Faculty/Presenter Disclosure

2018-03-12

‘Answering Questions about Medical Marijuana Use in Renal Failure Patients’

Patrick R. Mayo, BSc(Pharm), PhD, MTS Clinical Pharmacology/Pharmacometrics Clinical Pharmacist Palliative Care University of Alberta Hospital & Faculty of Pharmacy

• Faculty: Patrick R Mayo

• Relationships with commercial interests: – Grants/Research Support: University of Alberta – Speakers Bureau/Honoraria: None – Consulting Fees: Aurinia Pharmaceuticals Inc. Contravir Pharmaceuticals – Other: Employee of Alberta Health Services

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Medical Marijuana and the Renal Patient • What’s the current situation? • Is there biological plausibility for cannabinoid use in renal disease? • Review the clinical literature on efficacy and safety? (Short, even shorter in CKD!) • Is there a novel way to gather patient data for cannabinoid use in a non-prescription environment?

Medical Marijuana?

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Cannabis has by-passed scientific standard and has now entered mainstream medicine worldwide.

‘Medical’ Marijuana and The Renal Patient

Symptom Control Treatment of Renal Disease? • Fatigue • Fibrosis • Lack of Well-Being • Ischemia-Reperfusion Injury • Pruritus in Transplant • Anorexia • Decrease damage in AKI • Pain (neuropathic?)* • Anxiety • Glycemic control • Dyspnea • Nausea

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Disconnect Lines of Evidence

Basic Scientific Research

Clinical Evidence

Public Perception

Website Promises

Here are some of the benefits that CBD provides to kidney disease patients: •Enhanced kidney functions •Repair of the damaged organs through its anti-inflammatory effects •Relieved pressure and better sleep •Keeping the heart safe while maintaining the right cholesterol levels •Reduced blood pressure •Strengthened immune system thereby enabling the body to fight infections.

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WOW!

Conflation of Basic Science with Clinical Outcomes?

Reproduces some studies completely

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‘Information websites Usually culminate In ‘retail’ page

Website Promises

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Davison, Sara N., and Joseph S. Davison. "Is there a legitimate role for the therapeutic use of cannabinoids for symptom management in chronic kidney disease?" Journal of pain and symptom management 41.4 (2011): 768-778.

Symptom Burden • A role for marijuana is plausible • Evidence exists for neuropathic pain

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Rein, Joshua L., and Christina M. Wyatt. "Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD." American Journal of Kidney Diseases 71.2 (2018): 267-274.

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Rein, Joshua L., and Christina M. Wyatt. "Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD." American Journal of Kidney Diseases 71.2 (2018): 267-274.

Endocannabinoid Pharmacology

Two Main Endogenous Ligands

• Affinity for CB1 (Ki  61 – 543 nM) • CB1 (Ki  58 – 572 nM) • Affinity for CB2 (Ki  279 – 1940 nM) • CB2 (Ki  145 – 1400 nm) • TRPV1 • Concentrations ~ 800 x ANA • Orphan G-protein Coupled Receptors • Orphan G-protein Coupled Receptors

Promiscuous Binding or Experimental Errors?

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Current Working Hypothesis: Retrograde Signaling

Anadamide (AEA) 5 6 Fatty-acid amide Hydrolase (FAAH) 4 2-AG Monoacylglycerol Lipase (MGL) 1

2 3

CBD? CBD?

Transient receptor potential cation channel subfamily V member 1: AKA Capsaicin receptor, Vanilloid Receptor

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Cannabinoid Signalling in the Kidney

Park, Frank, et al. "Cannabinoids and the kidney: effects in health and disease." American Journal of Physiology-Renal Physiology 313.5 (2017): F1124-F1132.

Cannabinoid Signalling in the Kidney

Park, Frank, et al. "Cannabinoids and the kidney: effects in health and disease." American Journal of Physiology-Renal Physiology 313.5 (2017): F1124-F1132.

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Role of Endocannabinoids in Renal Physiology

CB1-Related CB2-Related • AEA diuresis • Proteinuria • Na+/H+ exchanger & • Agonists improve renal Na+/K+/Cl- cotransporter function in models of CKD inhibition in thick ascending • Agonists reduce markers of loop of Henle renal injury following • Proteinuria bilateral renal ischemia- • Antagonists improve renal reperfusion. function in models of CKD

Knockout Mice

All drugs seem to work in Knockout Mice!

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Approved Cannabinoids: What do we have? • Dronabinol: Withdrawn 2012 • Nabilone: N/V Post Chemo – Small Fibromyalgia Trial: Sleep Benefit – Neuropathic Pain? – Canada-wide shortage December 2017 • Tetranabinex/nabidiolex (THC/CBD-Like 1:1) SATIVEX- Buccal spray solution – Adjunctive relief of advanced cancer pain; & MS – neuropathic pain/spasticity – May decrease voids/day if urinary dysfunction

1. Nabiximols (Sativex) (CBD/THC 1:1) 2. Dronabinol (Marinol)* 3. Nabilone (Cesamet)

* Dronabinol no longer available in Canada

Meng, Howard, et al. "Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis." (2017): 1638-1652.

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Pooled Efficacy: Analgesia

Nabilone & Nabiximols

Nabilone

Nabiximols

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Central vs Peripheral Neuropathic Pain Central

Peripheral

EBM Clinical Evidence of Efficacy

Petit-Zeman, Sophie, and Louise Locock. "Health care: Bring on the evidence." Nature 501.7466 (2013): 160-161.

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Summary

1. Post-Chemo Nausea & Vomiting 2. MS Related Spasticity 3. Neuropathic Pain

Allan, G. Michael, et al. "Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms." Canadian Family Physician 64.2 (2018): e78-e94.

Evidence Says!

Allan, G. Michael, et al. "Simplified guideline for prescribing medical cannabinoids in primary care." Canadian Family Physician 64.2 (2018): 111-120.

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“Medical cannabis is a current reality and is here to stay”

Fitzcharles & Eisenberg (2018)

Fitzcharles MA, Eisenberg E. Medical cannabis: a forward vision for the children. European Journal of Pain. 2018. doi:10.1002/ejp.1185

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Clinical Trials Gov: 09March2018 • 655 trials in 488 Disease Conditions with marijuana • 1 Kidney Disease (Withdrawn: PK

Randomized Double Blinded Study Sativex)

Novel Drugs?

• AZ11713908 is a peripherally restricted full CB1R agonist and partial/inverse CB2R: Failed • Taranabant (MK-0364) for obesity due to its anorectic effects stopped in phase III depression and anxiety. • The CB1/CB2 receptor agonist AZD1940 did not reduce post- operative pain • BIA 10-2474: FAAH Inhibitor: 1 Dead, 4 Brain Damaged, 1 OK

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Novel Study Methods

• Internet-based randomized controlled trials • Establish a repository of data • Patients take a known product (CBD: THC standardized) • Pool results across province and Country in CKD patients

Mathieu, Erin, et al. "Internet-based randomized controlled trials: a systematic review." Journal of the American Medical Informatics Association 20.3 (2013): 568-576.

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Nof1 Trials?

• Double-blinded, multiple-crossover, comparative trials of effect. • Indicated whenever there is substantial uncertainty regarding the comparative effectiveness of different treatments. • More robust than a standard trial of a medication in a clinic. • Data can be pooled and statistically analyzed as case series, case-cohorts or other designs.

1. N-of-1 trials oﬀer a pragmatic approach to evidence based clinical practice. 2. Rather than forcing patients into an all or none fit with a rigid parallel group-based trial protocol, N-of-1 trials can be ﬂexible and adapt around the individual.

-from Vohra, Sunita, et al. "CONSORT extension for reporting N-of-1 trials (CENT) 2015 Statement." Journal of clinical epidemiology 76 (2016): 9-17.

Excellent Resource: Kravitz RL, Duan N, eds, and the DEcIDE Methods Center N-of-1 Guidance Panel (Duan N, Eslick I, Gabler NB, Kaplan HC, Kravitz RL, Larson EB, Pace WD, Schmid CH, Sim I, Vohra S). Design and Implementation of N-of-1 Trials: A User’s Guide. AHRQ Publication No. 13(14)-EHC122-EF. Rockville, MD: Agency for Healthcare Research and Quality; February 2014. www.effectivehealthcare.ahrq.gov/N- 1-Trials.cfm

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Conclusions • Mechanistic data suggests a role for THC:CBD in renal disease – Renal Regulation – Palliation of Symptoms • Paucity of Clinical Evidence • Adopting an novel trial strategies could allow for the systematic evaluation of marijuana products for patients with kidney disease.