Opioid use in COPD: balancing benefits and harms. St. Michael s Hospital, University of Toronto

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1 Opioid use in COPD: balancing benefits and harms Nicholas Vozoris MHSc, MD, FRCPC Assistant Professor St. Michael s Hospital, University of Toronto

2 Conflicts of interest None None of my own drug safety research has been funded by the pharmaceutical industry

3 Structure of presentation Discuss the epidemiology of prescription opioid drug use in COPD Discuss current approaches for prescribing opioids for refractory dyspnea in COPD and review and synthesize the available evidence from RCTs and observational studies Discuss potential approaches to mitigating opioid-related respiratory complications in COPD

4 COPD: a disease of multiple and complex comorbidities Muscle wasting Ischemic heart disease Muscular pain & weakness Congestive heart failure Metabolic syndrome Depression and anxiety Dementia Insomnia Osteoporosis

5 Frequency of opioid use in COPD Incident opioid use among communitydwelling older adults with non-palliative COPD across Ontario, ~70% Prevalent opioid use among individuals with advanced oxygen-dependent COPD across Sweden, ~50% 1 Vozoris et al., Br J Clin Pharmacol, Ahmadi et al., Int J Chron Obstruct Pulmon Dis, 2016

6 Other concerning patterns of opioid use in COPD High doses (> 30 mg morphine equivalents per day) frequently used Scripts lasting >30 days Repeat dispensings Multiple opioid dispensings on the same day Early refills Ekstrom et al., BMJ, 2014 Vozoris et al., Br J Clin Pharmacol, 2016

7 Opioids may be more frequently given in COPD than inhalers! Prevalent respiratory drug use among community-dwelling older adults across Ontario with non-palliative COPD over 6 months Incident opioid drug use among community-dwelling older adults with non-palliative COPD across Ontario over 5 years ~ 70% Vozoris et al., Eur Resp J, 2016

8 Approaches to prescribing opioids in advanced COPD for refractory dyspnea 1. The Australian approach 1 once-daily, sustained-release, oral tablet morphine sulphate mg with possible up-titration to a maximum of morphine sulphate 30 mg per day 2. The Canadian approach 2 1 Abernathy et al., BMJ, Marciniuk et al., Can Resp J, 2011 initially standing immediate-release liquid morphine sulphate, starting at 0.5 mg twice daily with possible weekly up-titration based on clinical re-evaluation followed by possible eventual substitution with a sustained-release preparation

9 What RCTs tell us about opioids for COPD Dyspnea scores Ekstrom et al., Ann Am Thorac Soc, 2015

10 What RCTs tell us about opioids for COPD Measures of exercise tolerance Ekstrom et al., Ann Am Thorac Soc, 2015

11 What observational studies tell us about opioids in COPD Prospective cohort study involving ~2250 individuals with oxygen-dependent COPD across Sweden, , evaluating prevalent opioid use Ekstrom et al., BMJ, 2014

12 What observational studies tell us about opioids in COPD Retrospective cohort study involving ~150,000 individuals with non-palliative COPD across Ontario, , evaluating incident opioid-only formulation use 30-day hazard ratio (95% CI) Number needed to harm Outpatient respiratory exacerbations 1.27 ( ) 91 ER visits for COPD or pneumonia 1.64 ( ) 143 Hospitalizations for COPD or pneumonia 1.54 ( ) 125 ICU admissions for COPD or pneumonia 1.27 ( ) COPD or pneumonia-related death 4.76 ( ) 167 All-cause death 4.01 ( ) 28 Vozoris et al., Eur Resp J, 2016

13 What observational studies tell us about opioids in COPD Retrospective cohort study involving ~150,000 individuals with non-palliative COPD across Ontario, , evaluating incident opioid use Opioid-related adverse respiratory events extended to: Individuals with less severe COPD Receipt of both short- and long-acting opioid formulations Receipt of low dose opioid formulations (< 30 mg morphine equivalents per day) Vozoris et al., Eur Resp J, 2016

14 How do we put the available data together? Are opioids good or bad in COPD? Clinical studies Observational studies Small numbers of subjects Highly selected subjects Subject drop-out Controlled drug use Large numbers of individuals Individuals from the broader population Complete follow-up Non-controlled drug use

15 Striking a GOLD balance Oral and parenteral opioids are effective for treating dyspnea in COPD patients with very severe disease.however, morphine used to control dyspnea may have serious adverse effects and its benefits may be limited to a few sensitive subjects GOLD 2016

16 Mitigating opioid-related respiratory harms My thoughts: Using low-doses, with slow and careful up-titration, with close monitoring, likely helpful however, low dose opioids were associated with increased respiratory-related morbidity and mortality in a large, population-based Canadian study 1 What may be more important though is selecting the right patient more work needs to be done understanding who the right patient is 1 Vozoris et al., Eur Resp J, 2016

17 Mitigating opioid-related respiratory harms: insights from clinical trials Clinical trials showing that opioids are efficacious for reducing dyspnea in COPD often excluded the following groups of patients: Individuals with frequent or recent respiratory exacerbations Individuals with hypercapnea Individuals with comorbid sleep breathing disorders Individuals with comorbid cardiac disease Individuals with comorbid cognitive and psychiatric disease Individuals with a history of adverse reaction to opioids

18 Concluding thoughts Opioids are frequently prescribed to individuals with COPD, likely for a variety of reasons is this best practice? Clinical trials show that opioids reduce refractory breathlessness (but not exercise tolerance) in COPD are the statistically significant differences clinically meaningful? Opioids are associated with increased respiratory-related morbidity and mortality in the broader COPD population The results of clinical and observational studies on opioids in COPD are likely complementary and not contradictory Patient selection may be key to mitigating opioid-related adverse events