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Learning objectives

MEDICAL MARIJUANA IN CHRONIC NEUROPATHIC PAIN Amy Wong BScPhm-PharmD Student August 15, 2012

• Describe the pharmacology of cannabis • Describe the differences in pharmacokinetics between smoked and oral forms of cannabis • Describe the long-term complications from use of cannabis • Define and describe the characteristics of neuropathic pain • Describe access to medical marijuana from Health Canada • Evaluate the place in therapy of cannabis-derived products in neuropathic pain

PMHx

Meet our patient

• Previous back injuries and surgeries with poor recovery • No other conditions

• 37 yo female • 2006: injured low back at work after falling off a chair • 2011: referred to pharmacists to review medication use and optimize pain management ▫ Diagnosed with chronic pain disorder ▫ Chronic severe major depressive disorder

Medication review Current medication

Indication

Approx. start date

Comments

M-Eslon 50mg qAM then 30mg BID

Low back pain

June 2012

-rotated from hydromorphone -rates pain with meds at 78/10 -pain control fluctuates according to activities -MED = 135-140mg

Neuropathic pain

Feb. 2012

-dose increased recently

Venlafaxine 225mg Neuropathic pain, QD mood

Dec. 2011

-mood is better; less tearful

Statex 5mg/tab -takes 5-6 tabs/day Pregabalin 100mg TID

Medical marijuana?

Neuropathic pain?

Social Hx • Current smoker: ½ pack cigarettes/day • Smokes 4-6 joints of marijuana/night ▫ Mood, sleep and pain • Mixes marijuana in the butter and uses it prn when increased leg pain

Physical Exam • Peripheral neuropathic pain in back and legs ▫ shooting, burning, pins/needles sensation • Requires walker for assistance

Medical marijuana in Canada • Marijuana Medical Access Regulations • Compassionate end-of-life care or symptoms associated with: ▫ MS, spinal cord injury/disease, cancer, HIV/AIDs, epilepsy, severe arthritis ▫ debilitating symptoms of other medical conditions

• License to possess and produce marijuana or have someone grow it for you Health Canada. Medical Use of Marijuana

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Neuropathic pain

Cannabis sativa

• Pain initiated or caused by a primary lesion or dysfunction in the nervous system • Clinical characteristics: ▫ Spontaneous pain  burning, tingling, shooting, numbness, weakness

▫ Stimulus evoked pain

▫ Marijuana: dried leaves/stalks/flowers/seeds ▫ Hashish: resin secreted by plants ▫ Hashish oil: product of extraction from resin by organic solvents

• Contains over 60 cannabinoids

▫ ∆9-THC: main psychoactive compound

 allodynia, hyper and hypo-esthesia, dysesthesia

• Peripheral or central pain syndromes International Association for the Study of Pain

• Concentration of THC varies depending on preparation ▫ Joint = 6-20% THC ▫ Hashish oil = 15-30% THC

Brands B et al. Drugs & Drugs Abuse

Pharmacokinetics

Pharmacology • Acts on cannabinoid receptors ▫ CB1-R are found throughout brain ▫ CB2-R are found in immune cells

• Short-term dose-related effects ▫ ▫ ▫ ▫ ▫ ▫

• Marijuana, hashish and hashish oil are obtained from the plant Cannabis sativa

Disinhibition, relaxation, sedation Euphoria Impairment of short-term memory and concentration ↑ HR, orthostatic hypotension Bronchodilation ↑ appetite

Smoked cannabis

Oral cannabis

Absorption

50% of the THC in a joint

25-30% of a smoked dose (1st pass metabolism)

Onset of action

minutes

0.5-2 hours

Duration of action

2-3 hours

prolonged (slow absorption from gut)

Distribution

neocortical, limbic, sensory and motor areas

-extremely lipophilic -peak concentration in 4-5 days

Metabolism

-by liver into 20+ metabolites with long t1/2 -some active metabolites

Elimination

-t1/2 = 7 days -complete elimination = 14- 30 days -metabolites 25% excreted into urine, 65% back into gut

Brands B et al. Drugs & Drugs Abuse

Clinical question P I C O

Adult patients with peripheral neuropathic pain Smoked cannabis Standard of care (adjuvant medications) 1) Efficacy in pain relief as per VAS, NRS 2) Safety

Ashton CH. Pharmacology and effects of cannabis

Goals of therapy • Reduce burning, shooting, pins/needles sensation to a level that allows for daily function • Reduce pain by 30% on NRS • Prevent long-term opioid-related complications ▫ Endocrine abnormalities, increased disability, opioid-related hyperalgesia

• Prevent additive CNS adverse events from medications and marijuana • Prevent mood from worsening

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Literature search

Guidelines

• Search terms: ▫ Medical marijuana, smoked cannabis, cannabinoid, nabilone/Cesamet, Sativex, neuropathic pain

• Restricted to RCTs, systematic reviews and meta-analyses • PubMed, Medline, Embase, Cochrane database, neuropathic pain guidelines

Ware et al – smoked cannabis • RC, DB, PC, 4-period crossover (each period = 5d study drug +9d washout) • N= 23 P

    

I

 C

Neuropathic pain ≥3mo caused by trauma or surgery with allodynia or hyperalgesia Mean baseline pain score =68.9mm on 100mm VAS 61% on concurrent opioids, 52% on antidepressants and 43% on anticonvulsants 82% have used cannabis in the past 25mg caps ranging in 3 different potencies of THC: o 2.5%, 6%, 9.4% Each capsule was opened, lit and smoked via pipe TID

• 2007 Canadian Pain Society Guidelines for Chronic Neuropathic Pain: ▫ Cannabinoids are 4th line agents ▫ Mentions use of Sativex (THC:CBD) buccal spray based on study in pain due to multiple sclerosis

• No mention in 2010 Neuropathic Pain Special Interest Group (NeuPSIG) guidelines

Outcomes 9.4% THC

*only 9.4% THC was statistically significant vs placebo

Placebo

Difference

P-value

Confidence Interval

0.023

0.02 - 1.4

50% of pts were able to identify the period in which they were on 9.4% THC and the placebo period ▫ Unblinding ▫ Final adverse effects report completed at the end

• No dose titrations allowed even though duration of analgesic effect of smoked cannabis is 2-3h

Prescription cannabis-derived products Sativex

Cesamet

Active Ingredients

THC & Cannabidiol

Nabilone

Approved indications

-spasticity related to MS -neuropathic pain related to MS -cancer pain

-cancer-induced nausea and vomiting

Dosing

-initial: 2 sprays/day -usual: 4-8 sprays/day -most require ≤12 sprays/day

1 – 2mg bid

Dosage form

Buccal spray

Capsules

ODB

EAP

Full benefit eCPS, Lexi-Comp

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Frank et al – nabilone 

P

Outcomes



RC, DB, crossover (each treatment period =6 wks + 2wk washout in between), ITT N=96

  

Chronic neuropathic pain, 20% due to injury/surgery Mean baseline pain score =69.6mm on 100mm VAS 40% with past use of antidepressants, anticonvulsants or weak opioids

Nabilone

Dihydrocodeine

Difference

P-value

Confidence Interval

1º outcome: Mean pain intensity on VAS 59.93

58.58

1.35

N/A

Clinically relevant response (>10mm decrease in VAS) 3

12

9

N/A

2º outcomes: Anxiety, depression, weekly average hours of sleep: no statistical differences

I

Nabilone caps titrated up to 2mg/day

C

Dihydrocodeine titrated up to 240mg/day *a weak opioid, similar analgesia effect as codeine

Safety: Nabilone: “sickness” Dihydrocodeine: tiredness, nightmares

Frank B et al. BMJ. 2008;336(199)

Nurmikko et al - Sativex P

       

RC, DB, PC, MC , ITT 5 wks long with open-label extension study of Sativex x 52wks N=125 20% peripheral neuropathic pain and allodynia Mean baseline pain score =7 on NRS ~30% in each arm on concurrent antiepileptics or TCAs ~10% in each arm on concurrent strong opioid; 50-60% on weak opioid 20% prior cannabis use

I



Sativex o Mean 11 sprays/d (self-titrated to max 48 sprays/d)

C



Placebo with mean 19 sprays/d Nurmikko TJ et al. Pain. 2007;133;210-220

Summary • Cannabinoids provide small and clinically insignificant benefit in chronic neuropathic pain • Limitations of studies ▫ Underpowered, high drop out rates, comparator choices ▫ External validity  type of neuropathic pain, background analgesic regimen, current cannabis usage

Outcomes Sativex

Placebo

Difference

P-value

Confidence Interval

1º outcome: Change from baseline pain score on NRS -1.48

-0.52

-0.96

0.004

-1.59 to -0.32

% of patients with 30% reduction in pain 26

15

N/A

% of patients with 50% reduction in pain 20

8

N/A

Safety: GI effects (dry mouth, nausea, vomiting) 49%

32%

17%

0.003

N/A

Open-label extension of Sativex: (71% of study group) • Daily dosage and change in NRS remained similar • 63% withdrew  side effects or lack of efficacy

Long term effects • Amotivational syndrome ▫ ↓ drive, ambition, motivation ▫ Poor judgment ▫ ↓ capacity to carry out complex tasks

• • • •

Bronchitis, emphysema, respiratory tract cancer CV system? Immune system? Sexual functioning? Brands B et al. Drugs & Drugs Abuse

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Care plan • Recommend against any form of cannabis products at this time for neuropathic pain ▫ Provide education on long-term complications

• Encourage taper in current marijuana use • Continue opioid regimen • Continue with venlafaxine and pregabalin ▫ Pregabalin can be increased to max. 600mg/day

Monitoring plan Parameter

Baseline

Degree of change

When and by whom?

Back pain

7-8/10

Reduced to 5/10 and/or to a level tolerable for daily function

Q 2 wks by MD, RPh, Patient

Tearful episodes

None

No increase

Drowsiness, dizziness

None

No increase

At next appt by MD, RPh, Patient

Blood pressure

No hypertension diagnosed

No increase to >140/90

At next appt by MD

Dry mouth

None

No increase

Bowel movement

1 BM q week

1 BM once daily

At next appt by MD, RPh, Patient

Burning, shooting, pins/needles

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Learning Objectives By the end of this presentation, attendees should be able to: 



MANAGEMENT OF OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY





Explain key points regarding hypertrophic cardiomyopathy as a disease state Recognize the lack of evidence for medical management of hypertrophic cardiomyopathy Compare different pharmacologic treatments based on mechanisms and available evidence Decide on appropriate course of action for patient presented

Sidika Dhalla, BScPhm/PharmD Student

Presentation Outline     

Patient Case Clinical Question Review of Evidence Treatment Plan Monitoring

Mr. HD 

History of Present Illness 

Experiences mild ‘episodes’ occasionally, ever since he can remember



Chronic fatigue ever since he can remember



Symptomatic episodes more frequent since he ran out of disopyramide one week ago



Diagnosed with hypertrophic cardiomyopathy in 2006

Mr. HD 

72 year old male, NKDA  Presented

to ER after experiencing four consecutive short (approx. 10 sec) episodes of chest pain, shortness of breath and dizziness  On his walk from parking lot to appointment at the hospital  Admitted to hospital and sent for coronary angiography to rule out CAD cause of symptoms

Mr. HD Past Medical History Hypertrophic Cardiomyopathy

Medications Bisoprolol 1.25 mg once daily Disopyramide 150 mg TID

Hypertension – well controlled

Bisoprolol 1.25 mg once daily Hydrochlorothiazide 12.5 mg once daily

Hyperlipidemia – well controlled Coronary Artery Disease

Atorvastatin 20 mg once daily

Osteoarthritis

OTC naproxen PRN Celecoxib PRN

ASA 81 mg once daily

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What is HCM?

Review of Systems CNS

Normal



HEENT Resp CV

Presented with episodes of chest pain, resolved while in hospital. Vitals: BP=90/60 HR=29-42 bpm range (sinus bradycardia) Angiography results: no significant coronary stenosis. ECHO: LVOT gradient at rest = 10 mmHg, QTc = 394

Kidney/liver

SCr=76 mmol/L LFTs – normal

Endocrine

HbA1c=5.5%, TSH= 2.33

Heme/lytes/ Normal fluid



 

  

Hypertrophic cardiomyopathy is a genetic cardiac disorder caused by a missense mutation in a gene that encodes proteins of cardiac sarcomere Massive hypertrophy of left ventricle >15 mm LV wall thickness Disorganization of collagen fibres in the heart Affects 1/500 adults Mortality 30 mm Hg is characteristic of obstruction at rest Mitral valve regurgitation Diastolic dysfunction Myocardial ischemia



Sudden death



 

Reduced outflow

Mitral valve

Hypertrophied left ventricle

↑ obstruc on, ↑ LV ou low gradient 

What is HCM? 

Symptoms 

Most patients remain asymptomatic until older age

Shortness of breath  Angina  Syncope  Fatigue  Arrhythmias

Treatment 

 Surgical

septal myectomy chamber pacing  Alcohol septal ablation  Dual



** questionable correlation between extent of LV outflow obstruction and extent of symptoms

Invasive/Surgical



Pharmacological  Beta

blockers channel blockers  Disopyramide  Calcium

 Negative inotropy

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Negative Inotropy 

Mechanism of benefit: the effect of catecholamines that exacerbate LV outflow tract obstruction

The Problem… 

 Block

 Reduce

 Slow

the heart rate and prolong diastole, allowing increased ventricular filling

 Reduce

 

Medline, Pubmed search terms: hypertrophic cardiomyopathy, obstructive hypertrophic cardiomyopathy, management of HCM, beta blockers, calcium channel blockers, disopyramide, left ventricular outflow obstruction Citations in ACC/AHA guidelines Citations in NEJM and European Journal of Cardiology Reviews

ACC/AHA Guidelines on HCM, 2011 

Verapamil therapy (starting low dose, max 480mg/d) is recommended for the treatment of symptoms (angina, dyspnea) in patients with obstructive or nonobstructive HCM who do not respond to beta-blocking drugs or who have side effects or contraindications to betablocking drugs. 

 Available

through Special Access

Clinical Question: Is combination therapy with a beta blocker and calcium channel blocker a reasonable alternative to combination beta blocker and disopyramide for symptomatic control in patients with obstructive HCM?

anginal symptoms

Search Strategy 



LV outflow gradient

Mr. HD ran out of his disopyramide 1 week prior to presentation in hospital – good control in past Disopyramide is now off the market

ACC/AHA Guidelines on HCM, 2011 For symptomatic patients:  Class I  Beta-blocking

drugs are recommended for the treatment of symptoms (angina or dyspnea) in HCM but should be used in caution in patients with sinus bradycardia or severe conduction disease. (Level of Evidence: B)  If

low dose ineffective, titrate dose to HR