TIK: Imnnaliorul Journal of the MdklfeM. 2l<7), 789-fiQS.

1986

The Use of Anticholinergic Drugs for Smoking Cessation: A Pilot Study

Nicholas Bachynsky," MD
Tit Phyiittoiu' CUnlc Homion. r*df ttVJA

*kbiir#ct A plllll study of 500 cases drown TIUIU 3 total papulation of 3,100 patients reports on a smokirg cessation program In a private praeUcc clinic. A new protocol offers promise fci treatment bated on vn Initial injected doie of atropine, scopolamine, and chlorproinazinc administered subcuUneously to vllmnBte physiological withdrawal sympiomi, followed by a 2-weeV oral midicalior. regimen, and follow-up every 7 months for i 12-monlti perlol. The sludy held that 9 2 . 1 % of Hie malt patients and 80.7% of female paiienlt remained nonsmokers at (he end ' of 2 months; 42.3% of the mea and 36.9% of the women remained nonsmokers at Die end of 12 monns. a curruilative tolal of 39.8%. INTRODUCTION Since ihe intioduclion of lofcacco Into Europe by the Spaniards, nicotine has become ihe most widespread form of jubilance dependency in the world (Coril, 1932; Rimell. 1971). Cigrette smoking is legal and heavily advertised; thus, it is encouraged as an acccptible mod: of public behavior though cigarette unoking probably causes more morbidity and mortality lhan all oilier drugs combined (Wry People Smoke, 1 9 B ) . It is ihe single major cause of cancer mortality In the United States (MMWi, 1982). Recent studies show that the inci*Addicu loquciii for icpcinu to the aahor: Diraclor. Too Phyiicuni'Clinic. 6333 Soulhwest Kiecway.Houston.Taui77074. 789 Oopyifchl i9S6by Marecl Dekfcu. I..: 007O-773X/8W?[07-078S3.JO/O

750

HACMYNSKY

ANTICHOLlNr.Hr.lC DKUGS FOR SMOKING CESSATION

'91

dence of developing coronary heart disease (CUD) It directly related to ilic number of cigarettes smoked; IHOM imoklng more than 20 cigarettes a day and (hose who begin smoking before the age of 20 are three to five times more likely to suffer coronary bean disease than nonsmokers (Ramidale et al.). Up to 30% of deaths from CUD can be attributed to cigarette smoking(MMWR, 1984;Cashin et al., 1984). The expense of Heating diseases caused by smoking is currently being assessed. Osier et at. (1984) estimate that "male heavy smokers between the ages of 40 and 44 will generate, on JtheJ average, over SSb,000 in additional costs of illness duiiftg their lifetimes, while for womtn. these costs will be over $19,000" (p. 384). The decision lo cease smoking does not ensure permanent cessation. Although definitive data are not available, over ihe past decade it has been esij. mated that three-fourths of the smokers have tried to stop, but only about 20 to 25% actually succeed (Wliy People Smoke. 1983; Russell. 1971). Recidivism among those who quit smoking equals that of heroin addicts 75% (Russell and Feycribend, l9?8;Pomerleau, Adkins,and Piertschuk, 1978). Clinical experience and a search of Ihe literature indicate that a decision to slap smoking often, means choosing a suppoit program (Hunt and Bcspaltc, 1981). This study repoits encouraging results found in a pilot test of new medical protocols not previously described or repotted. The program consists of a prescribed anticholinergic drug regimen aimed a i eliminating physiological withdrawal symptoms. Treatment achieves positive effects for persons who enroll in the program with the intention of remaining nonsmokers. Drug inleiTCntion treatment reduces the extreme discomfort of withdrawal usually experienced by smokers that urges them to return lo smoking. The scientific basis of this medical technique is described in the next section (Theory). This yearlong pilot study had four purposes: 1. 2. 3. 4. To ttit through medical observation if a piesciibcd drug regimen does, in effect, eliminate physiological withdrawal symptoms. To identify and describe demographic characteristics common to I sampling of patienltin the program. To monitor Tor both expected and unexpected immediate effect. To track cessation behavior.

smoking cessation. A number of approaches have been attempted including electroshock, hypnosis, psychotherapy, and counselling through support groups (Myrsten, Elegerot, and Edgren, 1977; Pedeison.SciSmgeour, and Ufcoe, 1979; Crosz, 1978-1979). However, it is well documented that a smoker desiring to cease smoking and remain a nunimoker must address both physiological and psychosocial effects. For best success, Ihe patient must have a specific motivational reason |SMR] to slop smoking, and social reasons seem to impose sironger motivation than medical reasons (Russell and Feyerabend, 1978; Elser and Sutton, l978;MaIotte e l i ! . , 1981).

THEORY
Nicotine is addictive, having a neurobiochemlcal bails (Jarvik, 1979). Nicotine has an agonistic action al the nicotine receptor sites in the cholinergic nervous system (Birdsall. Burgen, and Hulme. 1978; Rosecrans, 1979) (Fig. I). lis primary action upon prolonged use is that of a blocking agent. While this activity is less documented in the central than In the peripheral nervous syterm, the preponderance of such nicotine receptors appears to be located centrally I the midbrain level (Welncr, l974;Popot and Changeux. 1984). With chronic nicotine use, biochemical tolerance and physiological dependency are developed by increased acetylcholine accumulation mediated by enzyme induction und/or derepression through choline acetyl transferase (Brlmblecombe, 1974; Wills, 1970; Dahlstrom, Booj, Heiwall, and U i s s o n , 1980; Kelchum el al., 1973) (Fig. 2), A "tobacco withdrawal syndrome" providing for nicotine abstinence thus comes about by elimination of the nicotine blockade at specific nicotine-cholinergic synapses. Tolerance and dependency, developed by Increased acetylcholine synthesis activity, are replaced by wllhdiawal, which results from excessive acetylcholine rebound stimulation (Jarvik, 1979; Dahlstromelal., 1980; Ketchv m e t a l . , 1973) (Fig. 3). The final biochemical Interpretation of nicotine withdrawal is through acetylcholine inter synaptic stimulation of predominately muscarinic cholinergic lies at higher neuronal levels, including the cerebral cortex (Hfrschoin arid Rosecans, 1974). Usual clinical symptoms include a decrease in heart rate and blood pressure, increased Irritability, nervousness, gastrointestinal disturbances, electroencephalogram changes, and a temporary decrease in the ability to concentrate. Tests of a variety of anticholinergic and other drugs found that only scopolamine and d-amphetamine decreased smoking (puffing pattern) In monkeys. By using animal paradigms ai a model for human nicotine dependency, Click, JirvUc, and Naksmura (1970) showed the effecllvenesi of parasympathetic nervous system antagonists. Clinical data gathered from medical patients, as reported

The underlying assumption held that the absence of uncomfortable physiological withdrawal symptoms and the perception of (his relief serve is a positive reinforcement for cessation, increasing the chance of a smoker's changing his behavior, Research dining (he past decide has emphasized responsibility for one's own health and the need to educate Ihe public about the physical benefits of

792

ANTICHOLINERGIC DRUGS FOR SMOKING CESSATION

79J

MUSCARINIC RECtpTORS

NICOTINE BtCtPTOHi

NICOTINE (SMOKl)
/BLOCIUNGX \ ACINI I

fNAPTlC /ESICtL

IN( REA5ED SYNAPTIC VISICLES

Pig. 1. NpJl chrilnwglc Unimiiik>r.

Pij. 2. NKolino blockjdo: tncicaiod nnuouiniinlltci lyntheih.

794

BACHYNSKY

ANTICHOLINERGIC DRUGS FOR SMOKING CESSATION

mCRIAStO
MUSCftBINIC"
w w

IHAmMISSION

- ^

-^V

ROTORS ^ h1_ ^ < ( BOMMMlNr KU.LI IOi<b ^ (HteOUNDt

NICOTINE ^V RECtPTORS - * r

"W ' r -

'SYNAPTIC VESICLES Fig. 3. Hfccttoe withdrawal: rebound ninubilon,

Fig. 4. Aniicholineifcic blockifc of nkooiloc withdiival.

BACHYNSKY 7* in this pilot study, demonstrate the usefulness o f their research. Aniicholinergic drugs cT predominately at muscarinic sites In the cerebral cortex. By blocking these sites, we prevent the ultimate Interpretation o f the Inteisynapilc rebound phenomenon caused by excessive acetylcholine stimulation at lower nicotine m l i l b n m - U v e l receptors cicated by cessation o f chronic nicotine (tobacco) use Since withdrawal symptoms t o nicotine cessation are most pronounced during the first 24-48 hours, Immediate and high levels of anticholinergic activity are achieved by injecting described anticholinergic drugs in the subcutaneous areas over the mastoids. Nicotine is eliminated i n approximately 3 days. t u t It may lake approximately 2 weeks to reduce withdrawal symptoms ( G o ) d i i e i n and Coldslcin, 1%B). Consequently, oral medication is recommended 10 maintain a l o w level o f anticholinergic Activity Tor a peno J up t o 2 weeks. This technique i i based on laboratoiy evidence that approximately 2 weeks arc required for a significant decrease in enzyme synthesis o f the end product (acetylcholine). T h e anticholinergic method helps patients develop an aversion t o cigarettes by also effecting taste and sensory receptors. The effect of dry m o u t h , for ex* ample, while disadvantageous in many instances. Is helpful where It is a come* quence of therapeutic techniques. METHODS

ANTICHOLINERGIC DRUGS TOR SMOKING CFSSATION l a blc I Smoking Ct tut Ion Record {500 Co*ei>' A6< (mala, 267; female. 233) No. y c u s smoking Years IS 6-10 11-13 16-20 21-23 26-30 31-40 41-50 Cues 19 71 86 77 5) 98 76 12 Ni. ci,;-1clit1 srnuhed pei d*V No. (lis. 1-10 11-20 31-40 41-63 6) 6) Ci 2 70 HI 166 99 SC

Ml

''''""
Ate ranee Ca 35 158 141 115 44 6 1 15-25 26-35 36-45 46-55 36-55 66-75 76-80

Noiuinoh*--. aflu WmoDlhi Months O* 2 4 0 1 12

Cam
500 *J5 344 327 102 199

21-30

Main-39.9 yr SO: 11.4

Mean: 19.3 yr SO: 10.9

M a n 35.4 ct&t SO: 14,9

U e d i m : 6.5 aftf nonsmoking time

D i l i woie ga(heie4 iiiaipiively fiom charts of tin Physician*' Clinic.

Criteria f o r acceptance into the program l n : t u d e d : 1. The desire and willingness to H o p smoking No medical contraindications for the uie o f anticholinergic drugs, as w i t h acute-angle glaucoma, prostatic hypertrophy, or cardiac arryirunias(Csln ct a l 1984) The baseline screening protocol Included checkpoints: 1. 2. 3. 4. 5. 6. Assessment of medical history Routine cltesl X-iay Urinalysis Electrocardiogram Blood w o i k , complete b l o o d c o u n t , scru^i clcclrotylcs. and an SMA-12 panel Assessment o f surgical history for previous* occurrence o f idiosyncratic or prolonged refractory times i n the dissipation o f a n t k h o l i n e i g i c drug effects but was not l i m i t e d l o , these

For l l i t i pilot study, leliospectivc, longitudinal da\a were collected over a 2fc.year period, 1980 to mid-1983, using the smoking cessation p r o t o c o l . For purposes of this initial report, demographic and other characteristics o f the program's seir-selectuig population were comhined to better profile the smoke- w h o is likely to seek out and complete this approach to smoking cessation. Pour p r i m a r y variables were used to describe the program population and (he pilot group: Age at entrance into the program Sex Number uf cigarettes smoked per day Reason ftn wantli\g to slop smoking The pilot study describes a single treatment group consisting o f a cohort o f 500 adult patients from total study population of 3,700 patients tracked for a 12-mnnlh period (Tables I and 2 ) , A systematic convenience sample was drawn f r o m patients' cherts and clinic recordings o n follow-up log books. Patients Tot the treatment program were sciT-refcrrais, those attracted by public advertisement media, and physician referrals. They paid for the program by private payment or medical insurance coverage.

2.

A l l patients meeting the program criteria ugned an Informed consent t o Lignei treatment which spells out the expected effctjis as well as possible-hut not necessarily a n i l c i p a t e d - u n i o w a i d reaction-.

BACHVNSKY

ANTICHOLINERGIC DRUGS FOR SMOKING CESSATION

709

rb!t>2
Bsuhne Averagetof Yttri Smoktd tnd Numbir of Cl$amtct Smohfd i>*f 0*y by StM _ Averse numbe; of descent! imofccd p f i day 37.8 33.6 35.5

questionnaire (see the A p p e n d i x ) . Results were l i b u U e d b/ staff o f the Physicians' Clinic and entered i n t o patient charts. The t n t e i p l a j between S M R and medical intervention could f u r t h e r refine k n o wedge o f f i c t o r s thai enhance or i n h i b i t success and affect a smoker's chance "or bng-term cessation ( G o l d stein and Goldstein, 1968).

' Male Fomak Tolal

Avenuje y o u i imoktxt 21.4 20.8 21.1

RESULTS 1 . Preliminary findings indicate thai this (Jiatmrnl p n t o c o l is successful for a large number o f paiienls. Success is desc.ibed at t v o points In l i m e : cross-sectionally, where (he patient has or has no. ceaied tc smoke, and longitudinally, l o determine the length o f smoking absthence over a 12-month observation p e r i o d . T h e use o f anticholinergic drugs o r smoking cessation is a technique easily administered In the office oT ; private p a c l i l i o n e i and accessible t o most practicing physicians. Future Intake should focus o n a thorough rinco treatment Is b y physical (chemical) means. be w o r t h w h i l e to determine SMRs, b u t this may because paiienls w o u l d n o i choose to participate reason l o d o so. physical assessment ( w o r k u p ) I s y d o l o g i c j l usscsmicnl muy >rovt a sei*-se|ect(on process v i f h o u t a rood or immediate

THE PROTOCOLS OF TREATMENT

Having c o n u n l c d l o treatment w i t h anticholinergic drugs, patients submitted t o the r o l l o w i i u set of protocols: 1. 2. The | n l i i ! f ) i (Cixhes an iniikil intramuscular i i i j c c l i n n of u 2-ml l a l b n solut i o n w i t h scopolamine 0.2 m g arid atropine 0.2 mg. The patient o m o n i t o i c d In the physician's office w i t h the r o o m darkened for u n i i i i i m i m p c i i u d o f 5 niinules, f o l l o w e d by an B K S H U M 1 o f normal pupillary constriction and m i l d xerostomia, Given t h a i factors in Step 2 are w i t h i n n o r m a l l i m i t s , t w o additional injections are adailmilcied subcutancously over each mastoid area. The tola] drag icgimcr is atropine 0.2 m g , scopolamine 0.2 mg, and c h l o i p i o m a zinc 10 mg. OnebaJf of the t o l a l solution is injected in each site, The patient again is monitored in itio physician's office f o r a m i n i m u m period of 5 r r i n u l c t . Given lha( ifae response Is w i t h i n the sange of anticipated effects, the patient Js allowed t o leave the office w i t h instructions n o t to drive, not l o consume alcohol, and not l o lake medications w i t h a synergistic effect for 24 hours. Arceplable anticipated effects include moderate xerostomia, lightheadedness, and some d i f f i c u l t y in focusing. Day 2 t h r o u i h Day 1 1 , the patient is l o lake a prescribed oral a n t i c h o l i n ergic drug tint is k n o w n t o act o n the c e n t r a l , rather than t h e peripheral, nervous syslcu. The most c o m m o n l y used drugs arc t r l h e x p h e n i d y l hydrochloride, b c i i i i i o p i n c mesylate, or scopolamine patches.

3.

4. 5.

2. Findings support the main purpose o f thi s t u l y , indicating that 434 (86.8%) of the 500 patients o f the pilot study stepped srmxing al 2 m o n t h s ; J99 (39.8%) remained nonsmokers at ihe end o f the ysar. Results o f the program arc higher than Ihe general p o p u l a t i o n of snoke s who attempt l o stop smoking ( C o n d i o t t e and U c h t e n s t e i n , 1981) (Fig. 5). Further study rs needed l o reporl w i t h confidence an z n l i c i p a t c d program rucccss rat* for Ibis particular smoking cessation p r o t o c o l . If, however, the average s m o k n g cessation program finds an average o f 2 0 % o f Ihe paiienls abstinent J ! 6 raonlht (Hunt and Ikspsfec, 1 9 8 1 ) , this methodology m a y offer the i i n a b i l i t y o f cessation l o a greater percentage o f smokers. 3. Table 3 summarizes motivational charadeisltct o f subjects lesled at the beginning o f Ihe cessation program. The study (onesided hat in long-term cessation, Ihe patient must perceive a specific motivational rrason ( S M R ] t o stop smoking. Smokers w h o c o u l d clearly identfy i n S N R w i r e more successful in smoking cessation t h a n those w h o c o u l d n o t . S o c a ) reasons repiesenied a SMR among 63.6% o f ihe paiienls w h o slopped anok-ng a "iill 12 m o u t h s the need to satisfy a spouse, children, friends, o r c m o l o y e condiiiuns-whereas only 30.7% slopped w h o had medical reasons for d r i n g :i>. SfcRs include such concerns as ( I ) social acceptance i n a peer g r o u p ; (2)inlcspcrsooal relationships; ( 3 ) Intolerance in a w o r k station o r business she; (4) p e s s u n from a sexual partner; (S) parental disapprobation; ( 6 ) cosmetic effects, (Deluding stained iv.- ih and w r i n k l e d lips; and ( 7 ) complaints about Ihe (ten<h o f tibacco.

6.

Tracking patents during the 12 n i o n i h period was a task sequiring systematic review. Subjects responded favoiably l o follow-up a c t i v i t y , for periodic contacts provided them w i t h motivation l o continue cessation. Follow-up Information on smoking status was self-reported by patients' responses to telephone contacts every 2 months and mailings utilizing a brief, tersely worded

HO O

BACHYNSKY

ANTICHOLINERGIC DRUGS FOR SMOKING CESSATION Table 4 ,_,_.. AffcoCftw Lavcti at Builin* and 7tvo Fillaw- Up Ptrlodi Smoker baiellne Nicotine fcml A* 388 212 % 57.6 42.4 Low [0.3 mg) HglidJmg) N 244 191 2 mo nonsmoker % 56.9 43.1 N
J?J

goi

100

12 mo aonunokei % 62.B 37.)

39. i
?K>

74

NUMBER OF 'ATIENTS 500 Cases)

795 300 378 7S.8H 400 43* 3S5 71.C46

MO 0 1 4 6 0 HOI

MONTHS NONSMOKING Fig. 5. SucociifuInDMjnokai.

4. Table 4 indicates Out a greater percentage of smokers of low-nicotine cigarettes were able (o stop smoking for a period of 12 months than smokers of high-nicotine cigarettes. We ate cognizant of the fact Dial 60.8% of the participants enrolled in (he program enlered as smokers of low-nicotine cigarettes. (See Table 1.) Therefore, we encountered a design group with positive motivation to slop smoking since (he majority had, in this way, demonstrated a practice intended (o reduce nicotine dependency. In 1964 the World HeaUh Organization substituted the single term "dependence" to describe physic*! or psychological "Iwblluation" or "addiction." Physical dependence includes "lolcruncc of the effects o f . . . (a) drug due primirily to changes al synapses" and "withdrawal symptoms resulting from reboind over-acdvity at synapses when intake of the drug is reduced or discontinued" (Russell, 1971, p . 2). Nicotine dependency is characterized as Increase*! acetylcholine synthesis activity resulting from nicotine blockade at specific nicoiine-chollnerglc synapses. Chronic nicotine use causes increased acetylcholine accumulation. Smokers of low-nicotine cigarettes help themselves because lower levels of acetylcholine buildup enable earlier and less painful wilhdawa). 5. Experience ui till* pilot group showed that 39.5% of those who stopped smoking a period of 12 months used regular cigaitties; but only ) 1% of those who smoked mentholated cigarettes were able to stop. It is possible thai smokers of mentholated cigarettes may have a greater Isvel of nicotine dependency because mentholatum has a soothing action on the respiratory membrane, thus permitting deeper inhalation and retention of smoke with higher levels of nicotine titration and dependency.
Total*

TiMt J
Union to' Bn\Bilng thm Progum Subjects Male Koason Social Medical Missing valuer A
1

Female * rV J 54 31 216 % (26.6) (JO.6) C06.2) (43.6)

A' 318 116 66 500

7: (6J.6) (2i.2> OJ.2) (100.0)

CONCLUSIONS
I. Development of a rigorous program of smoking cessation ujing anticholinergic drugs requires establishment of piotoccls for (1) patient selection, (2) conduct of a physical examination, (3) administration of drugs, (4) followup activity, and (5) evaluation of short-term and long-term success and failure. The short-term measuie it completion and compllarce within ireatnsent of (he

185 62 282

(37 0} (12,4) (56.4)

35 (0?m

Tout

S02

IACHYNSKY

ANTICHOLINERGIC DRUGS FOR SMOKING CESSATION

833

program. The intermediary, long-term measure requires follow-up of past Healment. By establishing criteria foi protocols and following these protocols in clinical practice, physicians could obtain data for a longitudinal study of smoking cessation based upon medical intervention techniques. 2. A sustained research effort is desirable In aspects of smoking cessation with drug Intervention protocols. Specifically, medical science would benefit from scientific reports treating the following concerns: A prospective longitudinal study with supporting standardized Intervention, recordkeeping, and administrative follow-up. Improved behavioral modification supporl lo complement physical/medical treatment. Outcome measures related to smoking cessation, including quit levels, patient evaluations of the program (strong points and weak points), and physiological measures (including self-reporting) such as improvements in respiratory or cardiovjsculiir stains rc|K>r(cd in pus ( c a u t i o n or self-worth assays. Development of an operational definition of a program's "success" or "failure" at both (he Individual level and the clinic program level. Articulation of demographic sociopsychologlca) descriptors to afford more precise intake data (patient profiles) and complementary follow-up information (changes in status). APPENDIX THE PHYSICIANS* CLINIC 6535 SOUTHWEST FREEWAY HOUSTON.TEXAS 77074 SMOKING CESSATION PROGRAM PATIENT FOLLOW-UP LETTER

When you have completed this form, please return U lo us in the enclosed selfaddresied envelope. Thank you.

1.

Are you smoking now' YES NO

2.

If your answer lo quetllon I was "yes," how many months after completing the Clinic's treatment did you re-slarl? I 2 4 S 6 7 S 9 10 I I CIRCLE ONE 12

3.

If you have re-starled snofcfng, why?

STRESS (Chcet one or both) Olher [Pbaseexplain]:

HABIT

ACKNOWLEDGMENT J. H. Glasser, PhD, Atsutint Professor of Biometry and Computer Design at the University or Texas Heilth Science Center, Houston, Texas, was statistical reviewer of data in this study. The author is grateful to Dr. Glasser for his professional insights in Ihe development of this study and for his recommendations for future research. REFERENCES

Dear In oui continuing follow-up lo determine the effectiveness of our Clinic's smoking treatment program, we ask that you answer the questions below. DIRDSALL, N.I.M., BURCEN. 4.S.V., nd HULUE, E.C. Correlation bet won Ihe bL-iduie pioportios and phvnuoologGU rorponici of muiearinicrecepttxi. In D. 1. Jenden (ed.), Cholinergic Hccnaittimt an*. Ptyctiophamucology, Vol. 24. New York; Plenum Pica, l?78,pp.2J-33.

l>4

BACHYNSKY

AHT1CI ICUfliiHCIC DRl>CS FOR SMOKING CEJiSATiOK

1 S O

BRIMBLECiMBE, R.Yf. Aiiiirholincjuxjse igenis. )TI Dnj Acrlant nn Ctinlintrtic Syilemt. Bdliinwc: Ufl[voJBiy ftuh. Viat, 197*. pp.94-9 CASH1N, W.L, IRO0KS, 5.H., ttLANKENHQftN. D.ll SELZLR, R.H.. SANMAHCO. M.E.. n d BLNJAUrtiUlT. B. CoinputeiUtd H ) | V lurking and Icjkiri meiniewisfli In ctxumry incioeumi- A pilol jludy (empuJpe. tmslfrj Willi nr:iijmciktjt, ^J/ifro. srfcroiirSl: 195-iOU, 19*4. COKDJO'ITE M.M., and LlOTTE-PfSTElN, E. 3tlr-affkzc> ami leLapsc in miukire Cfcrtal n iniijim"!./ tojJii-'r. C/fn Piftliol. 4S: tit S!fl, I >91, C O R n , C . r1 Hiitarfof Smokirti. N t h Yurk: llsltuttlt Bfjo, 1 T O . DAHLITItO*, A.. BOG-J, J.. rlElWAI.L, J>.0 and LARSS)N t P,A, The effect u[ -hto'.iii. <dcot]nband tvilhdfjmj or inlii-neuicn.pl dynftntjej of flcclylchulinc and Hilled enIJ/fflOl '3 * Pr^jariENoniC ncujon fyilflm of Ihc i^t- *4rta PUyiitot. Stand. 11Q: L i-10d 1980, EISEH, J.B., md SUTTON. S..S. 'Comomol and dlisorum' smokers m d i h i iel/-allrlbu ion q/ jfdin|lDp.J4ali/d'iv, #Fhafr ] : 99-IOS, 1978. CLICK, S.P.. M R VlK, M.E., tnd NAKAMURA, U.K. inMJtion by diuji of Dr.eHnE behiYtoi Inmo-.'.ktyt. IYIIUFC 111-. 959-9T1, August 1?, U>Q. GOLDSTEIN. A.. smJ GOLDSTEIN. D.B. Enzyma aipsnion theory of ttrur; lolcur.t-. nj phyi<al dependence / W . Alive. Rn.Mttit.Dft. 4t' 3.S5 167. 1 94B CHOS?., H J.NItolinu addktfon.: TresLmcnt wilti ntttJLci.1 hipfioiSi. 3. bulimia Sia)t Mat. ABOC. tat 2. 71:43^J.J97*;rH \ 79:43-45. 1939. niHscilOELN. | , D , and ROSECftANS, /.A. Siudltum thsifms rourie and (he eflccl ot

hAUSDALB. D.R.. FARtCDEft E.B.. BKAV. C . L , BEMNEIT, D.H., WARD, C , awl DLTCN. D.C. Soicikiu and rorniuiry ailciy dilute nic^ied by jentinp cmoAAJ^ aifcriognptiy. Br. M . J. 390: 197-100.19BS. ROSECHANSr J.A. Wicoliic ai a dimlmbuiive itimuhji to ticbjiioi: I n chaiacierkatlim and iclevaqca 10 imokine brhavtor. In N.A. kjiingiot (ed.). Cita/ctle Sx>tt"t JJ B Dtptni'ttt Pnxta. :4ill0ful InAllult on Dinj Afauii. Dbpjitrotnl of HiiiTth, Eduttno and lVslfu:c Euhticslion No. [ADM) 79 800. Waihinglan. DC: U.S. Govornmani Piimine Orlicc, 197 J.fp. JoS*. RUSS ELL. M.A. H. Cigar P[ -e uriokin^: Nat lami hirtac* of a dcpandencB illrd tt, dr. J. 4tr<f Psychol. [ 1 ) : I - I S , , 9 7 1 . RUSSELL, M A M . , tmE FEVER ABEND, C. Ctluette trucking: A dtpindenn on MiKTinjcoiin* toll, piu(JiieBb RtK a: 19-JJJ, I97B. 9flNER, N. NcurolianiTTillBj syjlem Lr the ctniial iHiioai lyncm. in A. Vtnud^Lii and N. IVclner <ad|.), Drugs ami rfu Drvilapttit Brain. Sw York: rlrnum F I E I I . 1974. PPIOJ Ml. Wlty PfopW SmoXt Citirrlttt. fubLcallon (fHJj; 93 J019S. U.S. DtpulmcBI nl HediK inif XuntinRtKuscai |9S],pp. l-J, WILLS, J.H, AnrJdiDlinediciie a^enn. In A-C KuFimar, [ed.(, TTir/nfmuiwnaJ t'mytbpttHa of rVrarilhl10Jii and Thtwptulicf Onloid: Pcjfjmjn r>:ii, 1970. pp. 9J-70.

rfiufcnffic md idicneiiic icteplm hhickef* an Ihe sinusal effeei or lUMltiH, Plj>cAnriJi srmeelofu A 0: . 3 1 3G. 197 ). HUNT. *f,A., mi BESTAlEC, D.A. An evikigilcn oTcvneil intlhadiorngilL'yiniinial.
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