Commonplace to Condemned: the Discovery That Tobacco Kills, and How Richard Doll Shaped Modern Smoking Cessation Practices

Andrew J. Juren, MD, Jiri Frohlich, MD, FRCPC, Andrew Ignaszewski, MD, FRCPC

Commonplace to condemned: The discovery that tobacco kills, and how Richard Doll shaped modern smoking cessation practices

Dr Richard Doll’s unpopular conclusion in 1950 that smoking causes lung cancer and heart disease led to a dramatic shift in social practices and medical interventions.

ABSTRACT: Sixty years ago, smoking n the early 1950s 80% of middle- was a favorite pastime. Few sus- aged men in the UK smoked and pected that this seemingly in nocu- Ionly 0.5% said they had never ous habit was responsible for the touched a cigarette. The Second World skyrocketing incidence of lung can- War was over and it was a time of cer in the UK following the Second social progress and general merri- World War. Dr Richard Doll pioneer ed ment. Nevertheless, an ominous threat re search that demonstrated the link loomed on the horizon. The incidence between smoking and lung cancer of lung cancer in young men skyrock- and showed its detrimental ef fect eted after the war and rapidly over- on the cardiovascular system. Today took tuberculosis as the major cause the health risks of smoking are well of death in the UK.1 This alarming de- known, yet millions of people die pre- velopment resulted in considerable maturely each year due to the dam- investment by the Medical Research Photograph courtesy of CJ DUB - Wikimedia Commons Sir Richard Doll, 1912–2005. aging effects of this habit. Smoking Council (MRC) to determine the epi- cessation can lead to dramatic im- demiology of the disease. Today, less ics at Cambridge. After enjoying a provements in health, so it is impor- than 30% of men in the UK smoke and lively dinner at Trinity College, which tant for physicians to understand the the knowledge that smoking causes included several pints of his fellows’ factors that prevent pa tients from lung cancer and cardiovascular dis- home-brewed beer, Doll failed his quitting and the resources available. ease is well established, all because of math exam the next morning. He was The greatest success rates for smok- the work of one scientific pioneer who ing cessation result from combining dared to threaten social convention Dr Juren assists with research in the medical and psycho social support. with statistics.2 Healthy Heart Program and will begin a family medicine residency in July at St. John Dr Richard Doll Hospital and Medical Center in Detroit, Sir (William) Richard Shaboe Doll Michigan. Dr Frohlich is a professor of was born in 1912 in Hampton, Mid- pathology and laboratory medicine at the dlesex. His father Henry was a physi- University of British Columbia and a found- cian who pressured his son to pursue ing director of the Lipid Clinic at St. Paul’s a medical career because it would pro- Hospital. Dr Ignaszewski is head of the Divi- vide financial stability. Doll, howev- sion of Cardiology at St. Paul’s Hospital, er, was more interested in the elegance medical director of the Healthy Heart Pro- This article has been peer reviewed. of numbers and enrolled in mathemat- gram, and a clinical professor at UBC.

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so irritated with himself that he de - rates of lung cancer in the UK.3 the study questionnaire accurately and clined the university’s offer to let him Doll’s research, activism, and care- were relatively easy to follow through rewrite the test and instead exclaimed, ful statistical science established the the UK’s registry of physicians. Ques- “Oh, damn it, I won’t do mathematics, standard for evidence-based modern tionnaires were completed by over I’ll do medicine as you want, Father.”3 medicine. Because of his work on the 40 000 doctors, of whom 87% were No one could have guessed that a health hazards associated with smok- smokers, and 789 deaths were ana- career change instigated by a few too ing, Britain experienced the world’s lyzed. Again, the results published in many drinks would result in the pre- greatest decrease in premature death, 1956 showed that increased mortality vention of thousands of premature with the rate of men dying before age from lung cancer and coronary throm- deaths worldwide and the evolution of 70 dropping from 20% in 1970 to bosis was directly related to the amount scientific medical research. 5% in 2005, the year of Doll’s own smoked.5 death. Doll’s accomplishments include Doll sent follow-up questionnaires over 400 publications and 20 major to the surviving doctors and published scientific awards, including honorary the results in 1957, 1966, 1971, 1978, degrees from 13 universities. In 1971 1991, and 2001. He undertook a final he was knighted by Queen Elizabeth 50-year assessment in 2004. Over II for his great service to humanity. 30 000 doctors were retained in the Doll’s research, study for the full 50 years, allowing activism, and Doll’s unpopular discovery for the analysis of more than 25 000 In 1950 Doll began interviewing pa - deaths. The conclusion of the final careful statistical tients with lung, stomach, colon, or study showed that over half of the science established rectal cancer from 20 London hospi- deaths were due to lung cancer, chron- tals in order to pinpoint an underlying ic obstructive pulmonary disease the standard for environmental or social factor that (COPD), or ischemic heart disease evidence-based would explain the dramatic rise in related to smoking, and that long-term lung cancer. Initially, he believed that smokers lived an average of 10 years modern medicine. tar from road construction was to less than nonsmokers. Doll was also blame, since it was known to release able to determine that smoking cessa- many carcinogens into the air.2 A study tion at 50 years of age cut the risk of of more than 700 lung cancer patients premature death in half, while cessa- younger than 75 and the same number tion at 30 nearly eliminated the risk of age- and gender-matched controls altogether.6 Doll graduated from St. Thomas’ revealed the common link: smoking. Hospital Medical School in London in This initial study demonstrated that Health risks associated 1937. During his education and early smoking was strongly related to lung with smoking career, he delivered babies in slums cancer, but not to other lung diseases The health risks associated with smok- around the city and became a political nor to cancers of other organs. Doll ing are now well understood and doc- revolutionary, rallying for social re - concluded that “smoking is a factor, umented, thanks to Doll’s pioneering forms that would grant patients of all and an important factor, in the pro- research. The major cardiovascular economic backgrounds access to med- duction of carcinoma of the lung.”4 and respiratory considerations are sum- ical care.1 Doll served in the Royal He himself had been an avid smoker marized by Godtfredsen and Prescott7 Army Medical Corps during the Sec- for 19 years, but quit in 1949 as he and outlined below: ond World War, but was so disgusted began to realize its deleterious effects • Smoking more than doubles the risk by the pompousness of the senior staff on his health. of cardiovascular disease (including that he turned away from clinical Intense resistance to the idea that a myocardial infarct, stroke, peripher- practice and back to his passion for pastime as enjoyable as smoking was al arterial disease, abdominal aortic numbers to begin a career in epidemi- responsible for lung cancer spurred aneurysm, and chronic heart fail- ology. In 1947 the MRC offered Doll Doll to begin another massive study in ure); there is a dose-response rela- a research position with Dr Austin 1951. This time he targeted doctors tionship between the inherent risk Bradford Hill to investigate the rising because they were likely to complete and the amount of tobacco smoked.

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• Incidence of myocardial infarct un - How to diagnose Table 1. Fagerström test for nicotine der age 35 is highly associated with tobacco addiction dependence.9 heavy smoking, and continued smok- Most patients are willing to reveal ing is the greatest predictor of a re - their smoking status; however, statis- • How soon after waking do you smoke peat heart attack. tics show that only 8% of smokers quit your first cigarette? Longer than 60 minutes (0 points) • Although Doll enraged antismoking without help. Therefore, the challenge 31 to 60 minutes (1 point) lobby groups by denying the danger for physicians lies in recognizing 5 to 30 minutes (2 points) of secondhand smoke, secondhand when patients are ready to receive help Less than 5 minutes (3 points) smoke is now known to be a consid- and knowing how to move recalcitrant • How many cigarettes do you smoke erable health concern. When Europe smokers to the realization that they each day? and North America banned smoking need help.9 10 or fewer (0 points) 11 to 20 (1 point) in public locations, this decreased Diagnosis of nicotine dependence 21 to 30 (2 points) the incidence of myocardial infarcts can be made using simple tools, such More than 30 (3 points) by 17%. as the abbreviated Fagerström test Scoring key for nicotine dependence: • More than 50% of chronic heart fail- (Table 1 ). These tools enable the phy - 5–6 points = heavy ure is due to ischemic heart disease sician to determine the degree of 3–4 points = moderate associated with smoking. addiction, but do not indicate whether 0–2 points = light • Smoking increases the risk of lung the patient is interested in addressing cancer, COPD, some interstitial lung it. An understanding of the psycho- Table 2. Stages of readiness to change.9 diseases, and upper respiratory tract logical stages through which smoking infections. COPD patients are also patients progress before being willing 1 Precontemplation more susceptible to community- to quit (Table 2 ) allows the doctor to Not planning to quit within the next acquired pneumonia. identify where patients are in their 6 months Remarkably, the cardiovascular risk thinking about cessation. The physi- 2 Contemplation Considering quitting within the next profile is almost completely reversible cian may then use motivational inter- 6 months if the individual stops smoking before viewing techniques to move the pa tient 3 Preparation the age of 35, and benefits can be seen through these stages to a realization of Planning to quit within the next 30 throughout the cardiovascular system. the need for change that will result in days Smoking cessation prevents coronary action. This often involves discussing 4 Action Has successfully quit for less than heart disease, reduces stroke risk, and the impact that smoking is having on 6 months halts the progression of peripheral the patient’s life and on loved ones, as 5 Maintenance arterial disease. Ex-smokers and non- well as the short- and long-term health Has successfully quit for at least smokers with abdomi nal aortic aneur- risks to which they are exposing them- 6 months ysms have identical risk profiles for selves. Every patient has a unique death and rupture, but the risk is much story; the physician should consider Table 3. Five A’s model for facilitating higher in those who continue smok- the circumstances surrounding the smoking cessation.10 ing. Lung function also shows im - patient’s choice to begin smoking, the provement with smoking cessation, social and physiological factors com- Ask about tobacco use during every office visit even in people who have already pelling them to persist in the habit, and all smokers to quit developed symptoms. The forced ex- the fear and shame associated with Advise the patient’s willingness to quit piratory volume in 1 second (FEV ) is their inability to quit. Assess 1 Assist the patient in his or her attempt the same in individuals who quit smok- to quit ing before age 30 as it is in nonsmok- How to facilitate Arrange follow-up contact ers; however, smoking reduction does smoking cessation not show this benefit.7,8 Smoking ces- Physicians can facilitate smoking cessation is so beneficial to health that sation with the help of the Five A’s that even when a patient is motivated physicians should know how to assist (Table 3 ) recommended by the US to stop smoking, and is treated appro- their patients by diagnosing tobacco Public Health Service and described priately, many health effects associat- addiction and supporting those ready in more detail by Okuyemi and col- ed with smoking cessation, such as to quit a dangerous habit. leagues.10 Physicians should know weight gain, can act as deterrents to

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Table 4. Negative health effects of smoking cessation.8 quitting. The key to overcoming these deterrents is to prepare, reassure, and Effect What patient needs to know encourage patients to persist in mak- Weight gain (with an average increase in The increased risk of cardiovascular disease ing this positive change for their BMI of about 1kg/m2) can be both a associated with a higher BMI does not health and to manage their symptoms. deterrent to abstain from and an excuse to counterbalance the much greater risks of Some of the negative effects of smok- resume smoking. continued smoking. ing cessation and what patients need Increased incidence of hypertension is The cardiovascular benefits of smoking cessation to know about them are summarized greater in people who stop smoking (decreased arterial stiffness and improved lipid (OR=1.8) than in smokers (OR=1.3) due to profile) dramatically outweigh the risks of in Table 4 . unknown mechanisms. Blood pressure (BP) increased BP. Numerous pharmacological inter- may rise independent of weight change. ventions are available for patients who Increased sputum production and Sputum production and infections decrease over wish to stop smoking; however, the respiratory tract infections are seen time if the patient continues to abstain. Those greatest success rates are achieved by following an attempt to stop smoking, who continue smoking have a substantially combining medical and psychosocial partially due to decreased levels of increased risk of bacterial pneumonia, influenza, secretory immunoglobulin A. and tuberculosis. support. Up to 35% of smokers are able to abstain from tobacco for 1 year Constipation affects 17% of those who stop Constipation peaks at 2 weeks after smoking smoking and may be severe in 9%. cessation and usually abates at around when a combination of nicotine re- 4 weeks. Symptoms can be treated with diet, placement therapy (NRT), bupropion, fibre, water, and exercise. and behavioral modification tech- Mouth ulcers may occur in 40% of patients Ulcers typically resolve within 4 weeks in the niques are utilized.9 within 2 weeks after smoking cessation and majority of patients, and are not a side effect of may be severe in 8% of patients. smoking cessation medications. Medical support Altered drug metabolism by cytochrome Following smoking cessation, there may be a Nicotine withdrawal in addicted indi- P450 1A2 (CYP1A2) is associated with need for dose changes of analgesics, viduals is characterized by craving, smoking. anticoagulants, antidepressants, muscle nervousness, restlessness, irritability, relaxants, anticonvulsants, antipsychotics, cancer treatments, antiemetics, antiarrhythmic mood lability, anxiety, drowsiness, agents, beta blockers, and other medications. sleep disturbance, impaired concen-

Table 5. Nicotine replacement therapies.

Therapy Mechanism and dose Risks Patch Provides a constant dose of nicotine through the skin, peaking at 6–12 hours Health risks, such as platelet disturbances, are after application. Most common side effect is local skin irritation, which is more not as serious as the risks associated with common with the 24-hour patch than the 16-hour patch. This can be reduced by continued smoking. Patients who continue to changing the locations of the patch. Sleep disturbance is more common with smoke while using the patch may experience the 24-hour patch and with increased doses, but there is no statistical nicotine toxicity. difference in quit rates between the 24- and 16-hour patches.

Gum Available in 2-mg and 4-mg doses, with a higher dose recommended for patients who smoke more than 25 cigarettes per day. One piece of gum is chewed every 1–2 hours for the first 6 weeks, 2–4 hours for the next 3 weeks, and 4–8 hours for the last 3 weeks.

Gum is considered a Category C drug Lozenge Available in 2-mg and 4-mg doses. Those who smoke within 30 minutes of during pregnancy, while all other forms waking up should use the higher dose. Utilization is the same as for gum. of NRT are Category D. Use cautiously after an acute cardiovascular event, Inhaler Each cartridge contains 4 mg of nicotine. The patient should use 6–16 cartridges knowing that the benefits typically per day for 12 weeks and then slowly taper the usage over the next 6–12 weeks. outweigh the risks. Nasal spray Each spray contains 0.5 mg of nicotine, and this method of administration provides the fastest dose. The patient should use one or two sprays in each nostril every hour for 3–6 months and then slowly taper the usage over the next 4–6 weeks.

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tration, increased appetite, and weight Varenicline (Champix) is consid- Table 6. Smoking cessation resources for 9 gain. Nicotine replacement therapy ered the most effective smoking ces- BC patients. mitigates these symptoms during early sation aid and works by facilitating abstinence, and therefore doubles the dopamine release and maintaining • Smokers Help Line: 1 877 455-2233 9-11 cessation rate. In general, NRT has partial stimulation of the alpha-4 beta- • “On the Road to Quitting” workbook few side effects, with most complaints 2 nicotinic acetylcholine receptors.12,14 www.hc-sc.gc.ca/hc-ps/pubs/tobac- being specific to the method of admin- In a study of patients with stable cardio- tabac/orq-svr/index-eng.php istration (i.e., itchiness at the patch vascular disease, varenicline use was • Resources for BC adults www.quitnow.ca site, jaw pain with gum, mouth and shown to be effective and resulted in a • Resources for BC young adults throat irritation with the inhaler and nonsignificant decrease in death from (ages 19–29) lozenge, and a runny nose with the all causes. The study suggested that www.quittersunite.com inhaler). The various types of nicotine varenicline is safe, but was not pow- • Resources for Canadian teens replacement therapies are summa- erful enough to conclusively establish www.quit4life.com rized in Table 5 . the safety of the drug.14 A further meta- Bupropion (Zyban) is recommen - analysis demonstrated an absolute risk ded for smoking cessation along with increase of 0.24% for a major cardio- Teaching patients behavior modi- NRT. The rate of smoking cessation vascular event in those using vareni- fication techniques can also make the after 1 year of treatment with this drug, cline versus placebo.15 However, given difference between a successful at - together with minimal or moderate varenicline’s ability to more than dou- tempt to stop smoking and a series of counseling, ranges from 23% to 33%. ble the rate of smoking cessation (OR frustrating relapses. Some effective Bupropion works by inhibiting norep- 2.41; 95% CI, 1.91–3.12) the benefits strategies include the removal of trig- inephrine, serotonin, and dopamine of this medication appear to outweigh gers associated with smoking from the reuptake, and is weakly antagonistic the associated risks.12,14 patient’s surroundings. Eliminating to nicotinic receptors. It can be used for cigarettes, lighters, matches, and ash- smoking cessation and reduction.9,10 Psychosocial support trays from the home makes it more Clonidine (Catapres) and nor- Repeated reinforcement of the need to difficult for the patient to indulge. tripty line (Pamelor) are second-line stop smoking from nonthreatening Choosing to go where smoking is not agents,9,10 neither of which was includ- sources is associated with a high com- permitted may also be helpful. For ed in a recent meta-analysis published pliance rate.16 Physicians should ask example, rather than going to the patio in the Canadian Medical Association about smoking at every visit, follow where co-workers typically smoke and Journal.12 Clonidine is an alpha-2 up with the patient, evaluate relapse socialize during breaks, the patient receptor agonist that is used primarily triggers, and encourage abstinence.9,10 could choose to visit a nearby coffee as an antihypertensive agent. It has However, this burden does not need to shop where smoking is prohibited. At been shown to effectively decrease the fall on the physician alone. Many home, hobbies such as knitting or withdrawal side effects of multiple jurisdictions provide smoking coun- model building can keep the patient’s drugs, including nicotine.13 The side selors, group therapy, and smokers’ hands occupied. Another helpful strat- effects of clonidine include postural help lines. There are also numerous egy can be habitual replacement. When hypotension, rebound hypertension, online resources for patients in British the urge to smoke is felt, the patient dry mouth, drowsiness, dizziness, and Columbia who wish to stop smoking can turn to a healthier habit, such as sedation. Nortriptyline is a noradren- (Table 6 ), including a workbook call - chewing gum or eating carrot sticks. ergic tricyclic antidepressant that sig- ed “On the Road to Quitting,” which Habitual replacement allows the pa- nificantly reduces most withdrawal reminds patients of the health, social, tient to handle an object in a similar symptoms. Its side effects include dry and financial benefits of quitting as it manner to a cigarette without the dele- mouth, dysgeusia, gastrointestinal up- guides them through the cessation terious health risks. set, drowsiness, sleep disturbance, process. This workbook is available Despite all these techniques and possible cardiac dysrhythmias, and online, and anyone can order up to 10 strategies, the most critical psychoso- toxicity if taken in excessive amounts. English and 10 French print copies cial factor in successful smoking ces- Most studies have examined its effec- for free. It can also be provided in sation is support from family and close tiveness in combination with intense large print, diskette, audiocassette, friends. The physician is advised to counseling in depressed patients.13 and braille form.15 meet with the patient and his or her

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partner to talk about the importance The health benefits noted in patients who of support and accountability. If the stop smoking altogether are not found in partner is also a smoker, the risk of relapse is extremely high and the part- patients who simply reduce their nicotine ner should be strongly encouraged to consumption. However, many of these risks are commit to a program of abstinence as well. dose-dependent, so reduction in the amount smoked could decrease the patient’s probability Reduction vs cessation of a significant cardiovascular event. The benefits of smoking reduction have been debated in the medical lit- erature.9,10,16 In general, the health benefits noted in patients who stop co use on the cardiovascular system. Clin Respir J 2011;5:187-194. smoking altogether are not found in Physicians can help their patients 8. Gratziou C. Respiratory, cardiovascular patients who simply reduce their nico- by diagnosing tobacco addiction and and other physiological consequences of tine consumption. However, many of recommending the combined use of smoking cessation. Curr Med Res Opin these risks are dose-dependent, so nicotine replacement therapy, a med- 2009;25:535-545. reduction in the amount smoked could ication such as bupropion or vareni- 9. Mallin R. Smoking cessation: Integration decrease the patient’s probability of a cline, and psychosocial support. of behavioral and drug therapies. Am significant cardiovascular event. One Fam Physician 2002;65:1107-1114. study suggests that smoking reduction Competing interests 10. Okuyemi KS, Nollen NL, Ahluwalia JS. is critical for patients who want to stop None declared. Interventions to facilitate smoking ces- smoking16 because the combination of sation. Am Fam Physician 2006;74:262- smoking and NRT can maintain the References 271. patient’s nicotine dose while reducing 1. Wood J. Life of a revolutionary. Universi- 11. Nides M. Update on pharmacologic the amount of time the patient engages ty of Oxford website. Last updated 13 options for smoking cessation treat- in the activity. This gives patients a May 2010. www.ox.ac.uk/media/science ment. Am J Med 2008;121(4 suppl 1): sense of control over their smoking _blog/091111.html. S20-31. patterns and helps them change their 2. Sir Richard Doll: A life’s research. BBC 12. Eisenberg MJ, Filion KB, Yavin D, et al. behaviors. Gradual accomplishments News. Last updated 22 June 2004. Pharmacotherapies for smoking cessa- further motivate the patient to stop http://news.bbc.co.uk/2/hi/health/38269 tion: A meta-analysis of randomized con- smoking, and reduce the severity of 39.stm. trolled trials. CMAJ 2008;179:135-144. withdrawal symptoms. Physicians 3. McKie R. The Observer profile: Richard 13. Frishman WH, Mitta W, Kupersmith A, et ought to support patients who are Doll. Topic of Cancer. The Guardian 7 July al. Nicotine and non-nicotine smoking motivated to reduce their nicotine 2002. www.guardian.co.uk/education/ cessation pharmacotherapies. Cardiol intake, and provide information and 2002/jul/07/research.highereducation. Rev 2006;14:57-73. encouragement to move them toward 4. Doll R, Hill AB. Smoking and carcinoma 14. Rigotti NA, Pipe AL, Benowitz NL, et al. complete abstinence. of the lung. Preliminary Report. 1950. Efficacy and safety of varenicline for Bull World Health Organ 1999;77:84-93. smoking cessation in patients with car- Summary 5. Doll R, Hill AB. The mortality of doctors in diovascular disease: A randomized trial. Millions of people die prematurely relation to their smoking habits: A pre- Circulation 2010;121:221-229. each year as a result of smoking. For- liminary report. 1954. BMJ 2004;328: 15. On the road to quitting: Guide to becom- tunately, fewer smoking-related deaths 1529-1533. ing a non-smoker. Ottawa: Health Cana- occur today than in the past because of 6. Doll R, Peto R, Boreham J, et al. Mortal- da; 2007. www.hc-sc.gc.ca/hc-ps/alt_ the pioneering work of Dr Richard ity in relation to smoking: 50 years’ obser- formats/pdf/pubs/tobac-tabac/orq- Doll, who established the standard for vations on male British doctors. BMJ svr/cbns-gdnf-eng.pdf. evidence-based modern medicine and 2004;328:1519-1528. 16. Le Houezec J, Säwe U. Smoking reduc- demonstrated the link between smok- 7. Godtfredsen NS, Prescott E. Benefits of tion and temporary abstinence: New ing and lung cancer. Doll also con- smoking cessation with focus on cardio- approaches for smoking cessation. J Mal firmed the detrimental effect of tobac- vascular and respiratory comorbidities. Vasc 2003;28:293-300.

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