1

Choices Before Opioidsfor CNCP

Dr. Edith Baxter

Isobel Fleming

Dalhousie Academic Detailing Service

Feb 2019

1

2

.

Dalhousie Academic Detailing Service and the Drug Evaluation Unit are funded by the Nova Scotia Department of Health and Wellness.

Content is controlled solely by the Office of Continuing Professional Development

2

3

Dr. Edith Baxter has no actual or potential conflict of interest with this topic or presentation

Isobel Fleming has no actual or potential conflict of interest in relation to this topic or presentation

Disclosure

3

OBJECTIVES

Following the presentation, participants should

• Understand the complexities of chronic non-cancer pain (CNCP)

• Appreciate the components of treatment management

• Understand the evidence for the various non-opioid pharmacological options for managing CNCP including cannabinoids

http://www.medicine.dal.ca/departments/core-units/cpd/programs/academic-detailing-service.html

4

Acute vs Chronic

Acute•Tissue injury

Chronic•Central sensitization

5

4 P’s of pain management

•Pharmacological

•Physical

•Psychological

•Preventive

•Understanding pain in less than 5 minutes•https://www.youtube.com/watch?v=5KrUL8tOaQs

6

Non-pharmacological

•Interventions

•Pain self-management programs

7

Pearls in CNCP

•Management not cure

•Long-term holistic approach, focusing on incremental gains in function

•Patient specific and easily measureable goals

•Realistic expectations

•Six step approach

8

Goals for Pharmacotherapy

•Improvement in functioning

•Reduction in pain of 30% to 40%

•Avoid sedation

9

Pharmacotherapy

•Few benefit from any one therapy

•Start low and go slow

•Trial of 2 weeks at a tolerated/titrated dose is adequate

•If not offering ANY benefit, discontinue

•If offering some benefit but intolerant of higher dose, consider combo

10

Evidence

•Rated as low to very low quality

•Trials short in duration

•High dropout rates

•Blinding lost due to adverse effects

•Most use pain scales not improvement in function

11

Evidence

•Acetaminophen cannabinoids

•Neuropathic pain

•Fibromyalgia

•Chronic low back pain

•Osteoarthritis

12

Evidence

In the following review of the evidence for therapeutic consideration

•The therapeutic considerations are often “off-label”.

•Results are based on trials versus placebo.

•Recommendations are often based on low quality evidence and consideration of potential harm reduction compared with opioid alternatives.

•Evidence would suggest a trial is warranted.

13

14

Cannabinoids

Simplified guideline for prescribing medical cannabinoids in primary care

Allen GM, Finley CR, Ton J, Perry D, et al.

Canadian Family Physician 2018 Feb;64(2):e78-94

15

Cannabinoids Canadian Family Physician 2018 Feb;64(2):e78-94

16

CannabinoidsLimitations to the evidence include

•High risk of bias

•Long term consequences are unknown

•Products available can have far higher concentrations of THC and CBD than those researched

•Some patients not cannabinoid naïve

•Pharmaceutically produced cannabis oil products are becoming available before the scientific literature to inform benefits and harms

17

Nonsteroidal anti-inflammatory drugs

Choosing Wisely Canada recommends not to prescribe NSAIDs in patients with hypertension, heart failure or chronic kidney disease of all causes, including diabetes.

•Cardiovascular risk

•Risk of gastrointestinal ulceration and bleeding

Recent review of managing NSAID risk in Pharmacist Letter

18

Gabapentinoids

Gabapentin & pregabalin

•Diversion

•Opioid related death

Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: A

population-based nested case-control study. Plos Medicine. Available at https://doi.org/10.1371/journal.pmed.1002396

Gomes T, Greaves S, van den Brink W , Antoniou T, Paterson JM, Martins D, Juurlink DN. Pregabalin and the Risk for Opioid-related Death: a Nested

Case-Control Study. Ann Intern Med 2018; 169(10): 732-4.

19

What about Tramadol?

IT’S AN OPIOID

•Health Canada making change to Narcotic status

•Dual mechanism of action

•Opioid effects reliant on an active metabolite (CYP 2D6)

•Some evidence of limited benefit in CNCP conditions reviewed

•Risk of addiction, misuse and abuse.

http://www.medicine.dal.ca/departments/core-units/cpd/programs/academic-detailing-service.html

20

Cases: Monica•60 year old female

•Pain story: previous anterior cervical disc fusion

• Fibromyalgia

•Neck pain: sharp, stabbing, aching

•Hypertension, smoker

•Current medications: lorazepam 2mg at hs, mirtazapine 30 mg, atacand16 mg

•Previously failed trials of TCAs and gabapentinoids (inefficacy and sedation)

21

Monica

•Feels cannabis oil has been helpful

•Unable to obtain a consistent supply for CBD oil and would like medical document

22

Dried cannabis, oils, edibles•Varying concentrations of THC and CBD

•RCTs of inhaled cannabis have not used concentrations of THC higher than 9.5%

•If prescribing inhaled cannabis, CFPC recommends restricting THC to less than 9.5%

•No RCTs with oils or edibles

•Most common drug-drug interactions: •Additive effects with CNS depressants•Additive tachycardia and/or hypertension with anticholinergics

Pharmacokinetics•Onset of physiologic effect

•5-10 min INHALATIONAL, 30min-3 hour ORAL

•Duration of physiologic effect•2-4 hrs INHALATIONAL, 4-5 hrs ORAL (can be up to 24 hours for both)

•Distribution•Fatty tissue, and tissues with high perfusion: heart, lung, brain, liver

•Excretion•Metabolized in liver by CYP 450 enzymes, excreted 2/3 in feces, 1/3 in urine

Simplified guideline recommendation summary: (Allen et al CFP Feb 2018)

•Management of pain: Recommend AGAINST medical cannabinoids for acute pain, headache, Rheumatologic pain (including OA and back pain) owing to lack of evidence and known harms

•Neuropathic pain: Recommend AGAINST medical cannabinoids as first or second line therapy.

•Could consider medical cannabinoids for refractory neuropathic pain:•Discuss benefits and risks•Have had reasonable therapeutic trial of at least 3 therapeutic agents•Are used as adjunctive agents

Systematic review of systematic reviews for medical cannabinoids Allan et al CFP, Feb 2018

•31 relevant systematic reviews identified, 23 were for pain

•7 of 23 pain systematic reviews provided meta-analysis

•5 of 7 reported outcome of 30% or more pain reduction

•new meta-analysis of 15 RCTs for medical cannabinoids for pain•5 RCTs examined inhaled cannabis for neuropathic pain vs. placebo•10 RCTs examined buccal spray (nabiximol) vs placebo•13/15 examined neuropathic pain•2/15 examined cancer pain

Estimated benefit•Outcome 30% reduction in chronic (neuropathic + cancer)

•Cannabinoid 39% vs Placebo 30%

•NNT 11

•Quality of evidence Very low

Adverse Events

Allen, CFP 2018

Adverse cardiovascular effects of cannabis•Proposed pathophysiological pathways for adverse cardiovascular effects of cannabis:

•delta 9 THC related:•Increase in cardiac output•Increased myocardial oxygen demand•Increased catecholamine levels•Postural hypotension

Singh, Cardiol Ther 2018

Adverse cardiovascular effects

•Case reports of atrial fibrillation in cannabis users 14 years old

•Case reports of ischemic stroke temporally related to cannabis use

•In one series five individuals had recurrence of cerebrovascular ischemic symptoms after resuming cannabis use, post hospital discharge

•Case reports of temporally linked cannabis use to acute MI•Many have been young men with no pre-existing coronary artery disease

Singh, Cardiol Ther 2018

Associations between Cannabis use and Cardiovascular risk factors and outcomes?

•13 studies examined risk factors: lipid levels, glucose levels, diabetes and obesity

•11 studies examined outcomes: MI, stroke and CV mortality

•Data not pooled due to heterogeneity of outcomes

•Insufficient evidence that cannabis can increase or decrease CV risk factors

•Insufficient evidence for association between cannabis use and CV outcomes

Associations Between Marijuana use and

Cardiovascular Risk Factors and Outcomes: A

systematic Review Ravi et al Ann Intern Med 2018

Peter•60, spinal stenosis, OA

•Awaiting revision surgery for knee replacement

•Pain managed with Tramadol 300 mg/day

•Other medications: eletriptan 40 mg (averages 6/month)

•Develops symptoms of major depressive episode

•Brings in Rx for citalopram 20 mg

33

Peter

•Is there a maximum recommended tramadol dose to reduce the risk of serotonin syndrome when used concomitantly with other serotonergic drugs?

•No evidence to support a dose limit

34

Peter

• According to product monograph:

• “Development of potentially life-threatening serotonin syndrome may occur with use of tramadol products, particularly with concomitant use of serotonergic drugs such as SSRIs…

- … and with drugs which may impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors)”

*All SSRIs are CYP2D6 inhibitors

35

Peter•Recommended approach:

•Start the second drug at a lower than usual dose

•Discuss with patient the initial minor symptoms of serotonin syndrome (eg: akathisia, tremor, altered mental status)

•Document

•Be aware of other factors (eg: herbal products or illicit substances)

Ann Pharmacother 2012;46(12): 1712-6

36

Daniel•OA affecting multiple joints, especially knees and hands

•Acetaminophen – ineffective

•Vascular risk factors: ex-smoker, dyslipidemia, family history

•Meds: rosuvastatin 10 mg, sildenafil 100 mg prn, naproxen 500 mg bid

•Good pain relief with NSAID, but has epigastric burning and discomfort

37

Options?•Discontinue naproxen and try topical NSAID

•Add in PPI and continue naproxen

•Switch him to a cox-2 inhibitor

38

Topical NSAIDs•American College of Rheumatology 2012 Guidelines:

•Technical expert panel: no preference for using topical rather than oral NSAIDs

39

Do different NSAIDs have different cardiovascular risk?Coxib and Traditional NSAID trialists’ collaboration

Meta-analysis of 754 RCTs with 350 000 patients with low to moderate CV risk

COX-2 inhibitors, compared with placebo, increased all cause mortality and major CV events

Diclofenac (150 mg/day): similar risks to COX-2s for mortality and CV events

Naproxen (1000 mg/day) has less CV events and mortality than COX-2

Lancet 2013;382(9894):769-79

Tools for Practice: NSAIDs and Cardiovascular Safety Jan 28, 2018

40

NSAIDs and Cardiovascular risk•Tools for Practice: Tools to communicate with patients

•“Choosing high risk NSAIDs (taken daily) can cause ONE additional CV event over five years in:

•100 low-risk patients (baseline 5% ten-year CV risk)

•25 high-risk patients (baseline 20% ten-year CV risk)”

41

NSAIDs and Cardiovascular risk•Two more recent RCTs showed similar risk of CV events between celecoxib and NSAIDs

•SCOT trial Eur Heart J. 2016;23:1843-50

•PRECISION trial N Engl J Med 2016;375:2519-29

•Limitations to these studies:•Enrolled lower risk population than planned•High discontinuation rate of study medication•Industry funded•Comparison of non-equipotent doses

42

NSAIDs and Cardiovascular riskPRECISION trial

Mean daily dose

Celecoxib 209 ± 37 mg

Naproxen 852 ± 103 mg

Ibuprofen 2045 ± 246 mg

Event rates for primary outcome

Celecoxib 2.3%

Naproxen 2.5%

Ibuprofen 2.7%

N Engl J Med 2016;375:2519-29

43

NSAIDs and Cardiovascular risk

44

SUMMARY

•Therapy for CNCP should be individualized.

•For most agents, a trial is warranted.

•Set realistic goals based on function

Potential benefits and harms of each treatment option can vary considerably depending on the patient, the chronic condition and the dose/intensity of the intervention. (RxFiles)

45