Grants/Research Support: Allergan, Valeant, Lily, Merz Speakers Bureau/Honoraria: Allergan, CCIC/Bayer Consulting Fees: Allergan, Bayer, Biogen

Transcription

1 Grants/Research Support: Allergan, Valeant, Lily, Merz Speakers Bureau/Honoraria: Allergan, CCIC/Bayer Consulting Fees: Allergan, Bayer, Biogen Investments: Pfizer, Merck

2 Raise awareness of the use of medicinal cannabinoids in non-cancer pain and spasticity, including historical use Understand the clinical evidence of cannabinoids in the treatment of spasticity Knowing how to prescribe cannabinoids for spasticity and pain First evidence in China as medicinal use 3000BC for many ailments including rheumatic pains Medicinal use in Middle East, Southeast Asia, South Africa and South America

3 Athrava Veda- sacred text of Hinduism ( BC) referred to bhang sacred grass; uses included relaxant and analgesic The leaves of this plant cure flatus -I I believe that it is used in chronic pains.

4 New English Dispensary (1764) hemp roots to skin for inflammation used to relieve Queen Victoria s labour pains observed use in India 1839 found a tincture of hemp to be effective analgesic, muscle relaxant and anticonvulsant Provided cannabis to pharmacists in England in 1842

5 numerous articles written on therapeutic use of Cannabis indica including muscle relaxant analgesic Extracts of cannabis adopted into the British and then American Pharmacopeia 1915 Sir W Osler of migraines: Cannabis indica is probably the most satisfactory remedy

6 potency variable, short shelf life oral route eractic absorption availability of alternate Tx - Bayer produced Aspirin 1899, soon #1 drug worldwide smoking by certain classes of people earned reputation as drug of abuse Illegal in Canada in 1923 Marihuana Tax Act of 1937 (US) difficult to obtain for medical purposes opposed by AMA Removed from pharmacopeias British 1932, American 1941

7 Cannabinoids extracted from the Cannabis sativa L. plant (> 60) Most active: delta-9-tetrahydrocannabinol (Δ-9 THC), cannabidiol (CBD), and cannabinol (a breakdown product of THC 1 ) Effects of THC: analgesia, muscle relaxation, antiemetic, appetite stimulant and psychoactive agitation or depression 2 Effects of CBD: analgesia, anticonvulsant, muscle relaxation, anxiolytic, neuroprotective, anti-oxidant and anti-psychotic activity 2 1. Perez J. Drugs Today. 2006; 42 (8): Sativex Product Monograph. Bayer Inc, August 11, Toronto, ON Nabilone/Cesamet (synthetic analog THC) Dranabinol/Marinol (delta 9 THC) Sativex (THC/cannabidiol) Raw cannibis

8 Nitrogen analogue to THC, synthetic cannabinoid Onset mins, T1/ hrs Marketed in Canada, US, Europe, UK, Mexico as Cesamet Indicated for post chemotherapy nausea, and in the US for AIDS related anorexia Only in Mexico is pain indication Studies on fibromyalgia 1, pain from spasticity 2, neurogenic pain, spasticity in SCI 3 1 Skrabek RQ, Galimova L, Ethans K, Perry D (2008). J Pain 9 (2): Wissel J, Haydn T, Müller J, Brenneis C, Berger T, Poewe W, Schelosky LD. (2006). J Neurol. 253 (10): Pooyania S, Ethans K, Szturm T, Casey A, Perry D. Arch Phys Med Rehabil 2010 May;91(5): Oral capsule 0.25mg, 0.50 mg, 1.0 mg start with 0.5 mg qhs, slowly titrate to bid or tid as tolerated. May compound 0.25 mg syrup Maximum recommended dose is 6 mg/day Urine no THC excretion therefore safe for athletes

9 Marketed as Marinol Available in US, Canada, Germany, and others Indicated for post chemotherapy nausea/vomiting, and, in the US, for anorexia and wasting with AIDS 2.5mg, 5mg, 10mg capsules; start with 2.5 mg qhs and increase up to 10 mg bid or tid Onset mins, T1/2 4-6 hrs metabolites long T1/2 Onset hour, peak 2-4 hours, duration 4-6 hours, but the appetite stimulant effect of may continue for 24 hours or longer Tachyphylaxis and tolerance may occur Oromucosal spray 2.7 mg THC and 2.5 mg CBD per spray. Rest are minor cannabinoids, terpenoids, sterols, triglycerides and other plant components. Benefit is the synergistic interaction between CBD and THC, with a reduction in psychoactivity and enhanced cannabinoidmediated clinical effects. Oromucosal- helps avoid the high first pass effect associated with oral administration Approved in Canada for neuropathic pain and spasticity in multiple sclerosis and cancer pain, in Europe for spasticity in MS

10 Start: 1 spray every 4 h (maximum of 4 sprays on first day); increase as tolerated Average dose is 5-10 sprays/day; limited experience with doses higher than 12 sprays/day, high interpatient variability Directed to below the tongue, or towards the inside of the cheeks. The site should be varied. onset mins, duration 6-8 hours Dizziness 46 %, reduces to 23% longterm 24 1 year 20 Sprays per Day n=80 n=80 Median Study Week Note: Error bars represent +/- standard error 1. Adapted from Wade et al. Mult Scler. 2006; 12:

11 Most frequently reported adverse events during clinical trials: vertigo diarrhoea dry mouth nausea asthenia fatigue application site reaction disturbance in attention dizziness, somnolence Disorientation Addiction potential of nabilone low, street value nonexistent 1. Sativex Product Monograph. Bayer Inc, August 11, Toronto, ON Onset mins, peak achieved end of smoking, rapid decline in 30 min 20-60% bioavailability much higher peak plasma concentrations than oral much shorter duration of effect than oral

12 Chong et al. Mult Scler 2006; 12: ; Wade et al. Mult Scler 2006; q12: ; Aldington et al. Eur Resp J 2008; 31: ; Potter et al. J Forensic Sci 2008; 53: 90-4.

13 Largely smoked- increases the risk of lung cancer, heart disease 3 x higher tar than cigarette, 5 x higher carboxyhemoglobin, 50% higher content procarcinogens difficult to control dosing most human data for medical use derived from open, uncontrolled studies and case reports Smoked cannabis is not appropriate as a medicine

14 The Evidence

15 Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain, 2008 Feb;9(2): DBRPCT, 40 subjects, 4 week rx decreased VAS (-2.04, P<.02), FIQ (-12.07, P<.02), and anxiety (-1.67, P<.02) in the nabilone treated group at 4 weeks cf placebo Spasticity is a common symptom of SCI and MS Prevalence is up to 84%, ranging from minimal to severe 1 Can be problematic in many realms: affecting ambulation, transfers, seating, dressing, and can cause pain, interfere with hygiene, and make nursing care difficult It is often spasticity, rather than weakness, that causes much of the disability affecting lower limbs in people with MS and in incomplete SCI 1. Rizzo et al. Mult Scler. 2004; 10 (5):

16 Inter-disciplinary: physiatrists (or neurologist with rehab focus), physiotherapists, occupational therapists, nurses, orthotists, the patient and their care-givers Obtainable goals need to be identified by patient, caregivers, and team. If there are no significant spasticity related problems or any reasonably obtainable goals, then treatment not needed Physical and pharmaceutical management, as well as education and setting realistic goals, all used together Different strategies may be required at different disease stages eg MS

17 Current medications for spasticity include: baclofen, tizanidine, dantrolene, botulinum toxin, anticonvulsants, benzodiazepines, and cannabinoids No one medication is first line - based on patient presentation Generalized problematic spasticity- baclofen or tizanidine usually first-line. Focal problematic spasticity -botulinum toxin/phenol Medications introduced one at a time, at low doses, gradually work up, with instructions on when to stop increasing when side effects become intolerable or benefits are acceptable Intrathecal baclofen can be considered in severe, problematic spasticity when other therapies have failed or are intolerable Ashworth scale: Developed by Ashworth in 1964 and modified by Bohannon in ,2 reliable and well-validated measure of spasticity 3 However, limitations - it is too insensitive to identify small but clinically significant effects of medications 4 Numerical Rating Scale: Validated, 0 10, patient self-reported scale measuring the severity of spasticity 5,6 20% improvement is the minimum clinically important difference, 30% improvement representing much improved 5,6 1. Ashworth. Practitioner. 1964; 192: Bohannon et al. Phys Ther. 1987; 67: Nuyens et al. Clinical Rehabilitation. 1994; 8: Zajicek et al. Lancet 2003; 9395: Farrar et al. Clin Ther. 2008; 30: Anwar et al. NeuroRehabilitation. 2009; 24:

18 Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study) Zajicek et al/uk MS research Council, The Lancet 2003;362: RPCT n=630; oral cannabis, placebo and THC Ashworth primary outcome No significant change in Ashworth (10 muscle groups) Patient reported significant improvement in spasticity, spasms, and pain in both oral extract and THC (p=0.003) Felt by medical community that wrong primary measure reason for negative trial Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler. 2004, Vaney et al DBRPCT crossover, 57 subjects Measures: daily self-report of spasm frequency and symptoms, Ashworth Scale, Rivermead Mobility Index, 10-m timed walk, nine-hole peg test, paced auditory serial addition test (PASAT), and the digit span test. RESULTS: no statistically significant differences, trends in favour of active treatment seen for spasm frequency, mobility and getting to sleep. 37 patients received at least 90% of prescribed dose, improvements in spasm frequency (P = 0.013) and mobility were seen (P = 0.01).

19 Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial. Wissel et al. J Neurol Oct;253(10): DBRPCT crossover trial 11 subjects The 11-Point-Box-Test -significant decrease in pain on nabilone (p < 0.05), while spasticity, motor function and activities of daily living did not change Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol Mar;14(3):290-6, Collin C et al Sativex 124 pts, placebo 65 pts, DPRPCT 6 weeks daily subject-recorded Numerical Rating Scale of spasticity (p<0.045) Mean sprays/day: 9.4 MAS, subjective measure of spasms NS 8 dropouts, 6 active tx, 2 placebo NRS for Sativex: reduction of 1.18 points versus placebo (P=0.048) Sativex: 40% showed a 30% reduction in NRS spasticity compared with 21.9% on placebo (P=0.014)

20 The treatment of spasticity with Delta9- tetrahydrocannabinol in persons with spinal cord injury. Spinal Cord. Hagenbach et al 2007 Aug;45(8): tx d THC, 7 placebo 1) spasticity sum score (SSS) using MAS decreased from to 8.92 (p<0.001 cf placebo) 2) self-ratings of spasticity no comment in abstract Pooyania S, Ethans K, Stzurm A, Casey A, Perry D. Arch Phys Med Rehabil 2010 May;91(5): DBRPCT cross-over pilot, 11 subjects Primary outcome -Ashworth of selected most spastic muscle group- significant decrease on active treatment, mean difference of (SD=0.85, p=0.0039). Secondary Total Ashworth score (p=0.0010). VAS (p=0.0762), global impression, pendulum no difference

21 Sativex, MS spasticity Collin et al. Neurological Research. 2010; 32 (5): Sativex (n=167) vs placebo (n=170), 14 weeks, max 24 sprays/day Primary endpoint: 0-10 NRS change from baseline Secondary endpoints: Responder analysis= 30% improvement Timed 10-m walk test Barthel ADL CGIC NRS for: spasms, pain, fatigue, tremor, bladder symptoms, sleep Ashworth Two QoL

22 ITT: NRS for Sativex: reduction of 1.05 points versus placebo: 0.82 points (P=0.219) PP (79% of study population): NRS for Sativex: reduction of 1.30 points versus placebo: 0.84 points (P=0.035) Most common reason for exclusion from ITT: early termination of treatment with poor response Pos hoc analysis: Most spasticity responders had 30% improvement in NRS for fatigue, spasms, bladder, tremor, pain and sleep 35 40% of subjects will see a 30% or more improvement in spasticity when taking Sativex subjects who achieve a 20% response in the first 4 weeks of treatment are highly likely to eventually experience an ongoing improvement of 30% or more Novotna et al. Eur J Neurol Multicentre, Phase III, randomized, doubleblind, placebo controlled EDSS =6.0, baseline NRS Enriched study design utilising a single blind responder analysis in Phase A All remained on their existing medications throughout the study 572 enrolled, 272 responders (>20% improvement), 300 non-responders 241 randomised, 124 Sativex, 117 placebo

23 Phase A Sativex Phase B Sativex or Placebo Mean spasticity 0-10 NRS (±SE) Screening Baseline Study period (week) Sativex Placebo Endpoint P= Adapted from Novotna et al. Eur J Neurol. 2011; epub Endpoint Sativex (%) Placebo Difference P-value NRS 30% responder Spasms frequency Sleep disruption NRS < % Confidence Interval Lower Upper Difference P-value Barthel ADL index SGIC CGIC-impression of function PGIC ADL: Activities of daily living; SGIC, CGIC and PGIC: Subject, caregiver and physician global impression of change, respectively

24 Zajicek JP et al. MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry (2012). doi: /jnnp , online July 12, 2012 Tetrahydrocannabinol 5-25 mg (144) extract versus placebo (135) Patients' assessment of change from baseline: Relief from muscle stiffness after 12 weeks was 29.4% vs 15.7%, p.0.004, also significant for body pain, spasms and sleep quality Spasticity is a major contributor to disability in MS and SCI and can have a detrimental effect on quality of life Patients often respond to cannabinoids as addon therapy, and statistically significant and clinically relevant improvements in spasticity were seen in these patients in a relatively short period of time However based on the Sativex studies, it would only be the patients who respond to a four week trial that would be eligible to continue with their cannabinoid Fibromyalgia patients have significant pain reduction with Nabilone

25 1.A nerve impulse reaching the synapse stimulates the release of neurotransmitters (the yellow molecules). These cross the synapse and bind to receptors on the post-synaptic cell, initiating a series of events. 2.One of these events is the release of endocannabinoids (the red molecules) which are released locally, crossing the synapse in the opposite direction of the nerve impulse. 3.The endocannabinoids bind to pre-synaptic CB 1 receptors (the light blue receptors) inhibiting the release of further neurotransmitters, whether the neurotransmitters are inhibitory (e.g., GABA) or excitatory (e.g., glutamate). This is an example of negative feedback system. 4. Phytocannabinoids mimic the action of these endocannabinoids. In this way, they are able to augment the effect that endocannabinoids have in regulating the transmission of impulses from one nerve to another. CNS forum. Cannabinoid receptors 2009.

26 Dronabinol ( mg) Medical cannabis (12.5% THC) Nabilone ( mg) Cannabinoids in Canada* Oral capsule; start with 2.5 mg qhs and increase up to 5 mg bid Approved for chemotherapy-induced nausea and vomiting and anorexia associated with HIV/AIDS Authorized use via Marihuana Medical Access Regulations (MMAR-Health Canada) Average 2 grams per day (4 joints) Not formally approved as prescription drug (NOC) Oral capsule; start with 0.5 mg qhs, slowly titrate to bid as tolerated Maximum recommended dose is 6 mg/day Approved for chemotherapy induced nausea and vomiting Availability and Cost 2.5 mg capsule: $2.05/dose 5.0 mg capsule: $4.10/dose Cost $5/gram Availability and Cost 0.25 mg capsule: $1.64/dose 0.50 mg capsule: $3.29/dose 1.0 mg capsule: $6.58/dose THC/CBD (2.7 mg THC mg CBD) Oromucosal spray; start at 1 spray every 4 h to a maximum of 4 sprays on first day; increase as tolerated Average dose is 5 sprays/day; limited experience with doses higher than 12 sprays/day Approved for neuropathic pain and spasticity in multiple sclerosis and cancer pain Availability and Cost $2.72/dose *Statements on medical cannabis from provincial and territorial licensing bodies and coverage status on provincial formularies in Canada are listed on the CCIC website, 1. Cesamet Product Monograph, Valeant Pharmaceuticals., Marinol Product Monograph, Solvay Pharma., Sativex Product Monograph, Bayer Inc, Clark AJ et al., 2005.