Threats to Lung Function: What Can We Do About Them?

Educational Objectives

The goals of this program are to improve the outcomes of smoking cessation therapies and the management of chronic obstructive pulmonary disease (COPD). After hearing and assimilating this program, the clinician will be bet­ter able to:

1.   Describe the pharmacologic addiction and conditioned responses to nicotine.

2.   Discuss the outcomes of nicotine replacement therapy, as well as other pharmacologic therapies for smoking cessation.

3.   Distinguish cravings from other withdrawal symptoms associated with smoking cessation.

4.   Explain the spirometric classification system determined by the Global Initiative for Chronic Obstructive Lung Disease.

5.   Manage COPD using a combination of nonpharmacologic and pharmacologic approaches.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning commit­tee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any iden­tified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Rennard has received grants from AstraZeneca, Bio­mark, Centocor, and Novartis. He has served as a consultant or advisor for Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, DEY, Eaton Associates, GlaxoSmithKline, MedaCorp, Mpex Pharmaceuticals, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United BioSource, Uptake Medical, and VantagePoint. He has been a speaker for AstraZeneca, Novartis, Net­work for Continuing Education, Pfizer, and SOMA. In his lecture, Dr. Rennard presents information that is related to off-lable or in­vestigational use of a therapy, product, or device. Dr. Chavey and the planning committee reported nothing to disclose.

Acknowledgments

Dr. Rennard was recorded at 17th Annual Educational Meeting, A Midsummer Night's Wheeze, held July 10-12, 2009, in Huntington Beach, CA, and jointly sponsored by the California Society of Allergy, Asthma, and Immunology, the Office of Continuing Medical Education, and Keck School of Medicine at the University of Southern California. Dr. Chavey was recorded at the 45th Annual Northern Michigan Summer Conference Update on Common Clinical Concerns in Primary Care, presented June 22-26, 2009, in Bellaire, MI, by the University of Michigan Medical School. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Smoking Cessation: A Medical Approach

Stephen I. Rennard, MD, Larson Professor of Medicine, Section of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha

Overview: common to take up smoking during adolescence; deaths attributed to smoking (1991)  —  >400,000; »50% from heart disease; »25% from lung cancer, 20% to 25% from chronic obstructive pulmonary disease (COPD); numbers based on statistical models; increased mortality due to smoking may not motivate adolescents to quit; morbidities, eg, exacerbation of asthma symptoms, should be emphasized; public health perspective valuable; nonmedical approaches to cessation effective

Cigarette cost:  increase (from $1 to $3 Canadian dollars per pack) resulted in reduction (40% to 15%) in number of children who took up smoking; www.monitoringthefuture.org  —tracks smoking behaviors in children; cigarette use in students  —  since 1995, steady and significant drop in numbers of children who took up smoking (partly due to cigarette cost); largest impact seen in states (eg, California) with aggressive and comprehensive programs

Tobacco plants: produce nicotine (as biotoxin) to ward off insects; biotoxin  —  acts on receptors in insect nervous system; people have similar receptors; long history of using nicotine for psychoactive effects

Nicotine effects: in placebo-controlled double-blinded study,  nicotine caused as much euphoria (on arbitrary scale) as did cocaine or morphine, and more than amphetamine; when required dose considered, nicotine 10 times more potent; nicotinic receptors  —  located on axons and nerve bodies of presynaptic dopaminergic neurons; found in me­solimbic system; modulate release of dopamine, like other drugs (eg, alcohol, opiates); reasons people smoke  —  improve mood; lose weight (typically »2 kg); craving  —  not in Diagnostic and Statistical Manual of Mental Disor­ders Fourth Edition (DSM-IV) criteria for nicotine withdrawal; depression  —  added to withdrawal symptoms in DSM-IV; often severe; addiction  —  occurs in 85% of smokers; nicotine mechanism  —  increased receptor expres­sion (unlike other agonists); biologic changes induced by nicotine lead to withdrawal; Pavlovian effect  —  linking smoking with certain behaviors; smoking becomes conditioned response; in rat studies, nicotine potentiates nonad­dictive cued responses

Smoking Cessation

Overview: most smokers have attempted to quit; relapse  —  tends to occur during cravings; withdrawal symptoms  —  most develop within first 3 days; peak 3 days to 1 wk; wane by 1 to 2 wk; cravings  —  long-term concern, unlike other withdrawal symptoms; occur within several days; decrease in frequency but not in intensity; can occur years after quitting; associated with cued behaviors; likened to grief response; inform patient that cravings will subside regardless of choice to smoke; relapse prevention  —  some data suggest medical treatment; behavioral interventions also necessary

Nonpharmacologic approaches: meta-analysis of 56 studies  —more time spent intervening leads to higher quit rates (from »9% to >20% with >10 min of intervention); maximal benefit  —  90 min of intervention; 7 to 8 sessions per quit attempt; consider referral to group therapy

Pharmacologic Approaches

Nicotine: pharmacokinetics  —  peaks of nicotine cause euphoria; lipid soluble and reaches brain quickly (10-20 sec after inhalation); effect depends on how much drug reaches brain and rate of change at receptors; redistributes in body and metabolized in several hours; nicotine peaks cause highs; withdrawal occurs when concentration dips below certain level; treatment provides steady nicotine levels to eliminate withdrawal and reinforcing "hits"; can help eliminate cued behaviors and pleasure associated with nicotine

Nicotine replacement: JAMA study  —  compared to placebo, more people quit using 14-mg patch and even more us­ing 21-mg patch; 5 replacement formulations  —  transdermal patch, chewing gum, inhaler, nasal spray, and loz­enge; 2008 meta-analysis  —  each formulation doubles quit rate, compared to placebo; nasal spray (1 mg/nostril)  —  delivers nicotine faster than does nicotine gum, lozenge, and patch; patient acceptability varies; some off-label data to support combinations of formulations; patch  —  provides steady release of nicotine; pro­vide additional formulation if needed; chewing gum  —  effective in clinical trials, but less so in practice; re­quires proper chewing to release nicotine and absorb into buccal mucosa; nicotine in saliva can irritate stomach lining; lozenge has similar issues

Nebraska nicotine patch study: double-blinded randomized controlled trial (RCT) in 21 primary care offices; 2 visits  —prescription for intervention (placebo or drug) and 1-wk follow-up (greatly improves cessation); aver­age total visit time 17 min; accrued patients 3 ways; "well-visit" patients  — suggestion to quit smoking during  routine visit with physician; majority of participants; »7% quit on active patch (vs 0% on placebo); "self referrers"  —  requested to be involved in study or to have help with smoking cessation; 30% quit using active patch and 15% placebo; similar to that seen in clinical studies; selection bias;  "sick visit" patients  —  unscheduled visit for predefined problem or scheduled visit with new problem; quit rates similar to those of self-referrers, regardless of patient complaint; conclusion  —  motivation key; may be possible to exploit other comorbidities

Drug therapy

Varenicline (eg, Chantix) partial agonist (binds to receptor with more affinity, so often more potent than full ago­nist); Gonzales et al (JAMA 2006)  —  compared to bupropion, varenicline decreased satisfaction, enjoyment, and cravings associated with smoking; 2 phase III trials  —  at 12 wk, 44% quit using varenicline vs 30% bupropion and 18% placebo; side effects  —  nausea (0.5 mg twice daily causes nausea in 16%; 1 mg twice daily 30%); in­somnia; abnormal dreams (intense but not necessarily disturbing) gastrointestinal side effects  —  avoid by ramp­ing up dose, starting with 0.5 mg once daily; psychiatric side effects  —  agitation, depressed mood, suicidal ideation, and behavior; smoking cessation itself can be associated with depressive symptoms; July 2009 US Food and Drug Administration (FDA) boxed warning on psychiatric side effects; studies ongoing to determine fre­quency of side effects; must be appropriately monitored

Bupropion: began as treatment for depression; studies show can be used for smoking cessation; significantly better for cessation than transdermal nicotine patches; combined approaches work better together than either alone (not statistically significant) at 11 wk; side effects  —  increased risk for seizures and somnolence; same boxed warning as that used for varenicline

Conclusion: smoking  —  medical condition with genetic predisposition; complex interaction between genes and envi­ronment; multifactorial physiology  —  pharmacologic addiction and conditioned response; current approach  —  Department of Health and Human Services states anyone willing to quit should be given best possible chance to succeed; smoking should be regarded as chronic relapsing disease; choose appropriate behavioral support, educa­tion, and motivation; 75% of people in United States who smoke want to quit

COPD: Inpatient, Outpatient, Your Patient

William E. Chavey, MD, MS, Associate Professor, Department of Family Medicine, University of Michigan Medical School, Ann Arbor

Global initiative for chronic Obstructive Lung Disease (GOLD) definition of COPD: preventable and treatable disease; some significant extrapulmonary effects may contribute to severity; airflow limitation  —  characteristic of pulmonary component; not fully reversible; usually progressive; associated with abnormal inflammatory response of lung to noxious particles or gases

Risk factors: many extracted from GOLD guidelines; 1) genes  —  eg, a₁-antitrypsin deficiency; 2) exposure to particles  —  tobacco smoke, occupational dust, biomass fuels (especially for indoor pollution caused by, eg, wood-burning stoves); 3) lung growth and development  —  for premature infants, lung development affects function later in life; oxidative stress; 4) sex  —  adolescent females more likely to start smoking; 5) age  —  length of time exposed to outdoor pollution and secondhand smoke; longer duration of smoking; 6) respiratory infections —  history of tu­berculosis; 7) socioeconomic status  —  risk factor for smoking; living in areas with higher levels of pollution; job it­self; 8) nutrition; 9) comorbidities; 10) asthma

Traditional view of COPD: main components  —  chronic bronchitis, emphysema, and airflow obstruction; patients have various combinations (eg, emphysema without COPD)

GOLD criteria: allows objective measurements using spirometry; significant proportion of patients do not have clas­sic phenotypes (eg, emphysema, bronchitis, asthma); many patients with asthma have COPD; cigarette smoking  —  9% of never-smokers, 11% ex-smokers, and 31% of current smokers develop COPD within 25 yr; COPD patients  —  55%  asthmatic; 36% never-smokers (despite clear link between cigarette smoking and COPD); COPD extrapulmonary effects  —  weight loss, nutritional disturbances, skeletal muscle dysfunction, and depression (latter not listed by GOLD guideline as extrapulmonary effect); comorbidities  —  coronary artery disease, osteoporosis and fractures, respiratory infection, diabetes, sleep disorders, anemia, glaucoma, cancer risk; many have to do with cig­arette smoking or extrapulmonary effects

Impact: fourth leading cause of death in world; very few large-scale trials that show significant improvement in out­comes; increasing cigarette use will increase impact

GOLD spirometric classification system: stratification does not necessarily represent distinct groups; describes ob­jective criteria for defining COPD; helps identify obstructive component; forced expiratory volume in 1 sec (FEV₁) to forced vital capacity (FVC) ratio <70%  —  main criteria for diagnosis and definition of obstruction; FEV₁ >80% of predicted  —  mild; 50% to 80% FEV₁/FVC  —  moderate; 30% to  50%  —  severe; FEV₁ <30% or FEV₁ <50% with chronic respiratory failure  —  very severe; obstruction  —  not always COPD; typical to see increased carbon monox­ide diffusing capacity and hyperinflation; 2009  —spirometry became Healthcare Effectiveness Data and Informa­tion Set measure for COPD patients >40 yr of age; must be performed 730 days before or 180 days after diagnosis; spirometry  does not necessarily change outcome; American Thoracic Society and European Respiratory Society  —  recommend spirometry for all smokers and those with family history of chronic respiratory problems; GOLD  —  recommends spirometry in patients with symptoms and/or risk factors; American College of Physicians and US Preventive Services Task Force  —  recommend against screening asymptomatic individuals, irrespective of risk fac­tors (speaker agrees); symptomatic patients  —  confirm COPD diagnosis with spirometry; look for other causes of dyspnea in patients without COPD; surveillance spirometry  —  no consensus on use; Mannino et al (2006)  —  mortality stratified by GOLD severity; category zero no longer used; "restricted" group (FEV₁/FVC >70% with re­duced FVC) studied, although not included in GOLD category; GOLD category 3 or 4  —  survival rates wane

Managing COPD

Minimize exposure to toxins: smoking cessation single most effective intervention to reduce risk of developing COPD and stop progression; »25% of Americans smoke; of these, »70% see physician each year; ask, advise, as­sess, assist, arrange; recommendation  —  for each visit, ask about smoking habits; requires reinforcement; talk to ad­olescents

Disease education: not well studied; cost effectiveness unclear

Nutrition counseling: malnutrition in COPD associated with poor prognosis; obesity can be comorbidity; little evi­dence to support role of dietary counseling; Weekes et al (2009)  —small, randomized trial; intervention group re­ceived dietary advice; significant improvement in weight gain and symptom score, but no improvement in activities of daily living or respiratory function; decreased body mass index (BMI) in 25% of patients with stage II to IV

Pharmacologic and surgical therapy: does not change course of disease or mortality

Bronchodilators: prn or scheduled; for long-term use, inhalers preferred over nebulizer; consider alternative breath-activated devices; long-acting b-agonist (LABA)  —  may be more effective than short-acting; pay attention to side effects with comorbidities (eg, coronary artery disease), and keep patients from overuse; anticholinergics  —  long-acting more effective than short-acting; may work synergistically with inhaled b-agonists; may improve effec­tiveness of pulmonary rehabilitation; can be costly

Xanthines: do not use

Corticosteroids: regular use of inhaled corticosteroids (ICS) may reduce frequency of flares for symptomatic pa­tients with stage III to IV disease; recommended for long-term management; inform patient that stopping use can lead to flare; long-term use increases risk for pneumonia; only moderate-to-high doses tested; combining with b-agonist improves effectiveness but increases risk for pneumonia; not all patients respond similarly; oral steroid trial not effective way to gauge responsiveness to inhaled; no role for long-term oral steroids (can be issue for fre­quently admitted patients); ICS and increased risk for pneumonia (Singh et al; 2009)  —  meta-analysis of RCTs using inhaled steroids vs placebo with or without LABA; at ³24-wk follow-up, 60% increased relative risk for pneumonia (significant); 71% increased risk for serious pneumonia, irrespective of LABA use; no impact on overall mortality

Mucolytics: not shown to have positive effect

Antitussives: discouraged because cough itself may be protective

Immunizations: influenza vaccine can reduce death rate by 50% in COPD patients; pneumococcal vaccine recom­mended at diagnosis and again after 65 yr of age

Pulmonary rehabilitation: improves  —