Sylvia C. Bagge, RN, BSN, PHN

Kaiser Permanente Hospice Department,

Oakland, California 2000-2006

Maitri AIDS Hospice, San Francisco,

California 2006-2012

ACMPR Certified (March 2017 Academy of

Applied Pharmaceutical Science, Toronto)

1

The Potential of Cannabinergic Medicines

For Symptoms Associated With The “Difficult

Road” At End-of-Life

copyright©sylviacbagge.20

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NIGHTINGALEINTELLIGENCE.COM 2

Learning Objectives

Review model of the “usual road” v. the “difficult road” associated with the dying process (Freemon 1981)

Identify clinical contexts in which PST is associated with sub-optimal outcomes, resulting in an on-going occurrence of refractory symptoms

Name the five functions of the endocannabinoid system (ECS), and define endocannabinoid (eCB) tone

Identify neuroprotective actions of ECS, and the evidence–base for potential investigation of cannabinergic compounds to address refractory symptoms at end-of-life

Identify factors of safety, effectiveness, and access, relative to the use of cannbinergic compounds with an end-of-life population

3

Abbreviations used in this

presentation:

endocannabinoid system (ECS)

endocannabinoid (eCB)

Palliative sedation therapy (PST)

Blood brain barrier (BBB)

4

Freemon, F.R. (1981). Delirium and organic psychosis. In: Organic

mental disease. Jamaica, NY: SP Medical and Scientific Books,

81–94.

THE USUAL ROAD

normal to sleepy,

lethargic, obtunded,

semicomatose,

comatose, and finally,

death

THE DIFFICULT ROAD

normal to restless,

anxious, tremulous,

cognitively impaired,

with possible

hallucinations, delirium,

myoclonic jerks,

seizures, and finally,

coma followed by

death 5

Incidence of the “difficult road” at end-of-life

Sue Haig (2009) estimates 25% to 80% of patients experience terminal agitation at end-of-life.

De La Cruz et al. (2015) report delirium in half of the patients with cancer that were admitted to an acute palliative care unit at Grey Nun’s Hospital in Edmonton, Alberta.

Lawlor et al. (2000) report the presence of terminal delirium in 88% of patients dying from cancer.

A 2010 study of high-grade glioma patients by Sizoo et al. examined symptoms during the dying process, and reported seizures in 45% of those patients. The same study also reports 52% of patients experiencing seizures at end-of-life had greater than one episode of seizure activity, 11% of patients who had been seizure-free throughout their course of illness had their first seizure at end-of-life, and 7% of patients died during seizure activity.

Tradounsky (2013) reports that patients with slow-growing primary brain cancers, such as Oligodendrogliomas, and low-grade astrocytomas, have a very high risk for seizures, with a prevalence of 70-100%. 6

Conditions other than cancer in which the

“difficult road” is a common problem, based

upon this presenter’s experience:

Long-term AIDS diagnosis

Long-term history of crack-cocaine use

Long-term high doses of opioid medicines

Long-term treatment with anti-psychotic medicines

End-stage liver disease

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Current medications, including the option of PST for

refractory symptoms, effectively manage symptoms

associated with the “difficult road” for most individuals.

Although the literature expresses that it should not be an

option of first choice (Henry 2016, Maltoni et al. 2014), PST

is now widely used to address refractory symptoms at

end-of-life. Since its emergence as an intervention during

the 1990’s, and its official acceptance by the American

Medical Association in 2008, PST has significantly improved

end-of-life outcomes.

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PST is not always successful and/or effective. A 2008 literature review reveals

a palliative sedation effectiveness rate of 74%-91%, as measured by

perception of clinicians and family members (Claessens et al. 2008). A 2017

study of 1181 home deaths by Pype et al., report 63 palliative sedations, with

11 of these resulting in a suboptimal outcome.

Unsuccessful PST is defined as not achieving sufficient sedation (required

doses can be difficult to deliver in home and acute-care settings due to

issues such as (1) IV and subcutaneous routes being problematic for some

individuals at end-of-life, and (2) benzodiazepine tolerance is not

uncommon at the end of a long course of illness).

Ineffective PST occurs in situations where it appears that sufficient sedation

has been achieved, but break-through symptoms still occur, such as

involuntary movement/jerking, twitching, and hiccups.

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New medicines are needed to address persistent symptom-

management problems at end-of-life. If the number of options

available for symptom control at end-of-life is increased, the

ability of clinicians to individualize care will be expanded.

“Even with the optimal use of current medications, symptom-control is still unacceptable for

many people. Currently available medications offer great benefit to a minority of patients,

some benefit to an additional group, and no benefit or harm to others. In symptom-control,

development of new drugs is advancing at a glacial pace, contrasting to the rapid

advances seen in many other disciplines……New therapies are needed requiring an accelerated effort to investigate further the pathophysiology, neurobiology, and

pharmacogenetics of distressing symptoms, and factors contributing to variations in drug

response (p.533).

Currow, D.C., Abernathy, A.P., Fallon, M., & Portenoy, R.K. (2017). Repurposing Medications For Hospice/Palliative Care Symptom Control Is No Longer Sufficient: A Manifesto For Change.

Journal of Pain and Symptom Management, 53(3), 533-539.

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How can the numbers of individuals experiencing the “usual road”

at end-of-life be increased?

Individuals that experience the “usual road” are able to endure the

dismantling of homeostatic control systems without the triggering of

symptomatic events. These individuals are able to maintain a “death

associated dynamic equilibrium” (DADE) in the context of expected insults,

such as drug toxicities, sepsis, tissue-trauma, hypoxia, and intracranial

pressure.

Individuals with cancer and other conditions associated with long-term

dysregulation, including structural changes to brain/CNS tissues, come to

the dying process with a disadvantage. For this group, the dismantling of

homeostatic control systems is already in progress. 11

The therapeutic effects of cannabis and other

cannabinergic plant compounds are accomplished

indirectly, via the effects of the endocannbinoid

system (ECS).

The interaction of cannabinergic compounds with

the ECS increases endocannabinoid (eCB) tone,

which in turn, augments a particular set of protective

and regulatory mechanisms. The overall functions of

the ECS were summarized by Di Marzo, Melck,

Bisogno, & De Petrocellis (1998) as “relax, eat, sleep,

forget and protect” (p. 528). This summary continues

to be widely accepted and cited.

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ECS cheat sheet:

Components of the ECS include:

Endocannabinoids Anandamide (AEA) (Devane et al. 1992), and 2-Arachidonoylglycerol

(2-AG) (Mechoulam et al. 1995). The level of their activity establishes a basal

endocannabinoid tone, such as with neurotransmitters. The concept of eCB tone was

introduced by Ethan Russo in 2001 as the causative factor in a proposed condition called “Clinical Endocannabinoid Deficiency.” This condition associates certain diseases and

symptoms with decreased eCB tone. The concept of eCB tone is now widely accepted,

and its meaning and implications have been refined (Howlett et al. 2011).

ECS receptors CB1 (largely in CNS)(Devane et. al. 1988), and CB2 (largely in periphery/immune system, except in the context of CNS trauma) (Munro et. al. 1993).

Other less-studied receptors are under investigation.

eCB tone is also regulated by the degrative enzymes fatty acid amide hydrolase (FAAH),

and monoacylglycerol lipase (MAGL), specific to AEA and 2-AG respectively (Long et. al. 2009). FAAH and MAGL have been investigated as potential targets for drugs aimed

increasing endocannabinoid tone in order to achieve a therapeutic outcome, such as

modulation of pain and inflammation (Ahn et al. 2008, Petrosino et al. 2009).

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The ECS can be targeted by:

compounds in cannabis

compounds in plants other than cannabis. Beta-

caryophyllene, A Phytocannabinoid Acting on CB2 Receptors, presented by Zimmer et al., at the IACM 5th

Conference on Cannabinoids and Medicine

synthetic cannabinoids developed for research and

medicine

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The neuroprotective Effects of the ECS may be

well-matched to the challenges associated with

the “difficult road.”

protective against secondary pathways of

damage

reduces neuropsychiatric symtoms (2 ECS

mechanisms)

protection of the blood brain barrier

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WHY PROTECTING AGAINST SECONDARY PATHWAYS OF

DAMAGE MIGHT BE BENEFICIAL AT END-OF-LIFE

Trauma resulting from a head-injury and trauma resulting from a stroke

share similar pathways of secondary damage (Leker & Shohami 2002).

These chemicals also play a role in the dying process.

Prevention of secondary pathways of damage with a neuroprotective

agent has been shown to minimize the sequalae of head trauma

(Mechoulam et al. 2002).

Within the dying process, trauma and tissue-injury are expected, and

protecting against secondary pathways of damage may minimize the

slippery slope of CNS-excitement and dysregulation that create the

conditions for additional symptomatic events to occur.

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Secondary pathways of damage: glutamate

“Excitability in the human CNS is predominantly mediated by glutamate

and recent compelling evidence points to the role of glutamate in

excitotoxic damage resulting in seizures..” (Santosh & Sravya 2017).

the ECS plays a central role in the dampening down of glutamate

activity in excitotoxic neurons (Parker 2017; Russo 2016a)

CB1 receptors are located directly on Glutamatergic neurons (Howlett et

al. 2002).

ECS plays a role in modulation of seizure threshold, and severity of seizure

activity (Wallace et al. 2002).

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Secondary pathways of damage: inflammation

CB2 receptors are associated with an anti-inflammatory effect, and are

normally found mainly in peripheral tissues of the immune system

In the presence of inflammation/trauma, CB2 receptors that are normally

found mainly in peripheral tissues, express on cells of brain and nervous tissue

(Atwood & Mackie 2010; Benito et al. 2008; Maresz et al. 2005; Pertwee 2008;

Golech et al. 2004).

These CB2 receptors provide neuroprotection via the inhibition of

proinflammatory chemicals, and reduction of leukocyte chemotaxis into the

brain (Pancher & Hasko 2008).

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Neuropsychiatric symptoms: cognitive impairment

The ECS may be very helpful for end-of-life symptoms associated with a

neuroinflammatory component. The role of neuroinflammation in

neuropsychiatric illness has been established, and the literature suggests

that cannabinoids may improve symptoms in this context.

Najjar et al. (2013 )state that “multiple lines of evidence support the

pathogenic role of neuroinflammation in psychiatric illness.” (p.1).

Pre-clinical studies show improvement of neuropsychiatric symptoms with

cannabinoids in the context of neuroinflammatory conditions such as

Alzheimer’s disease (Aso & Ferrer 2016; Scotter et al. 2010), Parkinson’s

disease (More & Choi 2015), and AIDS-associated neurodegenerative

disease (Benito et al. 2008).

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Neuropsychiatric symptoms: anxiety/panic/fear

The ECS modulates adaptation to, and integration of, fear, anxiety and stress. Lutz, Marsicano, Maldonado & Hillard (2015) write:

“The endocannabinoid (eCB) system has emerged as a central integrator

linking the perception of external and internal stimuli to distinct

neurophysiological and behavioural outcomes (such as fear reaction,

anxiety and stress-coping), thus allowing an organism to adapt to its

changing environment. eCB signalling seems to determine the value of fear-

evoking stimuli and to tune appropriate behavioural responses, which are

essential for the organism's long-term viability, homeostasis and stress

resilience; and dysregulation of eCB signalling can lead to psychiatric

disorders (p. 705).”

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Integrity of the blood brain barrier & cerebral edema

Steroids provide significant improvement for many, and relief for some, but a

modulator of the blood-brain barrier (BBB) during the dying process may

improve outcomes for this group of individuals.

The ECS is a modulator of the BBB:

Raphael Mechoulam (2010) reports that 2-AG reduces cerebral edema and

inflammation following trauma to brain tissue by regulating the influx of

proinflammatory molecules such as cytokines, reactive oxygen intermediates,

and glutamate into brain tissue through the BBB.

Fujii et al. (2014) report that CB1 receptor activity reduces cerebral edema by

minimizing infiltration of leukocytes through the BBB following brain injury in an

animal model.

Hind et al. (2015) report in vitro evidence that endocannabinoids provide

protection in the context of stroke through a number of mechanisms, and

additionally may be important in normal BBB physiology. 21

Three concluding thoughts regarding cannabis for

an end-of-life population