P&T News: February/March 1999

Smoking Cessation

Charles S. Dayton, R.Ph.
Jeff S. Wilson, M.D.
Peer Review Status: Internally Peer Reviewed by Joel V. Weinstock, M.D., Director of Gastroenterology/Hepatology

Smoker Demographics
In 1965, more than half of all men and 34% of women in this country over 18 years of age smoked cigarettes.¹ People smoked in the classroom, in hospitals, and every venue accessible by the public. By 1993, the incidence of smoking had decreased to less than one-third of men and little over one-fifth of women. However, 50 million people in the U.S. continued to smoke. Recently, there has been an increase in the number of cigarette smokers in the 25-year-old and younger age group. In particular, the number of high school seniors in Iowa who report smoking regularly has risen from 15% to 24% between 1990 and 1996 .²

Health and Economic Impacts of Cigarette Smoking
Death Rates
In the U.S., there are an estimated 470,000 premature smoking-related deaths per year.³ These premature deaths represent more than the following causes of death combined: alcohol-related deaths, infectious diseases, exposure to toxic agents, firearms/gunshot wounds, high-risk sexual behavior, and motor vehicle fatalities.³

Cancer
Lung cancer is the most common cause of cancer-related death in the U.S. Cigarette smoking is the major risk factor for lung cancer. After 10 years of not smoking, a patient has a 30 to 50% decrease in risk of developing lung cancer. After 15 to 20 years, this risk returns toward the incidence for nonsmokers, though it may never return totally to baseline in previously heavy smokers. The health impact on oral cancers is even more dramatic. After 5 years of smoking cessation, there is a 50% reduction in the incidence of oral cancer.³

Heart Disease
Smoking is a major risk factor for the development of heart disease. The risk of cardiovascular disease is reduced by 50% within the first year after the patient stops smoking, and continues to decline toward that of a non-smoker. After several years of abstinence, the risk of cardiovascular disease may return to that of a nonsmoker. ³

Chronic Obstructive Pulmonary Disease
The primary risk factor for the development of chronic obstructive pulmonary disease (COPD) is cigarette smoking. An estimated 14 million persons in the U.S. suffer from COPD. ¹ 1991, COPD ranked as the fourth leading cause of death in this country. Ten to fifteen percent of all smokers will develop clinically significant airflow obstruction while smoking. ¹

Economics of Smoking-Related Illness and Cessation
One study estimated that in 1993 there were $50 billion in direct total medical care costs assigned to smokingrelated illness in the U.S. ³ This amounted to almost $30 billion in hospital charges, $15.5 billion in physician fees, $4.9 billion in nursing home charges, $1.8 billion in prescription drug costs, and $900 million in home health care fees.

Smoking cessation programs are cost effective. Current stop smoking guidelines are calculated to cost about $3500 per life year saved.⁴ That figure includes counseling time, materials, and drug costs. The cost to perform the currently suggested mammography screening on women 40 to 49 years of age is approximately $52,000 for every life year saved. Similarly, the cost is approximately $23,000 per life year saved to screen men at 40 years of age for hypertension . ⁴

Smoking Cessation Intervention by Health Care Professionals
A meta-analysis of nine studies examined the impact of identifying smoking status of clinic patients on rates of clinician interventions. ⁵ The rate of intervention was less than 40% in the group in which no intake questions were included, but climbed to 66% when smoking status was included on the clinic intake document. Clinic documents ascertaining data about the patient's current state of health, such as blood pressure, temperature and heart rate, should also include smoking status identification. When there is no smoking status identification in place, the estimated cessation rate of patients is 3% per year. Implementation of smoking status identification increased the cessation rate to 6.4%. By increasing quit rates from 3% to 6% in the population who smoke (50 million in the U.S.), an increase from 1.5 million to 3 million people who quit smoking per year could be realized, with further decreasing numbers over time.

When a physician, pharmacist, nurse, physician assistant, or any other health care provider counsels patients alone, a quit rate of about 12% is realized. When multiple health care providers counsel a patient about smoking cessation, the quit rate increases to 25.5 %. ⁵

A meta-analysis of five studies examined the efficacy of inpatient smoking cessation strategies. The cessation rate, even without smoking cessation counseling, is high. Quit rates are higher when patients are sick. Quit rates increase from a baseline of 18% to 23% after counseling. Clearly, motivation to stop smoking increases when patients become acutely ill. ⁵

The Agency for Health Care Policy and Research (AHCPR) has set forth guidelines to assist primary care health care workers in establishing smoking cessation programs. The major strategic points in smoking cessation counseling in this program are:

• Ask - Systematically identify all tobacco users at every visit. Expand the vital signs to include smoking status.
• Advise - Strongly urge smokers to quit in clear, strong and personalized language. Encourage clinic staff to reinforce the cessation message and support the patient's quit attempt. Identify smokers willing to make a quit attempt. Ask every smoker if he or she is willing to make a quit attempt at this time.
• Assist - Aid the patient in quitting. Help the patient with a quit plan.
• Arrange - Schedule a follow-up contact, either in person or via telephone.

Resources to aid in the development of stop smoking programs are available from AHCPR. ⁵ A book entitled Clinical Practice Guidelines on Smoking Cessation may be obtained from this agency, either by request or via the World Wide Web (http://text.nlm.nih.gov/tempfines/is/tempD146530.html)

Many patients stop smoking on their own. For smokers unable to quit, referral to a smoking cessation program and pharmacologic intervention is recommended.

Pharmacology of Nicotine
Nicotine is the drug in tobacco responsible for addiction to cigarettes and other tobacco products. Nicotine dependence meets the American Psychiatric Association's criteria for a substance use disorder. Nicotine has a similar addiction liability profile to cocaine, morphine, or amphetamine (Figure 1). ⁶ When advising patients about the value of smoking cessation, an understanding of the addictive properties of nicotine is essential.

The pharmacology of nicotine absorption while smoking is illustrated in Figure 2. ⁷ When smoking the first cigarette of the day, blood nicotine levels rise rapidly, and with continued smoking throughout the day, a steadystate level of blood nicotine is achieved. Nicotine levels are at their nadir when a smoker awakens in the morning. The first cigarette of the day Is the most satisfying and hardest to give up. Nicotine transdermal patches, on the other hand, release drug evenly over a 16- or 24-hour period (Figure 3). ⁸ With standard nicotine patch therapy, blood nicotine levels are typically lower than daytime levels achieved by heavy smokers (Figures 2 and 3). Figure 4 ⁷ illustrates comparative nicotine absorption from one cigarette, chewing tobacco, oral snuff, and 4 mg of nicotine polacrilex gum. Abrupt withdrawal from cigarette smoking may lead to nicotine with- Four or more of the following signs characterize nicotine withdrawal syndrome (Am Psychiatric Association, 1994):

• Dysphoric or depressed mood
• Insomnia
• Irritability, frustration, or anger
• Anxiety
• Difficulty concentrating
• Restlessness or impatience
• Decreased heart rate
• Increased appetite and weight gain

Nicotine replacement blunts but does not eliminate these symptoms. The efficacy of regimens containing nicotine for smoking cessation has been summarized by a series of meta-analysis studies. Three such analyses with nicotine gum were reviewed by the AHCPR.⁵ With nicotine gum, at 12 months, smoking cessation rates approached 18%, compared to about 12% in the placebo group. Both groups received counseling along with either placebo or nicotine gum. Similar meta-analysis studies of the nicotine patch indicate an approximate doubling of the quit rate compared to placebo. It is important to remember that most smoking cessation studies rely not only on the drug component, but also on counseling. Results are better when counseling is employed.

Nicotine Replacement Products
Nicotine replacement products, approximate length of use, and costs are described in Table 1. The highest dose nicotine patch is indicated for heavy smokers. One may begin with a lower concentration if the patient is a relatively light smoker (< 0 cigarettes per day). Dosing should be individualized. Nicotrol transdermal patch is available in a 15 mg for 16 hours per day form and is used for 6 weeks. This is marketed to enable people who have trouble sleeping or have other nocturnal nicotine side effects to remove the patch while sleeping. Nicotine polacrilex chewing gum is effective, but requires careful instruction on proper use. Table 1. Summary of Nicotine Replacement Products

Product	OTC/Rx	Directions for Use	AWP Cost
Transdermal Patches
HabitrolTM # (Novartis)	Rx	7 mg/24 Hours for 2-4 weeks, then discontinue 14 mg/24 Hours for 2-4 weeks* 21 mg/24 Hours for 4-6 weeks	$110 for 30 $116 for 30 $122 for 30
Nicoderm CQTM# (SK Beecham)	OTC	7 mg/24 Hours for 2 weeks, then discontinue 14 mg/24 Hours for 2 weeks* 21 mg/24 Hours for 6 weeks	$98 for 30 $104 for 30 $110 for 30
ProstepTM (Lederle)	Rx	11 mg/24 Hours for 2-4 weeks (Optional), then discontinue 22 mg/24 Hours for 4-8 weeks	$35 for 7 $38 for 7
NicotroITM (McNeil)	OTC	15 mg/16 Hours, for 6 weeks, then discontinue	$43 for 14
Nasal Spray
Nicotrol NSTM (McNeil)	Rx	0.5 mg/spray. Max 5 sprays/hr, 40 doses daily (do not sniff, swallow, or inhale)	$36 for 10 ml (0.5mg/Inh)
Inhaler
Nicotrol InhalerTM (McNeil)	Rx	10 mg (4 mg delivered) per cartridge Use 6 cartridges per day for 3-6 weeks, max of 16 cartridges per day for 12 weeks, then reduce gradually over 12 more weeks.	$41/kit (Kit=42 cartridges/ 1 mouthpiece 10 mg/cartridge)
Chewing Gum
NicoretteTM chewing gum (SK Beecham)	OTC	Nicotine polacrilex chewing gum Available as 2 mg and 4 mg Use 4 mg if greater than 1 pack per day smoker Begin every 1-2 hours, and gradually decrease Max 24 pieces per day	$48 for 108 (2 mg) $54 for 108 (4 mg)

Bold = Product currently stocked at UIHC
* May begin with 14 mg patch for light smokers, or under 100 pounds.
AWP = Average Wholesale Price
NS = Not a stocked product at UIHC
# The Pharmacy and Therapeutics Subcommittee considers Nicoderm CQTM and HabitrolTM to be therapeutically equivalent and may be used interchangeably at equal milligram strengths.

Subjects were smoking on entry, but stopped while on the patch.

A nicotine nasal spray has been introduced recently. Nicotine is absorbed through the mucus membranes of the nose. The drug should be sprayed in the nose and left there to let absorption occur. There is a high incidence of mucus membrane irritation, with 81% of patients treated reporting mild to moderate nasal irritation after 3 weeks of use (Data from McNeil).

Additionally, an inhaler form of nicotine is also available. This product is marketed as a 10 mg container, delivering 4 mg of drug over 20 minutes per cartridge. This devise does not mimic nicotine blood concentrations achieved from smoking cigarettes. Most absorption of nicotine from the inhaler takes place in the buccal mucosa and is therefore relatively slow to reach the blood stream.

No one form of nicotine replacement therapy has been shown to be superior. Health care providers are encouraged to prescribe enough nicotine. Patients smoke at differing rates. The amount of nicotine extracted from each cigarette also varies, depending on how aggressively it is smoked.

Precautions for Using Nicotine Replacement Products
Patients with cardiovascular disease may be treated safely with nicotine replacement products.9 Nicotine replacement therapy is likely to be less dangerous to the patient than continued smoking. The health care provider must weigh the benefits of smoking cessation using nicotine, versus the risks of using these products in cases of cardiovascular disease. Patients with cardiovascular disease treated with nicotine replacement should be carefully instructed not to smoke when using nicotine products.

The FDA warns against using nicotine products during pregnancy. All nicotine replacement product labeling contains this warning and behavioral methods of smoking cessation are preferred. However, nicotine therapy is likely to be less dangerous to the fetus than continued cigarette smoking. In addition to nicotine, pregnant smokers are exposed to carbon monoxide and other toxins in cigarette smoke. Nicotine replacement therapy may be considered during pregnancy if the increased benefits of smoking cessation outweigh the risks of nicotine replacement therapy and potential concomitant smoking. Skin reactions are a potential adverse event with the use of the transdermal patch. These reactions may be treated with low-dose topical steroid products.

For cost comparison, a carton (10 packs) of premium cigarettes sells for, approximately $27. A week's supply of nicotine patches costs $28, while a 7-day supply of cigarettes also costs $28 for a one and one-half-pack-per-day cigarette smoker.

Bupropion for Smoking Cessation
The antidepressant bupropion (Wellbutrin^TM) has been marketed solely for smoking cessation under the trade name Zyban^TM. Bupropion has given clinicians another option for pharmacotherapy of smoking cessation. The mechanism of action of bupropion is not well understood. However, it is thought to work on the neurochemistry of nicotine addiction by enhancing brain dopamine levels and affecting noradrenergic neurons. Dopaminergic and noradrenergic pathways are involved in nicotine addiction and withdrawal.

Bupropion has a mean elimination half-life of 21 hours and is 84% protein bound. Steady-state plasma concentrations for bupropion and hydroxybupropion are achieved in 5 days, while some other metabolites take as long as 8 days to reach steady state. Bupropion is primarily metabolized by the liver to hydroxybupropion by way of the CYP2B6 enzyme system.

Zyban^TM is begun at a dose of 150 mg daily and may be increased to 150 mg twice daily after 3 days. Therapy should continue for a total of 7 to 12 weeks. The patient, in consultation with a health care provider, sets a "target quit smoking date" of 10 to 14 days into treatment. The optimal duration of treatment with Zyban^TM is unknown, although the manufacturer recommends no longer than 12 weeks.

Bupropion is contraindicated in patients with seizure disorders. Also, Zyban^TM should not be used in patients receiving Wellbutrin^TM, Wellbutrin SR^TM, or any other medication that contains bupropion. Additionally, MAO inhibitors (e.g., phenelzine, tranylcypromine) should-not be used in conjunction with bupropion, and patients suffering from bulimia or anorexia should not receive bupropion therapy. Rates of adverse occurrences are listed in Table 2.¹⁰

Table 2. Bupropin HCl Adverse Events¹⁰

	ZybanTM (%)	Placebo (%)
Insomnia	31-40	18-21
Dry Mouth	1--11	4-5
Rhinitis	12	8
Dizziness	8-10	6-7
Anxiety	8	6

Bupropion is rated as pregnancy category B. Animal data reveal no fetal abnormalities, but human studies are lacking. The manufacturer recommends using behavioral methods of smoking cessation as a first option. As in the case of nicotine replacement products, good clinical judgement should be used when counseling a pregnant patient who smokes.

Results of a study using bupropion in smoking cessation are shown in Table 3.¹¹ Point prevalence quit rates are rates of abstinence for a given study week. Results of two dosing regimens show that point prevalence quit rates at one year are significantly better with bupropion administration plus counseling than placebo plus counseling. Interestingly, using either 150 mg of bupropion daily or twice daily made no significant difference in quit rates.

Results of a trial in which nicotine replacement therapy, bupropion alone, and a combination of nicotine replacement therapy and bupropion are shown in Table 4.¹² Rates of smoking cessation using point prevalence data are comparable for bupropion and bupropion plus nicotine replacement therapy (p=0.22). However, both therapies were superior to placebo. Contrary to past published data, nicotine replacement therapy alone did not appear to be superior to placebo (p=0.84). This confounding finding needs further study before judging bupropion to be superior to nicotine replacement therapy for smoking cessation.

Zyban^TM is appropriate therapy for patients who previously failed to quit smoking using nicotine replacement therapy. Additionally, it appears that using Zyban^TM as initial therapy may be considered. The clinician must exercise good clinical judgement after carefully assessing the needs of the individual patient.

Table 3. Bupropion HCl - Results of Clinical Trials¹¹
Smoking Cessation Data at One Year with Bupropion

	Placebo (N=153)	Bupropion 150 mg Daily (N=153)	Bupropion 150 mg BID (N=156)
Point Prevalence (Measured Weekly)	12.4%	22.9%	23.1%
P value, compared to placebo	--	P=0.02	P=0.01

Summary
Smoking cessation is an important issue for all health care providers. Stopping smoking improves the health of the patient and can conserve health care resources. Smoking cessation is cost effective and should be advocated by all health care professionals.

Table 4. Bupropion HCl Plus Nicotine Replacement Therapy-Results of Clinical Trials12 Smoking Cessation Data at One Year
XXXX	Placebo (N=82)	Nicotine Patch (N=152)	Bupropion (N=129)	Bupropion + Patch (N=181)
Point Prevalence (Measured Weekly)	15.6%	16.4%	30.3%	35.5%*
P value, compared to placebo	--	P=0.84	P less than or equal to 0.001	P less than or equal to 0.001
*P value compared to bupropion alone=0.22

References

1. Am J Respir Crit Care Med. 1995;152:S77-SI20.
2. Iowa Department of Public Health Statistics, 1997.
3. US Department of Health and Human Services: The Health Benefits of Smoking Cessation: A Report of the Surgeon General (DHHS publication No. [CDC] 90-8416), Rockville, Maryland, US Government Printing Office, 1990.
4. JAMA 1997; 278:1759-66.
5. Fiore MC, Bailey WE, Cohen SC, et al. Smoking Cessation: Clinical Practice Guidelines No. 18. Rockville, MD: Agency for Health Care Policy and Research; April 1996 Publication No. 96-0692.
6. Chest 1988; 93S:37S-55S.
7. N Engl J Med 1988; 319:1318-30.
8. Clin Pharmacol Ther 1993; 54:98-106.
9. N Engl J Med 1996; 335:1792-8.
10. Glaxo-Wellcome, Inc. Product Insert, Zyban, 1997.
11. N Engl J Med 1997; 337:1195-202.
12. N Engl J Med 1999; 340:685-91.

Citalopram
Tablets: 20 mg, 40 mg
Citalopram (Celexa® - Forest/Parke-Davis) is a selective serotonin inhibitor (SSRI) indicated for the treatment of depression.

Emergency Contraceptive Kit
Kit: 4 contraceptive tablets each containing levonorgestrel 0.25 mg and ethinyl estradiol 0.05 mg; pregnancy test; and patient information booklet
This kit is indicated for the prevention of pregnancy after unprotected coitus.

Paricalcitol
Injection: 5 mcg per 1 ml
Paricalcitol (Zemplar® - Abbott) is a synthetic Vitamin D analog and is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.

Repaglinide
Tablets: 0.5 mg, 1 mg, 2 mg
Repaglinide (Prandin® - Novo Nordisk) is an oral hypoglycemic agent that lowers blood glucose by stimulating the release of insulin for the pancreas. It is indicated for use in patients for the treatment of type 2 diabetes mellitus as monotherapy or in combination with metformin. 

Additional Actions:

Heparin 100 units per ml Injection
A 1 ml vial of preservative-free injection has been added to stock.

Mycophenolate Mofetil Injection
An injectable formulation of mycophenolate (Cellcept® -Roche) has been added to stock.

Nandrolone Decanoate Injection
A 200 mg per ml concentration has been added to stock.

Drugs Deleted From Stock:

Nonoxynol 9 (Deflen®) Vaginal Foam
Discontinued due to low use. Nonoxynol 9 vaginal contraceptive gel 2% (Gynol 11® Contraceptive Jelly) is available.

The contents of the trays will remain unchanged, and each drug's location within the tray (relative to other drugs and supplies) will also be unchanged.

The new containers will gradually be phased into use during the next several months as the trays currently located in patient care areas are used or their contents expire. The conversion should be completed by this summer.

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