The authors are with the Department of Psychiatry, New York MedicalCollege, 5 East 102nd St., New York, N.Y. 10029. where Dr. Resnick isAssistant Professor, Dr. Volavka is Associate Professor, Dr. Freedmanis Professor and Chairman, and Ms. Thomas is an Instructor.

This work was supported in part by contract HSM 42-72-207 with theNational Institute of Mental Health and the Health Services and Men-tal Health Administration and by a contract with the New York StateDrug Addiction Control Commission.

The authors acknowledge the collaboration of Thelma Jones, M.D.,and Rhea Dornbush, Ph.D., and the assistance and cooperation of Is-rael Kesselbrenner, M.D.. Director of Kirby Hospital. and PeterCrown, Ph.D.

646 AmJ Psychiatry 131.6.June 1974

Studies of EN-1639A (Naltrexone): A New Narcotic AntagonistBY RICHARD B. RESNICK, M.D., JAN VOLAVKA, M.D., ALFRED M. FREEDMAN, M.D., AND MURIEL THOMAS, R.N.

The narcotic antagonist EN-1639A (naltrexone) wasstudied in 37 heroin addicts andfound to be clinicallyuseful. with a low incidence ofside effects, lack of tox-icily. high degree ofacceptabiity to the patient. and ca-pacily to antagonize the euphoric effects ofheroinfor upto 72 hours after a single oral dose. Thesefindings pro-vide a basis for expanding studies ofthe clinical efficacyof naltrexone in the treatment ofopiate dependence.

DURING INDUCTION to maintenance levels of cyclazocine,which is the narcotic antagonist most widely used for thetreatment of heroin addiction, patients may experiencedysphoric effects. Although tolerance to this agonistic ac-tivity develops, the presence of these effects has been alimiting factor in cyclazocines acceptance as a treatmentmodality. The narcotic antagonist naloxone, althoughvirtually devoid of agonistic activity, has a duration ofaction too short for general clinical usefulness.

On the assumption that the longer duration of activityof cyclazocine might be related to the n-methylcyclopro-pyl side chain on the benzomorphan molecule, a similarn-methylcyclopropyl substitution of naloxone was syn-thesized by Endo Laboratories. This compound, naltrex-one, was found in preliminary studies to be free of majoragonistic activity, with a dose of 50 mg. per day produc-ing a degree of blockade to the effects of morphine com-parable to 4 mg. per day of cyclazocine (1).

This report summarizes the results of a study under-taken to assess the clinical effects of naltrexone, the dura-tion of its narcotic blocking activity, its acceptability topatients, and its usefulness as a treatment for heroin ad-diction. The subjects were 37 patients from a specialstudy ward of Kirby Hospital in New York City whowere detoxified from opiates and induced to naltrexonebetween January and April 1973.

METHOD

The patients were volunteers and were addicted to ei-ther heroin or methadone at the time of admission to theprogram. Some patients volunteered for treatment fol-lowing a period in a methadone maintenance program.One patient had previously been maintained on 10 mg.per day of cyclazocine.

The patients ranged in age from 2 1 to 40 years(mean = 28.3 years). They were predominantly black orPuerto Rican, of low income and low education levels,and had a high incidence of unemployment and use ofpublic assistance. Their opiate addiction had lasted from2 to 20 years.

Before starting on naltrexone, the 37 patients were de-toxified from opiates with decreasing doses of meth-adone. They were then kept drug free for at least oneweek before the administration of naltrexone. Duringthis time each patient received a complete physical exam-ination and the following laboratory tests: chest x-ray,SMA-6, SMA-12, complete blood count, reticulocytecount, platelet count, erythrocyte sedimentation rate, andurinalysis. These examinations were repeated beforeeach patients discharge from the hospital and at monthlyintervals thereafter. Patients were followed in the out-patient clinic, where they were maintained on naltrexoneat daily doses of 120 mg. to 200 mg.

All patients received placebo naltrexone before start-ing on active medication. A symptom checklist was com-pleted at least every other day beginning with the first dayon placebo. During the latter half of this study we incor-porated the procedure of administering intravenous nal-oxone (0.4 mg.) at least one day before the patient beganactive naltrexone. This was done to test for precipitatedabstinence symptoms that might be mistaken for naltrex-one side effects.

The patients blood pressure, temperature, and pulsewere measured before they received medication and everyhour for six hours after medication while they were re-ceiving placebo naltrexone, on their first day of activenaltrexone, and on days when their naltrexone dose wasincreased (except for the initial six patients, for whomthese measurements were taken every day).

The naltrexone was administered as a single oral dailydose. Initial subjects were given a starting dose of 20 mg.per day. Subsequent patients were started on 30, 40, or 50mg. per day. The daily dose increments were 10 or 20 mg.per day.

Patients were stabilized for three to five days at vary-

RESNICK, VOLAVKA, FREEDMAN, AND THOMAS

AmJ Psychiatry l3l.6.June 1974 647

ing dosages during this induction period before beingtested for narcotic blockade by the intravenous adminis-tration of heroin. Twenty-seven patients received heroinchallenges; these were done before induction to naltrex-one and at 6 hours, 24 hours, 48 hours, and 72 hours afterthe patient received various doses of naltrexone (not all27 patients received all the challenges). The patients re-ceived placebo on the days before the 48-hour and 72-hour challenges. Following the challenges they were giventhe next scheduled dose of naltrexone.

Just before the patients received the heroin, their pu-pils were photographed after three minutes accommoda-tion to the dark. We used a specially designed Polaroidcamera with electronic flash. An aqueous solution of 10mg./cc. of heroin was then freshly prepared. The testdose of 2.5 cc. (25 mg.) of heroin was administered intra-venously over a period of 15 to 20 seconds. Another pho-tograph of the pupils was taken in five minutes-again,after accommodation to the dark.

We then determined the subjective effects of the in-jection through the use of a heroin effects questionnaire.Depending on the results of the initial post-naltrexonechallenge the patient was either maintained on the samedose of naltrexone and challenged again after a longer in-terval or inducted to a larger dose before being chal-lenged again. Some patients also received placebo chal-lenges by intravenous administration of saline.

Ten of the patients were abruptly withdrawn from 200mg. per day of naltrexone, after receiving the medicationfor three to eight weeks, by substitution of naltrexoneplacebo for five days. Following this withdrawal periodthey were reinducted on active medication with a startingdose of 50 mg.

RES ULTS

Untoward Effects During Initial Two Days on Naltrex-one

Approximately 30 percent of the patients (13 out of 37)experienced some untoward effects during the two daysfollowing the first dose of naltrexone. Only those effectsthat failed to occur while patients had been on placebowere taken into account. Six patients felt tired or slug-gish, seven felt nervous or irritable, and nine had diffi-culty falling asleep at night. These effects were rated asmild or moderate in intensity and in most instances sub-sided within a few days, even with further increments indose. Gastrointestinal symptoms were reported by fivepatients: Two complained of abdominal pains, two had

nausea, and one vomited after meals.The other 24 patients reported no effects after starting

active naltrexone. No patient reported the persistence ofeffects following stabilization on a fixed daily dose.

Our clinical impression is that these untoward effectsmay, in part, have been the result of precipitated absti-nence from the opiate. This is supported by the followingobservations:

1. After the initial dose of naltrexone the frequency ofgastrointestinal upset decreased with increasing doses.

2. The untoward effects noted were similar to thosethat occur during protracted drug abstinence.

3. The incidence of untoward effects was lower inpatients who entered the study after we introduced test-ing with naloxone, even though these patients receivedlarger initial doses, and fewer untoward effects were evi-dencei at a starting dose of 50 mg. (4 out of I 7, or 24percent) than at 25 mg. (9 out of2O, or45 percent).

4. Of seven patients who received their starting dose ofnaltrexone four weeks or more after their last opiatedose, none experienced any untoward effects.

5. Of four patients who initially experienced some un-toward effects at a 20-mg. starting dose, none experi-enced any untoward effects when reinducted on 50 mg. ofnaltrexone after five days on placebo to test for nal-trexone withdrawal reactions.

One patient reported that he was tripping, like onLSD, following an initial dose of4O mg. This effect to-tally subsided within 60 seconds after he was given 0.4mg. intravenous naloxone. This patient had taken LSDfive times in the past two years (the last time being sixmonths earlier); this LSD-like effect began after hesmoked marijuana before receiving naltrexone and be-came intensified about one-half hour after the naltrexonewas administered.

Untoward Effects During Period ofDaily IncrementsTwenty-two of34 patients experienced no untoward ef-

fects while the dose was being increased to a daily dose of120 to 200 mg.

We found no consistent difference between the in-cidence or intensity of untoward effects appearing withlO-mg.-per-day increments as compared to 20-mg.-per-day increments. There appeared to be wide individualvariation in dose response. Effects reported during theincrement periods were transient and were the same asthose which occurred following the initial dose-i.e., feel-ings of being tired or sluggish, feeling irritable, and hav-ing difficulty sleeping. These effects subsided sponta-neously or were relieved by the addition of 10-20 mg. perday of diazepam.

One patient who had no complaints when receiving in-crements of 10 mg. per day as he was inducted to 120mg. per day developed symptoms of feeling not right,like I wasnt here, floating, inability to concentrate,and slight dizziness when the increments were increasedto 20 mg. during his succeeding induction to 200 mg. perday.

Five patients complained of abdominal cramps, some-times accompanied by mild nausea, but had no vomitingor changes in bowel habits. These complaints were vari-able and appeared to be unrelated to dosage.

One patient with a history of duodenal ulcer experi-enced the severe epigastric pain typical of his previous ul-cer attacks; this was relieved by antacids. He had a nega-tive upper-gastrointestinal and gall bladder x-ray series.Headache was a fairly common transient symptom.

Toxicity

Blood pressure appeared unchanged at all doses, with

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648 AmJ Psychiatry 131:6,June 1974

TABLE IBlockade of Subjective Efficts of 25 ng. Heroin at Varying Times and with Varying Doses of Na/i rexone*

Dose

Time of Challenge

6 Hours 24 Hours 48 Hours 72 Hours

20 mg. 2 blocked2 not blocked

2 not blocked

40mg. 3 blocked4 not blocked

50 mg. 3 blocked60 mg. I blocked I not blocked80 mg. 4 blocked I blocked

2 not blocked120 mg. I blocked 9 blocked 6 blocked 5 not blocked160 mg. 3 blocked 5 blocked I blocked

2 not blocked200 mg. I blocked 3 blocked

2 not blocked4 blocked5 not blocked

*This includes the results of 72 challenges performed on 26 subjects and excludes results for one subject, whose results are given in table 2.**One subject was originally not blocked at this dose and time; on rechallenging he was blocked.

the suggestion ofa trend toward narrowed pulse pressure.Heart rates fluctuated without apparent relation to dos-age. There appeared to be no fluctuations in body tem-perature related to dosage.

Two patients with mild hypertension showed no signif-icant blood pressure changes related to naltrexone. Con-trol of their hypertension was maintained with diuretics(Hydrodiuril, Aldactone) and, for one ofthem, reserpinein addition. No adverse drug interactions were noted withnaltrexone.

Changes in laboratory tests were not statistically sig-nificant or indicative of toxicity.

Withdrawal EffectsNo withdrawal effects were noted before the 48-hour

and 72-hour challenges at naltrexone doses ranging from60 mg. to 200 mg.

Of the 10 patients abruptly withdrawn from 200 mg.per day of naltrexone by substitution of placebo for fivedays, 8 experienced no effects during the withdrawal pe-nod. One patient accurately differentiated placebo fromactive medication. During the placebo days he com-plained he felt bad, tired, sluggish, and had headaches.One patient had abdominal pains and chills for one day,beginning one-half hour after his first dose of placebo.

Blockade to Heroin

When heroin challenges were done prior to patientsreceiving the antagonist (N = 12), all patients reportedfeeling high. The amount of money they stated theywould be willing to pay for the heroin shot rangedfrom 5 to 20 dollars, with a mean of 12 dollars. After 11placebo challenges by intravenous administration of sa-line, no patient reported he felt high, and all patientsplaced a zero dollar value on the shot.

Table 1, which excludes one patient reported sepa-rately, summarizes the results of 72 heroin challengesdone at varying time periods after specified doses of nal-

trexone in 26 subjects, using the patients subjective re-ports as the criterion for blockade. Patients who did notreport experiencing a high from the heroin and whovalued the shot at zero dollars were rated as blocked.Patients who reported feeling high, appeared sleepy orhigh, or placed a dollar value on the shot were ratedas not blocked.

All patients in this group reported experiencing com-plete blockade 24 hours after a 50 mg. or larger dose ofnaltrexone. All but two patients reported blockade 48hours after a 120 mg. or larger dose. One of these twopatients was subsequently rechallenged 48 hours after re-ceiving 200 mg. of naltrexone and evidenced blockade. Infour out of nine trials blockade was reported 72 hours af-ter a dose of 200 mg.

One patient required 200 mg. per day of naltrexone toachieve blockade at 24 hours. Six additional challengesdone on this patient at various time periods and withvarying doses of naltrexone indicated that he was receiv-ing no or only partial protection from heroin effects(table 2). The subjective effects he reported, however, de-creased with increased doses of naltrexone. This last find-ing is consistent with results obtained from other subjectswho received multiple challenges.

We found pupillary constriction to be a highly sensitiveindex of heroin effect. No patient reported effects fromheroin without having associated pupillary constriction.Some had slight pupillary constriction with absent orminimal subjective effects. The average pupillary con-striction in the challenges reported by patients as blockedwas 0.87 mm. In the nonblocked challenges, the averageconstriction was 2.22 mm. The average pupillary con-striction after 25 mg. of heroin in patients unprotected bynaltrexone was 4.10 mm. There was a positive relation-ship between degree of pupillary miosis and subjective ef-fects as measured by the amount of money the subjectstated he would be willing to pay for the shot (see fig-ure 1).

FIGURE 1Means and Total Ranges for Decrease in Pupillarv Diameter AfterIntravenous Heroin Versus Amount of Monet Subject Would BeWilling To Par for a Single Shot

4.0

EE

3.0z0

0

0)z00>-

-J

1.0a-

C

DISCUSSION

$0-2 $2-4 #{182}4-6PRICE WILLING TO PAY

Narcotic antagonists have been shown to be effectivetherapeutic agents in the treatment of opiate depen-dence (2-3). Their use is based upon a conditioning the-ory of narcotic addiction (4). For the period in which thenarcotic antagonist is taken the detoxified addict is pro-tected against readdiction and can be engaged in a reha-bilitation program during which his conditioned drug-seeking behavior may be altered. Following this period of

RESNICK, VOLAVKA, FREEDMAN, AND THOMAS

AmfPsychiatrv 131:6,June 1974 649

TABLE 2Subjective Effects of 25 mg. Heroin on One Subject at Varying Times and with Varting Doses of Naltrexone*

Effects

Dose

20mg. 40 mg. 80mg. 120 mg. 160 mg. 200 mg.

6-hour challengeBlockage Not blockedValue of shot $10Heroin effect score 9

24-hour challengeBlockage Partial Partial Partial BlockedValue of shot $5 $3 $2 $0Heroin effect score 3 2 Not available 0

48-hour challengeBlockage Partial PartialValue of shot $5 $5Heroin effect score 4 Not available

*fore receiving naltrexone the subject was willing to pay $15 to $20 for a heroin shot and scored 14 (out of a maximum score of 15) on the heroin effects question-naire.

treatment the narcotic antagonist can be discontinuedwithout the patients experiencing withdrawal effects.

The relative absence of dysphoric effects of naltrexoneand its ability to provide effective narcotic antagonismfor 24 hours following a single initial dose (50 mg.) formost patients, without the need for a slow inductionschedule, as is the case with cyclazocine, makes it a po-tentially more useful therapeutic agent.

Furthermore, the relative ease with which patients canbe inducted to doses providing effective narcotic antago-nism for 72 hours is advantageous when compared withcyclazocine (5). The untoward effects reported in thisstudy may in part be due to precipitated abstinencesymptoms, to which they are similar (6).

In this report no attempt has been made to analyze thedegree of blockade experienced by patients who were notcompletely blocked. Even a mild or transient heroin ef-fect was rated as not blocked. It is likely that under clini-cal conditions there would be a greater incidence of nar-cotic blockade (after an equal time period and equal

I naltrexone dose) because the amount of pure heroin used$6-8 $8-b by addicts in the streets is most frequently less than 25

mg. per injection.We are currently studying the effects of parenterally

administered naltrexone, including the relationship be-tween plasma levels ofthe medication and its narcotic an-tagonist effect. These studies may help elucidate the ex-tent to which individual variations in narcotic blockingactivity are due to gastrointestinal absorption or meta-bolic factors and also may provide a basis for judging thefeasibility of incorporating naltrexone into a slow-releaseimplant.

To be clinically useful in treating opiate dependence anarcotic antagonist should be orally effective, non-addicting, and should provide blockade to heroin formore than 24 hours following a single dose. Naltrexoneappears to fulfill these criteria.

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650 AmJ Psychiatry 131:6,June 1974

REFERENCES

I. Martin WR, iasinski DR. Mansky PA: Naltrexone, an antagonistfor the treatment of heroin dependence. Arch Gen Psychiatry28:784-791, 1973

2. Resnick R, Fink M, Freedman AM: A cyclazocine typology inopiate dependence. Am J Psychiatry 126:1256-1260, 1970

3. Resnick R, Fink M, Freedman AM: Cyclazocine therapy of opiatedependence a progress report. Compr Psychiatry 12:49 1-502, 1971

4. Wikler A: Dynamics of drug dependence. Arch Gen Psychiatry28:611-616, 1973

5. Resnick R, Fink M, Freedman AM: High-dose cyclazocine therapyof opiate dependence. Am J Psychiatry 13 1:595-597, 1974

6. Martin WR, Jasinski DR, Haertzen CA, et al: Methadone-a re-evaluation. Arch Gen Psychiatry 28:286-295, 1973