United States Patent (19) 11 Patent Number: 4,683,231 Glassman (45) Date of Patent: Jul. 28, 1987 54 METHOD OF PREVENTING WITHDRAWAL (56) References Cited SYMPTOMS ASSOCATED WITH THE U.S. PATENT DOCUMENTS CESSATION OR REDUCTION OF TOBACCO SMOKING 4,575,510 3/1986 Sjoerdsma ........................... 514/813 Primary Examiner-Stanley J. Friedman 75) Inventor: Alexander H. Glassman, Teaneck, Attorney, Agent, or Firm-John P. White 73 Assignee: Research Foundation for Mental 57 ABSTRACT Hygiene, Inc., New York, N.Y. In human subjects accustomed to smoking tobacco the withdrawal symptoms associated with the cessation or 21 Appl. No.: 852,650 reduction of tobacco smoking may be prevented by 22 Filed: Apr. 16, 1986 administering to the subject an effective amount of an alpha-2 adrenergic agonist such as clonidine hydrochlo Related U.S. Application Data ride for a suitable period of time. 62) Division of Ser. No. 585,900, Mar. 2, 1984, Pat. No. Alternatively, such withdrawal symptoms may be pre 4,588,739. vented by administering to such a person an effective amount of alprazolam. 51 Int. Cl." ............................................ A61K 31/395 52 U.S. C. ..................................... 514/220; 514/813 58) Field of Search ................................ 514/813, 220 7 Claims, 2 Drawing Figures U.S. Patent Jul. 28, 1987 Sheet 1 of 2 4,683,231 U.S. Patent Jul. 28, 1987 Sheet 2 of 2 4,683,231 FIGURE 2 OBSESSION WITH CIGARETTES - "CRAVING" 4,683,231 1. 2 BRIEF DESCRIPTION OF THE FIGURES METHOD OF PREVENTING WITH DRAWAL SYMPTOMS ASSOCIATED WITH THE FIG. 1 shows the global ratings obtained at the end of CESSATION OR REDUCTION OF TOBACCO each experiment day, double-bind, assessing the diffi SMOKING culty in not smoking. A 100 mm line was used with 10 being extremely difficult not to smoke and zero being no thoughts or desire to smoke. Clonidine hydrochlo This application is a division of U.S. Ser. No. 585,900, ride was significantly better than placebo (p<0.001) as filed Mar. 2, 1984, now U.S. Pat. No. 4,588,739. was alprazolam (p<0.05). The difference between BACKGROUND OF THE INVENTION 10 clonidine and alprazolam just failed to reach signifi Within the description which follows various publi cance (p<0.1). cation are referenced by arabic numerals. Full citations FIG. 2 shows the severity of craving plotted on an for these publications may be found at the end of the hourly basis during the first seven hours of treatment specification immediately preceding the claims. The with clonidine, alprazolam and placebo. 15 disclosures of these publications in their entireties are DETAILED DESCRIPTION OF THE hereby incorporated by reference into this application INVENTION in order to more fully describe the state of the art to which this invention pertains. The withdrawal symptoms associated with cessation In 1978, Gold, Redmond and Kleber demonstrated or significant reduction in tobacco smoking, e.g., ciga that clonidine dimished the opiate withdrawal syn 20 rette smoking, in a human subject accustomed to regu drome in chronically addicted human subjecs (1). Cloni lar or habitual smoking may be prevented or avoided by dine is a presynaptic alpha-2 noradrenergic agonist. administering to the subject an effective symptom-pre Central noradrenergic function had previously been venting amount of an alpha-2 adrenergic agonist for a implicated in the action of opiates without anatomical suitable period of time. specificity since the 1960's (2, 3). By the mid-1970's, 25 Although the detailed experimental results which evidence accumulated indicating that a major anatomi follow concern clonidine hydrochloride, one of ordi cal connection between the central adrenergic and opi nary skill in the art to which the invention pertains ate systems existed in a small nucleus of the dorsal pons. would understand the results to apply to alpha-2 ago the locus coeruleus. This nucleus accounts for nearly nists generally (22). Such alpha-2 agonists include in half of the noradrenergic neurons and produces the 30 addition to clonidine hydrochloride, guanabenz acetate, majority of norepinephrine in the mammalian brain (4). guanfacine, lofexidine, xylazine, tiamenidine, a-methyl These adrenergic cells are densely populated with opi norepherine, azepexole, indoramin, 6-allyl-2-amino ate receptors (5), and either enkaphalins (6, 7) or opiates 5,6,7,8-tetrahydro-4H-thiazolo 4, 5-dazepine diHCl (8, 9) and alpha-2 adrenergic agonists (10, 11) decreased 35 and analogs thereof. their firing rate. Opiate withdrawal results in a marked The alpha-2 adrenergic agonist may be administered increase in this firing rate (12). Extensive data has now by various known methods such as orally or intrave accumulated in both animals (13, 14, 15, 16) and man nously. The presently preferred method is oral adminis (17, 18, 19, 20) confirming Gold's observation that tration. The effective amount of alpha-2 adrenergic clonidine diminishes opiate withdrawal syndromes and 40 agonist may be any amount from about 0.001 to about that the diminished withdrawal behavior is related to 10.0 mg administered daily, preferably from about 0.02 the diminished firing rate in the adrenergic nuerons to about 2.0 mg. The presently preferred amount of (21). The present invention relates to the discovery that clonidine hydrochloride is about 0.1-1.0 mg, e.g. about alpha-2 adrenergic agonists such as clonidine markedly 0.2 mg. Desirably, the alpha-2 adrenergic agonist is after the acute withdrawal syndrome associated with 45 administered int wo or three doses, each succeeding cigarette smoking and suggests that central adrenergic dose being preferably given about 4 to 8 hours after the overactivity is a common feature in the pathophysiol preceding dose. Administration of the alpha-2 adrener ogy of withdrawal syndromes seen with cigaretts, alco gic agonists is continued for a suitable period of time to hol and opiates. The invention also relates to the discov accomplish the desired result. Presently, the preferred ery that such withdrawal symptoms may be prevented 50 suitable time period is about 3 to 6 weeks. As an alternative to the administration of an alpha-2 by alprazolam. adrenergic agonist such as clonidine hydrochloride, this SUMMARY OF THE INVENTION invention also contemplates the use of alprazolam. In human subjects accustomed to smoking tobacco Thus, the invention also provides a method of prevent the withdrawal symptoms associated with the cessation 55 ing in a human subject accustomed to Smoking tobacco or reduction of tobacco smoking may be prevented by the withdrawal symptoms associated with the cessation administering to the subject an effective symptom-pre or reduction of tobacco smoking which involves admin venting amount of an alpha-2 adrenergic agonist such as istering to the subject an effective symptom-preventing clonidine hydrochloride for a suitable period of time. amount of alprazolam for a suitable period of time. Preferably, administration is oral, the effective amount 60 Preferably, the alprazolam is administered orally and is an amount between about 0.02 and 2.0 mg daily and daily in two or three doses each of which is adminis the period of administration is from about 3 to 6 weeks. tered within 4 to 8 hours after the preceding dose, the Although less preferred, the withdrawal symptoms daily amount administed being from about 0.1 to 10.0 associated with the cessation or reduction of tobacco mg. preferably about 0.5 to 2.0 mg, e.g. about 1 mg, for smoking may alternatively be prevented by administer 65 about 3 to 6 weeks. ing to a smoker an effective amount of alprazolam, i.e., The following experimental details are set forth to aid from about 0.1 to 10 mg daily, for a suitable period of in an understanding of the invention but are not in time, e.g., about 3 to 6 weeks. tended to, and should not be construed so as to, limit in 4,683,231 3 4. any way the invention as defined by the claims which treatment had helped them to do without cigarettes and follow hereinafter. rated this on a scale from 1-10. In order to avoid crossover effects, subjects were EXPERIMENTAL DETAILS asked to resume their normal smoking pattern after each Methods 5 experimental day. A minimum of four normal smoking Individuals smoking more than 30 cigarettes per day days separated each experimental day. After the third were recruited to participate in a double-blind, triple session, each subject was offered a two-week trial with crossover study of the effects of an alpha-2 adrenergic the experimental treatment of his or her choice. agonist on the acute smoking withdrawal syndrome. In Global ratings of the difficulty in not smoking were addition to a placebo control, a benzodiazapine-like 10 compared by means of T tests. Treatment effects on drug, alprazolam, was used as the third experimental individual scales were obtained by averaging the scale condition. At the dosing ratio often to one, alprazolam scores during the period from the first to the sixth hour has been shown to be equally anxiolytic and slightly less after the first doses. These averages were compared by sedative than diazepam (23) in anxious medical patients. ANOVA. Because it was not clear that these scale All subjects were in good health and were drug-free 15 scores represented interval measurements, they were except for two female volunteers who used medication converted to rankings and the more conservative Fried for birth control. All subjects were instructed to refrain man non-parametric two-way analysis of variance was from smoking for twenty-four hours on three separate performed. occasions. On each occasion they were told not to RESULTS Smoke after going to bed and to report without smoking 20 at 8:30 AM the next morning.