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/Presenter Disclosure • 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 1 2018-03-12 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? 2 2018-03-12 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 3 2018-03-12 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. 4 2018-03-12 WOW! Conflation of Basic Science with Clinical Outcomes? Reproduces some studies completely 5 2018-03-12 ‘Information websites Usually culminate In ‘retail’ page Website Promises 6 2018-03-12 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 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. 7 2018-03-12 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. 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. 8 2018-03-12 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? 9 2018-03-12 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 10 2018-03-12 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. 11 2018-03-12 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! 12 2018-03-12 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. 13 2018-03-12 Pooled Efficacy: Analgesia Nabilone & Nabiximols Nabilone Nabiximols 14 2018-03-12 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. 15 2018-03-12 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. 16 2018-03-12 17 2018-03-12 “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 18 2018-03-12 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 19 2018-03-12 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. 20 2018-03-12 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 21 2018-03-12 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. 22.