EXPERIMENTAL
NEUROLOGY
46,644-648
(1975)
RESEARCH Tetrahydroaminoacridine MAURICE
S.
ALBIN,
Antagonism D.
MALCOLM PAUL
Departments
NOTE
A.
ORR,
LEONID
HENDERSON
of Anesthesiology and Neurological Laboratory, University of Pittsburgh Pittsburgh, Pennsylvania Received
to Narcotic
October
BIJNEGIN,
Addiction AND
1 Surgery, School 15261
and the Neuroanesthesia of Medicine,
7, 1974
Tetrahydroaminoacridine (THA ; Tacrine ; 1,2,3,4-tetrahydro-S-aminoacridine) is a potent cholinesterase inhibitor (6) that has mild neuromuscular blocking action and has been used in man to reverse psychotic episodes precipitated by some anticholinergic psychotomimetics (4, 5, 7). Animal studies have suggested its effectiveness in reducing both sleep (anesthesia) time and postanesthetic emergence delirium following phencyclidine (1, 2) [l-( 1 phenyl cyclohex) piperidine hydrochloride] (22). The incidence of postanesthetic behavioral side effects following ketamine hydrochloride (11, 12, 14, 15, 23, 24) was markedly reduced in animal (1, 2) and human subjects (3) following THA dosing. Morphine antagonism by THA has been reported in a number of animal speciesand in man (8, 9, 13, N-20) ; this has consisted of rapid arousal, respiratory stimulation, decrease in euphoria, and no inhibition of the cough reflex. A study by Stone, Moon and Shaw (21) involving the treatment of intractable pain with morphine and THA indicated attenuation of physical dependence. They state in their conclusions that THA “is a partial antagonist to the narcotic analgesics,enabling morphine to be given (10-100 mg q.i.d.) without producing narcosis or respiratory depression. The patient does not become addicted, and, though tolerance still develops, the dose of morphine may be reduced or withdrawn without withdrawal symptoms. An additional advantage of THA is that it is stable and can be combined in the same 1 This investigation was supported in part by a grant from the Alcoa Foundation. Please address all correspondence to Dr. Maurice S. Albin. We thank Antoinette Perry for all her help. 644 Cwnight $3 197’S by Academic Press, Inc. All rig ts o reproduction in any form reserved.
NARCOTIC
TABLE ABSTINEKCE
“0”
= No change Behavior
-apprehension -restlessness -handling -vocalization -posture
-Score
SYNDROME
“ - 1” = Moderate Involuntary -muscle -muscle -muscle -tremor -convulsions -dehydration -weight -strabismus
645
ADDICTION
somatic rigidity tenderness weakness
1 PROFILE
change Sympathetic -yawning -perspiration -piloerection -pallor
loss
-Score -Total
(ASP)
-Score Score
SCORING
“-2”
= Marked
change
Parasympathetic -rhinorrhea -1acrimation -cough -miosis -abdominal -anorexia -nausea -salivation -diarrhea -retching -vomiting
cramps
-Score
ampoule with morphine, thus making administration a very simple matter. The successful use of the combination in a series of 54 patients over a period of more than a year is described.” It is hard to comprehend why further work on this compound relating to the problem of drug addiction was not carried out after publication of this article in the British Medical Journal in 1961. Our research unit has been interested in THA during the past two years because of its psychopharmacological effects against the phencyclidine derivatives. An initial review of the literature has made it almost impossible to ignore the potentialities of THA related to decreasing addiction liability of the centrally acting opiates. With this is mind a pilot study was initiated to evaluate the role of THA in attenuating physical dependence during chronic morphine administration and withdrawal in the rhesus monkey. Using the constant dosing technique as developed by Seevers (16, 17) and Deveau (lo), 14 rhesus monkeys were divided into two groups of seven each with Group 1 (MS) receiving 3.0 mg/kg morphine sulfate parenterally every 6 hr for 30 days. Group 2 (MS-THA) received a mixture of 3.0 mg morphine sulfate and 1.0 mg/kg THA parenterally every 6 hr for 30 days. Physical dependence was monitored in both groups on the 14th and 28th day of drug dosing by the administration of 2.0 mg/kg Nalorphine parenterally to provoke an abstinence syndrome. On day 30 all medication was terminated and the monkeys observed during the ensuing 2 wk. Each animal was evaluated during the entire period according to an Abstinence Syndrome Profile (ASP) which rated symptom clusters
646
ALBIN
00
5
-..,10
ET AL.
Wlrhdraw 15 20 TNCill*“e ;,;E’(;yl;5~ ’ Li7
‘5‘5 ’ . ‘4D
’ hs
FIG. 1. Differential responses (hatched area) of Group 1 (MS only) and Group 2 (MS-THA) to Nalline challenge on day 14 and day 28 and after drug withdrawal on day 30. The P valueson days 14,28 andafter drug withdrawal were < 0.01,< 0.05 and < 0.01respectively.
(behavioral, involuntary somatic, sympathetic and parasympathetic) by assigning a “0” for no change, “1” for moderate change and a “2” for marked change from the norm (Table 1). Thus, the higher the total score, the more intense the abstinence symptomatology. As can be seen from Fig. 1, precipitation of withdrawal by Nalorphine on day 14 and 28 showed marked differences between the two groups,Group 1 (morphine sulphate only) evincing ASP ratings significantly higher (hatched lines) than the animals of Group 2 (THA-MS) . The P values on day 14 and day 28 were < 0.01 and < 0.05 respectively. The most intense reaction differences occurred on day 34 (three days after drug cessation) with the ASP rating of Group 1 more than double that of Group 2. This difference was statistically significant (P < 0.01). We have concluded from this pilot study that THA appears to attenuate the physical dependence to morphine sulfate and hence decreaseabstinence syndrome responses. The most significant potential use of these findings could be in the reduction of addiction liability to morphine and other addictive centrally acting narcotics.
NARCOTIC
ADDICTION
647
REFERENCES M. S., L. BUNEGIN, L. C. MASOP& JR., and P. J. JANNETTA. 1974. Ketamine-induced postanesthetic delirium attenuated by tetrahydroaminoacridine. Exp. Neural. 44 : 126-129, 2. ALBIN, M. S., L. BUNEGIN, P. J. JANNETTA, and L. C. MASSOPUST JR. 1974. Tetrahydroaminoacridine (.THA) 1. Effect of postanesthetic emergence responses and anesthesia sleep time after ketamine, phencyclidine and thiamylal in animals. IV Europ. Cong. Anesth., Excerpta Medica (in press). 3. ALBIN, M. S., and E. MARTINEZ-AGUIRRE. 1974. Tetrahydroaminoacridine (THA) 2. Modification of postanesthetic emergence responses and anesthesia sleep time after ketamine hydrochloride (KH) in the human. IV Europ. Cong. Anesth., Excerpta Medica (in press). 4. BELL, C., S. GERSHON, B. CARROLL, and G. HOLAN. 1964. Behavioral antagonism to a new psychotomimetic-JB-329. Arch. Znt. Pharmacodyn. 147: 9-24. 5. BELL, C., and S. GERSHON. 1964. Experimental anticholinergic psychotomimeticsantagonism of yohimbine and tacrine (THA). Med. Exp. 10: 15-21. 6. BENVENISTE, D., L. HEMMINGSEN, and P. JUUL. 1967. Tacrine inhibition of serum cholinesterase and prolonged succinylcholine action. Acta. Avtesthesiol. Stand. 11: 297-309. 7. BROWN, H. 1971. Some anticholinergic-like behavioral effects of trans (-) -A8 tetrahydrocannabinol. Pharmacologia (Berl.) 21 : 294-301. 8. CLARK, R. S. J., and J. W. DUNDEE. 1%5. Studies of drugs given before anaesthesia IX-morphine with tacrine. Brit. J. Anaesth. 37: 779-784. 9. DE LA LANDE, I. S., and G. A. BENTLEY. 1955. The action of morphine and antagonists of the narcotic action of morphine on acetylcholine synthesis in brain. Austral. J. Exp. B&l. 33: 555-566. 10. DEVEAU, G. A. 1964. Pharmacologic techniques for evaluating addiction liability of drugs. In “Animal and Clinical Pharmacologic Techniques in Drug Evaluation.” J. H. Nodine and P. E. Siegler [Eds.]. Year Book Medical Publishers, Chicago, Ill., pp. 406-410. 11. DOMINO, E. F., P. CHODOFF, and G. CORSSEN. 1965. Pharmacological effects of CI-581, a new dissociative anesthetic, in man. CZin. PharmacoE. Therup. 6: 279-291. 12. FINE, J., and S. C. FINESTONE. 1973. Sensory disturbances following ketamine anesthesia-recurrent hallucinations. Anesth. Analg. Curr. Res. 62 : 428-430. 13. GERSHON, S., D. W. BRUCE, N. ORCHARD, and F. H. SHAW. 1958. Amiphenazole and morphine in production of analgesia. Brit. Med. J. 2: 366-368. 14. KNOX, J. W. D., J. G. BOVILL, R. S. J. CLARKE, and J. W. DUNDFX. 1970. Clinical studies of induction agents-ketamine. Brit. J. Anaesth. 42: 875-885. 15. PENDER, J. 1972. Dissociative anesthesia. J. Am. Med. Assoc. 215: 11261130. 16. SEEVERS, M. H. 1936. Opiate. addiction in the monkey-l. Methods of study. .?. Pharmacol. Exp. Therap. 56: 147-156. 17. SEEVERS, M. H., and G. A. DEVEAU. 1963. Physiolagical aspects of tolerance and physical dependence. In “Physiological Pharmacology.” W. S. Root and F, C, Hofmann [Eds.]. Academic Press, New York, pp. 565-640. 18. SHAW, F. H., and G. BENTLEY. 1949. Some aspects of the pharmacology of morphine, with special reference to its antagonism by 5-amino-acridine and other chemically related compounds. Med. J. Ausfral. 2: 868-874, 19. SHAW, F. H., and G. A. BENTLEY. 1955. Morphine antagonism, Ausfral. J. E+: BioC. 33 : 143-152. 1. ALBIN,
648
ALBIN
ET AL.
20. SHAW, F. H. 1960. The treatment of severe pain. &it. J. Cl&. Pratt. 14: 23-28. 21. STONE, V., W. MOON, and F. H. SAW. 1961. Treatment of intractable pain with morphine and tetrahydroaminoacrine. Brit. Med. I. 1: 471-473. 22. TAYLOR, R. L., J. I. MAURER, and J. R. TINKLENBERG. 1970. Management of “bad trips” in an evolving drug scene. J. Amer. Med. Ass. 213: 422-425. 23. VIRTUE, R. W., J. M. ALANIS, M. MORI, R. T. LAFARGUE, J. H. K. VOGEL, and D. R. METCALF. 1967. An anesthetic agent-2-orthochlorophenyl, Z-methylamino cyclohexanone HCl (CI-581). Anesthesiology 28 : 823-833. 24. WINTERS, W. D. 1967. The neurophysiology of anesthesia. Anesthesiology 28: 65-80,
NEUROLOGY
46,644-648
(1975)
RESEARCH Tetrahydroaminoacridine MAURICE
S.
ALBIN,
Antagonism D.
MALCOLM PAUL
Departments
NOTE
A.
ORR,
LEONID
HENDERSON
of Anesthesiology and Neurological Laboratory, University of Pittsburgh Pittsburgh, Pennsylvania Received
to Narcotic
October
BIJNEGIN,
Addiction AND
1 Surgery, School 15261
and the Neuroanesthesia of Medicine,
7, 1974
Tetrahydroaminoacridine (THA ; Tacrine ; 1,2,3,4-tetrahydro-S-aminoacridine) is a potent cholinesterase inhibitor (6) that has mild neuromuscular blocking action and has been used in man to reverse psychotic episodes precipitated by some anticholinergic psychotomimetics (4, 5, 7). Animal studies have suggested its effectiveness in reducing both sleep (anesthesia) time and postanesthetic emergence delirium following phencyclidine (1, 2) [l-( 1 phenyl cyclohex) piperidine hydrochloride] (22). The incidence of postanesthetic behavioral side effects following ketamine hydrochloride (11, 12, 14, 15, 23, 24) was markedly reduced in animal (1, 2) and human subjects (3) following THA dosing. Morphine antagonism by THA has been reported in a number of animal speciesand in man (8, 9, 13, N-20) ; this has consisted of rapid arousal, respiratory stimulation, decrease in euphoria, and no inhibition of the cough reflex. A study by Stone, Moon and Shaw (21) involving the treatment of intractable pain with morphine and THA indicated attenuation of physical dependence. They state in their conclusions that THA “is a partial antagonist to the narcotic analgesics,enabling morphine to be given (10-100 mg q.i.d.) without producing narcosis or respiratory depression. The patient does not become addicted, and, though tolerance still develops, the dose of morphine may be reduced or withdrawn without withdrawal symptoms. An additional advantage of THA is that it is stable and can be combined in the same 1 This investigation was supported in part by a grant from the Alcoa Foundation. Please address all correspondence to Dr. Maurice S. Albin. We thank Antoinette Perry for all her help. 644 Cwnight $3 197’S by Academic Press, Inc. All rig ts o reproduction in any form reserved.
NARCOTIC
TABLE ABSTINEKCE
“0”
= No change Behavior
-apprehension -restlessness -handling -vocalization -posture
-Score
SYNDROME
“ - 1” = Moderate Involuntary -muscle -muscle -muscle -tremor -convulsions -dehydration -weight -strabismus
645
ADDICTION
somatic rigidity tenderness weakness
1 PROFILE
change Sympathetic -yawning -perspiration -piloerection -pallor
loss
-Score -Total
(ASP)
-Score Score
SCORING
“-2”
= Marked
change
Parasympathetic -rhinorrhea -1acrimation -cough -miosis -abdominal -anorexia -nausea -salivation -diarrhea -retching -vomiting
cramps
-Score
ampoule with morphine, thus making administration a very simple matter. The successful use of the combination in a series of 54 patients over a period of more than a year is described.” It is hard to comprehend why further work on this compound relating to the problem of drug addiction was not carried out after publication of this article in the British Medical Journal in 1961. Our research unit has been interested in THA during the past two years because of its psychopharmacological effects against the phencyclidine derivatives. An initial review of the literature has made it almost impossible to ignore the potentialities of THA related to decreasing addiction liability of the centrally acting opiates. With this is mind a pilot study was initiated to evaluate the role of THA in attenuating physical dependence during chronic morphine administration and withdrawal in the rhesus monkey. Using the constant dosing technique as developed by Seevers (16, 17) and Deveau (lo), 14 rhesus monkeys were divided into two groups of seven each with Group 1 (MS) receiving 3.0 mg/kg morphine sulfate parenterally every 6 hr for 30 days. Group 2 (MS-THA) received a mixture of 3.0 mg morphine sulfate and 1.0 mg/kg THA parenterally every 6 hr for 30 days. Physical dependence was monitored in both groups on the 14th and 28th day of drug dosing by the administration of 2.0 mg/kg Nalorphine parenterally to provoke an abstinence syndrome. On day 30 all medication was terminated and the monkeys observed during the ensuing 2 wk. Each animal was evaluated during the entire period according to an Abstinence Syndrome Profile (ASP) which rated symptom clusters
646
ALBIN
00
5
-..,10
ET AL.
Wlrhdraw 15 20 TNCill*“e ;,;E’(;yl;5~ ’ Li7
‘5‘5 ’ . ‘4D
’ hs
FIG. 1. Differential responses (hatched area) of Group 1 (MS only) and Group 2 (MS-THA) to Nalline challenge on day 14 and day 28 and after drug withdrawal on day 30. The P valueson days 14,28 andafter drug withdrawal were < 0.01,< 0.05 and < 0.01respectively.
(behavioral, involuntary somatic, sympathetic and parasympathetic) by assigning a “0” for no change, “1” for moderate change and a “2” for marked change from the norm (Table 1). Thus, the higher the total score, the more intense the abstinence symptomatology. As can be seen from Fig. 1, precipitation of withdrawal by Nalorphine on day 14 and 28 showed marked differences between the two groups,Group 1 (morphine sulphate only) evincing ASP ratings significantly higher (hatched lines) than the animals of Group 2 (THA-MS) . The P values on day 14 and day 28 were < 0.01 and < 0.05 respectively. The most intense reaction differences occurred on day 34 (three days after drug cessation) with the ASP rating of Group 1 more than double that of Group 2. This difference was statistically significant (P < 0.01). We have concluded from this pilot study that THA appears to attenuate the physical dependence to morphine sulfate and hence decreaseabstinence syndrome responses. The most significant potential use of these findings could be in the reduction of addiction liability to morphine and other addictive centrally acting narcotics.
NARCOTIC
ADDICTION
647
REFERENCES M. S., L. BUNEGIN, L. C. MASOP& JR., and P. J. JANNETTA. 1974. Ketamine-induced postanesthetic delirium attenuated by tetrahydroaminoacridine. Exp. Neural. 44 : 126-129, 2. ALBIN, M. S., L. BUNEGIN, P. J. JANNETTA, and L. C. MASSOPUST JR. 1974. Tetrahydroaminoacridine (.THA) 1. Effect of postanesthetic emergence responses and anesthesia sleep time after ketamine, phencyclidine and thiamylal in animals. IV Europ. Cong. Anesth., Excerpta Medica (in press). 3. ALBIN, M. S., and E. MARTINEZ-AGUIRRE. 1974. Tetrahydroaminoacridine (THA) 2. Modification of postanesthetic emergence responses and anesthesia sleep time after ketamine hydrochloride (KH) in the human. IV Europ. Cong. Anesth., Excerpta Medica (in press). 4. BELL, C., S. GERSHON, B. CARROLL, and G. HOLAN. 1964. Behavioral antagonism to a new psychotomimetic-JB-329. Arch. Znt. Pharmacodyn. 147: 9-24. 5. BELL, C., and S. GERSHON. 1964. Experimental anticholinergic psychotomimeticsantagonism of yohimbine and tacrine (THA). Med. Exp. 10: 15-21. 6. BENVENISTE, D., L. HEMMINGSEN, and P. JUUL. 1967. Tacrine inhibition of serum cholinesterase and prolonged succinylcholine action. Acta. Avtesthesiol. Stand. 11: 297-309. 7. BROWN, H. 1971. Some anticholinergic-like behavioral effects of trans (-) -A8 tetrahydrocannabinol. Pharmacologia (Berl.) 21 : 294-301. 8. CLARK, R. S. J., and J. W. DUNDEE. 1%5. Studies of drugs given before anaesthesia IX-morphine with tacrine. Brit. J. Anaesth. 37: 779-784. 9. DE LA LANDE, I. S., and G. A. BENTLEY. 1955. The action of morphine and antagonists of the narcotic action of morphine on acetylcholine synthesis in brain. Austral. J. Exp. B&l. 33: 555-566. 10. DEVEAU, G. A. 1964. Pharmacologic techniques for evaluating addiction liability of drugs. In “Animal and Clinical Pharmacologic Techniques in Drug Evaluation.” J. H. Nodine and P. E. Siegler [Eds.]. Year Book Medical Publishers, Chicago, Ill., pp. 406-410. 11. DOMINO, E. F., P. CHODOFF, and G. CORSSEN. 1965. Pharmacological effects of CI-581, a new dissociative anesthetic, in man. CZin. PharmacoE. Therup. 6: 279-291. 12. FINE, J., and S. C. FINESTONE. 1973. Sensory disturbances following ketamine anesthesia-recurrent hallucinations. Anesth. Analg. Curr. Res. 62 : 428-430. 13. GERSHON, S., D. W. BRUCE, N. ORCHARD, and F. H. SHAW. 1958. Amiphenazole and morphine in production of analgesia. Brit. Med. J. 2: 366-368. 14. KNOX, J. W. D., J. G. BOVILL, R. S. J. CLARKE, and J. W. DUNDFX. 1970. Clinical studies of induction agents-ketamine. Brit. J. Anaesth. 42: 875-885. 15. PENDER, J. 1972. Dissociative anesthesia. J. Am. Med. Assoc. 215: 11261130. 16. SEEVERS, M. H. 1936. Opiate. addiction in the monkey-l. Methods of study. .?. Pharmacol. Exp. Therap. 56: 147-156. 17. SEEVERS, M. H., and G. A. DEVEAU. 1963. Physiolagical aspects of tolerance and physical dependence. In “Physiological Pharmacology.” W. S. Root and F, C, Hofmann [Eds.]. Academic Press, New York, pp. 565-640. 18. SHAW, F. H., and G. BENTLEY. 1949. Some aspects of the pharmacology of morphine, with special reference to its antagonism by 5-amino-acridine and other chemically related compounds. Med. J. Ausfral. 2: 868-874, 19. SHAW, F. H., and G. A. BENTLEY. 1955. Morphine antagonism, Ausfral. J. E+: BioC. 33 : 143-152. 1. ALBIN,
648
ALBIN
ET AL.
20. SHAW, F. H. 1960. The treatment of severe pain. &it. J. Cl&. Pratt. 14: 23-28. 21. STONE, V., W. MOON, and F. H. SAW. 1961. Treatment of intractable pain with morphine and tetrahydroaminoacrine. Brit. Med. I. 1: 471-473. 22. TAYLOR, R. L., J. I. MAURER, and J. R. TINKLENBERG. 1970. Management of “bad trips” in an evolving drug scene. J. Amer. Med. Ass. 213: 422-425. 23. VIRTUE, R. W., J. M. ALANIS, M. MORI, R. T. LAFARGUE, J. H. K. VOGEL, and D. R. METCALF. 1967. An anesthetic agent-2-orthochlorophenyl, Z-methylamino cyclohexanone HCl (CI-581). Anesthesiology 28 : 823-833. 24. WINTERS, W. D. 1967. The neurophysiology of anesthesia. Anesthesiology 28: 65-80,
