This compound, hereinafter designated I-O-1,2is a meperidine congener related to alphaprodine, differing from the latter only in that a pyrrolidine ring has been substituted for the piperidine in alphaprodine. In rats, mice and dogs I-O-1 has an analgesic potency comparable to codeine 123. During chronic administration of I-O-1 and codeine, tolerance develops to the analgesic effects of both compounds at a comparable rate 1. It lacks substantial antipyretic (rats), anti-inflammatory (guinea pigs), antitussive (dogs), constipating (rats), respiratory depressant (dogs) and cardiovascular effects (except in high doses, dogs) 1. It resembles meperidine in excitatory and hypothermic actions in high dosage 1. When a single dose of I-O-1 was administered to chronically morphinized dogs, there was no evidence of cross tolerance 4. When I-O-1 was given in maximally tolerated dosage chronically for six weeks to dogs and rats, nalorphine did not precipitate physical dependence in dogs, and abrupt withdrawal of the drug was not followed by definite signs of abstinence. Only questionable signs were observed in rats 4. In monkeys, I-O-1 did not suppress abstinence from morphine 5.
Author: H. F. FRASER
Pages: 37 to 43
Creation Date: 1964/01/01
This compound, hereinafter designated I-O-1,2is a meperidine congener related to alphaprodine, differing from the latter only in that a pyrrolidine ring has been substituted for the piperidine in alphaprodine. In rats, mice and dogs I-O-1 has an analgesic potency comparable to codeine [ 1] [ 2] [ 3] . During chronic administration of I-O-1 and codeine, tolerance develops to the analgesic effects of both compounds at a comparable rate [ 1] . It lacks substantial antipyretic (rats), anti-inflammatory (guinea pigs), antitussive (dogs), constipating (rats), respiratory depressant (dogs) and cardiovascular effects (except in high doses, dogs) [ 1] . It resembles meperidine in excitatory and hypothermic actions in high dosage [ 1] . When a single dose of I-O-1 was administered to chronically morphinized dogs, there was no evidence of cross tolerance [ 4] . When I-O-1 was given in maximally tolerated dosage chronically for six weeks to dogs and rats, nalorphine did not precipitate physical dependence in dogs, and abrupt withdrawal of the drug was not followed by definite signs of abstinence. Only questionable signs were observed in rats [ 4] . In monkeys, I-O-1 did not suppress abstinence from morphine [ 5] .
Using patients with chronic pain, Cass & Frederik [ 6] compared in a double-blind, cross-over study the analgesic effectiveness of I-O-1 (50 and 100 mg), acetylsalicylic acid (600 mg), codeine sulfate (30 mg), and a placebo. They found that 50 mg of I-O-1 could not be distinguished from 600 mg of acetylsalicylic acid, and although 100 mg of I-O-1 was less effective than 30 mg of codeine (P < 0.01), the pain relief scores did not diverge greatly. None of these drugs in the dosages used caused adverse side effects.
On the other hand, Houde, Belleville & Wallenstein [ 7] compared I-O-1 orally (150 and 300 mg) with acetylsalicylic acid and concluded that 300 mg of I-O-1 were equivalent to 550 mg of acetylsalicylic acid in terms of peakeffect and equivalent to 500 mg in terms of totaleffect. However, subjective or observed untoward effects were noted in 21 of 39 patients with 300 mg of I-O-1, whereas after 600 mg of acetylsalicylic acid the incidence of undesirable effects was only 6 of 39. Nausea, vomiting, and dizziness were more prevalent and severe after I-O-1 than after aspirin.
1 From the National Institute of Mental Health Addiction Research Center, PHS Hospital, Lexington, Kentucky.
2 A generous sample of 1,2-dimethyl,3-phenyl,3-propionoxy pyrrolidine hydrochloride was supplied by Parke, Davis & Company, and also by Mead Johnson & Company. The identity of these samples was established by both firms, and the product used in the addiction assays was a mixture of equal parts of samples provided by both firms.
Telford & Keats [ 8] compared the analgesic potency of I-O-1 with that of a placebo in postoperative patients, using intramuscular doses of 50, 100, 200 and 400 mg/70 kg. Analgesia, greater than that of a placebo, was not observed until 200 mg/70 kg had been given, and 400 mg/70 kg was no more effective than 200 mg. With the higher doses, frequent subjective side effects (dizziness, drunkenness and grogginess) were reported. These authors thought that intramuscularly administered I-O-1 may be more of a sedative than an analgesic agent in relieving post-operative pain.
Since experiments in animals suggested that I-O-1 had low addictiveness and since its analgesic potency in certain human studies was comparable to that of codeine, the addiction liability of I-O-1 was investigated.
The general methods employed in evaluating addictive characteristics of opiate-like drugs have been described by Fraser & Isbell [ 9] and Fraser et al. (10). Detailed methods and results are presented for each experiment.
Effects of Single Oral Doses of I-O-1
The methods employed have been described in detail (10). In a preliminary single-blind experiment (19 trials in non-tolerant subjects), I-O-1 induced no definitive effects until 200 to 300 mg were given orally. In the latterdosage, a partial spectrum of morphine-like effects was obtained in certain subjects. When the dosage was increased to 400 mg, a more definite but still incomplete pattern of morphine-like effects was observed.
Since the compound appeared to be less effective than codeine in inducing morphine-like effects, a "double-blind" experiment was set up in which d-propoxy-phene (400 mg) was compared with I-O-1 (400 mg) in the same 11 subjects. Both drugs were given orally on a randomized basis at weekly intervals, using the single dose opiate questionnaire (patient's and observer's ratings). The parameters evaluated at hourly intervals for six hours included "felt drug ", identified as "dope" (opiate), opiate symptom score, and degree of "liking".
In addition, the aides measured pupillary diameter at hourly intervals for six hours.
Results. - I-O-1 was identified as "dope" by 4 of 11 subjects, as a barbiturate by 2, and as a "blank" by 5. In these same 11 subjects d-propoxyphene was identified as "dope" by 6, as a blank by 2, and 3 subjects were unable to classify the effects. I-O-1 induced a "sleepy" sensation more commonly than one would anticipate from a typical opiate. I-O-1 showed a tendency to be less potent than d-propoxyphene for the parameters ( d) identified as "dope", ( b) opiate symptoms score, and ( c) decrease in pupillary diameter (figure 1). However, none of these differences were statistically significant.
"Liking" scores were quite similar for both drugs (figure 1).
Effect of Single Subcutaneous Doses of I-O-1
Methods. - Sixteen tests were made, using a dose range of 8 to 400 mg, according to methods described for single oral doses except that no double-blind study was performed.
Results.-Neither patients nor aides observed any effects from the above doses, and the medication was classified consistently as a "blank".
Effect of Single Intravenous Doses of I-O-1
Methods(see procedure for single oral doses). - A preliminary experiment indicated that 300 mg induced a partial pattern of morphine-like effects, so a randomized cross-over, double-blind experiment was set up to compare morphine sulfate (20 mg), d-propoxyphene (180 mg), and I-O-1 (300 mg) in the same 12 subjects. Since both I-O-1 and d-propoxyphene in this dosage might provoke a convulsion, all drugs were prepared in 5 ml of solution and injected slowly over a period of two minutes. Such a slow rate of intravenous injection greatly reduces the intensity of drug effect; in fact it is difficult to identify morphine by this procedure since no subjective "tingling" or objective flushing is observed.
Results.- These are presented as average total response scores (summation of the scores for the six hourly observations) for the various parameters, including effect on pupillary diameter for the three drugs (table 1). I-O-1 was the least effective agent in provoking morphine-like effects (table 1).
Twenty-four-hour Substitution of I-O-1 for Morphine in Patients Addicted to Morphine
Methods. - I-O-1 was substituted for morphine during a 24-hour interval in 11 patients addicted to 240 mg of morphine sulfate daily [ 9] . The results were compared with the usual dosage of morphine continued (180 mg divided into three doses) in the same patients, and with a placebo substituted for morphine in these patients [ 9] .
Results. -With a total dose of 1,000 mg in 24 hours in 10 subjects, and 900 mg in one subject, I-O-1 partially suppressed symptoms of abstinence; the average TAS score for the 11 observations was 108.6 ± 11.8. When morphine was continued in the same patients, the average TAS score was 43.4 ± 6.7; and when a placebo was substituted, the average score was 154.4 ± 13.0 (figure 2). The scores for morphine and placebo were both significantly different from those of I-O-1 [ 11] .
![Full size image: 14 kB, FIGURE 2 This figure compares in a cross-over experiment the average intensity of abstinence in 11 subjects when I-O-1 and a placebo were substituted for morphine, and when the customary dosage[...]](/images/odccp/bulletin/bulletin_1964-01-01_1_page005_img002_large.gif)
|
Parameter being evaluated |
|||||
|---|---|---|---|---|---|
|
Drug |
"Feel drug" |
Identified as "dope" |
Opiate symptome score |
"Liking" score |
Decrease in pupil diameter |
|
Morphine
|
4.67 ± 0.61
|
4.58 ± 0.65
|
19.17 ± 4.45
|
7.50 ± 1.35
|
10 04 ± 1.56
|
|
d-Propoxyphene
|
3.42 ± 0.55
|
3.17 ± 0.67
|
13.42 ± 2.93
b
|
6.50 ± 1.29
|
7.40 ± 1.21
a
|
|
I-O-1
|
2.50 ± 0.62
a
|
1.92 ± 0.74
b
|
7.25 ± 2.56
b
|
4.25 ± 1.25
a
|
4.54 ± 1.19
b
|
aIndicates that the value is significantly different from morphine (P < 0.05).
b Indicates P is < 0.01 by the paired t-test. Note that all parameters are significantly different from morphine in the case of I-O-1, but only two parameters are significantly different in the case of d-propoxyphene. When I-O-1 and d- propoxyphene were compared, significant differences were observed for the parameters, the opiate symptom score, and decrease in pupillary diameter (P < 0.01).
Direct Addiction to 1-0-1 Orally
Methods. - The study was conducted on a double-blind basis in 5 subjects [ 9] . I-O-1 was compared with a placebo, both agents being administered in identically appearing capsules. Each patient was observed for three days while receiving placebos, then l-O-I was administered in an increasing dosage schedule for 18 successive days, and each patient maintained on the maximum tolerated dose for approximately 42 additional days. At this time medication was discontinued abruptly by substituting on a double-blind basis identically appearing placebo capsules, and patients observed for symptoms and abstinence for 10 days. The precautions taken and observations made in all parts of the experiment were as those described by Kolb & Himmelsbach [ 12] and by Himmelsbach [ 13] . In addition, during the entire study the chronic dosage questionnaire (patient's and observer's ratings) was completed daily at 7 p.m. [ 10] , and each patient was challenged with 5 mg of nalorphine just prior to discontinuing the drug [ 9] . During the placebo period and at bi-weekly intervals thereafter complete blood counts, urinalyses and two tests for liver function (cephalin flocculation and thymol turbidity) were carried out.
Results. - The initial dose level was 200 mg three times daily, and an attempt was made to increase this at a rate of 25 mg/dose daily. However, on the second day of the test patients were nauseated and vomiting, and in 4 of the 5 patients it was not possible to exceed 675 mg of I-O-1 daily; in fact it was necessary to reduce the dose below this amount on certain days (figure 3). Although 3 of these patients identified the medicine as "dope" 90%, 34 % and 16 % of the time, they commented "the drug makes me feel bad" 82%, 76% and 30% of the time; and after 18 days of medication, they elected to discontinue the test (figures 3 a and 3 b). Although given the same opportunity, the other 2 patients decided to continue medication, but after 39 days they finally elected to discontinue the test. Specific effects reported or observed included nausea (which in some patients was continuous), constipation, a moderate degree of respiratory depression, miosis, difficult micturition, "sleepy and/or dull-headed ", and a gradual progressive loss of weight in 4 of the 5 subjects (figure 4). The high incidence of vomiting while taking I-O-1 was outstanding; for example, subject No. 1 had 2l such episodes, and tolerance to this effect did not develop in any of the subjects (figure 4).
There were no significant abnormalities in the blood count, urinalyses or liver function tests
When I-O-1 was discontinued abruptly, all patients displayed mild to moderate signs of abstinence. The daily point scores are shown in table 2, and were slightly greater than those observed when d-propoxyphene was withdrawn in comparable experiments [ 14] , and slightly less than those observed when codeine was withdrawn abruptly [ 15] [ 9] .
Patients Nos. 4 and 5, while manifesting withdrawal symptoms, were questioned as to their attitude about I-O-1. Their response may be summed up by the statement by one of them: "I wouldn't buy it; in fact, I wouldn't take it for free even if I were kicking a habit."
![Full size image: 37 kB, FIGURE 4 This figure illustrates (1) the average daily weight for 5 subjects during a cycle of addiction to oral I-O-1; (2) the incidence of vomiting (each X represents an episode); and (3) the[...]](/images/odccp/bulletin/bulletin_1964-01-01_1_page005_img005_large.gif)
Intensity of abstinence (daily point scores) after abrupt withdrawal of I-O-1 in direct addiction test
|
Day of withdrawal |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Subject |
Days on drug |
Daily dose (mg) |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
| 1 | 17 | 600 | 3 | 16 | 13 | 15 | 5 | 11 | 9 | 9 | 9 | 6 |
| 2 | 17 | 600 | 6 | 10 | 13 | 11 | 10 | 8 | 7 | 3 | 5 | 9 |
| 3 | 17 | 825 | 1 | 13 | 9 | 9 | 10 | 12 | 3 | 8 | 4 | 5 |
| 4 | 39 | 675 | 17 | 24 | 18 | 13 | 15 | 12 | 14 | 16 | 12 | 8 |
| 5 | 39 | 675 | 11 | 19 | 12 | 12 | 11 | 14 | 12 | 14 | ||
a This patient developed an upper respiratory infection, hence scores on these days were not calculated.
When patients were challenged with 5 mg of nalorphine, only mild autonomic signs or subjective effects, or both, were observed or reported.
These studies - effect of single doses, substitution tests in morphine-dependent patients, and direct addiction assays - would indicate that I-O-1 has substantially less abuse liability than codeine, and suggest that its addictiveness is more properly related to that of d-pro-poxyphene [ 15] [ 14] The low abuse liability of I-O-1 was well demonstrated by the oral direct addiction test. In this study, despite the fact that I-O-1 was frequently identified as "dope", this sought-for sensation was counteracted by undesirable effects, including a sleepy or " dull-headed sensation ", persistent nausea and vomiting. The low attractiveness of I-O-1 to opiate addicts is emphasized by the fact that during the direct-addiction test all 5 patients elected to discontinue the drug (3 after 17 days, and 2 after 39 days). In a parallel direct addiction test with d-propoxyphene, all 5 subjects, although not enthusiastic about the medication, completed the test.
An important factor in the abuse of a compound is its potency and pattern of effects when injected. It is significant therefore that I-O-1 subcutaneously, even in doses of 400 mg, was identified as a placebo. Intravenously, despite the fact that a larger dose of I-O-1 (300 mg) was used when it was compared with d-propoxyphene (180 mg), fewer morphine-like effects were induced.
1,2-dimethyl,3-phenyl-3-propionoxy pyrrolidine hydro-chloride (I-O-l) has been evaluated for addictiveness in former opiate addicts. These experiments indicate that I-O-1 has substantially less addictiveness than codeine and probably less addictiveness than d-propoxyphene.
Winder, C. V., Wax, J., Serrano, B., Scotti, L., Stackhouse, S. P. & Wheelock, R. H.: Pharmacological studies on 1,2-dimethyl-3-phenyl-3-propionoxypyrrolidine (CI-427), an analgetic agent. J. Pharmacol. exper. Therap., 133 : (1) 117-128, 1961.
002Kissel, J. W., Albert, J. R. & Boxill, G. C.: The pharmacology of methoxydine, a new analgetic agent. J. Pharmacol. exper. Therap ., 134: (3) 332-340, 1961.
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004Albert, J. R., Wheeler, A. G., Hawkins, H. C. & Kissel, J. W.: Preclinical evaluation of prodilidine hydrochloride for physical dependence and tolerance. The Pharmacologist, 3 : (2) 66, 1961.
005Deneau, G. A., McCarthy, D. A. & Seevers, M. H.: Physical dependence liability studies in the monkey. Add. 1, Min. 20th Meet., Comm. Drug Addiction and Narcotics, Ntl. Res. Council. Washington, D.C., Natl. Acad. Sci. (Jan.) 1959.
006Cass, L. J. & Frederik, W. S.: A new nonnarcotic analgesic, prodilidine hydrochloride . Curr. Therap. Res., 3 : (3) 97-106, 1961.
007Houde, R. W., Belleville, J. W. & Wallenstein, S. L.: The Annual Report from the Memorial Cancer Center. Clinical studies of morphine, codeine, aspirin, 1,2-dimethyl-3-phenyl-3-propionoxypyrrolidine hydrochloride and alpha- dl-3-acetoxy -6-methylamino-4,4-diphenylheptane. Personal communication.
008Telford, R. J. & Keats, A. S.: Personal communication.
009Fraser, H. F. & Isbell, H.: Human pharmacology and addiction liabilities of phenazocine and levophenacylmorphan. Bull. Narcotics, 12 : (2) 15-23, 1960.
010Fraser, 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. Pharmacol. exper. Therap., 133 : (3) 371-387, 1961.
011Edwards, A. L.: Statistical methods for the behavioral sciences , New York City, Rinehart, 1954.
012Kolb, L. & Himmelsbach, C. K.: Clinical studies of drug addiction. III. A critical review of the withdrawal treatments with method of evaluating abstinence syndromes. Amer. J. Psychiat., 94 : (4) 759-797, 1938.
013Himmelsbach, C. K.: Studies of certain addiction characteristics of ( a) dihydromorphine (Paramorphan), ( b) dihydrodesoxy-morphine- d (Desomorphine), ( c) dihydrodesoxycodeine- d (Deso-codeine), and ( d) methyldihydromorphinone (Metopon). J. Pharmacol. exper. Therap., 67 : (2) 239-249, 1939.
014Fraser, H. F. & Isbell, H.: Pharmacology and addiction liability of dl- and d-propoxyphene. Bull. Narcotics, 12 : (1) 9-14, 1960.
015Fraser, H. F., Isbell, H. & Van Horn, G. D.: Human pharmacology and addiction liability of norcodeine. J. Pharmacol. exper. Therap ., 129: (2) 172-177, 1960.
