Part I. I-C-26: 1. Effect of single oral doses in non-tolerant opiate addicts
2. Twenty-four-hour substitution of I-C-26 for morphine in patients addicted to morphine
Part II. I-D-20 1. Effect of single oral doses in non-tolerant opiate addicts
2. Effect of single subcutaneous doses in non-tolerant former addicts
3. Twenty-four-hour substitution of I-D-20 for morphine in patients addicted to morphine
Summary and Conclusions
Author: A. B. WOLBACH, Jr., H. F FRASER
Pages: 25 to 28
Creation Date: 1963/01/01
Dextro-3-Dimethylamino-1, 1-diphenylbutyl ethyl sulfone hydrochloride (WIN 1161-3, hereinafter designated as I-C-26), a derivative of methadone, and ethyl 1-(2-carbamylethyl)-4-phenylpiperidine-4-carboxylate hydrochloride (WIN 13,187-2, hereinafter designated as I-D-20), a derivative of pethidine (meperidine), have been developed as antitussive drugs by the Winthrop Laboratories. The effective antitussive doses in man have been found to be 2 to 4 mg for I-C-26, and 50 mg for I-D-20 (1, 2).
I-C-26 is 1.8 times as potent as codeine phosphate in suppressing the cough reflex in cats and dogs, and 4.5 times as potent as meperidine as an analgesic in rats (1). It causes depression of respiration and blood pressure in the dog and rabbit. The antitussive, respiratory, and hypotensive effects are antagonized by nalorphine. In monkeys, doses of 21 mg/kg of I-C-26, or more, cause severe respiratory depression and convulsions. Human studies (1) have revealed "no evidence of side effects or tolerance to doses of 1 to 4 mg." However, parenterally, 10 mg of I-C-26 is equivalent to 3 mg of morphine sulfate in suppressing abstinence in monkeys, and Deneau & Seevers (3) have classified its "physical dependence capacity" as "intermediate." These observations in monkeys may underrate the ability of the drug to suppress abstinence, since I-C-26, which is quite unstable in solution, was given parenterally.
I-D-20 has approximately one-half the antitussive potency of codeine phosphate in cats (4). This action is delayed in onset and is not antagonized by nalorphine. No analgesic effect has been observed in rats after doses of as much as 120 mg/kg. There is only slight depression of respiration and blood pressure with I-D-20, and nalorphine is reported to potentiate rather than antagonize the former action. No serious toxicity has been observed in monkeys with doses up to 24 mg/kg. However, doses of over 500 mg/kg produced clonic- tonic convulsions in rats. Deneau & Seevers (5) found that 7.5 mg of I-D-20 subcutaneously is equivalent to 3 mg of morphine sulfate, and they have classified the "physical dependence capacity" of this drug as "high". It should be pointed out, however, that monkeys, as compared with man, are hypersensitive to meperidine derivatives. Human studies (2) have revealed no signs of toxicity or unpleasant side effects with a dose of 50 mg.
In view of the fact that both I-C-26 and I-D-20 are effective antitussive agents, and since both drugs could be of clinical value if non-addicting, the following experiments to evaluate their addiction liabilities were carried out.
The subjects used in these studies were healthy adult white or negro males serving sentences for violation of federal narcotic laws. All subjects volunteered for the experiments. I-C-26 and I-D-20 * were administered as the hydrochloride, and morphine as the sulfate.
The tests employed to evaluate the addiction liabilities of these drugs included the following: (1) administration of single doses for the detection of morphine-like (euphoric) effects and the titration of the dosage which produced maximum safe opiate-like effects, and (2) evaluation of their effectiveness in preventing symptoms of abstinence from morphine by substituting the drugs for morphine for a 24-hour period in patients addicted to morphine. Specific details will be described under each experiment.
1. Methods. Twenty-five single doses of I-C-26 were administered orally to 20 non-tolerant former addict volunteers. The initial dose was 1 mg. This was gradually increased until 70 mg were being given. When the same subject was used, administrations of the drug were separated by an interval of one week. The patients did not know the identity of the drug, but the observers were aware of it (" single-blind" procedure). Both subjects and an aide-observer were required to fill out a single-dose opiate questionnaire at hourly intervals (six hourly observations) following administration of the drug [(6)] , [(7)] .
We are indebted to Dr. A. Scribner of Winthrop Laboratories, New York, N.Y., for supplies of WIN 1161-3(I-C-26) and WIN 13, 187 (I-D-20).
Results. In six trials with doses less than 25 mg, no definite subjective or objective effects were recorded. With progressively larger doses there was an increasing number of positive responses from both patients and aides. The effects were variable and inconsistent until a dosage level of 60 mg was attained. At this dosage level, a consistent pattern of morphine-like effect was produced in all 7 subjects who received it. In several subjects, drug effects were reported for as long as 24 hours after administration.
Methods. The methods employed in this experiment were those outlined by Fraser et al. (7, 8, 9). Eleven subjects who had been stabilized on 240 mg of morphine sulfate daily were given a total dose of 240 mg of I-C-26 during the first 24 hours after abrupt withdrawal of morphine. The drug was administered orally in four 60-mg doses throughout the 24-hour substitution period. In a "negative" control experiment, using a comparable schedule, the same subjects were given saline placebo injections. In a "positive" control experiment, the same subjects received their usual doses of morphine sulfate. Intensity of abstinence was measured by Total Area Scores (TAS scores) calculated from the hourly point scores (10) for eleven observations, from the 14th through the 24th hour for each test condition (I-C-26, placebo, and morphine). Methods of calculating TAS scores were those employed by Fraser et al. (6).
Results. Following the 24-hour substitution of I-C-26 for morphine in tolerant subjects, the mean TAS score (6) (± the standard error of the mean) was 36.64 ± 6.40 (figure 1). Mean TAS scores obtained with placebo and morphine in 24-hour substitution were 171.95 ± 13.78 and 43.41 ± 6.75, respectively (figure 1). Further statistical comparison between the above scores using the paired "t" test technique (11) revealed that the intensity of abstinence during the 24-hour substitution of I-C-26 for morphine was significantly less than with placebo (p 0.01). In addition there was no significant statistical difference (p > 0.05) between the intensity of abstinence during 24-hour substitution of I-C-26 for morphine and the intensity of abstinence during continuation of the usual doses of morphine.
Summary and Conclusions. Dextro-3-dimethylamino-1, 1-diphenylbutyl ethyl sulfone hydrochloride (I-C-26) in single oral doses of 25 to 70 mg induces morphine-like effects, and it effectively suppresses abstinence from morphine. It is therefore concluded that I-C-26 has addictiveness comparable with that of morphine.
Methods of evaluating opiate effect were the same as outlined in part I. Thirty-six doses of I-D-20, ranging between 10 mg and 1,000 mg, were administered orally to 23 non-tolerant patients.
Results. In 13 trials with doses less than 180 mg, no definite subjective or objective effects were recorded. Above this dosage level, some subjects reported such effects as "I feel the medication," but they were not able to state whether or not the drug was "like an opiate" until a dose of 600 mg was reached. Both the subject and the observers noted opiate-like effects at this level, but 700 mg in one subject produced positive responses in only three of six observations (patients), and no observable opiate effects were reported by the aides, except decrease in pupillary diameter. Four subjects were tested with 800 mg in an attempt to produce a more consistent morphine-like pattern of response. This dose was more consistently identified as "dope," but was still classified by some of the patients as "other than dope," and "goof ball' (barbiturate). Pupillary changes were considerably less than that observed with 600 mg. For this reason, 900-mg and 1,000-mg doses were employed with little or no difference in the pattern of response. Occasionally observers reported "drowsy," "sleepy," "on the nod," and "coasting," but such observations were inconsistent, occurring in only 3 of the 8 subjects receiving 1,000 mg. Since emesis occurred once effects with 900 mg, and since pupillary with 1,000 mg were less than those at 800 mg, no further attempts were made to exceed an oral dose of 1,000 mg in any non-tolerant subject.
Methods. Fifteen doses of I-D-20, ranging between 20 mg and 175 mg, were administered subcutaneously to 14 patients using the same methods described above.
Results. No subjective or objective effects were observed. Since no definite morphine-like effects were observed or reported with these doses, and since serious toxicity had been observed with high doses of I-D-20 in 24-hour substitution for morphine (see below), it was decided not to pursue this evaluation any further.
Methods. This experiment was conducted in a similar manner to the 24-hour substitution of I-C-26 in part I. Eight of the 11 subjects used in part I were employed in this study. All were stabilized on morphine sulfate, 240 mg daily. The dosage of I-D-20 used during the 24-hour period of substitution was 4,500 mg divided into three oral doses of 1,500-mg each. "Positive" and "negative" controls were obtained as before.
Results. The dosage of I-D-20 used in the experiment is considerably higher than that attained in the single dose study above. This was judged to be a more appropriate dose for subjects already tolerant to a high dosage of morphine. However, during the 14th hour of his substitution test, the 8th subject to be studied had a grand mal convulsion lasting approximately three minutes. The patient was sedated with sodium amytal and no additional seizures or sequelae were observed. In view of this convulsive episode further 24-hour substitution of I-D-20 was immediately cancelled in the 3 remaining patients.
Total area scores were calculated and analysed statistically, as in Part I. Following the 24-hour substitution of I-D-20 for morphine in 8 tolerant subjects the mean TAS score (± standard error of the mean) was 100.31 ± 11.91 (figure 1). Mean TAS scores obtained from this same group of 8 subjects with placebo and morphine were 169.25 ± 18.40 and 48.81 ± 7.04, respectively. Statistical comparison of the above scores revealed that the intensity of abstinence during the 24-hour substitution of I-D-20 for morphine was significantly less than placebo (p 0.01). Therefore enormous doses of I-D-20 suppressed abstinence from morphine only partially.
Discussion. Since I-D-20 in single oral doses induces an incomplete pattern of morphine-like effects and partially suppresses abstinence from morphine, it has some degree of addictiveness. Although I-D-20 was not compared directly with codeine and d-propoxyphene for relative abuse liability, the latter may be interpolated from other analogous experiments. All these observations indicated that I-D-20 has less addictiveness than codeine (12,5). As compared with d-propoxyphene, single oral and subcutaneous doses of I-D-20 induced less characteristic morphine-like effects than did single doses of d-propoxyphene (8), and when the dose of I-D-20 was increased above 600 mg the degree of pupil- lary constriction was less than that observed with 600 mg. Both I-D-20 and d-propoxyphene partially suppressed symptoms of abstinence from morphine, but it was not possible completely to suppress abstinence with either drug by augmenting the dosage (8) since both drugs at the highest dosage employed provoked grand mal convulsions in certain subjects (7). Therefore, although quantitative comparisons are not possible from the data, qualitatively in man I-D-20 approximates d-propoxyphene in addictiveness. The discrepancy in addictiveness of I-D-20 between monkeys (high) and man (low) is noteworthy, and is in reverse to that observed in the case of phenazocine and levophenacylmorphan (9) for these species.
Ethyl 1-(2-carbamylethyl)-4-phenylpiperidine-4-carboxylate hydrochloride (I-D-20) in single oral doses of 180 to 1,000 mg induces an incomplete morphine-like pattern of response which varies from subject to subject, even with doses of 1,000 mg. Administration of the drug subcutaneously produces no increased response over the oral route in dosages of 20 mg to 175 mg. Orally, 4,500 mg of I-D-20 in 24 hours suppressed symptoms of abstinence from morphine only partially. One convulsion occurred in one patient receiving this dose of the drug. It is therefore concluded that the addiction liability of I-D-20 is low.
WINTHROP LABORATORIES: A summary of experimental laboratory data on WIN 1161-3. Unpublished data, 1959.002
BICKERMAN, H. A.: Personal communication.003
DENEAU, G. A. & SEEVERS, M. H.: Personal communication.004
WINTHROP LABORATORIES: A summary of experimental laboratory data on WIN 13,187. Unpublished data, 1958.005
DENEAU, G. A. & SEEVERS, M. H.: Annual report on drug evaluation. Add. 1, p. 7, Min. 21st Meet., Comm. on Drug Addiction & Narcotics, Natl. Res. Council. Washington, D.C. Natl. Acad. Sci. 1960.006
FRASER, H. F. VAN HORN, G. D., MARTIN, W. R., WOLBACH, A. B., & ISBELL, H.: Methods for evaluating addiction liability. ( a) "Attitude" of opiate addicts toward opiate-like drugs, ( b) A short term "direct" addiction test. J. Pharmaeol. Exper. Therap., 133: (3), 371-387, 1961.007
FRASER, H. F., MARTIN, W. R., WOLBACH, A. B. & ISBELL, H.: Addiction liability of an isoquinoline analgesic, 1-(p-Chloro-phenethyl)-2-methyl-6, 7-dimethoxy-l, 2, 3, 4- tetrahydroisoquinoline. Clin. Pharmacol. Therap., 2: (3), 287289, 1961.008
FRASER, H. F., & ISBELL, H.: Pharmacology and addiction liability of dl- and d-propoxyphene. Bull. Narcotics, 12: (1), 9-14, 1960.009
FRASER, H. F. & ISBELL, H.: Human pharmacology and addiction liabilities of phenazocine and levophenacylmorphan. Bull. Narcotics, 12: (2), 15-23, 1960.010
HIMMELSBACH, C. K.: Studies of certain addiction characteristics of (a) dihydromorphine (" Paramorphan "), (b) dihydrodesoxymorphine-d (Desomorphine), (c) dihydrodesoxycodeine-d (" Desocodeine "), and (d) methyldihydromorphinone (Metopon). J. Pharmacol. Exper. Therap., 67: (2), 239-249, 1939.011
EDWARDS, A. L.: Statistical methods for the behavioral sciences. New York, Rinehart & Co. 1954.012
FRASER, H. F., ISBELL, H. and VAN HORN, G. D.: Human pharmacology and addiction liability of norcodeine. J. Pharmacol. Exper. Therap., 129: (2), 172-177, 1960.