What to do when cannabis gets admitted€¦ · Hematology/ Oncology Potential increased risk of nasopharyngeal carcinoma Potential for increased risk of lung cancer, however, data

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Kari L. Franson, PharmD, PhD, BCPPAssociate Dean and Associate Professor

Department of Clinical PharmacyUniversity of Colorado

Skaggs School of Pharmacy & Pharmaceutical Sciences

I have nothing to disclose and no conflicts of interest or funding sources

I will be discussing unapproved drugs and unapproved uses for drugs

What to do when cannabis gets admitted

Objectives

At the completion of this activity, the participant will be able to:

1. Guide patients & clinicians regarding the issues of

if, when, where, and how to use cannabis safely and,

in regard to therapeutic uses, effectively

2. Describe the legal issues that arise when hospital patients are using cannabis lawfully under state laws

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Number of states with various approved medical conditions

Wong FH, Borgelt LA, Franson KL. Int Med Rev 2018

Alzheimer’s disease (11) Epilepsy/seizures (29) Nausea (21)

ALS (18) Glaucoma (27) Pain (25)

Arthritis (3) Hepatitis C (12) Parkinson’s disease (10)

Cachexia (24) HIV/AIDS (28) Peripheral neuropathy (5)

Cancer (28) Multiple sclerosis (15) PTSD (24)

Crohn’s disease (19) Muscle spasticity (22) Tourette’s syndrome (4)

A provider asks “What can you tell me about the diseases that medical marijuana has been approved for?”

I believe that patients gain the most benefit using medical cannabis for:

A. Nausea and vomiting control

B. Appetite stimulation

C. Pain control

D. Seizure control

E. Feeling of euphoria

Tell me what you think

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National Academies: Health Effects of Cannabis

• Conclusive or substantial evidence that cannabis or cannabinoids are effective:

• as anti-emetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids)

• for treatment of chronic pain in adults (cannabis)• for improving patient-reported multiple sclerosis (MS)

spasticity symptoms, but limited evidence for clinician-measured spasticity (oral cannabinoids)

National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: 10.17226/24625.


• Moderate evidence that cannabinoids, primarily nabiximols, are effective:

• to improve short-term sleep outcomes in patients with sleep disturbance associated with obstructive sleep apnea, fibromyalgia, chronic pain, and MS.


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National Academies: Health Effects of Cannabis• Limited evidence that cannabis or oral cannabinoids are

effective for:• increasing appetite and decreasing weight loss associated with

HIV/AIDS (cannabis and oral cannabinoids)• improving symptoms of Tourette syndrome (THC capsules)• improving anxiety symptoms in individuals with social anxiety

(cannabidiol)• improving symptoms of post-traumatic stress disorder

(nabilone)• better outcomes (i.e., mortality, disability) after a traumatic

brain injury or intracranial hemorrhage – statistical association



• Limited evidence that cannabis or oral cannabinoids are ineffective for:

• improving symptoms of dementia (cannabinoids)• improving intraocular pressure associated with glaucoma

(cannabinoids)• reducing depressive symptoms in individuals with chronic

pain or MS (nabiximols, dronabinol, and nabilone)


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National Academies: Health Effects of Cannabis• No or insufficient evidence to support or refute that

cannabinoids are effective for:• cancer-associated anorexia cachexia syndrome and anorexia nervosa• cancers, including glioma• irritable bowel syndrome • epilepsy• spasticity in patients with paralysis due to spinal cord injury• chorea and certain neuropsychiatric symptoms associated with

Huntington’s disease• symptoms associated with amyotrophic lateral sclerosis (ALS)• Parkinson’s disease or levodopa-induced dyskinesia• dystonia• treatment for mental health outcomes in individuals with schizophrenia or

schizophreniform psychosis• achieving abstinence in the use of addictive substances


Chemotherapy induced nausea and vomiting

•Small studies compared THC (dronabinol, nabilone) to dopamine antagonists

• Dronabinol showed anti-emetic efficacy over neuroleptics (but high risk of bias) NNT = 3.4

• Depression (13%), hallucinations (6%), paranoid delusions (5%), occurred, but patients preferred cannabis over control (RR 0.33; 95% CI 0.24-0.44)

• Smoking relief 70-100% vs. capsule relief 76-88%

• The standard of care for prevention of CINV for highly and moderately emetogenic chemotherapy is: 5-HT3 receptor antagonist, dexamethasone, aprepitant/fosaprepitant

Tramer MR, Carroll D, Campbell FA, et. al. BMJ 2001; Musty RE, Rossi R J Cannabis Ther 2001; Todaro B. J Natl Compr Canc Netw. 2012Machado Rocha FC, Stefano SC, De Cassia Haiek R, et. al. Eur J Cancer Care 2008

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Chronic (neuropathic and cancer) pain

• Review of trials with >30% reduction in pain

• 2 cancer pain trials

• 6 neuropathic pain trials

• Concluded moderate quality of evidence to support the use of cannabis for chronic pain

Whiting PF, Wolff RF, Deshpande S, et al. JAMA 2015Grant I. Report to the State of California 2010

Common analgesics for neuropathic pain*to achieve 30% reduction in pain

Multiple sclerosis-associated spasticity

• American Academy of Neurology (AAN) evidence-based guideline recommendations

• Oral cannabis extract, synthetic THC, Sativex®• Several double-blinded RCTs > 1,000 patients

• Subjectively improved spasticity and pain• Sativex also helped with urinary frequency

• Objective measures not significant

• Smoked cannabis• Data inadequate to determine safety/efficacy

Yadav V, Bever C, Bowen J, Bowling A, et. Al. Neurology 2014

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Cachexia and appetite stimulation

• 8 controlled studies in AIDS- or cancer-related cachexia• 3 studies of smoked marijuana (up to 67 patients)

• Others used dronabinol• Non-statistically significant weight gain, increase appetite, and

improve functional status• Megestrol 750 mg weight gain > dronabinol 5 mg

• Combo did not lead to additional weight gain• Cancer patient results were less consistent

Abramovici H. Health Canada 2013Timpone JG, Wright DJ, Li N, et. al. AIDS Res Hum Retro 1997

Post-Traumatic Stress Disorder

• A few RTC show improved symptoms

• Observational study >2200 Veterans from 1992-2011

• Never users, stoppers, continuing users and starters• Adjusted for covariates of baseline symptoms, drug &

alcohol use, violent behavior and employment • Marijuana use associated with worsening of PTSD

symptom severity, violent behavior, and alcohol & drug use

Wilkinson ST, J Clin Psychiatry 2015

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Seizures

• Uncontrolled case series in intractable childhood-onset epilepsy• CBD : THC ratio 20 : 1• Median monthly seizure frequency

• Baseline 30.0 (interquartile range [IQR] 11.0–96.0)

• After 12 week treatment 15.8 (IQR 5.6–57.6)

• Some weaned patient from another AED after starting CBD

• Adults case reports and patient surveysSeizure exacerbation with discontinuationGerman study no effect

Friedman D, Devinsky D, NEJM 2015Gloss D, Vickery B. Cochrane Database Syst rev 2014

Glaucoma

• Systemic administration of cannabis ↓ IOP by 30%

• Pilot study of 6 patients ↓ IOP for 2 hours

• Uncontrolled study 9 patients with open-angle glaucoma THC qid ↓ IOP

• Patients appeared to develop tolerance, and all discontinued the study

Flach AJ. Trans-American Ophthalmological Society 2012

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How would you respond to a 40 yo patient who asks you to help them use cannabis for cancer pain?


NIDA (http://drugabuse.gov/sciencefair/)

The patient asks “Are you worried I am going to get addicted?”

http://drugabuse.gov/sciencefair/

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Lifetime dependency risk with use

32%

Hall and Degenhardt. Lancet. 2009Strahny A. CBHSQ Report. 2013

23%17% 15%

9%

%

0

25

50

75

100

MJ addiction risk in teens

Brain development in adolescence

Limbic region• Immediate rewards

• Impulsive behavior

Cortex• Long term gain

• Thoughtful behavior

http://erichengelhardt.net/neuro-facts.html accessed 5/28/2013

A mother asks “Is cannabis going to fry my son’s brain?”

http://erichengelhardt.net/neuro-facts.html

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Meier MH, et al. Proc Natl Acad Sci. 2012

Persistent cannabis users show neuropsychological decline from childhood to midlife Prospective study of 1,037 individuals followed from birth

(1972/1973) to 38 years of age Within-person IQs :

Never used 100.64 Used, never regularly 101.24 Used regularly 90.77

Impairment of learning, memory, and executive functions

Effect on neuropsychological functioning

Chronic cognitive effects of cannabis

(A) Relation between amount of marijuana smoked2 and Repetition of Numbers Task, number

correct for the high Shipley IQ group (squares) and the low Shipley IQ group (circles). (B)

Relation between amount of marijuana smoked2 and performance on the Stroop task for the

high Shipley IQ group (squares) and the low Shipley IQ group (circles)

Bolla KI, et al. Neurology, 2002

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Pierre JM. Current Psychiatry. 2011

Multiple studies have demonstrated an increased risk of psychosis in THC users• 3 meta-analyses have shown an odds ratio of 1.4 to 2.9• Risk with cannabis use is up to 3 fold higher compared to those

who did not use cannabis• After control for a variety of confounding factors including

other drug use and socioeconomic variables

Cannabis and psychosis

Potential AEs from chronic cannabis useRespiratory Increased sputum production, wheezing, bronchitis

Potential increase in chronic bronchitis, emphysema, and airway

inflammation

Gastrointestinal Cannabinoid hyperemesis syndrome

Genitourinary Increased risk of failing a drug test

Reproductive Menstrual cycle disruption

Decreased sperm count

Impotence and decreased libido

May decrease lactation

Hematology/

Oncology

Potential increased risk of nasopharyngeal carcinoma

Potential for increased risk of lung cancer, however, data is inconclusive.

Many products may contain other carcinogens. Cannabis smoke contains

known carcinogens.

Metabolic/Endocrine Potential to increase insulin resistance in adipose tissue24

The patient asks “Are there other effects of cannabis besides in the brain?”

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Acute cardiovascular effects of THC

Heart rate HRV

• The variation in the time interval

between heartbeats (RR-interval)

• ↓ HRV is a predictor of mortality

after MI

L Zuurman, et al. Br J Clinical Pharmacology. 2008

Kaplan-Meier estimates of post-MI survival among 87

cannabis users and 174 propensity-matched nonusers.

Frost L, et al. American Heart Journal. 2013

Cannabis use and long-term mortality among survivors of AMI

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How would you respond to the patient who says “no one has ever died from using cannabis”?


THC dosing is known; but not known for other CBsTypical “effective” dosing of inhaled THC

• Low dose < 7 mg

• Medium dose = 7 – 18 mg

• High dose > 18 mg

There is a known tolerance to THC down regulation of CB1 receptors, and G-protein activation

High probability of tolerance with chronic use, and low with intermittent

Chronic = daily for a week, intermittent = weekly

L Zuurman, et al. Br J Clinical Pharmacology. 2008

The patient asks “I still want to try it…How much should I take?”

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PK profile of smoked THC

• Smoking cannabis turns ~50% of the THC content into smoke

• Up to 50% of inhaled smoke is exhaled again, and some undergoes localized metabolism in the lung

• Bioavailability of a inhaled dose of THC is between 10-25%

• Effects are perceptible within seconds and fully apparent in a few minutes

• Effects last about 3 hoursStrougo A, et al. J Psychopharmacology. 2008

A patient asks “How often should I take it?”

PK profile of oral THC

• Onset of effect is delayed: 1-3 hours due to slow absorption from the gut

• Bioavailability of THC after oral ingestion ranges from 5-20% in the controlled environment of clinical studies

• Weight, metabolism, gender and eating habits play a role in absorption

• Effects last about 6 – 12 hours

Agurell S, Halldin M, Lindgren JE, et al. Pharmacological reviews. 1986

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PK profile of oromucosal THC/CBD - Sativex

• One study did not find difference between oral THC capsules and oromucosal spray PK

• Peak concentration THC 1.5 hours

• Peak concentration CBD 1.3 hours

• 2-fold inter-patient variability in peak THC and CBD levels

Karschner EL, Clin Chem 2011

Further dosing considerations

• THC substrate of CYP3A4 & 2C9

• CBD substrate of CYP3A4 & 2C19

• Possible drug interactions• ↑ sedation, ataxia: CNS depressants, anticholinergics• ↑ heart rate: sympathomimetics• ↑ effects of: hexobarbital, hydrocortisone, clozapine,

phenytoin, warfarin• ↓ effects of: propofol, indinavir, theophylline

Horn JR, Pharmacy Times 2014

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Vaporizing cannabis plant or concentrate

• Same immediate effects and benefits as smoking• Heats 285 - 392°F vaporizing CBs• Conductive vs. convective heating

Images from: www.cannastick.com; https://spendabit.co/go?q=vape&offset=0 ; www.procon.org

Dabbing cannabis concentrates

• CBs are extracted by solvents

• Butane hash oil (BHO), dabs, earwax, butter or shatter

• >90% of CBs

• Superheat nail (with blow torch) and add dab

• Users quickly develop tolerance

Images from: https://www.zamnesia.nl/dabbing/2365-glazen-olie-bong-blaze-swirl.html

http://www.cannastick.com/

https://spendabit.co/go?q=vape&offset=0

http://www.procon.org/

https://www.zamnesia.nl/dabbing/2365-glazen-olie-bong-blaze-swirl.html

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Edible baked goods, candies, tinctures

• Edibles have CBs added, or are infused with CB butter, oil or alcohol

• Colorado 10mg serving size and 100mg maximum/package

• Doesn’t release toxins

• Discreetly consumed

• Must exit dispensary in child resistant packaging

• Now also prohibit edibles that resemble animals, people or fruit

Images from: http://www.leafscience.com/2015/10/27/beginners-guide-marijuana-edibles/

Cannabis infused creams, lotions and oils

• THC not charged, but lipophilic properties limit it getting to site of action

• Most products claim no psychoactive effects, so THC not getting absorbed

• Patch with occlusion and vehicle to enhance absorption

Images from: http://www.vaildaily.com/news/14759677-113/soaking-in-the-cannabis-what-topical-thc-products-can-dohttp://www.americanpharmaceuticalreview.com/Featured-Articles/170872-Lipids-in-Transdermal-and-Topical-Drug-Delivery/

http://www.leafscience.com/2015/10/27/beginners-guide-marijuana-edibles/

http://www.vaildaily.com/news/14759677-113/soaking-in-the-cannabis-what-topical-thc-products-can-do

http://www.americanpharmaceuticalreview.com/Featured-Articles/170872-Lipids-in-Transdermal-and-Topical-Drug-Delivery/

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So how can I help?

https://teens.drugabuse.gov/drug-facts/marijuana

C.R.S. 12-42.5-123. Unprofessional conduct -grounds for discipline

1) The board may suspend, revoke, refuse to renew, or otherwise discipline any license or registration ….

(c) Has violated:…(III) Any state or federal law pertaining to drugs;

https://www.colorado.gov/pacific/dora/Pharmacy_Laws

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Institutions carry risk for allowing cannabis use

• Because they are accredited through the Center for Medicare & Medicaid Services, hospitals could be found to be in violation, lose federal funding, and face penalties

• The Joint Commission Standard MM.03.01.05 policy states:

“The hospital safely controls medications brought into the hospital by patients, their families, or licensed independent practitioners.”

Borgelt LM & Franson KL. Hosp Pharm 2017,582(2):89-90.http://www.jointcommission.org/assets/1/6/Sample-Medications_HAP.pdf Accessed Dec 2016.


• Joint Commission Standard MM.03.01.05 includes the following elements of performance:

• The hospital defines when medications brought into the hospital can be administered

• Before use, the hospital identifies the medication and visually evaluates the medication’s integrity

• The hospital informs the prescriber and patient if the medication brought into the hospital is not permitted

http://www.jointcommission.org/assets/1/6/Sample-Medications_HAP.pdf Accessed Dec 2016.

http://www.jointcommission.org/assets/1/6/Sample-Medications_HAP.pdf

http://www.jointcommission.org/assets/1/6/Sample-Medications_HAP.pdf

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• The Washington Health Care Association template

http://www.whca.org/files/2013/04/sample-medical-marijuana-policy.pdf (Accessed Aug 2016)


• The institution may choose to access the cannabis product through the FDA’s expanded access (compassionate use) program

• This program allows access for an individual patient or more widespread use when the disease state is serious and a sponsor is actively developing the product

http://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm Accessed Aug 2016.

http://www.whca.org/files/2013/04/sample-medical-marijuana-policy.pdf

http://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm

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I believe that patients are most likely to access cannabis at my institution by:

A. Compassionate use processes

B. Following Joint Commission Standard MM.03.01.05processes

C. Changing law


Review today’s session

Provided information for you to guide patients & clinicians regarding the issues of

if, when, where, and how to use cannabis safely and,

in regard to therapeutic uses, effectively

Described the legal issues that arise when hospital patients are using cannabis lawfully under state laws

Documents

What to do when cannabis gets admitted€¦ · Hematology/ Oncology Potential increased risk of nasopharyngeal carcinoma Potential for increased risk of lung cancer, however, data