C O N F I D E N T I A L

Medical Utility of Cannabinoids

Department of Psychiatry Addict ions Update ConferenceUniversi ty Park Marr iott

June 1-2, 2017

PerryG.Fine,MDProfessorofAnesthesiology

PainResearchandManagementCenters

CANNABIS VS. CANNABINOIDS

• Cannabis– > 0.3% THC dry weight = marijuana– < 0.3% THC dry weight = hemp

• (Phyto)Cannabinoids– THC, CBD, many others

• Endogenous Cannabinoids– anandamide, many others

CANNABIS

ScientificClassification

Kingdom: Plantae

(unranked): Angiosperms

(unranked): Eudicots

(unranked): Rosids

Order: Rosales

Family: Cannabaceae

Genus: CannabisL.

Species

•Cannabissativa L.•Cannabisindica Lam.•Cannabisruderalis Janisch

PRE COMMON ERA

• 2000-3000 years ago– Relics from India, Egypt, China ascribe

medicinal value to cannabis• Neuralgia• Headache• Toothache• Pain of childbirth

COMMON ERA

• 1st century: “Materia Medica” by Greek physician Discorides, accompanying Roman army, describes analgesic benefits of cannabis

• 2nd century China: cannabis mixed with wine as a successful anesthetic for major surgery

• 2nd century: Galen describes analgesic properties of cannabis

MODERN ERA• George Washington reportedly used cannabis for

dental pain.• Napolean Bonaparte’s army physicians publish

articles extolling virtues of cannabis for pain.• 1850: Cannabis accepted into U.S. Pharmacopoeia:

many compounds marketed by mainstream pharmaceutical companies

• 19th and early 20th century temperance movement led to legal prohibitions

• 1937 Marihuana Tax Act• 1970 Controlled Substances Act

CANNABINOID PHARMACOLOGY

• The Endocannabinoid System: – Endogenous Receptors

• CB1: widespread throughout CNS except brainstem and some peripheral tissues

• CB2: widely distributed, including microglia– Role in immune function and inflammation

– Endogenous Ligands• Anandamide: first identified endogenous

cannabinoid receptor ligand

BIOLOGICAL ACTIONS MEDIATED BY CANNABINOID RECEPTORS

• Analgesia• Cognition and memory• Locomotor activity• Endocrine functions• Temperature control and heart rate• Nausea and vomiting• Intraocular pressure

CommonEndogenousandExogenousCannabinoidStructures

Δ9-tetrahydrocannabinol (THC) Cannabidiol (CBD)

Anandamide

AREAS WHERE THERE IS PRECLINICAL DATA SUGGESTING POTENTIAL THERAPEUTIC EFFICACY

• Pain• Epilepsy• Spasticity• Inflammatory Diseases (e.g. IBD, UC)• Adenocarcinomas (e.g. prostate)• Glycemic control (Type 2 and IDDM)• Myocardial preservation during ischemia

CLINICAL EVIDENCE BASE: MODEST EFFECT SIZE FOR CANNABIS AND CANNABINOIDS

• Adults with chemotherapy-induced nausea and vomiting

• Adults with chronic pain• Adults with MS-related spasticity• Children with intractable epilepsy

TheHealthEffectsofCannabisandCannabinoids:Thecurrentstateofevidenceandrecommendationsforresearch.NationalAcademiesofScience,EngineeringandMedicine,January2017

PERIPHERAL NOCICEPTOR HYPEREXCITABILITY AND SENSITIZATIONMechanisms Symptoms Targets

Hyperexcitability

Sensitization: Inflammation within nerves

Sensitization: Reduced activation threshold

Ectopic impulse generation; oscillations in dorsal root

ganglion

Cytokine release Spontaneous pain Cytokines, α3 glycine receptor

(CBD)

Heat allodynia or cold allodynia

Reduced threshold to heat or cold

TRPV1 receptor (anandamide)

Reduced threshold to mechanical stimuli

Static mechanical allodynia

Sympathetically maintained pain

Adapted from: Baron R. Nature Clinical Practice Neurology. 2006;2(2):95-106.; Mendell JR, et al. N Engl J Med. 2003;348(13):1234-1255.; Woolf CJ, et. al. Lancet. 1999;353:1959-1964. TCA = Tricyclic antidepressant; TNF- α = tumor necrosis factor- α; NSAID = Nonsteroidal anti-inflammatory drug; ASIC = Acid-sensing ion channel; TRPV1 = Transient receptor potential vanilloid 1

ASIC receptor

CB1, CB2 receptors, histamine and α receptors,

Reduced threshold to histamine or norepinephrine

Sodium channels, CB2 receptors

Spontaneous pain (shooting)

GABA-ergic or opioidergic interneurons decreased

Spontaneous pain (ongoing), dynamic mechanical allodynia, punctate

mechanical hyperalgesia

Amplification of C-fiber input, gating of Aβ-fiber and Aδ-fiber input

Spontaneous pain (ongoing), dynamic mechanical allodynia,

punctate mechanical hyperalgesia

CENTRAL DORSAL HORN HYPER-EXCITABILITYMechanisms Symptoms Targets

Central sensitization, increased synaptic transmission

Intraspinal inhibitory interneurons decreased

Changes in supraspinal descending modulation

CB1, CB2 receptors, µ, receptors, calcium channels

(α2-δ), NMDA receptors, NK1 receptors, sodium channels,

intracellular cascades

GABAB receptors or µ receptors

Inhibitory control (5-HT, noradrenaline) decreased

Spontaneous pain (ongoing), dynamic mechanical allodynia, punctate mechanical hyperalgesia

5-HT receptors, α2 receptor, CB1, CB2 receptors

Adapted from: Baron R. Nature Clinical Practice Neurology. 2006;2(2):95-106.; Mendell JR, et al. N Engl J Med. 2003;348(13):1234-1255.; Woolf CJ, et. al. Lancet. 1999;353:1959-1964. NMDA = N-methyl-D-aspartic acid; NK-1 = neurokinin; GABAB = Gamma-aminobutyric acid receptor – subtype B; 5-HT = 5-hydroxytryptamine (serotonin) receptor; α2 = alpha 2 adrenergic receptor

Amplification of C-fiber input, gating of Aβ-fiber and Aδ-fiber input

Spontaneous pain (ongoing), dynamic mechanical allodynia,

punctate mechanical hyperalgesia

GABA-ergic or opioidergicinterneurons decreased

Spontaneous pain (ongoing), dynamic mechanical allodynia, punctate

mechanical hyperalgesia

CANNABINOIDS AND NEUROPATHIC PAIN RAHN EJ, HOHMAN AG. NEUROTHERAPEUTICS 2009;6:713-37

• Chronic constriction injury• Partial sciatic nerve ligation• Spinal nerve ligation• Chemically-induced diabetic neuropathy• Chemotherapy-induced neuropathy• HIV-associated neuropathy• Demyelenation-induced neuropathy• Post herpetic neuralgia (PHN)

CLINICAL TRIALS OF CANNABINOIDS FOR NEUROPOATHIC PAIN

• HIV (n=50): Abrams et al• Chronic NP pain (n= 61) Notcutt et al, Karst et al• MS (n=875) Zajicek et al, Svendsen et al, Wade

et al, Rog et al• Brachial plexopathy (n=48) Berman et al• Peripheral neuropathy (n=125) Nurmmikko et al

PERIPHERAL NOCICEPTOR HYPEREXCITABILITY AND SENSITIZATIONMechanisms Symptoms Targets

Hyperexcitability

Sensitization: Inflammation within nerves

Sensitization: Reduced activation threshold

Ectopic impulse generation; oscillations in dorsal root

ganglion

Cytokine release Spontaneous pain Cytokines, α3 glycine receptor

(CBD)

Heat allodynia or cold allodynia

Reduced threshold to heat or cold

TRPV1 receptor (anandamide)

Reduced threshold to mechanical stimuli

Static mechanical allodynia

Sympathetically maintained pain

Adapted from: Baron R. Nature Clinical Practice Neurology. 2006;2(2):95-106.; Mendell JR, et al. N Engl J Med. 2003;348(13):1234-1255.; Woolf CJ, et. al. Lancet. 1999;353:1959-1964. TCA = Tricyclic antidepressant; TNF- α = tumor necrosis factor- α; NSAID = Nonsteroidal anti-inflammatory drug; ASIC = Acid-sensing ion channel; TRPV1 = Transient receptor potential vanilloid 1

ASIC receptor

CB1, CB2 receptors, histamine and α receptors,

Reduced threshold to histamine or norepinephrine

Sodium channels, CB2 receptors

Spontaneous pain (shooting)

GABA-ergic or opioidergic interneurons decreased

Spontaneous pain (ongoing), dynamic mechanical allodynia, punctate

mechanical hyperalgesia

Amplification of C-fiber input, gating of Aβ-fiber and Aδ-fiber input

Spontaneous pain (ongoing), dynamic mechanical allodynia,

punctate mechanical hyperalgesia

CENTRAL DORSAL HORN HYPER-EXCITABILITYMechanisms Symptoms Targets

Central sensitization, increased synaptic transmission

Intraspinal inhibitory interneurons decreased

Changes in supraspinal descending modulation

CB1, CB2 receptors, µ, receptors, calcium channels

(α2-δ), NMDA receptors, NK1 receptors, sodium channels,

intracellular cascades

GABAB receptors or µ receptors

Inhibitory control (5-HT, noradrenaline) decreased

Spontaneous pain (ongoing), dynamic mechanical allodynia, punctate mechanical hyperalgesia

5-HT receptors, α2 receptor, CB1, CB2 receptors

Adapted from: Baron R. Nature Clinical Practice Neurology. 2006;2(2):95-106.; Mendell JR, et al. N Engl J Med. 2003;348(13):1234-1255.; Woolf CJ, et. al. Lancet. 1999;353:1959-1964. NMDA = N-methyl-D-aspartic acid; NK-1 = neurokinin; GABAB = Gamma-aminobutyric acid receptor – subtype B; 5-HT = 5-hydroxytryptamine (serotonin) receptor; α2 = alpha 2 adrenergic receptor

Amplification of C-fiber input, gating of Aβ-fiber and Aδ-fiber input

Spontaneous pain (ongoing), dynamic mechanical allodynia,

punctate mechanical hyperalgesia

GABA-ergic or opioidergicinterneurons decreased

Spontaneous pain (ongoing), dynamic mechanical allodynia, punctate

mechanical hyperalgesia

DorsalHorn

BRAIN

THE “ANALGESIC FORMULARY” OF THE FUTURE

Descending Modulation

PeripheralSensitization

Central Sensitization

PNS

CannabinoidsLocal AnestheticsTopical AnalgesicsAnticonvulsantsTricyclic AntidepressantsOpioids

CannabinoidsAnticonvulsantsOpioidsNMDA-Receptor AntagonistsTricyclic/SNRI Antidepressants

CannabinoidsAnticonvulsantsOpioidsTricyclic/SNRI Antidepressants

SPINALCORD

CNS

C O N F I D E N T I A L

ADVERSE EFFECTS OF SHORT-TERM USE OF MARIJUANA

• Impaired short-term memory• Impaired motor coordination• Altered judgment• Risk of paranoia, psychosis (high dose)

Volkow ND et al. N Engl J Med, 2014; 37(23): 2219-2227

C O N F I D E N T I A L

ADVERSE EFFECTS OF LONG-TERM OR HEAVY USE OF MARIJUANA

• Addiction (9% overall; 17% adolescent initiation; 25-50% daily users)

• Altered brain development• Poor educational outcome• Cognitive impairment (lower IQ early use)• Diminished life satisfaction and achievement• Chronic bronchitis• Risk of chronic psychosis disorders in those predisposed

Volkow ND et al. N Engl J Med, 2014; 37(23): 2219-2227

REFERENCES FOR CLINICAL TRIALS

• Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007;68:515–21.

• Notcutt W, Price M, Miller A, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia 2004;59:440–52.

• Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003;290:1757–62.

• Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005;76:1664–9.

• Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 2004;329:253.

REFERENCES FOR CLINICAL TRIALS

• Wade DT, Makela PM, House H, et al. Long-term use of a cannabis based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 2006;12:639–45.

• Rog DJ, Nurmiko T, Friede T, et al. Randomized controlled trial of cannabis based medicine in central neuropathic pain due to multiple sclerosis. Neurology 2005;65:812–19.

• Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 2003;17:18–26.

• Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain 2004;112:299–306.

• Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, doubleblind, placebo-controlled clinical trial. Pain 2007;133:210–20.