U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration
Pharmacological Adjuncts in

Smoking Cessation

Editors:

John Grabowski, Ph.D.

Division of Clinical Research

National Institute on Drug Abuse

Sharon M. Hall, Ph.D

Langley-Porter Institute

University of California, San Francisco

NIDA Research Monograph 53

1985

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Pharmacological Adjuncts in

Smoking Cessation
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i v
Foreword

The relationship between tobacco use and detrimental effects on

health is clear. It is less clear how we can best assist those who

are dependent on tobacco in their efforts to control or abstain

from its use.

Tobacco dependence, with its pharmacological and behavioral

complexity, has been the object of numerous and diverse forms of

intervention. No single technique has been generally effective.

This is not surprisng. Rather, substantial clinical and laboratory

research efforts have pointed to multiple determinants in the

maintenance of the behavior. This in turn dictates that the most

effective interventions will, likewise, have multiple components.

In general, administration of drugs to treat drugs dependence is

neither novel nor universally effective; this generalization

certainly holds true for tobacco. Over the years, many drugs have

been tried as treatments for tobacco dependence; most have been

proven to be ineffective when tested under well designed research

conditions. Yet, given the millions of smokers who have difficulty

stopping their use of tobacco, the potental value of a pharmacological agent as an adjunct to the treatment of tobacco dependence

is evident.

Recently, several agents have been introduced or recommended on the

basis of controlled trials. This volume reviews and samples the

most recent literature and scientific work on nicotine and tobacco

dependence. The findings point to the utility of integrating

behavioral and pharmacological treatment strategies in tobacco

dependence and have implications for the development of therapeutic

interventions for other dependence disorders.

Jerome Jaffe, M.D.

Acting Director

National Institute on Drug Abuse

v

Contents

Foreword

Jerome Jaffe. . . . . . . . . . . . . . . . . . . . . v

1

Tobacco Use, Treatment Strategies, and Pharmacological

Adjuncts: An Overview

John Grabowski and Sharon M. Hall . . . . . . . . . . . . .

Rational Basis for Chemotherapy of Tobacco Dependence

R. Nemeth-Coslett and Jack E. Henningfield. . . . . . . . .

The Titration Hypothesis Revisited:

Smoking Intensity

Nicotine Gum Reduces

Ronald I. Herning, Reese T. Jones, and Patricio Fischman. .

Cardiovascular Effects of Nicotine

by ECG and Echocardiography

Gum and Cigarettes Assessed

Janine Krivokapich, Nina G. Schneider, John S. Child, and

Murray E. Jarvik. . . . . . . . . . . . . . . . . . . . . .

Characterization of Tobacco Withdrawal: Physiological and

Subjective Effects

Dorothy Hatsukami, John R. Hughes, and Roy Pickens. . . . .

Short-Term Effects of Nicotine Gum

John R. Hughes and Dorothy Hatsukami. . . . . . . . . . . .

Nicotine Gum vs. Placebo Gum: Comparisons of Withdrawal

Symptoms and Success Rates

Nina G. Schneider and Murray E. Jarvik. . . . . . . . . . .

Nicotine Chewing Gum in Smoking Cessation: Efficiency, Nicotine

Dependence, Therapy Duration and Clinical Recommendations

Karl Olov Fagerstrom and Bo Mellin. . . . . . . . . . . .

Theoretical Background and Clinical Use of Nicotine Chewing

Gum

M. A. H. Russell and M. J. Jarvis . . . . . . . . . . . .

Psychological and Pharmacological Approaches to Smoking

Relapse Prevention

Sharon M. Hall and Joel D. Killen . . . . . . . . . . . .

List of NIDA Research Monographs . . . . . . . . . . . . . . . .

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27

42

56

68

83

102

110

131

144

vii

Tobacco Use, Treatment

Strategies, and Pharmacological

Adjuncts: An Overview

John Grabowski, Ph.D., and Sharon M. Hall, Ph.D.

INTRODUCTION

The colorful history of tobacco use has been reviewed by several

authors (e.g., Bell and Grabowski 1983; Jaffe and Kanzler 1981;

Surgeon General's Report, (USDHEW) 1964, 1979; Ray 1972; Jarvik 1970

and has been described in numerous historical treatises and papers.

The suggested hazards of tobacco use were enumerated shortly after

its introduction to Europe in the 16th century. At the same time

its presumed virtue as a general purpose medicament was extolled

(Ray 1972). Since then the proponents and opponents of tobacco use

have vigorously debated their positions. Ample evidence of

potential harm has accumulated indicating disease conditions

correlated with tobacco use. These data have been presented in many

scientific articles and in the summaries provided by the Surgeon

Generals' Reports between 1964 and 1984.

The wealth of findings on adverse health effects of tobacco use have

generated vigorous efforts in two domains. The first is development

of techniques to prevent young nonusers from initiating tobacco

use. The second is to establish optimal techniques for eliminating

tobacco use in those who smoke or otherwise consume tobacco

products. A concise statement of the character of the dilemma is

often attributed to Mark Twain: “I can quit smoking if I wish; I've

done it a thousand times." Recent restatements of this problem by

scientists are evident in the change of focus from cessation alone

(i.e., quitting). to maintenance of cessation (e.g.. USDHHS 1980;

Hall 1980, 1984).

Efforts to eliminate tobacco use began a short time after its

introduction. Diverse remedies have been described, some ludicrous,

others macabre. In recent years, five categories of reasonable

cessation efforts have had prominence, including: (1) public

intervention or information campaigns, (2) "self-help" programs, (3)

group support programs, (4) individualized behavioral intervention

programs, and (5) pharmacological interventions. Although

identified as distinct and separate, many efforts, of course, have

combined elements of the various approaches. Indeed, most recently

1
it has become evident that optimal programs may include combinations

of behavioral intervention, group support, and use of

pharmacological adjuncts (e.g.. Hall and Killen, this volume).

INFORMATION AND LEGISLATIVE MASS INTERVENTIONS

The five cessation intervention categories differ in a variety of

ways. One dimension is degree of external intervention which

usually covaries with the size of the population intervened upon.

For example, there have been several forms of governmental efforts

to reduce tobacco use. One is announcements to the press. Although

these efforts have been ongoing for many years, they became clearly

focused following publication of the first Surgeon General's Report

(USDHEW 1964). Other widely distributed public health messages are

the advertising campaigns developed by the National Cancer

Institute, National Heart, Lung, and Blood Institute, Office on

Smoking and Health, and the National Institute on Drug Abuse.

Still another media-based effort is that developed by the National

Cancer Institute and the National Heart, Lung. and Blood Institute.

The program had a local television news personality go through his

or her personal smoking cessation program in full view of the

public. Throughout the several weeks of the program, viewers were

encouraged to follow the instructions and guidance by the status

model provided. These broad-based public efforts reach large

numbers of people, with varying degrees of effect. An advertising

campaign reaches many people but can, by virtue of the technique,

convey only simple messages. The "Status Model" strategy reaches a

lesser number. provides many specific and clear instructions on

smoking cessation techniques, but has no genuine followup

interaction provisions.

Other broad efforts with less personal "direction" have taken the

form of substantial tax increases on tobacco products and labelling

of tobacco products as well as advertising (in the United States,

cigarettes only) with warnings. Indeed, the rotational warning

label system used in other countries will soon be introduced in the

United States.

Taxation, an indirect mechanism, can have a dramatic effect on many

people if properly implemented. To the extent that price affects

purchase, consumption is likely to be dramatically altered if the

increase is large. Data from a Canadian report (Ontario Council of

Health 1982) indicated a clear relationship between cigarette price

and consumption. With some exceptions, it is evident that cigarette

consumption is highest in countries where price is lowest. In those

countries where extremely high taxes have been levied (e.g.,

Norway), the consumption of manufactured cigarettes declines, but

there is increased likelihood that smokers will "roll their own."

However, they do not override the effect of the tax; i.e.,

consumption remains lower than before the tax. The Canadian report

suggests that the optimal taxation is one which doubles the price.

It results in decreased consumption but does not induce a dramatic

shift from manufactured to hand-rolled cigarettes. It appears that

2
price increases are most likely to decrease purchases by young

people (Lewit 1983). This may generate a considerable benefit in

prevention.

Large-scale programs sacrifice precision, are variably successful,

and resultant indicators of change are indirect. However, it is

probable that these advertising and social intervention approaches

have had an effect, since major shifts in populations smoking and

numbers of smokers have occurred. Since at least some of these

efforts are based on advertising strategies with documented

effectiveness, parallel consequences in affecting smoking behavior

can justifiably be assumed.

Nevertheless, it has been suggested that mass communication

strategies do have limits. For example, they appear to require an

underlying foundation of receptive personal views, social influence,

and environmental circumstances favorable to enhancement of the

message (USDHHS 1982, 1984). In the case of tobacco use, this

change in perspective is only gradually occurring. In addition, it

is unclear whether the message and favorable conditions extend to

all forms of tobacco use or are limited to cigarette use. If

current public understanding of hazards is limited to cigarette

smoking, one unfortunate effect of current mass communication

efforts might be a shift by some individuals from one preparation

form to another (e.g., cigarettes to chewing tobacco).

Overall it appears likely that just as an integrated effort is

optimal at the individual level, it is necessary to combine diverse

elements in the health and behavior messages aimed at broad

audiences. Legislative, health agency, and broadcast media efforts

in concert will be most effective, interacting with the messages

provided at the individualized program level.

SELF-HELP PROGRAMS IN SMOKING CESSATION

There has been recent emphasis on self-help and other "costeffective" approaches. The concept of self-help has gained popularity for a number of reasons. Popularity derives in part from

popular notions of "self-control," "free will," and "bootstrap"

progress. Such efforts are also considered to be economical of time

and money by some. Evidence of less immediate cost in a given

program can probably be provided. However, "self-help" programs may

rely heavily on diverse long-term efforts which are both expensive

and time-consuming. Thus, the actual effectiveness of the program

may reflect decades of costly advertising, legislation. and

influence on the individual and his or her social group. These

efforts include the time and money spent in preparing elaborate

self-help materials, as well as media and other public health

efforts supportive of nonsmoking. Also, the success rates for

unassisted self-help "bibliotherapy" (Glasgow and Rosen 1978) are

generally not substantial, although some favorable results have been

noted (USDHHS 1982).

3
Self-help materials probably require a user well versed in the

strategy and goal of the self-help approach. The level of

sophistication required of the user may deter some individuals and

preclude success of others. Thus, it is likely that such materials

are best used in concert with instruction from a knowledgeable

professional. It is perhaps ironic that substantial efforts have

been made to develop intensive clinically guided therapies for users

of various other drugs associated with less persistent drug-seeking

than cigarettes. The cigarette smoker is more often relegated to

the self-help efforts.

A comment is warranted about the individuals who quit "cold turkey,"

without assistance. In this culture, the volume and scope of the

antismoking campaigns and materials are such that most, if not all,

smokers have been influenced in some degree, and thus have received

some aid in quitting. It should also be noted that only a small

percentage (10%-27%) of those who engage in "spontaneous cessation"

continue as nonsmokers for 1-5 years. In addition, as many as 90%

of smokers verbalize an interest in quitting. There- fore, the need

for effective intensive interventions remains.

GROUP AND SOCIAL SUPPORT PROGRAMS

A number of public agencies (e.g., American Cancer Society; National

Heart, Lung, and Blood Institute), private nonprofit groups (e.g.,

American Lung Association). and for-profit groups (e.g., Smokenders)

have implemented smoking cessation programs. The common element in

the programs resides in use of a standardized intervention package

with groups which meet regularly. Social pressure and social

reinforcement are common treatment mechanisms. The leaders of all

such programs typically strive to develop behavioral analysis skills

in the participants. The smokers (now exsmokers) learn to examine

the behavior itself and the conditions under which it occurs, and

they plan a cessation date. Some form of followup intervention is

characteristic. These programs have varying degrees of success,

which may be influenced by many factors, including leader expertise

and subject characteristics. Unfortunately, few data are available

on the long-term results of such programs. That is. all tend to be

effective in producing cessation, but the rate at which cessation is

maintained is not clear. Furthermore, it is likely that particular

intervention strategies will be more effective with some people than

with others. Indeed, the problem in terms of success is likely to

parallel that observed for the common treatment approaches for many

behavioral disorders. That is, there is a need to match each client

with an appropriate therapy.

INDIVIDUALIZED PROGRAMS

Individualized smoking programs are uncommon. The number of

cigarette smokers who actually seek a clinician for an

individualized behavioral intervention program is probably minimal,

although no data are available. However, this does not take into

4
account physician-implemented, pharmacological interventions which,

with the introduction of nicotine gum, will likely be extremely

common but lacking in meaningful behavioral intervention

components. For example, 700,000 prescriptions for the gum were

written in its first 2-1/2 months on the market (Consumer Reports

1984). The appropriateness of applied behavioral techniques

coinciding with administration of this pharmacological adjunct is

unknown, despite the manufacturer's efforts to educate physicians in

its optimal use. However, the effort may well be enhanced by recent

coverage in professional information sources (e.g., JAMA 1984).

A substantial literature of case reports, as well as more systematic

experimental analyses of smoking behavior and cessation attempts has

been reviewed. The primary problem with individualized programs

will be, of course, that they are costly. On the other hand, if

individualized programs, or standardized programs with latitude for

individual modification, can be demonstrated to be effective for

many clients. the long-term benefits in reduced medical costs may be

substantial. It appears that integrated programs of the sort

described by Hall and Killen (this volume) or Pomerleau and

Pomerleau (1977) will prove most useful in the quest for successful

intervention. Again, the broader view suggests that all will be

more effective against a backdrop of concerted public health

advertising, legislation, and other social interventions.

PHARMACOLOGICAL INTERVENTIONS

Over the years, a wide range of agents has been proposed as possible

pharmacological adjuncts for treatment of cigarette smoking. In an

interesting review, Kozlowski (1984) has noted that completely

ineffective pharmacological techniques have been promulgated as

"cures" for tobacco use. Various studies have also examined

mechanisms by which pharmacological agents demonstrably effective

for other purposes might alter cigarette smoking.

Pharmacological Interventions for tobacco use derive from several

assumptions in part related to putative "reasons" for smoking.

While many properties of nicotine align it with prototypic

"stimulant-like" drugs, cigarette smokers often refer to calming

effects.

Multiple possible origins exist for these reported disparate

effects. There may, of course, be dose-dependent variations in the

dominant effect of nicotine (Domino 1973). The behavioral effects

of nicotine may be dependent on the baseline level of activity of

the individual. This has been amply demonstrated with other

behaviorally active agents. Thus, a rate-dependent decline, or

"subduing effect," may occur under conditions of high activity,

while rate-increasing, or "activating" effects may emerge when

baseline activity is low. The possibility of interaction between

certain classes of behavior and observed effect may be important.

Interaction of doses, behaviors, and environmental conditions may be

perceived as enhancing or decreasing activity. For example,

5
increasing focus of attention and decreased distractibility may,

despite their derivation from a stimulant action, be effectively

calming to the smoker.

An entirely different and seldom considered mechanism by which

"sedative" actions might be achieved are those associated with

regulation of carbon monoxide levels or potential interactions

between this gas and nicotine. Thus, while nicotine is likely the

dominant pharmacological reinforcer in tobacco use, maintenance of

comparatively high carbon monoxide levels cannot be ignored in terms

of potential behaviorally relevant physiological effects. Finally,

another source for the apparent disparity in the reported effects of

smoking may also reside in the pharmacological profile of nicotine

itself. While nicotine is often noted for its similarity to drugs

such as dextroamphetamine. it differs along several dimensions

(Domino 1973), although the effects on standard measures of rates of

behavior are similar. The critical issue in all such discussions

appears to be dose. It must be recalled that the doses obtained via

smoking are relatively low, and it is in the low dosage range that

primarily stimulant-like effects have been reported.

Depending on the effects of nicotine thought to be dominant in

maintaining tobacco use, sedatives, anxiolytics, or stimulants might

be administered to decrease cigarette smoking. Indeed, the range of

options parallels that for other forms of pharmacological

intervention in cases of drug dependence. Another alternative

approach is blocking of nicotine's effects. The most obvious and

direct strategy, however, is to administer nicotine itself in an

alternative form. Several authors have provided overviews of the

rationale for various pharmacological strategies for smoking

cessation (e.g.. Kozlowski 1984; Schuster et al. 1977; Jarvik

1973). In the main, these reside in substitution for the presumed

primary effect.

The optimal and practically unattainable drug would, of course,

reduce cigarette use independent of the subject or client's "desire"

to stop smoking. Sedatives and anxiolytics have generally been

noted to be ineffective in reducing smoking in either acute or

longer term demonstrations (e.g., Whitehead and Davies 1964;

Schuster et al. 1977; Kozlowski 1984). Thus the notion of parallels

with "anxiety-reducing" agents is minimized despite the common

subjective report of this property of tobacco self-administration.

Conversely, the view of tobacco use as having generalized energizing

characteristics for which other "stimulant-like" drugs might

substitute is countered by the results of Whitehead and Davis (1964)

and Schuster et al. (1977). Indeed, Schuster et al. (1977) reported

acute increases in cigarette smoking as a function of dextroamphetamine administration.

Other drugs administered to decrease tobacco use have included

lobeline, naloxone, propranolol, alkalizing agents, and

mecamylamine. Schuster et al. (1977) demonstrated that lobeline has

no practical effect at the doses recommended. It is nevertheless

sold over the counter under several brand names. Naltrexone. a

relatively short-acting narcotic antagonist, has been reported to

6
reduce puffs/cigarette, and number of cigarettes over its duration

of action (Karras and Kane 1980), although the elaborate

neurochemically based rationale for its effectiveness is not

compelling, since general reductions in food and water intake have

also been observed. Nevertheless, given the current availability of

longer acting variants, e.g., naltrexone, further research might be

of interest. In addition, some investigators appear to be defining

more precisely the specific neuroregulatory and reinforcement

mechanisms of smoking (Pomerleau and Pomerleau 1984). Propranolol,

an effective antihypertensive which has also been noted to relieve

some physiological correlates of anxiety, has been reported to be

ineffective in a large double-blind study (Farebrother et al. 1980).

The rationale for the use of sodium bicarbonate or other alkalizing

agents to change urine pH and thereby sustain nicotine blood levels

has complex underpinnings. As Schachter et al. (1977) noted,

increasing urine alkalinity "can have at best trivial effects on

plasma level nicotine." Nevertheless, the approach gained some

acceptance because of presumed interactions between stress, nicotine

metabolism, and urine pH, and the belief that the alkalizing effect

would, under certain conditions, not be trivial. There are at

present few proponents of using the alkalizing strategy in smoking

cessation programs. However, much has been published in the

scientific and popular press on the topic.

One other proposed pharmacological intervention, mecamylamine, is

logically reasonable but may be lacking practical merit. It has

been argued, as is mentioned by Henningfield and Nemeth-Coslett

(this volume) and Henningfield et al. (1982) that mecamylamine, as a

nicotine blocking agent, might be a useful adjunct in smoking

cessation. There is clear evidence of mecamylamine's effectiveness

in blocking nicotine's action at doses which have no untoward

effects. Theoretically, its value is apparent, and a cogent case

for its utility was made more than a decade ago by Jarvik (1973).

However, Jaffe (1973) noted, with respect to use of narcotic

antagonists in treatment of opiate abuse, that antagonist treatment

is "largely a promise unfulfilled." The problem parallels that

arising in the use of dlsulfram in the treatment of ethanol abuse,

or naltrexone for opiates, i.e., patients select other options.

In the main, pharmacological adjuncts without at least modest

inherent reinforcing properties have not been widely accepted by

patients (e.g., Grabowskl et al. 1979; Grabowski 1984). In this

regard, mecamylamine would likely be no exception, particularly when

more reinforcing options such as nicotine exist. Nevertheless, the

potential utility of the drug in patients who are "highly motivated"

or for whom nicotine is contraindicated is considerable.

Effectively blocking nicotine's direct effects may therefore have

promise if combined with behavioral intervention strategies.

Indeed, the potential clinical utility of mecamylamine has been

demonstrated in a study by Tennant et al. (1983) and was considered

a "viable withdrawal treatment for some case of recalcitrant

nicotine dependence." The most obvious pharmacological adjunct is

nicotine itself, and it is the major focus of the present volume.

Introduction of a nicotine-laced chewing gum approved by

7
the U.S. Food and Drug Administration in the spring of 1984 has

generated considerable interest in both the scientific and lay

communities. It has been extensively discussed in the scientific

and quasi-scientific literature and lay press (e.g., Consumer

Reports 1984). The origins of the widespread interest are likely

three-fold. First, the U.S. distributor has, of course, made

sweeping publicity efforts. Second, the scientific community is

encouraged not only by the therapeutic implications of the product,

but also by its usefulness in human research requiring nicotine

administration. Third, it is probable that much of the

cigarette-using population of the U.S. has been awaiting a "magic

bullet" which would eliminate the behavior and alleviate all

discomfort coinciding with cessation, however ill-advised this view

may be.

The rationale for administration of nicotine gum to maintain

cigarette abstinence is clear. It entails substitution of one

nicotine preparation form for another. It parallels in some

respects administration of methylphenidate or antidepressants for

treatment of cocaine abuse (Kleber and Gawin 1984; Khantzian 1983),

the use of methadone for heroin abuse, or perhaps controlled

administration of various sedatives or anxiolytics in the treatment

of alcohol abuse.

Since nicotine is dominantly "stimulant-like" at the lower doses

typically self-administered by tobacco users, the

cocaine-methylphenidate analogy is perhaps most apt (e.g..

Henningfield and Nemeth-Coslett, this volume). Therefore, positive

reinforcing effectiveness, rather than "withdrawal symptoms," may be

the primary factors maintaining self-administration (Hatsukami et

al., this volume). Substitution of a distinctly similar alternative

agent, or the same agent in a different form, is reasonable. It

precludes the loss of reinforcing effects of self-administration

while terminating the behavioral components which exist at high

strength in long-time smokers.

Krivokapich et al. (this volume) have evaluated cardiovascular

effects of nicotine gum. They have further substantiated its

apparent absence of pronounced cardiovascular effects within the

recommended dosage range. Given the fact that for individuals in

good health, the effects of nicotine at standard doses are

relatively safe, clear advantages exist in self-administration of

nicotine via the buccal route, rather than combined with the diverse

chemical and particulate constituents in cigarette smoke. Indeed,

while not specifically approved for treatment of chewing tobacco

use. nicotine-laced gum conceptually approximates the behaviorally

ideal adjunct in this case also.

The issue of effectiveness of nicotine gum in smoking cessation is,

of course, as complex as the behavior itself. As discussed by

Herning and Jones (this volume). differing behavioral patterns exist

among smokers, most of which lead to inhalation of significant

amounts of nicotine; these can be modulated by administration of

gum. Henningfield and Nemeth-Coslett (this volume), among others,

make an excellent case for the role of nicotine in the maintenance

8
of cigarette smoking and report data concerning the characteristics

of nicotine self-administration via the buccal route (gum

preparation form).

Further supporting the case for nicotine self-administration as an

important factor in maintaining cigarette smoking for some

individuals is the report by Hatsukami et al. (this volume) which

provides data suggesting the importance of positive reinforcement as

a major factor sustaining smoking behavior. Their data add to the

case that behavioral correlates of smoking and cessation, rather

than physiological symptomatology per se, must be the primary focus

of cessation maintenance efforts. The data also further support the

potential usefulness of nicotine-laced chewing gum in attaining this

goal. Hughes and Hatsukami (this volume) further delineate the

physiological and behavioral parameters of nicotine administered via

the buccal route.

The crucial issue concerning nicotine gum as a pharmacological

adjunct is whether it does, in fact, increase cessation maintenance,

an issue explicitly addressed in this volume by Schneider and

Jarvik. Russell and Jarvis, Fagerstrom and Melin, and Hall and

Killen. It is evident that smoking is a behavior modulated and

determined by complex interacting behavioral, social, sensory, and

pharmacological factors.

Schneider and Jarvik (this volume) address the clinically pertinent

individual characteristics. Their data point to the relationship

between degree of behavioral dependence on cigarette smoking and the

effectiveness of the gum. Russell and Jarvis (this volume), in

addition to providing a thorough review, address the relevance of

individual social factors and the role of the clinician in cessation

efforts. They note on one hand the direct effect of the gum, but

likewise note that whatever placebo effects may exist can be used to

advantage.

Fagerstrom is among the most experienced investigators of the gum's

effects in clinical settings. Fagerstrom's notable efforts with

both development of innovative measures of dependence and analysis

of the usefulness of the gum in clinical settings have been of value

to numerous investigators. These studies and strategies are

reviewed in this volume.

It appears that behavioral programs combined with nicotine gum and

emphasis on relapse prevention produce the best outcome (e.g., Hall

et al. 1985; Hall and Killen, this volume). These group-based

procedures, which rely on social reinforcement, including a variety

of specific positive reinforcement and punishment techniques, and

which include followup support, will likely prove the most

beneficial strategy for most smokers.

AN INTEGRATED VIEW OF PHARMACOLOGICAL ADJUNCTS AND TREATMENT

Concerns which have existed about pharmacological adjuncts for other

drug-use problems also prevail with respect to nicotine gum and

9
would likely arise for any other new agent. Many of these concerns

were addressed during the course of the U.S. Food and Drug

Administration's review of data in support of efficacy of nicotine

gum.

The fundamental question, of course, is whether or not the gum will

effectively enhance smoking cessation. If nicotine is the primary

pharmacological agent maintaining tobacco use, then administration

of nicotine in alternative forms providing similar nicotine blood

levels should be effective in terms of the pharmacological

component. Nicotine gum does this, but there are differences in

onset characteristics which make it less likely to be effective as a

reinforcer (although Henningfield and Nemeth-Coslett, this volume,

indicate that chewing characteristics can alter onset).

If it is effective as a reinforcer, the question arises whether it

is likely to be misused or used excessively for its positive

reinforcing effects. An objective analysis suggests that this is

possible, although the most likely form of "misuse" will probably be

continuation of use beyond the tentatively recommended period of 3

to 6 months. Indeed, several investigators have already suggested

that use of the gum at higher doses for longer periods will probably

generate more favorable long-term abstinence percentages.

Interestingly, this parallels data available for other substitution

treatments (Dole and Nyswander 1983).

The issue is whether "misuse" or prolonged use of the gum is likely

to be a significant problem. In Switzerland, where the gum is

available without prescription, no significant problems have been

reported. In any case, another point arises when prolonged use is

considered. Chronic use of the gum results in nicotine levels

paralleling those which an individual would attain through smoking.

These are achieved without the bolus and rapid onset produced by

smoking which could arguably be a problem to individuals with

cardiovascular problems. Thus, the hazards of carbon monoxide,

hydrocarbons, particulate matter, and numerous chemicals are

eliminated when the individual chews the gum rather than smokes

cigarettes. Obviously, the gum does not have the hydrocarbon and

chemical hazards associated with chewing tobacco. Overall, the

health advantages in terms of reduced risk using the gum are

numerous.

Questions about conditions of use and usefulness do exist. Results

of many studies with the gum have been equivocal. Others have

produced more favorable results. However, as with other

pharmacological adjuncts for drug abuse or tobacco use which have

been mentioned, the gum is not a "magic bullet" or panacea. It is

likely that many people will at first use the gum without success.

The critical determinants of successful use appear to be related to

whether the gum is, in fact, used as a pharmacological adjunct in

conjunction with an appropriate array of behavioral intervention

techniques and environmental influences. This volume and the

literature in general adequately amplify the need for such a

combined strategy in this and other areas of health and behavior.

10
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Analysis and Treatment of Smoking Behavior. National Institute

on Drug Abuse (NIDA) Research Monograph 48. Washington, DC:

Supt. of Docs., US Govt. Print. Off., 1983. pp 1-5.

Benowitz, N.L. The use of biologic fluid samples in assessing

tobacco smoke consumption. In: Grabowski. J., and Bell, C.S.

(eds.) Measurement in the Analysis and Treatment of Smokinq

Behavior. NIDA Research Monograph 48. Washington DC: Supt. of

Docs., US Govt. Print. Off., 1983. pp 6-26.

Domino, E.F. Neuropsychopharmacology of nicotine and smoking. In:

Dunn, W.L. (ed.) Smoking Behavior: Motives and Incentives.

Washington, DC: V.H. Winston and Sons, 1973. pp 5-29.

Farebrother. M.J.B.; Pearce, S.J.; Turner, P.; and Appleton, D.R.

Propranolol and giving up smoking. British Journal of Diseases

of the Chest, 74: 95-96, 1980.

Glasgow, R.E., and Rosen, G.M. Behavioral bibliotherapy: A review

of self-help behavior therapy manuals. Psychological Bulletin

85:(1):1-23. 1978.

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Recent developments and clinical usage. Clinical Behavior

Therapy Review 1:1-20, 1979.

Goldberg, S.R., and Spealman, R.D. Nicotine as punisher: Effects

of chlordiazepoxide and mecamylamine on responding suppressed by

intravenous nicotine injection or by electric shocks. In:

Harris, L.S. (ed.) Problems of Drug Dependence, 1982.

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Docs., U.S. Govt. Print. Off., 1983. p 372.

Grabowski, J .; O'Brien, C.P .; Greenstein, R.; Ternes, J.; Long, M.;

and Steinberg-Donato, S. Effects of contingent payment on

compliance with a naltrexone regimen. American Jounral of Drug

and Alcohol Abuse 6: 355-365, 1983.

Grabowski, J. Profiles of ideal drugs for therapeutic social use.

Paper presented at the 92nd Annual Meeting of the American

Psychological Association, August 1984.

Hall, S.M. Self-management and therapeutic maintenance: Theory

research. In Karoly, P., and Steffan, J. (eds.). Improving the

Long-Term Effects of Psychotherapy. New York: Gardner, 1980. pp

263-300.

Hall, S.M .; Tunstall, C.D.; Rugg, D.L.; Jones, R.G.; and

Benowitz, N.L. Nicotine gum and behavioral treatment in smoking

cessation. Journal of Consulting and Clinical Psychology

52:372-382, 1984.

Henningfield, J.E. Measurement issues in cigarette smoking

research: Basic behavioral and physiological effects and

patterns of nicotine self-administration. In: Grabowski, J.,

and Bell, C.S. (eds.) Measurement in Analysis and Treatment of

Smoking Behavior. NIDA Research Monograph 48. Washington, DC:

Supt. of Docs., U.S. Govt. Print. Off., 1983.

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Henningfield. J.E.; Katsumasa, M.; Johnson, R.E.; and Jasinski, D.

Rapid physiological effects of nicotine in humans and selective

blockade of behavioral effects by mecamylamine. In Harris, L.S.

(ed.) Problems of Drug Dependence, 1982. NIDA Research

Monograph 43. Washington, DC: Supt. of Docs., U.S. Govt.

Print. Off., 1983. pp 259-265.

Jaffe. J.H. Pharmacological and Societal Factors in the Management

of Drug Dependence. In: Braude, M.C.; Harris, L.S.; May, E.L.;

Smith, J.P.; and Villarreal, J.E. (eds.) Narcotic Antagonists.

New York: Raven Press, 1973. pp 3-7.

Jaffe, J.H., and Kanzler, M. Nicotine: Tobacco use, abuse and

dependence. In: Lowinson, J.H., and Ruiz, P. (eds.) Substance

Abuse: Clinical Problems and Perspectives. Baltimore, MD:

Williams and Wilkins, 1981. pp 256-273.

Jarvik, M.E. The role of nicotine in the smoking habit. In:

Hunt, W.A. (ed.) Learning Mechanisms in Smoking. New York:

Aldine, 1970. pp 155-190.

Jarvik, M.E. Further observations on nicotine as the reinforcing

agent in smoking. In: Dunn, W.L. (ed.) Smoking Behavior:

Motives and Incentives. Washington, DC: V.H. Winston and Sons

1973. pp 33-49.

Journal of the American Medical Association 252: (Special issue on

tobacco use.) November 23, 1984.

Karras, A., and Kare, J.M. Naloxone reduces cigarette smoking. Life

Sciences 27: 1541-1545, 1980.

Kozlowski, L.T. Pharmacological approaches to smoking

modification. In: Matarazzo. J.D.; Weiss, S.M.; Herd, A.J.; et

al. Behavioral Health: A Handbook of Health Enhancement and

Disease Prevention. New York: Wiley, 1984.

Lewit, E.M. Economics of cigarette smoking. Paper presented at the

14th Annual Meeting of Environmental Mutagen Society, San

Antonio, March 1983.

Lucchesi, B.R .; Schuster, C.R.; and Emley, G.S. The role of

cigarette smoking frequency in man with observation on certain

cardiovascular effects associated with the tobacco alkaloid.

Clinical Pharamcology and Therapeutics, 8: 789-796, 1967.

Ontario Council of Health. Smoking and Health in Ontario: A Need

for Balance. A Report for the Ontario Council of Health,

Toronto; 1982.

Pomerleau, O.F., and Pomerleau, C.S. Breaking the Smoking Habit: A

Behavioral Program for Giving Up Cigarettes. Champaign, IL:

Research Press. 1977.

Pomerleau, O.F., and Pomerleau, C.S. Neuroregulators and the

reinforcement of smoking: Towards a behavioral explanation.

Neuroscience and Behavioral Reviews 8: 503-513. 1984.

Ray, O.S. Drugs, Society and Human Behavior. St. Louis: C.V. Mosby

co., 1972.

Rosenberg, J; Benowitz, N.L.; Jacob, P.; and Wilson, K.M.

Disposition kinetics and effects of intravenous nicotine.

Clinical Pharmacology and Therapeutics 28: 517-522. 1980.

Schachter. S: Kozlowski, L.T.: and Silverstein. B. Effects of

urinary p

H

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Psychology: General 106: 13-19, 1977.

Schuster, C.R., and Johanson, C.E. An analysis of drugseeking

behavior in animals. Neuroscience and Behavioral Reviews

5: 315-323, 1981.

12
Schuster, C.R.; Lucchesi, B.R.; and Emley, G.S. The effects of

d-amphetamine, meprobamate and lobeline on the cigarette smoking

behavior of normal human subjects. In: Krasnegor, N. (ed.)

Cigarette Smoking a Dependence Process. NIDA Research Monograph

23. Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off.,

1979. pp 91-99.

Tennant, F.S.; Tarver, A.L.; and Rawson, R.A. Clinical evaluation of

mecamylamine for diethdrawal from nicotine dependence. In:

Harris, L.S. (ed.) Problems of Drug Dependence, 1983. NIDA

Research Monograph 49. Washington, D.C.: Supt. of Docs., U.S.

Govt. Print. Off.. 1984. pp 239-246.

U.S. Department of Health. Education, and Welfare. Smoking and

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of the Public Health Service. Center for Disease Control. PHS

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(PHS)79-50066, Washington, D.C.: Supt. of Dots., US Govt.

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U.S. Department of Health and Human Services. The Health

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U.S. Department of Health and Human Services. The Health

Consequences of Smoking. The Changing Cigarette: A Report of

the Surgeon General. DHHS Pub. No. (PHS)81-50156. Office of

the Assistant Secretary for Health. Rockville, MD. Office on

Smoking and Health, 1981.

U.S. Department of Health and Human Services. The Health

Consequences of Smoking. Cancer: A Report of the Surgeon

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Secretary for Health. Rockville, MD: US Office on Smoking and

Health, 1982.

U.S. Department of Health and Human Services. The Health

Consequences of Smoking. Cardiovascular Disease: A Report of

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of Health and Human Services, Office of the Assistant Secretary

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Department of Health and Human Services, Office of the Assistant

Secretary for Health, Rockville, MD: Office on Smoking and

Health, 1984.

13
AUTHORS

John Grabowski, Ph.D.*

Department of Psychiatry

School of Medicine

Louisiana State University, Shreveport

Shreveport, Louisiana 71130

Sharon Hall, Ph.D.

Center for Social and Behavioral Sciences

University of California, San Francisco

1350 Seventh Street

San Francisco, California 94143

*Current Address:

Treatment Research Branch

Division of Clinical Research

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, Maryland 20857

1 4
Rational Basis for Chemotherapy

of Tobacco Dependence

R. Nemeth-Coslett, Ph.D., and Jack E. Henningfield, Ph.D.

The forms of tobacco use are many, and it is likely that their

number is matched by equally varied controlling variables. All the

usual forms of tobacco use, however, share at least one

commonality: nicotine is extracted from the tobacco and ingested in

a manner that permits its distribution to the central nervous

system. The tobacco cigarette is the prevalent means of nicotine

self-administration in Western society, and cigarette smoking is the

primary form of tobacco use addressed by legislative, research, and

treatment efforts.

In 1983, the United States Public Health Service categorized

cigarette smoking as a form of drug dependence in which nicotine was

held to be the critical substance (USPHS 1983). Consistent with the

drug dependence model of cigarette smoking, in 1984 a

pharmacotherapeutic aid (nicotine gum) for the treatment of tobacco

dependence was approved by the Food and Drug Administration. This

paper will briefly review nicotine dependence and its implications

for the use of chemotherapy in the treatment of tobacco dependence

with respect to cigarette smoking.

TOBACCO DEPENDENCE: A DECEPTIVELY COMPLEX PHENOMENON

At first brush. tobacco dependence would seem readily amenable to

study. In the form of cigarette smoking. the behavior is public,

practiced by many, and appears to involve a simple act with a simple

product. However, cigarette smoking has resisted many attempts at

quantitative study, and studies have yielded data which often

appears contradictory at the most elemental levels. For instance,

the role of dose in the control of cigarette smoking has remained

unclear despite decades of study. Since dose-response relations are

arguably the most critical quantitative relations to be assessed in

pharmacologic studies, the absence of consensual agreement as to the

nature of dose-response relations has undoubtedly hindered the

understanding and treatment of cigarette smoking.

There are specific reasons for some of the ambiguity concerning the

role of dose in cigarette smoking. Table 1 provides a partial list

of factors which obscure quantitation of dose-response functions.

15
These factors and others have been more thoroughly discussed

elseswhere (cf. Benowitz, 1983; Henningfield, 1983, 1984;

Kozlowski, Rickert, Robinson and Grunberg, 1980). In brief,

compared to most other forms of drug self-administration, cigarette

smoking involves a wider variety of confounding factors. In alcohol

studies, for instance, ounces of ethanol ingested can be specified

with great reliability, and resulting blood ethanol levels are

related in some orderly fashion to these values. Similarly, in

studies of sedatives, stimulants and opioids, the number of

milligrams of actual drug which is swallowed or injected may be

readily specified. In the case of cigarette smoking there is often

disagreement as to which parameter to specify and the means of

specification. One consequence of these difficulties was to delay

the positive classification of cigarette smoking as a form of drug

dependence. The next two sections will provide the evidence for

this classification.

TABLE 1. Obstacles to the quantitation of doseresponse functions in studies of cigarette smoking.

o Many reports do not include any quantitative

measure of dose.

o Multiple dose parameters (e.g.. nicotine, tar

and CO are frequently confounded.

o Substances of possible functional significance

(e.g., tar. CO, CO2) are especially difficult

to specify since they are not even present in

an unlit cigarette.

o Federal Trade Commission dose level estimates

are not necessarily related to either cigarette

content or yield by the smoker.

o The behavior of cigarette smoking varies across

smokers and even across puffs within a single

cigarette.

o A variety of factors may affect absorption of

smoke constituents (e.g., smoke pH, inhalation

depth).

COMMONALITIES AMONG CIGARETTE SMOKING AND DRUG ABUSE

For centuries, a variety of parallels have been drawn between

tobacco use and the use of opiates, alcohol and other substances.

It seemed obvious to many observers of social behavior and

physiologic effect that these substances were different from other

substances of ingestion. such as food. Indeed, the American Indians

knew that as other vegetables were "food for the stomach," "tobacco

provided food for the spirit." Beyond these general observations, a

variety of points common to cigarette smoking and classically

studied forms of drug dependence (e.g., narcotic addiction and

alcoholism) have been identified. The various commonalities have

been described in greater detail elsewhere (Henningfield, Griffiths

and Jasinski; 1981; Jaffe and Kanzler, 1979) and are summarized in

Table 2.

16
TABLE 2. Common factors in tobacco use and drug dependence.

o Spread is socially mediated and is persistent.

o Patterns of relapse are similar following

treatment.

o Use persists in face of damage (individual &

social).

o Personality types overlap.

o Centrally (CNS) acting substance (drug) is

delivered.

o The drug is a reinforcer for animals.

o Deprivation increases drug seeking behavior.

o Tolerance develops with repeated use.

o "Therapeutic effects" may be produced.

o Patterns of self-administration and doseresponse functions are orderly.

These commonalities among various forms of drug dependence and

tobacco use provide a rational basis for the theory that tobacco use

may occur as a form of drug dependence. In brief, tobacco use,

particularly in the form of cigarette smoking, is an orderly

behavior that is lawfully controlled by the same behavioral and

pharmacologic variables as are more commonly studied forms of drug

dependence. The commonalities also suggest that treatment

strategies which have proven effective in drug dependence may be

applied to the treatment of cigarette smokers.

NICOTINE AS A DEPENDENCE-PRODUCING DRUG

While any substance may, under some conditions, be compulsively

used, substances characterized by a certain constellation of

features are likely to be compulsively used and abused under a much

broader range of conditions, including those which lead to damage.

In brief, the compound must be psychoactive (produce centrally

mediated effects on mood and feeling states), must have euphoriant

qualities similar to those of reference drugs (e.g., morphine,

amphetamine. ethanol). and must serve as a biologic reinforcer (be

voluntarily self-administered). Other qualities such as the ability

to produce tolerance and physiologic dependence are interesting and

may be of functional significance but are neither necessary nor

sufficient determinants of drug dependence.

Two lines of study involving human subjects were undertaken by the

Addiction Reseach Center of the National Institute on Drug Abuse.

The first involved pharmacodynamic analyses which assessed the

psychoactivity of nicotine and its possible qualities as a

euphoriant. A variety of parameters were assessed when nicotine was

given in the form of tobacco smoke and intravenous injections. The

second line of study assessed the reinforcing properties of

intravenous nicotine in cigarette smokers. The intravenous studies

were critical in determining whether nicotine, in the absence of the

usual confluence of stimuli involving the cigarettes themselves

17
(e.g., social and cultural), was characterized by the constellation

of pharmacologic properties typical of those of known drugs of abuse.

Psychoactivity and Euphoriant Properties of Nicotine

The initial study showed that nicotine was psychoactive and produced

orderly effects on measures of psychoactivity (Henningfield et al.

1985). Following either smoke inhalation or i.v. administration,

nicotine was discriminated from placebo, and dose strength estimates

were directly related to nicotine dose. These self-reported effects

peaked within about 1 minute and dissipated within 3 to 5 minutes.

Certain physiologic responses were also dose-related and showed

similar temporal patterns of onset and offset: heart rate, pupil

diameter, electroencephalographic response (Lukas and Henningfield

1983). A subsequent study showed that the ganglionic blocker,

mecamylamine. attenuated physiologic and self-reported effects of

nicotine (Henningfield et al. 1983). Variability of response on

self-report measures was lower when nicotine was given intravenously

than when it was given in the form of tobacco smoke, suggesting that

the stimuli provided by cigarette smoking confound discrimination of

the effects of nicotine.

Euphoria is objectively defined by the observation that

administration of the drug, under controlled experimental

conditions, produces dose-related increases in scores on the Liking

scale of the Single-Dose Questionnaire, and scores on the Morphine

Benzedrine Group (MBG or Euphoria) scale of the Addiction Research

Center Inventory (ARCI) (Jasinski et al. 1984). In this study,

nicotine, like drugs known to be abused, produced significant

dose-related increases in scores on both the Liking and MBG scales

(Henningfleid and Jasinski 1982; Jasinski et al. 1984).

Additionally, intravenous injections of nicotine were most commonly

identified as a prototypic euphoriant drug (cocaine) by subjects

with extensive drug abuse histories.

These studies confirmed that nicotine produced critical functional

effects of tobacco smoke and that nicotine is a psychoactive drug

with properties of a euphoriant. These findings are consistent with

those obtained in animal drug discrimination studies in which it has

been shown that nicotine is readily discriminated and that its

discriminative properties are more stimulant-like than

depressant-like (cf.. review by Henningfield and Goldberg 1984).

Reinforcing Properties of Intravenous Nicotine

The ultimate test of whether nicotine is a dependence-producing drug

is, in the abstract, a very simple test: namely, to determine if

nicotine injections serve as positive reinforcers and thereby

strengthen behavior leading to their administration. Practically,

however, there are many difficulties in the safe and ethical conduct

of such a study, and the initial study was only completed about 2

years ago (Henningfield et al. 1983). The critical finding of this

study was that intravenously available nicotine was

self-administered by each of the subjects tested. Furthermore,

18
patterns of self-administration were similar to those of humans

smoking cigarettes or of animals self-injecting cocaine in analogous

experimental preparations (Griffiths et al. 1980).

When saline was substituted for nicotine, patterns of injection were

irregular and total number of Injections generally was lower. In a

subject who stated that he disliked taking injections of any kind,

the pattern of acquistion was similar to that of animals which are

given access to intravenous nicotine for the first time (see

Goldberg et al. 1982): Number of injections gradually increased

across sessions; then, when saline was substituted for nicotine, the

number of injections rapidly declined across sessions. Subsequent

studies showed that nicotine was preferred to saline when both

substances were concurrently available (Henningfield and Goldberg

1983a); that mecamylamine pretreatment attenuated the nicotine

preference (Henningfield 1983); and that the lever was pressed as

many as 1600 times per nicotine injection (study in progress).

The human self-administration study findings are consistent with

animal studies in which nicotine has been shown to serve as a

positive reinforcer in a variety of species including primates and

nonprimates, and under a variety of experimental conditions (cf.

review by Henningfield and Goldberg 1983b). It is noteworthy that

establishment of nicotine as a reinforcer in animals eluded many

investigators until effective confluences of parameters were

discovered. Such Initial difficulty was not unique to nicotine but

also characterized initial efforts to determine whether or not

ethanol would serve as a reinforcer in animals (Melsch 1977).

CIGARETTE SMOKING AS A FORM OF DRUG DEPENDENCE: SUMMARY AND

IMPLICATIONS FOR NICOTINE-BASED CHEMOTHERAPY

Nicotine is a prototypic drug of abuse, and many cigarette smokers

are likely to be dependent. Strong, albeit circumstantial, evidence

was provided by observations of the many critical commonalities

between cigarette smoking and more commonly studied forms of drug

dependence. Direct evidence was that the drug itself (nicotine, in

isolation from tobacco smoke). was characterized by a profile of

pharmacologic effects typical of that of known drugs of abuse such

as opiates, stimulants, and alcohol. These data indicate that the

role of nicotine in cigarette smoking is similar to the role of

other constituent drugs of abused substances. That is, despite the

apparently lower biologic reinforcing efficacy of nicotine than some

of the more commonly studied drugs of abuse (Henningfield and

Goldberg 1983b), the functional role of nicotine in tobacco smoke is

similar to the role of cocaine in coca leaf use, to the role of

morphine in opium poppy use, to the role of tetrahydrocannabinol

(THC) in marijuana use, and to the role of ethanol in alcoholic

beverage consumption.

The perspective that cigarette smoking often occurs as a form of

drug dependence has specific implications for chemotherapeutic

treatment strategies. A variety of nonspecific chemotherapeutic

approaches to the treatment of cigarette smokers has been

19
reported. Most provide little documented efficacy; they have been

reviewed elsewhere (Grabowski and Hall, this volume; Gritz and

Jarvik 1977; Jarvik 1977).

One specific chemotherapeutic approach for drug dependence is to

substitute a safer and more manageable form of the drug for the

substance of abuse. The ultimate goal of such an approach is

subsequently to withdraw the patient from the substituted drug. The

currently available substitution pharmaceutical is the nicotine

resin complex or nicotine chewing gum (American Hospital Formulary

Service 1984). Use of nicotine gum in treatment of cigarette

smoking is the subject of other chapters in this monograph and will

not be discussed in detail here. Rather, a few observations will be

made, following directly from the above-presented data, which show

that cigarette smoking is a form of drug dependence. In addition,

some preliminary data which bear on these observations will be

presented.

Effective chemotherapy of other kinds of drug dependence is complex

and involves systematic application of a variety of pharmacologic

and behavioral strategies (cf. Grabowski et al. 1983). A major

pharmacologic factor concerns the dose level of the chemotherapeutic

drug. Table 3 summarizes a few of these dose-related issues.

TABLE 3. Dose-related issues in chemotherapy of drug dependence

o Dose must be sufficient to provide relief of

withdrawal or deprivation effects.

o The rate of drug entry to the CNS is critical and

may determine whether the particular route of

administration used provides an acceptable

substitute.

o Patient compliance in taking the therapeutic agent

may vary as a function of dose.

o The degree to which nontherapeutic drug taking is

suppressed may vary as a function of dose.

The importance of control over dose suggested the need for further

study of such relations regarding the nicotine-delivering chewing

gum. Two issues were of interest. The first was the possible

functional effects of the rate at which individual pieces of gum

were chewed. Since the nicotine in the gum is bound to an

ion-exchange resin, chewing is required for its release; thus, rate

of chewing should be one determinant of the rate at which nicotine

is extracted from the gum. Results from a preliminary study of the

effects of chewing rate are described below. The second issue

concerned the fact that only one dose level of the gum is

commercially available. In preliminary studies we found that rates

of voluntary smoking were not affected by scheduled administration

of either placebo or 2 mg gum, but were suppressed when subjects

were given 4 mg gum (Jasinski et al. 1984; Nemeth-Coslett and

Henningfield 1985). Furthermore, in a subpopulation of

20
heavy-smoking male polydrug abusers, little subjective or

physiologic response was observed following administration of either

2 mg cr 4 mg gum. This observation suggested that, as is the case

with other therapeutic drugs. there is a wide range of individual

variability in response to a given dose, and that doses which are

not tolerated by some patients may be safe and even necessary for

others. Results from a preliminary study are also presented below in

which such subjects were given either two or four pieces of 4 mg gum

to chew.

PRELIMINARY STUDY: EFFECTS OF CHEWING RATE RESPONSE TO NICOTINE GUM

Four male subjects (average age = 34 years, range = 20-50)

participated while residing on a pharmacology research ward. Their

average weight was 75 kg (range = 67-100kg). and they smoked an

average of 30 cigarettes per day (range 20 to 40 cigarettes, each

delivering 1.1 mg nicotine). Mean scores on the Fagerstrom

Tolerance Questionaire (Fagerstrom 1978) were 10.0 (range = 9-11).

During predesignated days, each subject was cigarette deprived for 8

hours, after which time a l-hour test session was begun.

Physiologic and self-report measures were collected during the

initial 10 minutes of the test session. Subjects were then provided

with one 4 mg piece of nicotine gum (Nicorette) which they were

instructed to chew at a fixed rate for the next 10 minutes. Rates

were set at one chew every 1, 2, 4, or 8 seconds, and compliance was

assured by a nurse who observed that the subject was chewing in

response to a timed "beep" which had been pretaped on a recorder.

Each subject was exposed to the four different chew rates using a 4

x 4 Latin Square design. Most physiologic and self-reported

responses were measured at 5-minute intervals. Visual line analog

scores of positive ("pleasurable") and negative ("unpleasurable")

were collected at 15-second intervals for the first 240 seconds

after gum chewing and then at 5-minute intervals for the remainder

of the test session. Additionally, measures of expired air carbon

monoxide level were collected immediately before and after each

session.

Preliminary analysis of the data suggests that chewing rate altered

magnitude and duration of self-reported effects of the gum. Figure

1 shows the total visual line analog score (sum of negative and

positive responses) at each observation for subject CO. Variability

across subjects was considerable, however, and precluded meaningful

lumping together of the data. No chewing rate produced significant

increases on scales of the Addiction Research Center Inventory or

the Single-Dose Questionnaire (Jasinski et al. 1984).

21
MINUTES POST-GUM

FIGURE 1. Values of self-reported scores on a

visual line analog scale, summed from both pos

negative effects, as a function of chewing rate

the gum was chewed (x-axis).

lo-centimeter

itive and

and time after

This study suggests that chewing rate does make a difference in the

response to gum-delivered nicotine. It also raises several

additional issues, some of which are being addressed in an ongoing

study in which the amount of nicotine extracted from the gum, and

nicotine plasma levels, will be assessed. An immediate implication

is that the same kinds of difficulties in quantification of

dose-response relations which occur when subjects are given

cigarettes to smoke under uncontrolled conditions may arise when

subjects are given gum to chew with no specification of the rate at

which It is to be chewed.

PRELIMINARY STUDY: HIGH DOSES OF NICOTINE GUM

This study assessed the safety and effects of nicotine in subjects

who were known to be relatively insensitive to 2 mg gum. The

average age of the subjects was 33 years (range = 23-53). and they

had smoked an average of 13 years (range = g-17). Their mean score

on the Fagerstrom Tolerance Questionaire was 9.7 (range = 8-11).

Subjects chewed either two or four pieces of 4 mg gum (total

nicotine dose either 8 mg or 16 mg). Each piece of gum was chewed

at a rate of 1 chew every 2 seconds for 10 minutes. Two subjects

were tested at each of the dose levels twice a day for 2 days while

two other subjects received one dose a day for 2 days. Immediately

following gum chewing, subjects were asked to report verbally any

side effects, their liking for the gum, and to rate the strength of

the gum. Additionally, a staff nurse was required to record any

observable signs or symptoms displayed by the subject.

22
The most common signs reported by the staff nurse were belching and

hiccups. which showed a slight increase following exposure to 16 mg

when compared to 8 mg. Other signs included restlessness, watery

eyes, and irritability. However, for the six observations collected

at each of the two doses, no observable effect was noted on four of

the occasions following B mg chewing, and no effect was noted on two

occasions following 16 mg chewing.

Subjects reported nausea and throat irritation more than any other

symptoms. One subject reported no effect at either the 8 mg or 16

mg dose. Other complaints included nervousness, dizziness,

headache, and heartburn. There was little increase at the 16 mg

dose when compared to the 8 mg dose. Two subjects reported a

dose-related increase in magnitude of effects between 8 mg and 16

mg, and three of the four subjects said that they would not

voluntarily chew four pieces again but would chew two pieces. Two

of these three subjects reported effects similar to those produced

when marijuana was smoked ("high") at both doses and reported liking

the feeling. The fourth subject reported no effects at either dose

and identified the drug as placebo ("blank").

This study showed that high doses of nicotine-delivering chewing gum

can be safely given. It is not clear what specific subject

characteristics determine the tolerable dose level. For example,

both body weight and level of nicotine intake would be factors of

suspected importance. It is also remains to be determined whether

high doses are of greater therapeutic efficacy for this population

of cigarette smokers. The high doses produced some effects

characteristic of those produced by drugs of abuse ("high"), but did

not elevate scores on objective scales used to quantitate abuse

liability.

DISCUSSION

A variety of theoretical, social, and treatment implications result

from the identification of cigarette smoking as a form of drug

dependence which is functionally similar to other forms of drug

dependence. One implication related to nicotine-based chemotherapy

is the role of dose, whether altered by chewing rate or by amount of

nicotine-containing gum that is chewed. The results of the

preliminary studies which were described raised more questions than

they answered. However, some tentative conclusions may be drawn.

First, rate of chewing may have functional consequences with regard

to the effects produced by the gum. Second, subjects can tolerate

higher chew rates and gum dosage levels than are typically employed

in current treatment approaches (e.g.. Hughes and Miller 1984).

The observation that manipulations which affect the effective dose

of a chemotherapeutic agent may have functional consequences is not

surprising. Dose is a critical factor in other kinds of

chemotherapy, and studies with nicotine in human and animal subjects

show that nicotine's effects are dose related. Additionally,

clinical observations (e.g.. one patient's description of how he

used the nicotine gum: "I chew quick till I get the taste, then I

23
taper off") suggest that some patients have discovered on their own

that chewing rate makes a difference in the effects of the gum.

What is surprising is the lack of attention paid to dose in many

studies of the behavioral pharmacology of the gum and of its

treatment efficacy.

The finding that cigarette smoking may occur as a form of drug

dependence offers exciting possibilities, burdens, and hope:

Possibilities of applying chemotherapeutic treatment strategies to

the treatment of cigarette smoking; the burdens of closely examining

existing cigarette treatment programs and applying fundamental

principles from drug dependence and alcoholism programs; and hope

that these efforts will improve on the past rather dismal treatment

programs. As shown by Hall and Killen elsewhere in this monograph.

treatment approaches which apply both behavioral and pharmacologic

treatment strategies are more effective that those which address

only the pharmacologic or the behavioral aspects of tobacco

dependence.

ACKNOWLEDGMENT

Dr. R. Nemeth-Coslett is supported

Pharmaceutical Company through the

in the Sciences. The provision of

Merrell Dow Pharmaceutical Company

gratefully acknowledged.

REFERENCES

at NIDA/ARC by the Merrell Dow

Foundation for Advanced Education

the nicotine and placebo gum by

for the studies reported here is

American Hospital Formulary Service. Drug Information

84 (Supplement B). Bethesda, Maryland: American Society of

Hospital Pharmaceuticals, 1984. pp. 39B-44B.

Benowitz, N.L. Biochemical measures of tobacco smoke

consumption. In: Grabowski, J., and Bell, C.. eds. Measurement

in the Analysis and Treatment of Smoking Behavior. National

Institute on Drug Abuse Research monograph 48. DHHS Pub. No.

(ADM) 83-1285. Washington, D.C.: Supt. of Docs., U.S. Govt.

Print. Off., 1983. pp. 6-26.

Goldberg, S.R.; Spealman, R.D.; and Goldberg, D.M.

Persistent high-rate behavior maintained by intravenous

self-administration of nicotine. Science, 214:573-575, 1981.

Grabowski, J.; Stitzer, M.L.; and Henningfield. J.E.,

eds. Behavioral Intervention Techniques in Drug Abuse

Treatment. National Institute on Drug Abuse Research Monograph

46. DHHS Pub. No. (ADM) 84-1282. Washington, D.C.: Supt. of

Docs., U.S. Govt. Print. Off., 1984.

Griffiths, R.R.; Bigelow, G.E.; and Henningfield, J.E.

Similarities in animal and human drug taking behavior. In:

Mello, N.K., ed. Advances in Substance Abuse: Behavioral and

Biological Research. Greenwich, CT: JAI Press, 1980. pp. 1-90.

Gritz, E.R. Smoking behavior and tobacco abuse. In:

Mello, N.K., ed. Advances in Substance Abuse: Behavioral and

Biological Research. Greenwich, CT: JAI Press, 1980. pp.

91-158.

24
Gritz, E.R., and Jarvik, M.E. Pharmacological aids

for the cessation of smoking. In: Steinfield, J.; Griffiths,

w.; Ball, K.; and Taylor, R.M., eds. Proceedings of the Third

World Conference -- Smoking and Health, Vol. II. Washington,

D.C.: Supt. of Docs. U.S. Govt. Print. Off., 1983. pp. 575-591.

Henningfield, J.E. Measurement issues in cigarette

smoking research: Basic behavioral and physiologic effects and

patterns of nicotine self-administration. In: Grabowski, J.,

and Bell, C.. eds. Measurement In the Analysis and Treatment of

Smoking Behavior. National Institute on Drug Abuse Research

Monograph 48. DHHS. Pub. No. (ADM) 83-1285. Washington, D.C.:

Supt. of Docs., U.S. Govt. Print. Off., 1983. pp. 27-38.

Henningfield, J. E. Behavioral pharmacology of cigarette smoking. In: Thompson, T., and Dews, P.B. eds. Advances

in Behavioral Pharmacology, vol. IV, in press.

Henningfield, J.E., and Goldberg, S.R. Control of

behavior by intravenous nicotine injections in human subjects.

Pharmacol Biochem Behav 19:989-992, 1983 (a).

Henningfield, J.E., and Goldberg, S.R. Nicotine as a

reinforcer in human subjects and laboratory animals. Pharmacol

Biochem Behav 19:1021-1026, 1983 (b).

Henningfield, J.E., and Goldberg, S.R. Behavioral

Pharmacology: The Current Status. Seiden, L.S., and Balster,

R.L., eds. New York: Alan R. Liss, 1984.

Henningfield, J.E.; Griffiths, R.R.; and Jasinski,

D.R. Human dependence on tobacco and opioids: Common factors.

In: Thompson, T.. and Johanson. C.E., eds. Behavioral

Pharmacology of Human Drug Dependence. National Institute on

Drug Abuse Research Monograph No. 37. Washington, D.C.: Supt.

of Docs., U.S. Govt. Print. Off., 1981. pp. 210-234.

Henningfield. J.E.; Myasato, K.; and Jasinski, D.R.

Abuse liability and pharmacodynamic characteristics of

intravenous and inhaled nicotine. J Pharmacol Exp Ther, in

press.

Henningfield, J.E.; Miyasato, K.; and Jasinski, D.R.

Cigarette smokers self-administer intravenous nicotine.

Pharmacol Biochem Behav 19:887-890, 1983.

Henningfield, J.E.; Miyasato, K.; Johnson, R.E.; and

Jasinski, D.R. Rapid physiologic effects of nicotine in humans

and selective blockade of behavioral effects by mecamylamine.

National Institute on Drug Abuse Research Monoaraph 43.

Problems of Drug Dependence 1981. Washington,-D.C.: Supt. of

Docs., U.S. Govt. Print. Off.. 1982. pp. 259-265.

Hughes, J. R., and Miller, S. A. Nicotine gum to help

stop smoking. JAMA, in press.

Jaffe, J.H., and Kanzler, M. Smoking as an addictive

disorder. In: Cigarette Smoking as a Dependence Process.

National Institute on Drug Abuse Research Monograph 23. DHEW

Pub. No. (ADM) 79-800. Washington, D.C.: Supt. of Docs. U.S.

Govt. Print. Off., 1979, pp. 4-23.

Jarvik, M.E. Can drug treatment help smokers? In:

Steinfeld, J.; Griffiths, W.; Ball, K.; and Taylor R.M., eds.

Proceedings of the Third-World Conference -- Smoking and Health,

Vol. II. Washington, D.C.: Supt. of Docs. U.S. Govt. Print.

Off., 1977. pp. 509-513.

25

485-874 o - 85 - 2
Jasinski, D.R.; Johnson. R.E.: and Henningfield, J.E.

Abuse liability assessment in human subjects: Trends in

Pharmacol Sci 5:196-200, 1984.

Kozlowski, L.T.; Rickert, W.S.; Robinson, J.C.; and

Grunberg, N.E. Have tar and nicotine yields of cigarettes

changed? Science 209:1550-1551, 1980.

Lukas, S., and Henningfield, J.E. EEG correlates of

physiological and behavioral effects of intravenous nicotine in

humans. Paper presented at the 2nd World Conference on Clinical

Pharmacology and Therapeutics, Washington, D.C., 1983.

Meisch, R.A. Ethanol self-administration: Infrahuman

studies. In: Thompson, T., and Dews, P. B. eds. Advances in

Behavioral Pharmacology. New York: Academic Press, 1977. pp.

35-84.

Nemeth-Coslett, R., and Henningfield, J.E. Doserelated effects of nicotine delivering chewing gum on rate of

cigarette smoking. Manuscript in preparation, 1985.

U.S. Department of Health and Human Services, Public

Health Service. Why People Smoke Cigarettes. Washington,

D.C.: Supt. of Docs. U.S. Govt. Print. Off., 1983.

AUTHORS

R. Nemeth-Coslett

Jack E. Henningfield

National Institute on Drug Abuse

Addiction Research Center

4940 Eastern Avenue

c/o Baltimore City Hospitals

Baltimore, Maryland 21224

26
The Titration Hypothesis

Revisited: Nicotine Gum Reduces

Smoking Intensity

Ronald I. Herning, Ph.D., Reese T. Jones, M.D.,

and Patricio Fischman, M.D.

INTRODUCTION

Smokers alter puffing and inhalation patterns in response to

changes in the characteristics of the cigarettes they smoke.

Increasing ventilation or decreasing draw resistance increases

smoking intensity (Dunn 1978; Sutton et al. 1978; Henningfield

and Griffiths 1980). Shortening cigarette length increases

puffing rate and the total number of cigarettes smoked (Goldfarb

and Jarvik 1972; Gritz et al. 1976; Ashton et al. 1978; Russell

et al. 198Oa). When smokers take more puffs per cigarette, the

intercigarette interval increases (Griffiths et al. 1982). When

forced to smoke at more frequent intervals, they reduce puff

volume (Gritz et al. 1983). Smokers who switched from middle to

low tar cigarettes increased their puff size and a mathematically

derived exposure index, but not the number of puffs, puff duration, interpuff interval, or butt length (Pawbone et al. 1978).

Decreasing the machine-determined nicotine yield of cigarettes

increased the number of cigarettes smoked in the 16 studies

reviewed by Stepney (1980). Decreasing machine-determined nicotine delivery of cigarettes smoked increases puff volume (Adams

1978; Creighton and Lewis 1978; Herning et al. 1981; Gust and

Pickens 1982). Only Dunn and Freiesleben (1978) reported no

relationship between puff volume and decreased machine nicotine

delivery.

These studies support the nicotine titration hypothesis. That is,

smokers adjust their smoking patterns to obtain an optimal dose of

nicotine from whatever cigarette they are smoking. Presumably,

this dose produces some optimal blood or brain level of nicotine.

Had nicotine blood levels been measured in these studies, the

titration hypothesis might have been confirmed.

Studies where smokers were given cigarettes of different machinedetermined yields and nicotine blood levels were obtained do not

appear to support the titration hypothesis. When smokers are

switched from mid-nicotine yield cigarettes to high machine yield

cigarettes, nicotine blood levels are higher (Ashton et al. 1979,

27
1981; Benowitz et al. 1982). when smokers are switched from midto low-yield cigarettes, the corresponding blood levels decrease

(Russell et al. 1972; Ashton et al. 1979 1981; Benowitz et al.

1982). If smokers actually titrate, the nicotine blood levels for

the different cigarettes should be similar. However, only Russell

et al. (1972) found equal blood levels when cigarettes yielding

1.32 mg and 3.2 mg nicotine were compared. Hill and Marquardt

(1980) noted similar nicotine metabolite levels (cotinine) when

tar and nicotine machine yield were manipulated.

Thus, these cigarette-switching studies have adequately demonstrated that subjects change puffing patterns in the direction

predicted by the titration hypothesis, but they have failed to

show that the adjustment leads to similar blood levels. The

interpretation of these studies is complicated because high- and

low-yield commercial cigarettes contain equivalent amounts of

nicotine (Renowitz et al. 1983), and blood nicotine or cotinine

levels do not correlate with machine yield of nicotine in large

samples of smokers (Russell et al. 1980b; Benowitz et al. 1982;

Herning et al. 1983b).

Supplemental nicotine or pharmacological manipulations which modulate nicotine's effects or its excretion alter smoking patterns.

Oral doses of nicotine or infusions reduced smoking (Johnston

1942; Lucchesi et al. 1967; Jarvik et al. 1970). Stolerman et al.

(1973) found mecamylamine, a nicotine antagonist, increased smoking rate. Naloxone, an opiate antagonist, reduced the number of

puffs on a cigarette as well as the number of cigarettes smoked

per day (Karras and Kane 1980). The manipulation of urinary pH

to alter nicotine excretion modified cigarette smoking (Schachter

et al. 1977). Except for a study by Kumar et al. (1977, experimental alterations which either blocked nicotine effects or

increased nicotine blood levels produced the expected changes in

smoking behavior.

The latter studies provide support for the nicotine titration

hypothesis and support the use of supplemental nicotine as adjunct

to smoking cessation therapy. Slow release buffered nicotine gum

(Nicorette) now available provides the researcher another opportunity to test thenicotine titration hypothesis in controlled

laboratory studies. The previous studies giving supplemental

nicotine did not measure nicotine blood levels. Although smoking

behavior changed, there is no evidence that the experimental manipulation produced similar nicotine blood levels. If subjects are

indeed titrating nicotine, blood levels should be equal when

supplemental nicotine and placebo are given. The present study

evaluates whether smokers given placebo or nicotine gum reduce

the intensity with which they smoke as compared with smokers given

placebo and whether blood levels are reasonably similar on nicotine and placebo gum test sessions.

28
METHODS

Subjects

One female and five males served as subjects. They were 31.7 ±

3.3 (mean and standard deviation) years old The subjects smoked

30.8 ± 7.4 cigarettes per day with 6.0 ± 26 of these cigarettes

smoked in the morning. All subjects had smoked for at least 10

years and smoked their current brand for 2 years or more. The

machine-determined nicotine yield of their current cigarette was

1.14 ± 0.19 mg. They smoked their current brand during each of

the two ad lib smoking sessions.

Experimental Procedure

During each of two morning sessions, the subjects smoked their

self-selected brand of cigarette while chewing either nicotine or

placebo gum in a counterbalanced order. The subjects were asked

to remain abstinent from cigarette smoking from the night before.

The experimental sessions lasted 4 hours. The subject sat in a

comfortable reclining chair during this time and either read or

listenedto music. During this period the subject could smoke at

anytime. Before and 2 minutes after smoking, blood was drawn for

nicotine &terminations. Expired breath samples were collected 10

minutes after each cigarette and tested for carbon monoxide level.

During smoking, puff and inhalation patterns were monitored (see

below). During the first half hour of each hour the subjects

chewed either placebo gum or gum containing 2 mg of nicotine in a

buffered slow release resin (Nicorette, supplied by Merrell Dow)

according to the instructions in the package insert. Before and

25 minutes after chewing, blood was drawn for nicotine levels.

During a given morning session, each subject received four pieces

of one type of gum or the other. The gum was administered in a

double-blind fashion The lab sessions were separated by 5 or

more days. Heart rate and blood pressure were measured at halfhour intervals.

Measurement of Smoking Patterns

Puff volume and duration were measured by a single transducer

flow meter. The flow meter consists of a plastic cigarette holder

connected via flexible tubing to a Statham pressure transducer

(Model PM5TC). Each cigarette smoked was precalibrated with known

air flows, as in our previous studies (Herning et al. 1981 1983a,b).

Inhaled volume and duration were measured by an Ambulatory Monitoring inductance plethysmograph Respitrace). The plethysmograph

was calibrated with a Collins (Model 06031) water spirometer using

the method described by Watson (1979).

The analog signals from the flow meter and plethysmograph were

digitized every 40 ms from start of the puff for a period of 8

seconds. Puff and inhalation measures were numerically calculated

from digital values. We calculated puff volume from flow using

numerical integration which involves dividing the area under the

flow curve into small trapezoids. These trapezoids are then added

29
together to obtain volume. Puff duration is the interval from

start to end of puff where the flow values are nonxero. Inhaled

volume is volume at maximal inhalation after a puff. The duration

of inhalation is interval from start of the puff to maximal inhalation. Thus, it is half the actual duration of inhalation. Puff

and inhalation duration were measured to the nearest 1/25 of a

second while interpuff interval was measured to the nearest second.

Biochemical Measures

Blood samples were drawn from a forearm vein at half-hour intervals, immediately before smoking, and 2 minutes after the last

puff. Samples were assayed for nicotine using the gas chromate

graphic method described by Jacob et al. (1981). An Ecolyzer

(Series 2000) monitor was used to determine the CD levels from the

expired breath samples.

Data Analysis Concerns

We hypothesized that the subjects would reduce the frequency and

intensity of smoking when given nicotine gum compared to placebo.

Since our hypothesis implied the direction each measure would

change when the subjects chewed nicotine gum, one-tail probability

values were appropriate for the t-test on these smoking measures.

For example, our hypothesis tests especially for reduction in the

number of cigarettes smoked on the nicotine gum day as compared to

the placebo day.

We also hypothesized that nicotine blood levels would be equal on

both test days. Thus, in such a test the area under the nicotine

blood level curves (AUC) on both sessions should be equal. This

statistical test is a test of the null hypothesis. Such a test

presents some statistical problems. The lack of differences, if

observed, could be due to excessive variability in the measures or

to no actual difference in the means. One cannot be sure. One

method to protect against this problem is basing the test against

the null hypothesis by adjusting the probability levels to make

finding a difference easier. Thus, for the test on nicotine AUC,

a probability level of 0.10 was used. An additional problem in

testing whether nicotine blood levels are equal revolves around

the issue of what is a biologically significant difference in

levels. Certain differences in the WC may be found, but are they

biologically important? Thus, testing the titration hypothesis

has some practical problems.

RESULTS

The area under the curve (AUC) for nicotine tended to be higher

during the nicotine gum session (2945 ng•min•ml-1) as compared to

the placebo gum session (1925 ng•min•ml-1). This difference was

significant (t=2.16, df=l,5, p<.10) at the increased probability

level. That is, our test subjects appear not to be titrating.

The individual nicotine curves are presented in figures 1, 2, and

3. Before it was concluded that the subjects were not titrating,

an unexpected complication was noted. Three of the subjects had

30
FIGURE 1. Nicotine blood level curves for Subjects 1 and 2. Bars

indicate placebo or nicotine gun chewing periods.

31
FIGURE 2. Nicotine blood level curves for Subjects 3 and 4. Bars

indicate placebo or nicotine gun chewing periods.

32
FIGURE 3. Nicotine blood level curves for Subjects 5 and 6. Bars

indicate placebo or nicotine gun chewing periods.

33
higher blood nicotine levels on the gum day. These subjects

smoked all or the majority of their cigarettes during the nicotine

session while actually chewing the nicotine gum. Both theactive

and placebo gum have an alkaline buffer which increases buccal

absorption of the nicotine. These subjects were perhaps obtaining

more nicotine with the gum than they might have without chewing

it We tested for this possibility. A two factor analysis of

variance with gum (placebo versus nicotine) and smoking period

(chewing versus not chewing) as factors was used to test for any

differential increase in nicotine blood levels while chewing gum

The increase in nicotine blood levels with smoking was significantly (F=4.4, df=1,53, p<.05) larger when the subjects were

chewing gum (8.0 mg/ml) than when they were not chewing (5.1

mg/ml). Thus, regardless of the type of gum, nicotine blood

level increased more during periods of gum chewing. Under such

unexpected nicotine delivery conditions, titration may have been

difficult.

Smoking patterns were modified by the nicotine gum. The mean

number of cigarettes smoked during the I-hour session was significantly less (t=2.23, df=5, p<.05, one-tailed) for the nicotine gum

(4.3) than the placebo gum session (5.3). Mean interpuff interval, puff volume, puff duration, inhaledvolume, and inhaled duration are listed in table 1 for all subjects on both test sessions.

The means are calculated from all puffs during a given session.

To simplify the analysis of these measures, a single exposure

index (EI) was calculated for each session from equation (1).

where N equals the number of cigarettes smoked.

Each EI is calculated by (2) for each cigarette.

EIi=(b0+b1•MDOSEi+b2•NPi+b3•IPIi+b4•PVI+b5•PDi+b6•IVi+b7•IDi) (2)

MDOSEi

= machine determined yield for cigarette i

Npi = number of puffs for cigarette i

IPIi = interpuff interval for cigarette i

PVi = puff Volume for cigarette-i

PDi = puff duration for cigarette i

IVi = inhalation volume for cigarette i

IDi = inhalation duration for cigarette i

The b0, b1 . . . b7 were derived from a multiple regression of the

above measures used to predict the increase blood nicotine levels

in a large sample (N=104) of smokers used in our previous study

(Herning et al. 1983b). Thus, the bi's were calculated from an

independent sample of subjects. The bi's were 15.35, 8.35, -0.18,

-0.25, 0.12, -3.06, -4.46, and 0.59, respectively.

34
TABLE 1

Mean Smoking Patterns for Placebo and Nicotine Gum Session

No. of

Smoking Measure

Subject Type Cigar- No. of Interpuff Puff Inhaled

Number of Gum ettes Puffs Interval volume Duration Volume Duration

(sec) (ml) (sec) (L) (sec)

1 Placebo 6 51

Nicotine 4 36

2 Placebo 8 7 4

Nicotine 7 73

3 Placebo 6 43

Nicotine 5 38

4 Placebo 3 34

Nicotine 4 48

5 Placebo

Nicotine

6 Placebo

Nicotine

Placebo

Nicotine

4

3

5

3

5.3±

1.7

4.3±

1.5

22

20

46

33

45.0±

17.5

41.3±

18.0

51.5±17.7

54.1±20.2

37.4±20.0

29.±15.3

54.2±35.3

45.7±27.1

39.5±25.5

29.6±17.1

71.8±28.0

66.1±42.9

45.5±28.6

38.1±30.2

49.3±14.8

43.1±16.5

49.1±16.1

58.±20.6

54.9±15.8

41.7±15.4

43.8±18.6

46.2±21.3

45.7±12.7

49.2±8.8

65.8±24.5

83.2±28.6

22.1±8.7

18.6± 6.7

47.2±14.6

49.9±19.6 1.9±0.5

2.2±0.6

2.4±0.6

1.8±0.5

1.7±0.7

1.8±0.7

2.1±0.9

1.6±0.7

1.5±0.4

2.1±0.7

2.2±0.6

1.2±0.4

1.1±0.4

1.8±0.4

0.68±0.22

0.46±0.16

0.67±0.15

0.44±0.12

0.45±0.10

1.77±0.64

0.82±0.47

1.32±0.47

1.14±0.64

1.67±0.73

0.42±.14

0.58±0.23

0.68±0.35

1.03±0.70

2.7±0.5

3.1±0.6

4.6±1.2

4.4±1.4

3.2±0.8

3.9±1.4

4.0±1.3

3.4±0.8

5.0±1.3

4.8±2.0

4.4±2.0

3.3±1.5

4.1±1.1

3.8±0.8
The EI for the placebo session (81.6) was significantly larger

(t=2.l4, df=5, P<.05) than the corresponding EI (63.6) for the

nicotine gum session. The area under the curve for CO tended to

be lower on the nicotine session (2222 PPM•sec) than the placebo

session (2606 PPM•sec), but the difference in means was not significant. Although CO did not clearly indicate increased smoking on

the placebo day, it paralleled the EI measure. The values for

each subject are plotted in figure 4. Points below the diagonal

line indicate an increase in the intensity of smoking on the

placebo day. Points above the diagonal line indicate an increase

in the intensity of smoking on the nicotine day. Distance from

the diagonal line indicates the magnitude of change. The plots

are remarkably similar. Subject 4 is the only smoker not reducing

his smoking behavior while on the nicotine chewing gum.

Heart rate (F=4.65, df=9,45, P<.05) increased over the smoking

session from a pre mean of 62.9 to a maximum of 69.2. No difference in the increase was observed on the two test sessions. The

changes in systolic blood pressure over a given session or over

both sessions were not statistically significant from the pre

test. Diastolic blood pressure increased with smoking from a pre

mean of 69.3 to a maximum level of 75.2. This increase, although

significant (F=3.17, df=9,45, p<.05), was similar on both test

sessions. The maximal increase for both heart rate and diastolic

blood pressure occurred at the 2-hour sample No further increases were observed.

DISCUSSION

Nicotine chewing gum reduced the frequency and intensity of

smoking in our subjects. The change in smoking behavior was

reflected in a composite index of number of puffs, inter-puff

interval, puff volume, puff duration, inhaled volume and duration.

A decrease in carbon monoxide was also observed, but the difference in CO AUC between sessions was not statistically different.

The composite exposure index appeared to be the more sensitive of

the two measures. Since the composite index weights all aspects

of smoking behavior, individual differences in regulation can be

taken into account. However, a very simple measure of smoking,

that is, number of cigarettes smoked, was also significantly

reduced. Whether smoking behavior measures were simple or COmplex, our subjects smoked less on the nicotine gum session than

on the placebo session.

The reduction in smoking is similar to that found by Johnston

(1942) and Lucchesi et al. (1967) with intravenous doses of nicotine and by Jarvik et al. (1970) with nicotine tablets. It is

unclear why Kumar et al. (1977) did not find such a reduction in

smoking intensity. One possible reason is that the subjects in

the Kumar experiment were not abstinent before testing as were

the subjects in other studies and thus were relatively nicotine

satiated at the time of testing.

36
PLACEBO GUM

FIGURE 4. The CO AUC values (top) and exposure index values

(bottom) are plotted for each subject on both test sessions.

The placebo session values are plotted on the x-axis and nicotine

session values are plotted on the y-axis. Each point is labeled

with a subject number. Values below the diagonal indicate increased smoking intensity on the placebo day.

37
In previous studies testing the titration hypothesis by administering supplemental nicotine while the subjects were free to

smoke, nicotine blood levels were not measured. If subjects are

titrating, one might expect the nicotine blood levels to be

similar in sessions where supplemental nicotine was given and

sessions where no supplemental nicotine was administered. Despite

variability, the nicotine levels were higher in the nicotine gum

session at the 0.1 level of significance The increase in nicotine levels was due to half the subjects smoking their cigarette

while chewing gum on nicotine sessions. The gum (both placeboand

nicotine) changed the pH of the mouth which resulted in increased

nicotine absorption. The increased nicotine absorption may have

made titration more difficult.

Since only six subjects were tested, these results mayor may

not generalize to a heterogeneous sample of smokers. Different

results might he obtained with less dependent or older, more

dependent smokers Cur sample of smokers were in their late

twenties and early thirties, had smoked for 10 years, and were

now smoking one and a half to two packs a day.

In our study, the nicotine AUC was different between sessions.

However, differences in nicotine blood levels between the two

experimental sessions did not produce significant cardiovascular

changes between sessions. Thus, it could be argued that the

differences in blood levels between sessions were not physiologically meaningful. Smokers may have a range of blood levels

which are sufficient to produce the cardiovascular andsubjective

effects they desire or to reduce the withdrawal symptoms they seek

to avoid. Precise titration to identical blood levels may not be

necessary.

SUMMARY

Supplemental nicotine gum reduced the intensity of smoking in six

one-and-a-half to two-pack-a-day smokers. The study involved two

4-hour self-paced smoking sessions where nicotine and placebo

chewing gum were administered in a double-blind fashion. Puff

volume, puff duration, inhaled volume, inhaled duration, and

interpuff interval were calculated for each puff on each cigarette. Blood was drawn for nicotine levels at regular intervals as

well as before and after each cigarette Cardiovascular measures

were made at regular intervals. The nicotine gum reducedsmoking

frequency and intensity as predicted by the titration hypothesis.

Precise titration (i.e., equal nicotine blood levels on both test

days) was confounded by changes in smoked nicotine delivery produced by the gum. The gum, whether placebo or active, increased

smoked nicotine absorption. However, while nicotine blood levels

were slightly higher on nicotine gum day, the differences may not

be biologically meaningful since heart rate and blood pressure

increases were similar on both days. Difficulties testing the

titration hypothesis are discussed.

38
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cigarette smoking: Manipulation of number of puffs per bout,

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Kumar, R.; Cooke, E.C.; Lader, M.H; and Russell, M.A.H Is nicotine important in tobacco smoking? Clin Pharmacol Ther 21:520-

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40
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Middlesex, U.K., 1979.

ACKNOWLEDGMENTS

Research supported in part by Grants No. DA02088, DA00053 and

DA01696 from the National Institute on Drug Abuse and funds provided by Merrell Dow pharmaceuticals, Inc.

AUTHORS

Ronald I. Herning, Ph.D.*

Assistant Professor of Medical Psychology

Langley Porter Psychiatric Institute

University of California, San Francisco

San Francisco, California 94143

Reese T. Jones, M.D.

Professor of Psychiatry

Langley Porter Psychiatric Institute

University of California, San Francisco

San Francisco, California 94143

Patricio Fischman, M.D.

Resident, Langley Porter Psychiatric Institute

University of California, San Francisco

San Francisco, California 94143

* Current Address:

NIDA Addiction Research Center

P.O. Box 5180

Baltimore, Maryland 21224

41
Cardiovascular Effects of Nicotine

Gum and Cigarettes Assessed by

ECG and Echocardiography

Janine Krivokapich, M.D., and Nina G. Schneider, Ph.D.

John S. Child, M.D., and Murray E. Jarvik, M.D., Ph.D.

INTRODUCTION

Cigarette smoking is one of the most firmly established risk

factors for coronary heart disease (Kannel 1981). This risk can

be dramatically reduced by discontinuation of cigarette smoking

(Doll and Peto 1976; Hammond and Garfinkle 1969; Kannel 1981).

Unfortunately, smoking cessation programs have low long-term success rates (Evans and Lane 1980; Raw 1978; Schwartz 1979).

Several investigators attribute the maintenance of smoking

behavior to a dependence upon nicotine (Gritz 1980; Jarvik 1970;

Russell 1980). Nicotine induced withdrawal symptoms and nicotine

seeking may account for cessation difficulty and high relapse

rates. Nicotine chewing gum was introduced as a means of treating

the pharmacological dependence during cessation of smoking (Ferno

et al. 1973). The 4 mg dose results in blood levels of nicotine

similar to a cigarette although without the “bolus” effect (see

Russell and Jarvis in this volume). The 2 mg dose results in even

lower blood levels. The purpose of using nicotine gum is to

prevent abrupt withdrawal from nicotine and consequent symptoms

and craving while supplying a substitute oral activity. Several

recent studies attest to its efficacy in the alleviation of

withdrawal (Hughes et al. 1984; Schneider et al. 1984; West 1984).

Enhanced success rates in smoking cessation have been demonstrated

in a number of recent placebo-controlled trials (Fagerstrom 1982:

Hjalmarson 1984; Jarvis et al. 1982; Killen et al. 1984; Schneider

et al. 1983). Since its introduction in the United States in

1984, this preparation is now widely available by prescription for

the treatment of smoking dependence.

The purpose of this study was to examine and compare the acute

effects on the cardiovascular system of nicotine delivered by

smoking cigarettes versus chewing nicotine gum. Low and high

nicotine cigarettes (0.2 mg and 2 mg) and 2 mg and 4 mg nicotine

gum formed the four treatment conditions with each subject serving

as his own control for all conditions. Cardiovascular evaluation

included blood pressure, heart rate, electrocardiographic

monitoring, and N-mode echocardiography, performed before and at

42
intervals up to 90 minutes after nicotine was introduced in eith

form to healthy male smokers. Psychological responses wer

elicited to determine whether there were any subjective response

to treatment.

MATERIALS AND METHODS

Subjects

Fourteen paid volunteers were obtained through advertisements i

the UCLA school newspaper. Subjects selected were males wh

smoked at least one pack a day for two years or more and who wer

healthy and active. Exclusion criteria included any history o

cardiac, respiratory, gastrointestinal, or peripheral vascula

disease. Subjects were required to be free of medications. On th

first day of the study, a brief medical history was taken and

pertinent physical examination was performed on each subject by

cardiologist. This was followed by obtaining a resting bloom

pressure (BP) measurement, a 12-lead electrocardiogram (ECG), an

an M-mode echocardiogram (ECHO). If these tests were all withi

normal limits and the echocardiogram was easily obtainable and o

good quality technically (i.e. the subject was echogenic), the

subject was recruited for an additional four days of study. S i

males, ages 23 to 32 (mean age 27.3 ± 3.6 years), formed the final

study group. Subjects smoked an average of 26 ± 5 cigarettes pe

day for an average of 8.8 ± 5.1 years. Results of the

cardiovascular tests were available to subjects' physicians upo

request.

Materials

High nicotine (2.0 mg) and low nicotine (0.2 mg) cigarettes were

provided by the National Cancer Institute. Merrell Dow Pharmaceuticals of Indianapolis, Indiana, provided 2 mg and 4 mg nicotine gum which was manufactured by A.B. Leo in Sweden. The gum

(Nicorette) contained nicotine bound to an ion exchange resin

which permitted the controlled release of nicotine. The gum was

buffered to allow for rapid absorption through the buccal mucosa.

Chewed gum was sealed in plastic containers and returned to

Merrell Dow Pharmaceuticals for determination of residual nicotine. The residual amount was then subtracted from the initial

dose to estimate the nicotine dose delivered.

Measurements

Cardiovascular measurements were taken in the supine position. A

sphygmomanometer was used to obtain the systolic and diastolic

blood pressure (BP) from the right arm in mm mercury (Hg). The

mean BP was calculated as the difference between the systolic and

diastolic BP, divided by three, and added to the diastolic BP.

Electrocardiograms were taken with a Hewlett-Packard

electrocardiograph. Standard echocardiographic techniques were

used to obtain M-mode echocardiograms. The following measurements

from the echocardiogram were made in triplicate and averaged wing

a mini-computer (ECHO COMP by Digisonics, Inc., Houston, Texas):

43
1) left ventricular end-diastolic dimension (LVEDD) in mm at the

onset of the R wave of the simultaneously recorded

electrocardiographic lead II; 2) left ventricular end-systolic

dimension (LVESD) in mm; 3) left ventricular ejection time

(LVET) in seconds from the duration of aortic valve systolic

opening; and 4) heart rate. From these measurements the left

ventricular fractional shortening percent (FS%=LVEDD-LVESD/LVEDD)

and velocity of circumferential fiber shortening (VCF=FS%/LVET)

were calculated.

Carbon monoxide levels were measured by having the subject hold

his breath for 20 seconds and then exhale into a carbon monoxide

(CO) collection bag. The CO level was measured in parts per

million on an Ecolyzer. A baseline CO level was taken on the

first day of the study before the subjects were asked to abstain

from smoking after 12 am on the day of study. On the following

four treatment days, CO levels were obtained prior to treatment

after abstinence from cigarettes for at least 11 hours and at 10

and 90 minutes after the beginning of each treatment.

psychological measures were obtained to determine whether subjects

experienced subjective state changes over time and across

treatments. Four items were tested on a lo-point verbal scale. The

four items were: Are your hands shaky? Is your heart beating

faster? Do you feel more alert? and Do you feel lightheaded?

This scale was used previously and found sensitive to subjective

changes from pre- to post-smoking (Schneider 1978). On the 10-

point scale 1 represented “not at all" and 10 represented “very

much.” In order to reduce random error and give the subject an

opportunity to respond as exactly as possible, the immediately

preceding response was read to the subject just before he gave his

cur rent response.

Protocol

After informed consent was obtained, potential subjects who were

still smoking were individually screened at 11:00 AM on Mondays.

Six subjects were recruited for an additional four days of study.

Subjects underwent testing of the four conditions (2 mg and 4 mg

nicotine gum and 0.2 mg and 2 mg nicotine cigarettes) from 11:00

AM to 1:00 PM on the next four days in a randomly assigned order.

Subjects were asked to abstain from smoking after 12:00 AM on each

test day but not prior to the initial Monday visit. In addition,

they were to abstain from caffeine in any form after 9:00 AM on

each treatment day. Smoking abstinence was verified by testing

the exhaled carbon monoxide levels. The dose of nicotine in the

gum or cigarette was unknown to the investigator at the time of

testing and the echocardiograms and ECG’s were read by two

observers without knowledge of subject identity or of test

condition.

On each test day, baseline heart rate (HR), BP, ECG, and ECHO were

performed with the subject supine in a hospital bed prior to

smoking a test cigarette or chewing a gum. Following the baseline

measurements, repeat RR, BP, ECG leads 1, aVF, and V5, and ECHO of

44
the left ventricle and aortic root were performed at 5, 10, 20,

30, 45, 60, and 90 minutes after the test condition was started.

The test questions were repeated at 5, 30, 60, and 90 minutes

after the beginning of a treatment and carbon monoxide measurement

was made at 10 and 90 minutes.

Smoking and chewing procedures were strictly controlled as follows: The cigarette was lit and held by the subject, who was

instructed to take one puff every 30 seconds, hold each puff in

for 5 seconds, exhale, and relax for 25 seconds. The timing was

monitored and 10 puffs were completed in 5 minutes. For the gum

treatment the subject chewed hard for 5 seconds and then held the

gum in the cheek (for absorption) for 25 seconds. This cycle was

timed and repeated every 30 seconds for 30 minutes. This

procedure maximized and controlled the nicotine release while

minimizing side effects.

Design

The design of the study was a 2x2x8 factorial for HR, BP, and

echocardiographic measures, The first factor was type of treatment (gum vs. cigarettes); the second factor was dose (high vs. low

nicotine); and the third factor was the 8 time periods at which

measurements were taken. Psychological testing results made up a

2x2x5 factorial and CO measurements a 2x2x3 factorial.

Statistics

Repeated measures analysis of variance (ANOVA) with trends were

performed on the data using a BMDP Statistical Software Program.

One-way analysis of variance was used to compare baseline values

across treatments for each measure. F tests for repeated measures

were used to compare differences between baseline and 5 minute

values and baseline and 30 minute values for heart rate and mean

BP. These analyses were pre-planned and based on data for peak

blood levels of nicotine reported after cigarette smoking (5

minutes) and after gum chewing (30 minutes) (Russell et al. 1980).

Level of significance was chosen as p < 0.05 unless otherwise

stated.

RESULTS

Nicotine Content in Chewed Gum

The average amount of nicotine absorbed by the subjects from the 2

mg and 4 mg nicotine gum was 1.1 ± 0.2 mg and 2.7 ± 0.4 of nicotine, respectively. These were estimated from values obtained for

nicotine remaining in chewed gum. Thus, the high dose nicotine

gum appeared to supply at least twice as much nicotine as the low

dose nicotine gum. Five of six subjects reported an aversive or

burning taste with the 4 mg gum and two of six subjects reported a

burning taste with the 2 mg gum. Additional side effects

consisted of nausea and belching in two subjects, and soreness of

the throat in two others.

45
Carbon Monoxide Levels

Baseline levels of CO obtained before the subjects were asked to

abstain from smoking are listed in table 1. CO levels obtained

immediately prior to each treatment and at 10 minutes and 90

minutes after the treatment began are also listed in table 1 with

ANOVA statistics presented in table 2. A main effect of condition

(p=0.02) was noted which can be attributed to the significant rise

in CO at 10 minutes for the cigarettes compared to the gum. The

condition x time interaction was significant at the p<.005 level.

There was no significant main effect of dose or dose x treatment

interaction.

Heart Rates

The baseline and post-treatment HR responses are listed in table 3

as means ± SD for each condition with ANOVA statistics listed in

table 2. The means are plotted in figure 1. There were no

TABLE 1. Carbon Monoxide Levels (ppm)

2

26.0

3

5.0

4

26.0

5 6

57.0 40.0

1

25.0

X ± SD

29.8±17.4

C1

Pre

10'

90'

CH

Pre

10'

90'

GL

Pre

10'

90'

G H

Pre

10'

90'

17.0

13.0

14.0

14.0

4.5 11.0 10.0 21.0 12.9±5.8

7.5 22.0 19.0 33.0 20.4±10.5

6.0 16.0 14.0 27.0 15.0±6.8

6.5 17.0

* 25.0

9.0 18.0

4.0

10.0

6:0

11.0 8.5 21.0 11.3±6.5

20.0 19.5 30.0 20.9±7.4

16.0 13.5 23.0 14.2±6.2

17.5 12.5 3.0 11.0 8.0 21.0 12.2±6.5

* 14.5 4.0 12.0 9.0 20.0 11.9±6.0

15.0 11.5 3.5 9.0 7.0 14.0 10.0±4.4

19.5

12.5

10.5 4.0 11.0 8.0 24.0 12.8±7.5

12.0 5.0 16.0 9.0 25.0 13.4±7.6

10.5 4.0 13.0 8.0 19.0 11.2±5.1

Sub

Base

Base, CO levels on Day 1 of study prior to abstention; CL,

cigarettes containing low (0.2 mg) nicotine; CH, cigarettes

containing high (2 mg) nicotine; GL, gum containing low (2 mg)

nicotine; GH, gum containing high (4 mg) nicotine; Pre,

immediately prior to intervention after at least 11 hours

abstention from cigarettes: ppm, parts per million: Sub, subject;

*, 10 minute CO measurement had not been added to protocol at the

time of study.

46
Cond

Dose

Time

Cond X Dose

Cond x Time

Dose x Time

Cond x Dose

x Time

TABLE 2. Analysis of Variance Statistics (p values)

CO HR SBP DBP MBP LVEDD LVESD

0.02 0.61 0.74 0.54 0.57 0.92 0.76

0.18 0.01 0.01 0.06 0.31 0.11 0.20

0.005 0.001 0.001 0.0009 0.0001 0.08 0.0004

0.12 0.67 0.71 0.26 0.30 0.78 0.87

0.0005 0.003 0.001 0.10 0.01 0.37 0.11

0.77 0.29 0.96 0.43 0.61 0.51 0.33

0.70 0.16 0.57 0.53 0.85 0.91 0.50

FS% VCF

0.69 0.95

0.88 0.87

0.0008 0.09

0.54 0.16

0.46 0.99

0.61 0.43

0.24 0.11

Cond, condition of cigarette vs gum; dose, low vs high nicotine; CO, carbon monoxide; HR,

heart rate; SBP, systolic blood pressure (BP); DBP, diastolic BP: MBP, mean BP; LVEDD,

left ventricular (LV) end diastolic dimension; LVESD, LV end systolic dimension; FS%,

fractional shortening; VCF, velocity of circumferential fiber shortening; n=6 for all

measures except n=4 for CO.
significant differences among the baseline values. A main effect

of time (p=0.001) was observed with an increase in heart rate from

baseline for all conditions with a return to near baseline values

by 90 minutes. The significant dose effect (p=0.01) indicated

that the higher doses of nicotine regardless of condition had a

greater effect on heart rate than the lower doses. This dose

effect was not interactive with time or condition. A significant

condition x time interaction (p=0.003) revealed different peaks in

time dependent on treatment (i.e., cigarettes vs. gum). The peak

HR for the 90-minute study period was recorded at 5 minutes after

the intervention began for the 0.2 mg and 2 mg nicotine cigarettes

with an increaseover baseline of 7% and 28%, respectively. The

increase in HR noted with the 2 mg nicotine cigarettes was

significant (p<0.001). There was an insignificant 6% increase in

baseline HR with the 2 mg nicotine gum observed at 5, 20, and 60

minutes. The peak HR for the 4 mg nicotine gum recorded at 30

minutes post-treatment represented a 12% increase which was also

not significant (p=0.18).

Electrocardiograms

No changes occurred in the QRS complexes, ST segments, or T waves

in leads 1, avF, or V5 at any time during the various interventions. In addition, no ectopy was detected.

TABLE 3. Cardiovascular Measures

GH

Mean BP

Baseline

5 min

10 min

20 min

30 min

45 min

60 min

90 min

Systolic BP

Baseline 101±7 103±10 103±10 106±8

5 min 103±9 112±7 lOl±7 lO1±12

10 min lOO±12 lO4±7 lO2±7 103±9

20 min 97±ll lO2±lO 98±7 103±6

30 min 96±10 lOl±7 99±8 102±9

45 min 97±7 99±10 99±6 l01±10

60 min 96±l2 lOO±7 97±5 lO2±1O

90 min 97±ll l00±9 99±9 104±11

CL CH GL G H

Heart Rate

67±9

72±9

70±11

7O±9

66±ll

65±9

62±1O

66±9

64±7 64±9

82±10 68±lO

74±l0 65±ll

73±7 68±ll

69±9 66±7

71±7 65±lO

70±11 68±11

66±8 60±5

67±7

71±9

72±8

75±6

75±9

72±7

69±8

65±11

CL CH GL

72±3 73±8 7l±7

74±2 8O±8 7O±5

7l±6 75±4 71±5

68±7 73±8 70±4

67±5 7l±6 7O±4

67±5 69±7 72±2

67±6 7l±6 70±3

68±6 73±3 7l±3

Diastolic BP

57±3 58±8 56±7

60±3 64±7 55±5

57±6 60±5 56±7

53±8 58±7 57±4

52±6 55±6 56±4

53±6 55±7 58±2

52±5 57±6 57±3

53±6 60±2±57+4

73±7

73±8

74±8

73±5

73±7

73±6

70±6

73±5

57±8

59±7

59±9

58±7

59±7

58±7

54±8

58±7

CL, low (0.2 mg) nicotine cigarettes; CH, high (2 mg) nicotine

cigarettes: GL, low (2 mg) nicotine gum; GH, high (4 mg) nicotine

gum; heart rate in beats/min; BP in mm Hg; values are means ±SD.

48
Figure 1. Mean heart rate in beats/min plotted versus time

(minutes) for the four test treatments: , low (0.2 mg) nicotine

cigarettes; , high (2 mg) nicotine cigarettes; , low (2 mg)

nicotine gum; , high (4 mg) nicotine gum. n=6. B, baseline.

Figure 2. Mean blood pressure in mm Hg plotted versus time

(minutes) for the four test treatments: , low (0.2 mg) nicotine

cigarettes: , high (2 mg) nicotine cigarettes: , low (2 mg)

nicotine gum; , high (4 mg) nicotine gum. n=6. B, baseline.

49
Blood Pressure

The systolic, diastolic, and mean blood pressurevalues for the

four conditions are listed in table 3. The mean BP is plotted in

figure 2. No significant differences among baselinevalues for

treatment conditions for systolic, diastolic, or mean BP's were

noted. There was a significant condition x time interaction for

systolic (p=0.001) and mean (p=0.01) BP. 'Ibis is attributed to an

increase in both of these measures for cigarettes at 5 minutes in

contrast to a decrease or no change in these measures after gum

treatment (table 3). A peak rise in systolic BP of 2% and 9% and

peak rise in diastolic BP of 4% and 12% were recorded at 5 minutes

for the 0.2 mg and 2 mg nicotine cigarettes, respectively. The

systolic BP did not rise above baseline for the 2 mg and 4 mg

nicotine gum, and the diastolic BP rose less than 4% at anytime

interval for both the 2 mg and 4 mg nicotine gum. The mean blood

pressure rose a maximum of 3% and 10% for 0.2 mg and 2 mg nicotine

cigarettes, respectively, at 5 minutes. The mean BP did not rise

more than 1% above baseline at any time for the nicotine gum.

Echocardiographic Measures

The mean values for LVEDD and LVESD from ECHO are listed in table

4 in mm. No significant differences among baselines for the 2

variables were observed. A significant time effect for LVEDD of

0.08 and for LVESD of 0.0004 was present. However, there were no

significant effects on LVEDD or LVFSD by dose or condition, and no

significant interactions (table 2). The normal range for LVEDD in

our laboratory is 38 - 57 mm and the normal LVESD is 21-39 mm. No

value for the LVESD or LVEDD was out of the normal range during

any part of the study.

The fractional shortening (FS) per cent is normally between 28%

and 488. The values obtained in this study appear in table 4 and

were all within the normal range. There was a significant

(p=0.0008) main effect of time. The maximum change from baseline

values was recorded over the first 10-20 minutes post-treatment

and was a decrease of 3%, 3%, 11% and 9% for 0.2 mg and 2 mg

nicotine cigarettes and 2 mg and 4 mg nicotine gum, respectively.

By 90 minutes, FS% was within 3% of baseline values. There were

no significant condition or dose effects or any significant interactions between or among condition, dose, and time (table 2).

Finally, the velocity of circumferential fiber shortening (VCF)

was within the normal range of 0.89 - 1.60 at all times for all 4

conditions (table 4). No significant time, dose, or condition

effects or any significant interactions were found (table 2).

Psychological testing

The only significant change (p<0.05) in subjective state reported

for the 4 questions was for "Do you feel lightheaded?" . For this

question there was a significant condition x time interaction

(p<O.004) manifested by a significant increase in perceived lightheadedness at 5 minutes for the 2 mg nicotine cigarettes, only.

50
TABLE 4. Echocardiographic Measures

CL

Baseline

5 min

10 min

20 min

30 min

45 min

60 min

9O min

Baseline

5 min

10 min

20 min

30 min

45 min

60 min

90 min

33±3 34±2

35±1 35±3 l.l5±0.06 1.09±O.10 1.13±O.11 1.12±0.03

34±3 34±3 1.07±0.13 1.13±0.10 1.07±O.09 1.14±0.11

33±4 33±2 31±3 33±3 l.O8±0.11 l.O4±0.08 l.O2±0.14 1.07±0.10

33±3 34±2

33±3

33±3 32±4 1.08±0.13 l.lO±0.12 1.10±0.10 1.05±0.13

35±3 33±3 34±3 1.14±O.12 1.03±0.11 1.05±O.09 l.O5±O.13

34±3 34±2 34±2

35±3

33±3

37±2 34±3 35±1

1.08±0.12 1.08±0.12 l.96±O.lO 1.12±0.14

1.06±0.14 1.15±0.12 l.ll±O.09 l.ll±0.06

34±2 33±2 34±4 34±3 l.lO±0.lO 1.07±0.10 1.08±0.10 1.06±0.16

CL, low (0.2 mg) nicotine cigarettes; CH, high (2 mg) nicotine cigarettes: GL, low (2 mg)

nicotine gum; GH, high (4 mg) nicotine gum; LVEDD, left ventricular end diastolic dimension

in mm; LVESD, left ventricular end systolic dimension in mm; FS, fractional shortening in %;

values are means ±SD.

50±2 50±l 49±2 51±5 33±2 33±l 32±l 33±2

49±2 51±4

50±2 51±3

49±2 50±4 33±2 34±3 32±l 33±2

49±2 51±5

50±2 51±3 48±2 52±5

34±3 34±2 34±2 34±2

32±2

49±1 51±3 49±2

33±2 34±3 34±2

52±5 32±2 34±2 33±2 34±3

49±3 34±3

50±1

51±3 49±2 5l±5 32±2 33±2 33±l

50±5 49±2 51±4 32±2 32±4 32±l 33±3

48±2 50±2 50±3 51±6 32±2 33±2 32±2 34±3

FS VCF

CH GL GH CL CH GL GH

LVEDD LVESD
DISCUSSION

This study was designed to compare the cardiovascular effects of

smoking a 0.2 mg or 2 mg nicotine cigarette with chewing a 2 mg or

4 mg nicotine gum and to begin to examine the safety of using

nicotine gum as a method of smoking cessation.

The work of the heart, or oxygen demand, is dependent on four

major factors: RR, preload, afterload, and contractility. RR can

easily be directly measured. A significant increase in RR above

baseline was noted only for the 2 mg nicotine cigarettes and

consisted of a 28% increase from 64 ± 7 to 82 ± 10 beats/min noted

at 5 minutes. Tachmes et al. (1978) reported heart rate and BP

responses in eight healthy smoking subjects (five men and three

women) before and after smoking low nicotine (0.3 mg) and high

nicotine (2.0 mg) cigarettes. Their plotted mean values recorded

at baseline and at 5 minutes after smoking agree almost precisely

with our data, although S.D’s were not reported. The increase in

AR from baseline to 5 minutes for both low and high nicotine

cigarettes was significant at p<0.05 in their study. The

difference in sample size (n=8 vs. n=6) may account for the

difference. Aronow et al. (1971) performed a similar study in

male patients with a history of angina and found an increase in HR

from 71.0 ± 11.0 to 86.8 ± 9.2 after smoking a high nicotine

cigarette (2 mg) and an increase from 72.4 ± 11.1 to 81.0 ± 9.4

after smoking a low nicotine cigarette (0.3 mg). Both of these

increases were significant.

The peak HR for the 4 mg nicotine gum was recorded as a 12%

increase at 20 and 30 minutes, but this change was not

significant. The timing of the peak HR correlates with previously

reported peak plasma nicotine levels after chewing gum (McNabb et

al. 1982; Russell et al. 1980). Wyberg et al. have reported a 15%

increase in HR at 30 minutes after chewing nicotine gum containing

4 mg of nicotine for 30 minutes using a similar protocol (NYberg

et al. 1982). This corresponded with peak whole blood nicotine

levels which were also recorded by them at 30 minutes. Thus, a

single dose of nicotine gum resulted in no significant change in

HR in contrast to the significant increase observed with a single

high nicotine cigarette over the 90 minutes studied. However, it

is noteworthy that the peak HR achieved with 4 mg nicotine gum was

greater than that observed with 0.2 mg nicotine cigarettes.

The mean BP, which is dependent on both the systolic and diastolic

pressures, provides an indirect measure of afterload on the heart.

The only significant changes (p<0.05) observed in the systolic,

diastolic, and mean BPS were a 9%, 12%, and 10% increase from

baseline noted at 5 minutes for the 2 mg nicotine cigarettes. The

systolic and diastolic BPs recorded after gum chewing began were

all less than the baseline, although not significantly less,

indicating no effect of nicotine gum on BP. We did not observe

the 7% increase at 30 minutes in systolic BP reported previously

with 4 mg nicotine gum (Nyberg et al.). Their protocol differed

from ours in that their subjects chewed the gum for 10 seconds

instead of 5 seconds every 30 seconds. This may have been

52
responsible for the higher absorption of nicotine that they

reported of 3.3 mg (range 2.9-4.0 mg) and may have resulted in the

increase in systolic BP at 30 minutes.

The two remaining determinants of cardiac work are the preload (or

stretch on the left ventricle) and contractility. The

echocardiographically derived LVEDD provides a measure of preload,

and FS% and VCF provide measures of contractility. None of these

echocardiographic measures showed treatment effects. Thus,

nicotine gum in a single dose given to healthy males with no known

cardiovascular disease does not increase the work of the heart or

adversely affect its function.

Raeder et al. (1979) assessed cardiac contractility using PEP,

(pre-ejection period corrected for HR) and PEP/LVET in healthy

male smokers and found no significant changes related to smoking

low nicotine (0.1 mg) and high nicotine (2.6 mg) cigarettes. Our

data is in agreement with this study but is in slight variance

with a study by Rabinowitz et al. (1979) in 16 subjects (14

smokers). They reported an increase in LVEDD of 6% (cf. our 2%

increase), in LVESD of 3% (cf. our 3% increase), and an increase

in VCF of 13% from 1.12 ± 0.06 to 1.26 ± 0.09 (cf. our 4%

increase) after smoking a high nicotine (2.5 mg) cigarette.

The experimental studies were performed after subjects had

abstained from cigarettes for at least eleven hours. Mean

baseline CO values for our six subjects were 29.8 ± 17.4 while

smoking, and 12.4 ± 6.2 after abstaining for at least 11 hours.

This average 58% reduction in CO levels is similar to data for 27

subjects previously studied with CO levels of 43.3 ± 15.3 while

smoking and 16.4 ± 6.7 after abstinence for less than 1 day

(unpublished data). This represented a 62% reduction in CO levels

and was consistent with abstinence.

As expected, CO levels increased for both cigarette conditions

immediately post-treatment, and such differences were not observed

for the gum conditions. The results are similar to previously

reported values (Aronow et al. 1971). No significant difference

in the increase in CO levels at 10 minutes between the 0.2 mg and

2 mg nicotine cigarettes indicated that the differential increase

in HR seen with the 0.2 mg vs. 2 mg nicotine cigarettes was likely

due to the nicotine content and could not be ascribed to a

variation in CO levels.

The only significant change in subjective state was an increase in

lightheadedness reported at 5 minutes for the 2 mg nicotine

cigarettes. The value for 0.2 mg nicotine cigarettes was increased at 5 minutes but not significantly. This subjective

sensation may have been related to the increased CO and/or the

rapid delivery of nicotine by cigarette smoking. It is unlikely

that the increase in HR noted would be perceived as an increase in

lightheadedness.

In summary, our study has shown no significant effect of 2 mg or 4

mg nicotine gum after a single dose on HR, BP, electrocardio53
graphic parameters, or echocardiographic measures of left ventricular function. This suggests that this modality may be a safe

method from a cardiovascular perspective to use as an adjunct in

smoking cessation therapy. We did not, however, examine the

cardiovascular effects after multiple doses of gum as would be

used clinically or give the gum to patients with significant

cardiovascular or pulmonary disease. Both of these issues will

require further study of nicotine gum.

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carbon monoxide level after smoking hi h-, low-, and nonnicotine cigarettes. Ann Intern Med 74:697-702, 1971.

Doll, R.; and Peto, R Mortality in relation to smoking: 20 ears

observation in male British doctors. Br Med J 2:1525-1536,

1976.

Evans, D.; and Lane, D.S. Long-term outcome of smoking cessation

Am J Public Health 70:725-727, 1980.

Fagerstrom, K-G. A comparison of psychological and pharmacological treatment in smoking cessation. J Behav Med 5:343-351,

1982.

Ferno, O.; Lichmeckert, S.J.A; and Lundgren, C.E.G. A substitute

for tobacco smoking. Psychopharmacologia 31:201-204, 1973.

Gritz, E.R. Smoking behavior and tobacco abuse. In: Mello, N.K.,

ed. Advances in in Substance Abuse. Greenwich CT: JAI Press, 1980.

pp. 91-158.

Hammond, E.C.; and Garfinkle, L. Coronary heart disease, stroke

and aortic aneurysm. Factors in etiology. Arch Environ Health

19:167-182, 1969.

Hjalmarson, RI. Effect of nicotine chewing gum in smoking

cessation: a randomized, placebo-co

JAMA 252:2835-2838, 1984.

Hughes, J.R.: Hatsukami, D.K,: Pickens, R.W.: Krahn, D.: Malin,

S.; and Luknic, A. Effects of nicotine gum on the tobacco

withdrawal syndrome. Psychopharmacology 83:82-87, 1984.

Jarvik; M./E. The role of nicotine in the smoking habit. In:

Hunt, W.A., ed. Learning Mechanisms in Smoking. Chicago: Aldine

publishing Company, 1970. pp. 155-190.

Jarvis, M.J.; Raw, M.; Russell, M.A.H.; and Feyerabend, C.

Randomised controlled trial of nicotine chewing-gum. Br Med J

285:537-540 1982.

Kannel, W.B. Update on the role of cigarette smoking in coronary

artery disease. Am Heart J 101:319-328, 1981.

Killen, J.D.; Maccoby, N.: and Taylor, C.B. Nicotine gum and

self-regulation training in smoking relapse prevention.

Behavior Therapy 15:234-248 1984.

McNabb, M.E.; Ebert, R.V.; and McCusker, K. Plasma nicotine

levels produced by chewing nicotine gum. JAMA 248:865-868,

1982.

Nyberg, G.; Panfilov, V.; Sivertsson, R.; and Wilhemsen, L.

Cardiovascular effects of nicotine chewing in healthy nonsmokers. Eur J Clin Pharmacol 23:303-307, 1982.

Rabinowitz, B.D.; Thorp, K.; Hube, G.L.; and Abelmann, W.H. Acute

hemodynamic effects of cigarette smoking in man assessed-by

systolic time intervals and echocardiography. Circulation

60:752-760, 1979.

Raeder, E.A.; Burckhardt, D.; Perrachoud, A.; Blum, P.; Amrein,

P.; and Herzog, H. Effects of smoking and inhalation of carbon

monoxide on systolic time intervals and blood pressure. Chest

75:136-140, 1979.

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Raw, M. The treatment of cigarette dependence. In: Israel, Y.;

Glaser, F.B.; Kalant, R.E.; Popham, W.; Schmidt, W.; and Smart,

R.G, eds. Research Advances in Alcohol and Drug Problems. New

York: Plenum, 1978. pp. 441-485.

Russell, M.A.H. Nicotine intake and its regulation. J Psychosom Res 24:253-264, 1980.

Russel, M.A.H.; Raw, M.; and Jarvis, M.J. Clinical use of

nicotine chewing-gum. Br Med J 280:1599-1602, 1980.

Schneider, N.G. The effect of nicotine on learning and short-term

memory.

1978.

University Microfilms (#79-06196), Ann Arbor, Michigan,

Schneider, N.G.; Jarvik, M.E.; Forsythe, A.B.; Read, L.L.;

Elliott, M.L.; and Schweiger, A. Nicotine gum in smoking

cessation: a placebo-controlled, double-blind trial. Addict

Behav 8:253-262, 1983.

Schneider, KG; Jarvik, M.E.; and Forsythe, AR Nicotine versus

placebo gum in the alleviation of withdrawal during smoking

cessation. Addict Behav 9:149-156, 1984.

Schwartz, J.L. Smoking cures: Ways to kick an unhealthy habit.

In: Jarvik, M.E.; Cullen, J.W.; Gritz, E.R.; Vogt, T.M.; and

West, L.J., eds. Research on Smoking Behavior. National

Institute on Drug Abuse, Research Monograph 17. DHEW Pub. No.

(AMD) 78-581. Washington, D.C.: Supt. of Docs., U.S. Govt.

Print. Off., 1979. pp. 122-146

Tachmes, L.; Fernandez, R.J.; and Sackner, M.A. Hemodynamic

effects of-smoking cigarettes of high and low nicotine content.

Chest 74:243-246, 1978

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J. Psychosom Res 28:379-386, 1984.

ACKNOWLEDGMENTS

The authors acknowledge the assistance of Stephanie Thessomboon in

obtaining echocardiograms, Stacey Posner in administering the

treatments, and Laura Read in data analysis. Alan B. Forsythe,

Ph.D, provided statistical assistance in the analyses of the data

This work was supported by a grant from Merrell Dow

Pharmaceuticals.

AUTHORS

Janine Krivokapich M.D. Nina G. Schneider Ph.D.

John S. Child, M.D.

Department of Medicine

Murray E. Jarvik M.D., Ph.D.

University of California,

Department of Psychiatry and

Biobehavioral Sciences

Los Angeles

Los Angeles, CA 90024

University of California,

Los Angeles, CA 90024;

and Psychopharmacology Unit,

V.A. Medical Center, Brentwood

Los Angeles, CA 98073

55
Characterization of Tobacco

Withdrawal: Physiological and

Subjective Effects

Dorothy Hatsukami, Ph.D., John R. Hughes, M.D., and

Roy Pickens, Ph.D.

Tobacco deprivation has been found to produce many symptoms in

chronic smokers. While increased craving for tobacco is most commonly reported, a wide variety of other symptoms have also been

reported, including changes in physiological, psychomotor and subjective functioning (see Jaffe and Jarvik 1978; USDHEW 1979; Shiffman 1979). This observation has led to the belief that a tobacco

withdrawal syndrome exists which implies a physical dependence to

tobacco. However, at the present time, it is unclear if all or any

of the reactions following tobacco deprivation are in fact indicators of physical dependence. This uncertainty exists in part

because of the lack of systematic and comprehensive studies of

tobacco withdrawal similar to the classical studies such as those

which have examined opiate withdrawal symptoms (Himmelsbach 1942).

The classical studies of withdrawal phenomena have tended to examine a variety of signs and symptoms in a prospective fashion with

measurements obtained on repeated occasions both during baseline

and drug deprivation. In contrast, most previous investigations on

tobacco withdrawal symptoms have been either retrospective, employed only a limited number of measures, employed no baseline

period or failed to include control groups. Furthermore, in order

to define reactions to tobacco deprivation as a true withdrawal

syndrome, it is necessary to rule out the possibility that these

symptoms are attributable to removal of drug action, to a loss of a

reinforcer, or a disruption of a habit. A careful examination of

tobacco withdrawal is important not only to better understand factors which maintain smoking, but also to develop more effective

smoking treatment procedures. For example, if specific signs and

symptoms after tobacco deprivation are due to pharmacological withdrawal, then pharmacological intervention to treat these symptoms

may provide the best treatment outcome.

Over the past few years we have been conducting studies to determine reliable and valid indicators of tobacco withdrawal. We have

also attempted to determine if nicotine replacement can reduce the

number or intensity of tobacco withdrawal symptoms. Two studies

have been completed describing the characteristics of tobacco

withdrawal, and one study has been completed determining if

withdrawal symptoms can be alleviated with nicotine replacement.

This paper will describe the results of these studies, as well as

investigations currently underway.

56
TOBACCO WITHDRAWAL SYMPTOMS IN A CONTROLLED ENVIRONMENT

In the first study (Hatsukami et al. 1984), a prospective examination of tobacco withdrawal symptoms was undertaken while subjects

(chronic smokers) lived in a controlled environment. Subjects were

hospitalized in the General Clinical Research Center of the University of Minnesota Hospitals. This Center is a federally funded

unit established to support clinical research, and contains its own

staff of physicians, nurses, and dieticians as well as its own

biochemical laboratory and kitchen facilities. In the study, subjects (N=27) were hospitalized for seven consecutive days. For the

first 3 days, they were allowed to smoke ad lib while a battery of

tests (see table 1) was administered 1-2 times a day. For the next

4 days, subjects in the experimental group (N=20) were required to

abstain from all tobacco use, while subjects in the control group

(N=7) were allowed to continue to smoke ad lib. Compliance was

monitored by random carbon monoxide breath samples and observations

by the nursing staff.

The study has yielded several interesting findings. First, few of

the measures changed significantly after tobacco deprivation. Of

the 37 measures examined, significant effects were found with only

9. Physical measures that changed significantly were a decrease in

heart rate, and increases in caloric intake and body weight. Subjective measures increasing significantly were craving for tobacco,

confusion and depression-dejection scores on the POMS, and reports

of number of awakenings and duration of awakenings during the sleep

period. The only other significant change was reports by observers

that the subject had difficulty concentrating (table 2). The remaining 28 measures in table 2 did not change following tobacco

deprivation.

As part of the study, the time course of withdrawal measures was

examined over the 4 days of tobacco deprivation. Self-report symptoms such as craving for tobacco, confusion, number of awakenings and duration of the awakenings, and depression-dejection

peaked within 24 to 72 hours after tobacco deprivation and then

declined. Caloric intake increased over the first 72 hours of

tobacco deprivation and decreased after 96 hours, while weight continued to increase. Similarly heart rate decreased initially with

a slight increase after 96 hours of deprivation. This finding

would indicate that some of these symptoms may not solely be due to

the removal of a pharmacological effect.

There may be several reasons for our failure to find significant

changes in measures that other studies have reported following

tobacco deprivation. One reason may be our inclusion of a control

group. We found that addition of the control group eliminated findings that would have been significant if only a baseline/deprivation comparison had been made. For example, restlessness increased

significantly from baseline to the deprivation period for subjects

in the experimental group. However, there was also an increase in

this measure for subjects in the control group over the same period

of time. Thus, the inclusion of a control prevented an erroneous

57

485-874 0 - 85 - 3
Table 1

Measures Employed in the Studies on Tobacco Withdrawal Symptoms and

Effects of Nicotine Gum on Tobacco Withdrawal Symptoms

Measures Study I Study II Study III Study IV

(Inpatient) (Outpatient) (Nicotine (Recent

Gum) Investigation)

Objective Measures

Vital Signs

Heart Rate

Supine

Orthostatic

Blood Pressure

Supine Systolic

Supine Diastolic

Orthostatic Systolic

Temperature

Respiratory Rate

Appetitive Behavior

Body Weight

Caloric Intake/Eating

Fluid Input

Fluid Output

Psychomotor Behavior

Level of Activity

Reaction Times

Simple

Choice

Errors

Tremor

Self-Report Measures

Shiffman-Jarvik Tobacco

Withdrawal Questionnaire1

Profile of Mood States

Scale2

Self-Rating Checklist3

Stanford Sleep Scale4

Behavioral Qbservation

Checklist5

1 Includes scores on craving for tobacco, stimulation/sedation, appetite, psychological discomfort, physical symptoms scales.

2 Includes scores on anxiety-tension, anger-hostility, depression-dejection,

fatigue, confusion. vigor scales.

3 Incluses ratings of cigarette craving, irritability, anxiety, difficulty concentrating, restlessness. headache, drowsiness, gastrointestinal disturbances,

fatigue, impatience, hunger, eating, somatic complaints.

4 Includes reports on number of awakenings. durations of awakening, duration of

5 For Study I, includes observations on restlessness, argumentativeness, slow

sleep. quality of sleep, latency of sleep.

movements, drowsiness, poor concentration. For Study II. includes observations

on irritability, anxiety, restlessness and impatience.

58
Table 2

Significant Changes Following Tobacco Deprivation

and Effects of Nicotine Gum on Tobacco Withdrawal Symptoms

Measures Study I Study II Study III Study IV

(Inpatient) (Outpatient) (Nicotine (Recent

Gum) Investigation)

Objective Measures

Heart Rate

Supine

Drthostatic

Body Weight

Caloric Intake/Eating

Tremor

Self-Report Measures

Shiffman-Jarvik

Craving

POMS

Tension-Anxiety

Depression-Dejection

Confusion

Anger-Hostility

Vigor

Self-Rating Checklist

Craving

Irritability

Anxiety

Difficulty Concentrating

Restlessness

Impatience

Hunger

Somatic Complaints

Sleep Problems

Standard Sleep Scale

Number of Awakenings

Duration of Awakenings

Behavioral Observation

Checklist

Difficulty Concentrating

Irritability

Anxiety

Restlessness

Impatience

a measure not employed in study

+ increase

- decrease

* significant effect of nicotine gum on tobacco withdrawal symptoms

59
conclusion from being drawn, as would have happened if data from

only the experimental group had been analyzed.

A second reason we found few tobacco withdrawal symptoms may be

related to the type of environment in which the study was conducted. In a controlled hospital environment, subjects are not

exposed to many of the stimuli that are typically associated with

their smoking. If environmental factors play a role in determining

the intensity of tobacco withdrawal symptoms (Pomerleau 1981), then

hospitalization may have minimized the intensity of those symptoms.

The third reason for our failure to find withdrawal symptoms that

others have reported may be the large between-subject variability in

our data. This would reduce the likelihood of our obtaining a statistically significant effect. For example, for blood pressure

and temperature, some subjects showed an increase, other showed no

change, while still others showed a decrease on these measures.

Across subjects, such effects tend to cancel out, leaving no net

change for the group.

TOBACCO WITHDRAWAL SYMPTOMS IN THE NATURAL ENVIRONMENT

In the first study, lack of environmental stimuli typically associated with smoking was suggested as one reason for relatively few

withdrawal symptoms being found. A second study was therefore conducted to examine tobacco withdrawal symptoms as they occur in the

natural environment. This study was part of a larger investigation

designed to examine the effects of nicotine gum on tobacco withdrawal symptoms (Hughes et al. 1984). The project was conducted

with outpatients who returned to the smoking clinic for measurement

of withdrawal symptoms. After two evenings of baseline measurement, subjects were randomly assigned to either nicotine or placebo

gum groups in a double-blind manner. Subjects were then asked to

stop smoking, chew nicotine gum or placebo gum ad lib, and return

to the smoking clinic for measurements on the first, second, and

fourth evenings of tobacco deprivation.

For our present purposes, only data from the placebo group (N=49)

will be examined. (The effect of nicotine gum on tobacco withdrawal

symptoms will be described in a later part of this paper.) Since

the study was double-blind, the effects of subject and experimenter

expectancy on tobacco withdrawal symptoms were controlled. The

measures employed in this study are shown in table 1.

In this study, the physiological measures that changed significantly following tobacco deprivation were supine and orthostatic

heart rate. Both decreased with tobacco deprivation. Measures on

the self-rating checklist that changed significantly were craving

for tobacco, irritability, anxiety, impatience, difficulty concentrating, and restlessness. All increased with tobacco deprivation.

The results obtained with the Profile of Mood States (POMS) were

similar to the results obtained with the self-rating checklist,

where significant increases in the anger-hostility, anxiety-tension, and confusion scores, and decreases in the vigor score were

60
obtained. Behavioral observations by others tended to confirm the

self-report results, where significant increases in irritability,

anxiety, restlessness, and impatience were obtained. Other significant changes reported by subjects included decreased tremulousness, increased hunger, increased eating, increased somatic complaints, and increased number of awakenings during sleep and sleep

problems. As in the first study, most of these withdrawal symptoms

began shortly after onset of tobacco deprivation and peaked 24-48

hours later.

Compared to the inpatient study, the outpatient study found a

greater number of significant changes following tobacco withdrawal

(see table 2). The symptoms found in common in the two studies

were a decrease in heart rate and increases in craving for tobacco,

difficulty concentrating, eating behavior, and number of awakenings

during sleep. Unlike the previous study, however, the outpatient

study results included no statistically significant increase in

body weight, duration of awakening during sleep, or depressiondejection score on the POMS. On other common measures, a decrease

in tremulousness, an increase in anger-hostility and tensionanxiety scores, and a decrease in vigor score on the POMS were

found in the outpatient study but not in the inpatient study.

EFFECTS OF NICOTINE ADMINISTRATION ON TOBACCO WITHDRAWAL SYMPTOMS

Do tobacco withdrawal symptoms result from nicotine deprivation?

Other studies attempting to answer this question have focused on

whether frequency of smoking cigarettes is related to severity of

withdrawal and have obtained equivocal results (Shiffman 1979). In

the present study, however, we attempted to determine whether nicotine gum relieves tobacco withdrawal symptoms. This study is important not only in determining whether physiological dependence on

nicotine can occur, but also for clinical reasons. If relapse to

smoking is related to the appearance of aversive nicotine withdrawal

symptoms following tobacco deprivation, then attenuation of withdrawal symptoms by other forms of nicotine administration could

improve smoking cessation success rates (Russell et al. 1980).

Subjects were 100 smokers who met the criteria for Tobacco Dependence and who had a history of Tobacco Withdrawal as defined by the

DSM III criteria (APA 1981). Subjects were randomly assigned to

either a nicotine (2 mg) gum or placebo gum group. Following 2

days of smoking baseline, all subjects were required to undergo

4 days of tobacco deprivation, during which time they were

instructed to chew the gum (either nicotine or placebo) on a PRN

basis. Measures employed are shown in table 1. Only those symptoms that changed signficantly following tobacco deprivation in the

placebo group were examined in the analysis.

The nicotine gum group reported significantly less irritability,

anxiety, difficulty concentrating, restlessness, impatience, and

somatic complaints after smoking cessation than the placebo gum

group on the self-rating checklist. Reductions in these withdrawal

symptoms were confirmed by subjects' scores on the Profile of Mood

6 1
States and by observer ratings. Nicotine did not reduce the increase in cigarette craving, hunger, eating, and insomnia, or the

decrease in tremulousness and supine heart rate that occurred after

smoking cessation. The effect of the nicotine was evident on the

first day of deprivation and throughout the 4-day tobacco deprivation period.

In summary, it appears the nicotine relieves some, but not all, of

the symptoms of tobacco deprivation. There are a number of factors

which may account for the failure of the gum to relieve all tobacco

withdrawal symptoms. For example, the gum dose that was used in

the study may have been inadequate. Second, it may be that nicotine must be given in a bolus form (i.e., as delivered in smoking)

to relieve some symptoms of withdrawal (Russell and Feyerabend

1978). Third, there may be other psychoactive ingredients in tobacco in addition to nicotine which are correlated with physiological dependence on tobacco (Jarvik 1981). Fourth, tobacco withdrawal symptoms may be controlled by behavioral or psychological as

well as a pharmacological factors (Falk 1971; Jaffe and Jarvik

1978).

CURRENT INVESTIGATIONS

A study is currently being undertaken to determine the withinsubject reliability of tobacco withdrawal symptoms. The study

employs a modified single-subject A-B-A-B experimental design.

Following an intial 48-hour period during which baseline measures

are obtained while subjects smoke ad lib, subjects are required to

undergo a 96-hour period of tobacco deprivation. After the deprivation period, subjects are asked to resume smoking for a 96-hour

period (during the latter half of which additional baseline measures are obtained). This second baseline period is followed by a

second 96-hour tobacco deprivation period. Preliminary analysis of

the data from three subjects showed that decreases in supine heart

rate and in vigor score on the POMS, and increases in caloric intake, anger-hostility, and number of awakenings during sleep occurred

consistently both within and across subjects during both periods of

deprivation. In five out of six measurement periods, craving and

confusion score on the POMS also increased. Measures which showed

consistent effects of tobacco deprivation within but not across

subjects include orthostatic heart rate change. All other variables showed inconsistent changes between and within subjects over

the two tobacco deprivation periods.

SUMMARY

In total, our studies show that changes which occur reliably and

consistently in chronic smokers after tobacco deprivation include:

(1) decreased heart rate, (2) increased caloric intake/eating, (3)

increased number of awakenings during sleep, (4) increased craving

for tobacco, and (5) increased confusion, as measured by the POMS.

Other changes that were found to occur after tobacco deprivation in

some but not all of our studies include decreased orthostatic heart

rate, increased irritability, and decreased vigor score on the

POMS.

62
Previous investigators have found a consistent effect of tobacco

deprivation on heart rate (Gilbert and Pope 1982; Knapp et al. 1963;

Parsons and Hamme 1975; Weybrew and Stark 1967; Glauser et al. 1970;

Myrsten et al. 1977; Murphee and Schultz 1968). Although decreased

blood pressure (Knapp et al. 1963; Murphee and Schultz 1968) and

changes in other vital signs such as temperature (Gilbert and Pope

1982; Myrsten et al. 1977; Ague 1974) have been reported, our present studies and studies by others (Weybrew and Stark 1967; Glauser

et al. 1970) failed to find a significant deprivation effect on

these measures. Perhaps the contradictory findings are a function

of the reliability of the measures themselves or of the population

tested.

Caloric intake has been found to increase in both animals and

humans after nicotine or smoking cessation (Gruneberg 1982; Myrsten

et al. 1977; Wack and Rodin 1982). These results are consistent

with studies which have found that smoking cessation causes an

increase in body weight (Wack and Rodin 1982). However, previous

studies disagree on how smoking cessation causes weight gain. Our

inpatient study is believed to be the first to simultaneously

measure changes in caloric intake, fluid retention, and physical

activity after tobacco deprivation. In the study, caloric intake

increased but fluid retention and physical activity did not change.

The increases in weight may not be accounted for solely by

increases in caloric intake. There may be other factors such as

decreased basal metabolic rate which cause the increase in weight.

Other studies have also reported sleep disturbance or insomnia

among tobacco-deprived smokers (Larson et al. 1961; Weybrew and

Stark 1967). Studies directly monitoring sleep have found a

decrease in duration awake (Soldatos et al. 1980), increased REM

sleep (Soldatos et al. 1980; Kales et al. 1970; Parsons et al.

1975), and increased Stage IV (>50% delta waves) sleep (Parson et

al. 1975; Parsons and Hamme 1975). Thus, objective data indicate

that after tobacco deprivation smokers actually sleep longer, which

contradicts subjective reports of insomnia.

Difficulty concentrating after tobacco deprivation has also been

reported by other investigators (Weybrew and Stark 1967; Frankenhauser et al. 1971; Myrsten et al. 1977; Wynder et al. 1967). The

difficulty may be reflected in poor performance shown by tobaccodeprived smokers on driving simulation (Heimstra et al. 1973) and

vigilance (Ashton and Stepney 1982) tasks. Furthermore, smokers

deprived of tobacco have shown an increase in slow wave activity

(Ulett and Itil 1969) and slower dominant alpha frequency (Knott

and Venables 1977) which are associated with a hypoexcitation state

and perhaps a decrease in attention (Knott and Venables 1977;

Ashton and Stepney 1982).

Subjective reports of craving for tobacco, increased irritability,

and decreased vigor have been widely cited in other studies (Shiffman 1979). Craving for tobacco has been found to be the most prevalent withdrawal symptom reported by exsmokers, with up to 90

percent of smokers who quit reporting a craving for tobacco (Guil63
ford 1966). While most of these mood changes have been obtained by

self-report, two studies have employed objective measures of irritability or anger. Hutchinson and Emley (1973) found that masseter

muscle contraction increased in frequency in 7 of 8 subjects withdrawn from tobacco. Schechter and Rand (1974) found higher aggression scores in chronic smokers on the Buss Aggression Machine when

subjects were deprived of cigarettes than when allowed to smoke.

The time course for symptoms that were examined after tobacco

deprivation would suggest that some of the symptoms are not primarily due to the removal of a pharmacological effect and consequently

a return to values prior to the onset of smoking. The onset of

most symptoms was rapid (within 24 hours of onset of deprivation),

reached a peak in 36 to 72 hours, and then gradually declined.

Other investigators have also noted that the peak in tobacco withdrawal symptoms based on subjective reports occurs between 24 and

48 hours (Shiffman and Jarvik 1976). If these symptoms would have

been due to return to baseline, symptoms would not have shown the

"overshoot" or "rebound" pattern that has been found in the opiate

withdrawal syndrome (Himmelsbach 1942).

Our study indicates that nicotine appears to affect the occurrence

of some but not all symptoms of tobacco withdrawal. Previous studies have also found that administration of nicotine minimizes tobacco withdrawal symptoms (Hughes and Hatsukami, this volume). The

only symptom that has been consistently found to be reduced by the

administration of nicotine has been irritability.

Another method of determining whether tobacco withdrawal symptoms

are a result of nicotine deprivation is by examining the signs and

symptoms after nicotine gum deprivation. In a recent study, West

and Russell (in press) have shown that symptoms occur after cessation of long-term nicotine gum use. They found that among individuals who have been using 2 mg gum for at least a year, cessation

from gum use led to increases in reported irritability, depression,

hunger, tiredness and restlessness, and decrease in ability to concentrate and ability to cope. In addition, they found significant

decreases in heart rate. Interestingly, these symptoms are similar

to those we found among smokers undergoing tobacco deprivation

(i.e., irritability, hunger, decrease in ability to concentrate,

and decreased heart rate).

Inevitably, attempts to clarify the characteristics of tobacco

withdrawal generate questions that need to be addressed in further

investigations. More research is necessary to determine which

changes observed following tobacco withdrawal are specifically the

result of removal of the pharmacological effects of the drug and

subsequent return to baseline, the result of interrupting a positively reinforced behavior (Falk 1971), the occurrence of a disruptive event, or true pharmacological withdrawal symptoms. In

addition, further research is required to determine which symptoms

of tobacco withdrawal result from deprivation from nicotine.

Determination of the symptoms which are a result of behavioral

dependence or physical dependence on nicotine can lead to more

64
directed treatment approaches. For example, craving for tobacco

does not seem to be affected by nicotine replacement, therefore

behavioral management may be necessary for symptoms of craving

rather than pharmacological intervention with nicotine.

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AUTHORS AND ADDRESSES

Dorothy Hatsukami, Ph.D. Roy Pickens, Ph.D.

University of Minnesota University of Minnesota

Department of Psychiatry Department of Psychiatry

Box 393 Mayo Box 392

Minneapolis, MN 55455 Minneapolis, MN 55455

John R. Hughes, M.D.

University of Vermont. College of Medicine

Department of Psychiatry

Burlington, VT 05408

67
Short-Term Effects of Nicotine Gum

John R. Hughes, M.D., and Dorothy Hatsukami, Ph.D.

Pharmacological treatments of drug dependence vary in their

approach. Medications may make drug administration aversive (e.g.,

disulfiram). block the reinforcing effects of the drug (e.g.,

naltrexone), substitute for the drug (e.g., methadone), or relieve

the discomfort of drug withdrawal (e.g., benzodiazepines).

Based on these approaches, several types of medications, such as

taste adulterants, stimulants, and tranquilizers have been tested as

aids to smoking cessation (Kozlowski, in press; Raw 1978; Grabowski

and Hall, this volume). Most of these medications have not been

efficacious. Nicotine chewing gum is the exception (Hughes and

Miller 1984). The major hypotheses to explain the efficacy of

nicotine gum are that the gum substitutes for the reinforcing

effects of cigarettes or that the gum relieves tobacco withdrawal

symptoms.

This article will review studies of the short-term effects of

nicotine gum that test these two hypotheses. Although we will

attempt some conclusions, the reader should be aware that, as with

most drugs (Thompson and Johanson 1981), the effects of nicotine

depend on several conditions. For example, differences in dose,

duration and route of administration, drug history, external

stimuli, genetics, personality, rate of ongoing behavior, schedule,

time since drug ingested and tolerance can produce marked differences in nicotine's actions (Aston and Stepney 1982; Emley and

Hutchinson 1984; Gilbert 1979; Goldberg et al. 1983; Henningfield

1984; Henningfield and Goldberg 1983; Hughes, in press; Mangan and

Golding 1984). For example, differences in external stimuli (Goldberg et al. 1983). instructional set (Hughes et al., in press-a).

and schedule (Goldberg et al. 1983) can determine whether nicotine

will serve as a reinforcer or a punisher. Thus, when we summarize

"the" short-term effects of nicotine gum, the reader should realize

the results obtained in laboratory studies may not generalize to

those obtained in medical practice.

EFFECT ON SMOKING BEHAVIOR

The effects of nicotine on smoking vary widely both between and even

within studies (Brantmark et al. 1973; Ebert et al. 1984; Kozlowski

et al. 1975; McM Turner et al. 1977; Ohlin and Westling 1975;

Russell et al. 1976; Westling 1976). Of the 16 comparisons in these

studies, 7 showed nicotine gum decreased smoking and 9 did not.

68
These contradictory results may be due to differences in subjects

(those who were vs. were not trying to quit), sample size (8 vs. 92

Ss), design (within- vs. between-group design), dose (1 vs. 2 vs. 4

mg). schedule of dosing (e.g.. single vs. ad-lib administrations).

duration (30 min vs. 2 wks). and dependent measures (self-report vs.

objective measures and frequency vs. topographical vs. biochemical

measures). Whether any of these differences do, in fact, control

whether nicotine gum influences smoking might be determined by

looking for an association between positive results and a methodological procedure (e.g.. use of smokers trying to quit) across the

studies. Unfortunately, the small number of studies and the fact

that the different methods are confounded with each other prohibits

such an analysis. About the only conclusion that can be reached is

that, at this time, a conclusion cannot be reached.

EFFECT ON CIGARETTE CRAVING

Perhaps the major hypothesis to explain the efficacy of nicotine gum

is that the gum relieves craving for cigarettes during abstinence.

Tests of this hypothesis have thus far been restricted to examining

the effects of nicotine gum on subjects' endorsements of descriptions of craving, such as desire to smoke, thoughts about cigarettes, difficulty refraining from smoking, urges to smoke, hunger

for a cigarette, and awareness of not having a cigarette. Nicotine

gum decreased some of these measures of craving in some subjects in

three small studies (Russell et al. 1977; Ryden 1975; Schneider et

al. 1977). However, nicotine gum did not decrease these measures of

craving in large, placebo-controlled trials of the gum (Hughes et

al. 1984; Jarvis et al. 1982; Ohlin and Westling 1975; Schneider et

al. 1984; West et al. 1984). Thus, the weight of the evidence does

not support the hypothesis that the efficacy of nicotine gum is due

to its ability to relieve craving.

There are several reasons why nicotine gum might not reduce cigarette craving. First, the route of administration (oral vs. inhalation) might be crucial. Oral nicotine produces low levels of

nicotine (Hughes and Miller 1984) that might be insufficient to

reduce craving. However, previous studies have shown that nicotine

via other routes of administration, e.g.. capsules (Jarvik et al.

1970) or intramuscular (Johnston 1942) and intravenous (Henningfield

et al. 1983; Lucchessi et al. 1967) injections decrease smoking and

cigarette craving. Unfortunately, none of these studies reported

examining self-reported craving during abstinence. Oral nicotine

also does not reproduce the "bolus" injection of nicotine from smoking. Bolus injections may be essential to replicate the effects of

smoking (Russell and Feyerabend 1978). However, Kumar et al. (1977)

found that intravenous bolt of nicotine did not decrease smoking

frequency. Second, other ingredients in tobacco may control the

desire for a cigarette. Although there are several reasons to believe nicotine is the major psychoactive ingredient in tobacco, the

psychopharmacological properties of several thousand other compounds

in tobacco have not been tested (Jarvik 1977). Third, craving may

be controlled by environmental factors. Smoking occurs many times

per day, in a variety of situations, and produces a psychoactive

effect quite rapidly (i.e.. within 7 seconds); thus, the opportunities for environmental conditioning are great. Recent studies with

69
amphetamines suggest that once a conditioned drug response is established, the response may no longer be influenced by agonists or

antagonists of the drug (Benninger and Hahn 1983). If this is true,

then once tobacco craving is conditioned to environmental cues,

nicotine alone may no longer reduce craving.

A fourth possibility is that nicotine reduces craving only in the

more "dependent" smoker (Hughes. in press-b). The results of

Russell's study (1977) are consistent with this hypothesis in that

they suggest the reduction in cigarette craving by nicotine gum

varies widely across smokers. To test this hypothesis we divided

smokers in our study into a dependent and nondependent group according to their scores on the Tolerance Questionnaire (Fagerstrom

1978). We then compared the reduction in cigarette craving from

nicotine and placebo gum between the two groups. The reduction in

craving was the same for dependent and nondependent smokers; thus,

the hypothesis that nicotine reduces craving only in the more

dependent smoker was not supported.

Finally, there is the possibility that self-reported craving is a

poor measure. Perhaps better measures would be direct, objective

tests of nicotine self-administration during abstinence such as

concurrent access (Hughes et al., in press) to tobacco and nontobacco cigarettes or the amount of work to obtain nicotine or

tobacco (Griffiths et al. 1982).

The inability to document that nicotine gum reduces craving during

abstinence may have clinical implications. At present, when smokers

are prescribed nicotine gum, they are told the gum will reduce

cigarette craving. Perhaps instead smokers should be told not to

rely on the gum to relieve all craving and be encouraged to develop

a plan to deal with craving that does not respond to the gum (e.g.,

engaging in alternative behaviors or avoidance of cues). When

smokers are prescribed nicotine gum, they are also told to use the

gum whenever craving for a cigarette occurs. If nicotine gum does

not reduce craving, perhaps they could be told to use the gum on a

fixed time schedule instead of a PRN schedule. Fixed time schedules

might be preferable to PRN schedules as the former schedule helps

extinguish conditioned craving responses and decreases the probability that use of nicotine gum itself will become conditioned to

craving cues. Another alternative is that smokers should be told to

use the gum not when cigarette craving occurs, but rather when

withdrawal symptoms occur (see below).

EFFECT ON TOBACCO WITHDRAWAL

Abstinence from smoking induces a variety of withdrawal symptoms

(Hatsukami, this volume; Shiffman 1979). Several double-blind,

placebo-controlled studies have tested the effect of nicotine gum on

tobacco withdrawal. Some studies correlated withdrawal symptom

ratings into a total withdrawal discomfort score. These withdrawal

scores consisted of a single global self-report rating (Russell et

al. 1976; Westling 1976). number of symptoms reported (Puska et al.

1979). or a cumulative score based on the sum of intensity ratings

for individual symptoms (Fagerstrom 1982; Hughes et al. 1984; Killen

et al. 1984: Schneider et al. 1984). In all but one of these

70
studies (Puska et al. 1979). nicotine gum reduced total withdrawal

discomfort (see figure for an example).

In terms of individual withdrawal symptoms, the only effect of

nicotine that was consistent across studies was a reduction in

irritability, anger, and frustration (table 1). Depression was also

reduced by nicotine gum in two of the four studies.

Abstinence from cigarettes produces behavioral as well as selfreport changes (Hatsukami et al. this volume). Our study examined

the effects of nicotine gum on such behavioral changes by collecting

observer ratings of abstinent smokers. Observers (e.g., spouse or

employer) rated subjects who received nicotine gum less irritable,

anxious, restless, and impatient than subjects who received placebo

gum (table 2). Thus, nicotine gum produced behavioral changes that

occurred in the natural environment and were apparent to persons

near the smoker.

Abstinence often produces weight gain. Post cessation weight gain

may be due to several factors, e.g.. increased hunger, increased

consumption of sweets, decreased resting metabolic rate, or decreased motor activity (Grunberg. in press; Hatsukami et al. this

volume; Hughes et al. 1982; Wack and Rodin 1981). Nicotine decreases appetite, increases resting metabolic rate, and increases

physical activity (Grunberg, in press); thus, nicotine gum could be

expected to counteract the weight gain associated with smoking

cessation. Two double-blind placebo-controlled trials reported that

subjects who received nicotine gum reported less hunger (Jarvis

1982) and gained less weight (Bantmark et al. 1973) at 6-month

followup than subjects who received placebo gum. In contrast,

similar trials by Puska et al. (1979). Hall et al. (in press) and

Hjalmarson (1984) found no difference in weight gain or hunger between those on nicotine gum and those on placebo. Also, both West

et al. (1984) and we (Hughes et al. 1984) found that nicotine did

not reduce hunger during the first few days of abstinence.

Although this evidence suggests nicotine gum does not decrease post

cessation weight gain, clinical trials of nicotine gum may not be

fair tests. This is because some subjects in a clinical trial will

relapse to smoking. Since nicotine gum keeps people from smoking

and since abstinence increases weight. then nicotine gum will appear

to increase weight gain due to its-therapeutic efficacy. To truly

test the effect of nicotine gum on post cessation weight gain. a

study must prevent attrition-back to smoking and study the effect of

nicotine gum on weight gain only in abstinent smokers.

Another less well-documented effect of abstinence from smoking is

analgesia. Milgrom-Friedman et al. (1983) examined whether nicotine

gum would influence abstinence-induced analgesia. They studied nonsmokers, smokers smoking ad lib, abstinent smokers who chewed nicotine gum, and abstinent smokers who did not chew nicotine gum. Each

group had a tourniquet applied to one arm and then reported the time

to onset of pain and the time until the pain was intolerable. Abstinent smokers who chewed nicotine gum reported pain onset similar

to that of abstinent smokers who did not chew gum. Both these

groups had a pain onset longer than that of smokers smoking and

71
Figure. Mean and standard error of daily discomfort score by

experimental condition and drug group for our nicotine gum study

(Hughes et al. in press). Open circles = placebo, closed circles =

nicotine.

72
Table 1. Effects of nicotine gum on the commonly reported

symptoms of tobacco withdrawal

Brantmark Puska Jarvis Hughes West

et al. 1973 et al. 1979 et al. 1982 et al. 1984 et al. 1984

DSM-III Criteria

Irritability/Anger/Frustration

Anxiety/Tension

Difficulty Concentrating

Restlessness/Impatience

Headache

Drowsiness/Alertness

Gastrointestinal Problems

Other Criteria

Depression

Fatigue

Hunger

Insomnia

None None

None None

None None

Reduced

None

Reduced

Reduced

Reduced

Reduced

Reduced

None

None

None None

Reduced

None

None

None

None

Reduced Reduced

Reduced None

None

None
Table 2. Behavioral effects of nicotine guma

Variable

F value for

Group Baseline Abstinence Nicotine < Placebob

Irritability Placebo 0.4

Nicotine 0.5

Anxiety Placebo

Nicotine

Restlessness Placebo

Nicotine

Impatience Placebo

Nicotine

0.6

0.6

0.4 0.9

0.6 0.8

0.5

0.7

0.9

10.7**

0.6

1.1

0.7

4.7*

7.5*

1.0

10.5**

0.7

a

 All ratings based on scale of 0=not present, 1=mild, 2=moderate,

and 3= severe. All standard errors <0.15.

b

 F value for the interaction that the increase in the behavioral

rating would be less for the nicotine group than for the placebo

group, df=(1,79).

* p<.05

** p<.01

74
nonsmokers. Thus, nicotine gum did not reverse abstinence-induced

analgesia.

In summary, nicotine gum decreases both self-reported and observed

symptoms of tobacco withdrawal. The most consistent effect of nicotine gum is to decrease irritability/anger/frustration. Whether the

gum reduces other withdrawal phenomena, such as weight gain, is

unclear.

BIOCHEMICAL/PHYSIOLOGICAL EFFECTS

One hypothesis to explain the ability of nicotine gum to decrease

withdrawal symptoms is that the gum dampens the arousal associated

with tobacco withdrawal. The only biochemical effects of nicotine

gum that have been tested are its effects on serum glucose and excreted catecholamines. Gennser et al. (1975) and Manning and

Feyerabend (1976) reported that neither the 2 mg nor the 4 mg gum

changed the blood glucose of pregnant women. West et al. (1984)

reported that the fall in excreted catecholamines during abstinence

was similar in nicotine (2 mg) and placebo groups.

The physiological effects of nicotine gum that have been examined

are its effects on cardiovascular function, tremor, and, in one

study, evoked potentials. Most studies of the cardiovascular

effects of nicotine gum on nonsmokers and nonabstinent smokers

report that the 4 mg gum, but not the 2 mg gum, increases heart rate

(Fredholm and Sjorgen 1979; Gennser et al. 1975; Jarvik 1982;

Manning and Feyerabend 1976; Nyberg et al. 1982). Neither dose of

gum influenced EKG measures or blood pressure (Fredholm and Sjorgen

1979; Nyberg et al. 1982). A report that the 4 mg gum decreases

skin temperature (Fredholm and Sjorgen 1979) was not replicated

(Nyberg et al. 1982). Among the studies of the effect of nicotine

gum on the cardiovascular response of abstinent smokers, two

reported that nicotine gum 2 mg dampened the fall in heart rate

during abstinence (Schneider et al. 1984; West et al. 1984);

however, our study (Hughes et al. 1984) failed to replicate this

finding. In addition, our study (Hughes et al. 1984) found that

nicotine gum tended to reduce the increase in orthostatic response

(i.e., the increase in heart rate upon standing) after abstinence.

The two other physiological responses that have been studied are

tremor and evoked potentials. The 4 mg, but not the 2 mg, dose of

gum increased hand tremor in nonabstinent smokers (Shiffman et al.

1983). The 2 mg dose also failed to counteract the decrease in

tremor after abstinence in our study. Finally, nicotine gum has

been reported to have the same effect as smoking on visual evoked

potentials (Milgrom-Friedman et al. 1981).

In summary, the effects of the gum on biochemical and physiological

indices of arousal appear to be dose-dependent; i.e., the 4 mg gum

does cause some changes, but the 2 mg gum does not appear to have

any significant effects.

75
TIME COURSE OF NICOTINE EFFECTS

The time course of a drug's effects may be crucial to its ability to

produce therapeutic effects. The onset of nicotine gum's effects

appears quite rapidly (see figure). In two studies, the gum reduced

total withdrawal discomfort within 24 hours (Hughes et al. 1984,

West et al. 1984) and in a third study within 48 hours (Schneider et

al. 1984).

The duration of the effects of nicotine gum has not been well

studied. In our study, the effect of the gum tended to decrease

over four days (see figure) and a similar effect appeared to occur

in the study of Schneider et al. (1984). Unfortunately, no studies

have tracked gum effects over longer periods.

Schneider and Jarvik (1984) also demonstrated an interaction between

time of day and the effect of the gum such that the nicotine gum

reduced withdrawal symptoms later in the day more than it reduced

withdrawal symptoms earlier in the day. Whether this interaction

was due to diurnal variation in the intensity of withdrawal symptoms

or in the intensity of nicotine effects is unclear.

NICOTINIC VS. EXPECTANCY EFFECTS

Subjects in "double-blind" studies of psychoactive drugs can often

tell if they are receiving active drug (e.g., Brownell and Stunkard

1982, Johnson and Hughes 1976). There is anecdotal evidence that

smokers (Schneider et al. 1977) and their therapists (Fagerstrom

1982; Westling 1976) are able to discriminate nicotine from placebo

gum. Such knowledge of drug receipt may produce expectancies that

will influence tobacco withdrawal symptoms (Gritz 1980) and the

efficacy of nicotine gum (Fagerstrom and Strom 1981); thus, it is

particularly important to verify that any effects of nicotine gum

are not actually expectancy effects.

In our study we directly tested whether the reduction in withdrawal

symptoms by nicotine gum could have been due to subjects' identification of whether they received nicotine or placebo gum (Hughes

and Krahn, in press). Although many subjects in our study could

identify their drug assignment, the effect of nicotine gum on withdrawal discomfort was present independent of identification of drug

assignment (table 3).

SIGNIFICANCE

The studies reviewed indicate that nicotine gum does relieve

withdrawal discomfort. This fact might be interpreted to support

the hypothesis that tobacco withdrawal is due to nicotine deprivation (e.g.. Schachter 1978); however, the logic of this interpretation can be questioned. Demonstration that a drug relieves a

syndrome is consistent with, but not equivalent to, a demonstration

that the syndrome is due to deprivation of the drug or class of

drugs. Morphine relieves congestive heart failure but congestive

76
Table 3. Analysis of variance of withdrawal discomfort

score by drug group and belief of drug assignment

Placebo

Drug Group

Nicotine

Identification of Drug Assignment

Correct Incorrect Uncertain

5.34 2.14

(n=19) (n=15)

1.10 0.03

(n=34) (n=6)

3.03

(n=16)

0.74

(n=9)

F for main effect of drug group (1,90)=14.8, p<.001

F for interaction between drug group and belief (2,89)<1.0, p>.10

t for nicotine < placebo within correct identification group

(14)=14.4, p<.001

t for nicotine < placebo within incorrect identification group

(16)=1.7, p=.06

t for nicotine < placebo within uncertain (24)=2.1, pp.04

77
heart failure is not due to morphine deprivation. Several alternative explanations are available. Perhaps nicotine relieves

irritability, etc., regardless of its source.

Another interpretation of the finding that nicotine reduces withdrawal discomfort is that this indicates the efficacy of nicotine

gum is due to its ability to relieve withdrawal. However, none of

the previous studies have directly related reduction in withdrawal

discomfort by nicotine to improved long-term cessation success.

In summary, many of the short-term effects of nicotine gum are

consistent with theories that nicotine dependence plays a role in

maintaining smoking. However, other results directly contradict

this hypothesis and crucial tests of the hypothesis (e.g., does

nicotine gum relieve withdrawal which then improves cessation?) have

not been reported.

FUTURE RESEARCH

In the introduction we mentioned that several nonpharmacologic

factors can control nicotine's actions (e.g., instructional set).

Thus, one explanation for the many inconsistent results of studies

of nicotine gum is that nonpharmacologic factors that control nicotine's actions varied across the studies. If this is true, then

empirical studies are needed to determine those factors that are

necessary and sufficient for nicotine gum to have beneficial effects. For example, studies that contrast different doses (1 vs. 2

vs. 4 mg). durations of administration (1 vs. 3 vs. 6 months),

schedules (fixed time vs. ad-lib) or subjects ("dependent" vs.

"nondependent" smokers) must be more useful than simple outcome

studies pitting nicotine gum vs. a standard treatment.

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81
ACKNOWLEDGMENTS

Work included in this review was supported by grants from the

National Institute on Drug Abuse (2 ROl DA 02988 and DA 03728) and

Merrell Dow Pharmaceuticals and by funds from the State of Minnesota

to the University of Minnesota for psychiatric research. Steve

Miller of Merrell Dow Pharmaceuticals provided many of the

manuscripts reviewed.

AUTHORS

John R. Hughes, M.D.

Neuroscience Research Unit

Department of Psychiatry

University of Vermont College of Medicine

Burlington, Vermont 05405

Dorothy Hatsukaml, Ph.D.

Department of Psychiatry

Box 393 May Memorial Building

University of Minnesota

Minneapolis, Minnesota 55455

82
Nicotine Gum vs. Placebo Gum:

Comparisons of Withdrawal

Symptoms and Success Rates

Nina G. Schneider, Ph.D., and

Murray E. Jarvik, M.D., Ph.D.

Until recently, the importance of nicotine in smoking and the

existence of nicotine-specific withdrawal have been hard to

demonstrate empirically. Several investigators succeeded in

focusing attention on nicotine and presenting a strong case for

nicotine as the critical factor in smoking dependence (Gritz 1980b;

Jarvik 1970; Russell 1980; Russell and Feyerabend 1978). However,

smoking is a complex dependence in which pharmacological and

psychosocial reinforcement systems are confounded. What we have

needed is a direct means of testing the relative contributions of

these factors to why people smoke, to variations in individual habit

patterns, and to why cessation is difficult and relapse rates high.

The introduction of nicotine gum and its placebo counterpart (Ferno

et al. 1973) has provided a means of manipulating nicotine intake

independent of the behaviors associated with the habit. The idea of

varying nicotine levels and studying withdrawal is not new. Manipulation of nicotine was reported as early as 1942 by Johnston using

repeated doses of nicotine in injections. Johnston (1942) administered the injections to himself and several volunteers and reported

dysphoric reactions upon their abrupt cessation. In laboratory settings, intravenous nicotine studies provide basic Information for

the role of nicotine in smoking (Henningfield et al. 1983; Feyerabend et al. 1985). For application in cessation studies, the

intravenous method is impractical.

Surprisingly, snuff has not been used to vary nicotine levels in the

study of withdrawal nor in any formal cessation procedure. Given

that there are snuff users and absorption of nicotine is rapid

(Russell et al. 1980a). nasal snuff use may approximate the nicotine

delivery in a cigarette best while eliminating the habit reinforcers. Gritz et al. (1981) have noted that comparable levels of

nicotine can be achieved using chewing tobacco as with cigarettes.

In our own laboratory experience, we have found smokers reluctant to

switch to snuff in attempting cessation. Similarly, another means

of separating nicotine from the other reinforcers of smoke would be

in the use of nicotine-free cigarettes. These could be used in a

long-term cessation study and would allow alteration in nicotine

intake with controls for psychological variables. Unfortunately,

nicotine-free cigarettes have also been unacceptable to smokers even

for short periods in an experimental context.

83
Finally, one of the most promising tools for the study of the role

of nicotine in withdrawal and cessation may come with a transdermal

nicotine patch (Rose et al. 1984). This would allow, as does nicotine gum, the testing of withdrawal and cessation in a potentially

acceptable form and for prolonged periods of time.

For the present, we have access to nicotine gum in several doses.

Nicotine gum is both easily self-administered and well received by

smokers. It allows for the manipulation of nicotine intake during

smoking abstinence while holding psychosocial and sensory factors

constant. Russell et al. (1976a). Russell et al. (1977); Russell et

al. (1980b); and McNabb et al. (1982) have demonstrated that nicotine in gum can theoretically produce blood levels sufficient to

prevent nicotine withdrawal. In addition, the slow buccal absorption does not produce the peak nicotine "boll" delivered in smoke.

Controlling nicotine withdrawal and nicotine seeking should enhance

success rates if nicotine is important in cessation. In effect, the

active and placebo gums allow for systematic testing of the role of

nicotine in the appearance and alleviation of withdrawal and in the

cessation process.

The specific questions we addressed in testing may be summarized for

outcome as follows: 1) Will use of nicotine gum enhance success

rates over placebo? 2) Under what conditions (dispensed, clinicsupport) will this occur?

The specific questions regarding withdrawal are: 1) Is there

nicotine-specific withdrawal? 2) Can nicotine replacement with gum

be effective in alleviating or preventing withdrawal? 3) Are

certain symptoms or emotional states more responsive to nicotine

replacement than others?

While there are many questions concerning selection of smokers (see

Jarvik and Schneider 1984) and parameters for proper use, the

present article will focus on outcome and withdrawal data. Results

are summmarized for two studies (clinic and dispensary) in which

outcome and withdrawal have been tested. Both published and

previously unpublished findings are reported.

OUTCOME

In several of the initial gum studies, titration was the focus of

study (Brantmark et al. 1973; Russell et al. 1976b; Turner et al.

1977). In the first two studies, active gum reduced tobacco

consumption compared to placebo controls. However, the efficacy of

nicotine gum is best studied when total smoking abstinence is

required. Several efforts to study total cessation with nicotine

gum were marred by lack of chemical verification (e.g., Puska et al.

1979). absence of long-term followup (e.g., Malcolm et al. 1980) or

inadequate controls. Raw et al. (1980) found improved cessation

rates with nicotine gum but compared those results to a

"psychological" control tested 2 years earlier.

Prior to our study, several investigators reported the advantage of

nicotine gum over placebo, depending, in part, upon the support

84
conditions. Jarvis et al. (1982) implemented a cessation study in

which clinic support was provided and cessation was verified with

carbon monoxide. Nicotine gum significantly elevated success rates

at 1 year compared to a lower dose "placebo" control. The placebo

in that study was an unbuffered 1 mg nicotine gum which could

produce an active effect if enough was chewed (20 pieces). However,

conceptualized as a dose-response study, the results suggest that

the more nicotine replacement, the greater the success. Jarvis et

al. (1982) also reported that success rates were elevated for

nicotine gum when restarts were included. For a detailed

description of this study, see Russell and Jarvis, this volume.

Fagerstrom (1982) reported striking success rates in a Swedish

clinic for both nicotine and placebo groups with a significantly

higher success rate for the active gum subjects at 6 months. This

significant effect, however, disappeared at 1 year although the

trends still favor the active gum. In this study, as in Jarvis et

al. (1982). success is attributed to the interaction between active

gum use and clinic support.

In the above studies, the subjects were studied by researchers

knowledgeable in the effects and appropriate use of gum. In a study

reported by the British Thoracic Society (1983). nicotine gum plus

advice and a smoking dangers booklet did not improve success rates

over advice alone, advice plus the booklet, or placebo gum plus

advice and the booklet. Rates were low (between 8-12%) across

groups. The authors attribute their poor findings to the population

(chest clinic patients who may have been unmotivated) and to poor

instructions but concluded that their study reflects instructed use

in the real world. In a critique of that study, Jarvis and Russell

(1983) take issue with that conclusion and point out additional

flaws in the study. To those criticisms it should be added that

nicotine gum in the British Thoracic Society study (1983) was given

with "instructions to substitute it for a cigarette when there was

an urge to smoke." From our own pilot work, we have found that

allowing any smoking with chewing undermines cessation.

The issue of what conditions of support may be necessary for success

with nicotine gum was the focus of our outcome testing (Schneider et

al. 1983). Two studies had been designed to test the efficacy of

nicotine vs. placebo gum use. In one, clinic support was provided

for both groups; in the other, gum was "dispensed" with minimal

intervention. The latter was intended to mimic administration of,

gum by physician prescription where little support and/or followup

may be provided. The most recent clinical replications (Hall et al.

1984; Hjalmarson 1984; Killen et al. 1984) and recent physician

studies (Jamrozik et al. 1984; Russell et al. 1983) are discussed

later.

Method

In both studies, subjects were heavy smokers (30-35 cigarettes a

day) in good health who had tried repeatedly to quit smoking. The

studies were double-blind, and subjects were allowed to chew the gum

ad lib both in terms of daily number of pieces and length of time on

gum. The clinic study included measures of withdrawal which are

85
described in the next section. Baseline questionnaires and repeated

measures testing are listed in table 1. The tests listed under

repeated measures were all given at baseline with the exception of

the questionnaires on side effects and gum use.

TABLE 1

Materials

Baseline Materials - All Subjects

1 .

2.

3.

4.

5:

8:

9.

10.

11.

12.

13.

14.

Consent Forms

Subject Bill of Rights

Health Screening

Smoking and Quitting History

(includes demographics)

Motivation Questionnaire

Expectations Questionnaire

Why I Smoke

Smoking Occasions

Why I Want to Quit

Fagerstrom Tolerance Questionnaire

Weight Questionnaire

Gum Instructions

Address Sheet

Subject Comments and Questions

Repeated Measures - Clinic Groups

1. Pulse Rate

2. Weight

3. Daily Abstinence - 2 Scales:

Schneider Smoker Complaint Scale (SCS)

Shiffman-Jarvik Scale

4. Mood Checklist

5. Carbon Monoxide

(as verification in all groups;

as feedback in clinic groups)

6. Side Effects

7. Gum Use - Satisfaction and Open-Ended Remarks

Treatment

Treatment consisted of either 2 mg nicotine gum or placebo gum. The

low dose (2 mg) was chosen to avoid side effects associated with

4 mg gum although eventually mixed use of both doses may prove advantageous (see Schneider et al. 1977). Subjects were instructed to

chew each piece slowly for 20 to 30 minutes to insure the release of

nicotine. Buccal absorption was explained. Weaning from nicotine

may be said to begin with the switch from cigarettes to gum in terms

of both the slower absorption and reduced speed of reinforcement.

With 2 mg gum the immediate blood levels are reduced compared to

86
4 mg gum or a 1.2 mg cigarette as noted earlier. Three-month

prolonged use of 2 mg gum has also recently been shown to produce

significantly less nicotine than cigarettes or 4 mg gum (McNabb

1984). The oral-manipulative component of gum use was expected to

aid cessation while not disrupting extinction of smoking behaviors.

Procedure

Subjects were given the baseline questionnaires for survey purposes

and for assessment of their selective and predictive value.

Baseline scores were obtained for all repeated measures and tests

(see table 1).

Sixty subjects participated in the clinic study - 30 subjects in the

nicotine group and 30 subjects in the placebo group. Total

abstinence was required and was verified at all test intervals

(including daily the first week) with carbon monoxide expired air

analyses. Following baseline testing (always on a Friday), clinic

subjects were instructed to quit the next Monday morning and were

given pieces of gum to take home. Subjects then came to the

laboratory dally for 1 week for testing (withdrawal, CO, pulse rate,

gum use, weight) and for individual support sessions with the

experimenter. The sessions lasted between l/2 and 1 hour. Clinic

subjects were also asked to fill out withdrawal scales at home in

the morning and evening for the first week of abstinence (see

withdrawal section). Followup test intervals (including ail

measures and support) occurred weekly for 4 additional weeks and

then at 3 months, 6 months, and 1 year. Not counting baseline, this

amounted to a total of 12 visits for subjects completing the study.

The dispensary groups consisted of 13 nicotine gum subjects and 23

placebo gum subjects. Testing at baseline was identical for clinic

and dispensary groups. However, subjects in the dispensary groups

did not return to the laboratory for first-week testing and

support. One appearance was required (on Thursdays) for gum

supplies and CO verification of abstinence in the first week.

Thereafter, subjects appeared once a week for 4 more weeks and at 3

months, 6 months, and 1 year for verification and supplies. No

testing (besides CO) was allowed at any of the followup intervals.

Thus, the baseline testing and abstinence checks served as minimal

intervention compared to the clinic groups.

Results

Results of the clinic study and dispensary study appear in Schneider

et al. (1983). A survival analysis was performed on outcome curves

for both groups in the clinic study. The success rates are

presented in figure 1. The nicotine group was significantly more

successful than the placebo group in abstinence over time (p<.03).

87
FIGURE 1

Clinic Group Success Rates: Nicotine vs. Placebo Gum

Adapted from Schneider et al. (1983). Copyright 1983, Pergamon

Press, Ltd.

As can be seen from figure 1, the differences between groups are

most apparent at 3-4 weeks and at 6 months. The groups are fairly

equivalent during first-week treatment and separate by the second

week with a peak difference at 6 months (28%). Between 6 months and

1 year, relapse in the nicotine group reduces the difference to 10%.

Success curves for the two dispensary groups are presented in figure

2. The data in figure 2 indicate that neither 2 mg nor placebo gum

was effective in cessation when no support or guidance was offered.

After 1 week, both groups had dropped to the same level and by 1

year, low rates of 8% for nicotine and 13% for placebo were

observed. It should be noted that subjects stopped using gum in the

dispensary groups within the first few days to 1 week of the study.

The only difference in the clinic and dispensary groups following

baseline testing and instructions was the first-week support and

testing provided for the clinic groups. It is assumed that the

clinic appearances indirectly and directly encouraged the subjects

to continue gum use.

With support, nicotine gum clearly enhanced short-term (6-month)

success rates over placebo (Schneider et al. 1983). These clinic

results are consistent with the placebo-controlled findings of

88
FIGURE 2

Success Rates: Dispensary Study

Adapted from Schneider et al. (1983). Copyright 1983, Pergamon

Press, Ltd.

Fagerstrom (1982) and Jarvis et al. (1982), although in the latter

success rates between treatments were still significant at 1 year.

The differences between the groups in the Jarvis et al. (1982) study

were as high as 47% with nicotine gum vs. 21% treated with an unbuffered 1 mg nicotine placebo. When a stricter criterion of outcome was used in which no relapses between the initial assessment

and end assessment were allowed, these figures remained significant

at 31% in the active group vs. 14% in the placebo group.

In a study comparing nicotine gum to placebo gum (Hjalmarson 1984),

success rates w

the active gum

(1984) and Kill

combination wit

format. In Hal

nicotine gum wi

ment by itself,

treatment plus

ere also doubled at 1 year, with 29% abstaining in

group vs. 16% in the placebo group. In Hall et al.

en et al. (1984), the value of clinic support in

h active gum use was demonstrated in a different

l et al. (1984), subjects were assigned to either

th minimal intervention, intensive behavioral treator to a combination of the intensive behavioral

nicotine gum. The combination of the nicotine gum

plus the intensive treatment produced better success rates than the

other two conditions. This was significant at the 3-month and

6-month intervals, but not at 1 year. This was validated with blood

cotinine levels and those with the higher levels appear to be helped

89

485-874 0 - 85 - 4
more by nicotine gum than those with lower levels at the start of

the study. Interestingly, and in contrast to the physician studies

to be discussed below, the low contact nicotine gum group did better

than the behavioral only group; however, the low contact group did

meet four times over a 3-week period, which in itself constitutes

some intervention.

In Killen et al. (1984) the subjects were assigned to one of three

conditions: nicotine gum only, skills training only, or a combination of skills training and nicotine gum. There was some intervention in the nicotine gum only group in that they attended a

clinic weekly for 7 weeks to receive gum and complete assessments.

Abstinence rates at 10-l/2 month followup were 23% for nicotine gum

only, 30% for skills training only, and 50% for a combination of the

skills training plus nicotine gum. Carbon monoxide and thiocyanate

levels verified the subjects' reports of abstinence. In this study

a combined treatment doubled the rates obtained with nicotine gum

alone.

The studies which look at some form of dispensary tactic show mixed

results. In our study, simply dispensing nicotine or placebo gum

resulted in early failure and in no differences between the groups.

Similar findings were observed in the British Thoracic Society

(1983) and Jamrozik et al. (1984) studies. The British study has

been correctly critiqued by Jarvis and Russell (1983) and, in

general, problems with dispensing may be due to inadequate

instruction and training in proper gum use.

While the clinical studies clearly show that support systems are

instrumental in producing successful cessation, we cannot conclude

that dispensing cannot be successful. It may be that variables

involving the carefully instructed use of the active gum may play a

part in its viability as a smoking cessation tool. For example,

Russell et al. (1983) reported a study in which there was a

nonintervention group; a second group receiving advice to stop

smoking, a booklet, and a warning of followup; and a third group

receiving the same as the second group but with the offer of

nicotine chewing gum. The results showed that the overall rate of

cessation is lower than anything observed in clinics. For the

no-advice group there was a 3.9% success rate, for advice only a

4.1% success rate, and for advice plus nicotine gum an 8.8% success

rate. However, when the data were analyzed by the amount of gum

used, those subjects who used more than one box of gum had a

long-term success rate of 24% after validation. This is a

surprisingly high success rate considering the very minimal

intervention in this study. It suggests that if we can identify the

use variables which enhance success, we can increase success rates

with the dispensing of gum. This is particularly important in that

physicians can prescribe this preparation and have the opportunity

to help in the treatment of cigarette smoking.

In a variation of the low contact physician studies, Fagerstrom

(1985) looked at short- vs. long-term followup with nicotine gum vs.

no gum. He found significant differences between nicotine gum and

90
no gum groups at 1 year with validation. Again, the rates were

lower than in any of the clinical studies, but differences were

still observed. At 12 months the following was reported for four

groups: a group given advice, long-term followup, and nicotine gum

showed a 27% success rate. Advice, short-term followup, and

nicotine gum yielded a 22% success rate. Advice, long-term

followup, and no gum reduced success to 15%. Finally advice,

short-term followup, and no gum produced a low 3% success rate.

The clinic and physician studies taken together show that success

rates can be enhanced 1) with active gum compared to no gum or

placebo, and 2) with support vs. minimal or no behavioral

intervention. It should be noted that in the present study it is

not necessarily known which aspects of the support system

contributed to success. On the one hand, individual attention and

problem-solving were offered by the experimenters. Lowered carbon

monoxide levels served as positive feedback. Test taking, in

itself, may have helped by allowing the subject an outlet for

dysphoria and the difficulty of quitting. Thus, strong

psychological support was provided in the first week and ensuing

followup visits. On the other hand, by coming to the laboratory

daily, the subject was encouraged to continue using the gum. Side

effects and fears associated with use could be allayed and increased

use tested in a "safe" setting. It may be this initial monitoring

of use per se that accounts for success.

One final issue that also has not been systematically tested is that

of length of use. Several investigators have observed post hoc that

longer use (3 to 4 months) may be a significant factor in outcome

(Russell et al. 1980b, 1983; Wilhelmsen and Hjalmarson 1980) and

that by extending use past at least one box, success rates can be

elevated.

In summary, initial use and prolonged use of nicotine gum may both

figure prominently in outcome. We cannot conclude from the present

work that the enhancement of success with clinical support is due to

psychological factors alone. Use variables (dose, number of pieces,

length of time on gum, instructions) must be defined through

controlled evaluation. We suggest that appropriate dose and

carefully instructed use are critical and that intervention should

focus on long-term relapse prevention. Ultimately, a combination

consisting of physicians advising patients to stop, treatment of

pharmacological dependence, and long-term behavioral training and

support could provide the most valuable smoking cessation intervention to date.

WITHDRAWAL

Underlying the development of nicotine gum and its use in cessation

are the assumptions that nicotine withdrawal occurs and that its

alleviation through a replacement procedure will improve success

rates. The questions are 1) Can nicotine-specific withdrawal be

demonstrated? and 2) If so. will replacement other than in bolus

smoke delivery be effective? If nicotine gum alleviates or prevents

91
symptoms compared to placebo, then it is effective. By inference,

withdrawal symptoms (to the degree they are relieved) can be

attributed to the removal of nicotine per se. Ultimately, symptom

relief should correlate with short-term and/or long-term success in

cessation.

In the early studies using nicotine gum, titration effects, by

combining gum and smoking and continued partial reinforcement with

smoking, precluded the assessment of withdrawal. Brantmark et al.

(1973) acknowledged that their attempts to measure withdrawal were

rendered "meaningless" because of the simultaneous use of gum and

smoking. In Puska et al. (1979) the same problem is encountered.

In a recent and interesting study by West et al. (1984), smokers'

baseline blood levels were taken and compared in one group with a

switch to an ultra-low nicotine cigarette. It was observed that

plasma nicotine concentrations dropped 60% when they were switched

to the ultra-low cigarette. A slight drop in heart rate and an

increase in hunger were observed with the lowered levels. However,

it was not paralleled by typical withdrawal symptoms such as

irritability. Ironically, this is consistent with the concept of a

lesser replacement of nicotine with nicotine gum. That is. in both

instances the partial amount of nicotine obtained provides enough

nicotine to alleviate irritability. Although some physiological

changes were observed in this study, nicotine-specific withdrawal

will probably be best demonstrated by comparing nicotine replacement

to no replacement.

In Jarvis et al. (1982). withdrawal symptoms were measured in

nicotine and placebo groups during total abstinence from smoking.

Ratings of withdrawal were taken once a week and averaged across 6

weeks. Unfortunately, abstinence was confirmed with carbon monoxide

breath analyses only at 1 year and not at earlier intervals. It

should also be noted that not all subjects attended all sessions,

although this probably occurred for both groups. The authors used

an unbuffered 1 mg nicotine gum as their placebo which, as they

point out, can produce a pharmacological effect when enough is

chewed (20 pieces). In this sense, the study is a dose-response

comparison. Given these qualifications, this remains one of the few

early tests of withdrawal during total abstinence. Jarvis et al.

(1982) reported significantly "less irritability" and "less hunger"

for the 2 mg group compared to the 1 mg unbuffered controls.

Several other symptoms were reduced in the 2 mg group but these

differences were not significant.

In our clinic study, withdrawal measures were obtained daily for 5

days for 50 subjects remaining abstinent. Twenty-six subjects

formed the nicotine group and 24 formed the placebo group. To

insure completion of scales, the scales were given in the laboratory

(in-lab) each day. Carbon monoxide tests were also taken daily to

confirm self-reported abstinence.

Pulse rate was taken as a physiological measure of withdrawal.

Subjective responses were obtained using a Smoker Complaint Scale

(SCS), the Shiffman-Jarvik (1976) Scale, and a mood checklist.

9 2
Ratings were obtained for four physical symptoms associated with

withdrawal from smoking (Shiffman 1979). Because of item wording

and scaling problems in the Shiffman-Jarvik Scale, the study focus

was on the SCS. This scale was derived from smokers' reports on the

nature of withdrawal symptoms experienced in previous cessation

attempts. These reports were obtained from pilot subjects and

subjects in a "cold turkey" study. Responses were scaled so that I

represented "very definitely not" and 7 represented "very definitely." The SCS consisted of the following 14 items: anxiety,

irritability, fluctuations in mood, craving for cigarettes, concern

about weight, trouble sleeping, disorientation, impaired concentration, depression, feeling left out, restlessness, hostility,

annoyance, and frustration. Where items overlapped with the

Shiffman-Jarvik Scale (e.g., irritability), responses were checked

for consistency between the scales. The mood checklist is described

in the following section along with those results. The four

physical items included: nausea, constipation, diarrhea, and

headache.

Results

Pulse rate and SCS total scores appear in Schneider et al. (1984).

Pulse rates decreased significantly for placebo subjects (15 bpm

over 5 days) compared to a slight reduction in those using active

gum (4 bpm over 5 days). For SCS totals a repeated measures ANOVA

with trends was performed on the data. A significant effect of

treatment was observed (p<.03) as well as a significant quadratic

treatment x time interaction (p<.Ol). The pattern was as follows:

baselines did not differ between groups (separate ANOVA); for both

groups there was a rise from baseline to Day 1; thereafter,

withdrawal in the placebo group continued to increase in severity

while symptom reduction occurred in the nicotine group. Differences

between groups were significant for Days 2, 3, and 4, By Day 5, the

group scores tended to merge. When baselines were covaried, the

results were the same except that the quadratic component became

linear. Figures for the pulse rate and withdrawal findings by

treatment are presented in Schneider et al. (1984).

We also attempted to look at which items were more sensitive to

nicotine replacement than others (previously unreported data, table

2). As can be seen from table 2. almost every symptom on the SCS

scale except for weight concern and craving showed a significant

increase from baseline smoking levels to abstinence days. In

addition, annoyed, hostile, irritable, and fluctuations in mood

showed significant changes between groups with frustration and

depression showing borderline effects.

Craving and weight concern showed no effects on the SCS. From the

Shiffman-Jarvik Scale, craving was assessed by asking the question

differently in two ways: Do you have an urge to smoke right now?

and do you miss a cigarette? On that questionnaire those two items

showed significant quadratic treatment effects at the p<.05 level.

Given that craving is one of the most important issues, these three

items taken together suggest that semantics are going to be a key

93
TABLE 2

Item Analyses for the SCS Scale*

Withdrawal Symptom Main Effect Main Effect Interaction

Time Treatment

Annoyed p<.001** p<.OO8

Hostile p<.001** p<.03 p<05**

Irritable p<.OOl p<.05 P<.03

Fluctuations in Mood p<.Ol p<.05 P<.04

Frustration p<.001** p<.O6 ns

Depression p<.002** p<.07 ns

Left Out p<.02** ns ns

Anxiety p<.OOl ns ns

Concentration p<.001 ns ns

Disorientation p<.OOl ns ns

Restlessness p<.OOl ns ns

Trouble Sleeping ns ns P<.01

Concern About Weight ns ns ns

Craving ns ns ns

*Analyses of Variances were performed on each item and included

baseline and 5 days of abstinence.

**These differences disappeared when baseline was used as a

covariate. Thus, there was an initial rise from baseline (still

smoking) to abstinence days but no additional differences in

temporal course beyond that rise.

issue in assessing "craving." These data represent a preliminary

analysis of the item-by-item data for this study. Hunger on the

Shiffman-Jarvik Scale was significantly reduced with nicotine gum

(p<.05) compared to placebo gum, whereas for the item measuring

weight concern no differences were found.

It should be kept in mind that with ad lib use we are not certain to

what degree differences in amount of chewing accounted for the

results. For example, where there are no differences between

groups, it may be that more pieces of 2 mg gum or a higher dose is

indicated, particularly in the first week. In a current

uncontrolled clinical trial it has been observed that lethargy,

spaciness, and disorientation respond to the 4 mg dose of gum where

the 2 mg dose is less effective. Also, consistent and minimal use

of 2 mg gum (10 to 15 pieces daily) helped reduce symptoms such as

anxiety, irritability, and restlessness better than low level (5 to

6 pieces daily). A dose-response study should define the extent to

94
which symptoms can be alleviated with nicotine gum (Schneider,

unpublished data; manuscript in preparation).

above

SCS

into

figure

3. The number of subjects within each category were as follows:

nicotine gum female (12); nicotine gum male (14); placebo gum female

(14); placebo gum male (10).

An ANCOVA was also performed on the withdrawal data described

for treatment x sex. Thus, these results are the same as the

totals described above except that conditions are subdivided

male and female. The treatment x sex findings are graphed in

The main effect of treatment was significant (p<.O5), and there is

little overlap between treatments (both placebo groups vs. both

nicotine groups in figure 3). The pattern (with baselines covaried)

showed a significant quadratic component (p<.Ol) with all groups

reporting withdrawal at Day 1. separating during the middle 3 days,

and merging at Day 5. No main effect of sex was observed and there

were no interactions between treatment and sex over time. This may

have been a consequence of the small sample size when groups are

divided in this manner. It is tempting to explore possible gender

effects further in a larger sample. As Gritz (1980a) has noted,

male/female differences have received little attention.

The pattern of responding suggests that nicotine gum may not be

effective in first-day withdrawal. This could be a consequence of

anticipation factors, of inadequate dose (including the initial

Baseline Day 1 Day 2 Day 3 Day 4 Day 5

FIGURE 3

SCS Withdrawal Responses by Treatment and Gender

95
change from inhalation bolus to gum). improper gum use (subjects may

have waited for first clinic visit). or may be attributable to

changes with cessation (e.g., loss of ritual behaviors). The

effectiveness of the gum becomes apparent as cessation progresses.

A dose-response study should clarify whether symptoms can be

alleviated entirely with replacement.

In addition to totals, specific items, and sex differences, we

looked at a time-of-day effect in compliant subjects. Subjects were

asked to fill out the withdrawal scales at home in the morning and

evening. Of the 50 abstinent subjects providing the in-lab data, 3.2

cooperated in filling out the home scales. These results have been

reported in Schneider and Jarvik (1984). The basic finding was a

treatment x time-of-day effect. For placebo subjects, the severity

of withdrawal symptoms was significantly higher than nicotine

subject responses and increased in the evenings compared to a more

stable withdrawal level in the nicotine group. The results indicate

that withdrawal varies within a given day as well as across days and

that nicotine is implicated in these fluctuations.

Mood Effects

A mood checklist (items were taken from the POMS mood scale)

included 27 items reflective of positive and negative states.

Thirteen items were positive: active, alert, carefree, cheerful,

clear-headed, considerate. efficient, friendly, full-of-pep, lively,

optimistic. proud, and relaxed. Thirteen items were negative:

angry, bad-tempered, confused, hopeless, miserable, muddled,

nervous, sad, shaky, spiteful, tense, unworthy, and worn-out. One

item was dropped (ready-to-fight) because some subjects perceived

this as positive and others as negative. In responding, the subject

checked as many of the adjectives as applied at the moment. There

was no mandatory responding on a scale as required with the SCS

items. Responses were recorded as total number checked for the 13

positive items and total checked for the 13 negative items. These

totals were obtained for baseline scores and for each of the 5 days

of abstinence. For the positive items, the results (previously

unreported) are presented in figure 4.

A repeated measures ANOVA with trends was performed on the positive

item totals for all days. The results showed a significant effect

of treatment (p<.Ol) as well as a significant quadratic treatment x

time effect (p<.02). Subjects on nicotine gum showed only a slight

decrease in positive responses checked. For placebo subjects, the

drop from baseline to Day 1 is fairly sharp and stays lowered

through the first few days. Note that for the SCS scores, the

effects are also quadratic but the separation between groups does

not occur until Day 2.

The results for negative items (also previously unreported) are

consistent with the positive affect pattern by treatment. Placebo

gum subjects showed a greater increase in negative responses than

nicotine subjects. The repeated measures ANOVA with trends showed

no significant main effects or overall interactions, so a

96
FIGURE 4

Positive Items Checked During

5 Days of Abstinence From Smoking

significant quadratic treatment x time effect was ignored. The

problem with the negative item testing was that a floor effect

occurred. Out of the 13 possible responses, mean responding ranged

from 0.50 to 1.70 for the placebo group and 0.53 to 1.11 for the

nicotine group. A review of the items suggests that a social

desirability effect may have been operating. The items are very

strongly negative and tend to go against feelings of self-worth that

a smoker trying to quit may be seeking. Because the items are

checked, there is no qualifying of the response. By contrast, we

were able to assess negative changes in state with the SCS through

use of scaled responding and through use of specific complaints

associated with smoking cessation.

The withdrawal findings for 5 days of first-week abstinence provide

support for the proposed mechanism of action with gum use during

cessation. Nicotine replacement alleviated or prevented symptoms

compared to nonreplacement with placebo. These findings have been

supported by recent reports in the literature of nicotine-alleviated

withdrawal (Hughes et al. 1984; West et al. 1984).

In the Hughes et al. (1984) study, symptoms of withdrawal were

measured in 100 smokers. After baseline measurement subjects

received either nicotine or placebo gum in a double-blind study and

were tested in the first, second, and fourth evenings of abstinence. Hughes et al. (1984) report reductions in irritability.

anxiety, difficulty concentrating, restlessness, and impatience

between groups, with nicotine gum alleviating the symptoms. The

97
nicotine replacement did not reduce increases in craving. hunger,

eating, insomnia, tremulousness, or supine heart rate after

cessation.

In West et al. (1984) 48 smokers were either given 2 mg nicotine gum

or a .5 mg unbuffered nicotine gum "placebo" for 24 hours of

cigarette deprivation. In that study, the 2 mg gum alleviated

irritability, depression, and difficulties with social interaction,

but not hunger or ability to concentrate. As in our study, the drop

in heart rate was reduced with active gum. In West et al. (1984)

and Hughes et al. (1984) the authors conclude that nicotine

replacement reduces symptoms of withdrawal and that nicotine

deprivation plays a significant role in producing these effects.

In a recent paper, West (1984) has summarized the four studies

representing tests of withdrawal during total abstinence. In

conclusion, we suggest that with proper dosage we may reduce most,

if not all, symptoms of withdrawal. Maintenance of higher blood

levels will be important while the person is already reducing levels

of nicotine from cigarettes. As the person adjusts to changing

levels, relief should require less and less replacement with gum.

However, we cannot view nicotine dependence and withdrawal as

operating only in the short term. Urges to smoke long after

cessation may represent conditioned nicotine-seeking and coping

behavior.

SUMMARY

Our data and that of researchers in the area clearly provide

evidence for nicotine-specific withdrawal and its relief with

nicotine gum. In addition, outcome efficacy is enhanced when

nicotine gum is combined with behavioral treatment.

Nicotine gum appears to be valuable both as a systematic tool and as

a means of combatting short- and long-term nicotine seeking that

contribute to maintenance of smoking and the inability to quit.

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AUTHORS

Nina G. Schneider, Ph.D.*

Murray E. Jarvik. M.D., Ph.D.

Department of Psychiatry and Biobehavioral Sciences

The Neuropsychiatric Institute

University of California

Los Angeles, California 90024

and

Veterans Administration Medical Center

West Los Angeles, Brentwood Division

(691/BlSlD)

Los Angeles, California 90073

*Program Director, Smoking Cessation

Mark Taper Center for Health Enhancement

University of California Medical Center

University of California

Los Angeles, California 90024

101
Nicotine Chewing Gum in Smoking

Cessation: Efficiency, Nicotine

Dependence, Therapy Duration, and

Clinical Recommendations

Karl-Olov Fagerstrom and Bo Melin

This paper will deal with four topics pertinent to nicotine gum:

(1) A review of the placebo-controlled trials of the nicotine gum;

(2) An analysis of how nicotine dependence interacts with nicotine

gum therapy; (3) An analysis of duration of nicotine gum therapy;

and (4) Experiences and recommendations derived from clinical

practice.

REVIEW OF CONTROLLED TRIALS WITH NICOTINE GUM

The review covers smoking cessation studies that satisfy the

criteria of (a) placebo control, (b) blindness, (c) randomization of

subjects, and (d) long-term followup.

Table 1 shows the studies that meet the above requirements. The

studies are characterized in terms of additional therapy format,

number of subjects, time of followup and abstinence rates.

TABLE 1 Outcome from Placebo-Controlled Cessation Studies

Trial % nonsmokers Follow- Additional

Active Placebo up at therapy

Fee, Stewart *+ 1982 13 9 1 year Lectures

Puska et al. * 1979 35 28 6 months Group

Fagerstrom 1982 49 37 1 year Individ.

Jarvis et al. 1982 47 21 1 year Group

Malcolm et al. 1980 23 5 6 months Individ.

BTS 1983 10 14 1 year None

Hjalmarson 1984 29 16 1 year Group

Schneider et al. 1983 30 20 1 year Group

Jamrozik 1984 10 8 6 months Indlvid.

N

352

160

96

116

210

802

205

60

200

* No CO-verification of claims

+ Only 18% of subjects were followed up

102
Eight of the nine studies show an advantage for the nicotine gum,

although it does not, in most cases, reach statistical significance. When the studies are analyzed in terms of setting and the

therapist's profession, it is evident that the best results are

obtained by psychologists experienced in smoking cessation therapy

and working in a cessation clinic with probably more motivated and

dependent patients (Fee and Stewart 1982; Fagerstrom 1982; Jarvis et

al. 1982; Hjalmarson 1984; and Schneider et al. 1983). That does

not mean that psychologists' interventions are inherently better.

Rather, physicians and other health care professionals would obtain

the same effects if they used it in the same ways as it is used

within a special cessation clinic.

NICOTINE DEPENDENCE

The concept behind the nicotine gum is that, while substituting

nicotine gum for cigarettes, the need for nicotine can be satisfied

while the psychosocial part of tobacco dependence may first be

addressed. In the next step the pharmacological dependence of

nicotine should gradually be dealt with. The smoker's dependence on

nicotine is, thus, a crucial factor in the therapeutic rationale of

the nicotine gum. Nicotine dependence varies considerably from

smoker to smoker, and a hypothesis would be that the more the smoker

is dependent on nicotine, the better the effect of the gum should be

relative to placebo or a non-gum condition. In Table 2 is a scale

(Fagerstrom Tolerance Questionnaire) for measuring the dependence of

nicotine among smokers (Fagerstrom 1978).

The questions are individually scored and summed to provide a

composite score in the range from 0 to 11, in which the higher

values reflect greater dependence. The results from the published

studies, where nicotine dependence has been related to nicotine or

placebo gum are presented in table 3.

The Fagerstrom (1982) study defines high dependence as 8 points and

above and low dependence as up to 6 points. In the second Fagerstrom report (1984), as in the rest of the studies, the patients

have been divided into halves, split by the median value 6 or 7

points. The followup times are for Fagerstrom (1984) and Jarvik et

al. (1984) 12 months, for Fagerstrom (1982) 6 months, and for

Christen et al. (1984) 6 weeks. As can be seen from table 3, the

increased likelihood among high nicotine dependent smokers to reach

long-term abstinence with the help of nicotine gum is greatly

enhanced.

DURATION OF NICOTINE GUM THERAPY

When smokers who are trying to quit are offered nicotine gum without

any instructions concerning how long they should use it, the

duration of use varies considerably. Some will only use a few

pieces of gum throughout the whole therapy, while 5-10% will have

difficulties in terminating nicotine gum use. How long then should

nicotine gum treatment be continued in order to secure the best

103
TABLE 2 The Fagerstrom Questionnaire

Questions

1 How soon after you wake do

you smoke your first

cigarette?

2 Do you find it difficult to

refrain from smoking in

places where it is forbidden;

e.g., in church, at the

library, in cinemas, etc?

3 Which cigarette would you

hate most to give up?

4 How many cigarettes a day

do you smoke?

5 Do you smoke more frequently

during the early morning

than during the rest of the

day?

6 Do you smoke if you are

so ill that you are in bed

most of the day?

7 What is the nicotine level

of your usual brand of

cigarettes?

8 Do you inhale?

Answers Points Score

Within 30 min 1

After 30 min 0

Yes 1

NO 0

The first one in 1

the morning

Any other 0

15 or less 0

16-25 1

26 or more 2

Yes 1

No 0

Yes 1

No 0

0.9 mg or less 0

1.0 mg - 1.2 mg 1

1.3 mg or more 2

Never 0

Sometimes 1

Always 2

long-term abstinence rates? At the moment there are few scientific

data on which to draw. Russell et al. (1980) suggest that "it might

be worth encouraging smokers to persist with the gum for at least 4

months." To support their view they rely on clinical experiences

and a finding from a trial by Raw in 1980, where 67% of the patients

using the gum for 3 months or longer were abstinent at 12 months in

contrast to the overall figure of 38%. Another figure, cited by

Russell et al. (1980). is a 68% 4-year abstinence rate obtained by

Wilhelmsen and Hjalmarson (1980) for the subjects who had used

nicotine gum for at least the first 4 months. However, the

abstinence rate at 4 years was the same for those persons who were

neither smoking nor chewing gum at 4 months after stopping smoking

(Hjalmarson 1982). In a placebo-controlled trial from the Addiction

Research Unit, Maudsley Hospital, some data pertinent to the length

104
TABLE 3 Abstinence Rates in Relation to Nicotine or Placebo Gum and

Nicotine Dependence

High dependent N Less dependent N

Nic. Placebo Nic. Placebo

gum gum gum gum

Fagerstrom (1982) 71% 39% 35 75% 65% 40

Fagerstrom (1984) 26

Christen et al. (1984) 46

5* 67 32 13 76

9 80 28 12 113

Jarvik et al. (1984) 41 8 17 0 30 8

* No gum

of chewing were reported by Jarvis et al. (1982). The l-year

abstinence rate for the subjects chewing for 3 months was 75% for

nicotine chewing and 62% for placebo gum. In another controlled

trial (Fagerstrom 1982), no difference in long-term abstinence rates

could be seen as a function of time on nicotine gum.

The fact that long-term chewers of nicotine gum generally have good

or excellent abstinence rates should not be surprising and may not

be caused by gum use. Both longer use and abstinence may be

modulated by a third variable such as motivation. A long-term

chewer is a former smoker who has managed to terminate, and maintain

non-smoking for a number of reasons. Nicotine chewing gum is one of

several factors in obtaining and maintaining abstinence, and it may

serve as both a dependent and an independent variable.

At the Smoking Cessation Clinic in Uppsala, Sweden, a prospective

study has been completed (Melin 1984). "Time on gum" has been

deliberately manipulated for 121 consecutive patients. They were

randomized into 1 (n=61) or 6 (n=60) months of nicotine gum use.

They were given access to the gum for their respective time without

instructions to continue chewing until the deadline. In addition to

nicotine gum, they received the standard, individual, cognitive

behavioral-oriented counseling offered at the clinic. The number of

sessions varied according to the subjects' need. Both 2 and 4 mg

doses of the gum were used, according to the need of the subject.

Figure 1 shows that the 6-month group is somewhat superior to the

one-month group at 3 and 6 months. However, the long-term

abstinence rates are equal, since many of the 6-month subjects

relapsed when gum therapy was discontinued at 6 months. Thirty-nine

percent were abstinent in the l-month group at 12 months follow-up

and 32% in the 6-months group.

Many subjects, forced to cease chewing nicotine gum at 1 month,

relapsed. Since their treatment protocol allowed for individual

variation in the number of sessions given each patient, a post hoc

analysis of number of sessions given the groups was made to determine if the nonpharmacological part of the treatment compensated for

discontinuing chewing. No significant difference was seen during

the first month. However, when the whole length of treatment was

reviewed, 5-7 months after quitting, the l-month group

105
months

Figure 1: Abstinence Rates Over Time for 1 Months and 6 Months

Nicotine Gum Treatment

had significantly more treatment sessions than the 6-month group

(8.5 compared to 7.2, t=2.0, p<.05). It appears that time on

nicotine gum was unintentionally traded for more nonpharmacological

treatment sessions.

Optimal time on nicotine gum may therefore interact with the degree

of psychological support given. The less support, the more the

ex-smoker has to rely on nicotine gum, and vice versa. At the

moment, no hard scientific evidence exists for recommending any

specific duration of nicotine gum therapy. The best advice

available today is to keep in close contact with the ex-smoker and

let him or her determine the duration.

EXPERIENCES AND RECOMMENDATIONS FROM CLINICAL PRACTICE

Many smokers feel anxious about terminating smoking. Smokers

seeking help often expect and are afraid of physiological and

psychological reactions that they have encountered in earlier

unsuccessful attempts. Describing the nicotine gum's effect on

physiological abstinence and concurrently conveying a skilled and

experienced therapist's commitment to giving psychological support,

usually creates a therapeutic effect on patients' anxiety and

instills a sense of optimism despite several prior cessation

attempts. Naturally, a warm and accepting attitude may increase the

likelihood of a favorable outcome. The therapeutic atmosphere with

renewal of nicotine gum prescription as well as other methods of

nonpharmacological support does motivate the patients to come to

scheduled appointments.

Consumption of gum is likely to vary across patients. Most patients

chew about 8-10 pieces of gum per day, but there are considerable

individual differences. The patients usually chew the gum for 2-3

months. After 3 months most of the patients cease chewing. About

5-10% will have difficulties in stopping using the gum and need

strong psychological support to finally break their addiction to

106
nicotine. One way to handle the patients who find it difficult to

give up using nicotine gum may be to have them switch to a

nicotine-free chewing gum. Sometimes patients may simply have

developed a new habit (gum chewing) and may be quite able to stop

using nicotine.

At the clinic in Uppsala. where the authors have been working, the

abstinence rate rose by about 15% when nicotine gum was introduced

in the treatment. However, it should also be kept in mind that

nicotine gum alone -is seldom sufficient. Nicotine gum is a complement to psychosocial treatment for helping people to stop smoking

(see Hall and Killen, this volume). We have not observed any severe

side effects in the 6 years during which nicotine gum has been used

in our clinic. As long as chewing instructions are appropriately

given, the adverse reactions usually involving taste and irritation

in throat and stomach can be well controlled. It is found that

nicotine gum is tolerated by approximately 90% of the smokers.

Recommendations

Nicotine gum should be used only when smoking is completely

terminated and not in conjunction with successive reduction of

smoking.

When nicotine gum is prescribed, it should be in sufficient

quantity and for a sufficiently long time period. The exact

quantity and time period are best judged by the patient. The

more nicotine-dependent smokers usually chew more pieces per

day, need nicotine gum for a longer period, and also tend to

prefer the 4 mg strength more often than the less dependent

smokers.*

Nicotine dependence should be assessed. If the smokers'

dependence score is in the upper half of the distribution

(usually about 7 points and above), it is a strong indication

for prescribing nicotine gum.

It is firmly recommended that a sample of nicotine gum should be

kept in the therapist's office. Let the patients chew a piece

of gum while instructed and supervised. This will facilitate

the acceptance of nicotine gum and the choice between 2 and 4 mg

dosage.*

Since many patients are at high risk for relapse when nicotine

gum therapy is discontinued, it is suggested that an appointment

be made with the patients after nicotine gum chewing has

terminated.

*Note: The 4 mg gum is not currently available in the U.S.

Dosage must be adjusted by number of pieces chewed.

107
REFERENCES

British Thoracic Society. Comparison of four methods of smoking

withdrawal in patients with smoking related diseases. British

Medical Journal, 286:595-597. 1983.

Christen, A.G., et al. Efficacy of nicotine chewing gum in

facilitating smoking cessation. JADA, 108:594-597, 1984.

Fagerstrom. K.O. Measuring degree of physical dependence to tobacco

smoking with reference to individualization of treatment.

Addictive Behavior, 3:235-241, 1978.

Fagerstrom, K.O. A comparison of psychological and pharmacological

treatment in smoking cessation. Journal of Behavioral Medicine,

5:343-351, 1982.

Fagerstrom, K.O. Effects of nicotine chewing gum and follow-up

appointments in physician-based smoking cessation. Preventive

Medicine, 13:517-527, 1984.

Fee W.M., Steward, M.J. A controlled trial of nicotine chewing gum

in a smoking withdrawal clinic. The Practitioner, 226:148-151.

1982.

Hjalmarson, A.I.M. Effect of nicotine chewing gum in smoking

cessation. JAMA, 252;20;Nov 23/30:2835-2838, 1984.

Hjalmarson, A.I.M. Personal communication, 1982.

Jamrozik, K., et al. Placebo controlled trial of nicotine chewing

gum in general practice. British Medical Journal, 289;29;Sept.

1984.

Jarvik, M.E., Schneider, N.G. Degree of addiction and effectiveness

of nicotine gum therapy for smoking. Am. J. Psychiatry, 141:6.

June 1984.

Jarvis. M.J., et al. Randomized controlled trial of nicotine chewing

gum. British Medical Journal, 285:537-540, 1982.

Malcolm, R.E., et al. The use of nicotine chewing gum as an aid to

stopping smoking. Psychopharmacology 70:295-296. 1980.

Melin, 8. Effekter av tva ollka administrationstider vid nikotintuggummi 1 rokavvanjnlngsbehandling. Institutionen for

till-lampad Psykologi. Uppsala University, Sweden, 1984.

Puska, P., et al. Nicotine-containing chewing gum in smoking

cessation: A double-blind trial with half-year follow-up.

Addictive Behaviors, 4:141-146, 1979.

Raw, M., et al. Comparison of nicotine chewing gum and psychological

treatments for dependent smokers. British Medical Journal,

281:481-482. 1980.

Russell, M.A.H., et al. Clinical use of nicotine chewing gum.

British Medical Journal, 281:1599-1602, 1980.

Schneider, N.G., et al. Nicotine gum in smoking cessation: A

placebo-controlled double-blind trial. Addictive Behaviors.

8:253-261. 1983.

Wilhelmsen. L. and Hjalmarson, A. Smoking cessation experience in

Sweden. Canadian Family Physician, 26:737-747, 1980

108
AUTHORS

Karl Olov Fagerstrom. Ph.D.

Leo Research Laboratory and Medicine Clinic

Helsingborg Hospital

Sweden

Bo Melin, B.A.

Department of Applied Psychology

University of Uppsala

Sweden

109
Theoretical Background and Clinical

Use of Nicotine Chewing Gum

M. A. H. Russell, FRCP, FRCPsych., and

M. J. Jarvis, MPhil.

If we accept the fact that the use of tobacco in its

various preparations is a form of drug addiction, even

though a pleasant one not affecting criminal statistics,

we can more readily help our patient when he finds that

his problem has gotten out of hand.

John L. Dorsey, MD, FACP, Baltimore, Maryland, 1936.

INTRODUCTION

For many years campaigns and treatments to promote smoking

cessation have had disappointing results. In our view, this is

because for most smokers cigarette smoking is a form of drug

dependence and our programmers have failed because they have not

taken this sufficiently into account. But the prospects are now

brighter for more successful intervention in the future.

Firstly, there is more widespread appreciation of the addictive

nature of smoking and, secondly, the development of nicotine

chewing gum has provided the first effective aid to overcoming the

pharmacological problem of withdrawal. But it is crucial that the

pendulum does not swing too far towards over-reliance on

pharmacological treatments and neglect of the important social and

psychological factors which are a fundamental part of all addictive

disorders. It is also important that the labelling of smoking as

an addiction does not lead to the belief that permanent cessation

is therefore impossible for smokers who are addicted. An addictive

state is in no way impossible to overcome, although it is likely to

be difficult and therefore to require commitment, planning, and

possibly support as well.

Another significant recent advance that gives grounds for expecting

more success in the future is the recognition of the value and

cost-efficacy of minimal intervention or self-help, and the

potential role of physicians in applying this approach. Most

110
important of all, perhaps, is the possibility that physician

advice could be combined synergistically with the use of nicotine

gum. Besides enhancing the efficacy of brief advice to stop

smoking, it is likely that the availability of nicotine chewing gum

will in turn encourage physicians to be more active in advising and

helping their patients to give up smoking.

It is our purpose first to discuss briefly the nature of smoking as

a form of drug dependence. This provides the theoretical basis for

developing pharmacological approaches to cessation. We then focus

on nicotine chewing gum as the first pharmacological approach with

proven efficacy and discuss the theoretical rationale for its use,

its mode of action, and various practical aspects necessary for

effective use in different settings. Finally, besides its use as

an effective aid to cessation, it has provided a means for

advancing knowledge of the role of nicotine in smoking.

SMOKING AS A FORM OF DRUG DEPENDENCE

People smoke cigarettes for many reasons - social, psychological,

sensory, behavioural, and pharmacological. But of all these the

pharmacological motives are the most powerful and the most

fur&mental. If tobacco contained no nicotine, there would be no

problem. People wouldn't smoke it, nor would they snuff it or chew

it.

Although people begin to smoke for social and psychological

reasons, pharmacological motives gradually take over as the smoker

learns to inhale and a regular dependent smoking pattern becomes

established. This escalation to dependence usually takes two or

three years but sometimes occurs far more quickly. Other factors

such as taste, smell, sensory irritation, and behavioural

components such as handling also become important. This is mainly

through frequent and close association with the pharmacological

effects of nicotine. In other words, they are secondary. Without

the presence of nicotine few people would develop a strong taste

for tobacco.

Many surveys have shown that at least three out of every four

smokers want to stop smoking or have tried to stop - some of them

many times. Surveys also show that only about one in three smokers

succeeds in stopping permanently before the age of 60. Thus most

people smoke not because they really want to, but because they

cannot easily stop. In other words, they smoke because they are

hooked and dependent on nicotine. Blood nicotine levels of smokers

vary widely, from 5 ng/ml to over 70 ng/ml, with an average level

for heavy smokers of about 35 ng/ml. The distribution of peak

blood nicotine concentrations just after a cigarette is shown in

figure 1 for a sample of heavy smokers. Although the curve for

smokers in the general population would be somewhat to the left,

measurable pharmacological effects are produced with blood nicotine

levels of 10 ng/ml or less. It is thus apparent that most regular

smokers inhale and absorb sufficient nicotine to produce

pharmacological effects.

111
FIGURE 1

Figure 1. Distribution of peak plasma nicotine

concentrations in a sample of 393 heavy smokers (250 women,

143 men) with a mean cigarette consumption of 30.1 per day.

Blood was taken 2 minutes after completing a cigarette during

the afternoon of a day of usual smoking. The average plasma

nicotine concentration was 35.8 ng/ml (SD 13.7) and was not

significantly different between men and women.

It is not our brief here to go into all the pharmacological effects

of nicotine or into the details of the evidence for its role in

smoking and the tobacco withdrawal syndrome. But it should be

emphasised that the modern cigarette is a highly efficient device

for getting nicotine to the brain. The smoke is mild enough to be

inhaled deeply into the alveoli of the lungs from where nicotine is

rapidly absorbed into the bloodstream to reach the brain within

about 7 seconds. This means that the inhaling cigarette smoker

receives a rapid intravenous-like "shot" or bolus of nicotine to

the brain after each inhaled puff. This contrasts with the slower

steady rate of absorption from chewing tobacco or non-inhaled cigar

smoking. Furthermore, the nicotine concentrations in the

post-inhalation boli must be many times higher than those measured

in mixed venous blood after completion of a cigarette. The pattern

of pharmacological effects is no doubt correspondingly different

following the different forms of intake.

PHARMACOLOGICAL APPROACHES

The concept of pharmacological approaches to smoking cessation is

not new. In 1936, Dorsey suggested the use of lo&line as a

112
substitute for nicotine because of some putative pharmacological

similarities (Dorsey 1936). But the pharmacological effects of

lobeline are weak. It does not substitute for nicotine in animal

experiments, and clinically it has never proved superior to

placebo. The story is similar for other potential substitutes.

Amphetamine, for example, increases smoking behaviour rather than

diminishing it, and sedatives have no effect in tranquillizing

doses. The subtle dual stimulant and sedative actions of nicotine

appear to be unique. Animals discriminate these actions from those

of all other drugs that have been tested (Hendry and Rosecrans

1982), and there is evidence for its effect on specific nicotine

receptors in the brain (Abood et al. 1981) in addition to its

classical effects on aceylcholine receptors.

Receptor blockade is another potential pharmacological approach.

A drug that blocks the rewarding effects of nicotine could

theoretically be used as an agent of extinction. Beta-adrenergic

blockade by propranolol has been shown to block the peripheral

effects of smoking on heart rate and blood pressure (Carruthers

1976). However it has no effect on reducing subjective

satisfaction from smoking and has no potential, therefore, as a

means to produce extinction. Mecamylamine, on the other hand, is a

blocker of the nicotinic receptors of acetylcholine and appears to

effectively block some of the subjective effects of nicotine

(Henningfield and Jasinski 1983). Its short-term effect is to

increase smoking behaviour (Stolerman et al. 1973), possibly in an

attempt on the part of smokers to overcome the receptor blockade.

But this is not an appropriate test of its potential as an aid to

smoking cessation. More prolonged use would be necessary to test

its capacity to produce extinction. It is our view, however, that

cognitive factors and the capacity of humans to discriminate

between conditions of smoking with and without mecamylamine make it

unlikely that an extinction model based on old-fashioned learning

theory would work. For similar reasons pharmacological aversion

therapy with drugs such as emetine and apomorphine is unlikely to

be effective. There is no punishment-model drug for smoking, such

as disulfiram for alcohol abuse. There is also no prospect of one,

since none of the known metabolites of nicotine are aversive in

realistic concentrations. All this leaves nicotine substitution as

the only feasible potentially effective pharmacological approach to

smoking cessation.

NICOTINE SUBSTITUTION

There are many potential routes for administering nicotine.

Besides the rate of absorption and other issues relating to

bioavailability, the therapeutic potential of a particular route

will also depend on factors such as safety and social

acceptability. A number of routes can be excluded immediately. In

the case of ingestion, absorption is slow and most of the nicotine

is metabolised by the liver to metabolites which are

113
pharmacologically inert. Nicotine suppositories or pessaries would

be inconvenient and unacceptable. Injections would need to be

repeated too frequently to be practical, and would not be feasible

for widespread use. Transdermal delivery certainly has potential

but has not yet been developed in the case of nicotine. This

leaves the three routes - lungs, buccal and nasal mucosae - which

have been used for tobacco for over 500 years.

Of these three routes, the rate of absorption through the lungs is,

as mentioned earlier, far and away the most rapid. This is simply

a matter of surface area, that of the lungs being roughly

equivalent to the size of a tennis court. Although it is

technically possible to produce aerosols with particles small

enough to reach the alveoli, to our knowledge no satisfactory

nicotine aerosol has yet been developed. We have seen and tested

four. They have been either too clumsy or have failed to produce

potentially useful blood nicotine concentrations. Irritancy to the

throat has been another major problem. A notable exception has

been the development of a vaporiser shaped like a cigarette

(Jacobson et al. 1982). Inhalation through this device enables

nicotine in vapour form to be taken into the lungs. It is not

excessively irritating and is capable of producing therapeutically

useful blood nicotine concentrations. If a problem of safety can

be overcome, such a device would be well worth further study.

The historical fact that tobacco has been chewed and taken as "wet"

snuff in the north and "dry" snuff in the nose suggests that

absorption of nicotine by either route is sufficient to produce

pharmacological effects. Blood nicotine concentrations after "wet"

and “dry” snuff have been shown to be equivalent to those produced

by cigarette smoking (Gritz et al. 1981; Russell et al. 1981).

Various nicotine-containing lozenges and tablets have been produced

from time to time for help with smoking cessation, but they have

never been systematically tested, and in most cases their nicotine

delivery has been inadequate for therapeutic value.

Nicotine-containing chewing gum, on the other hand, has been

extensively tested (see below). One possible limitation of

nicotine gum is that the rate of nicotine absorption is slow

compared with inhaled cigarette smoking. Preliminary study with a

nasal nicotine solution (NNS) used as a kind of liquid snuff shows

that nicotine is absorbed more rapidly and efficiently through the

nose than through the lining of the mouth (Russell et al. 1983a,

see figure 2). With refinements in flavour and acceptability, it

is possible that a form of NNS could be clinically useful for those

smokers who get insufficient help from nicotine gum or who have

problems with dyspeptic symptoms.

Finally, as a general principle , it is likely that more therapeutic

success might be expected from those forms of nicotine substitution

which also provide a sensory experience and a socially acceptable

behavioural component to act as substrates for conditioning as

acquired secondary reinforcers.

114
FIGURE 2

Figure 2. Plasma nicotine concentrations before, during, and

after chewing a single piece of nicotine chewing gum containing

4 mg (top) and 2 mg nicotine (bottom). The plasma nicotine

concentrations produced by smoking a cigarette are also shown as

are those produced by the non-inhaled smoking of a large Havana

cigar (top) and use of a single 2 mg dose of nasal nicotine

solution (NNS) (bottom). (Top is from Russell et al. Brit Med J,

280:1599-1602, 1980, and bottom from Russell et al. Brit Med J,

286:683-684, 1983). Copyright 1980 and 1983, The British

Medical Association.

115
NICOTINE CHEWING GUM

A nicotine-containing chewing gum was first developed more than 10

years ago by Ove Ferno in Sweden for use as an aid to smoking

cessation (Ferno et al. 1973). Its purpose is to ease withdrawal

symptoms by providing an alternative source of nicotine and, in

addition, a substitute oral activity. It enables the smoker to

break the habit in two stages. In the first stage, the smoker is

able to focus on overcoming the behavioural and psychological

components of dependence without at the same time having to cope

with nicotine withdrawal. The dependence on nicotine is overcome

at a later stage when there is no longer any urge to smoke.

It should be stressed, however, that the slower rate of nicotine

absorption through the buccal mucosa and the absence of

puff-by-puff high-nicotine boli (see above) make the gum an

incomplete nicotine substitute for smokers who inhale. For the

same reason cigarette smokers who inhale deeply gain little

satisfaction from cigars unless they too are inhaled. The purpose

of nicotine gum, therefore, is to relieve nicotine related

withdrawal symptoms rather than provide the same positive pleasure

as inhaled smoking.

The product

Since the early days of its development the nicotine-containing

chewing gum (Nicorette) has been considerably refined and improved.

It is available in two strengths, each piece containing either 2 mg

or 4 mg of nicotine (only the 2 mg strength is available in the

United States). The nicotine is bound to a resin and its release

depends on the rate and vigour of chewing. About 90% of the

nicotine is released after 30 minutes of normal chewing (Ferno et

al. 1973). The gum also contains a buffer to maintain the pH in

the mouth at about 8.5, at which the nicotine is well absorbed

through the buccal mucosa. Swallowed nicotine is absorbed and

rapidly metabolized in its first passage through the liver (Russell

and Feyerabend 1978).

Pharmacology

The rate of absorption of nicotine from the gum is relatively slow

(see figure 2). The peak plasma concentration is reached 15-30

minutes after starting to chew the gum, compared with 1-2 minutes

after completion of a cigarette. However, a 4 mg piece of gum

chewed every hour for 2-3 hours produces plasma nicotine

concentrations similar to those in heavy cigarette smokers (McNabb

et al. 1982; Russell et al. 1976a and 1977; see figure 3).

Cardiovascular effects, such as increase in heart rate and blood

pressure, produced by 4 mg gum match those after cigarette smoking,

but the 2 mg gum has less effect (Fredholm and Sjogren 1979; Nyberg

et al. 1982).

Effect on Ad Libitum Smoking Behaviour

In two short-term studies in subjects who were instructed to

smoke freely without making any deliberate attempt to reduce their

116
FIGURE 3

Figure 3. Plasma nicotine concentrations in the same subject

when smoking one cigarette per hour ad when chewing a piece of

4 mg nicotine gum every hour. (From Russell et al. Brit Med J,

1:1043-1046, 1976). Copyright 1976, The British Medical

Association.

117
smoking, nicotine chewing gum had a modest inhibitory effect on

smoking behaviour (Kozlowski et al. 1974; Russell et al. 1976b).

While chewing active gum, the subjects smoked fewer cigarettes,

smoked them less intensively, and inhaled less deeply (as measured

by COHb) than when chewing a placebo gum.

Effect on Withdrawal Symptoms

In an early short-term crossover study (Russell et al. 1976b),

nicotine chewing gum was rated as more satisfying than a placebo.

It was also rated as significantly more effective at putting the

subjects off cigarettes and as more helpful after stopping smoking.

In more recent clinical studies (see below), besides being more

effective than placebo in helping smokers to give up cigarettes,

active gum was significantly more effective than placebo at

relieving irritability, hunger, and sleepiness during the first 6

TABLE 1

Significance levels of changes in mood and other ratings

before and after 24 hours abstinence in subjects

receiving active nicotine chewing gum or placebo

Placebo

(n=21)

Active Difference

Gum between

(n=27) groups

Depressed .06 NS .025

Irritable .OOl NS .025

Less sociable .025 NS .05

Less composed in company .05 NS .Ol

At a loose end

Restless

Dizzy

.05 NS NS

.05 NS NS

.05 NS NS

Reduced concentration .025 .OOl NS

Hunger .OOl .OOl NS

Note: Ratings of all the withdrawal symptoms listed above

changed significantly in those on placebo gum. In those

on active gum, the only ratings to show significant

change were reduced concentration and increase in hunger.

Comparison of the changes in the two groups (3rd column)

shows that nicotine replacement provided by 2 mg nicotine

gum alleviated symptoms of depression, irritability,

reduced sociability and composure in company.

(See West et al., Brit J Addict, 79:215-219, 1984).

118
weeks of treatment (Jarvis et al. 1982). However, the active and

placebo groups differed in abstinence rates during this period, and

this may have partially accounted for the differences in withdrawal

symptom ratings.

In a study designed specifically to test the effect of partial

nicotine replacement on withdrawal symptoms during the first 24

hours of abstinence from smoking, 48 smokers were randomly assigned

to chew either active 2 mg nicotine gum or a placebo (West et al.

1984). Subjective ratings were recorded &fore and during

abstinence. The results in table 1 show that those who received

placebo gum experienced a number of withdrawal symptoms during

abstinence, whereas those given active gum experienced very few.

In other words, the active gum was successful in alleviating some

but not all the withdrawal symptoms. Similar findings have been

reported in other studies (Hughes et al. 1984; Schneider and Jarvik

1984). It is noteworthy that these results were achieved despite

the fact that plasma nicotine concentrations on the active 2 mg gum

averaged only 8.3 ng/ml compared with base-line smoking

concentrations of 31 ng/ml and 25 ng/ml for peaks and troughs

respectively (West et al. 1984). More effective nicotine

replacement with 4 mg gum and/or more experience of chewing could

lead to greater relief of withdrawal symptoms.

In view of the capacity of nicotine chewing gum to produce blood

nicotine levels comparable to smoking, albeit more slowly, in view

of its capacity to produce some of the pharmacological effects of

smoking, to inhibit ad libitum smoking, and to relieve tobacco

withdrawal symptoms, in addition to providing an oral substitute,

it would be suprising indeed if it were not also to prove a useful

aid to cessation.

CLINIC-BASED TREATMENT

Over the past 20 years, many kinds of treatment methods have

been tried to help people to give up smoking. These include

hypnosis, group treatment, acupuncture , aversion therapy, and other

psychological methods. None of these has been shown to give better

results than an equivalent amount of simple attention and support

which produces success rates ranging from about 10% - 25% abstinent

at l-year follow up. Drugs such as lobeline and tranquillizers

are no better than placebos, probably because they are inadequate

substitutes for nicotine (see above). In our view, the main

obstacle to success is the addictive nature of smoking. This is

the root of the problem and, until recently, none of the cessation

methods have been applied directly to it. However, since the

development of nicotine chewing gum, the situation has changed.

In a comparative study at our clinic (Raw et al. 1980), those

treated with nicotine gum had a success rate of 38% at l-year

follow up, compared with only 14% for those who had intensive

psychological treatments. More recently, in a double-blind

placebo-controlled trial (Jarvis et al. 1982) we obtained a success

rate of 47% not smoking at l-year follow up, compared with 21%

for those on placebo gum (see table 2). The active gum was also

119
significantly more effective than the placebo at relieving

withdrawal symptoms. In both these studies abstinence from smoking

was confirmed by carbon monoxide measures. Adverse side-effects

were limited to gastrointestinal symptoms such as nausea,

indigestion, and hiccups. These were minor and transient and in no

case warranted discontinuance of gum use. About 7% of the subjects

became dependent on active gum (none on placebo). Probably because

absorption of nicotine is less rapid than from smoking, the

dependence was also less severe and was usually overcome without

relapse to smoking. Similar results have been obtained in

placebo-controlled trials in Sweden and the U.S.A. (Fagerstrom

1982; Hjalmarson 1984; Schneider et al. 1983).

TABLE 2

Treatment with nicotine chewing gum (% abstinent)

Placebo Active Statistical

Gum Gum Significance

(n=58) (n=58)

Abstinent at 1 month 33% 62% p<.01

Abstinent at 1 year 21% 47% P<.01

Lapse-free abstinence 14% 31% P<.025

throughout 1 year

Jarvis et al. Brit Med J, 285:537-540, 1982. Copyright 1982,

Medical Association.

LIMITATIONS OF INTENSIVE METHODS

Intensive treatment and support at specialised smoking withdrawal

clinics can achieve l-year abstinence rates of up to 40%, but

the average is nearer 20%. Even if higher success rates could be

obtained, the clinic-based approach has two major limitations.

Firstly, only a minority of smokers will ever attend a clinic and,

secondly, if they did attend, there are simply too many smokers for

clinics to cope with. Few clinics in Britain attract as many

as 200-300 clients a year, and many of these attend only once and

so do not avail themselves of the treatment offered. A relatively

busy and effective clinic is unlikely to achieve more than 100

long-term ex-smokers per year and the yield of the average clinic

is probably below 50 per year.

120
THE MINIMAL INTERVENTION STRATEGY

The rationale behind this strategy is that the yield of long-term

ex-smokers will be greater if the therapist/counsellor/advisor

spends less time with more smokers rather than focusing on

intensive effort with a few. A method with a low but proven

success rate, achievable with minimal effort and readily applicable

to large numbers of smokers, could be more useful in terms of

public health than a time-consuming intensive method with a far

higher success rate. In this respect we have been impressed by the

powerful role that physicians could exercise. In the course of

their everyday work physicians have face-to-face access to the

majority of the 17 million cigarette smokers in Britain. Some 95%

of the British population attend their family physician at least

once in a 5-year period, and about 75% attend at least once in a

year. Attendance rates in other developed countries are unlikely

to be very different.

In a previous study we showed that brief advice against smoking

given by family physicians in their own style, together with a

leaflet and warning of follow-up, achieved a success rate of 5.1%

who stopped smoking within the first month and were still abstinent

at 1 year, compared with 0.3% in non-intervention controls

(Russell et al. 1979). It is emphasised that these results were

based on all cigarette smokers who attended the physicians'

offices, irrespective of whether they wanted to stop at the time or

whether they had or had not already got a smoking-related disease.

Although small, this effect was highly significant statistically,

and for the reasons stated above has the potential for creating

more ex-smokers than is ever likely to occur via intensive methods.

PHYSICIAN INTERVENTION WITH NICOTINE CHEWING GUM

We have recently completed a further study designed to see whether

the offer and prescription of nicotine chewing gum (2 mg Nicorette)

would enhance the efficacy of brief routine advice by physicians

(Russell et al. 1983b).

The target sample comprised all cigarette smokers, aged 16 or more,

who attended the offices of 34 family physicians in six group

practices during a 3 1/2-week period. They were assigned by week

of attendance (in a balanced design) to one of three groups.

Group 1 were non-intervention controls. Group 2 received advice

to stop smoking plus a booklet and a warning of follow up.

Group 3 received the same as Group 2 but, in addition, were

offered nicotine chewing gum. If the offer was accepted, a

prescription and instruction booklet were also given, A postal

follow-up was done after 4 months and again after 1 year.

Expired-air carton monoxide was checked in two-thirds of those

claiming abstinence at 1 year. The results are based on the 1,938

(89%) who had not moved to an unknown address or died during the

year. Among these 1,938 there were 327 who did not provide

adequate data. They were counted as continuing smokers. The main

results are shown in table 3.

121

485-874 0 - 85 - 5
TABLE 3

Minimal intervention by family physicians

No Advice Advice and

Advice Only Nicotine Gum

(N=584) (n=675) (n=679)

Tried to stop 36.6 46.1 61.1

Abstinent at 4 months 10.3 14.1 20.2

Still abstinent at 1 year

Self-report 6.0 6.4 11.9

Adjusted for 3.9 4.1 8.8

non-validation

Note: The results are showrr as percentages based on all

subjects in each group. All comparisons between the

nicotine gum and the other groups were significant at the

p<.OO5 level. (Russell et al. Brit Med J, 287:1782-1785,

1983). Copyright 1983, The British Medical Association.

As with the clinic based studies, use of the gum in a family

physician setting doubled the success rate achieved by advice

alone. Further analyses, which can be found in the full report

(Russell et al. 1983b), showed that the offer and availability of

the gum achieved its overall effect in three ways. It motivated

more smokers to try to give up smoking (p<.OOl), it increased the

success rate among those who tried (p<.05), and reduced the relapse

rate among those who had stopped at 4 months (p<.05) .

The greater efficacy of Group 3 intervention was achieved despite

the fact that the results are based on all subjects and that only

53% actually tried the gum. There was a complex relation between

initial cigarette consumption, gum use, and success rate. Heavier

smokers tended to use more gum, and heavy gum use was associated

with a higher success rate. In particular, the self-selected

subgroup (8% of Group 3) who used more than a box of gum (105

pieces) had a long-term success rate of 34.6% (24% after adjustment

for failed validation). These successes had had an initial

cigarette consumption prior to intervention averaging 23 cigarettes

per day compared with 13 and 12 per day for the successes in Groups

1 and 2 respectively and 12 per day for the remaining successes in

Group 3.

122
An 8.8% success rate may at first seem unimpressive compared with

rates of 40% obtained with intensive methods at specialised

clinics. It may help to get it in perspective. We calculated that

if the 34 physicians in this study were to continue the Group 3

procedure routinely, the net yield of long-term ex-smokers (over

and above the spontaneous cessation rate in the non-intervention

controls) mold average about 38 per physician in the first year.

Extrapolated to all 28,000 family physicians in Britain, and

assuming they could achieve similar results, the initial yield

would be around 1 million w-smokers a year, and possibly similar

results could be obtained for several ensuing years.

Finally, although higher success rates could undoubtedly be

achieved if physicians had the time for more intensive support and

follow up, we suggest that the overall yield of ex-smokers would be

greater if physicians allocated their time by spending a little of

it with many smokers rather than a longer time with a few.

Ideally, physicians should know, by enquiring if necessary, the

current smoking status of every patient they see, advise all

cigarette smokers to stop, and offer nicotine gum and an

instruction booklet to all those who want to stop but have little

confidence in being able to succeed without help. Such activity by

physicians could achieve more than most other approaches to smoking

cessation.

PRACTICAL ASPECTS OF GUM USE

Success rates achieved with the use of nicotine chewing gum depend

on many factors, including the degree of motivation and dependence

of clients, the intensity of psychological support in the short

term, and in the longer term the degree of care given to follow-up.

However, one factor is essential if the gum is to be used

successfully in any setting. This is adequate information on what

the gum will and will not do, and careful instruction on its use.

As mentioned previously, the gum is at best a partial substitute

for cigarettes and does not provide as much positive satisfaction.

It follows that it is a treatment aid rather than a complete

treatment. Smokers who approach it naively, hoping, as many do,

that it will somehow magically stop their smoking without the need

for any effort on their own part, are inevitably disappointed and

may wrongly conclude that the gum has nothing at all to offer. It

is therefore vital that clients be made aware of the positive and

negative aspects of the gum in order to gain maximum benefit from

its use. The failure of a recent multicentre trial of nicotine

chewing gum to achieve even a placebo effect may reflect among

other things inadequate attention to the crucial aspects of subject

instructions (British Thoracic Society 1983; Jarvis and Russell

1983). We summarise in appendix 1 the main points that we have

found helpful to communicate to clients.

123
Management of treatment with nicotine gum is relatively

straightforward. The main issues are firstly whether all patients

need the gum, and secondly whether long-term dependence on it is a

matter for serious concern. Motivation to give up cigarettes is a

prerequisite for success, and it is sensible to seek evidence of

this in serious unaided attempts to quit before considering the

offer of nicotine chewing gum. Light smokers are more likely than

heavy to stop without any formal help, but present evidence

suggests that their success rates, like those of heavy smokers, are

enhanced by use of the gum. The main point to resolve therefore

should be whether the client's history suggests that dependence as

opposed to lack of motivation has been the main block to achieving

smoking cessation.

Most people do not find it difficult to stop using the gum, but a

small minority do become dependent on it and may continue to use it

for a year or longer. While long-term use of the gum should be

discouraged, both because continuing dependence on nicotine

increases the risk of relapse to smoking and because of possible

health risks of gum use per se, in our view it is not advisable to

refuse to continue to prescribe to a client who is not smoking.

This is almost guaranteed to produce relapse to smoking, which is

far more harmful to health. We summarize in appendix 2 the main

issues of treatment management.

THEORETICAL IMPLICATIONS

Like most new treatments, nicotine chewing gum given with

enthusiasm no doubt has a strong placebo effect. Some people

dismiss this quality with scorn. In our view, this is mistaken.

As a principle, a safe placebo may be turned to better use than an

active treatment that carries a risk. Placebo response is a valid

and potentially useful psychological effect. It would seem

preferable in treatment situations to view it as an asset to be

used positively to enhance results rather than negatively as a

reason for undermining the value of treatment.

There is no doubt, however, that nicotine chewing gum has an effect

over and above that of the attention-placebo response. Besides

achieving higher success rates than placebo, it significantly

alleviates withdrawal symptoms, as has been discussed already.

There is one further point. In our placebo-controlled trial

(Jarvis et al. 1982) we found that among those who were abstinent

at 1 month, gum consumption (number of pieces per day) correlated

with pretreatment blood nicotine concentration in the active group

(r= .48) but not in the placebo group (r= .17). Pretreatment

cigarette consumption, on the other hand, correlated with gum use

in the placebo group (r= .47) but not in the active gum group

(r= .ll). These findings were statistically significant and point

to different processes underlying the use of nicotine gum and

placebo gum. The evidence for the specific efficacy of nicotine

chewing gum over and above that of attention-placebo factors is

summarized in table 4.

124
TABLE 4

SUMMARY OF EVIDENCE FOR SPECIFIC

EFFICACY OF NICOTINE CHEWING GUM

1. Can produce blood nicotine levels

similar to cigarette smoking.

2. Produces some pharmacological

effects equivalent to smoking.

3. Inhibits ad libitum smoking.

4. Clinical efficacy: doubles

long-term abstinence rates.

5. Subjectively helpful to smokers.

6. Reduces withdrawal symptoms.

7. Gum use correlates with

pretreatment blood nicotine;

placebo does not.

8. About 7% become dependent on

nicotine gum, none on placebo.

Besides its use as an effective aid to smoking cessation, nicotine

chewing gum has already proved a useful tool for research.

Firstly, it has stimulated a new wave of clinical trials in which

far more rigour has been applied than previously to important

methodological issues such as biochemical validation and success

criteria. Only recently, for example, has a clear distinction been

made between abstinence at 1 year follow-up and lapse-free

abstinence throughout the year.

Secondly, and more importantly, its effect compared with placebo in

enhancing smoking cessation success rates, in alleviating

withdrawal symptoms, and in inhibiting ad libitm smoking has

provided new evidence for the role of nicotine in smoking.

125
SUMMARY AND CONCLUSIONS

In our view, nicotine chewing gum is the most significant single

advance achieved so far in the whole field of smoking cessation.

It is the only treatment that has yet been shown to have a specific

effect over and above that of attention-placebo factors, and this

has been demonstrated repeatedly by several research groups in

different countries. It is suitable for use as an adjunct both to

intensive psychological methods of treatment and to minimal and

largely self-help types of intervention. In either case, it

approximately doubles the success rates achieved by intervention

without the use of gum. It can be administered effectively by

psychologists and family physicians and no doubt by other

adequately trained health professionals too.

The efficacy of nicotine chewing gum is not limited to the smokers

who use it. Its incorporation into a treatment or intervention

programme revitalises and maintains the morale of therapists.

Until the advent of nicotine gum it has required either a research

interest, financial reward, or a degree of masochism to remain for

long at the sharp end of the business of helping people to give up

smoking. Without a treatment capable of reducing withdrawal

symptoms, therapists became drained by having constantly to give

out encouragement and support to help their clients to tolerate

withdrawal long enough for the difficulties gradually to wane. The

rapid and tangible effect of the gum in relieving withdrawal

symptoms is a boost to the morale and confidence of client and

therapist alike. It is perceived as helpful even by those who

fail. This encourages people who relapse to return for further

therapy. A discouraging feature with other treatments has been the

tendency for those who relapse to avoid contact with their

therapists even to the extent of not responding to data collection

at long-term follow up.

In view of its efficacy, its potential for use in many settings,

its minimal demands on therapists' time, and its synergistic effect

in encouraging and boosting the confidence of clients and

therapists alike, it is possible that over a period of years

nicotine chewing gum could have a significant impact on national

smoking prevalence. But to achieve this, it is essential that it

be used correctly.

126
APPENDIX 1

INFORMATION FOR CLIENTS ABOUT NICOTINE CHEWING GUM

AND INSTRUCTI0NS ON ITS USE

The gum is not a magic cure. Personal commitment and effort are

still necessary for success.

The gum contains nicotine which is released as it is chewed and

absorbed through the lining of the mouth.

Absorption of nicotine is slower than from cigarettes; therefore

the gum does not give the same positive pleasure as smoking.

The gum does not stop the smoker from smoking, but it does make

it easier to cope without cigarettes after stopping.

The gum reduces craving for cigarettes and makes withdrawal

symptoms less severe.

Its use should be started after quitting cigarettes.

Each piece should be chewed for 20-30 minutes to allow all the

nicotine to be released.

The gum should be chewed gently, with frequent pauses. Too

vigorous chewing causes excessive salivation. Nicotine which

is swallowed is destroyed and wasted. It may also cause

indigestion.

A piece of gum should be chewed whenever the urge to smoke is

very strong. On average pack-a-day smokers use about 7 gums per

day.

The gum may taste unpleasant at first and irritate the throat.

Most people adapt to it after persisting for a day or two, but it

may take up to a week to get used to it.

The gum should be used for up to 3 months before attempting to

discontinue its use. Even then it is a good idea to carry a few

pieces in case of emergencies.

127
APPENDIX 2

MANAGEMENT OF TREATMENT WITH NICOTINE CHEWING GUM

Offer only to smokers who seriously want to quit, and have tried

previously without success or have little confidence in succeeding

without help, including light smokers who meet these criteria.

Give usual guidelines on quitting - e.g., setting a target day for

stopping, avoiding difficult situations, etc. The gum is probably

less suitable for gradual cessation, but can be readily

incorporated into most other programs.

Give verbal and written instructions to all clients, along the

lines suggested in appendix 1. In most countries a manufacturer's

booklet is available.

Discontinue the gum if the client continues to smoke. We usually

warn clients who have not quit by 2 weeks that they will get no

more if they have not quit by their next visit.

Consider 4 mg gum if the client uses more than 15 per day of the

2 mg strength. (4 mg gum is not yet available in the U.S.A.)

Encourage gradual withdrawal from gum after 3 months abstinence

from smoking. Most will not find this difficult. Longer term

dependence develops in a few, but may be preferable to relapse to

smoking, which is the probable alternative if the gum is withheld

from clients who feel they cannot do without it.

Unwanted effects such as sore mouth, hiccups, and gastric symptoms

are relatively common initially but are rarely a cause for

discontinuance. They are often a sign of excessively vigorous

chewing.

In our view the following conditions are cause for caution but do

not exclude use of the gum: pregnancy, peptic ulcer, coronary

heart disease, hypertension, peripheral vascular disease. In all

these conditions continued smoking is probably more harmful than

moderate gum use.

128
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ACKNOWLEDGEMENT

We thank the Medical Research Council for continued support over

many years.

AUTHORS

M.A.H. Russell, FRCP, FRCPsych. Psychiatrist

M.J. Jarvis, MPhil. Clinical Psychologist

Addiction Research Unit

Institute of Psychiatry

The Maudsley Hospital

London SE5 8AF, England

130
Psychological and Pharmacological

Approaches to Smoking Relapse

Prevention

Sharon M. Hall, Ph.D., and Joel D. Killen, Ph.D.

This paper reports data from two studies which examined the effects

of smoking treatments combining psychological and pharmacologic

treatment methods. Nicotine chewing gum (Nicorette) was used as a

pharmacologic aid to help achieve nonsmoking and maintain abstinence. Aversive smoking procedures were used to produce rapid

cessation. Cognitive behavioral skills training was included to

help subjects develop strategies for identifying and coping with

high risk episodes.

NICOTINE CHEWING GUM: A PHARMACOLOGIC THERAPY

The use of nicotine gum as a therapeutic agent is based on the

assumption that smokers smoke for nicotine. The evidence supporting

nicotine as the dependency-producing agent is suggestive but inconclusive. The dependency premise has led to proposals of nicotine

regulation or "titration." That is. it has been assumed that

smokers. once dependent, regulate nicotine through relatively stable

patterns of self-administration. Data supporting the nicotine

regulation model come mostly from experiments showing variation in

smoking rates accompanying experimental manipulation of nicotine

levels (for example, e.g., Mangan and Golding, 1978; Herning et al.

1981). However, the regulation in most studies is imprecise. Some

investigations. especially those correlating nicotine yield and

nicotine blood levels, have failed to demonstrate a regulation

effect (Kumar et al. 1977).

Initial trials with nicotine gum conducted in Great Britain and

other European countries produced mixed results. Russell et al.

(1976) compared 2 mg nicotine chewing gum with placebo in a

double-blind cross-over trial during which 43 smokers were either

smoking "as inclined" or were attempting cessation. Use of the gum

signficantly reduced smoking during the ad lib period, but differences between the two conditions disappeared when subjects attempted

to quit smoking. At 6-month followup, Puska et al. (1979) found 35%

abstinence for nicotine gum treatment subjects and 25% for placebo.

Malcolm et al. (1980) found 23% abstinence for gum treated subjects,

5% for placebo, and 14% for a no-drug control. Recent studies reported by Russell have produced higher abstinence rates, probably

due to improvements in the formulation of the gum and to better

instructions in its use. One year COHb validated abstinence rates

131
of 38% have been reported (Russell et al. 1980). These may be

increased to 67-68% for subsample which continue to use the gum for

at least four months (Russell et al. 1980; Wilhelmson and

Hjalmarsson 1980).

However, at least one recent placebo-controlled trial has failed to

demonstrate an effect for the active gum (British Thoracic Society

1983). and two others reported failures to maintain initial significant differences at 1-year assessments (Fagerstrom 1982; Fee and

Stewart 1982). a negative result replicated in a sample from the

United States (Schneider et al. 1983).

ADVANCED PSYCHOLOGICAL TREATMENTS

Multicomponent psychological interventions represent "state-of-theart" efforts in psychosocial approaches to smoking cessation the

relapse prevention (e.g.. Hall 1984). Treatments typically combine

aversive smoking strategies to produce quitting with behavioral

skill training. The skill training gives clients skills to successfully overcome high risk situations.

Results from controlled investigations of multicomponent programs

have been mixed. Although some have reported 12-month abstinence

rates above 50% (Delahunt and Curran 1976; Lando 1977), the data

from most of these studies are less than persuasive. Rates are

either lower (e.g., Danaher 1977). or they are based on selfreported abstinence without biochemical verification.

COMBINING PSYCHOLOGICAL AND PHARMACOLOGICAL APPROACHES

Most investigators agree that both psychological and pharmacologic

factors maintain smoking (Jaffe and Kanzler 1979). Therefore,

procedures enabling quitters to cope with the psychological factors

precipitating relapse combined with pharmacological management of

withdrawal symptoms may enhance long-term treatment outcomes. In

one such trial. Fagerstrom (1982) reported a 12-month abstinence

rate of 49%.

The two trials reported in this paper combined nicotine gum with

similar multicomponent psychological interventions. The studies

were designed and executed independently. One was Implemented at

Stanford University (Killen), the other at the University of

California, San Francisco (Hall).

THE STANFORD TRIAL

Sixty-four subjects were assigned to one of three maintenance

treatment conditions: (1) nicotine gum (n=22); (2) skills training

(n=20); (3) combined. The latter included gum plus skills training

(n=22). Abstinence was assessed at 6 and 15 weeks and 10.5 months

following cessation. Expired air carbon monoxide levels were

measured at all three points. Serum thiocyanate levels were

collected at 6 weeks.

132
Subjects

Subjects met the following criteria: (1) did not present cardiovascular cr pulmonary disease symptoms; (2) were not pregnant; (3)

paid a 50 dollar deposit; and (4) obtained physician's consent to

participate. Subject characteristics are presented in table 1.

TABLE 1

The Stanford Trial - Demographics

Mean number of cigarettes per day 31.7

Mean age 44.1

Mean number of years smoked 23.8

Mean (SD) expired air CO (PPM) 28.2 (12.5)

Mean (SD) blood cotinine (NG/ML) 192.9 (100.0)

Mean (SD) serum thiocyanate (UMOL/L) 165.9 (53.1)

Cessation Phase

A 7-week treatment program consisting of cessation and maintenance

phases was developed. The cessation phase occurred during week 1.

Maintenance training was conducted during weeks 2-7.

All subjects participated in the cessation phase, designed to

produce rapid quitting. Therapists met with participants in groups

of 10-12 in four consecutive 1.5-hour sessions. All smoking was

expected to cease after the third session so that subjects would

have achieved abstinence for 24 hours at session four.

During the first hour of each session, a four-step skills training

procedure was used to help participants develop strategies for

coping with the multiple determinants of smoking. In Step 1.

self-efficacy scales developed by Condiotte and Lichtenstein (1981)

were used to target high-risk situations. In Step 2, therapists led

group members in a discussion of potentially effective coping

strategies. In Step 3, therapists demonstrated how strategies for

selected target situations might be implemented. In Step 4.

participants rehearsed responses specific to personal high-risk

situations in front of the group. Therapists and group members

provided feedback following each rehearsal.

During the final 30 minutes of each session participants engaged in

an aversive smoke holding procedure. Imagery training with home

practice was used with smoke holding to promote more potent,

self-regulated use of aversion effects.

133
Maintenance Phase

Condition 1: nicotine gum. Subjects in this condition used

nicotine gum (2 mg) for 7 weeks. Nicotine gum was begun on day 1 of

the cessation phase. Participants were informed that-a variety of

psychophysiological withdrawal symptoms accompany cessation and may

increase the chance of relapse. They were instructed to chew nicotine gum at each occurrence of an urge, craving, or other symptom;

they were told that symptoms would diminish within 10 to 15 minutes

of onset. Participants were also told that the gum was only viewed

as an adjunct to cessation, and that skill development and practice

were essential to continued abstinence. They were instructed to

reduce gum usage beginning in week 3 in order to terminate gum use

completely at the end of treatment. Gum was not available beyond

week 7.

During the maintenance phase, participants in Condition 1 attended a

drop-in clinic for 20 minutes once a week beginning in week 2. At

each session participants received new gum supplies if desired and

returned unused portions of gum allotments distributed at the previous session. Carbon monoxide levels were measured and selfregulatory efficacy scales were completed.

Portions of the $50 deposit were returned for attending weekly

sessions.

Condition 2: skills training. Participants in Condition 2 met in

small, therapist-led groups during weeks 2 and 3 for additional

skills training designed to strengthen nonsmoking skills. Nicotine

gum was not administered.

In weeks 4-7 they directed their own maintenance program and

received performance feedback during weekly drop-in clinic

sessions. Participants used efficacy scales to target high-risk

situations and wrote treatment plans detailing the (a) problem

situation; (b) appropriate coping strategies; (c) change plan

implementation procedures; and (d) outcomes. Portions of the deposit were returned for completion of weekly homework assignments.

Condition 3: combined. During the maintenance phase, participants

in Condition 3 received the skills training program developed for

those in Condition 2 (ST). They also began; nicotine gum on day 1

and discontinued use at the end of treatment (week 7).

RESULTS

Abstinence rates are presented in table 2.

At 6 weeks, the rate for the combined group was significantly higher

than the rate achieved by the skills training condition only format

134
TABLE 2

Stanford Trial - Abstinence Rates

NG ST NG+ST

(n=22) (n=20) (n=22)

6-week followup

N 14 11 19

% Quit 64 55 86

15 week followup

N Quit 11 9 16

% Quit 50 45 73

10.5 month followup

N Quit 5 6 11

% Quit 23 30 50

(ST) (X2=3.63, p<.05, one-tailed), but not different from the gum

only format (NG). At 10.5 months, differences between the gum

formats were not significant at (p<.O5) but were in the predicted

direction (X2=2.46, p<.10, one-tailed). Carbon monoxide values

were used to verify self-report: at each assessment. Thiocyanate

was used to verify reports at 6 weeks. Ninety percent agreement was

obtained between biochemical measures.

Withdrawal Symptoms

A Tobacco Withdrawal Scale, developed by Bachman (unpublished) was

used to assess the frequency and severity of withdrawal symptoms

associated with cessation. Subjects rated the severity of each of

24 symptoms on a scale ranging from 0 (no symptom) to 4 (extremely

severe). Withdrawal symptoms were collected daily during weeks

2-4. At week 3. gum users reported significantly less severe

symptoms t(48)=2.39, (p<.O5). Differences at weeks 2 and 4 were not

significant but in the predicted direction.

Physical Dependence Predictors

A stepwise logistic regression analysis was conducted to examine the

utility of seven factors (Fagerstrom Tolerance Questionnaire,

reported cigarette consumption, withdrawal symptom severity, urge

severity, cotinine, expired-air carbon monoxide and serum

thiocyanate) in predicting resumption of smoking. Urge severity

accounted for about 14% of the relapse variance (X2=10.93,p<.009)

at the 15-week followup. Symptom severity accounted for about 3% of

135
the variance (X2

=3.95,p<.05). Suprisingly. cotinine failed to

predict relapse at any assessment.

Side Effects of Gum Use

Most users reported some side effects, but only three discontinued

use due to personal discomfort. Table 3 presents the most frequently reported side effects.

TABLE 3

The Stanford Trial - Reported Side Effects

Side Effect

oral soreness

hiccups

nausea

lightheadedness

mouth sores

jaw muscle ache

appetite loss

headache

heartburn

Percent Reporting

32

11

20

14

36

9

23

5

THE UNIVERSITY OF CALIFORNIA - SAN FRANCISCO TRIAL

Subjects

Subjects were 120 smokers who attended an orientation meeting and

(1) did not have cardiovascular or pulmonary disease; (2) were not

pregnant; (3) were between the ages of 21 and 55; (4) paid a $75

deposit; and (5) obtained physicians' concurrence about their health

status. Demographic and smoking characteristics of these subjects

at pretreatment are in table 4.

Subjects were assigned by order of entrance into treatment to one of

three treatment conditions. These were nicotine gum in a low contact group, entensive behavioral, or combined.

All subjects were told to stop smoking on the first day of treatment

and were precautioned against smoking outside the sessions thereafter. All meetings lasted 75 minutes.

136
TABLE 4

UCSF Trial - Sample Description (N=l20)

N %

SEX: Male 64 53

Female 56 47

Treatment Completion:

Treatment Completers 114 95

Dropouts 6 3

Years Smoked: l-5 Years 5 4

6-10 Years 15 13

11-20 Years 52 46

>20 Years 42 37

Pretreatment Blood X = 186.55

Cotinine Level SD = 92.94

(NG/ML) Range = 15-469

AGE X = 38

SD = 7.6

RANGE = 24-56

Intensive Behavioral Treatment

This treatment was modeled on that studied earlier in the senior

author's laboratory. In that trial, it produced 50% abstinence rate

at 6 months. and 39% at 1 year (Hall et al. 1982). The treatment

had two phases, a quitting phase and a relapse prevention phase.

The quitting phase consists of eight aversive smoking sessions held

during the first 3 weeks. Subjects puffed and inhaled every 30

seconds. Videotape feedback of the smoking sessions was used to

provide negative images for the smoker to use when tempted to smoke

outside the session. Carbon monoxide feedback was given before and

after each treatment session, to emphasize the physical effects of

smoking.

The relapse prevention phase had three components. These were

relaxation training, smoking situation training, and structured

feedback. Subjects were taught a modification of Benson's (1974)

relaxation method. They made a commitment to use this technique or

another of their choosing to combat feelings of tension and irritability. Subjects role-played typical relapse situations and

learned ways of rethinking responses to urges. Structured feedback

consisted of paper and pencil exercises with group discussion on the

costs of smoking and the benefits of quitting. CO levels were also

used as feedback during this phase of treatment.

137
Nicotine Gum plus Low Contact Group

Four treatment sessions were held over a 3-week period. Subjects

were given detailed instructions in use of nicotine gum, including

when and how to taper off the gum. During treatment sessions, use

of the gum was monitored, reading materials were discussed, and

individual plans to quit smoking were formulated. As part of that

plan, subjects made a commitment to the group to use specific

strategies. Materials presented included three booklets: a tip

sheet taken from the American Cancer Society, information on the

American Lung Association Tel-Med Phone line, and a magazine article

on nicotine gum. Gum was available for 6 months from study start.

Combined Treatment

The combined treatment was identical to the behavioral treatment

except that nicotine gum and instructions in its use were provided

and gum was available for 6 months from study start.

Assessments were held at weeks 0 (pretreatment), 3 (posttreatment).

12, 26. and 52. Abstinence was verified by CO. Plasma thiocyanate

analyses were used to verify abstinence at 26 and 52 weeks. Blood

cotinine and Tolerance Scores were collected at pretreatment.

RESULTS

Abstinence rates are shown In table 5.

TABLE 5

UCSF Trial - Abstinence Rates

Treatment Group

Low Contact Combined Behavioral

(N=43) (N=41) (N=36)

3-Week Assessment

N Abstinent

% Abstinent

12-Week Assessment

N Abstinent

% Abstinent

26-Week Assessment

N Abstinent

% Abstinent

52-Week Assessment

N Abstinent

% Abstinent

35

81

39 28

9 5 78

25 30 17

58 73 47

20 24 11

47 59 31

16 18 10

37 44 28

138
Differences between the Combined condition and the two single

modality treatment conditions considered together were significant

at weeks 3 (X2(1)=5.00, p<.O2), 12 (X2

(1)=4.50, p<.O3), and 26

(X2(1)=4.05, p<.04), but not at week 52 (X2(1)=1.40, p<0.24).

Hierarchial logistic regression indicated significant treatment

condition by cotinine level interventions. For subjects above the

median, differences in abstinence rates between gum and no gum

conditions were significant at all assessments at week 3 (X2(1)=

3.89, p<.05, 26 (X2(1)-4.71, p<.O3), and 52 (X2(l)= 5.31,

p<.05). A nonsignificant trend in the same direction was noted at

week 12 (X2=2.97, p<.08).

There were no significant differences between gum and no gum

conditions for subjects below the cotinine median. Results for the

Tolerance Scale followed a similar pattern, but differences between

gum and no gum for subjects above the median were significant only

at weeks 12 (p<.026) and 26 (p<.O27). Cigarettes per day showed a

similar pattern, but differences were significant only at week 26

(p<.O34).

Abstinence rates at each assessment for both gum and no gum

conditions for subjects above and below the median on cotinine are

shown in table 6.

TABLE 6

Number (and Percent) Abstinent at each Assessment

for Subjects High and Low

on Blood Cotinine in Gum and No Gum Treatment

Gum

(n=37)

Week 3 37 (93)

Week 12 27 (67)

Week 26 21 (53)

Week 52 16 (40)

DISCUSSION

Above

Cotinine

Median

No Gum

(n=17)

13 (68)

7 (37)

3 (16)

2 (11)

Below

Cotinine

Median

Gum No Gum

(n=40) (n=l9)

30 (al) 15 (88)

23 (62) 10 (58)

18 (49) 8 (47)

15 (41) 8 (47)

The two studies produced similar outcomes. In both, the intensive

behavioral treatment combined with nicotine chewing gum produced

some of the highest longer term abstinence rates ever reported,

139
especially in relatively early assessments. Biochemical

verification of self-reported abstinence strengthens the

persuasiveness of the findings.

The results suggest that nicotine gum should be combined with

considerable psychological support. While the short-term performance of subjects in Killen's gum-only format was encouraging,

only 23% remained abstinent at 45 weeks. Relapse rates for the

other conditions were not nearly so marked. Subjects in the

gum-only format may have been less prepared to cope with psychological factors, since their exposure to the behavioral intervention

was brief. Hall's low contact condition did not produce nearly so

sharp a relapse rate. Of these subjects, 37% were abstinent at 1

year. Several factors may have contributed to differences between

the two studies, including the long period of gum availability for

Hall's subjects, or the emphasis on self-reliance in the low contact

groups, or the formulation of a plan and commitment to use it. It

should be noted, however, that in both studies even the low contact

conditions provided more support than patients will probably receive

when the gum is administered as a prescription drug.

Physicians should be cautioned that mere prescription of the gum

cannot be expected to produce optimal performance. Psychological

and behavioral factors clearly influence outcomes and must be

addressed if treatments are to produce durable results. How the gum

will be combined with behavioral treatments in clinical practice is

unclear, and is likely to be neglected unless considerable effort is

directed to physician education. Research designed to develop and

evaluate physician-administered treatments combining both nicotine

and psychological interventions is clearly needed.

Controlled placebo comparison trials testing the effects of the gum

and standardized psychological treatments are essential to clarify

the importance of different mechanisms in the change process.

Fagerstrom (1982) has reported 6-month abstinence rates of 63% and

45% for active and placebo gum combined with psychological therapy.

Fee and Stewart (1982) reported posttreatment rates of 46% and 33%

for active and placebo gum respectively. Given their sample sizes,

the 18% difference reported by Fagerstrom and the 13% difference

reported by Fee and Stewart were statistically significant.

However, the so-called placebo effect of the gum would appear to be

important, since abstinence rates in both placebo conditions were

respectable. Thus, as Russell notes (this volume), the placebo

effect can be used to advantage. It should also be noted that

significant differences between the active and placebo gums vanished

at 12-month followups in both reports.

Periods of gum availability have ranged from 5 weeks (Fee and

Stewart, 1982) to 1 year (Schneider et al. 1984). Research on

different gum administration schedules is also needed. Russell

(1980) suggested that nicotine gum be available for at least 4

months. The data are mixed, but relapse may be, in part, a function

140
of the effects of tobacco dependence. However, we know very little

of the process by which presumed psychological and pharmacological

manifestations of dependence promoted relapse (Jarvik 1979).

The Stanford and UCSF trials examined several biochemical and

self-report measures of physical dependence. Previous work suggests

that cotinine may be a useful measure of chronic tobacco dependence

and might serve to identify those smokers most likely to relapse

following smoking cessation (Hall et al. 1984b; Zeidenberg et al.

1977). Findings from Hall's study support the earlier work. Subjects above the median cotinine level did poorly without nicotine

gum. Availability of the gum had little effect for subjects below

the median. Killen's data showed no correlation between cotinine

levels and abstinence. Reasons for differences in outcome are

unclear. Blood samples were drawn in Hall's study after an 8- to

12-hour cigarette fast. Thus, the levels reported represent constant levels, unconfounded by length of time since last cigarette.

This was not the case in Killen's sample, where time since last

cigarette was not controlled. However, this procedural difference

cannot entirely account for the differences between the two studies,

since Hall et al. (1984b) used procedures similar to those of Killen

in earlier work, and were able to predict outcome. In Hall's sample, cotinine was an especially good predictor when a median split

was used, suggesting measurement at some points of the distribution

may be more reliable than at others.

The Fagerstrom Tolerance Questionnaire was also examined in both

trials. Prediction of relapse was reasonably good only in the UCSF

study.

Killen also examined measures of withdrawal symptoms severity and

urge severity. Reported urge severity accounted for about 14% of

the relapse variance at the 15-week followup. This is one of the

first studies to demonstrate a relationship between urge, strength

and relapse. Although modest, the level of prediction achieved with

this measure compares well with the predictive power of measures

such as self-efficacy or cotinine which typically account for between 10% and 15% of the variance in treatment outcome. The results

suggest that further efforts to develop measures of smoking urge may

be warranted.

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ACKNOWLEDGMENTS

Preparation of this manuscript and research described in it funded

in part by Research Grant Number Da 03538 and ADAMHA Research

Scientist Development Award Number DA 00065. both from the National

Institute on Drug Abuse.

AUTHORS

Sharon M. Hall, Ph.D.

Center for Social and Behavioral Sciences

University of California, San Francisco

San Francisco, California 94143

Joel D. Killen, Ph.D.

Stanford University

Stanford, California 94305

143
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18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., ed.

GPO out of stock NTIS PB #276 337/AS $16

19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

Ph.D., ed.

GPO out of stock NTIS PB #293 807/AS $28

20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor, Ph.D., ed.

GPO out of stock NTIS PB #288 471/AS $22

21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

Ph.D., and Richard C. Stillman, M.D., eds.

GPO out of stock NTIS PB #288 472/AS $25

22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF

ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene Barnett,

Ph.D.; Milan Trsic, Ph.D.; and Robert Willette, Ph.D.; eds. NCDAI

out of stock

GPO out of stock NTIS PB #292 265/AS $35.50

23 CIGARETTE SMOKING AS A DEPENDENCE PROCESS. Norman A. Krasnegor,

Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-00895-8 $6 NTIS PB #297 721/AS $19

24 SYNTHETIC ESTIMATES FOR SMALL AREAS: STATISTICAL WORKSHOP PAPERS

AND DISCUSSION. Jos. Steinberg, ed. NCDAI out of stock

GPO out of stock NTIS PB #299 009/AS $23.50

25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman A.

Krasnegor. Ph.D., ed.

GPO ouf of stock NTIS PB #80-112428 $22

26 THE BEHAVIORAL ASPECTS OF SMOKING. Norman A. Krasnegor, Ph.D.,

ed.

GPO out of stock NTIS PB #80-118755 $17.50

27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE, INC. L.S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-00981-4 $9 NTIS PB #80-175482 $37

28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED-RELEASE PREPARATIONS. Robert Willette, Ph.D., and

Gene Barnett, Ph.D., eds. NCDAI out of stock

GPO out of stock NTIS PB #81-238875 $23.50

146
29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. NCDAI out of stock

GPO Stock #017-024-00982-2 $6.50 NTIS PB #80-178882 $17.50

30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES. Dan

J. Lettieri, Ph.D.; Mollie Sayers; and Helen Wallenstein Pearson.

eds. NCDAI out of stock

GPO Stock #017-024-00997-l $10 Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D.,

ed.

GPO out of stock NTIS PB #80-215171 $20.50

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz.

Ph.D.; Allison F. Fentiman, Jr., Ph.D.; and Ruth 8. Foltz.

GPO out of stock NTIS PB #8l-133746 $19

33 BENZODIAZEPINES: A REVIEW OF RESEARCH RESULTS, 1980. Stephen I.

Szara, M.D., D.Sc., and Jacqueline P. Ludford, M.S., eds.

GPO Stock #017-024-01108-8 $5 NTIS PB #82-139106 $13

34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #8l-194847 $34

35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980-1995. Louise G.

Richards, Ph.D., ed.

GPO out of stock NTIS PB #82-103417 $13

36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF MULTIDISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y. Ng, M.D.,

ed.

GPO out of stock NTIS PB #8l-240913 $19

37 BEHAVIORAL PHARMACOLOGY OF HUMAN DRUG DEPENDENCE. Travis

Thompson, Ph.D., and Chris E. Johanson. Ph.D., eds.

GPO Stock #017-024-01109-6 $7 NTIS PB #82-136961 $25

38 DRUG ABUSE AND THE AMERICAN ADOLESCENT. Dan J. Lettieri. Ph.D.,

and Jacqueline P. Ludford, M.S., eds.

GPO Stock #017-024-01107-O $4.50 NTIS PB #82-148198 $14.50

39 YOUNG MEN AND DRUGS IN MANHATTAN: A CAUSAL ANALYSIS.

Richard R. Clayton, Ph.D., and Hat-win L. Voss, Ph.D.

GPO out of stock NTIS PB #82-147372 $19

40 ADOLESCENT MARIJUANA ABUSERS AND THEIR FAMILIES. Herbert

Hendin, M.D., Ann Pollinger, Ph.D., Richard Ulman, Ph.D., and

Arthur Carr, Ph.D. NCDAI out of stock

GPO out of stock NTIS PB #82-133117 $13

147
41 PROBLEMS OF DRUG DEPENDENCE, 1981: PROCEEDINGS OF THE 43RD

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

Not available from GPO NTIS PB #82-190760 $41.50

42 THE ANALYSIS OF CANNABINOIDS IN BIOLOGICAL FLUIDS. Richard L.

Hawks, Ph.D., ed.

GPO Stock #017-024-01151-7 $5 NTIS PB #83-136044 $16

43 PROBLEMS OF DRUG DEPENDENCE, 1982: PROCEEDINGS OF THE 44TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #83-252-6927AS $40

44 MARIJUANA EFFECTS ON THE ENDOCRINE AND REPRODUCTIVE SYSTEMS.

Monique C. Braude. Ph.D., and Jacqueline P. Ludford, M.S., eds.

GPO Stock #017-024-01202-S $4 NTIS PB #85-150563lAS $14.50

45 CONTEMPORARY RESEARCH IN PAIN AND ANALGESIA, 1983. Roger M.

Brown, Ph.D.; Theodore M. Pinkert, M.D., J.D.; and Jacqueline P.

Ludford, M.S., eds.

GPO Stock #017-024-01191-6 $2.75 NTIS PB #84-18467O/AS $11.50

46 BEHAVIORAL INTERVENTION TECHNIQUES IN DRUG ABUSE TREATMENT. John

Grabowski, Ph.D .; Maxine L. Stitzer, Ph.D., and Jack E.

Henningfield, Ph.D., eds.

GPO Stock #017-024-01192-4 $4.25 NTIS PB #84-184688/AS $16

47 PREVENTING ADOLESCENT DRUG ABUSE: INTERVENTION STRATEGIES.

Thomas J. Glynn, Ph.D.; Carl G. Leukefeld, D.S.W.; and

Jacqueline P. Ludford, M.S., eds.

GPO Stock #017-024-01180-l $5.50 NTIS PB #85-1596637AS $22

48 MEASUREMENT IN THE ANALYSIS AND TREATMENT OF SMOKING BEHAVIOR.

John Grabowski, Ph.D., and Catherine S. Bell, M.S., eds.

GPO Stock #D17-024-01181-9 $4.50 NTIS PB 84-145184 $14.50

49 PROBLEMS OF DRUG DEPENDENCE, 1983: PROCEEDINGS OF THE 45TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01198-3 $12 NTIS PB 85-1515537AS $22

50 COCAINE: PHARMACOLOGY, EFFECTS, AND TREATMENT OF ABUSE. John

Grabowski, Ph.D., ed.

GPO Stock #017-020-01214-9 $4 NTIS PB 85-1503817AS $14.50

51 DRUG ABUSE TREATMENT EVALUATION: STRATEGIES, PROGRESS, AND

PROSPECTS. Frank M. Tims, Ph.D., ed. NCDAI out of stock

GPO Stock #017-020-01218-l $4.50 NTIS PB 85-150365/AS $17.50

52 TESTING DRUGS FOR PHYSICAL DEPENDENCE POTENTIAL AND ABUSE

LIABILITY. Joseph V. Brady, Ph.D., and Scott E. Lukas, Ph.D., eds.

GPO Stock #017-024-01204-l $4.25 NTIS PB 85-150373/AS $16

148
53 PHARMACOLOGICAL ADJUNCTS IN SMOKING CESSATION. John Grabowski,

Ph.D., ed.

54 MECHANISMS OF TOLERANCE AND DEPENDENCE. Charles Wm. Sharp,

Ph.D., ed.

GPO Stock #017-024-01213-1 $8.50

55 PROBLEMS OF DRUG DEPENDENCE, 1984. PROCEEDINGS OF THE 46TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01242-4 $9.50

56 ETIOLOGY OF DRUG ABUSE: IMPLICATIONS FOR PREVENTION. Coryl LaRue

Jones, Ph.D., and Robert J. Battjes, D.S.W., eds.

GPO Stock #017-024-01250-S $6.50

57 SELF-REPORT METHODS OF ESTIMATING DRUG USE: MEETING CURRENT

CHALLENGES TO VALIDITY. Beatrice A. Rouse, Ph.D., Nicholas J.

Kozel, M.S., and Louise G. Richards, Ph.D., eds.

GPO Stock #017-024-01246-7 $4.25

58 PROGRESS IN THE DEVELOPMENT OF COST-EFFECTIVE TREATMENT FOR DRUG

ABUSERS. Rebecca S. Ashery, D.S.W., ed.

GPO Stock #017-024-01247-5 $4.25

59 CURRENT RESEARCH ON THE CONSEQUENCES OF MATERNAL DRUG ABUSE.

Theodore M. Pinkert, M.D., J.D., ed.

GPO Stock #017-024-01249-l $2.50

IN PRESS

60 PRENATAL DRUG EXPOSURE: KINETICS AND DYNAMICS. C.

Nora Chiang, Ph.D., and Charles C. Lee, Ph.D.. eds.

61 COCAINE USE IN AMERICA: EPIDEMIOLOGIC AND CLINICAL

PERSPECTIVES. Nicholas J. Kozel, M.S., and Edgar H. Adams, M.S.,

eds.

62 THE NEUROSCIENCE OF DRUG ABUSE. Roger M Brown, Ph.D., and

David P. Friedman, Ph.D., eds.

63 PREVENTION RESEARCH: DETERRING DRUG ABUSE AMONG CHILDREN AND

ADOLESCENTS. Catherine S. Bell, M.S.; and Robert J. Battjes,

D.S.W., eds.

149

U.S. GOVERNMENT PRINTING OFFICE : 1985 O - 485-874
DHHS Publication No. (ADM) 85-1333

Printed 1985