TABLE OF CONTENTS

Introduction

Cigarettes are highly addictive substances, and the overwhelming majority of people who attempt to quit smoking relapse within days¹. In the United States, fewer than 10 percent of those smokers who quit smoking for a day remain abstinent one year later ². Primary care clinicians are in a unique position to influence smokers, because they have extraordinary access to this population. At least 70% of smokers see a physician each year³, and many of these cite a physician’s advice to quit as an important motivator for attempting to stop⁴. Unfortunately, only about half of current smokers have ever been asked about their smoking status or urged to quit⁵.

Today, physicians have more weapons to help stop smoking than ever before. An important part of this arsenal is nicotine replacement therapy (NRT). As of January 1999, nicotine replacement includes four delivery systems: gum, transdermal patch, intranasal spray, and oral inhalation. This overview will examine the evidence available for each of these systems and provide information regarding use, efficacy, and safety. These forms of nicotine replacement will be compared with one another and with cigarettes.

CIGARETTES

All widely marketed brands of cigarettes contain sufficient nicotine to establish and sustain dependence readily.² Each cigarette contains 6 to 11 mg of nicotine, of which the smoker absorbs 1 to 3mg. Therefore, the typical pack per day smoker absorbs 20 to 40 mg of nicotine each day.⁸ To date, smoking is the fastest delivery system for nicotine. Absorbed into the arterial system via the lungs, nicotine passes through the brain in as little as 10 to 19 seconds and reaches peak blood concentrations within five minutes.⁶ The elimination half life of nicotine is about two hours. Therefore, concentrations accumulate over six to eight hours during regular smoking.²

Nicotine gum was the first form of NRT to be approved by the Food and Drug Administration. The 2 mg form was approved in 1984, and the 4 mg form was approved in 1992. Both strengths of nicotine gum became over the counter products in April 1996.⁶

Nicotine gum has the most available evidence of any of the forms of nicotine replacement. In 1984, Hjalmarson, et al published a randomized, placebo-controlled, double-blind study which showed the effectiveness of 2 mg nicotine chewing gum as an adjunct to group therapy for smoking cessation. After one year, 29% of the 106 subjects treated with nicotine gum had remained abstinent throughout the year compared with 16% of the 99 subjects treated with placebo (p<.05) This study also found that adverse effects were few and not serious. In the nicotine group, 3% of the subjects were still using the gum after two years in comparison to no subjects in the placebo group using the gum over 6 months. ⁹

In 1995, Herrera N, et al showed that highly nicotine-dependent smokers need higher doses of nicotine replacement to improve smoking cessation. In a randomized, double-blind procedure, the high dependent smokers were given gum containing 4 mg of nicotine(87) or 2 mg of nicotine (81), and the smokers with medium or low dependence were given gum containing 2 mg (76) or placebo gum (78). In the high-dependent group, two year abstinent rates were 34% in the subjects given the 4 mg dose compared with 16% for those using the 2 mg dose. In the group with low or medium dependence, the two year abstinent rate was 39% for the subjects given the 2 mg dose and 17% for those given placebo gum. It should be noted that this study was performed in the setting of a behavior modification program.¹⁰

In contrast to smoking, nicotine gum provides slower, lower, and less variable plasma nicotine concentrations.² Approximately 50 percent of the nicotine from the gum is absorbed while chewing, and nicotine concentration peaks approximately 30 minutes after chewing a single piece.⁷ Therefore, 10 to 12 doses per day provide approximately 10 mg per day from the 2 mg form and 20 mg per day from the 4 mg form. This is about one third to one half the usual daily intake of a person who smokes 30 cigarettes a day.²

It is very important that patients be taught the proper techniques for using nicotine gum.⁷ The gum should be compressed a few times with the teeth until a peppery sensation is felt in the mouth. The gum should then be "parked" between the cheek and gum. This cycle should be repeated every minute or so for up to 30 minutes per dose.² Eating and drinking (except water) should be avoided 15 minutes prior to and during use of the gum. Acidic beverages such as coffee and fruit juices have been shown to reduce the absorption of nicotine.⁷

Before and while using nicotine gum, smokers must stop smoking.⁶ The prescription should specify a fixed dosing schedule. Initially (at least 1 to 3 months), regardless of withdrawal symptoms, patients should use at least one piece of gum an hour during waking hours. No more than 30 pieces of 2 mg gum or 20 pieces of 4 mg gum should be chewed per day.² To determine the initial starting dose, it has been proposed that patients smoking more than a pack per day or whose Fagerstrom scores for nicotine dependence exceed 6 should begin on the 4 mg dose. All others can begin with 2 mg.²

Patients should understand that it is possible to become addicted to nicotine gum. Therefore, it is not recommended that the gum be used more than 4 to 6 months. Gradual tapering of the dose is suggested to avoid the occurrence of nicotine withdrawal.⁷ In addition, patients should be taught to dispose of used gum properly to avoid inadvertent use by children or pets.

Major adverse effects of nicotine gum are infrequent and rarely deter use.¹¹ Common side effects include sour taste in the mouth, traumatic injury to the oral mucosa or teeth, jaw aches or fatigue, hiccups, throat irritation, or nausea. Tolerance to most adverse effects develops over the first week of use, and education about the proper techniques for using the gum have been shown to decrease adverse effects.⁷ It should also be noted that nicotine gum has been shown to delay, but not prevent, weight gain associated with smoking cessation.¹²

The nicotine patch became available in the United States in December 1991.⁶ The FDA has thus far approved four transdermal nicotine patches: Habitrol, Nicoderm and Nicoderm CQ, Nicotrol, and Prostep. Nicoderm CQ and Nicotrol are available over the counter, and the others are by prescription only.⁶ The four patches differ in size, shape, and total nicotine content, but there is no apparent difference in efficacy among the products. All of the patches deliver nicotine for a continuous 24 hour period, except Nicotrol which is used for only 16 hours.⁷

The best available evidence for the efficacy of transdermal nicotine patches was published in June 1994. Fiore et al performed a meta-analysis of double blind, placebo controlled nicotine patch studies of four weeks or longer with random assignment of subjects, biochemical confirmation of abstinence, and subjects not selected on the basis of specific diseases (eg. coronary artery disease). They compared smoking abstinence rates at end of treatment and at 6 month followup. Across 17 studies (n=5098 patients), they found that abstinence rates for the active patch were 27% (vs 13% for placebo) at the end of treatment and 22% (vs 9% for placebo) at 6 months. The combined Odds Ratios for efficacy of active patch vs placebo patch were 2.6 at the end of treatment and 3.0 at 6 months.¹³

The meta-analysis addressed other important issues as well as overall efficacy. It found that the 16-hour patch and the 24-hour patch were essentially equally efficacious. It found that intensive counseling enhanced clinical success with the pateh, but the patch was also effective with minimal adjuvant therapy. In addition, the study found that extending patch treatment beyond 8 weeks did not appear to increase efficacy, and the traditional practice of weaning patients from the patch did not have an added beneficial effect.¹³

Compared with nicotine gum, the nicotine patch provides more predictable, though often lower, levels of nicotine in the blood. Transdermal medications provide 0.9mg of nicotine per hour, achieving maximal systemic doses in two to three days, at which time the plasma nicotine concentrations are generally lower than a pack per day smoker.² The advantages of the patch include once daily dosing to increase compliance and a shorter duration of treatment than the gum.⁷

It is well established that the blood nicotine levels achieved from a 22 mg nicotine patch in abstinent smokers are lower than those achieved while the smokers were smoking their usual number of cigarettes.² Because of this, the question of higher dose nicotine patch therapy was raised. In November 1995, Dale et al published a randomized, double blind study looking at the percentage of nicotine replacement and smoking cessation. Seventy-one smokers were stratified according to light , moderate, or heavy smoking rates. Then the subjects were randomly assigned to 11-, 22-, or 44- mg/day dose of transdermal nicotine. Percentage of cotinine replacement ( a metabolite of nicotine), smoking abstinence rates, withdrawal symptoms, and nicotine toxicity were assessed at end of treatment(8 weeks), 3, 6, 9, and 12 months. ¹⁴

The results of the study showed a positive association between the week 2 patch dose and the biochemically confirmed smoking abstinence at the end of patch therapy (p=.007) but not for subsequent followup times. With the 44 mg dose, more subjects did achieve 100% or greater nicotine replacement without untoward adverse effects, except for one case of nicotine toxicity observed in a light smoker assigned to the 44 mg dose. In summary, the study did not show higher abstinence rates with the 44 mg nicotine patch, but it did show that the higher dose appeared to be safe in heavy smokers and the high dose patch was superior in relieving withdrawal symptoms.¹⁴ Perhaps, further studies are needed with various nicotine patch dosages.

As with the nicotine gum, dosing of the nicotine patch is very important.⁷ It is currently recommended that patients who smoke more than 10 cigarettes per day should be treated with the highest available dose of the brand used. In a study of patients who smoked one pack per day or more, those initially treated with 21mg per day had higher rates of cessation at all times than those treated with 14 mg per day.¹⁵ Those patients who smoke fewer than 10 cigarettes per day should start with the mid-range transdermal dose. Finally, those who smoke 5 or fewer cigarettes per day appear to have a low level of nicotine dependence and have few symptoms of withdrawal when they quit smoking. It is unclear if these patients benefit from nicotine replacement.²

Once prescribed, proper use of the nicotine patch should be explained to the patient. Before beginning transdermal therapy, the patient must stop smoking. On the patient’s quit day, the patch should be applied to a hairless portion of the skin after it has been cleansed with soap and water and then dried.⁷ The patch should be pressed onto the skin for about ten seconds. It is normal to feel a mild itching or tingling sensation for the first hour after topical patch application. In addition, the most common side effect associated with the patch is local inflammation of the skin at the site of application. This can be reduced by changing the location of the patch daily. However, the use of the patch should be discontinued if skin redness does not resolve within 4 days.²

As described earlier, use of the patch beyond eight weeks has not been proven to be beneficial, and weaning of the patch dose may be unnecessary.¹³ However, physicians may want to consider the patient’s preferences when deciding whether to wean the dose or not.

Nicotine nasal spray was approved in the United States in 1996 as a nicotine replacement therapy.⁶ It was designed for rapid delivery of nicotine into the system, mimicking the effects of cigarette smoking. Its fast delivery targets highly dependent smokers who need a faster stimulatory effect than current replacement treatments for successful abstinence.²

Three double blind, placebo controlled studies have shown that the nicotine nasal spray was more effective than placebo for short- and long-term sustained smoking abstinence.⁷ In August 1992, Sutherland et al published the first study which showed the efficacy and safety of the nicotine nasal spray as an adjunct to smoking cessation therapy. Two hundred twenty-seven cigarette smokers attending the Maudsley Hospital Smokers Clinic received four weeks of supportive group treatment plus active nicotine (0.5mg per shot) or placebo nicotine nasal spray. The main end point was biochemically validated complete abstinence from smoking. At one year, 26% of the subjects randomized to active nicotine spray were validated abstinent as opposed to 10% of those assigned to the placebo spray (p<0.001). The study found that the advantage of the active spray was greatest in the heaviest smokers. In addition, tobacco-withdrawal symptoms, craving for cigarettes, and weight gain in abstinent subjects were reduced by the active spray. No serious adverse effects were encountered, and only two subjects had to discontinue the spray as a result of minor irritant side effects.¹⁶

As stated earlier, two other randomized, placebo controlled, double blind studies have also shown the effectiveness of the nasal nicotine spray. In both studies, the three and six month abstinence rates were more than double the rate for the placebo. At one year, the nasal spray nearly doubled or more than doubled the rate of effectiveness compared with placebo, depending on the study.^17,18

Unlike the gum and the transdermal patch, the nicotine nasal spray is a prescription product. It is likely that the nasal spray has more potential for addiction than other forms of nicotine replacement, because the blood nicotine levels achieved are higher and faster than the patch or gum. In doses of 1-2mg the maximum concentration occurs within about 15 minutes, closely resembling the pharmacokinetics of nicotine after smoking.⁶ Approximately 43% of smokers started on the nicotine nasal spray will continue using the product 12 months after smoking cessation.²

The proper use of the nicotine nasal spray must be explained to the patient. Before using the spray, the patient must stop smoking. Prior to the quit date, the patient should be instructed on how to "prime the pump" to ready it for use. This involves pumping the contents of the pump toward a tissue or paper towel (six to eight times) until a fine mist appears. The pump is then ready for use. The patient should then blow his/her nose if it is not clear, and tilt the head slightly backward. While breathing through the mouth, the patient sprays once in each nostril, taking care not to intentionally inhale or sniff while spraying. The patient should then wait 2 to 3 minutes before blowing the nose.⁷

Each spray of the currently available device delivers 0.5 mg of nicotine. Therefore, each dose is 1 mg. It is recommended that patients use 1 to 2 doses per hour with a maximum of 5 doses per hour (40 mg/day maximum). Patients should be treated for 4 to 6 weeks and then weaned over an additional 4 to 6 weeks.⁶

Almost all patients report nasal and throat irritation, sneezing, and watery eyes during the first week of use. These symptoms do diminish, however, with continued use of the product. It is important for the physician to warn the patient that these effects will occur. If symptoms persist for longer than a week and are not diminishing, the patient should consult a physician and consider alternative therapies.⁷

The nicotine inhaler is the latest device to be introduced for nicotine replacement therapy. It was released in mid 1998. Unlike the other nicotine replacement therapies, the inhaler is intended to mimic the smoker’s hand-to-mouth ritual and the sensation of inhaled cigarette smoke in the back of the throat (produced by menthol).⁷

A one year, randomized, double-blind, placebo controlled trial was conducted by Tonnesen et al to evaluate the efficacy of the nicotine inhaler system. A total of 286 volunteers who smoked at least 10 cigarettes daily were recruited for the study through a local newspaper advertisement. The subjects were randomly assigned to nicotine inhalers (n=145) or placebo (n=141) to be used for 3 months followed by tapering for 3 months in the context of minimal levels of advice and support. Endpoints for the study were continuous smoking abstinence rates at weeks 6, 12, 24, and 52.¹⁹

The results of the study are encouraging. At one year, the smoking abstinence rate in the active inhaler group was 15% compared with 5% in the placebo inhaler group. The mean nicotine substitution after 2 weeks was 43% of smoking levels. The treatment was well tolerated, and no serious adverse effects were reported. In summary, the study showed an increase in smoking cessation rates with the nicotine inhaler in a low intervention context.¹⁹

The nicotine inhaler is supplied as a unit containing a mouthpiece, 42 cartridges stored in seven storage trays, and a plastic storage case. Each cartridge delivers nicotine 4 mg from a porous plug containing nicotine 10 mg.⁷ Smokers may require 80 puffs from the nicotine inhaler to obtain a dose comparable to that from 8 to 12 puffs from a cigarette.⁶

The nicotine is absorbed primarily in the buccal and pharyngeal mucosa, as little of the nicotine reaches the bronchi. Peak plasma concentrations of nicotine are reached in about 15 minutes after the completion of puffing. With this dosage form, the nicotine plasma concentration rises more quickly than with the gum, but it is slower than with the nasal spray.¹⁹

Initially 6 to 16 cartridges should be used throughout the day. Patients should take either shallow, frequent puffs or deep inhalations. It has been shown that frequent, continuous puffing over 20 minutes yields the best effects. The recommended duration of treatment is 3 months, and it is suggested that the inhaler not be used for longer than six months.⁷

The most common side effects associated with the inhaler are irritation in the mouth and throat and coughing. These adverse effects generally improve with continued use. In the Tonneson study referred to above, no subjects discontinued the inhaler secondary to side effects.¹⁹

In January 1994, Silagy et al published the first meta-analysis that included all four forms of currently available nicotine replacement therapy. The meta-analysis included published and unpublished randomized controlled trials of NRT that assessed abstinence at least 6 months after the start of therapy. Fifty-three trials (42gum, 9 patch, 1 intranasal spray, and 1 inhaler) with data from 17,703 subjects were found to meet the inclusion criteria and were included in the analyses.¹²

The results found that the use of nicotine replacement increased the odds ratio of abstinence to 1.71 (95% confidence interval 1.56-1.87) compared with those allocated to the control interventions. The odds ratios for the different forms of NRT were 1.61 for gum, 2.07 for transdermal patch, 2.92 for nasal spray, and 3.05 for inhaled nicotine. The odds ratio for abstinence with nicotine gum and transdermal patches was slightly greater if offered to smokers recruited from the community or those attending specialized clinics than if offered to smokers in primary care. However, the differences were not found to be significant.¹²

In 1996, the Agency for Health Care Policy and Research (AHCPR) published a clinical practice guideline for smoking cessation. An independent panel of scientists, clinicians, consumers, and methodologists held four meetings over 2 years to review evidence and develop guidelines. Approximately 3000 research articles and abstracts were reviewed to identify research reports appropriate for evaluation. In addition to the relevance of the content and topic, inclusion criteria were that the article concerned a randomized controlled trial, had a followup end point at least 5 months after the quit date, and was published in English in a peer-reviewed journal between 1975 and 1994. Once the panel believed it possessed sufficient data, it generated evidence statements that characterized recommendations that were derived from the findings. ⁴ The panel recommendations address three audiences: primary care clinicians, smoking cessation specialists, and health care administrators, insurers, and purchasers.

The AHCPR Guideline Recommendations for primary care clinicians emphasize the importance of systematically identifying all smokers , strongly advising all smokers to quit, and determining patient's willingness to make a quit attempt. Those patients not willing to commit to smoking cessation should receive a motivational intervention to promote subsequent quit attempts. When patients are willing to make a quit attempt, primary care clinicians should help the patient set a quit date and prepare the patient for the quit date. Self help materials and key advice including problem solving and social support should be provided. All patients attempting to quit should have followup contact scheduled.⁴

Finally, the panel identified nicotine replacement therapy (nicotine patches and nicotine gum) as the only pharmacotherapy available at the time to be effective as an aid to smoking cessation. (AHCPR did not evaluate the nicotine nasal spray and oral inhaler because neither form had been FDA-approved when the guidelines were written.⁷) The panel recommended that all patients planning a quit attempt be offered nicotine replacement therapy, unless there is a clear medical contraindication.

The panel opinion was that the nicotine patch was preferable to nicotine gum for routine clinical use. The preference was based on the findings that the nicotine pateh therapy had fewer compliance problems, and it required less clinician time and effort to train patients in its effective use. The panel did support the use of the gum in certain circumstances including patient preference, previous failure with the nicotine patch, and contraindications specific to nicotine patch use (eg, severe skin reactions). ⁴

All forms of nicotine replacement therapy appear to be effective in helping people to stop smoking. However, relapse rates for smoking remain high regardless of the therapy instituted. It is uncertain at this time which form of NRT is the most effective as there are no trials which compare the different types directly. In addition, there is very little evidence regarding the combination of different nicotine delivery systems, and combination therapy is not approved by the FDA.

As opposed to nicotine replacement alone, it is important for the physician to use a multi-faceted approach to smoking cessation. Adequate preparation prior to quitting and aggressive followup after the quit date are very important. Also, as stated in the clinical guidelines, a systematic approach in recording patient's smoking status in the chart will help keep the clinician organized for effective cessation efforts. Every smoker should be reminded of the benefits of cessation at each office visit, and the physician should offer help when the patient is ready.

When deciding on the best approach to quit smoking, the patient's preferences are essential. Some patients may want to try quitting without nicotine replacement therapy.

The pros and cons of this should be discussed with the patient, and the patient will have the final decision. The available forms of nicotine replacement therapy should be explained and offered to the patient when ready. Finally, every patient needs to understand that smoking is a chronic illness, and an unsuccessful quit attempt should be seen as a learning experience for future cessation efforts.

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