in CSF

• Substance P important for neuroprocessing, so it contributed to the abnormal pain processing

Lower levels of serotonin are found in fibromyalgia patients

• Serotonin important for descending pathway

• Blocked pain transmission for the periphery

• Blocked serotonin can contribute to the pain seen in fibromyalgia

CAM IN AUTOIMMUNE DISEASE

Complimentary Alternative Medicines have function in the

modulation and relief of symptoms associated with

autoimmune diseases.

These supplements all work differently and influence different components of the immune system:

• Adaptive immune system

• Innate immune system

• Histamine/allergic immune system

CAM THAT AFFECT INNATE IMMUNITY

Astaxanthin Curcumin Gymnema Vitamin A

Betaine HCl

with pepsin

DHEA L-Glutamine Vitamin C

Carnitine Ginger Pycnogenol Vitamin D

Cayenne pepper Green Tea Extract Resveratrol Vitamin E

Coenzyme Q10 Glutathione SAMe 5HTP

CAM THAT AFFECT ADAPTIVE IMMUNITY

Boswellia Green tea extract SAMe

Carnitine Glutathione Selenium

Cromolyn Peony Vitamin B6

Curcumin Resveratrol Vitamin D

CAM THAT AFFECT HISTAMINE/ALLERGIC IMMUNITY

Borage Oil Evening primrose Ketotifen Selenium

Capsaicin Curcumin Omega-3 Vitamin C

Cat’s claw Ginger Probiotic Vitamin E

Coenzyme Q10 Green tea extract Rosemary White willow bark

PROBIOTICS

Probiotics help the body regain a healthy balance

of bacteria in the gut

Regulation of intestinal microflora helps to

influence the development of mucosal and systemic immunity

Probiotics stimulate Th1 immunity

• One of the mechanisms that can suppress as Th-2 mediated allergic disease

Seen benefits in Diabetes mellitus type

1, Multiple Sclerosis, and Inflammatory

Bowel Disease

Right now only seen as a benefit for primary

prevention therapy for autoimmune diseases

L-GLUTAMINE

• Non-essential amino acid fundamental to the digestive and

immune systems

• Essential for lymphocyte function

• Helps repair damage to the gut

• Helps the gut lining to regrow and repair

• Increases number of cells in the small intestine along with

the number and height of villi of those cells

L-GLUTAMINE: USES

• Type 1 Diabetes Mellitus

• Crohn’s Disease

• Increase permeability of intestinal wall

• Improve the ability for vital substances to properly

come through the body

PROTEOLYTIC ENZYMES

• Common proteolytic enzymes: pepsin,

bromelain, papain

• Mechanism of Action

• Digest protein by aiding in the digestion process,

breaking it down into amino acids

• Safety

• Generally safe

BETAINE HYDROCHLORIDE WITH PEPSIN

Used to increase stomach acid

Lowers gastric pH by 4.5 units

Lack of acid in the gastric fluid can be

caused by autoimmune diseases

Can also be induced by infection (H. pylori) and medications (PPIs,

H2-RAs)

Stimulates immune function

BETAINE HYDROCHLORIDE WITH PEPSIN

Multiple Sclerosis

• 3.9 mg/kcal

• 37x what is found in the human diet

Hashimoto’s Thyroiditis

• Low stomach acid makes it more difficult to digest

• People with Hashimoto’s can be sensitive to gluten, dairy, and soy

• Because the proteins are difficult to digest

• Betaine with pepsin can help with better digestion

OMEGA-3 FATTY ACIDS

• Help reduce

inflammation

• Highly concentrated in

the brain and important

for cognition

• Side effects: flatulence,

bloating, belching,

diarrhea

OMEGA-3 FATTY ACIDS: USES

Rheumatoid Arthritis

Fish oils helps reduce symptoms of RA, including joint pain and morning stiffness

One study suggest that people with RA who take fish oil may be able to lower their dose of NSAIDs

Does not slow progression of RA, only treats symptoms

Systemic Lupus Erythematosus

EPA and fish oil may reduce symptoms of SLE

Two studies found that fish oil had no effect on lupus nephritis

Inflammatory Bowel Disease

Mixed results

Some studies suggest that omega-3 fatty acids may help when added to sulfasalazine

More studies needed

Have similar side effects to IBD: flatulence, belching, bloating, diarrhea

BORAGE OIL (BORAGO OFFICINALIS): USES

• Rheumatoid Arthritis

• Take in combination with

conventional treatment

• Decrease symptoms of RA after

6 weeks of treatment

• Improvement sustained for 24

weeks

• Can decrease number of tender

joints by 36%, swollen joints by

28%

• Dose: 1300 mg of oil daily

EVENING PRIMROSE (ONANGRACEAE)

• A wildflower

• Has 7 -10% GLA

• Same fatty acid in borage oil

• Side effects: nausea, diarrhea, rashes

• Do not take if have epilepsy

• Rheumatoid Arthritis

• Arthritis Research UK validated the effectiveness of evening primrose for RA

• Helps the immune system and joint function

• Dosage: 540 mg of the oil twice daily

• May take 6 months for clinical efficacy

VITAMIN D3

• Mechanism of Action

• Immunologic effect

• May inhibit autoimmune reactions that target

cells in the body

• Modulates the activity of immune cells

VITAMIN D3

• Plaque Psoriasis

• Used topically

• Can be used in combination with corticosteroids such as betamethasone

• Multiple Sclerosis

• Decreases risk of MS in women by up to 40% (dose-dependent, 400 IU daily)

• Rheumatoid Arthritis

• Increased vitamin D intake associated with lower risk of RA

• Systemic Lupus Erythematosus

• Lower vitamin D levels are linked to more aggressive lupus autoimmunity

• Supplement with vitamin D to lessen symptoms

• Diabetes Mellitus Type 1

• Helps prevent incidence and associated complications

COENZYME Q-10

• Biosynthesis of CoQ-10 is a 17-step process requiring riboflavin, niacin, pantothenic acid, pyridoxine, b12, folic acid, vitamin C, and other trace elements

• Generates ATP

• Has antioxidant effects

• Has anti-inflammatory effects by attenuating TNF-alpha on peroxisome proliferator-activated receptor gamma (not alpha)

• Immunomodulatory agent

• Needed for optimal function of the immune system

COENZYME Q-10: USES

Diabetes Mellitus Type 1

• Q-10 200 mg BID may reduce A1C

1

Fibromyalgia

• Q-10 200 mg daily for 84 days improves QOL such as physical fitness levels, social activities, overall health, and pain

2

DHEA

• Decreases with age

• Linked to a variety of chronic and degenerative diseases

• As a result of aging, immunity may become compromised due to poor regulation of cellular hormones that govern immune responses

• Has antioxidant effects

• Stimulatory effect on the immune system

• DHEA upregulates various parameters involved in the inflammatory pathway

DHEA

• Systemic Lupus Erythematosus

• Adjunct treatment

• Help improve SLE disease activity, frequency of flare-ups, muscle aches, oral ulcers, QOL and corticosteroid doses needed

• More evidence needs to be conducted

• Inflammatory Bowel Disease

• DHEA 200 mg/day orally for 8 weeks reduced symptoms

• Remission occurred in 6 of 7 Crohn’s patients and 6 of 13 UC patients

ACETYL-GLUTATHIONE

• Antioxidant that is naturally produced in the body

• Mechanism:

• During chronic inflammation during a period of sustained production of reactive oxygen species, antioxidant defense systems weaken

• Glutathione stimulates and inhibits immunological response to control inflammation

• Plays a role in detoxification

• Deficiency impairs the body’s ability to get rid of toxins, so glutathione helps to prevent this

GINGER

1

Mechanism of Action

• Inhibitory effect of 6-shogaol on the release of substance P

• Inhibit cyclooxygenase (COX) and lipoxygenase pathways, and leukotrienes

2

Dose

• Ginger extract 1000mg daily

3

Safety

• Safe orally when used appropriately

• Well-tolerated

GINGER

• Side Effects

• Abdominal discomfort

• Heartburn

• Diarrhea

• Drug Interactions: use with caution with these medications (dose adjustments may be necessary)

• Anticoagulant/Antiplatelet drug

• Nifedipine – major interaction

• Do not take – inhibits platelet aggregation significantly

CURCUMIN

• Also known as turmeric

• Mechanism:

• Anti-inflammatory effects

• Antioxidant effects

• Immunomodulatory effects

CURCUMIN

Also known as curcumin

1

Mechanism of Action

•Inhibits transient receptor potential vanilloid 1 (TRPV1)-mediated pain hypersensitivity

•Inhibits NF-kB activation

•Inhibits cyclooxygenase-2 (COX-2), prostaglandins, leukotrienes, and other cytokines involved in pro-inflammatory signaling

pathways

2

Dose

• 500mg twice daily (OA)

• 400mg three times daily (RA)

3

Safety

• Generally well tolerated

4

CURCUMIN

• Dyspepsia

• Nausea

• Vomiting

• Diarrhea

• GI upset

Side Effects

• Antiplatelet/anticoagulant drugs

• Antidiabetic drugs

Drug Interactions:

use with caution with

these medications

CURCUMIN

• Multiple Sclerosis

• Type 1 Diabetes Mellitus

• Rheumatoid Arthritis

• May reduce symptoms including morning stiffness, walking time, and joint swelling compared to baseline

• Curcumin 500 mg BID reduced RA symptoms more than diclofenac sodium 50 mg BID after 8 weeks

• Systemic lupus erythematosus

• Turmeric 1.5 g/day in 3 divided doses for 3 months can reduce systolic BP and improve kidney function compared to baseline inpatients with lupus nephritis

• Inflammatory Bowel Disease

• Curcumin 1.1 g/day orally for one month followed by 1.65 g/day for another month reduced symptoms of ulcerative colitis in patients taking 5-ASA and corticosteroids compared to baseline

• Study showed that taking 2 g/d orally with sulfasalazine or mesalamine for 6 months can reduce the risk of ulcerative colitis recurrence compared to placebo

BOSWELLIA

• The applicable part of boswellia is the gum resin

• Gum resin is obtained by pulling away the bark of the boswellia tree

• Gum resin contains up to 16% essential oils including

• Phenyl propanoids, terpenoids, flavonoids, and other phenolics

• Has immunomodulatory effects and may inhibit mediators of autoimmune disorders

• Reduce production of antibodies and cell-mediated immunity

5 – LOXIN (BOSWELLIA SERRATIA EXTRACT)

• Mechanism of Action

• Inhibit 5-lipoxygenase and reduces leukotriene synthesis

• Inhibits leukocyte elastase

• Dose

• 100-250mg daily by mouth

• Safety

• Often used to treat pain and inflammation usually associated with arthritis

• Well-tolerated orally

5 – LOXIN (BOSWELLIA SERRATIA EXTRACT)

• Side Effects

• Diarrhea

• Nausea

• Abdominal pain

• Heartburn

• Itching

• Headache

• Edema

• General Weakness

• Drug Interactions: dose

adjustment might need to be

made

• CYP1A2 substrates

• CYP2C19 substrates

• CYP2C9 substrates

• CYP2D6 substrates

• CYP3A4 substrates

• Immunosuppresants

BOSWELLIA: USES

• Inflammatory Bowel Disease

• Improve symptoms in ulcerative colitis

• Boswellia gum resin 350 mg TID significantly improved symptoms and disease markers of UC

• 82% of subjects achieved remission compared to 75% taking sulfasalazine

• Another study boswellial gum resin 300 mg TID improved symptoms and measures of disease pathology in about 90% of patients

• 70% achieved remission as compared to 40% in the sulfasalazine group

• Boswellia extract 1200 mg TID for 6 weeks may reduce symptoms of Crohn’s disease

MSM

• MSM in doses of 2.6 to 6 grams/day has been used

safely in studies lasting up to 12 weeks

• MSM is a naturally occurring compound found in

green plants

• MSM is an odorless metabolite of dimethylsulfoxide

(DMSO).

• MSM is primarily used for osteoarthritis. Preliminary

research suggests MSM might inhibit degenerative

changes in joints in animal models of osteoarthritis

40

MSM

• No Drug Interactions

• Nausea, diarrhea, bloating, headache, fatigue,

insomnia, and difficulty concentrating in clinical

studies

• These side effects do not appear to occur more often

than with placebo

• MSM has also caused pruritus and increased allergy

symptoms in some patients

41

S-ADENOSYLMETHIONINE (SAME)

• Distributed throughout virtually all body tissues and fluids.

• Concentrations are highest in childhood and decrease with age.

• Plays an essential role in 100s of biochemical reactions

• Transmethylation

• Transsulfuration

• Aminopropylation

• SAMe contributes to the synthesis, activation and/or metabolism

of hormones, neurotransmitters, nucleic acids, proteins,

phospholipids, and some drugs

42

S-ADENOSYL-L-METHIONINE (SAME)

• It is a naturally occurring molecule

• Distributed throughout body tissue and fluid

• It contributes to the synthesis, activation, and/or metabolism of

hormones, neurotransmitters, nucleic acids, proteins, phospholipids,

and some drugs

• Produced endogenously from homocysteine and 5-methyl

tetrahydrofolate

• Closely linked to vitamin b12 and folate metabolism

SAME: OSTEOARTHRITIS

• Multiple clinical trials show that taking SAMe orally is superior to placebo and

comparable to NSAIDs, including the COX-2 inhibitor celecoxib (Celebrex), for

decreasing symptoms associated with osteoarthritis.

• Has anti-inflammatory and analgesic properties

• SAMe is associated with fewer adverse effects than NSAIDs and is comparable in

reducing pain and improving functional limitation

• Significant symptom relief may require up to 30 days of treatment.

44

SAME USES

• Fibromyalgia, Rheumatoid Arthritis,

Ankylosing Spondylitis

• Oral use improved symptoms

• Clinical trials showed improvement in symptoms

compared to placebo and TENS therapy

D-PHENYLALANINE

• Essential Amino Acid- Milk and Meat

• Blocks the degredation of Enkephalins

• L-Phenylalanine found in food

• D-Phenylalanine protects endorphins

• Upregulates endogenous analgesic system

• No tolerance

• Benefit over time

• Contraindicated in Phenylketonuria, HTN, cancer, Parkinson, TD, MAO-I

46

PHENYLALANINE

• 4 weeks to efficacy

• D form 500mg BID to TID

47

DEVIL’S CLAW

• Orally, used for arteriosclerosis, osteoarthritis, rheumatoid arthritis, gout, myalgia,

fibrositis, lumbago, tendonitis, pleuritic chest pain, gastrointestinal (GI) upset or

dyspepsia, fever, and migraine headache.

• Well-tolerated when used daily for up to a year

• Anti-inflammatory mode of action

48

DOSING

• Osteoarthritis, a specific powdered devil's claw root product (Harpadol, Arkopharm)

dosed at 2.6 grams/day

• Back pain, a specific devil's claw extract (Doloteffin, Ardeypharm) providing 50-100 mg

harpagoside daily has been used

49

CAT CLAW6-8

• Mechanism of Action

• Antinociceptive effects through interaction with 5-HT2 receptors

• Used primarily for osteoarthritis and rheumatoid arthritis

• Dose

• 100mg by mouth daily

• Containing freeze-dried aqueous cat’s claw extract (uncaria gluianesis)

• Safety

• Safe when used short term (seen used up to 4 weeks

• Well tolerated

CAT CLAW6-8

• Side Effects

• Headache

• Fatigue

• Insomnia

• Abdominal pain

• Drug Interactions: use the following with caution

• Anticoagulant/Antiplatelet drugs

• Antihypertensive drugs

• Calcium channel blockers

• Protease inhibitors

EGG SHELL MEMBRANE9-11

• Mechanism of Action

• Extracted yolk immunoglobulin (IgY can be used in humans to provide passive immunity and help treat the specific conditions for which the hens were immunized against

• Contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues

• Dose

• 500mg

• Safety

• Well tolerated

EGG SHELL MEMBRANE9-11

• Side Effects

• Diarrhea

• Gas

• Bloating

• Drug interactions

• None known

UC-II12-15

• Also known as type II collagen

• Mechanism of Action

• Potential autoantigen

• Initiates and maintains the immune response

• Suppressor CD8+T cells can be stimulated in a trigger-specific and

effector-nonspecific way by contact with type II collagen in the joint

• Dose

• 40mg Daily

FEVERFEW21-23

• Mechanism of Action

• Inhibit serum proteases and leukotrienes

• Blocks prostaglandin synthesis by inhibiting phospholipase, which prevents the release of

arachidonic acid

• Dose

• 50-150 by mouth once daily

• Safety

• Well tolerated when used appropriately and short-term

FEVERFEW21-23

• Adverse Effects

• Skin rash (topical)

• Palpitations

• Heartburn

• Nausea

• Diarrhea

• Constipation

• Bloating

• Flatulence

• Drug Interactions: use

with caution in

combination with the

following medications

• Anticoagulant/antiplat

elet drugs

• Cytochrome P450

substrates

SELENIUM

• Organic molecule

• In broccoli, garlic, and other selenium-accumulating plants

• Essential for activity of selenoproteins such as glutathione peroxidase enzyme

• Anti-inflammatory effects by inhibiting ROS and activation of feedback mechanisms

• Antioxidant effects

• Immune system effects

• Selenium needed for proper functioning of neutrophils, macrophages, NK cells, T lymphocytes, and other immune mechanisms

SELENIUM: USES

Hashimoto’s Thyroiditis

• uding selenium reduced need for oral prednisone for symptom control in UC patients

• More evidence is needed to rate selenium for this Selenium 200 mcg daily in combination with levothyroxine reduced thyroid peroxidase by about 6-30% more than placebo after 3-12 months of treatment

• Selenium improves measures of QOL, well-being and mood

Rheumatoid Arthritis

• Selenium seen to improve QOL measures

• Selenium 200 mcg/day improved joint swelling, tenderness, and morning stiffness

• Also reduced need for supplemental cortisone and NSAIDs for symptom control

Inflammatory Bowel Disease

• Combination supplement incluse

MEDICAL MARIJUANA

WHAT IS MEDICAL MARIJUANA?10

• “Medical Marijuana refers to using the whole

unprocessed marijuana plant or its basic extracts

to treat a disease or symptom”

• The FDA has not recognized or approved the

marijuana plant as medicine

• The chemicals in marijuana are called

cannabinoids

• There are two FDA-approved medication that

contain cannabinoids

BACKGROUND1

• Marijuana is the female flowers and dried leaves of

the hemp plant called cannabis sativa

• 23 states and the District of Columbia have

legalized medical marijuana

• Cannabis is the plant that grows marijuana

• All marijuana can be considered medical-grade

since it all has some therapeutic effect

BACKGROUND4

• The potency of marijuana varies from strain to

strain

• As low as 2-3% THC

• As high as 30% THC

• Higher potency indicates that the patient will

need to consume less to receive the same

outcome of that with a lower dose and higher

quantity

WHAT ARE CANNABINOIDS?10

• Cannabinoids are chemicals that are related to the commonly known

ingredient in marijuana known as THC (delta-9-tetrahydrocannabinol)

• Another cannabinoid of interest is CBD

• There are over 100 other cannabinoids other than THC that is found in

marijuana

• Cannabinoids are similar to flavinoids that are found in chocolate

WHAT ARE CANNABINOIDS?10

• The body produces its own cannabinoids that help to regulate the following:

• Pleasure

• Memory

• Thinking

• Concentration

• Body movement

• Awareness of Time

• Appetite

• Pain

• Senses – taste, touch, smell, hearing, and sight

CANNABINOID RECEPTORS21-25

• Receptors are CB1 and CB2

• CB1 - mostly expressed in the brain, but also found in adipose tissue, liver, muscle, GI tract,

and in reproductive and cardiovascular tissues

• CB2 – mostly expressed in immune cells

• G-protein coupled receptors

CB1 RECEPTOR28

• Effects of CB1 are neuromodulatory

• Affect the following neurotransmitters:

• Acetylcholine, norepinephrine, dopamine,

serotonin, aminiobutyric acid, glutamate, and

D-aspartate

CB2 RECEPTOR28

• Present mainly on peripheral tissues and

central immune cells

• Activation of this receptor leads to:

• Immunosuppression

• Anti-inflammatory effects

• Anti-nociceptive effects

WHAT IS CBD?10

• Cannabidiol (CBD) is a cannabinoid, but it

does not affect mind or behavior

• It is useful in reducing pain and

inflammation, controlling epileptic

seizures, and possibly treating mental

illness and addictions

WHAT IS THC?10,11,31

• THC is short for Δ9-

tetrahydrocannabinol

• It is a potent antioxidant with

neuroprotective properties

• THC is a partial agonist for the CB1

receptor

• CB1 receptors regulate the release of

other neurotransmitters

WHAT IS THC?10,11

• THC increases appetite and reduces nausea

• THC may also decrease pain, inflammation,

and muscle control problems

• The FDA has approved the use of THC for

appetite and nausea reduction purposes

• Dronabinol

PHARMACOKINETICS & PHARMACODYNAMICS

FORMS OF MEDICAL MARIJUANA 2

• Smoked – most common form

• Capsules

• Vaporization

• Edible form

• Suppositories

• Liquid to drink

PHARMACOLOGY OF CANNABIS

• Cannabinoids are highly lipophilic and lipoprotein bound

• Volume of distribution (Vd) = 10 L/kg

• Blood concentrations are therefore not directly related to the drug effect

• The release from the lipid stores along with enterohepatic recirculation accounts

for retention of THC

• Terminal half-life is > 4 days in frequent users

PHARMACOLOGY OF CANNABIS

• Urine THC can be detected for days after

use

• Passive inhalation – requires very high

concentrations of smoke in a small

enclosed area

• Very unlikely

ONSET AND DURATION OF CANNABIS

• Physical and psychosocial effects commence within minutes after use

• Usually within 15 minutes

• Peak effects occur within 30 minutes to 60 minutes post-smoking and last 2-4 hours

• Psychosocial effects can stay for up to 4 to 8 hours depending upon route of

administration

• Oral has a slower onset, but longer duration

PSYCHOSOCIAL EFFECTS

• Effects do not depend on blood concentration

• Depends partially on the dose

• Effects are dose-dependent and route-dependent

• Lower dose effects: euphoria, relaxation, wide range from exhilaration to introspection, distortion of time and some visual hallucinations, memory distortions (especially short-term memory), hunger

• Higher dose effects: anxiety, tension, anger, confusion, hallucinations, paranoia, and panic attacks

PHARMACOKINETICS OF SMOKING THC31

• Bioavailability: 10-25%

• 50% of the THC content is delivered into smoke

• 50% of smoke is exhaled again

• 60% of inhaled smoke may be metabolized by the

lung

• Peak concentrations are reached within minutes

• T1/2 distribution: 0.5hr

• T1/2 elimination: 30hr

• Smoking THC mimics IV

PHARMACOKINETICS OF ORAL THC31

• Bioavailability: 5-20%

• Usually 1/3 of that smoked due to gastric

degradation and extensive first pass

metabolism effects

• High patient variability

• Can lead to increased toxicities because

delayed effect

• Multiple low peak concentrations reached in

1-3hr

• T1/2 absorption: 0.8hr

• T1/2 distribution: 3.8hr

• T1/2 elimination: 25hr

DOSE OF THC31

• Effective dosing of THC

• Low dose: <7 mg

• Medium dose: 7-18mg

• High dose: >18mg

• Tolerance to THC exists via the down regulation

of the CB1 receptors

• High tolerance occurs with chronic use

• Low tolerance occurs with intermittent use

VAPORIZATION

• Cannabinoids vaporize at a

temperature lower than combustion

• Results in lower percent of noxious

chemicals

PHARMACODYNAMICS OF THC32

• Elevation in heart rate: average >19bpm

• Increase in subjective feeling high

• Decrease in subjective alertness

• Increase in motor instability

• Body sway

PK/PD MODEL OF THC32

• In study by Zuuman et al, subjects were

given increasing doses (2, 4, 6, 8mg) of THC

via vaporizer at 1.5hr intervals

PK/PD MODEL OF THC32

MEDICAL CANNABIS IMPACT ON HORMONES

• Males:

• Decreases luteinizing hormone (LH)

• Decreases follicle stimulating hormone (FSH)

• Decreased Prolactin

• Decreased growth hormone (GH)

• Females: More sensitive than males to THC

effects

• Higher estrogen levels

MARIJUANA EFFECTSON THE BRAIN

MARIJUANA EFFECTS

• Hypothalamus: increased appetite

• Brain stem: nausea relief, lowered blood

pressure, drowsiness, decreased pain,

decreased spasticity, and decreased

tremor.

• Hippocampus: memory impairment

MARIJUANA EFFECTS

• Cerebral cortex: altered consciousness,

perceptual distortions, memory

impairment, delusions, hallucinations

• Cerebellum: loss of coordination

• Amygdala: changes in anxiety, pain

attacks, lowered traumatic memories,

decreased hostility

THE ROLE OF KETAMINE IN PSYCHIATRY, ADDICTION, AND PAIN

MANAGEMENT

BACKGROUND

• Ketamine first synthesized in 1960s as alternative to phencyclinde

• Initially, used as a dissociative anesthetic

• Limited use in contemporary anesthesia due to side effects, namely psychedelic

symptoms (Niesters et al. 2013)

• More commonly used in animal anesthesia (Morgan, Curran 2012)

• At subanesthetic doses, produces analgesia

PHARMACOLOGY

• A non-competitive antagonist of the NMDA receptor – blocks glutamate

action

• S(+) isomer has higher affinity for NMDA receptor than R(-) isomer

(Morgan, Curran 2012)

• Also interacts with monoaminergic, muscarinic, and opioidergic receptors

(Niesters et al. 2013)

PSYCHIATRIC EFFECTS

• Emergence symptoms after IV infusion – hallucinations, delusions, ‘out-of-body’

experiences

• Induces transient symptoms of schizophrenia in healthy patients but no

evidence linking chronic ketamine use to diagnosis of psychiatric disorders

• Frequent users exhibited profound impairment of long and short term

memory (Morgan, Curran 2012)

REWARD AND DEPENDENCE

• Increases dopaminergic modulation in the brain (similar to other addictive

substances) activates reward pathway

• Interaction with µ opioid receptors may contribute to its rewarding properties

• Some case reports of ketamine dependence but no large scale studies

undertaken so incidence of ketamine dependence is unknown

• Frequent users report increasing dose over time (tolerance) (Morgan,

Curran 2012)

ROLE IN ALCOHOL DEPENDENCE

• Study by Krupitsky and Grinenko 1997 demonstrated benefit of adding

ketamine psychedelic therapy (KPT) to standard therapy

• 65.8% of KPT group showed total abstinence > 1 year compared to 24% of

standard treatment group

ROLE IN DEPRESSION

• IV infusion of ketamine resulted in rapid antidepressant effect, but only lasted

1-2 weeks

• 0.5 mg/kg dosing was used in one study

• Response rates 24 h after ketamine infusion (71%) matched the rates after 6-8 weeks

(65%) of standard monoaminergic therapy (Naughton et al. 2014)

• Rapid reduction in suicidal ideation independent of antidepressant effect

(Caddy et al. 2014)

ROLE IN DEPRESSION

• Dissociative and psychotomimetic effects followed ketamine infusion but did

not last longer than 80 min (Caddy et al. 2014)

• Bottom line: ketamine’s antidepressant effects peak at 24 h post infusion and

generally last 1-2 weeks

ROLE IN DEPRESSION

• Clinical use?

• Can provide immediate relief until monoaminergic therapy takes effect

• Prevent loss of work or school days

• Reduce suicide

• Shorten hospital stays

• Overall, good safety profile associated with single dose of ketamine (not

enough info on repeated infusions) (Naughton et al. 2014)

ROLE IN PAIN MANAGEMENT

• Antagonism of NMDA receptor thought to modulate pain

• Potent analgesic at sub-anesthetic doses (0.5-1 mg/kg/hr) that prevents

sensitization of spinal neurons to painful stimuli (Morgan, Curran et al.

2012)

• Roles in acute, chronic, and cancer/palliative care pain

ROLE IN PAIN MANAGEMENT

• Acute pain

• Recommended to start 0.1 mg/kg i.v.

ketamine and titrating up with a limit of 0.5

mg/kg

• Dose required for treating acute pain can

lead to loss of consciousness in patients

(Persson 2013)

• Chronic Pain

• A 2003 review of chronic neuropathic pain

conditions concluded that evidence for the

efficacy of ketamine is moderate to weak

• Long-term efficacy and safety of ketamine is

not well-studied (Persson 2013)

ROLE IN PAIN MANAGEMENT

• Not well-established in cancer/palliative care pain (Persson 2013)

• May be used as adjuvant therapy if standard therapy is not effecive

• Caution since ketamine may upregulate mTor, which accelerates tumor growth

(Naughton et al. 2014)

• Complex Regional Pain Syndrome (CRPS)

• Current level of evidence is 2B – weak recommendation, moderate quality evidence

• Need large, well-designed controlled trials (Azari et al. 2012)

ROLE IN PAIN MANAGEMENT

• Ketamine in postoperative pain systematic review by Laskowski et al. 2012

• Treatment group: ketamine + opioid if necessary

• Placebo group: just opioid

• IV ketamine effective at reducing opioid consumption and delaying time to first

analgesic dose in patients with postoperative pain

• Increased neuropsychiatric effects associated with ketamine but reduced

postoperative nausea/vomiting (PONV) (Laskowski et al. 2011)

ROLE IN PAIN MANAGEMENT

• Postoperative pain (cont.)

• IV ketamine better in some situations

• Least opioid reduction in head and neck surgery

• Upper thoracic and abdominal surgeries had greater opioid reduction

• VAS pain scores > 7/10 showed greatest reduction in opioid use

• Site of surgery and intensity of pain affect the degree of opioid reduction

• Despite using more opioid, 78% of placebo groups experienced significantly more pain than ketamine treatment groups

• Implies that ketamine improves overall quality of pain control (Laskowski et al. 2011)

SUMMARY/CONCLUSION

• Ketamine is still undergoing experimental study in regards to its antidepressant

effects, not ready for consistent clinical use

• Ketamine has analgesic properties but has limited use in treating various types

of pain

• Well-designed, randomized clinical trials required to corroborate case reports

of efficacy

• Further investigation into ketamine’s mechanisms of action may elucidate how

to better utilize ketamine

REFERENCES

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THANK YOU

Sahar Swidan, Pharm.D., BCPS, ABAAHP, FAARFM, FACA

sswidan@umich.edu

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