- Email: [email protected]
Effects of sublingually given naloxone in opioid-dependent human volunteers
27
Drug and Alcohol Dependence, 25 (1990127-34 Elsevier Scientific Publishers Ireland Ltd.
Effects of sublingually given naloxone opioid-dependent human volunteers
Kenzie L. Preston, Department
of Psychiatry
in
George E. Bigelow and ha A. Liebson
and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21224 ILEA.) (Received July 31st. 19891
To determine whether sublingual naloxone could precipitate withdrawal in opioid-dependent subjects, naloxone was administered in increasing doses (O-8 mg in four or six sessions conducted over 2 days) to six heroin abusers and three methadone (30 mglday, p.o.1 maintenance patients. Two or three sessions were conducted per day with 2- to 2.5-h intervals between sameday sessions. Naloxone precipitated withdrawal in two of six heroin abusers and in all three methadone subjects. Naloxone is sufficiently absorbed sublingually to precipitate abstinence in dependent subjects, but naloxone doses up to l-2 mg can be administered sublingually to opioid abusers/addicts without precipitating withdrawal. Key words: opioid antagonist; naloxone; opioid withdrawal/physical administration
Introduction
Naloxone hydrochloride is an opioid antagonist that can block the acute effects of opioid agonists. Thus, it will reverse a narcotic overdose or surgical narcotic analgesia and associated respiratory depression [l] and will precipitate withdrawal symptoms in subjects who are physically dependent on opioids [2]. The potency of naloxone when injected is reported to be 50-250 times greater than when administered by the oral route [3,4]. Because of its low activity following oral administration, naloxone has primarily been used parenterally. However, some applications of orally given naloxone have been tested including its use in antagonist maintenance therapy of opioid abuse [5,6] and in combination products with opioid analgesics such as morphine Correspondence to: Kenxie L. Preston, Johns Hopkins/Key Medical Center, BPRU, D&West, 4940 Eastern Avenue, Baltimore, MD 21224, U.S.A.
dependence; human subjects; methadone; sublingual
[7], methadone [4,8], pentazocine [9] and tilidine [lo]. The purpose of combining naloxone with an opioid analgesic is to decrease the parenteral abuse of oral analgesics and takes advantage of the low oral activity of naloxone. Appropriate doses of naloxone can be combined with an opioid analgesic such that the naloxone is inactive and does not affect the analgesic actions of the opioid agonist when the combination is taken orally, but, if the combination is misused parenterally, the naloxone dose is active and is sufficient either to block the agonist’s effects or to precipitate withdrawal in a physically dependent abuser. Another opioid analgesic that may be suitable for combination with naloxone is the partial opioid agonist buprenorphine, a drug being tested for use in the treatment of opioid dependence [11,12]. Buprenorphine is administered therapeuticaly by the sublingual route. The purpose of this study was to evaluate the withdrawal precipitating capacity of naloxone when
0376~8716/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
28
given sublingually to human volunteers with low levels of opioid dependence, such as are commonly seen in patients applying for detoxification from street opioids, in order to estimate an appropriate naloxone dose range for combination with sublingual buprenorphine. This report describes the effects of sublingual administration of naloxone to two populations of subjects, patients who are not currently in treatment and who are applying for detoxification from street opioids (Studies 1 and 2) and patients who are currently in methadone maintenance treatment (Study 3). The methods used in the present study to measure opioid withdrawal are similar to those used previously to evaluate the effects of combinations of buprenorphine and naloxone and to assess the antagonist effects of butorphanol, nalbuphine and naloxone in methadone-dependent volunteers [13- 151. Methods
Subjects Nine subjects participated while residing in Table 1. Subj.
Characteristics Age
of subjects.
Weight Race (lb)
study 1 2 3
1”
study 4 5
2’
6
study 7 8 9
an 8-bed behavioral pharmacology research ward which has been described previously [16]. Demographic information is shown in Table 1. The subjects in Studies 1 and 2 were six adult male opioid-abusing volunteers who were applying for detoxification from opioids. All of the subjects met the criteria for methadone detoxification based on history and reported drug use. Urine drug screens of samples collected the day before or the day of admission of all six subjects confirmed the presence of opiates and/or methadone. These subjects received an initial dose of 20 mg methadone on the day of admission to the research ward which was one day prior to begining the study. Methadone 20 mg doses were given once every 24 h at 16:30 h thereafter. Following completion of the study, subjects were enrolled in a methadone detoxification program. The subjects in Study 3 were three adult male volunteers who were receiving methadone HC130 mg p.o. daily but were otherwise drug-free at the time of their research participation. These subjects had been receiving methadone maintenance treatment for at least 30 days and had been receiving 30 mg methadone daily for at least 7
Meth. dose (mg)
Years of opioid use
Current drug use (drug; times/day; approx. amount/day)
Highest dose of naloxone tested (mg)
Signs of withdrawal
40 40 27
126 176 152
B B B
20 20 20
16 15 7
Heroin; 3 times Heroin; 2-3 times; $150 Heroin; 2-3 times: $100-200
4 4 4
No No No
30 30
145 162
B B
20 20
15 14
Heroin; 23 times; $50-100 Heroin; 3-5 times; $200-300
8 4
No Yes
29
134
w
20
9
Heroin & Non-Rx Methadone 45 mg; one or both daily; $100
4
Yes
Methadone Maintenance 30 mg Methadone Maintenance 30 mg Methadone Maintenance 30 mg
4 1 4
Yes Yes Yes
3” 45 34 30
265 150 203
W w B
30 30 30
Doses of naloxone tested: placebo, 0.4,0.8,1,2,4. bDoses of naloxone tested: placebo, 2,4,8. ‘Doses of naloxone tested: placebo, 0.25,0.5,1,2,4.
12 12 a
29
days. Methadone doses were administered once every 24 h at 16:30 h (17 h prior to test sessions). On the basis of physical examination, history and laboratory chemistries, all subjects were found to be without significant medical or psychiatric disturbance other than their drug abuse. This project was approved by the appropriate Institutional Review Boards, and subjects gave their written informed consent prior to beginning the study and were paid for their participation. Drugs Each subject participated in experimental sessions on 2 consecutive days. Subjects in Studies 1 and 3 participated in three sessions on each day; subjects in Study 2 participated in two sessions on each day. Since the response to sublingually given naloxone was not known, doses of naloxone were presented in an ascending series. The ascending dose series was stopped whenever subject reactions were so intense that the subject threatened to discontinue participation or when the experimenter judged it ethically unacceptable to administer higher doses. In Study 1 doses of naloxone were increased to the maximum dose of 4 mg with no measurable response. Based on our experiences in Study 1, the dose-range was adjusted in Study 2 to a maximum possible dose of 8 mg naloxone. Subjects were informed that they would receive placebo and a range of doses of naloxone and that they might experience some withdrawal discomfort but were not informed of the ascending dosing schedule. All doses were given sublingually in a constant volume of 0.5 ml using an adjustable volume pipette. Number of test sessions/day, time Table 2.
Experimental session Experimental sessions were conducted in a quiet testing room. All subjective effect and psychomotor performance measures were presented on a computer screen. After a 15-min stabilization period, 15 min of baseline physiological recording was taken; a pupil photo was taken, and the subject answered subjective effect questionnaires. Approximately 30 min after the start of the physiological recording, subjects received either sterile water (placebo) or active drug sublingually. The session continued in the testing room for 1 - 2 h after each drug dosing. Between sessions conducted on the same day subjects left the session room and were allowed to relax in a supervised lounge/recreational area. Subjects were returned to the session room 5- 10 min prior to the next session, and the baseline was re-established. Physiological measures Four physiological measures were monitored continuously throughout each session in
Session schedule.
Experiment
1 2 3
intervals between drug administrations given on the same day and doses for each experiment are listed in Table 2. Naloxone hydrochloride powder was dissolved in sterile water and diluted to a constant volume of 0.5 ml with sterile water. Sterile water (0.5 ml) served as placebo. The drug was administered by a nurse, and the subject was instructed to hold the liquid under his tongue for 10 mins. The technician conducting the session closely observed the subject during this period to assure compliance. Naloxone doses were calculated on the basis of the salt.
Subjects
l-3 4-6 7-9
Sessions/day
3 2 3
Doses of naloxone (mg) Day 1
Day 2
0,0.4,0.8 092 0,0.25,0.5
1,2,4 493 1.0,2.0,4.0
Time interval between same-day sessions (h)
2 2.5 2.5 _
30
the experimental testing room: heart rate and blood pressure (measured automatically once per min), skin temperature (monitored using a skin surface thermistor taped to the middle finger of one hand) and respiration (monitored using a bellows placed around the lower chest and connected to a pressure sensitive switch). Pupil diameter was determined from photographs taken in ambient room lighting using a Polaroid camera with a 3X magnification. Pupil photographs were taken 15 min before drug administration and at 15-min intervals postdrug administration. Subject-rated and observer-rated measures Subjective effect and observer rating forms were completed 15 min before drug administration and at 15-min intervals post-drug administration. The subject was instructed to give answers describing how he felt at the time he filled out the questionnaires. The three questionnaires completed by subjects included visual analog scales, a pharmacological class identification questionnaire, and an adjective rating questionnaire. On the visual analog scales, the subject rated his current degree of ‘High’ and ‘Sick’ and the degree of ‘Any Drug Effect’, ‘Good Effects’, ‘Bad Effects’ and ‘Liking’ of the drug effects by placing an arrow along a 100 point line marked at either end with ‘none’ and ‘extremely.’ On the pharmacological class identification questionnaire, the subject categorized the drug effect as being most similar to one of the following ten classes of psychoactive drugs: placebo, opiates, opiate antagonists, phenothiazines, barbiturates and sleeping medications, antidepressants, hallucinogens, benzodiazepines, stimulants and other. The adjective rating questionnaire consisted of 37 items which the subject rated on a 5point scale from 0 Cno effect’) to 4 (‘maximum effect’). The items in the rating scale were divided into two subscales: (1) an opioid Agonist scale (nodding, heavy or sluggish feeling, dry mouth, carefree, good mood, energetic, turning of stomach, skin itchy, relaxed, coasting, soapbox/ talkative, pleasant sick, drive, drunken, friendly and nervous), and (2) a Withdrawal
scale (muscle cramps, flushing, painful joints, yawning, restless, watery eyes, runny nose, chills or gooseflesh, sick to stomach, sneezing, abdominal cramps, irritable, backache, tense and jittery, sweating, depressed/sad, sleepy, shaky (hands), hot or cold flashes, bothered by noises and skin clammy and damp). The Agonist and Withdrawal scales were scored by summing the ratings for each of all items in the respective scales to produce a total score for each scale. Observer ratings were completed by a research technician who was present during the entire session and who rated the subject’s drug effect at the same time intervals and using the same adjective list as the subject himself. The observer’s ratings were scored in the same way as the subject-rated scales. Observers also rated subjects for the presence or absence of six opioid withdrawal signs (lacrimation, rhinorrhea, yawning, perspiration, piloerection and restlessness) at each observation; total Withdrawal Sign scale scores were calculated by summing the number of items indicated as being present at each of the six postdrug observation periods. Results The effects of sublingual naloxone in the subjects recruited from waiting lists for methadone detoxification varied substantially. Subjects l-3 (Study 1) completed all experimental sessions, receiving doses up to naloxone 4 mg; no signs or symptoms of naloxone-precipitated withdrawal were reported consistently or observed for any of these subjects during any experimental session. Since no signs of withdrawal occurred at doses of naloxone up to 4 mg, subjects 4 - 6 (Study 2) were assigned to a dose schedule for up to 8 mg of naloxone to be given. Subject 4 showed no consistent signs or symptoms of withdrawal following the administration of naloxone at doses up to and including 8 mg. Subjects 5 and 6 showed slight signs and symptoms of withdrawal and identified the drug as an antagonist at naloxone 2 mg; following the administration of naloxone 4 mg, these
31
measures for subjects 1 - 6 (Street Addicts) are shown in Fig. 1. Overall, there was a trend for measures of withdrawal to increase after administration of naloxone 2 and 4 mg. On the Pharmacological Class Questionnaire, subjects l-6 identified placebo as an opioid antagonist in 12.5% of opportunities, 2 mg naloxone as an
subjects identified the drug as an antagonist and showed marked signs of withdrawal, including vomiting (Subject 5). Because of these intense effects at 4 mg naloxone subjects 5 and 6 were not tested with the 8 mg dose. Effects of naloxone 2 and 4 mg (the doses given to all six subjects in the street addict group) on selected
PUPIL DIAMETER
DRUG EFFECT VISUAL ANALOG SCALE 2M
5
1
4
-3
T
1
J
,
P
2
4
P
25
5
1
2
I
4
WITHDRAWAL SIGNS - TOTAL SCORE
SICK VISUAL ANALOG SCALE
SUBJECT-RATED WITHDRAWAL
OBSERVER-RATED WITHDRAWAL
100 80
A
0
-20
1 , P
2
Street Addicts
4
#
P
1
25
I
1
I
1
5
1
2
4
-10
Methadone Maintamed Subjects
Naloxone (mg)
Naloxone (mg)
Fig. 1. Dose effect functions are shown for the effects of sublingually given naloxone on representative subjective and objective indices of precipitated opioid withdrawal. Data are pres&ted as the mean sum of the responses (collected four times at 15 min intervals) for the first 66 min after drug administration and are shown separately for street addict subjects W= 6) and methadone maintained subjects Uv = 3. filled symbols; N = 2, open symbols). All measures (except Total Withdrawal Signs) are presented as changes from baseline: post-drug data only are reported for Total Withdrawal Signs. Brackets are f S.E.M.
32
opioid antagonist in 33.3% of opportunities, and 4 mg naloxone as an opioid antagonist in 37.5% of opportunities; for subjects 5 and 6 only these respective percentages were O%, 60% and 70%. It was clear from the first six subjects that naloxone could precipitate withdrawal in opioid dependent subjects, but there was considerable between-subject variability. One likely reason for this variability in response was that the degree of physical dependence differed among street addicts, due to their varied patterns and amounts of opioid use. Therefore, an additional group of subjects with known (and relatively low) levels of opioid use were tested - i.e. the 30 mg methadone-maintained subjects in Study 3. The responses to sublingually given naloxone in these methadone maintenance patients also varied, but to a lesser degree than in the street addicts. Subjects 7 and 9 completed the ascending dose series (receiving naloxone 4 mgl; in the third subject in this group (Subject 8) the ascending dose sequence was stopped following the administration of 1 mg naloxone because a moderate degree of precipitated withdrawal was produced. Figure 1 shows the mean across the three methadone-maintained subjects for selected measures; results from two subjects are shown for 2 and 4 mg naloxone. Drug Effect and Sick visual analog scales and the subject-rated Withdrawal adjective rating scale were increased with increasing doses of naloxone, as were the observer-rated Withdrawal adjective rating scale and the Total Withdrawal Signs scale. On the Pharmacological Class Questionnaire, methadone maintained subjects identified each drug treatment as opioid antagonist in the following percent of opportunities: placebo - 0%; 0.25 mg naloxone - 41.7%, 0.5 mg naloxone - 16.7%; 1 mg naloxone - 58.3%; 2 mg naloxone - 75%; 4 mg naloxone - 85.7%. Although overall the withdrawal syndrome produced by sublingual naloxone was similar to that produced by intramuscular naloxone in other studies [13 - 151, there were some differOnset of precipitated withdrawal ences. occurred at 30 min following sublingual admin-
istration of naloxone while onset of effects of intramuscular naloxone occurs within 15 min of administration. Skin temperature also did not show a decrease accompanying the onset of withdrawal with sublingual naloxone as is characteristically seen following intramuscular naloxone [13 - 151. Also, characteristic pupil dilation was not consistently seen in subjects showing sublingually precipitated withdrawal; subjects in Study 2 showed substantial pupil dilation while subjects in Study 3 showed only a modest increase in pupil diameter (Fig. 11. Increases in scales associated with opioid agonist effects (such as the Agonist adjective rating scale, liking, etc.1 were not seen following administration of any dose tested. Discussion
Among the six subjects using street heroin prior to participating in this study there were variable responses to sublingually given naloxone. Four subjects (l-4) showed no apparent signs of opioid withdrawal following doses of naloxone up to 4 mg; one of these subjects (41 also showed no withdrawal response to 8 mg naloxone. Two of the six subjects, however, showed marked withdrawal reactions following administration of 4 mg naloxone. One likely explanation is that differences in levels of opioid dependence accounted for these differences in response. Subjects’ reported drug use histories are compatible with this suggestion. Of the two street addicts who exhibited naloxone-induced withdrawal subject five reported a higher daily use of heroin than subjects l-4, and subject 6 reported using heroin and supplementing this with methadone (reportedly 45 mg) several times weekly. Although all of the subjects in Studies 1 and 2 were recruited from waiting lists for methadone detoxification at local treatment agencies, gave opiate positive urines prior to admission to the study, and were clinically judged to be opioid dependent, it is not known whether the four subjects who showed no response to sublingual naloxone were actually physically dependent and would have shown withdrawal reactions to naloxone administered by a parenteral route. Not
33
surprisingly, there is a sizable range of dependence levels among street addicts seeking treatment. Variability in response, and in some cases lack of response to naloxone among applicants for methadone treatment has been noted previously [l’i’]. It would have been advantageous to have tested each subject with parenteral naloxone both as a test for physical dependence and to compare directly the effects given of sublingually and parenterally naloxone. Because of the variability of both current drug use and naloxone response in Studies 1 and 2, Study 3 was conducted with subjects with known and relatively low physical dependence on opioids, methadone maintenance patients on low-dose treatment (30 mgl. Sublingually administered naloxone precipitated withdrawal in all three of these opioiddependent subjects. Although some variability in response to naloxone was seen, this variability was less than that found among the street addicts in the first two groups. These results suggest that, in our study, the street addicts seeking methadone detoxification had lower levels of physical dependence than that produced by administration of 30 mg methadone daily. Additional causes of the variability in the response to naloxone following sublingual administration may include, but are not limited to, variable absorption of drug among subjects and differences in compliance in holding the drug under the tongue for 10 min. We have no way of knowing the roles of these factors since we have no information about blood levels of naloxone in our subjects. Subjects were carefully observed following drug administration though we cannot rule out the possibility that some subjects may have swallowed some or all of the administered fluid before the allotted 10 min. However, previous work has shown this procedure to produce orderly dose-related effects with other sublingually administered compounds [12]. Although they were not specifically questioned about the taste, most subjects spontaneously indicated that the taste of the active naloxone doses was quite unpleasant.
Detection of naloxone by taste was not sufficient to produce withdrawal-like responses. In previous work [13- 151 we have shown that 0.1-0.2 mg naloxone given intramuscularly will precipitate withdrawal in subjects maintained on methadone 30 mg/day. This, in combination with the present findings, suggests a parenteral to sublingual potency ratio of approximately lo- to 20-fold for naloxone. Buprenorphine, in contrast, has approximately a 2-fold parenteral to sublingual potency ratio. Thus, a buprenorphine-naloxone combination product might be designed that would deliver little naloxone when taken by the appropriate sublingual route, but that would deliver a pharmacologically quite effective dose of naloxone if misused by the parenteral route. That precipitated withdrawal was observed in five of nine subjects validates both the biological delivery of naloxone by the sublingual route and the sensitivity of the measurement procedures for detecting these naloxone effects. The results in all nine subjects document that naloxone doses up to l-2 mg can be administered sublingually to opioid abusers/ addicts without precipitating detectable withdrawal signs or symptoms. This is 10 - 20 times the dose required to precipitate withdrawal by injection. Thus, the inclusion of naioxone in sublingual opioid products might be expected to reduce their potential for parenteral abuse by abusers. Acknowledgements This study was supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse. References 1 2 3 4
W.R. Martin, Ann. Intern. Med. 85 (1976) 765. D.R. Jasinski et al., J. Pharmacol. Exp. Ther., (1967) 420. H.G. Dayton and H. Blumberg, Fed. Proc., 686. J.G. Nutt and D.R. Jasinski, Clin. Pharmacol. (19’74) 156.
157
29 (1970) Ther., 15
34 5 6 7 8 9 10 11 12 13
M. Fink et al., Cur. Psychiatr. Ther.. 10 (1970) 161. A.A. Kurland, Int. J. Addict., 8 (1973) 127. P.K. Gupta and J.W. Dundee, Anaesthesia, 29 (19’74) 33. S.D. Parwatikar and RR. Knowles, Clin. Pharmacol. Ther., 14 (1973) 941. J. Legros et al., Arch. Int. Pharmacodyn. 271(1984) 11. F. Hoffmeister, Psychopharmacology, 90 (1986) 441. W.K. Bickel et al., Clin. Pharmacol. Ther., 43 (1988) 72. W.K. Bickel et al., J. Pharmacol. Exp. Ther., 247 (1988) 47. K.L. Preston et al., Psychopharmacology, 94 (1988) 484.
14 15 16 17
K.L. Preston et al., J. Pharmacol. Exp. Ther., 246 (1988) 441. K.L. Preston et al., J. Pharmacol. Exp. Ther., 248 (1989) 929. R.R. Griffiths et al., J. Pharmacol. Exp. Ther., 215 (1980) 649. C.P. O’Brien et al., Clinical pharmacology of narcotic antagonists. In: B. Kissin, J.H. Lowinson. and R.B. Millman Recent Developments in (Eds.1, Chemotherapy of Narcotic Addiction Vol. 311, The New York Academy of Sciences, New York, 1978, pp. 232 - 240.
Drug and Alcohol Dependence, 25 (1990127-34 Elsevier Scientific Publishers Ireland Ltd.
Effects of sublingually given naloxone opioid-dependent human volunteers
Kenzie L. Preston, Department
of Psychiatry
in
George E. Bigelow and ha A. Liebson
and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21224 ILEA.) (Received July 31st. 19891
To determine whether sublingual naloxone could precipitate withdrawal in opioid-dependent subjects, naloxone was administered in increasing doses (O-8 mg in four or six sessions conducted over 2 days) to six heroin abusers and three methadone (30 mglday, p.o.1 maintenance patients. Two or three sessions were conducted per day with 2- to 2.5-h intervals between sameday sessions. Naloxone precipitated withdrawal in two of six heroin abusers and in all three methadone subjects. Naloxone is sufficiently absorbed sublingually to precipitate abstinence in dependent subjects, but naloxone doses up to l-2 mg can be administered sublingually to opioid abusers/addicts without precipitating withdrawal. Key words: opioid antagonist; naloxone; opioid withdrawal/physical administration
Introduction
Naloxone hydrochloride is an opioid antagonist that can block the acute effects of opioid agonists. Thus, it will reverse a narcotic overdose or surgical narcotic analgesia and associated respiratory depression [l] and will precipitate withdrawal symptoms in subjects who are physically dependent on opioids [2]. The potency of naloxone when injected is reported to be 50-250 times greater than when administered by the oral route [3,4]. Because of its low activity following oral administration, naloxone has primarily been used parenterally. However, some applications of orally given naloxone have been tested including its use in antagonist maintenance therapy of opioid abuse [5,6] and in combination products with opioid analgesics such as morphine Correspondence to: Kenxie L. Preston, Johns Hopkins/Key Medical Center, BPRU, D&West, 4940 Eastern Avenue, Baltimore, MD 21224, U.S.A.
dependence; human subjects; methadone; sublingual
[7], methadone [4,8], pentazocine [9] and tilidine [lo]. The purpose of combining naloxone with an opioid analgesic is to decrease the parenteral abuse of oral analgesics and takes advantage of the low oral activity of naloxone. Appropriate doses of naloxone can be combined with an opioid analgesic such that the naloxone is inactive and does not affect the analgesic actions of the opioid agonist when the combination is taken orally, but, if the combination is misused parenterally, the naloxone dose is active and is sufficient either to block the agonist’s effects or to precipitate withdrawal in a physically dependent abuser. Another opioid analgesic that may be suitable for combination with naloxone is the partial opioid agonist buprenorphine, a drug being tested for use in the treatment of opioid dependence [11,12]. Buprenorphine is administered therapeuticaly by the sublingual route. The purpose of this study was to evaluate the withdrawal precipitating capacity of naloxone when
0376~8716/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
28
given sublingually to human volunteers with low levels of opioid dependence, such as are commonly seen in patients applying for detoxification from street opioids, in order to estimate an appropriate naloxone dose range for combination with sublingual buprenorphine. This report describes the effects of sublingual administration of naloxone to two populations of subjects, patients who are not currently in treatment and who are applying for detoxification from street opioids (Studies 1 and 2) and patients who are currently in methadone maintenance treatment (Study 3). The methods used in the present study to measure opioid withdrawal are similar to those used previously to evaluate the effects of combinations of buprenorphine and naloxone and to assess the antagonist effects of butorphanol, nalbuphine and naloxone in methadone-dependent volunteers [13- 151. Methods
Subjects Nine subjects participated while residing in Table 1. Subj.
Characteristics Age
of subjects.
Weight Race (lb)
study 1 2 3
1”
study 4 5
2’
6
study 7 8 9
an 8-bed behavioral pharmacology research ward which has been described previously [16]. Demographic information is shown in Table 1. The subjects in Studies 1 and 2 were six adult male opioid-abusing volunteers who were applying for detoxification from opioids. All of the subjects met the criteria for methadone detoxification based on history and reported drug use. Urine drug screens of samples collected the day before or the day of admission of all six subjects confirmed the presence of opiates and/or methadone. These subjects received an initial dose of 20 mg methadone on the day of admission to the research ward which was one day prior to begining the study. Methadone 20 mg doses were given once every 24 h at 16:30 h thereafter. Following completion of the study, subjects were enrolled in a methadone detoxification program. The subjects in Study 3 were three adult male volunteers who were receiving methadone HC130 mg p.o. daily but were otherwise drug-free at the time of their research participation. These subjects had been receiving methadone maintenance treatment for at least 30 days and had been receiving 30 mg methadone daily for at least 7
Meth. dose (mg)
Years of opioid use
Current drug use (drug; times/day; approx. amount/day)
Highest dose of naloxone tested (mg)
Signs of withdrawal
40 40 27
126 176 152
B B B
20 20 20
16 15 7
Heroin; 3 times Heroin; 2-3 times; $150 Heroin; 2-3 times: $100-200
4 4 4
No No No
30 30
145 162
B B
20 20
15 14
Heroin; 23 times; $50-100 Heroin; 3-5 times; $200-300
8 4
No Yes
29
134
w
20
9
Heroin & Non-Rx Methadone 45 mg; one or both daily; $100
4
Yes
Methadone Maintenance 30 mg Methadone Maintenance 30 mg Methadone Maintenance 30 mg
4 1 4
Yes Yes Yes
3” 45 34 30
265 150 203
W w B
30 30 30
Doses of naloxone tested: placebo, 0.4,0.8,1,2,4. bDoses of naloxone tested: placebo, 2,4,8. ‘Doses of naloxone tested: placebo, 0.25,0.5,1,2,4.
12 12 a
29
days. Methadone doses were administered once every 24 h at 16:30 h (17 h prior to test sessions). On the basis of physical examination, history and laboratory chemistries, all subjects were found to be without significant medical or psychiatric disturbance other than their drug abuse. This project was approved by the appropriate Institutional Review Boards, and subjects gave their written informed consent prior to beginning the study and were paid for their participation. Drugs Each subject participated in experimental sessions on 2 consecutive days. Subjects in Studies 1 and 3 participated in three sessions on each day; subjects in Study 2 participated in two sessions on each day. Since the response to sublingually given naloxone was not known, doses of naloxone were presented in an ascending series. The ascending dose series was stopped whenever subject reactions were so intense that the subject threatened to discontinue participation or when the experimenter judged it ethically unacceptable to administer higher doses. In Study 1 doses of naloxone were increased to the maximum dose of 4 mg with no measurable response. Based on our experiences in Study 1, the dose-range was adjusted in Study 2 to a maximum possible dose of 8 mg naloxone. Subjects were informed that they would receive placebo and a range of doses of naloxone and that they might experience some withdrawal discomfort but were not informed of the ascending dosing schedule. All doses were given sublingually in a constant volume of 0.5 ml using an adjustable volume pipette. Number of test sessions/day, time Table 2.
Experimental session Experimental sessions were conducted in a quiet testing room. All subjective effect and psychomotor performance measures were presented on a computer screen. After a 15-min stabilization period, 15 min of baseline physiological recording was taken; a pupil photo was taken, and the subject answered subjective effect questionnaires. Approximately 30 min after the start of the physiological recording, subjects received either sterile water (placebo) or active drug sublingually. The session continued in the testing room for 1 - 2 h after each drug dosing. Between sessions conducted on the same day subjects left the session room and were allowed to relax in a supervised lounge/recreational area. Subjects were returned to the session room 5- 10 min prior to the next session, and the baseline was re-established. Physiological measures Four physiological measures were monitored continuously throughout each session in
Session schedule.
Experiment
1 2 3
intervals between drug administrations given on the same day and doses for each experiment are listed in Table 2. Naloxone hydrochloride powder was dissolved in sterile water and diluted to a constant volume of 0.5 ml with sterile water. Sterile water (0.5 ml) served as placebo. The drug was administered by a nurse, and the subject was instructed to hold the liquid under his tongue for 10 mins. The technician conducting the session closely observed the subject during this period to assure compliance. Naloxone doses were calculated on the basis of the salt.
Subjects
l-3 4-6 7-9
Sessions/day
3 2 3
Doses of naloxone (mg) Day 1
Day 2
0,0.4,0.8 092 0,0.25,0.5
1,2,4 493 1.0,2.0,4.0
Time interval between same-day sessions (h)
2 2.5 2.5 _
30
the experimental testing room: heart rate and blood pressure (measured automatically once per min), skin temperature (monitored using a skin surface thermistor taped to the middle finger of one hand) and respiration (monitored using a bellows placed around the lower chest and connected to a pressure sensitive switch). Pupil diameter was determined from photographs taken in ambient room lighting using a Polaroid camera with a 3X magnification. Pupil photographs were taken 15 min before drug administration and at 15-min intervals postdrug administration. Subject-rated and observer-rated measures Subjective effect and observer rating forms were completed 15 min before drug administration and at 15-min intervals post-drug administration. The subject was instructed to give answers describing how he felt at the time he filled out the questionnaires. The three questionnaires completed by subjects included visual analog scales, a pharmacological class identification questionnaire, and an adjective rating questionnaire. On the visual analog scales, the subject rated his current degree of ‘High’ and ‘Sick’ and the degree of ‘Any Drug Effect’, ‘Good Effects’, ‘Bad Effects’ and ‘Liking’ of the drug effects by placing an arrow along a 100 point line marked at either end with ‘none’ and ‘extremely.’ On the pharmacological class identification questionnaire, the subject categorized the drug effect as being most similar to one of the following ten classes of psychoactive drugs: placebo, opiates, opiate antagonists, phenothiazines, barbiturates and sleeping medications, antidepressants, hallucinogens, benzodiazepines, stimulants and other. The adjective rating questionnaire consisted of 37 items which the subject rated on a 5point scale from 0 Cno effect’) to 4 (‘maximum effect’). The items in the rating scale were divided into two subscales: (1) an opioid Agonist scale (nodding, heavy or sluggish feeling, dry mouth, carefree, good mood, energetic, turning of stomach, skin itchy, relaxed, coasting, soapbox/ talkative, pleasant sick, drive, drunken, friendly and nervous), and (2) a Withdrawal
scale (muscle cramps, flushing, painful joints, yawning, restless, watery eyes, runny nose, chills or gooseflesh, sick to stomach, sneezing, abdominal cramps, irritable, backache, tense and jittery, sweating, depressed/sad, sleepy, shaky (hands), hot or cold flashes, bothered by noises and skin clammy and damp). The Agonist and Withdrawal scales were scored by summing the ratings for each of all items in the respective scales to produce a total score for each scale. Observer ratings were completed by a research technician who was present during the entire session and who rated the subject’s drug effect at the same time intervals and using the same adjective list as the subject himself. The observer’s ratings were scored in the same way as the subject-rated scales. Observers also rated subjects for the presence or absence of six opioid withdrawal signs (lacrimation, rhinorrhea, yawning, perspiration, piloerection and restlessness) at each observation; total Withdrawal Sign scale scores were calculated by summing the number of items indicated as being present at each of the six postdrug observation periods. Results The effects of sublingual naloxone in the subjects recruited from waiting lists for methadone detoxification varied substantially. Subjects l-3 (Study 1) completed all experimental sessions, receiving doses up to naloxone 4 mg; no signs or symptoms of naloxone-precipitated withdrawal were reported consistently or observed for any of these subjects during any experimental session. Since no signs of withdrawal occurred at doses of naloxone up to 4 mg, subjects 4 - 6 (Study 2) were assigned to a dose schedule for up to 8 mg of naloxone to be given. Subject 4 showed no consistent signs or symptoms of withdrawal following the administration of naloxone at doses up to and including 8 mg. Subjects 5 and 6 showed slight signs and symptoms of withdrawal and identified the drug as an antagonist at naloxone 2 mg; following the administration of naloxone 4 mg, these
31
measures for subjects 1 - 6 (Street Addicts) are shown in Fig. 1. Overall, there was a trend for measures of withdrawal to increase after administration of naloxone 2 and 4 mg. On the Pharmacological Class Questionnaire, subjects l-6 identified placebo as an opioid antagonist in 12.5% of opportunities, 2 mg naloxone as an
subjects identified the drug as an antagonist and showed marked signs of withdrawal, including vomiting (Subject 5). Because of these intense effects at 4 mg naloxone subjects 5 and 6 were not tested with the 8 mg dose. Effects of naloxone 2 and 4 mg (the doses given to all six subjects in the street addict group) on selected
PUPIL DIAMETER
DRUG EFFECT VISUAL ANALOG SCALE 2M
5
1
4
-3
T
1
J
,
P
2
4
P
25
5
1
2
I
4
WITHDRAWAL SIGNS - TOTAL SCORE
SICK VISUAL ANALOG SCALE
SUBJECT-RATED WITHDRAWAL
OBSERVER-RATED WITHDRAWAL
100 80
A
0
-20
1 , P
2
Street Addicts
4
#
P
1
25
I
1
I
1
5
1
2
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-10
Methadone Maintamed Subjects
Naloxone (mg)
Naloxone (mg)
Fig. 1. Dose effect functions are shown for the effects of sublingually given naloxone on representative subjective and objective indices of precipitated opioid withdrawal. Data are pres&ted as the mean sum of the responses (collected four times at 15 min intervals) for the first 66 min after drug administration and are shown separately for street addict subjects W= 6) and methadone maintained subjects Uv = 3. filled symbols; N = 2, open symbols). All measures (except Total Withdrawal Signs) are presented as changes from baseline: post-drug data only are reported for Total Withdrawal Signs. Brackets are f S.E.M.
32
opioid antagonist in 33.3% of opportunities, and 4 mg naloxone as an opioid antagonist in 37.5% of opportunities; for subjects 5 and 6 only these respective percentages were O%, 60% and 70%. It was clear from the first six subjects that naloxone could precipitate withdrawal in opioid dependent subjects, but there was considerable between-subject variability. One likely reason for this variability in response was that the degree of physical dependence differed among street addicts, due to their varied patterns and amounts of opioid use. Therefore, an additional group of subjects with known (and relatively low) levels of opioid use were tested - i.e. the 30 mg methadone-maintained subjects in Study 3. The responses to sublingually given naloxone in these methadone maintenance patients also varied, but to a lesser degree than in the street addicts. Subjects 7 and 9 completed the ascending dose series (receiving naloxone 4 mgl; in the third subject in this group (Subject 8) the ascending dose sequence was stopped following the administration of 1 mg naloxone because a moderate degree of precipitated withdrawal was produced. Figure 1 shows the mean across the three methadone-maintained subjects for selected measures; results from two subjects are shown for 2 and 4 mg naloxone. Drug Effect and Sick visual analog scales and the subject-rated Withdrawal adjective rating scale were increased with increasing doses of naloxone, as were the observer-rated Withdrawal adjective rating scale and the Total Withdrawal Signs scale. On the Pharmacological Class Questionnaire, methadone maintained subjects identified each drug treatment as opioid antagonist in the following percent of opportunities: placebo - 0%; 0.25 mg naloxone - 41.7%, 0.5 mg naloxone - 16.7%; 1 mg naloxone - 58.3%; 2 mg naloxone - 75%; 4 mg naloxone - 85.7%. Although overall the withdrawal syndrome produced by sublingual naloxone was similar to that produced by intramuscular naloxone in other studies [13 - 151, there were some differOnset of precipitated withdrawal ences. occurred at 30 min following sublingual admin-
istration of naloxone while onset of effects of intramuscular naloxone occurs within 15 min of administration. Skin temperature also did not show a decrease accompanying the onset of withdrawal with sublingual naloxone as is characteristically seen following intramuscular naloxone [13 - 151. Also, characteristic pupil dilation was not consistently seen in subjects showing sublingually precipitated withdrawal; subjects in Study 2 showed substantial pupil dilation while subjects in Study 3 showed only a modest increase in pupil diameter (Fig. 11. Increases in scales associated with opioid agonist effects (such as the Agonist adjective rating scale, liking, etc.1 were not seen following administration of any dose tested. Discussion
Among the six subjects using street heroin prior to participating in this study there were variable responses to sublingually given naloxone. Four subjects (l-4) showed no apparent signs of opioid withdrawal following doses of naloxone up to 4 mg; one of these subjects (41 also showed no withdrawal response to 8 mg naloxone. Two of the six subjects, however, showed marked withdrawal reactions following administration of 4 mg naloxone. One likely explanation is that differences in levels of opioid dependence accounted for these differences in response. Subjects’ reported drug use histories are compatible with this suggestion. Of the two street addicts who exhibited naloxone-induced withdrawal subject five reported a higher daily use of heroin than subjects l-4, and subject 6 reported using heroin and supplementing this with methadone (reportedly 45 mg) several times weekly. Although all of the subjects in Studies 1 and 2 were recruited from waiting lists for methadone detoxification at local treatment agencies, gave opiate positive urines prior to admission to the study, and were clinically judged to be opioid dependent, it is not known whether the four subjects who showed no response to sublingual naloxone were actually physically dependent and would have shown withdrawal reactions to naloxone administered by a parenteral route. Not
33
surprisingly, there is a sizable range of dependence levels among street addicts seeking treatment. Variability in response, and in some cases lack of response to naloxone among applicants for methadone treatment has been noted previously [l’i’]. It would have been advantageous to have tested each subject with parenteral naloxone both as a test for physical dependence and to compare directly the effects given of sublingually and parenterally naloxone. Because of the variability of both current drug use and naloxone response in Studies 1 and 2, Study 3 was conducted with subjects with known and relatively low physical dependence on opioids, methadone maintenance patients on low-dose treatment (30 mgl. Sublingually administered naloxone precipitated withdrawal in all three of these opioiddependent subjects. Although some variability in response to naloxone was seen, this variability was less than that found among the street addicts in the first two groups. These results suggest that, in our study, the street addicts seeking methadone detoxification had lower levels of physical dependence than that produced by administration of 30 mg methadone daily. Additional causes of the variability in the response to naloxone following sublingual administration may include, but are not limited to, variable absorption of drug among subjects and differences in compliance in holding the drug under the tongue for 10 min. We have no way of knowing the roles of these factors since we have no information about blood levels of naloxone in our subjects. Subjects were carefully observed following drug administration though we cannot rule out the possibility that some subjects may have swallowed some or all of the administered fluid before the allotted 10 min. However, previous work has shown this procedure to produce orderly dose-related effects with other sublingually administered compounds [12]. Although they were not specifically questioned about the taste, most subjects spontaneously indicated that the taste of the active naloxone doses was quite unpleasant.
Detection of naloxone by taste was not sufficient to produce withdrawal-like responses. In previous work [13- 151 we have shown that 0.1-0.2 mg naloxone given intramuscularly will precipitate withdrawal in subjects maintained on methadone 30 mg/day. This, in combination with the present findings, suggests a parenteral to sublingual potency ratio of approximately lo- to 20-fold for naloxone. Buprenorphine, in contrast, has approximately a 2-fold parenteral to sublingual potency ratio. Thus, a buprenorphine-naloxone combination product might be designed that would deliver little naloxone when taken by the appropriate sublingual route, but that would deliver a pharmacologically quite effective dose of naloxone if misused by the parenteral route. That precipitated withdrawal was observed in five of nine subjects validates both the biological delivery of naloxone by the sublingual route and the sensitivity of the measurement procedures for detecting these naloxone effects. The results in all nine subjects document that naloxone doses up to l-2 mg can be administered sublingually to opioid abusers/ addicts without precipitating detectable withdrawal signs or symptoms. This is 10 - 20 times the dose required to precipitate withdrawal by injection. Thus, the inclusion of naioxone in sublingual opioid products might be expected to reduce their potential for parenteral abuse by abusers. Acknowledgements This study was supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse. References 1 2 3 4
W.R. Martin, Ann. Intern. Med. 85 (1976) 765. D.R. Jasinski et al., J. Pharmacol. Exp. Ther., (1967) 420. H.G. Dayton and H. Blumberg, Fed. Proc., 686. J.G. Nutt and D.R. Jasinski, Clin. Pharmacol. (19’74) 156.
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M. Fink et al., Cur. Psychiatr. Ther.. 10 (1970) 161. A.A. Kurland, Int. J. Addict., 8 (1973) 127. P.K. Gupta and J.W. Dundee, Anaesthesia, 29 (19’74) 33. S.D. Parwatikar and RR. Knowles, Clin. Pharmacol. Ther., 14 (1973) 941. J. Legros et al., Arch. Int. Pharmacodyn. 271(1984) 11. F. Hoffmeister, Psychopharmacology, 90 (1986) 441. W.K. Bickel et al., Clin. Pharmacol. Ther., 43 (1988) 72. W.K. Bickel et al., J. Pharmacol. Exp. Ther., 247 (1988) 47. K.L. Preston et al., Psychopharmacology, 94 (1988) 484.
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K.L. Preston et al., J. Pharmacol. Exp. Ther., 246 (1988) 441. K.L. Preston et al., J. Pharmacol. Exp. Ther., 248 (1989) 929. R.R. Griffiths et al., J. Pharmacol. Exp. Ther., 215 (1980) 649. C.P. O’Brien et al., Clinical pharmacology of narcotic antagonists. In: B. Kissin, J.H. Lowinson. and R.B. Millman Recent Developments in (Eds.1, Chemotherapy of Narcotic Addiction Vol. 311, The New York Academy of Sciences, New York, 1978, pp. 232 - 240.