MANAGING CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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1 MANAGING CHRONIC OBSTRUCTIVE PULMONARY DISEASE Case study 63 report July 010 Independent, not-for-profit and evidence based, NPS enables better decisions about medicines and medical tests. We are funded by the Australian Government Department of Health and Ageing. Level 7/418A Elizabeth St Surry Hills NSW 010 PO box 1147 Strawberry Hills NSW 01 P F info@nps.org.au 01 National Prescribing Service Limited. ABN NPSCS0966

2 Inside Case study 63: Managing chronic obstructive pulmonary disease Scenario and questions page 3 Summary of results page 5 Results in detail Investigations for COPD page 6 Drug therapy in COPD page 7 Assessing drug therapy in COPD page 8 Assessing nicotine dependence page 10 Smoking-cessation strategies page 11 Commentaries Professor J Paul Seale page 13 Dr H John Fardy page 14 References page 15 This information is derived from a critical analysis of a wide range of authoritative evidence. NPS has taken reasonable care to ensure that the information is accurate and up-to-date at the time of creation. NPS does not warrant its completeness and excludes liability where permitted by law. Health care professionals must continue to rely upon their own skill, care and inquiries taking into account the individual circumstances of each patient when providing medical advice. Copyright: 010 National Prescribing Service Limited. This work is copyright. You may download, display print and reproduce this work in unaltered form only (retaining this notice) for non-commercial use either personally or within your organisation. Apart from any such use or otherwise as permitted under the Copyright Act 1968, all rights are reserved. Queries concerning reproduction and rights should be sent to copyright@nps.org.au.

3 Case study 63: Managing chronic obstructive pulmonary disease Scenario Damien, a 58-year-old brick layer comes for a review of the management of his chronic obstructive pulmonary disease (COPD) as his symptoms have become more troublesome over the past month. He was diagnosed with COPD twelve months ago. Damien was doing well on inhaled salbutamol as needed but for the past months has had a persistent cough and his breathlessness is more apparent. Last spirometry results (5 months ago, after his last COPD exacerbation) were postbronchodilator FEV 1 : 60% predicted and FEV 1 /FVC ratio: Damien smokes 5 cigarettes per day (30 years) and has on several occasions attempted to quit smoking without success. His regular medications are salbutamol (Airomir, Asmol, Ventolin) MDI 00 micrograms every 4 6 hours when required. He is also on atenolol (Noten, Tenormin) 50 mg for hypertension and atorvastatin (Lipitor) 10 mg for hypercholesterolaemia (both in the morning). He has no other medical conditions, and has no known allergies. On examination, BP is 135/85 mmhg, pulse 100, respiratory rate 0 and temperature 37 C. He is able to speak in whole sentences and there is no central cyanosis present. Auscultation of the chest reveals widespread expiratory wheezes with slightly reduced air entry on both sides. 1. Would you recommend any diagnostic imaging or pathology tests to assist in assessing Damien s current condition? yes (please specify) no Investigation: Reason:. Would you recommend continuing or adding on any of the following medicines* at this visit? (Mark all that apply i.e. for combination products, mark all ingredients.) regular salbutamol yes no eformoterol or salmeterol yes (alone) yes (with salbutamol) no ipratropium yes (alone) yes (with salbutamol) no inhaled corticosteroids yes(alone) yes (with salbutamol) no oral corticosteroids yes (alone) yes (with salbutamol) no tiotropium yes (alone) yes (with salbutamol) no atenolol yes (alone) yes (with salbutamol) no * salbutamol (Airomir, Asmol, Epaq,Ventolin); eformeterol (Foradile, Oxis); eformeterol/budesonide (Symbicort); salmeterol (Serevent); salmeterol/fluticasone(seretide); ipratropium (Atrovent); ipratropium/salbutamol (Combivent); tiotropium(spiriva); atenolol (Noten, Tenormin) 3

4 3. If you recommend starting another medicine for the management of Damien s COPD: a) When will you assess the efficacy of the medicine(s) b) How will you assess the efficacy? c) For the medicine(s) you recommended, what are the two most important points you will counsel Damien on? i) ii) 4. Damien is ready to quit smoking again and would like some help. a) How would you assess the severity of his nicotine dependence? b) Would you recommend drug therapy? yes, please specify: no, why not? Medication Dose Frequency Durationi a) c) What are two non-drug therapies you would recommend for Damien to assist him to quit smoking? i) ii) 4

5 Summary of results At the time of publication, 93 responses were received. This report summarises responses from 00 general practitioners. Case synopsis Damien, a 58-year-old brick layer, comes for a review of the management of his COPD, as his symptoms have become more troublesome over the past month. He smokes 5 cigarettes per day (30 years) and has on several occasions attempted to quit smoking without success. (See page 3 for more details.) Investigations for COPD When asked to recommend diagnostic imaging or pathology to assess Damien s current condition, respondents specified chest X-ray (56%) and pulmonary function tests (%). 14% of respondents would not recommend any further diagnostic imaging or pathology for Damien. Drug therapy in COPD More than half (67%) of respondents would recommend continuing salbutamol either alone or in combination with other therapies at the time of Damien s visit. 84% of respondents would add tiotropium (Spiriva) in combination with salbutamol or alone at the time of Damien s visit. Most respondents (9%) would not recommend continuing atenolol for Damien. Assessing drug therapy in COPD Nearly half of respondents (48%) would assess the efficacy of their chosen medicine 4-8 weeks after initiation. Pulmonary function tests were suggested by 45% of respondents, with 39% specifying spirometry, as a method to assess the efficacy of Damien s medicine. When recommending medicine(s) for Damien, respondents suggested that compliance (9%) and correct inhaler technique (1%) were the most important counselling points. Assessing nicotine dependence Most respondents (96%) would assess the severity of Damien s nicotine dependence by asking questions about his smoking history. Smoking-cessation strategies Most respondents (9%) would recommend drug therapy for Damien s nicotine dependence. From these respondents, 80% would recommend varenicline (Champix). Non-drug therapies that were recommended to assist Damien in quitting smoking included referral to a telephone counselling service (35%), regular follow-up with a GP or nurse (16%), and counselling (16%). 5

6 Results in detail Investigations for COPD Eighty-six per cent of respondents would recommend diagnostic imaging or pathology tests to assist in assessing Damien s current condition. More than half of respondents (58%) would recommend chest investigations, with 56% specifying chest X-ray, to assist in Damien s assessment. Table 1 summarises the responses. Table 1: Investigations to assess Damien s COPD Investigations % of respondents (n = 17)* Chest investigations 58 Pulmonary function tests Full blood tests 11 Sputum culture 3 ECG Liver function tests Other *Respondents may have more than one response Chest investigations included chest X-ray (56%) and chest CT scan (%) Pulmonary function tests included spirometry (19%) and non-specified pulmonary function tests (3%) Other included echocardiogram (1%), kidney function tests (<1%), and non-specified (<1%) Reasons for the recommended investigations were specified by respondents. Nearly half of respondents (48%) stated that the recommended investigations were to exclude other conditions such as cancer or pneumonia. This reasoning is reflected in the investigations shown above, with more than half of respondents (58%) recommending further chest investigations. Pulmonary function tests, specifically spirometry (19%), were recommended to assess Damien s lung function in light of his recent deterioration. Practice points Assess exacerbation severity using a combination of a thorough medical history, clinical examination and spirometry. Reserve the use of chest X-rays, electrocardiography and blood gas measurements for severe COPD cases (FEV 1 < 40%). 1, Identify alternative diagnoses and conditions that can mimic the symptoms of an exacerbation (e.g. pneumonia and arrhythmias) by using chest X-rays and electrocardiogram where appropriate. 1,3 Avoid using only peak expiratory flow (PEF) measurements and physical examination to diagnose or assess the severity of COPD, as both these methods lack adequate sensitivity 1 and alone are not diagnostic. 3 Use pulmonary function tests (including spirometry) to assess breathlessness in chronic chest disorders, as they play a role in diagnosing respiratory conditions and monitoring response to treatment. 4 Compare previous stable results of arterial blood gases and pulmonary function tests during exacerbations, as changes in these values are more important than the absolute vaules. 1,3 Perform annual spirometry tests for patients with mild to moderate COPD and at least biannually for patients with severe COPD, as part of a regular review. 4 6

7 Drug therapy in COPD Respondents were asked to recommend the continuation or addition of medicines at the time of Damien s visit. Sixty-seven per cent of respondents would recommend the continuation of salbutamol either alone or in combination. Table summarises the responses. Table : Recommended medicines for Damien s worsening COPD Medicine Eformoterol/salmeterol Ipratropium Inhaled corticosteroids Oral corticosteroids Tiotropium Atenolol Recommended in combination with salbutamol (%) Recommended alone (%) Not recommended (%) Number of respondents* *Respondents did not supply an answer for all available options Practice points Recommend the use of either short-acting beta agonists or ipratropium for initial pharmacotherapy, as they have similar efficacy. 3,5 The dose and/or frequency of their use can be increased during exacerbations. 5 Consider using regular long-acting bronchodilators (beta agonists and/or anticholinergics) for patients who remain symptomatic despite adequate dosing of short-acting bronchodilators and proper inhaler technique.,4 These provide greater effectiveness compared with regular dosing of short-acting bronchodilators. 3 Tailor pharmacotherapy to individual patient response, as there is insufficient evidence to favour one long-acting agent (tiotropium, salmeterol or eformeterol) over another. 3,4 Add a fixed-dose combination inhaler to therapy when FEV 1 is < 50% and two or more exacerbations have occurred in the past 1 months.,5 Fixed dose combination inhalers include: fluticasone with salmeterol (Seretide) budesonide with eformeterol (Symbicort). Reserve oral corticosteroids for short-term use (less than 14 days) to reduce the severity of exacerbations and shorten recovery time. 5 Their use is not recommended for maintenance therapy 4,5 due to an increased risk of adverse effects (e.g. bone density loss, hyperglycaemia and increased susceptibility to infections) without additional benefit.,5 Provide patients with a self-management plan and encourage prompt treatment response to exacerbations.,4 A sample of a written action plan is available at Reassess beta-blocker use because of the potential for antagonistic therapeutic actions when combined with beta agonists in respiratory conditions such as COPD. If the combination is considered necessary, a cardioselective beta blocker may be used under specialist supervision. 5 Fluticasone with salmeterol (Seretide 50/5 MD and Seretide 500/50 DPI strengths only) is PBS listed for COPD in people with FEV1 < 50% predicted who have a history of repeated exacerbations despite regular beta agonist treatment. Budesonide with eformoterol (Symbicort) is not PBS listed for COPD. 7

8 Assessing drug therapy in COPD Forty-eight per cent of respondents would assess the efficacy of the medicine they recommended after 4 8 weeks. The efficacy of the recommended medicine would be assessed by 45% of respondents using pulmonary function tests, with 39% of respondents specifying spirometry. Tables 3 and 4 summarise these results. Table 3: Assessment of medicine efficacy in COPD Time to assessment 0 weeks 4 weeks 4 8 weeks > 8 weeks Other* % of respondents (n = 00) * Other included after cessation of beta blocker (<1%), after a full investigation (<1%) and non-specified (%) Table 4: Assessment of medicine efficacy in COPD Assessment methods Perform pulmonary function tests Evaluate persisting symptoms Perform a thorough clinical assessment Measure the patient s exercise capacity Take a full patient history Other % of respondents (n = 00)* *Respondents may have more than one response Pulmonary function tests included spirometry (39%) and non-specified pulmonary function tests (6%) Other included use of asthma severity scale (<1%), measure blood pressure (<1%), and non-specified (1%) Practice points Review patients 4 8 weeks after starting new therapy. 1,4 Consider alternative treatment options if there is no improvement in symptoms and overall COPD management during the trial period 5. Use a range of measures to assess the effectiveness of bronchodilator therapy. These include : pulmonary function tests extent and rapidity of symptom improvement exercise capacity ability to perform activities of daily living adequately. Allow a longer trial period (3 6 months) to assess the effect of inhaled corticosteroids on exacerbations in moderate to severe COPD 1,5. 8

9 Respondents were asked to suggest important counselling points for medicines that were recommended for Damien s therapy. Compliance was the most important counselling point for 9% of respondents. Table 5 summarises these results. Table 5: Counselling points recommended for Damien Counselling points Compliance Correct inhaler technique Smoking cessation Potential side effects of medicine use Correct medicine management Need for regular follow-up Other Delayed effect of medicines Pulmonary rehabilitation % of respondents (n = 00)* *Respondents may have more than one response. Potential side effects of medicine use included recommending mouth rinsing after taking inhaled corticosteroids. Correct medicine management included medicines to avoid and correct medicine use in exacerbations and stable COPD. Other included limiting alcohol intake (%), regular blood pressure checks (1%), and non-specified (1%). Practice points Regularly reassess inhaler technique and if necessary demonstrate correct technique to maximise benefit from device use. 1,,5,6 Encourage patients to stop smoking, and offer support in smoking cessation at every available opportunity.,5,6 Smoking cessation is the most important intervention to prevent or delay the decline in lung function of people with COPD. -5 Ensure that patients understand that different medicines are sometimes necessary to manage their COPD at different times. A self-management plan can assist patients in identifying the appropriate use of their COPD medicines. 7 Advise patients to seek help early if symptoms are more troublesome or they are feeling worse. 7 Encourage multidisciplinary team involvement in the management of patients with COPD.,4,7 Areas of involvement that can benefit this patient group may include 4 : management of symptoms advice on nutrition and exercise advice on self-management options organisation of community services and assistance at home instruction on relaxation techniques. Offer pulmonary rehabilitation to patients with moderate to severe COPD 1 to reduce dyspnoea and fatigue, improve exercise capacity and positively effect quality of life. 1,8 Comprehensive programs involving exercise training, patient education and psychosocial support have the greatest benefits. 1 9

10 Assessing nicotine dependence Respondents were asked how they would assess the severity of Damien s nicotine dependence. Most respondents (96%) would ask Damien questions about his smoking history. Questions regarding how soon after waking the first cigarette is smoked and how many cigarettes are smoked each day were equally suggested (9%). Table 6 summarises the results. Table 6: Assessing nicotine dependence Questions to assess nicotine dependence How soon after waking is the first cigarette smoked? How many cigarettes are smoked per day? How many previous unsuccessful quit attempts have occurred? Have withdrawal effects been experienced? What is the patient s overall history of smoking? Other % of respondents (n = 00)* *Respondents may have more than one response Other included using the 5A strategy (% [see next section]), use of spirometry (<1%) and non-specified (<%). Practice points Ask about smoking habits to assess nicotine dependence, including: 4,5 the number of cigarettes smoked per day the time to the first cigarette after waking if there were any previous attempts to quit the patient s confidence and motivation to quit. Identify nicotine dependence in patients who: 9,10 smoke within 30 minutes of waking smoke more than 15 cigarettes per day or who have a history of withdrawal symptoms in previous quit attempts. 10

11 Smoking-cessation strategies Ninety-two per cent of respondents would recommend drug therapy to assist Damien in quitting smoking. Of these, 80% specified varenicline (Champix) as the drug of choice for Damien. Adverse effects were the main reason (7%) stated by the 8% who would not recommend drug therapy. When asked to recommend a non-drug strategy 34% suggested referral to a telephone counselling service (e.g. Quitline). Table 7 summarises the recommended drug and non-drug smoking-cessation therapies. Table 7 A: Drug therapies for smoking cessation Recommended drug therapies Varenicline (Champix) Nicotine-replacement therapy (NRT)* Bupropion (Zyban) Other B: Non-drug therapies for smoking cessation Recommended non-drug therapies Referral to a telephone counselling service (e.g. Quitline) Regular follow-up with GP or nurse Counselling Other therapies (relaxation, acupuncture and hypnosis) Alteration of daily tasks associated with smoking Written support materials (internet support program, stop quit brochure and quit plan) Exercise Support network (friends, family and support groups) Pulmonary rehabilitation Other % of respondents (n = 184) % of respondents (n = 00) *NRT included nicotine-replacement patches (9%) and non-specified NRT (9%) Respondents may have more than one response Regular follow-up with GP or nurse included advice on both health and financial benefits Counselling included individual counselling (13%), motivational interviewing (%), and cognitive behavioural therapy (1%) Practice points Use the 5As strategy (an evidence-based framework) to structure smoking cessation. 4,9,10 Ask and document smoking history at each visit Assess the motivation to quit and level of nicotine dependence Advise about the risk of smoking and benefits of quitting Assist in appropriate cessation strategies Arrange follow-up to encourage, support or maintain non-smoking. Consider pharmacotherapy in patients who smoke more than 10 cigarettes a day, as there is no evidence of benefit for people with low nicotine dependence. 5 Recommend nicotine replacement therapy (NRT), varenicline or bupropion as first-line options to help people quit smoking 10 (see NPS News 68: Helping smokers quit for advantages and disadvantages of first-line therapy smoking-cessation drugs). 11

12 Optimise the benefit of NRT by providing advice on choosing the right dose or using a combination of dosage forms depending on the patients preference, tolerance and needs. 1 Long-term effectiveness of combination NRT (using both patch and lozenge) compared with bupropion or nicotine patch monotherapy have been demonstrated in recent trials. 11,1 Combine pharmacotherapy and advice-based help to increase the rate of success of quit attempts, as the effects are additive. 10 Offer non-drug therapy to people with low nicotine dependence, people not willing to use pharmacotherapy, and in combination with pharmacotherapy to maximise chances of quitting. 10 Non-drug therapy includes: 5,10 counselling discussing behavioural and cognitive coping strategies 5,10 providing written information 10 referral to other assistance (e.g. Quitline) 5,10 arranging a follow-up visit for review 10 providing nutritional advice and implementing an exercise program. 5 Avoid recommending hypnosis and acupuncture to aid smoking cessation, as they have not been shown to be effective in controlled clinical trials. 4,9 1

13 Commentary 1 Professor J Paul Seale Clinical Pharmacology, University of Sydney & Consultant Physician, Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Sydney Key points Damien has smoking-induced COPD. At this stage the COPD severity is at the lower end of the mild category (FEV 1 60% predicted) but it will almost certainly progress, particularly with continued smoking. Currently available medications for COPD improve symptoms, exercise capacity and health-related quality of life and reduce the rate of exacerbations. However, none of them has been shown to reduce the rate of decline in FEV1. The only intervention that has been found to reduce this rate of decline is smoking cessation. Hence, every effort should be made to achieve this for him. His short-acting beta agonist (salbutamol) is no longer adequate, so he does need the addition of a long-acting bronchodilator. The most commonly prescribed drug is tiotropium once daily, which can be used in combination with his salbutamol (if necessary for dyspnoea). He needs to be seen at regular intervals (probably 6 monthly) so that if his FEV 1 falls to 50% predicted, the fixed-dose combination of fluticasone and salmeterol can be added. He appears to have had two exacerbations within about 6 months. The addition of tiotropium should reduce the frequency of his exacerbations, but if they recur later and his FEV 1 has declined, the addition of fluticasone salmeterol should help. Need for radiological (and other) investigations A chest X-ray is indicated. The reason for the chest X-ray is to investigate whether there is any infection or any feature to suggest malignancy. The only circumstances to justify a CT scan would be if any findings from the chest X-ray needed further exploration. Spirometry is also indicated so that it can be compared with the previous spirometry 5 months ago. Blood tests are not generally indicated unless there is a suspicion of infection, in which case white cell counts and inflammatory markers (such as C- reactive protein) may be helpful. Assessing response and counselling Improved symptoms, increased exercise tolerance and reduced exacerbations are useful indices of response to treatment. Objective measures of lung function are also useful, but spirometric improvement may be modest compared with symptomatic improvement. Advice and demonstration of correct inhaler technique is very important. This issue should be canvassed at each visit. It is also important to inform patients about potential side effects of the medications and what actions they should take if they develop any of them. Nicotine dependence The greater the total number of cigarettes per day, the greater the likelihood of nicotine dependence. The time of the first cigarette of the day is a reliable index. If the patient has the first cigarette with, or before, breakfast, nicotine dependence is highly likely. If the patient has not tried nicotine replacement therapy (NRT) before, then it is reasonable to explore this with them. If NRT has been tried in previous attempts to quit, varenicline is the drug of choice. A smoker s chances of quitting are increased if they have support from family and work colleagues in addition to formal counselling and cognitive behaviourial therapy. 13

14 Commentary Dr H John Fardy General Practitioner, Gerringong, NSW Regional Academic Hospital co-ordinator (Wollongong), Graduate School of Medicine, University of Wollongong Member, National Asthma Council GP Group; Member, Australian Lung Foundation COPD Co-ordinating Group. Key points Spirometry is critical in managing cases such as these. We need to know if Damien s airways obstruction is reversible (it heavily influences our management decisions) and if his COPD has progressed (each exacerbation can lead to loss of FEV 1 at an accelerated rate). Exploring elements of the history (see below) will influence our diagnosis and management. Comorbidities are common and can influence, magnify or confuse the clinical picture. Damien has a diagnosis of COPD based on the clinical history, examination and spirometry (of 5 months ago). As his breathing has deteriorated, it would be useful to know: if he had any respiratory disease when he was younger (specifically asthma) if any reversibility was demonstrated on any of his previous spirometries if has he been recently exposed to respiratory irritants in his workplace or recently started hobbies. when the atenolol for his hypertension was started a long time ago or months ago? with the -month increase in cough and worsening breathlessness, what is happening with sputum. Is it increasing in amount and purulence, over months or over the last week (acute exacerbation of COPD or perhaps pneumonia)? does he have any other possibly cardiac symptoms (apart from breathlessness) that may be elucidated by direct questioning (chest pain, chest pain and tightness with exertion, paroxysmal nocturnal dyspnoea, ankle swelling, etc). Smoking increases the risk of cardiac disease as well as lung disease. Respondents correctly identified that consideration should be given to stopping the atenolol, but Damien s pulse rate on examination is 100/minute, so, he is not substantially blocked, and the issues are: compliance with atenolol has Damien had some other side effect that has caused him to stop taking it or does he miss some (or all) doses? is he taking so much salbutamol that it is interfering with the atenolol? As there has been a deterioration in his breathing, a full (pre- and post-bronchodilator) spirometry would be very informative. Use of long-acting B agonists alone in asthma is contraindicated, so if he has significant reversibility on spirometry (due to mixed obstructive disease or atenolol), it is important to know this. If the diagnosis is acute infective exacerbation of COPD (AECOPD), Damien is a candidate for a trial of inhaled corticosteroids, as it would be his second AECOPD in 1 months. A chest X-ray is helpful if there is other clinical evidence of pneumonia or lung malignancy (including mesothelioma, as he has worked in the building industry). To facilitate smoking cessation: follow the 5As (Ask, Assess, Advise, Assist, Arrange). If you choose to only do the first (Ask) and then Act by referring the patient on to Quitline or a smoking cessation advisor, you will have made a difference. Nicotine dependence is an area with it s own literature and expertise. The management of nicotine dependence may well have changed since you, as a GP, last looked into it. There are a number of resources that may help if you wish to explore the topic further. 14

15 References 1. McKenzie DK, Abramson M, Crockett AJ, et al. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease. Version (accessed 5 January 010).. National Institute for Health and Clinical Excellence (NICE). Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: NICE, (accessed 14 March 008). 3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (accessed 7 December 009). 4. Therapeutic Guidelines: Respiratory. Version 4, Australian Medicines Handbook, Australian Government Department of Veteran's Affairs (DVA). Simplifying inhaler devices for Chronic Obstructive Pulmonary Disease (accessed 3 April 010). 7. Australian Government Department of Veteran's Affairs (DVA). Inhaled respiratory medicines: Optimising use in COPD (accessed 3 April 010). 8. Lacasse Y, Goldstein R, Lasserson TJ, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 006; CD Zwar N, Richmond R, Borland R, et al. Smoking cessation guidelines for Australian general practice. Practice handbook. 004 edition. Melbourne: The Royal Australian College of General Practitioners, /$File/smoking_cessation.pdf (accessed 10 December 009). 10. Zwar N, Richmond R, Borland R, et al. Smoking cessation pharmacotherapy: an update for health professionals (reviewed and updated April 009). Melbourne: The Royal Australian College of General Practitioners, oking_cessation_update09.pdf (accessed 10 December 009). 11. Smith SS, McCarthy DE, Japuntich SJ, et al. Comparative effectiveness of 5 smoking cessation pharmacotherapies in primary care clinics. Arch Intern Med 009;169: Piper ME, Smith SS, Schlam TR, et al. A randomized placebo-controlled clinical trial of 5 smoking cessation pharmacotherapies. Arch Gen Psychiatry 009;66: