Dependence potential of drotebanol, codeine and thebaine tested in rhesus monkeys *

Sections

Methods
Results
TABLE 2 Cross physical dependence test on codeine, thebaine and drotebanol in morphine-dependent and withdrawn monkeys a

TABLE 5 Intravenous cross self-administration a of codeine, thebaine and drotebanol with lefetamine b and saline in experienced monkeys
TABLE 6 Continuous intravenous self-administration of thebaine and drotebanol in naive and experienced monkeys
Discussion
Bibliography

Details

Author: Tomoji YANAGITA, Katsumasa MIYASATO, Nagaoki OINUMA, Hiroko KIYOHARA
Pages: 33 to 46
Creation Date: 1977/01/01

Dependence potential of drotebanol, codeine and thebaine tested in rhesus monkeys *

Tomoji YANAGITA
Katsumasa MIYASATO
Nagaoki OINUMA
Hiroko KIYOHARA
Department of Psychopharmacology, Medical Research Laboratory, Central Institute for Experimental Animals, 1433 Nogawa, Takatsu-ku, Kawasaki, Japan 211

Drotebanol (14-Hydroxy-dihydro-6 β-thebainol-4-methylether) is an antitussive synthesized by Sankyo Company, Japan. It is a white crystalline solid which melts at 165-167 °C and is stable to heat, light and air. Its hydrochloride salt is water soluble. Drotebanol is synthesized from thebaine through the steps of oxidation, catalytic hydrogenation, ether ring cleavage, methylation and Ponndorf reduction. Its structural formula is as follows:

Full size image: 5 kB

In animal pharmacology, a potent antitussive effect has been observed with drotebanol. Its potency is reported to be 14 to 25 times that of codeine phosphate in mechanical stimulation in guinea-pigs, 5 to 10 times in the ammonia gas method in guinea-pigs and 50 times in mechanical stimulation in dogs. Analgesic activity of drotebanol was 2 and 4 times as potent as that of codeine phosphate in guinea-pigs and mice respectively. It has also been reported that the respiratory depressant effect of the drug was not observable at the antitussive doses in unanesthetized dogs and was weaker than that of codeine phosphate in anesthetized cats and dogs (Kobayashi, Hasegawa, Mori and Takagi, 1970).

Clinically, a potent antitussive effect of drotebanol was observed by many investigators and it has been reported that the potency of the drug effect at oral doses of 4 mg/person was equal to or even stronger than that of codeine at 20 mg/person (Takijima et al., 1970).

Concerning the dependence potential of this drug, a study using rats was conducted in which the decrease of the body weights during withdrawal observations was more severe with codeine than with drotebanol after 4 weeks of sub-

*Partially supported by WHO Research Grant,1969-1973. cutaneous administration of the drug at equipotent dose levels (Kobayashi, Hasegawa, Mori and Takagi, 1970). Since drotebanol is a thebaine derivative and has a codeine-like pharmacological profile, its dependence potential, both physical and psychological, was studied in rhesus monkeys and compared with those of thebaine and codeine.

Methods

Male and female rhesus monkeys (Macaca Mulatta) imported from India, fed with vitamin C-enriched chow and conditioned for more than 3 months in a group housing cage were used in the present study.

  1. Gross behavioural observation of acute central nervous system effects in normal monkeys

    Healthy adult monkeys, housed in group housing cages, received codeine, thebaine or drotebanol at single doses of 4, 8, and 16 mg/kg s.c. Two to 4 animals were used for each dose level with saline as a control agent. The animals' gross behaviour was observed prior to and over 8 hours after administration, using a standardized protocol for gross behavioural observation, and a closed-circuit television was used as an observation aid. Rectal temperature was determined prior to, and 1 and 4 hours after administration of the drug.

  2. Cross physical dependence test in morphine-dependent and withdrawn monkeys

    Physical dependence on morphine was produced in monkeys by repeated subcutaneous administration of 3 mg/kg of morphine HCl every 6 hours for longer than 8 weeks. These animals were then withdrawn for 12 to 14 hours. When withdrawal signs developed, single doses of thebaine or drotebanol at 2 and 4 mg/kg or saline were administered s.c. to 2 or 4 monkeys for each dose level. Suppression of morphine withdrawal signs was observed for the following 5 hours. Severeness of the withdrawal signs was graded according to Seevers' criteria (Seevers, 1936), table 1.

  3. Withdrawal signs-precipitation test in morphine-dependent and non-withdrawn monkeys

    Monkeys physically dependent on morphine received a single dose of thebaine or saline 2 hours after the regular morphine injection and their withdrawal manifestation was observed for 3 hours. Thebaine at 2 and 4 mg/kg were each administered subcutaneously to 2 dependent monkeys. In addition to the above, thebaine at 2 and 4 mg/kg were each administered s.c. to 2 normal non-dependent controls.

  4. Physical dependence-producing test in normal monkeys

    Codeine at 4.0 mg/kg, thebaine at 3.0 mg/kg and drotebanol at 1.6 and 4.0 mg/kg were subcutaneously administered 4 times daily to 4 monkeys for each drug and for each dose level for 31 days. On the 14th and 28th days, precipitation tests were conducted by subcutaneous administration of levallorphane at 0.5 mg/kg or naloxone at 1.0 mg/kg. A natural withdrawal test was conducted from the 32nd day for 5 days. Throughout the experiment, body weight and rectal temperature were determined daily.

  5. Intravenous cross self-administration test in experienced monkeys

    Six monkeys were trained for intravenous self-administration of 1-1, 2-diphenyl-1-dimethyl-aminoethane-HCl (lefetamine or SPA), one of the standard reinforcing agents, 4 hours a day by a method described elsewhere (Deneau, et al., 1969; Yanagita, 1970). Then they were trained to discriminate between lefetamine and saline in self-administration of these agents. In the test, codeine at 0.06, 0.25 and 1.0 mg/kg; thebaine at 0.015, 0.06 and 0.25 mg/kg; and drotebanol at 0.06, 0.25 and 1.0 mg/kg were administered to 4 monkeys per drug for 3 days at a time, one unit dose level after another, in the order of lefetamine (always at 0.1 mg/kg/inj.), saline, test drug at the low dose; lefetamine, saline, test drug at the medium dose; and lefetamine, saline, test drug at the high dose. The number of self-administrations for the 4 hour test period was recorded daily for each monkey.

  6. Continuous intravenous self-administration test in experienced and naive monkeys

    Continuous intravenous self-administration of thebaine and drotebanol was conducted in 2 experienced and 2 naive monkeys. At the beginning, the response rate of lever pressing was observed with self-administration of saline for 1 week.

    Self-administration of thebaine at 0.1 mg/kg was conducted for 4 weeks at FR1 without time or dose limitation. Observation was continued with those that initiated active self-administration at this unit dose for another 4 weeks, then the unit dose was increased to 1.0 mg/kg. For those that did not initiate, the unit dose was also increased to 1.0 mg/kg and observation was continued. A naloxone withdrawal test was conducted by subcutaneous administration of the drug at 1.0 mg/kg, 1 week prior to the termination of self-administration. Upon termination of self-administration, a natural withdrawal test was conducted for 5 days.

    Self-administration of drotebanol at 2.0 mg/kg at FR1 was conducted for 4 or 6 weeks without time or dose limitation. Then a natural withdrawal test was conducted for 5 days.

    Since the continuous intravenous self-administration test using codeine has already been conducted and the results are available, it was not performed (Deneau, et al., 1969).

Results

  1. Acute gross behavioural effects of codeine, thebaine and drotebanol

Codeine produced in monkeys a decrease of awareness of other monkeys and man, eye rubbing and skin scratching at 4 mg/kg, and slow motor activity, drowsiness and further decrease of awareness at 8 or 16 mg/kg. Duration of the effects was relatively short, lasting up to 4 hours at 8 mg/kg and 6 hours at 16 mg/kg. There were no meaningful changes in rectal temperature.

Contrary to codeine, thebaine produced transient tremor, restlessness, hyperirritability and slight motor impairment at 4 and 8 mg/kg. At 16 mg/kg, vomiting and convulsions were observed. Duration of the effects was approximately 5 hours at 8 mg/kg.

Following subcutaneous administration of drotebanol at 4 mg/kg, the monkeys' spontaneous motor activity and awareness of other monkeys and man were reduced, and they manifested such morphine-like signs as mydriasis, skin scratching and drowsiness. At 8 and 16 mg/kg, motor impairment, catalepsia and salivation were observed, but no marked change was observed in rectal temperature. At 4 and 16 mg/kg the duration of the effects was about 6 and 10 hours, respectively. The above morphine-like effects of drotebanol were completely antagonized by subcutaneous administration of levallorphane at 0.5 mg/kg.

TABLE 1 Grade of withdrawal signs in morphine dependent monkeys (M. H. Seevers, 1936)

Mild I.II

Intermediate III.IV

Severe V.VI

Very severe VII.VIII

Apprehension, continual yawning,
Intention tremor, anorexia,
Extreme restlessness,
Docility in the normal excitable
rhinorrhoea, lacrimation,
pilomotor activity, muscle
assumption of peculiar
animal, dyspnoea, pallor,
hiccup, shivering, perspiration
twitchings and rigidity,
attitudes, vomiting, severe
strabismus, dehydration, weight
on face, chattering,
holding the abdomen
diarrhoea, erection and
loss, prostation, circulatory
quarrelling and fighting
 
continued masturbation,
collapse, death
   
inflammation of the eyelids
 
   
and conjunctiva, continual
 
   
calling and crying, lying on
 
   
the side with eyes closed,
 
   
marked spasticity
 
  1. Cross physical dependence of codeine, thebaine and drotebanol with morphine

    When morphine-dependent monkeys were withdrawn for 12 to 14 hours, they manifested intermediate to severe grades of withdrawal signs. A single subcutaneous dose at 16 mg/kg of codeine, an active control drug, suppressed the signs completely in 2 monkeys and incompletely in the other 2 monkeys. Thebaine did not suppress the signs at all. Drotebanol at 2 mg/kg suppressed the morphine withdrawal signs completely in 1 monkey within 30 min. after administration, but in the remaining 3 monkeys the suppression was incomplete and either intense tremor or muscle rigidity were observed throughout the test. At 4 mg/kg, complete suppression was observed in 3 monkeys. The withdrawal signs of the remaining 1 monkey were also considerably suppressed but apprehension and piloerection remained to some extent (table 2).

  1. Precipitation of morphine withdrawal signs by thebaine

Thebaine precipitated morphine withdrawal signs at single subcutaneous doses of 2 and 4 mg/kg in morphine-dependent and non-withdrawn monkeys (table 3). As previously observed, thebaine possesses some excitatory effects of monkeys' gross behaviour, so non-dependent monkeys were used as control for the morphine-dependent groups. As a result of careful comparative observation under a blind procedure, it was observed that the manifestations of the morphine-dependent monkeys produced by single subcutaneous administration of thebaine obviously differed from those of non-dependent monkeys, particularly at the dose of 4 mg/kg.

  1. Physical dependence on codeine, thebaine and drotebanol

When codeine, thebaine or drotebanol were subcutaneously administered to normal monkeys 4 times daily for longer than 2 weeks, physical dependence developed as observed in the levallorphane or naloxone precipitation tests (table 4). The type of withdrawal signs was similar to those observed in morphine-dependent monkeys, however, gastrointestinal manifestation such as anorexia, holding of the abdomen, vomiting and diarrhoea were less prominent with these drugs than with morphine. During the administration period, the monkeys of the thebaine and drotebanol 4.0 mg/kg groups lost weight. The withdrawal signs observed in the second precipitation test were generally more severe than those of the 14th day, even in those monkeys whose grades were judged to be the same as before. In the natural withdrawal test, the signs of all groups became most prominent 24 to 48 hours after injection of the last dose, but the severeness tended to be weaker than that of the second precipitation test with the codeine, thebaine and drotebanol 1.6 mg/kg groups. Contrary to this, in the drotebanol 4.0 mg/kg group, the severeness of the withdrawal signs was either the same as or even more pronounced than before. Most monkeys of all the groups lost weight during the natural

TABLE 2 Cross physical dependence test on codeine, thebaine and drotebanol in morphine-dependent and withdrawn monkeys a

Drug

Dose (mg/kg, s.c.)

No. of monkeys

Suppression of withdrawal signs( ) : No. of monkeys

Duration of complete suppression (approx. hours)

Saline
0.5 (ml)
4
none (4)
- -
Codeine
4 2
incomplete (2)
- -
  8 2
incomplete (2)
- -
  16 4
complete (2)
3
     
incomplete (2)
- -
Thebaine
2 4
none (4)
- -
  4 4
none (4)
- -
Drotebanol
2 4
complete (1)
2
     
incomplete (3)
- -
  4 4
complete (3)
3 - 4
     
incomplete (1)
- -

aPhysical dependence maintained by repeated subcutaneous administration of morphine HCl every 6 hours at 3.0 mg/kg, then withdrawn for 12 to 14 hours.

Drotebanol, codeine and thebaine tested in rhesus monkeys 39

TABLE 3 Withdrawal signs-precipitation test on thebaine in morphine-dependent and non-withdrawn monkeys a

Subject

Drug b

Dose (mg/kg s.c.)

No. of monkeys

Major precipitated signs and symptoms

Note

Morphine-dependent
Saline
0.5 (ml)
2
none
 
 
Thebaine
2 2
apprehension, tremor, muscle rigidity, holding of the abdomen, piloerection
severest in first 30 min. but continued for longer than 2 hours
    4 2
exaggeration of above signs retching and vomiting
 
Non-dependent (control)
Thebaine
2 2
transient tremor, restlessness
lasted 1 hour
    4 4
ibid., hyperirritability
 

aPhysical dependence maintained by repeated subcutaneous administration.of morphine HCl every 6 hours at 3 mg/kg.

bThebaine or saline administered 2 hours after morphine injection

TABLE 4

Physical dependence-producing test on codeine, thebaine and drotebanol in normal monkeys

 

Body weight (kg

Grade of withdrawal signs b

Precipitation test c

Drug

Dose (mg/kg,s.c. 4x/day for 31 days)

Monkey

Initial

End. of adm. period

Natural withdr. test a

14th day

28th day

Natural withdrawal test d

Codeine
4.0
No. 169 male
4.2 4.3 4.2
severe
severe
severe
   
No. 188 male
3.1 3.5 3.3
severe
severe
severe
   
No. 195 male
3.6 3.9 3.6
intermed.
severe
intermed.
   
No. 197 male
3.4 3.8 3.5
severe
severe
severe
Thebaine
3.0
No. 497 female
3.3 3.0 2.9
intermed.
intermed.
intermed.
   
No. 498 female
3.7 3.3 3.2
intermed.
intermed.
intermed.
   
No. 501 male
3.2 2.9 2.7
intermed.
intermed.
intermed.
   
No. 503 female
3.3 3.1 3.1
intermed.
severe
intermed.
Drotebanol
1.6
No. 245 female
3.1 3.3 3.2
intermed.
severe
intermed.
   
No. 251 male
3.1 3.2 3.1
intermed.
intermed.
intermed.
   
No. 261 female
3.4 3.9 3.7
severe
severe
intermed.
   
No. 283 male
3.5 4.0 4.0
severe
intermed.
intermed.
  4.0
No. 134 female
4.3 3.8 3.6
severe
severe
severe
   
No. 178 female
2.9 2.8 2.5
intermed.
intermed.
severe
   
No. 186 female
2.5 2.3 2.2
intermed.
severe
severe
   
No. 264 male
4.0 3.8 3.7
severe
severe
severe

aLowest weight during a 5-day natural withdrawal period.

bGraded by Seevers' criteria (see table 1).

cSingle dose subcutaneous administration of levallorphane at 0.5 mg/kg to the drotebanol and codeine groups and naloxone at 1.0 mg/kg to the thebaine group 2 hours after regular administration of the agonists.

dHighest grade during a 5-day natural withdrawal period.

  1. Reinforcing effect of codeine, thebaine and drotebanol tested in cross self-administration

The mean self-administration ratio for saline was 9.1 per cent, with the rate for SPA as 100 per cent, on an average for 4 monkeys (table 5). When codeine was available, all 4 monkeys self-administered the drug at ratios more than 2 times higher than those for saline at all 3 unit doses. The ratio was highest at 0.06 mg/kg and lowest at 1.0 mg/kg, although there was 1 monkey (No. 403) whose ratio did not change throughout the 3 unit doses.

In the test with thebaine, the average daily rates were 175 injections/4 hours for lefetamine and 24.3 for saline.

With thebaine, the ratio tended to be higher than that for saline in 3 monkeys, but the increase was not as remarkable as that for codeine. With drotebanol, 2 out of 4 monkeys showed obviously higher ratios than those for saline at 0.06 mg/kg.

  1. Reinforcing effect of thebaine and drotebanol in continuous self-administration

In self-administration of saline, 1 experienced monkey from both the thebaine and drotebanol groups showed relatively high rates of more than 10 inj./day. The remaining experienced monkeys from both groups and all naive monkeys took saline at a rate lower than 10 inj./day.

When the monkeys were allowed to self-administer thebaine at the unit dose of 0.1 mg/kg, 1 experienced and 1 naive monkey initiated self-administration. The other 2 monkeys did not initiate at this unit dose, so the unit dose was increased 4 weeks later to 1.0 mg/kg. This time these monkeys initiated active self-administration. The self-maintained daily dose levels in these monkeys reached a plateau within a week and were considerably stable from day to day. However, individual differences were observed in the self-maintained dose levels (table 6). During the administration period, the monkeys' appetites were normal and no marked behavioural changes were observed. A naloxone withdrawal test was conducted 1 week before a natural withdrawal test. Morphine-like withdrawal signs were precipitated by naloxone and the severeness was graded as severe for 2 monkeys and intermediate for the other 2. In the natural withdrawal test which was conducted upon termination of self-administration, withdrawal signs were generally weaker than those observed in the naloxone withdrawal test and were graded as intermediate in all 4 monkeys.

With drotebanol, all 4 monkeys initiated active self-administration at the unit dose of 2.0 mg/kg/inj. A steady increase of the daily dose level up to 4 weeks or more was observed in all monkeys. Individual differences in the self-maintained dose levels were less than those for thebaine. No marked depression or convulsions were observed in them. In this case, the naloxone withdrawal test was not conducted, and in the natural withdrawal test which was conducted after 4 or 6 weeks of self-administration, withdrawal signs similar to those observed in the physical dependence-producing test on this drug were observed.

TABLE 5 Intravenous cross self-administration a of codeine, thebaine and drotebanol with lefetamine b and saline in experienced monkeys

 

Per cent ratio of self-administration rate, SPA as 100 %

Drugs

Monkey

Unit dose: Saline (mg/kg/inj) (0.25ml)

0.015

0.06

0.25

1.0

Codeine
No. 332 female 3.5 kg
5.4
-
32.7 32.9 12.0
 
No. 348 female 4.8 kg
13.6
-
102.6 90.9 38.8
 
No. 402 female 4.8 kg
6.3
-
80.8 30.5 17.1
 
No. 403 male 3.8 kg
11.2
-
31.8 31.1 31.5
 
mean
9.1 ± 3.9
-
62.0 ± 35.4
46.4 ± 29.7
23.1 ± 12.1
Thebaine
No. 332 female 3.5 kg
11.8 17.7 17.0 8.1
-
 
No. 348 female 4.8 kg
21.6 21.8 3.4 18.6
-
 
No. 402 female 4.8 kg
15.0 33.9 21.3 10.8
-
 
No. 403 male 3.8 kg
18.5 22.4 33.4 29.6
-
 
mean
15.7 ± 5.6
22.5 ± 9.0
20.0 ± 12.4
19.0 ± 7.8
 
Drotebanol
No. 332 female 3.5 kg
9.6
-
26.5 9.7 4.5
 
No. 348 female 4.8 kg
21.9
-
79.4 36.5 15.5
 
No. 396 female 3.8 kg
20.8
-
25.7 16.3 6.5
 
No. 402 female 4.8 kg
19.1
-
22.0 8.0 8.0
 
mean
17.9 ± 5.6
-
38.4 ± 27.4
17.6 ± 13.1
8.6 ± 4.8

aSelf-administration for 4 hours daily. b 1-1,2-diphenyl-1-dimethyl-aminoethane-HCl

Drotebanol, codeine and thebaine tested in rhesus monkeys 43

TABLE 6 Continuous intravenous self-administration of thebaine and drotebanol in naive and experienced monkeys

Drug and unit dose

Monkey

Experienced a or naive

Saline for 7 days (injections / day at 0.25ml/ kg/inj)

Initiation of active self-administration

Observation period on drug (weeks)

Daily intake in average of 2.4 weeks (mg/kg/day)

Grade of withdrawal signs b

             

Naloxone c

Natural d

Thebaine (0.1 and 1.0 mg/kg/inj)
No. 105 male
experienced
22.5
+ at 0.1
8 at 0.1
4.3 at 0.1
intermed.
intermed.
  6.2 kg      
6 at 1.0
9.9 at 1.0
   
 
No. 375 female
experienced
3.0
- at 0.1
4 at 0.1
33.8 at 1.0
severe
intermed.
  4.3 kg    
+ at 1.0
7 at 1.0
     
 
No. 345 male
naive
1.0
+ at 0.1
8 at 0.1
4.3 at 0.1
severe
intermed.
  2.9 kg      
5 at 1.0
30.3 at 1.0
   
 
No. 382 female
naive
3.6
- at 0.1
4 at 0.1
21.6 at 1.0
intermed.
intermed.
  3.3 kg    
+ at 1.0
5 at 1.0
     
Drotebanol (2.0 mg/kg/inj)
No. 252 male
experienced
0.4
+
4 90.9
-
severe
  3.0 kg              
 
No. 253 male
experienced
17.7
+
4 84.5
-
severe
  3.7 kg              
 
No. 393 female
naive
4.6
+
6 56.8
-
intermed.
  3.4 kg              
 
No. 395 female
naive
4.6
+
6 98.3
-
severe
  4.3 kg              

aExperienced with self-administration of some other drug but deprived for more than 1 month.

bGraded by Seevers' criteria (table 1).

cNaloxone precipitation test conducted in late period at a single dose of 1.0 mg/kg, s.c.

dNatural withdrawal test conducted at the end of self-administration experiments for 5 days.

Discussion

The central nervous system effects of codeine in the rhesus monkey were somewhat morphine-like at the subcutaneous dose range observed, however, the effects were much weaker than those of morphine. Thebaine showed no indication of morphine-like effects. Although drotebanol is synthesized from thebaine its effects on the central nervous system were very similar to morphine, more so than those of codeine.

In the cross physical dependence test, both codeine and drotebanol suppressed morphine withdrawal signs, but thebaine did not. In this regard, too, drotebanol was not similar to thebaine. The approximate ED50 for complete suppression was 16 mg/kg for codeine and 3 mg/kg for drotebanol. Thus drotebanol was much more potent than codeine in this effect.

Since thebaine did not suppress morphine withdrawal signs, the precipitation test was conducted with naloxone. In normal monkeys, thebaine produced some signs which were similar to those observable in morphine-dependent and withdrawn monkeys; therefore the test was conducted very carefully under the blind procedure and the morphine-like withdrawal manifestation produced by thebaine was clearly identifiable by all 3 independent observers.

In the physical dependence-producing tests, all 3 drugs produced physical dependence, and the withdrawal signs were precipitable by morphine antagonists. The dose level for the first drotebanol group was selected by the maximal tolerable dose of 4 mg/kg, and the same dose level was used for codeine. In a comparison of the results for codeine and drotebanol, it was found that the physical dependence-producing potential of drotebanol at 4 mg/kg was similar to that of codeine at the same dose level. For the second drotebanol group, 1.6 mg/kg was chosen on the basis of the clinical equipotent dose ratio against 16 mg/kg of codeine; however, in a preliminary study, the physical dependence-producing potential of codeine at 16 mg/kg administered s.c. every 6 hours was found to be equal to that of drotebanol 4 mg/kg administered s.c. every 6 hours. Therefore, the physical dependence potentials of the 2 drugs at clinically equipotent dose levels were compared with the results obtained with 4 mg/kg of codeine and 1.6 mg/kg of drotebanol, both administered 4 times daily for a period of 31 days. In this case, the potential of drotebanol was obviously weaker than that of codeine. Although it can be said that in non-medical use of the 2 drugs their physical dependence potentials may be similar, in medical use drotebanol may possess a weaker potential.

The physical dependence-producing potential of thebaine was not known, and it was believed by many investigators that thebaine was not causing dependence. The results of both the physical dependence-producing and the continuous self-administration tests clearly demonstrated that thebaine produces physical dependence at least in rhesus monkeys. However, it is not known yet whether thebaine itself or some metabolites produce the physical dependence in monkeys.

In the intravenous cross self-administration tests, the numbers of the animals which showed a 50 per cent or more increase of the self-administration rate against that for saline at any unit dose were as follows: all 4 with codeine, 2 with thebaine and 2 with drotebanol. Among these animals the highest increase was observed with codeine, next with drotebanol and least with thebaine. These differences, however, are not directly attributable to the differences of the intensity of the reinforcing effect because the rate is an integration of such functions as intensity, unit dose and speed of elimination of the drug from the organs and blood stream.

In the continuous intravenous self-administration tests, thebaine and drotebanol showed definite reinforcing effects, both in experienced and naive monkeys, similar to those observed with codeine. During the self-administration period, these drugs did not produce marked depression or excitation such as were observable with morphine, pentobarbital, cocaine or amphetamines. From this observation, it can be said that the behavioural toxicity of these drugs during unlimited self-administration is relatively low.

The development of physical dependence on such drugs as pentobarbital (Yanagita and Takahashi, 1970), pethidine (Yanagita, 1970) and alcohol (Yanagita and Takahashi, 1973) is more marked by self-administration than by repeated manual administration, probably because of a higher bio-availability of the drugs in self-administration. With drotebanol, however, the severeness of the withdrawal signs in the continuous self-administration test was equal to or even less than that observed in the physical dependence-producing test, in spite of dose levels which were approximately 5 times higher in self-administration. This may indicate that the physical dependence potential of drotebanol reached a plateau at the dose regimen of 4 mg/kg s.c., 4 times daily for 31 days.

In summary, all 3 drugs produced substantial physical dependence in which withdrawal signs were precipitable by morphine antagonists, and they also possessed obvious reinforcing effects in rhesus monkeys.

In comparison of the physical dependence potentials of these 3 drugs, thebaine differed from the other 2 drugs in two ways: it was weaker than the others and did not suppress morphine withdrawal signs. Drotebanol was similar to codeine in that its physical dependence potential was somewhat limited that is, the very severe grade of withdrawal signs which can be observed as sudden death upon withdrawal from heavy self-administration of morphine or pethidine was never observed with drotebanol.

It should also be noted that the behavioural manifestations of the drug effects during the continuous self-administration period of these 3 drugs were less marked than those observable with such other drugs as morphine, pentobarbital, cocaine and amphetamines.

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