The naloxone test for opiate dependence

Naloxone tests for opiate dependence were given to 296 applicants for treatment with the

surrogate opiate levomethadyl acetate (LAAM. levo-alpha-acetylmethadol) and to /03 applicants

for treatment with the opiate antagonist naltrexone. Thirty-five of the 296 LAAM applicants

applied first for LAAM, then following detoxification. for naltrexone. There was a dramatic

decrease in withdrawal signs and symptoms when the subject went from an opiate-dependent to

a nondependent state. From our experience, we devised a scoring guide and testing procedure

based on objective signs. We propose a 2-step test, with an initial intramuscular dose. then (if

necessary) an intravenous dose. to determine an applicant's eligibility for surrogate opiate or

narcotic antagonist treatment.

Barbara A. Judson, M.S., David U. Himmelberger, M.S., and Avram Goldstein, M.D.

Palo Alto. Calif.

Addiction Research Foundation

An opiate addict who is to be admitted to amethadone or levomethadyl acetate (LAAM,levo-alpha-acetylmethadol) maintenance pro­gram should be physically dependent on anopiate. Federal regulations' require opiate­positive urine tests, fresh needle marks, andclinical judgment of current opiate dependence,but do not require the demonstration of a with­drawal syndrome. It is possible, therefore, forapplicants who are only occasional users ofheroin to be admitted to a maintenance prog­ram. The opposite problem is presented byapplicants for antagonist treatment using nal­trexone. These must not be physically depen­dent on an opiate, or a withdrawal syndrome(possibly severe) will be precipitated by the firstnaltrexone dose. Hence, a routine, objectivetest of opiate dependence would be highly de-

Supported by Grants DA-1199 and DA-923 from the NationalInstitute on Drug Abuse.

Received for publication Sept. IS. 1979.

Accepted for publication Nov. 10. 1979.

Reprint requests to: Barbara A. Judson. M.S .. Addiction Re­search Foundation. 701 Welch Rd .• No. 325. Palo Alto, CA 94304.

sirable. Such a test must be simple, quick, safe,and reliable. Among applicants for opiate main­tenance it must screen out those who are notphysically dependent; among applicants for an­tagonist treatment it must screen out those whoare dependent.

In 1973, Blachly! described a practical testfor dependence using naloxone (Narcan). In thisreport we describe our experience with a mod­ification of the Blachly procedure in 296 appli­cants for LAAM maintenance and 103 appli­cants for naltrexone treatment. Among thesewere 35 who applied for LAAM treatment,completed detoxification, and then applied fornaltrexone treatment. We have been able todemonstrate that the test results change frompositive to negative in the same people whenthey give up using heroin. This finding consti­tutes a validation of the test as an indicator ofopiate dependence.

Methods

Subjects. Eligibility requirements for appli­cants to the LAAM phase of the LAAM-

492 0009-9236/80/040492+ 10$01.00/0 © 1980 The C. V. Mosby Co.

Volume 27Number 4

naltrexone program were as follows: (1) aged18 yr or older; (2) evidence of heroin use for atleast I yr; (3) at least one documented superviseddetoxification attempt; (4) two opiate-positive*urine tests; (5) no serious medical or psychiatricillness; (6) if female, documented inability tobear children; (7) current opiate dependence, asevidenced by the naloxone test; and (8) abilityand willingness to give informed consent.

Two cohorts were admitted to the LAAMprogram. From the tests of the first 181 appli­cants (cohort I), signs and symptoms were re­corded to establish a data base for a standard­ized checklist; physicians made a global judg­ment as to whether or not a test was positive.These results were then used to devise analoxone test checklist for signs and symptomsand a scoring guide for signs, which were usedfor the next 115 tests (applicants for cohort II).

Patients were accepted onto naltrexone bothfrom the LAAM phase (after detoxification) andfrom the "street" (no previous experience withour program). Eligibility requirements for nal­trexone patients were the same as for theLAAM patients, with the exception of require­ments 3, 4, and 7 above. In order to be admittedto naltrexone treatment, applicants were re­quired to respond negatively to the naloxonetest.

Naloxone test. All tests were done by a phy­sician. Subjects disrobed from the waist up.Oral temperature and pulse were measured priorto testing. A naloxone hydrochloride solution,0.4 mg/rnl, was used. First, 0.05 ml (0.02 mg)was injected intradermally to make sure the sub­ject was not allergic to the drug (no allergicreactions have been seen or reported). If noreaction occurred within 10 min, 0.45 ml (0.18mg) was injected intramuscularly (deltoid) andthe subject was observed for 20 min. At the endof this time, oral temperature, pulse, signs, andsymptoms were recorded. On the basis ofBlachly's report, 1 gooseflesh over the upperarms or thorax was considered an important in­dicator of precipitated withdrawal, but theexamining physician was allowed to judge a test

'Urines showing morphine or codeine by thin-layer chromatogra­phy were considered "opiate positive." Applicants with metha­done-positive tests were not considered eligible, even if morphine orcodeine was also present, since we could not rule out the possibilitythat the applicant was in a methadone program.

Naloxone test 493

result positive even in the absence of this sign.If withdrawal signs were absent or minimal, afurther dose of 0.45 ml (0.18 mg) was givenintravenously. Oral temperature, pulse, signs,and symptoms were recorded 5 min after thisinjection. Applicants for LAAM who exhibitedclear withdrawal signs after either the in­tramuscular of intravenous dose were admittedto the program. Those who showed no (or min­imal) signs were denied admission to LA AMtreatment but were encouraged to abstain fromheroin for a few days, repeat the test, and startdirectly on naltrexone. Applicants for the nal­trexone program were required to show no (orin some cases, few) signs or symptoms ofwithdrawal after both intramuscular and intra­venous administration of naloxone. A positiveresponse on either dose ended the test, and theapplicant was told to abstain from heroin useand to return for retest.

Results

Cohort I LAAM. Of 181 applicants tested,clear withdrawal signs were displayed by 112(62%) after the intramuscular dose, and by allbut four of the remaining 69 after the intravenousdose. After the intramuscular dose the most fre­quent signs were gooseflesh, mydriasis, yawn­ing, sweating, and rhinorrhea. The most fre­quent symptoms were chills, cramps, feelingfeverish, and nausea. The pattern of signs andsymptoms was very much the same after theintravenous dose. Differences among our threephysicians were apparent in the manner of as­sessing signs and symptoms. For example, onerequired an intravenous test in 68% of the sub­jects he tested, another in only 16%. The testwas therefore standardized, with explicit scor­ing directions, for use with cohort II.

Cohort II LAAM. For administration of thenaloxone test to these 115 applicants, a check­list was used, constructed largely from the ob­servations on cohort 1. On a scale of 1 to 4(none, mild, moderate, severe; see scoringguide, Table I) the following signs were ratedby the physician: sneezing/coughing, yawning,lacrimation, rhinorrhea, shivering, restlessness,sweating, vomiting, gooseflesh, and mydriasis.The following symptoms were rated by the sub­ject, using the same scale: feeling feverish,

494 Judson et al. Clin. Pharmacol. Ther.Apri/1980

Table I. Scoring guide for objective signs on the naloxone test checklist

Score

None Mild Moderate SevereObjective sign (code 1) (code 2) (code 3) (code 4)

Sneezes, coughs 0 1-2 3-10 > 10; uncontrollablebouts

Yawns 0 1-2 3-10 > I0; uncontrollablebouts

Lacrimation 0 Barely noticeable water- Tearing, blinking, rub- Profuse weeping, tearsing of eyes; some bing at eyes, occa- running down face,blinking sional tears from wiping eyes with

comers of eyes handkerchief

Rhinorrhea 0 Barely noticeable Visible nasal secretion, Profuse secretion run-sniffmg swallowing postnasal ning from nose, con-

drip, wiping nose tinual use of handker-with handkerchief chief

Shivering 0 Barely noticeable shiv- Bouts of shivering in- Continuous uncontrol-ering , localized, volvingwhole body, lable shivering, teethtransient no teeth chatter chattering

Restlessness 0 Greater than normal Repeated movements of Continual movement,movement of limbs or extremities, shifting unable to sit still,body of body position walking around, tics,

chain smoking, etc.

Sweating 0 Barely noticeable moist- Readily visible wetness Sweat dripping fromness of palms, fore- of skin, palms, arm- forehead, armpits,head, armpits pits chest

Vomiting 0 Retching, spitting up 1-2 productions of >2; uncontrollablegastric contents vomitus vomiting

Gooseflesh (upper 0 Transient or intermittent Gooseflesh persisting Gooseflesh over mostarms and thorax gooseflesh of upper over 30 sec; barely of body; persistingonly, not peri- arms and/or thorax; palpable over 60 sec; readilyareolar) feels smooth on pal- palpable

pation

Mydriasis 0 Estimated pupil diam- 3-4 mm >4mmeter increases 1-2 mm

nausea, abdominal cramps, tired/listless, head­ache/dizziness, muscle/joint pains, and chills.The physicians were encouraged to note anyother sign or symptom, but only rarely did so.

Of the 115 applicants, clear withdrawal signsand symptoms were displayed by 66 (57%) afterthe intramuscular dose, and by all but five of theremaining 49 after the intravenous dose. Fig. Ishows the proportion of subjects exhibitingmild, moderate, and severe signs and symptomsafter the intramuscular and intravenous doses.Restlessness was the most common sign whenthe checklist was used, even though none of the

physicians listed it spontaneously for cohort Iapplicants. Otherwise, the results were similarfor both cohorts. The 49 applicants who had no(or minimal) response to the intramusculardose, but who displayed signs and symptomsafter the intravenous dose, showed a pattern re­sembling that in subjects who reacted to theintramuscular dose.

To examine the relationships between thevarious signs and symptoms, we performed astepwise cluster analysis for the intramusculardose, as described by King." The techniqueproduces clusters of variables from a product

Volume 27Number 4

PERCENT OF SUBJECTS (N=1l5)

Naloxone test 495

PERCENT OF SUBJECTS (N=49)

o 20 40 60 80

EJSCOIU: 2

3

III. DOSE

100 0 20 40 60 80 100

Fig. 1. Signs and symptoms after naloxone. Length of bar indicates percent of subjects showing thegiven sign or symptom to any degree. Scores: 2 = mild, 3 = moderate, 4 = severe; see scoringguide, Table I. Left: 0.18 mg intramuscularly (1M), 115 applicants for LAAM treatment. Right:0.18 mg intravenously (IV), 49 applicants who had no clear withdrawal reaction after intramusculardose.

moment correlation matrix in such a mannerthat variables within a cluster are most highlycorrelated, whereas variables from differentclusters are not so highly correlated. As shownin Fig. 2, three distinct clusters were apparent:sneezing, rhinorrhea, lacrimation, and yawn­ing; shivering, gooseflesh, mydriasis and chills;and less well correlated, vomiting, nausea, andcramps. Changes in temperature and pulse werenot useful indicators of dependence in this testprocedure.

Naltrexone. We present data on the 103applicants for naltrexone treatment to whom thestandardized naloxone test was administered. In67 (65%) of these there were no signs or symp­toms after the intramuscular dose, and 61 ofthem also had no reaction to the intravenousdose. Of the 42 applicants who showed at leastone sign or symptom after either dose, 28 startedon naltrexone. Ideally, acceptance for nal­trexone treatment would be limited to those whohad no signs or symptoms after either dose but

some of the items on the naloxone test checklistare indicative of anxiety as well as withdrawal(e.g., sweating and restlessness). If, in the es­timation of the examining physician, mild signsand symptoms were due to anxiety about thetest, the applicant was accepted for naltrexonetreatment. However, no applicant was acceptedwith a score above 2 (mild complaint) on anyitem.

Thus, two distinct groups started on naltrex­one treatment. In one, there had been no reac­tions to either naloxone injection. In the other,there had been one or more signs or symptoms ofmild degree (score = 2). Table II shows that, asmight have been expected, patients who had amild positive reaction to the naloxone test alsohad more symptom complaints during the firstweek of naltrexone treatment. Seventeen itemson the progress questionnaire" specifically relat­ed to withdrawal were used for these analyses.Most frequent complaints in this group were ofmuscle pains, "trouble with eyes" (probably

496 Judson et al. Clin. Pharmacal. Ther .April 1980

87

Step9 10 11 12 13 14 15 16 17 18 19 20

.--,c----r-.,--,--.....- r-t--.--r-"T"- "T"- ..--.--,6541

SneezeRhinorrheaLacrimation

Yawn

Shivering

GoosefleshMydriasis

Chills

RestlessnessSweating

vomitingNauseaCramps

PainsFeverish

HeadacheTired

Dec. PulseDec. Temp.

PulseTemp.

~J

Fig. 2. Stepwise clustering results for signs and symptoms after intramuscular injection of naloxonein 115 applicants for LAAM. Shading indicates the 3 major clusters. Selected values of the correla­tion coefficient are displayed, in parentheses, immediately to right of relevant steps.

Table II. Naltrexone experience of patients who had positive or negative reactions topreadmission naloxone test

Number of symptom complaints in first week on naltrexoneReaction to

naloxone test 0-2 Total

Positive 2 7 4 7 4 0 24Negative 22 II 4 10 3 0 50

Number of doses before dropout

1 I 2 I 3 I 4 >4 Total

PositiveNegative

25

oI

35

17

22 (79%)43 (70%)

2861

Positive = at least 1 sign or symptom of mild severity (score = 2) on intramuscular or intravenous test. Negative = no sign or symptom oneither intramuscular or intravenous test. Data are from symptom complaint questionnaire administered during second week of naltrexonetreatment; no data available for 15 patients who dropped out during first week. All patients who started on naltrexone are represented in lowersection of table, according to duration of naltrexone treatment; 3 doses per week were administered. Positive and negative groups differsignificantly on number of symptom complaints (p < 0.01, Wilcoxon 2-sample rank test), but not on number of doses before dropout.

pain in the extraocular muscles), and drowsi­ness. The discomfort experienced by this groupduring the first week of naltrexone treatmentwas not, however, sufficient to cause dropout,as shown in the lower portion of Table II.

Comparison of pre-LAAM and prenal­trexone test results. Of the applicants for nal­trexone treatment, 35 were from the cohort IILAAM group; therefore, the results of theirpre-LAAM naloxone tests were available. This

Volume 27Number 4

12

•

Naloxone test 497

o 5 10 15 20 25DIFFERENCES IN NALOXONE TEST GLOBAL SCORES

(LAAM SCORE - NALTREXONE SCORE)

10

I./)I-Z 8w

~0:

u,

0 6

I-ZW

~ 4wQ.

~

2,

-4

,

i

I '

,'r I,

I !r

I , ,, ! i:

-,

-r

•

•

,

-,

I

, '

,- -F

,r

Ii

30 35

Fig. 3. Differences in global scores (sum of all signs and symptoms) between pre-LAAM andprenaltrexone tests. Data represent 35 subjects who applied for both treatments. Asterisks indicatethe only 3 applicants for naltrexone who displayed gooseflesh in response to the naloxone test; thesewere not accepted for naltrexone treatment.

provided an unusual opportunity to compare thenaloxone test results on the same individualsunder two very different circumstances-first,when they were physically dependent on her­oin, and second, months later, when they haddetoxified from LAAM and claimed not to beopiate dependent.

Scores on the pre-LAAM and prenaltrexonetests for these 35 subjects were analyzed in a4 X 4 contingency table for each of the 17 signsand symptoms." As an example, Table IIIshows the result for gooseflesh. If the responseto naloxone were characteristic of each indi­vidual but unrelated to the state of opiate de­pendence, most of the numbers would be ex­pected to fall along the diagonal, from upperleft to lower right, with approximately equalnumbers above and below the diagonal. In-

Table III. Contingency table for goosefleshscores on pre-LAAM and prenaltrexone testsfor35 subjects who applied for naltrexone treat­ment after completing LAAM treatment

Prenaltrexone score

1 Total Ss

Pre-LAAM scoreI 3 0 0 0 3

2 II I 0 0 12

3 12 I I 0 14

4 6 0 0 0 6

Total Ss 32 2 0 35

Score I = none; score 4 = severe (see Scoring Guide, Table I).Numbers in boxes are numbers of subjects. For example, II subjectswho had score 2 at the pre-LAAM test later had score I at theprenaltrexone test.

498 Judson et al. Clin. Pharmacal. Ther.April 1980

264424

969

Intravenousdose

(n = 34)

46383325175

Percent of applicants

Intramusculardose

(n = U5)Sign

GoosefleshSweatingRhinorrheaSneezingLacrimationVomiting

Table IV. Percent of LAAM applicants withscore of 3 or 4 on 6 objective signs afterthe intramuscular and intravenous doses

I V DOSE

I M DOSE

10 NO

~~.~G?J~ ~O68

PERCENT PASS

Fig. 4. Flow chart for pre-LAAM naloxone test.Only scores of 3 or 4 are considered here. Numbersare percents of 111 applicants. Four of the 115applicants were excluded from this chart becausethey did not have any score of 3 or 4 after the in­tramuscular (1M) dose; however, because they wereaccepted by the physician without further testing, nointravenous (IV) results were obtained.

stead, the great majority of the patients fall intothe lower left area of the grid, indicating consis­tently higher scores on the pre-LAAM test thanon the prenaltrexone test. For each of the 17signs and symptoms, this deviation from expec­tation was significant (p < 0.01).

Fig. 3 shows the within-subject differences inthe sum of the scores for all signs and symptomsbetween the pre-LAAM and prenaltrexone testsfor these same 35 subjects. Pre-LAAM scoreswere higher than prenaltrexone scores (p <0.01, 2-tailed t test).

Naloxone test results and urine test results.

TOTAL PASS = 94% TOTAL FAIL = 6 ~(,

For 34 applicants who did not respond with a 3 or 4 score on theintramuscular dose, we examined the intravenous test result. Num­hers under "Intravenous dose" are percents of the 34 applicants inthis column.

An applicant for LAAM who met the otherqualifications had to produce two consecutiveopiate-positive urine samples on the days priorto taking the naloxone test. If the test was posi­tive, the applicant was given his first dose ofLAAM immediately, and another urine speci­men was obtained. In cohort II, 110 out of 115applicants responded positively to naloxone andwere admitted to LAAM treatment, but 14% ofthese proved to have an opiate-negative urine onthe day of admission. Presumably, they hadbeen able to abstain from heroin use for at least24 hr in anticipation of LAAM treatment.

Also of interest are the urine results in the 89applicants who started on naltrexone treatment.Thirty-five percent of these urines were opiatepositive, indicating some recent use of heroinor other opiates. Patients with opiate-positiveurine did not have a different dropout rate orsymptom complaint score during the first weekof naltrexone treatment, as compared with thosewho had opiate-negative urine.

Proposed naloxone test protocol. We sum­marize here the principles and findings thatprovide the basis for a standard protocol for apre-LAAM (or premethadone) naloxone test.

1. In evaluating the withdrawal reactions, itis important to choose indicators that, as muchas possible, are not under voluntary control.The purpose is to prevent applicants from suc­cessfully simulating withdrawal signs in order

Volume 27Number 4

to receive the surrogate opiate. Signs that couldnot be simulated easily are sneezing, lacri­mation, rhinorrhea, sweating, vomiting, andgooseflesh. These signs, of course, are on acontinuum, with sneezing being more easilysimulated than gooseflesh.

2. Since the cluster analysis (Fig. 2) indicatesthat different withdrawal signs may predominatein different people, optimally one should useobjective signs from different clusters.

3. Results from the prenaltrexone tests sug­gest that signs and symptoms of mild degree(score = 2) are probably not reliable indicatorsof physical dependence. We therefore proposethat only those signs rated moderate or severe(score 3 or 4) should be considered, thus elimi­nating much of the ambiguity in distinguishingbetween mild withdrawal reactions and anxiety.Table IV gives the observed frequency ofmoderate or severe reactions on each of the sixsigns listed above as acceptable criteria.

4. We used these frequencies to establish ahierarchical flow chart for determining the testresult (Fig. 4). We found that sneezing and lac­rimation gave completely redundant informa­tion, since every person scoring 3 or 4 on thesesigns also did so on one of the other signs. Thefour signs chosen as criteria-gooseflesh,sweating, rhinorrhea, and vomiting-includeone element from each major cluster. A personwho has a moderate or severe reaction (score 3 or4, see Table I) on any of the four criteria isconsidered to be opiate dependent.

Had this protocol been applied to the appli­cants in cohort II, it would have resulted, asFig. 4 shows, in 94% being accepted for LAAMmaintenance, while 6% would have been re­jected as not truly opiate dependent. Had thisprotocol been applied to the 103 naltrexoneapplicants, 92% would have been accepted fortreatment, and 8% rejected as being opiate de­pendent.

Discussion

The ability of narcotic antagonists to precipi­tate a withdrawal syndrome in subjects physi­cally dependent on narcotics was first describedby Wikler et al .' r using nalorphine (Nalline).He also showed that the intensity of withdrawal

Naloxone test 499

was related to the degree of dependence and thedose of narcotic antagonist. In rodents'': 15 andin man, 11 a standard dose of naloxone provokesa withdrawal syndrome, the severity of which isdirectly related to the degree of opiate depen­dence (i.e., to the frequency of administrationand dosage of the opiate).

After Wikler published his results with nalor­phine, this drug was used as a means of assess­ing narcotic use in probationers and parolees. In1973 Blachly' introduced naloxone testing as ascreening procedure for admission to metha­done programs. Despite his report that a con­siderable fraction of applicants were not physi­cally dependent, few clinics appear to haveadopted the naloxone test. There are two nota­ble exceptions. Wang l 4. 16 modified Blachly'stest and uses 0.8 mg intramuscularly. 0 'Brien 10

uses 0.4 mg intravenously. In both of thesemodifications there is the risk of precipitatingmore severe withdrawal than necessary to es­tablish the fact of physical dependence.

In our procedure, as in Blachly's originaltest, a small dose is first given intramuscularly,and then, if clear withdrawal reactions are notevident, an equal amount is given intravenous­ly. Some treatment personnel have expressed adislike for the naloxone test on the grounds that itcauses the addict undue discomfort. In our2-step procedure, however, withdrawal reac­tions have been readily tolerated, and haveprobably been less anxiety-producing than ifwe had waited for spontaneous withdrawal tooccur.

In principle, the naloxone test need not agreewith a urine test. A positive urine test meansonly that an opiate was used in the previous dayor two; it implies nothing about opiate depen­dence. A negative urine test means only that noopiate was used in the previous day or two, butit does not exclude opiate dependence (the per­son could be undergoing acute withdrawal). Weobserved both types of discrepancy. Of theapplicants for LAAM who reacted positively tothe naloxone test, 14% had an opiate-negativeurine on the same day. These subjects had pre­sumably discontinued heroin use in anticipationof entering our program. On the other hand, ofthe applicants for naltrexone who showed no

500 Judson et at.

sign or symptom in the naloxone test, one thirdhad opiate-positive urine on the same day.These subjects had been through various detox­ification procedures, and were no longer opiatedependent, but nevertheless had used heroin oc­casionally ("last fling") in anticipation of nal­trexone treatment.

In using the naloxone test for screeningapplicants for narcotic antagonist treatment, ithas been customary to give the challenge dose(0.4 mg or more) intravenously. 8, 12, 13 We be­lieve it is preferable to start with an in­tramuscular dose, Some applicants, eager tostart naltrexone because of law-enforcementpressure, lie about recent heroin use, and thenhave a strong withdrawal reaction to the in­tramuscular dose, An intravenous dose wouldhave caused them much more discomfort thanwas necessary to establish their ineligibility fornaltrexone.

An applicant who displays no signs or symp­toms after either the intramuscular or the intra­venous dose is certainly eligible for naltrexonetreatment. An applicant who displays anywithdrawal sign in moderate or severe degree(score 3 or 4) should not be given naltrexone.The reason is that the starting dose of naltrexone(usually 20 to 30 mg) is much larger than thenaloxone test dose, so that severe withdrawalreactions would surely occur. This prediction issupported by our finding of a strong relationshipbetween even mild signs on the naloxone testand symptom complaints during the first weekon naltrexone.

Mild signs or symptoms on the naloxone testpresent a dilemma. In some cases, these signsand symptoms may be due to nonpharmacologicfactors, such as anxiety or suggestibility, Inother cases the applicant was probably unable tobecome and remain abstinent in preparation fornaltrexone treatment, so further delay wouldprobably make matters worse, not better. Inthese cases, the first dose of naltrexone willprobably precipitate significant withdrawal dis­comfort, making the patient reluctant to con­tinue treatment. The deci sion to administer ordelay the first naltrexone dose, therefore, willdepend on the applicant's willingness to put upwith some discomfort and his ability to stayaway from opiates for a few days and return for

Clin. Pharmacal. Ther.April 1980

another naloxone test. We warn all applicantsthat if they have used opiates recently, or if theydo so shortly after the first naltrexone dose,*they may become' 'sick, " but that their discom­fort will be shortlived.

We had the unique opportunity to give thenaloxone test to the same 35 persons on twodifferent occasions-when they were presump­tively physically dependent on heroin and ap­plying for LAAM treatment, and months later,after detoxification from LAAM, when theywere presumptively not dependent on heroinand were applying for naltrexone treatment. It isknown that naloxone, even at doses as large as10 mg intravenously, is without effect in normalsubjects." 7 The question remains whether her­oin addicts or ex-addicts might have somespecial reactivity to naloxone, unrelated to theirstate of opiate dependence. Our data in these 35subjects show clearly that the naloxone test re­sult is, indeed, related to the state of opiatedependence.

We conclude that the 2-step (intramuscularthen intravenous) naloxone test, as describedhere, is an effective and humane procedurefor preventing the admission of nondependent"pseudo addicts" to surrogate opiate mainte­nance treatment, and for preventing the admis­sion of opiate-dependent persons to narcoticantagonist treatment. Urine testing providesinformation about recent narcotic use but ittells nothing useful about opiate dependence; itshould play no part in the admission screeningprocess for either type of treatment.

'We have observed, not infrequently, that use of heroin after thefirst naltrexone dose precipitates withdrawal symptoms. This neverhappens after the second or subsequent doses. The phenomenon is oftheoretical interest, but speculation on mechanisms would be inap­propriate here.

ReferencesI. Blachly PH: Naloxone for diagnosis in metha­

done programs. lAMA 224:334-335, 1973.2, Bowker AH: A test of asymmetry in contingency

tables, J Am Stat Assoc 43:572-574, 1948.3. Cheney DL, Goldstein A: Tolerance to opioid

narcotics: Time course and reversibility of phys­ical dependence in mice. Nature 232:477-478,1971.

4. Methadone, Food and Drug Administration, De­partment of Health, Education, and Welfare,

Volume 27Number 4

special requirements. Federal Register 39: 11681­11712 (March 29), 1974.

5. Goldstein A, Judson BA: Efficacy and side ef­fects of three widely different methadone doses.Proceedings of the Fifth National Conference onMethadone Treatment, National Association forthe Prevention of Addiction to Narcotics, pp.21-44, 1973.

6. Grevert P, Goldstein A: Effects of naloxone onexperimentally induced ischemic pain and onmood in human subjects. Proc Natl Acad SciUSA 74:1291-1294, 1977.

7. Grevert P, Goldstein A: Endorphins: Naloxonefails to alter experimental pain or mood in hu­mans. Science 199: 1093-1095, 1978.

8. Hollister LE, Schwin RL, Kasper P: Naltrexonetreatment of opiate-dependent persons. Drug Al­cohol Depend 2:203-209, 1977.

9. King B: Step-wise clustering procedures. J AmStat Assoc 62:86-101, 1967.

10. 0 'Brien CP: Experimental analysis of condition­ing factors in human narcotic addiction. Phar­macol Rev 27:533-543, 1976.

I I. O'Brien CP, Greenstein R, Ternes J, WoodyGE: Clinical pharmacology of narcotic an­tagonists. Ann NY Acad Sci 311:232-240,1978.

Naloxone test 501

12. Tennant FS, Tate JA, Ruckle JE: Clinical trial inpost-addicts with oxilorphan (Levo-BC-2605):A new narcotic antagonist. Drug Alcohol De­pend 1:329-337, 1976.

13. Volavka J, Resnick RB, Kestenbaum RS,Freedman AM: Short-term effects of naltrexonein 155 heroin ex-addicts. BioI Psychiatry 11:679-685, 1976.

14. Wang RIH, Wiesen RL, Lamid S, Roh BL: Rat­ing the presence and severity of opiate depen­dence. CUN PHARMACOL THER 16:653-659,1974.

15. Way EL, Loh HH, Shen FH: Simultaneousquantitative assessment of morphine toleranceand physical dependence. J Pharmacol Exp Ther167:1-8, 1969.

16. Wiesen RL, Rich CR, Wang RIH, Stockdale SL:The safety and value of naloxone as a therapeu­tic aid. Drug Alcohol Depend 2: 123-130, 1977.

17. Wikler A, Fraser HF, Isbell H: N-Allylnormor­phine: Effects of single doses and precipitationof acute "abstinence syndromes" during addic­tion to morphine, methadone or heroin in man(post-addicts). J Pharmacol Exp Ther 109:8-20,1953.