alcoholism and drug dependence, drug delivery to treat

8/14/2019 Alcoholism and Drug Dependence, Drug Delivery to Treat

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OL ISM A N D D R U G D EPEN DEN CE,

R O B E R T M . S W I F TBrown University and th e VA Medical Cen terProvidence, Rhode Island

EY W ORD SAddictive disordersAlcoholismBuprenorphineClonidineDisulfiramDrug abuseNaltrexoneNicotineOpioids

Addictive Disorders and Their TreatmentTreatment for Nicotine Dependence (Smoking)

Nicotine ReplacementOthe r Medications for Smoking C essation

Treatments for Opioid DependenceOpioid Detoxification: ClonidineOpioid Maintenance

Treatments for Alcohol DependenceDisulfiramNaltrexone

SummaryBibliography

and nicotine depende nce, afflict over 30 of Amer-

rugs, preoccupation w ith alcohol and d rugs, and u seOne way to reduce the impact of addictive disorders is

medical, psychological, and social inte rven tionsreduce or elimin ate th e harm ful effects of sub stanc es onher family and asso ciates, and others

removal of the drug from the body and the treatment ofphysiological withdraw al signs and symptom s tha t m ay oc-cur with drug discontinuation. R ehabilitation provides thepatient with strategies and techniques to avoid psychoac-tive substan ces, to develop better metho ds of coping withstress and distress, and to improve self-esteem and self-efficacy.Medications are frequently used as a component of bothdetoxification treatment and rehabilitation treatment,along with psychosocial thera pies, such as counseling andself-help groups (e.g., Alcoholics Anonymous). Pharma-cotherapies can treat alcohol and drug dependencethrough several mechanisms that may reduce some of theimpetus for drug use. These mechanisms and the medica-tions that may operate through these mechanisms are de-picted in Table 1.Controlled drug delivery systems are particularly ap-plicable to the treatment of addictive disorders. Severaladvantages of controlled drug delivery systems are as fol-lows:

They mimic the pharmac okinetics of the abuseddrug, including the rise and fall of plasma drug con-centrat ions. They facilitate the attain m ent of constan t plasm aconcentrations of drug to preven t intoxication symp-toms caused by high plasma concentrations and toprevent the development of withdrawal caused bylow plasma drug concentrations. They improve therapeu tic medication bioavailability They improve therape utic medication compliance indrug and alcohol treatment.

For a medication used as a substitution treatment, a con-trolled delivery system can be used to mimic the phar ma -cokinetics of the abused drug, without the dangers as-Table 1. M edications Used for Add iction TreatmentMedication property Examp leSubsti tution treatme nt with a Methadone maintenancecross-tolerant medication trea tm ent for opioiddependence; transderm alnicotine or nicotine gum forsmoking cessationAdm inistration of agents to Transd ermal clonidine inblock the signs and opioid detoxification andsymptoms of withdrawal withdrawalAd min istratio n of a Depot naltrex one for opioidmedication to block drug dependenceintoxicationAversive thera py Depot disulfiram trea tme nt inalcoholismAdm inistration of a Depot naltrexone in alcoholmedication to suppres s dependencecraving

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ine withd rawa l, withou t the inhere nt dan gerssmoking . Two of the se n icotine delivery m ethod s can ac-e rise and fall of pla sm a nicotine levels th ats with smoking. Patie nts w ith addictive disorders arely noncom pliant with medications and may eith er

EATMENT FOR NICOTINE DEPENDENCE SMOKING)atm ent of nicotine dependence provides several ex-of the therap eutic use of controlled medication de-

Nicotiana ta-yused for centuries by Native Americans in rituals

U.S. are daily use rs of cigarettes (one-thirdadu lts), and 10 million use ano the r form of tobacco (5).er of Am ericans who smoke has

The medical consequences of nicotine use are common

To maximize the absorption of nicotine, tobacco prod-e usually smoked in pipes, cigars, or cigarettes, or

-life of 30 to 60 m inu tes.Nicotine ha s several effects on the pe riph eral a utonom icnergic receptors in parasy mp athetic an d sy mpa thetic

petite suppression. The factally attrac tive to young w omen.Repeated use of nicotine produces tolerance and depen-

of dependent individuals relapse within one year of

viduals is followed by a withdrawal syndrome character-ized by increased irritability, decreased attention and con-centration, an intense craving for and preoccupation withnicotine, anxiety, and depression (6,7). Withdrawal symp-toms begin within several hours of cessation of use or re-duction in dosage, and typically last about a week. In-creased app etite with weight gain occurs in the weeks andmonths following cessation of chronic nicotine use.The tre atm en t of nicotine dependence consists of reduc-ing or stopping use of tobacco use and minimizing nicotinewithdrawal symptoms. Brief education and advice onsmoking cessation provided by physicians has been shownto be effective in helping patients stop smoking, and it isnow recommended that all physicians provide their pa-tients with smoking cessation tools (8,9). The most suc-cessful tre atm en t pro gram s use cognitive-behavioral tech-niques to educate patients about the health hazards oftobacco and provide the patient with behavioral methodsof coping with urg es. Such p rogram s can achieve 25-45abstinence rates at 6 to 12 months. Although some pro-grams use gradual reduction in tobacco use over days toweeks (nicotine fading) for detoxification, others suggestabru pt d iscontinuation (cold turkey).

Nicotine ReplacementPharmacologic therapy with nicotine replacement is in-creasingly popular in the treatment of nicotine depen-dence. The principle of nicotine replacem ent thera py is toprovide the nicotine-dependent patient with nicotine in aform not associated w ith the carcinogenic and ir rita nt ele-me nts in tobacco products. The substitution of tobacco withalternativ e nicotine delivery systems allows the p atien t toaddress behavioral aspects of the habit without having toexperience nicotine withdrawal. At a later time, plasmanicotine levels can be reduced a nd e ventually discontinuedin a slow and controlled fashion. Several systems of con-trolled nicotine delivery have been developed and intro-duced into clinical practice.

Transdermal Nicotine. Thin film impr egn ated w ith vari-ous doses of nicotine (7 mg, 14 mg, and 21 mg) are madeinto adhesive patches for transde rm al adm inistration. Nic-otine patches deliver a predictable a mo unt of nicotine an dachieve steady-state plasma nicotine levels in the rangesachieved by smoking 10 to 30 cigarettes per day. The la-beled dose refers to the am ou nt of nicotine delivered ra th erthan the amount of nicotine present in the patch. Trans-derma l nicotine is well absorbed, but th e peak plasm a con-centrations are delayed by up to 10 hours after patch ap-plication.Placebo-controlled clinical trials with transdermal nic-otine show efficacy in smoking cessation treatment. Nico-tine replacement therapy with transdermal nicotine sig-nificantly reduces nicotine withdrawal symptoms andincreases the likelihood of successful smoking cessation(10,11). A recent m eta-a naly sis of 17 studies involving over5 000patients indicated that transdermal nicotine patcheproduced quit rates of27.1 at end of trea tm en t and 21.8at 6 m onth follow-up, com pared to 13.1 and 8.4 for pla-cebo grou ps, respectively.


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Transdermal nicotine is used as follows. After stopping

tient is asleep. Typical trans der-r 2 to 4 weeks, an interm ediate dose patch

Nicotine Gum. This gum is a sweet, flavored polacrilexowly wh en the resin is chewed. Up to 90 of the nico tine

unt of release and th e rate of release depend s upon theand duration of chewing. Nicotine is absorbed acrosse to peak concentration of 15min utes after s tart of chewing. The gum is m arkete dorette and has recently been made available as a n

Patients must be instructed in the proper use of thes chewed slowly and in term ittently whenev erouth or tongu e is perceived, chewing should cease for

use a a nd o ther side effects of nicotine toxicity. The gu mt with n icotine blood levels tha t rise an d fall, mim icking

ation (13). Recent studies suggest th at the 4

symp toms of nicotine toxicity and occlusive in-Most patients achieve stable gum u se within a few days

planned after th e daily ma intenan ce dose is established.

the end of the second month. Pa tien ts are typ-f t reatm ent.

Nicotine Nasal Spray. Nico tine ha s recent ly becomee in a solution for intra nas al adm inistration, to bes source of nicotine replacemen t during smoking ces-ent. The medication is administered in a con-juL of metered spray

daily dose of 40 mg. When nicotine is adm inistered intra-nasally, the time to peak plasma concentration is 4 to 15minutes. The bioavailability of nicotine nasal spray solu-tion is approxima tely 53 , although peak plasm a concen-trations achieved vary considerably due to individual dif-ferences in absorption an d varia tions in usage. Rhinitis orother nasal abnormalities may reduce absorption, reducepeak plasma nicotine concentrations, and increase thetime to peak plasma concentrations. Side effects of thespray include irritation of the nasal and pharyngeal cavi-t ies,in a ddition to the physiological side effects of nicotineIt is recommended that tapering of nasal nicotine dosesbegin after 2-4 weeks and that use not exceed 8 weeks tominimize t he chances of developing dependence on the nic-otine spray.

Nicotine Inhaler. Nicotine replac em ent usi ng a nicotineinhale r (sometimes called a sm okeless cigarette) to delivernicotine orally by inhalation through a plastic tube hasrecen tly become availab le and is mar ke ted a s the NicotrolInhaler. An active, disposable nicotine cartridge consistingof a porous plug impregnated with 10 mg of nicotine isplaced in the plastic tube, and the patient inhales througha p lastic mouthpiece a s if smoking a cig arette. The devicedelivers a dose of 13 jugnicotine per puff for up to 400puffs.The delivered nicotine is prima rily absorbed throu gthe buccal mucosa. This method most mimics smoking, asit involves bringing the device to the mouth and inhalingto obtain nicotine dosing. In a study of 247 smokers whohad previously failed other nicotine replacement therapycontinuous abstinence rates were 28 with the activedrug, compared to 18 with the placebo inha ler (15). Com-mon side effects include dyspepsia, transient coughing,and mouth irr i tat ion.Other Medications for Smoking Cessation

Clonidine: Oral and Patch. Clonidine ha s been found tobe effective in the tr eat m en t of smoking cessation and theamelioration of nicotine withdrawal symptoms, reducingcigarette craving and other symptoms of nicotine with-drawal in dependent cigarette smokers who stopped coldturke y (16). Several other inv estigators h ave confirmed theefficacy of clonidine in reducing nicotine withdrawal andimproving quitting r ate s. However, in other studies on thetreatment of nicotine withdrawal, the effects of clonidinehave been more equivocal.A transderm al clonidine therapeutic system, marketedas Catapres-TTS, was developed for the treatment of hy-pertension and is approved by the U.S. FDA for that in-dication. The medication is incorporated into a transder-ma l delivery device designed to adh ere to the skin (a patch )and to provide stable thera peu tic levels of drug for periodof one week. A microporous me mb rane controls the r ate ofclonidine delivery to the skin surface, whereup on the drugdiffuses into th e sk in. The dose received is propo rtional tothe patch surface area. Bioavailability and efficacy studiesdemonstrate comparability to oral clonidine preparations(17). However, due to cutaneous compartmental pharmacokinetics, there is a delay of 48 to 72 hours before thetherap eutic blood levels are achieved and a similar persis-


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ter th e pa tch is removed. A largelticenter clinical trial used tran sde rm al clonidine com-The clonidine doses used in th is stu dy w ere 0.1 to 0.2day. Although the re w as some decrease in nicotinewal symptoms with clonidine, there w as no signifi-

Side effects of clonidine include hypotension and seda-

As with othe r forms of tre atm en t for nicotineery program .

ems in the U.S., with a n estim ated opioid ad-population of greate r th an 500,000. These pa tients areultiple medical sequelae of intraven ous drug use, in-ons (especially hu m an immunodifficiency vi-

Opiate drugs affect organ systems due to stimulation of

oid receptors, which are designated by the Greek le tters, /c, and 3 (20). Drugs that act primarily throughju-ffects include heroin, morph ine, and meth adone;

ars to bind endogenous opioid p eptides.The treatment of opioid dependence includes detoxifi-

the opioid-dependent patien t.Detoxification: Clonidine

activity, intestina l hyperactivity, hyp ersensitivity

withd rawa l is 1-3 days and du rationays. For longer-acting opiates, such as methado ne,Clonidine hydrochloride is an imidazoline derivative

a- 2 adrenergic re-

ceptors and blocks the release of central and peripheralnorepinephrine. Noradrenergic neurons in the locus ceru-leus of the brain show increased neuronal activity duringopiate withdrawal and this effect can be blocked by a-2adrenergic agonists such as clonidine (21). On the basis ofthis observation, clonidine was tested clinically as ablocker of opioid withdrawal signs and symptoms (22,23).Subsequent double-blind clinical trials confirmed that clo-nidine was more effective than placebo and slightly lesseffective then a slow methadone taper in reducing signsand sym ptoms of opiate withdraw al in both inpatien ts andou tpa tien ts. Clonidine was found to be effective in pa tien tswithdra wing from either short-acting opioids, such as her-oin, or long-acting opioids, such as methadone. However,clonidine was never formally approved by the FDA for thetreatment of withdrawal in opioid-dependent patients.Although most studies have been performed using oralclonidine, clonidine is available as a transdermal deliverysystem (described earlier), and this m odality has been usedsuccessfully to trea t opioid with draw al (24). Ad vanta ges ofthe clonidine transdermal system include attainment ofmore constant plasma levels of clonidine (i.e., the avoid-ance of peaks and troughs) and the psychological benefitof an ad dicted p atie nt n ot taki ng pills to relieve discomfort.A disadvantage of transdermal clonidine is a lag time ofup to 72 hours for medication effect after applying thepatch to the skin. Because of the lag time application ofthe clonidine tran sde rm al patch and the atta inm ent of newsteady-state blood levels, supplementation of the patchwith the more rapidly absorbed oral clonidine may be re-quired to treat emergent withdrawal symptoms. Likewise,hypotension from overmedication with transdermal cloni-dine will tak e seve ral hour s to resolve after dose redu ction.

When used clinically to treat opioid withdrawal, cloni-dine suppresse s approximately 75 of opioid withdrawa lsigns and symptoms, especially autonomic hyperactivity(tremor, piloerection, tachycardia), anxiety, and gastro-intestinal symptoms (cramps and diarrhea). Clonidine isadministered in increasing doses such that opioid with-drawal signs and symptoms are decreased but blood pres-sure is m aintaine d. A typical schedule for transd erm al clo-nidine uses 0.1 mg on day 1 following discontinuation ofopiates, 0.2 mg on day 2, 0.3 mg on day 3, and 0.4 mg onday 4. This maximal dose is continued for 5-7 additionaldays for short-acting opioids and 10-14 additional days forlong-acting opioids.Opioid withdrawal symptoms not significantly amelio-rated by clonidine include drug craving, insom nia, and ar-thralgias and myalgias. Insomnia is best treated with ashort-acting hypnotic such as chloral hydrate, and painmay respond to nonnarcotic analgesics such as a nonste-roidal antiinflammatory medication or acetaminophen.Side effects of clonidine include dry mouth, sedation, andorthostatic hypotension. Clonidine should be used cau-tiously in hypotensive p atien ts an d in those receiving otherantihypertensive, an tidepressants, s t imulants, or antipsy-chotics.Opioid MaintenanceThe most widely used pharmacological treatments foropioid-dependent individuals include pharmacological


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erap y w ith naltrexone. AU of these medications

e, thereb y de creasing t he subjective effects of illicitlyinistered opiates, and by stabilizing mood, thereby de-

Methadone Maintenance. Me thado ne is a synthe tic opi-wh ich is orally active, possesses a long dura tion of ac-oduces minim al sedation or high, and ha s few side

Since its introduction in 1965, methadone mainte-s become a major mod ality of long-term trea tm ent

Although orally administered, an elaborate medicationistration of this m edication. Me thadone is dissolved in

one, which patien ts may self-administer. However,f illicit drug us e. Doses of m ethad one usu ally r ang e

e generally associated with better retentionMany studies have shown the efficacy of methadone

, decreased criminal activity, increased em- Methadone is most effective in the context of a pro-

es, and adequ ate m ethadon e dosing. The use of metha-cellent recent review of

L-a-Acetylmethodol Acetate (LAAM). A long-acting,

LAAM are similar to methadone. Studies on LAAM haveshown it to be equal or superior to me thadon e ma intenan cein reducing IV drug use, when used in the context of astructured maintenance treatment program (28). The ad-vantages of LAAM include a slower onset of effects and alonger duration of action than methadone. This allowsLAAM to be adm inistered only 3 times per w eek, reducingthe cost of prepa ration and monitoring of medication an dreducing the use of take-home medications that may bediverted to illicit use. Patien ts tr eated with LAAM shouldbe started on 20 mg adm inistered 3 time s weekly, with th edose increased weekly in 10 mg increments as necessary.Doses up to 80 mg 3 tim es weekly ar e safe an d effective.

Sublingual Buprenorphine. Bu pren orph ine is a par tia lagonist opiate medication (mixed agonist-antagonist),originally used medically as an analgesic. It has highaffinity for the fi opioid receptor and the K receptor. Buprenorphine possesses both agonist and antagonistpropertiesagonist prope rties predom inate at lower dosesand antagonist properties predominate at higher doses.Cessation in buprenorphine in dependent individuals re-sults in a withdrawal syndrome that is much milder thanthat observed with pure opioid agonists. These propertiesof the d rug suggested its use as a mainten ance medicationin the treatment of chronic opioid dependence. However,oral buprenorphine has poor bioavailability and only par-enteral preparations of the medication are used.Sublingual (SL) administration is an effective way ofadm inistering m edication tha t m ay not be orally active. SLadm inistration of bupren orphine resu lts in effective med-ication plasm a levels and was therefore tested in the trea t-ment of opioid dependence. In the setting of a structuredtrea tm en t program , daily dosing of SL bupreno rphine w asfound to effective in the m ainten ance trea tm en t of narcot-ics addicts, reducing illicit drug use (29-31). Buprenor-phine may also reduce concomitant cocaine use in opiateaddicts (32).Buprenorphine doses usually range from 4 mg per dayto up to 16 mg per day, administered sublingually. Advan-tages of buprenorphine include a milder withdrawal syn-drome upon discontinuation and less potential for abuse,as agonist effects diminish at higher doses. Opioid-dependent patients may be started on 2 to 4 mg bupren-orphine immediately after opiates are discontinued, andthe dose of bupren orphine titrate d to 8 to 16 mg over sev-eral days (33).

Naltrexone. Opioid antag onist thera py reduces the useof illicit drugs by blocking the effect of the drugs at neu-rotra nsm itter receptors, leading to decreased use. There issome evidence that opiate antagonists may block cravingfor opiates as well. Naltrexone (Trexan) is a long-acting,orally active opioid antagonist, which when taken regu-larly, entirely blocks uopioid receptors and thus blocks theupho ric, analgesic, an d se dative p rope rties of opioids (34).Oral naltrexone is administered either daily to detoxifiedopioid user s a t a dose of 50 mg, or 3 time s weekly at dosesof 100 mg, 100 mg, and 150 mg. Although naltrexone isquite effective when taken as prescribed, most studieshave demonstrated poor medication compliance among


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Because of the low compliance with oral naltrex one for-

nce. Two parente ral depot formulations of naltrex-

nd to resu lt in plasm a naltrexo ne levels tha t would ef-ively block exogenous opioids and th at are s table for atal organic solvent used

ng continued testing.

accum ulates in the body, produc-flushing, diapho resis, dyspnea, nau-

iram m ust be able to unders tand its benefits an d risks.

As increased disulfiram compliance improves tre atm en ts, there has b een intere st in t he development of long-

ical trials w ith recently abstin ent h um an alcoholics,cts treated w ith the opioid antagon ist naltrexone ha d

ceiving naltrexone also report decreased craving and de-creased high from alcohol. Naltrexone is thought to act byblocking the alcohol-induced re leas e of dopam ine in the nu-cleus accumbens and other brain areas that control thereinforcing properties of drugs and alcohol.One factor that appears important for the efficacy ofnaltrexone is medication compliance. Two placebo-controlled clinical trials with oral naltrexone demon-strated significant efficacy in reducing drinking only insubjects th at showed high compliance with medication in-gestion (44,45). Thu s, there is intere st in the developmentof alternative drug delivery systems for naltrexone thatwill enhance compliance and optimize medication effectsto improve treatment.A recent report comparing oral naltrexone with inject-able sustained-relea se n altrexone microspheres (35) in 20pa tien ts found com parable effects of th e two different prep -ara tion s in reduc ing alcohol consu mp tion (46). Side effectsof the oral and sustained-release preparations were alsosimilar. More research needs to be conducted on thesustained-relea se forms of naltrexon e; however, the initialresults are encouraging.SUMMARYControlled d rug delivery system s have been applied to thetrea tm en t of several addictive disorders, including nicotinedependence, opioid dependence, and alcohol dependence.In the case of nicotine dependence, several commercialproducts a re ava ilable, giving clinicians and pa tients con-siderable flexibility in drug dosing. Controlled drug deliv-ery systems are currently being studied in the mainte-nance tre atm ent of alcoholism and opioid dependence.BIBLIOGRAPHY

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alcoholism and drug dependence, drug delivery to treat

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