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11

The InternationalJournal of the Addictions, 11(1),95-115,1976

to Diazepam Addiction
M.D. BarryM. Maletzky,
Woadland Park Mental Health Centel Poftland. Aregon

JamesKlotter, M.D.
SanBernadino County Hospital San Bernadino, California

Abstract Literature is reviewed which raises the question of diazepam's addicting potential. To explore this issue, 50 subjects referred irom medical,surgical,and psychiatricclinicswere evaluatedby interview regarding their use of diazepam.Repliesto a standardized interview were combined with physicians'ratings of addiction under two conditions:without and then with the knowledge that the drug in questionwas diazepam. A computer-aided analysisof thesedata, including a correlation matrix, revealed surprisingly strong evidence for diazepam's capacity to elicit tolerance and withdrawal in this sample. Ps-vchiatric patients were no more "addiction-prone" in this regard than patients given diazepam for medical conditions. Of equal significance, physicians' impressions of addiction were significantly altered toward a more favorable view when they learnedthat the drug in question was diazepam.Implications for 95 c-opyright A :-976 by Marcel Dekker, Reserved. thiswork nor Inc. All Rights Neither maybereproduced electronic or rransmitred in anyformor by anymeans, or T^tlttl mech-anical, inch.rding photocopying, microfilming, or by any informaandrecording, "uu )torage andretrieval system, withoutpermission in writingfrontthepublisher.

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MALETZKYAND KLOTTER psychiatric and medical practice are discussed,and suggestions for further controlled researchoffered.

A cursory reading of the available literature would lead one to a sanguineview of diazepamaddiction. Indeed, the "Warnings" section of the Valium package insert admitting to the occurrence of withdrawal symptomsleads one to believethat addiction can only occur should the usual doses be exceededor the user be an alcoholic, drug addict, or "addiction-prone," a state further undef,ned. In a fashion similar to chlordiazepoxide, diazepam has engendereda host of articles attesting to its freedom from addicting properties. A careful scrutiny, however,raisesseriousquestionsabout such optimistic conclusions. Of 27 artic,les (Constant and Gruver, 1963; Grayson, 1962; Katz, Aldes, and Rector, 1962;Kelley, 1962;Cromwell, 1963;Levy,1963; Burdine, 1964; Dorfran, 1964; Fowlkes, Strickland, and Peirson, 1964; Bowes, 1965; Burnett and Holman, 1965; Vilkin and Lomas, 1962; Randall et al., 1961; Susses, Linton, and Herlihy, 1961 ; Chesrowet al., 1962; Feldman, 1962; Kelley, 1962; Kerry and Jenner, 1962; Merliss, Turner, and Krumholz, 1962; Pignataro, 1962; Proctor, 1952; Cromwell, 1963; Dorfman, 1963; Love, 1963; McGovern et al., 1963: Rathbone, 1963;Ryan, 1963)reviewedin which diazepamwas claimed to be free of addicting properties,none conductedsufficientcontrols to merit dismissing this question. Most such reports claimed, usually as an after-thought, "no evidenceof addiction was observed" (Constant and Gruver, 1963). In fact, no trials of withdrawal with systematic observations were attempted (Constant and Gruver, 1963; Grayson, 7962; Katz, Aldes, and Rector, 1962; Kelley, 1962;Cromwell, 1963; Levy,1963; Burdine,7964; Dorfran, 1964; Fowlkes, Strickland, and Peirson, 1964; Bowes , 1965; Burnett and Holman, 1965) and no data regarding tolerance collected (Vilkan and Lomas, 1962; Randall et al., 1961 ; Susses,Linton, and Herlihy, l96l; Chesrowet al., 1962;Feldman, 1962;Kelley, 1962:Ke:ry and Jenner, 1962; Merliss, Turner, and Krumholz, 1962;Pignataro, 1962; Proctor, 7962; Cromwell, 1963; Dorfman, 1963; Love, 1963; McGovern eta|.,1963;Rathbone,1963;Ryan, 1963). Table I presents salientfeatures of thesestudies in chartlike form. The overacceptance of diazepam's safety in this regard hrrs been surprising in the light of evidence that other minor tranquilizers can be addicting (Haizlip and Ewing, 1958; Phillips, Judy, and Judy, 1957; Anonymous, 1959; Arneson, 1961; Hollister, Motzenbacker, and Degan,

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MALETZKY AND KLOTTER and suggestions ical practice are discussed, J researchoffered. i the available literature would lead one t0 a m addiction. Indeed,the "Warnings" section of :rt admitting to the occurrence of withdrawal rclievethat addiction can only occur shouldthe I or the user be an alcoholic, drug addict,or -e further undefined. o chlordiazepoxide, diazepam has engendered a ; to its freedom from addicting properties.6 i, raisesseriousquestionsabout such optimistrc es (Constant and Gruver, 1963; Grayson,1962: 1962;Kelley, 1962;Cromwell, 1963;Levy, 1963r 1964; Fowlkes, Strickland, and Peirson,19641 tnd Holman, 1965; Vilkin and Lomas, 1962; ;ses,Linton, and Herlihy, 1961 ; Chesrowet al., ielley, 1962; Kerry and Jenner, 1962; Merliss, t962 ; P ignataro, 1962 ; Proctor, I 962; Cromwell, -ove, 1963; McGovern et al., 1963; Rathbone, ved in which diazepam was claimed to be freeof controls to merit dismissrng ? conducted sufficient_ h reports claimed, usually as an after-thought, )n was observed" (Constant and Gruver, 1963). thdrawal with systematic observations were atGruver, 1963; Grayson, 7962; Katz, Aldes,and 6 2 ; C r o m w e l l ,1 9 6 3 ;L e v y , 1 9 6 3 ;B u r d i n e ,1 9 6 4 ; Bowes, 1965; ;. Strickland. and Peirson, 19641, collected tolerance 965) and no data regarding and Linton, Susses, 62; Randall et al., 7967; Kerrv 1962; Kelley, 1962; et al., 1962;Feldman, s, Turner, and Krumholz, 1962; Pignataro,1962; I , 1 9 6 3 ;D o r f m a n , 1 9 6 3 ;L o v e , 1 9 6 3 ;M c G o v e r n features salient Table 1 presents )63; Ryan, 1963). ike form. cf diazepam's safety in this regard has beensur;vidence that other minor tranquilizers can be Ewing, 1958; Phillips, Judy, and Judy, 1957; and Degan' :son, 1961; Hollister, Motzenbacker,

TO DIAZEPAM ADDICTION

9'l

E s s i g ,I 9 6 4 ; M a c K i n n o n , 1 9 6 7 ;F i n d l e y ,R o b i n s o n , r96l;Domino,1962: 1972)' .indPeregrino, may be falsely basedupon a narrow concept of addicSuchacceptance withdrawal symptoms mimic those of heroin or alcohol, a rion:unless yet one of the most severewithdrawals,the ,rrn.unnot be addicting; amphetamine abuse (Bartholomew, 1970), following lonr-ssedstate possible withdrawal symptoms.An analogous of situato a variety ",,'.r,, a cardinal symptom withdrawal of from this for meprobamate: exists Jion and Ewing, 1958; Phillips et al., 1957; (Haizlip Anonymous, is anxiety drug 959), 1 might also have been prematurely considered safe in this Diazepam resardon the basis of optimistic earlier reports regarding its close conScrutiny of such reports is of interest. Lawrence chlordiazepoxide. sener, stated "no withdrawal symptoms to chlordiazehas itlOO;,iot example, although all patients noted a recurrenceof their observed, poride were or tension, craving for alcohol, etc, when . . . originalsynlptoms-anxiety (emphasis hours" ,,tirhonmedication 24-48 added). Moore (1962) for "patients gynecologic asked that they be put back on that discovered it had been after discontinued . . . but this was due to chlordiazepoxide stresses rather physiologic than to any renewed demand for or conrinued informed the are riot authors made We how this distinctron. rhe<lrug." is producedby Williams' (1961)statementthat "there confusion Further to be no addiction to chiordiazepoxide,though there is a tendency ilppears dependence upon it. Between24-36 hours after withdrawal of ro develop thr'medicine, thereis recurrenceof symptoms." There would be no a priori rcason not to considerthis a sign of withdrawal instead. lndeed,severalreports have raised questions concerning addiction to diazepam. Cromwell (1963),even while reaffirming diazepam'sefficacyto tranquilize, notedthat the drug was extremely"well-accepted" asevidenced hv patients'regular requestfor a new supply. While Cromwell thought tiris "unusual," he failed to more fully evaluate such requests. Aivazian t 196.1) describes a patient who experienced seizures in abruptly discontinutng diazepam. Barten (1965) notes the occurrenceof a toxic psychosis duringwithdrawal,while Edgley (1970)points to the more common manil.statlons of tremor and agitation among severalpatientson abrupt discirrltinuance. Hollisteret al. (1963)also noticedwithdrawal,including one :cizure, in 6 of l3 patients whosedrug was abruptly discontinued; however, tnc\t' authors, as in a previousstudy of withdrawal from chlordiazepoxide rr(/hl),usedunusually high dosesand administeredthe drug to schizo-

Table I Absttacts of Articles Reviewed Concerning Use of Diazepam Author Kelley

Year No. Ss

Type Ss 46

Av Ageo

Usual dose 5-10mg

Duration of treatment

Criteria for addiction

1962

109 Private psychiatrist 3t Private medical

tid 1-48 weeks "No signs.. . of habir (av 14 weeks) uatron and addiction." No criteria l-2 weeks "No indication of . . . habituation." No criteria -too brief to determine None

Cromwell

1963

50

2-5 mg bid to qid

Pignataro
@

1962

67

"Chronic, refractory," psychiatrist

U. Modalage 30-39

5 mg bid to qid l-11 months (Maintenance) 2 mg tid 20-30 mg/day 2.5-15mslday U 4-34 weeks ll

Ryan Randall Grayson

1963 1961 1962

50 18 M

Headachepatients U Psychiatric patients Private dermatologist

None None "No indication of . . . habituation." No criteria "No signs of . . . habituation." No criteria. Study originated with investigator's concern
over addiction barbiturates mcprobamate with and

U. Range: 2t-70 40.1

Burnett and Holman

1965

216 Generalpractice: U 98 emotional 47 disorders, psychogenic disorders,7l organic with

emotional "complications"

8-20 mglday

4 daysto 15 months

_ l

l{at hb()ne

I9.1

55 Privatc interl)al n r e d i c i n ep a t i e n t s in "psYchological distress"

? . - 5r r r g t r i d t r r lO mg qid

li wccks

Ncccs\ilry tlos;rge stating

t() ttlfrca!\c rcinwhcn drug. No

KerrY and Jenner

1962

75

Clinical psychiatrist, patients complaining of anxiety Chronic psychiatric inpatients Muscular-skeletal disorders

5l

l0 mg tid

2 weeks

criteria; no rnention of habit or addiction No criteria

Feldman Katz, Aldes, and Rector Merliss,Turner, and Krumholz Proctor Dorfran

1962 1962

t42 84

36

94 days Av of 4 weeks

No criteria "No indication of . . . habituation." No criteria No criteria

U. Range2G-27 2.540 mglday

1962 1962 1964

80
5l

U. Modal 3G-40 10 mg tid Chronic state hospital Patients

Private psychiatrist Private psychiatrist;most with "dePression"

6 weeks

U. Range25-58 5-10 mg tid to qid U 5 mg tid

Av of 11 weeks No criteria 1 weekto 2 years instances of "No . most addiction reduced their dosage.. . ." No criteria "Many patients reported the drug was 'wonderful' and assought rePeated surance that more would be available." No criteria
(continued)

t37

Love

t963

74

46 Neurosis; 28 somatic disorders

Range22-83

1-10 mg bid to tid

2 daysto 3* months

Table I Author Dorfman Linton, Susses, and Herlihy Year 1963

No. ^Ss

(continued) Duration of treatmenr U 2 weeksto 6 months Criteria for addiction No criterta No criteria

Type Ss U

Av Age"

Usual dose 5mgtid 15-30 mg/day

Bowes

Privatepsychiatrist IJ Medicalschool 1961 psychiatric clinic.Complaintsof anxiety-tension 1,965 > 500 Private psychiatrist

U. Range2246

5 mg tid and l0 mg hs

Vilkin and Lomas

1962

B3 Privatepsychiatrist

U. Range lzt-78

5 mg tid

6 months

Constant and Gruver

1963

183 Generalpsychiatrist

U. Range lzl-78

6-30 mg/day

2 days to 1l months

Mccovern

et al

1963

423

Private allergy patients

U. Range 1-75

Varied with age; modal

5 rng tid

I week to 7 months (2OO

-' 4 weeks)

of 500 "overly All dependent." "addictive personGradual alities." was withdrawal neededusing chlordiazepoxide in hospital No examples of patients able to stop diazepam. No criteria "No evidence of . . . addiction or extreme dependence was observed."No criteria No criteria

196:l

l5l

lvlcdrc:rl schot>l dcrmatol()gy clinic: "Enrotronal disturbanceswere,.. major factors" causative or aggravating

2.5-10 rng;day

2,17 wccks, av 6 wecks

No signs of habituation, addiction, or "psychological dependency" on discontinuance. No

criteria 44

Fowlkes, Strickland, and Peirson

1964

JJ

Hospitalized patients with major neuromusculardisordersand spasticity General psychiatric patients (77 hospitals)

-5mg tid

2 years

"No evidenceof tolerance." No criteria

Burdine

1964

r08

39

10-80 mg/day

3 days to 7 months

Chesrowet al. Kelley Cromwell " U : Unspecified.

Hospital psychiatric patients 1962 > 100 Private psychiatrist 1963 50 Private medical

1962

58

72 U U

2 mg tid 5-10 mg tid 5 mg tid

4-6 months U U

"No signs of habituation or drug abuse in those taking diazepam as needed.,' No criteria No criteria No criteria No criteria

r02

MALETZKYAND KLOTTER

phrenics, not usually treated with "minor" tranquilizers. Clare (1971) describesa woman with evidenceof withdrawal from diazepam, but her casewas intertwined with barbituate and alcohol abuse as well. Even as strong a proponent of "minor" tranquilizer useas Bowes(1965)discovered five casesof diazepam addiction among his patients. In the light of apparentconfusion in the literature regarding the addicting propertiesof diazepam,and in the light of its wide distribution, we have made an attempt to answer the following questions: 1. Are patients able to adhere to prescribeddosesof diazepam? 2. Are patients able to discontinue diazepam? 3. What symptoms occur upon abrupt discontinuance? 4. Can we predict which patients might develop tolerance or withdrawal if such conditions indeed exist?

METHODS
Subjects Our subjects were collected from the records of a neuropsychiatry clinic on a military installation in the SoutheasternUnited States.The study was conducted from August to December 1972.Subjectswere also referred from physicians in medical, surgical, and general outpatient clinics. Such referrals were solicited by requesting information from physicians on any patients currently taking diazepam. We were thus able to uncover a wide range of patients taking this drug. The first 50 such referrals constituted our sample; no exclusionswere made. This sample included 3l female and 19 male subjectswith an average age of 34.3 years (19-63). While just 12had a history of psychiatric difficulties (including 9 referred from the Neuropsychiatry Clinic), 29 were given the drug for psychiatric reasons,usually anxiety secondaryto an organic illness.The 12 subjectswith a psychiatric history included 6 diag" nosed neurotic, 5 personality disorders, and I schizophrenic.The large number of femalesin such a sampleis of interest: recentreports indicatea higher incidenceof women using "minor" tranquilizers (Mellinger, Balter, and Manheimer, l97l; Parry et al., 1973). Structured Interview Each subjectunderwenta structuredinterview, as presentedinTable 2. The interview, devisedby the authors, was ciesigned to investigatesubject

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MALETZKY AND KLOTTER

variables,use-of-drugdata, and effectsupon discontinuing the drug. It was conducted by social work and psychology technicians within the clinic setting. All interviewerswere instructed in the operational definitions of terms, for example, agitation as the presenceof an unpleasantincreasein motor activity. Although other information and conversation were pereachinterviewerattempted to elicit the basic missibleand evenencouraged, so much of the data collectedin in Table l. Because information presented this manner was both subjective and retrospective,each interviewer attempted to corroborate these data by asking similar questions of at least one other person familiar with the subject, usually a spouse'Interviewers of the in locating and interviewing such personsfor 92o/o were successful subjects. Physicians'Analysis Following completion of interviews, each form was reviewed by a group of four generalpractitioners,five generalsurgeons,three internists, and two orthopedic surgeons.Each was asked, "Do you believe this subject is addicted to the substance in question?" Each answeredon a scaleof (very (not much) in a fashion similar to the last question 0 at all) to 4+ the structured interview (Table 2). No physician asked of each subject on of nature the drug in question. However, after answerwas informed of the physician was informed of diazepam's question each blindly, ing this the to rate degreeof addiction. again asked identity and

Assessment
Frequency and AmplitudeData analysisof all data was undertaken to yield freA computer-assisted quenciesand amplitudes for this population for each variable, including completepopulation distribution statistics.Data were combined into three useof diazepam(variables6-9, seeTable 2), addicting potential categories: (variables16 and l7). Reliability (variables l0-15), and physicians'ratings coefficients were determined for variables l4 (interviewer's withdrawal severity ratings) by assigningtwo other interviewers for each of 20 ransubjects,and for variables 16 and 17 (physicians'addiction domly-selected rating) by assigningtwo other physiciansfor each of 20 randomly-selected exceeded 90o/o. subjects.In each case,reliability coefficients

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ADDICTIONTO DIAZEPAM C o r r e l a t i oM n atrix

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A correlation matrix for all variableswas generatedby computer in an effort to determine if individual variablescould predict future difficulties rvith diazepam.

RESULTS
F r e q u e n ca yn d A m p l i t u d e Data Percentage data are presentedin Tables 3-6. Complete data, including population distributions, are availablefrom the author, but because of the large number of variablesinvolved, in the main only means and standard deviations(SD's) will be discussed. U s eo f D i a z e p a m Table 3 presentsthe data for variables 6-9. As can be seen, subjects took an average of 15.9mg (SD 9.3) of diazepam daily, a doseconsidered routine. Only l4 of the 50 subjects took 20 mg or more of this drug daily. They had been taking this amount an averageof 25.9months (SD 20.l), with only l0 subjectstaking diazepamfor lessthan a year and l5 taking it 3 years or more. Over half (26) the subjectswere using other minor tranquilizers, chiefly chlordiazopoxide and meprobamate.On a 0 ("no help") to 4 + ("very much") scaleof assessing how helpful diazepamhad been in alleviating symptoms for which it was prescribed, 3 subjects rated it 0, 1 6 1 + ( " v e r y l i t t l e " ) , i 6 2 + ( " m o d e r a t e " ) ,1 3 3 f ( " m u c h " ) a t d , 2 4 + ("extreme"), yielding an overall mean rating of 1.9 (SD .99).

Table3 Subjects' Use of Diazepam Mean Variable6. Amount taken,mg 15.98 Variable 7. Durationtakingdrug, 25.98 months Variable8. Other tranquilizers Variable9. Help from irug 1.90 Range 5-50 1-96 Standard deviation 9.31 20.15 Standarderror of mean

1.32 2.85

(26 yes,24 no)

0++

0.99

0.14

MALETZKY AND KLOTTER AddictionPotential

Tables 4a and 4b presentthe data for variables 10-15. Among all subjects, 30 (60%) did not decrease diazepamon their own. Of the 20 subject5 who did, many recalled a recurrenceof symptoms, chiefly anxiety and insomnia, and quickly increasedtheir dose. Half of thesesubjectsincreasec diazepam without asking their physicians, usually secondaryto inability to cope with some external stress.Once increased,they found it diftcult to taper: of the 25 subjects involved, only 10 subsequentlydecreased their dose to what was originally prescribed.Twenty-four subjectsattempted to stop diazepam abruptly at some point. Twenty-two resumed the drug, usually within I week, while only two subjects(8o/" of those stopping the drug and just 4o/oof the total sample) were able to stop diazepam and remain without the drug for a period greater than severalweeks. Interviewers,asked to judge withdrawal severityin these24 subjectsafter questioning each on the symptoms experiencedwithin i week of discontinuing diazepam,rated one subject as 0 ("none"), four as I + ("light"), nine as 2+ ("moderate"), eight as 3* ("great"), and two as 4+ ("severe"). Thus 79o/o of this sample experiencedwithdrawal symptoms of moderate to extreme severity. Such symptoms are presented in Table 5 with the
Table 4a Subjects' Abuse of Diazepam-Number of Subjects Yes Variable 10. Decreaseon own Variable 11. Increase on own Variable 12. Unsuccessfully stop (N :24 who attemptedto stop) Variable 13. Successfully stop (N: 24 who attempted to stop)

(%) (60) (50) (e2) (8)

No

(%)
(40) (50) (8) (e2)

30 25 22 2

20 25 2 22

Table 4b Subjects' Abuse of Diazepam-Number of Subjects None Little Variable 14. Withdrawalseveritv Variable 15. Dependencyself-rating

01+2+

4+
Moderate Great Severe

20

49 Mean : 2.33 t48 M e a n: 1 . 1 6

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ADDICTION TO DIAZEPAM Table 5 Major Symptoms upon Abrupt Discontinuance of Diazepam-Numbers of Subiects (N : 24)
Symptom

symptom Number experiencing

LJ

Percentage

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Anxiety Agitation Insomnia Tremor Diaphoresis Pain Depression Nightmares

18 14 10 7
o

95 75
)6 A1

29 25 t'l
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percentage of these24 subjectsexperiencingeach. It will be seenthat anare prominent and xiety, insomnia, tremor, diaphoresis,and restlessness in disconthe difficulties Despite withdrawal syndrome. a common form tinuing diazepam,arelative few of the total believedtheywere"dependent" on diazepam. Twenty subjects rated themselves0 ("none") when asked about their dependencyon the drug, 14 rated I + ("slight"), 8 rated 2* ("moderate"), 4 rated 3* ("great"), and 4 ruted 4* ("severe")' It is of interestthat among the l0 subjectsrated 3 + and 4+ by their interviewers equally distressedwhen for withdrawal severity, only 5 rated themselves undergoing abstinencefrom the drug. P h y s i c in as ' R a t i n g s Table 6 presentsthe data for variables 16 and l7' Without the knowledgethat diazepamwas the drug in question, the physicians'panel judged
Table 6 Physicians' Ratings of EstimatedAddiction-Number

of Subiects

None Slight Moderate Great Severe Variable16.Ratingswithout the knowledgeof which drug was involved Variable17. Ratingswith the knowledgethat the drug was diazepam 19 It
ll

1+

2+

3+

4+

36

108

MALETZKY

AND KLOTTER

1 9s u b j e c t s a s 0 ( " n o a d d i c t i o n " ) ,l l a s 1 + ( " s l i g h t " ) , 1 l a s 2 + ( " m o d e r a t e " ) , 6 a s 3 + ( " g r e a t " ) , a n d 3 a s 4 * ( " s e v e r e " ) ;t h u s 2 0 ( 4 0 " / "o f t h e sample)were feit to be moderately addicted. On the other hand, once the panel discoveredthe name of the drug, they rated 36 subjectsas 0, 9 as I +, just 10o/o and 5 as 2+ ; in other words, in theselatter circumstances of the moderately addicted and one as severely sample was adjudged addicted. Comparing the ratings done blindly and then with the knowledgeof which drug was involved yielded statistically significant differences(p < .OS, y2) at each level. Correlation Data Too large a number and variety of significanf@ <.05) correlations were discoveredto be commented upon fully here. A complete matrix is available upon request from the authors. The following are pertinent: The older the subject, the greater the amount of diazepam taken (r : .402). A psychiatrichistory was positivelycorrelatedwith physicians' ratings of addiction, both open and blind (r : .338, .298); conversely, a purely organic history wasnegativelycorrelatedwith theseratings (r : - .302, - .298). A history of purely organic problems was negatively correIatedwith subjects' (r : -.3a3). evaluations of their dependency The greater the amount of diazepamtaken, the lesshelp it was reportedto be (r : -.312). The greater the amount taken, the greater the withdrawal severity (r : .345). However, the greater age of subjectstaking higher doses was not significantly correlated with withdrawal severity. The longer the drug was taken, the greater the withdrawal (r: .350). The more diazepam helped the patient, the greater the probability in unsuccessfully stopping (r : .350). The more the drug helped,the greaterthe withdrawal severity (r : .354). The tendency to increasethe dose was positively correlated with the withdrawal severity(r : .469). The greater the withdrawal severity, the greater the physicians'

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ADDICTIONTO DIAZEPAM blind ratings (r : .582). On the other hand, once physicians learned the drug's identity, the withdrawal severity had no relationshipto the addictionratings(r : .114). Severalfindings were of interest for their lack of correlation. Thus the presence of a neuropsychiatrichistory was correlatedonly with physicians' estimatesof addiction, but not with any other criteria of dependencyor addiction employed. Similarly, sex of subjectswas neither positively nor negativelycorrelated with any other variable. Computer attempts to group variablesinto a factor analysiswere not successful,verifying what gross observation of the data suggested:no combination of variables seemedable to predict greater or lesservulnerability to addiction. DISCUSSION The discussionthat follows correspondsto the original questionsasked in formulating this research. I. Are Patients Able to Adhere to Prescribed Doses of Diazepam? Of 50 subjects, 42 adjustedtheir own dosage;ofthese, 25 consistentlyadjusted it upward. Diazepam may be vulnerable to self-manipulation becauseof its capacity to produce immediate positive effects,a trait it shareswith addicting substances,such as alcohol or amphetamines,as opposed to nonaddictingpsychotropic drugs, such as chlorpromazine and imipramine. The fact that half the sample increasedtheir own dose suggests, but does not document,tolerance.When asked,14 of these25 replied they increased their dose becausethe prescribedamount was not as helpful as before. 2. Are Patients Able to Discontinue Diazepam? Of 24 subjectswho artempteddiscontinuance,22 were unsuccessful and returned to the drug. They unanimously commentedthat they wished to be free of relianceupon diazepam, but seemed rated abstainers unabie to be so. Theseunsuccessful themselves significantly higher on dependencyscoresthan the remainder of the sample. 3. What Symptoms Occur upon Abrupt Discontinuance? As Table 5 . oocuments, most subjects experienced anxiety, restlessness, insomnia, tremor, and diaphoresis.Many subjectscomplainedof the samesymptoms upon abstinencefor which the drug was prescribed. Yet the anxiety complainedof initially was usually secondaryto an organic illness; upon 109

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110

MALETZKY AND KLOTTER

discontinuancethe physical complaint almost always was gone, yet the anxiety present. It appearedjust as likely that the symptoms noted on abrupt discontinuancewere secondaryto an abstinencesyndrome as they I were related to an ongoing condition which the drug had suppressed. For I example,severalsubjectscomplained of extreme anxiety upon abstinence, [r yet had been free of anxiety when the drug was initially prescribed. In addition, symptomssuch as tremor, diaphoresis,and eveninsomnia, which had been rare prior to taking diazepam, emerged when the drug was stopped. A reanalysisof our data revealsthat of the 24 subjectsdiscontinuing diazepam,l7 complained of symptoms not presentbefore taking the drug. It would seemlogical to assumethat, rather than the onset of "psychic" distress at some point during the diazepam regimen, these symptoms developedde novo upon abstinence.It is unclear from thesedata whether gradual discontinuancewould have mollified thesesymptoms. What symptoms suffice to determine a physiological withdrawal ? Withdrawals from amphetaminesand tobacco differ qualitatively from alcohol or heroin withdrawal, yet such drugs are considered bona fide addicting substances nonetheless. Data from animal laboratoriesconfirms addicting qualities of amphetamines and other minor tranquilizers as well (Schuster and Thompson, 1969; Findley, Robinson, and Peregrino, 1972). The distinctions between "dependence" and addiction may be vague in some cases,superficialin others. 4. Can We Predict llhich Patients Might Develop Tolerance or I4ithdrawal ? Those taking high dosesof diazepam (greater than 15 mg daily) for long periods of time (over 12 months) who believethe drug has significantly helped them, and who have increasedtheir dose on their own, stand a greater chance of developing serious symptoms upon its abrupt discohtinuance.However, neither age, sex, psychiatric history, nor the presenceof current psychiatric problems have the slightestrelationship to drug use and abuse variables. It is disappointing to find no individual predictive of potential danger with diazepam. The "addiccharacteristics tion-prone" individual would certainly seetnto possess some past drug or alcohol history, at leasta psychiatric history, and to be more commonly a woman. A review of our data revealed7 of 50 patients admitting to prior drug or alcohol abuse; no differences were found betweenthis subpopulation and the remainder. Thesedata partially refute the "addiction-prone" conceptand raisethe possibilitiesof either equal addicting potential among all subjects,as animal data would predict (Schulsterand Thompson, 1969; Findley, Robinson, and Peregrino, 1972), or susceptibility grounded in

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factors not examinedhere (for example,marital status or geneticconstitution). When physicianswere informed that the drug involved was diazepam, they modified their positions considerablyin the direction of lessaddiction. Often physicianscommented, with relief, that "it was only Valium," thus could not be dangerous. Nonmedical psychiatric specialists,performing the interviews,had relatively little preknowledgeof diazepam'spresumed safetyand rated signiflcantlyhigher addiction levelsfor almost all subjects. The retrospective,uncontrolled nature of most of the data reported hereinmakesthis study merely suggestive. Ideally, hospitalizednormal subjects might be given diazepam, blood levels checked, and physiological withdrawal monitored, including EEG's. Such a prospectivestudy is being planned. Nonetheless, these data support previous research (Aivazian, 1964; Barten, 19651. Edgley, 1970; Hollister et al., 1963; Clare, 1971) raising suspicions of diazepam's capacity to produce genuine addiction. Tolerance was partially demonstrated and symptoms of withdrawal occurred upon abrupt discontinuance;such symptoms were not always similar to those for which the drug was initially prescribed, Moreover, withdrawal symptoms seemedso uniform as to delineatea discrete syndrome, similar to that seen upon discontinuance of other minor tranquilizers. In addition, many subjects not thought to be "addiction-prone" developedwhat appeared to be both tolerance and withdrawal. These subjects,given the drug for medical reasons and without a psychiatric history, werejust as likely as psychiatricpatients to develop toleranceand withdrawal. It appearsas if the prescribingphysician needsto cultivate as much care in prescribing diazepam as in other potential drugs of abuse. Diazepam treats no specificpsychiatricillness,as opposed,for example, to lithium or chlorpromazine. This is not to deny its value in certain neurologicsyndromes (Tudo, 1971)or as a temporaryaid in behaviortherapy (Bandura, 1969).It is a common belief that reliance upon nonspecific tranquilizers may inhibit the acquisition of coping skills in the face of stress(Klerman, 1970; Anonymous, 1972). Beyond these issues, minor tranquilizer use, in adults, may predisposetoward drug use in children (Smartand Fejer, 1972).Because of thesefactors and because of diazepam's addicting qualities, we have limited its use in our neuropsychiatricclinic and encouragedmedical colleagueslikewise. Prescriptions for diazepam and chlordiazepoxide in the military hospital supplying our base have decreasedfrom 35,000 to 2,500 tablets weekly over the past 2 years. Our neuropsychiatric practice is presently minor-tranquilizer free without

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serioussequelae. There is no reasonto doubt diazepam'sefficacyin reducing levels of anxiety, but it is believed the data offered herein raise the question of at what price ?

S UM M A R Y
In order to further investigatethe addicting properties of diazepam, 50 medical and psychiatric subjects were interviewed concerning their diazepam use. While this sample was not taking excessively high doses, nor using the drug great lengths of time, many had extreme difficulty in decreasingor discontinuing their dose, rather finding it easierto increase. Most who increasedfelt they required more to achievethe samebenefitsas previously. Most who decreased or stoppedtheir drug abruptly experienced aL afiay of symptoms thought of as withdrawal, including agitation, anxiety, insomnia, diaphoresis, and tremors; many such patientsdid not have similar symptoms before taking the drug. Those taking more diazepamover longer periods, who felt it was more helpful and who needed to increase their dose, were the more likely to develop severesymptoms on abstinenceand to be unable to do without diazepam.Yet age, sex, and the presence or absence of a history of psychiatric, alcoholic, or drug-related problems had no bearing on development of toleranceor withdrawal, thus raisingquestions about the validity of the "addiction-prone" concept. Physicians, asked to rate the quantity of addiction, were far more sanguine once they learned the drug in quesfion was diazepam. The reluctanceto consider diazepaman addicting substancedespitethe evidence may stem from prior anecdotal reports. Yet scrutiny of the literature, coupled with the presentdata, argue for caution in prescribing and supervising diazepam pending further, more sophisticatedstudy.
REFER ENCES AIVAZIAN, G.H. Clinical evaluationof diazepam. Dis. Nerv. Syst.25:491495,1964. ANONYMOUS. Meprobamate. Med. Lett. Drugs Ther. l:34, 1959. ANONYMOUS. A Study of Health Practices and Opinions,conductedby National AnalystsInc., for the Food and Drug Administration,Washington,D.C., 1972. ARNESON, G.E. The risksof the new psychotropic drugs.J. La. StateMed. Soc.113: 372-376.1961. BANDURA, A. Principles of BehaviorModification. New York: Holt, Rinehart and Winston, 1969,pp. 485+86.

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BARTEN,H.H.Toxicpsychosiswithtransientdysmnesicsyndromefollowingwithdrawalfrom Valium. Am' J. Psychiarry122 1210-1211,1965' l91o' addiction' Med' J' Aust' I: 1209-1214' BARTHOLOMEw, A.A. Amphetamine BowES'H.A.Theroleofdiazepam(Valium)inemotionalillness.Psycftosomatics6.. 1965. 136-340, practice'Am' J' Psychiatry127:. BURDINE, W.E. Diazepamin a generalpsychiatric 1964. s89-592, with valium in generalpractice' BURNETT, R.E., and HoLMAN, R.E. Experience 65: 36-41,1965' Med. Times R.W' 8.J., KAPLITZ,5.8., BREME, J'T ' NUSCI, J', and SABATIN' CHESRCW, '4m' patient' elderly disturbed the in ill and "I' The useof valium in the chronically 1962. Geriatr.Soc. 10: 667-6'71, 1971' CLARE, A.W. Diazepam,alcohol,and barbiturateabuse'Br' Med' J' 4:340' and CONSTANT, G.A. Preliminaryreport on the use of a new agent in depression 37,1960' 2ll. Sys/' Nerv. Dir. tension statements. in coNsTANT, G.A., and GRUVER, F.A. Preliminary evaluation of diazepam 1963' 80-84, psychiatric Psychosomatics disorders. CROMWELL,H.A.Apsychosomaticapproachtointernalmedicine'Colo'GP2l.6-17' 19 6 3 a . drugs in internal CROMWELL, H.A. Controlled evaluation of psychotherapeutic 1963b' 70:2239-2244' medicine. Clin. Med. of tranquilizingdrugs' C/rn' PharmacolTher' DOMINO, E.F. Human pharmacology 3: 599-664, 1962. Dis' Nerv' Sy'rt'24: 693DORFMAN, W. Recentadvances in psychopharnracology' 694,1963. DORFRAN, W. Some experiences in ,,total" treatmentof patients with emotional illness. Psyclos omatics 5 : 3 51-354, 1964. EDGLEY, R. Diazepam,nitrazepam and the N.H.S. Med' J' Aust' 33:29'7-298'19'70' ESSIG,C.F. Addiciion to nonbarbiturate sedativeand tranquilizing drugs. C/rn' Pharmacol. Ther.5: 334.343.1964. 3 (Suppl. FELDMAN, p.E. An analysis J. Neuropsychiatry of diazepam. of the efficacy 1): 562,1962. FINDLEY, J.D., ROBINSON, W.W., and PEREGRINO, L. Addiction to secobarbital preference and chlordiazepoxide monkeyby meansof a self-infusion in the rhesus procedure. p harmaco Psy cho log ia (Berl) 26 : 93-114' l9-l2. FOWLKES, E,W:, STRICKLAND, D.A., and PEIRSON, G.A. CONTTOI Of SPASIiC steLtes in neurological Am. J. Phys.Med. 44 9-19,1964' patientswith diazepam. GRAYSON, L.D. A new psychotherapeutic drug usedin dermatology.Gen.Pract. 2 5 : 9 - 1 11 . 962. HAIZLIP, T.M., and EWING, J.A. Meprobamate habituation.N. Engl. J. Med.258 I I81_1 l 86. 1958. HoLLISTER,L.E., BENNETT, J.L., KIMBELL, I., sAVAGE, c., and oVERALL, J E Diazepamin newly admitted schizophrenics. Dis' Nerv. Syst.24: 746-749, 1963. HOLLISTER,L.E., TCACMOTZENBACKER, F.P., ANdDEGAN, R.O. WithdTAWAI ttonsfrom chlordiazepoxide (Berl) 2: 63-68' ("Librium"). Psychopharmacologia I961.

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KATZ, R.A., ALDES, J.H., and RECTOR, M.A. A new approachto musclerelaxa3:91-95' 1962. tion. J. Neuropsychiatry agent for the managementof psychiatri. KELLEY, J.W., A new pharmacological disorders. CIin. Med. 69: 1789-1790'1962a. of psychiatricdisorderswith diazepam.Clin. Med.69: KELLEY, J.W. Management 122-129,1962b. comparisonof diazepam KERRY. R.J., and JENNER, F.A. A doubleblind crossover (Librium) in the treatmentof neurotic (valium Ro 5-2807)with chlordiazepoxide anxiety. Psy chophar macolog i a (BerI) 3 : 302-306, 1962. KLERMAN. G.L. Drugs and socialvalues.1nI.J. Addict. 5:312-319' 1970. l. Neuropsychiatry of alcoholism. in the treatment LAWRENCE, F.E. Chlordiazepoxide 2: 93-100.196O. dermatoses. of recalcitrant to the management approach LEVY, S.W. A psychosomatic 4 : 334-337, 1963. Psychosomatics Dis' Nerv' Syst.24: 693-694, LOVE, J. Diazepamin treatmentof emotionaldisorders. 1963. MACKINNON, A.V. Favorite prescriptionsin general practice. Practitioner 198: 80-84. 1967. MCGOVERN, J.P.,HAYWOOD, T.J., THOMAS, O.C., and FERNANDEZ' A'A. Psychosomatics derivativein various allergic diseases. Studieswith abenzodiazepine 4:203-211,1963. IvIELLINGER. G.D., BALTER, M.8., and MANHEIMER, D.I' Patternsof psyArch. Gen.Psychiatry 251 drug useamongadultsin San Francisco. chotherapeutic 389-394,19'71. IvIERLISS,TURNER W.J., and KRUMHOLZ, W'A. Double-blind comparisonof and chlorpromazine in psychotic patients' f Neurodiazepam-chlordiazepoxide psychiatry3 (Suppl. 1): 562,1962. An evaluation symptomsin gynecology: MOORE, S.F.,JR. Therapyof psychosomatic 4:249-257, 1962. Curr. Ther. Res. of chlordiazepoxide. PARRY, H.J., BALTER, M.8., MELLINGER, G.D., CISIN' I.H., and MANI{EIdrug rse' Arch. Gen.Psychiatry MER, D.I. National patternsof psychotherapeutic 28:769-783,1973. addiction.Nortluvest PHILLIPS, R.M., JUDY, F.R., and JUDY, H.E. Meprobamate Med. 56: 453454, 1957. disorders. in refractorypsychiatric with chemotherapy PIGNATARO, F.P. Experience Curr. Ther.Res.4: 389-398.1962. PROCTOR, R.C. The improved managementof incapacitatinganxiety states'.I. Neuropsychiatry3 : 151-154,1962. RANDALL, L.O., HEISE,G.A., SCHALLEK, W,, BAGDAR, R.E.,BANZIGER,R,' BORIS, A., MOE, R.A., and ABRAMS, W.B. Pharmacologicaland clinical class. agent of the benzodiazepine studieson Valium, a new psychotherapeutic Curr. Tlter. Res.3: 405425,1961. drug in internal medicine,a conRATHBONE, R. The role of a psychotherapeutic 1963. trolled evaluationin privatepractice.Med. Times91: 1186-1192, 3: 63-65, Headache RYAN, R.E. Myalgia of the headand its treatmentwith diazepam. 1963. of and behavioraldeSCHUSTER, C.R., and THOMPSON, T. Self'administration pendence Pharmacol.9:483-502,1969, on drugs.Arr. Res.

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and their parents; SMART, R.G., and FEJER, D, Drug use among adolescents gap in mood modification. 79: 153-160, J. Abnorm.Psychol. closingthe generation 1972. J.N., LINTON, P.A., And HERLIHY, C.E. Anxiety and depression in SUSSES, states-treatmentwith Valium, a Librium analog. P$,borderlineschizophrenic chosomatics 2 : 256-260,19 61. Electroencephalogram TUDO, I. Valium treatmentin statusepilepticus, CIin. Neurophysiol.30: 365-367 , 1971. WILLIAMS, M.W. Clinical impressions on the use and value of chlordiazepoxide practice" in psychiatric South.Med. J. 54:922-926,1961.

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