14 Narcotic Antagonists as Analgesics Clinical Aspects ARTHUR S. KEATS and JANE TELFORD
Division of Anesthesiology, Baylor University College of Medicine, Houston, Tex.
The demonstration that nalorphine is a potent nonaddicting analgesic
in man stimulated a
search among other narcotic antagonists
for
potent analgesics without the psychotomimetic effects of nalorphine. Most recently a series of benzomorphan derivatives capable of antag onizing meperidine analgesia in animals was surveyed in man for analgesic activity and psychotomimetic
effects.
Of the six
deriv
atives studied, two were shown to have the desired
characteristics
without
psychotomimetic
of
potent effects.
analgesia To
date,
one of these has also been shown to be with out addiction liability of the narcotic type in man.
The study of these benzomorphan de
rivatives permitted correlations to be drawn among
analgesia,
narcotic
antagonism,
chotomimetic effects, respiratory
psy
depression,
and addiction liability.
• η 1954, Lasagna and Beeeher (8) demonstrated that nalorphine, which at that • time was known to be a potent antagonist of many of the actions of narcotics, was in itself an analgesic in man. This demonstration was of considerable significance, first, because the analgesic activity of nalorphine could not be demonstrated by several techniques in laboratory animals and, second, because nalorphine possessed no morphine-like addiction liability when studied in postaddicts (4). These observations suggested that despite general skepticism a potent nonaddicting analgesic had in fact been identified in nalorphine. Early studies in our laboratory confirmed the analgesic activity of nalor phine in man and we estimated that nalorphine was approximately as potent an analgesic as morphine on a milligram basis (5). We also confirmed that nalorphine produced other effects remarkably similar to those of morphine, including sedation, nausea, vomiting, mental clouding, and respiratory depres170
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171
sion., As others had (8), we found that nalorphine, unlike morphine, also produced psychotomimetic effects in approximately 20% of patients (6). The most disturbing of these were hallucinations, disorientation, and other depersonalization phenomena. This high incidence precluded the routine clinical use of nalorphine as an analgesic, since the side action liability of morphine is low when used clinically Following this lead, however, we postulated that a clinically useful nonaddicting potent analgesic could more likely be found among the narcotic antagonists than among compounds which showed classical morphine-like characteristics by animal screening techniques. We therefore investigated a number of compounds which were available to us in sufficient quantity for clinical testing and which demonstrated morphine antagonistic activity in animal studies. Most of these compounds, which were derived from the morphine and morphinan nucleus, did not show analgesic activity in animal assays and screening for analgesia was of necessity carried out in man. Among these narcotic antagonists, some were found to produce potent or moderate analgesia, but in each instance the analgesia was associated with a certain incidence of psychotomimetic effects similar to those which followed nalorphine (11). Following the synthesis of benzomorphans by May and Fry (10), Archer and his associates (1 ) prepared a number of benzomorphan derivatives showing a wide range of potency as antagonists of meperidine analgesia in animals. These compounds were made available to us. They were screened in man primarily for analgesic and psychotomimetic activity, since these were limiting characteristics in the search for a potent nonaddicting analgesic. When analgesia in the morphine range was obtained without psychotomimetic activity, other parameters of drug action were investigated. To date, we have studied five of these benzomorphan antagonists. A sixth has been studied by Lasagna and DeKornfeld (9), whose preliminary results have been included. This study suggests that compounds with potent antimorphine activity in animals associated with potent analgesia in man are also associated with psychotomimetic effects in man. Conversely compounds with low antimorphine potency in animals associated with potent analgesia in man are without psychotomimetic activity. The study of two of these compounds in postaddicts (2, 3) also suggests that compounds possessing antimorphine activity in animals, possess little or no addiction liability. At least one of these compounds promises to be a clinically useful, nonaddicting potent analgesic which may represent an important contribution to therapeutics (7).
Methods The methods used in these assays were presented in detail in a recent publication (11). For orientation, the following brief description is included. The drugs studied, their chemical relationships, and the designations by which they are known in this and other publications are presented in Table I. A l l drugs were given intramuscularly and all studies were double blind. Analgesic potency was determined in postoperative patients following major surgical procedures. The drug to be studied and a placebo (saline) were alternated in individual patients as often as every hour as necessary to obtain relief from pain. The degree of analgesia produced by each injection was
172
MOLECULAR MODIFICATION IN DRUG DESIGN Table I.
Benzomorphan Derivatives Studied in Man
R NAME
R*
R
- C H 2 CH2C6H5
PHENAZOC1 NE
3
- C H 2 CH
=
CH2
SKF
10047
C H
-CH2CH
=
CH2
WIN
19362
CH CH
3
2
5
WIN 2 9 M
CH
3
- C H C H = CHCI(CIS)
CH
3
-CH
WIN
20740
CH
3
- C H C H =C(CH )
2
WIN
20228
- C H C H =C(CH )
2
WIN
20264
C2H5
2
2
2
2
-Δ 3
3
estimated by technicians who interviewed patients before and after drug administration. One dose of drug and one of placebo were considered a pair. The frequency of analgesia in 20 to 30 pairs of doses (usually 10 to 15 patients) was compared and expressed as analgesic potency of the drug relative to the placebo. Several dose levels of each drug were studied in successive groups of patients in order to obtain a dose effect relationship. From such data, it is difficult to estimate the dose of the drug which produced analgesia equivalent to that of morphine. Morphine was not used as the reference standard, since the compounds with which it would be alternated in the same patient possessed antimorphine activity. The question of antagonism of morphine analgesia would always be present. Therefore estimates of analgesic potency relative to morphine were crude and limited to estimates of doses which achieved the range of potency expected of morphine when studied in this fashion with a placebo. Postoperative patients were observed during analgesic assays for the ap pearance of gross psychotomimetic activity such as hallucinations, disorientation, uncontrollable excitement, and profound sedation. In addition, preoperative patients who were receiving no medications and were awaiting elective surgery were given these drugs at several dose levels. They were interviewed before and at three periods after injection for a variety of subjective effects which were characteristic of both morphine-like and nalorphine-like activity. Respiratory depression was estimated in healthy young subjects in whom a respiratory stimulus response curve was determined in response to inhalation of three mixtures of carbon dioxide in oxygen. Simultaneous measurements were made of alveolar ventilation and alveolar C 0 tension at each gas mixture. These provided the data for the curves. A control and two postdrug curves were obtained. The degree of displacement of these curves to the right repre sented respiratory depression. 2
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Narcotic Antagonists—Clinical
Results The results of these assays are summarized in Table II, which also includes data on morphine, nalorphine, and phenazocine for comparison purposes. The estimates of relative analgesic potency and relative psychotomimetic activity were derived from data collected in our laboratory for all compounds, except WIN 20,740. This compound was studied by Lasagna and DeKomfeld (9). Relative analgesic potency is expressed as the number of milligrams of each compound estimated to produce analgesia equivalent to 10 mg. per 70 kg. of morphine in man. For two compounds, S K F 10,047 and W I N 29M, both of which produced definite analgesia, the dose equivalent to morphine was not achieved. Studies with these compounds were discontinued at the doses indicated because of the severity of psychotomimetic effects which appeared. Relative psychotomimetic potency could not be expressed in milligrams because of the lack of a scale for quantitating such activity. Instead, compounds were ranked according to the intensity of psychotomimetic effects observed at any dose studied. The relative potency estimates of these compounds as narcotic antagonists were derived from the milligram potency data of Archer et al. (I), utilizing antagonism of meperidine analgesia as the test object. Three grades of activity (0, +, ++) were arbitrarily used. Table II. Comparison of Pharmacological Effects of Benzomorphan Antagonists Studied in Man
Drug
Analgesic Dose, Mg./70Kg.
Morphine Nalorphine Phenazocine S K F 10,047 W I N 19,362 W I N 29M W I N 20,740 W I N 20,228 W I N 20,264
10 10 3.5 15 + 5 2 + 0.25 20 30
Psychotomimetic Effects
0
++ 0 ++ +0 0
Respiratory Depression
+ + + + + +
Potency as Narcotic Antagonist (Animal)
0
++ 0 ++ +
It is immediately apparent from Table II that all compounds studied produced some degree of analgesia, ranging in milligram potency from 0.25 mg. for W I N 20,740 to 30 mg. for W I N 20,264. Potency as a narcotic antagonist was not strongly related to analgesia in man, since W I N 20,740 and S K F 10,047 were equally effective in antagonizing meperidine analgesia in the animal, but WIN 20,740 was at least 60 times as potent as an analgesic in man. Strong antagonist activity in the animal was consistently associated with psychotomimetic effects in man. The only compounds which did not produce bizarre mental effects were relatively inactive as meperidine antagonists (WIN 20,228 and W I N 20,264). W I N 20,228 when administered intramuscularly to almost 200 patients in doses ranging from 0.14 to 0.56 mg. per kg. failed to produce definite psychotomimetic effects. Four patients received 3.0 to 6.0 mg. per kg. of W I N 20,228 intravenously without psychotomimetic effects (7). Comparable studies with large doses of W I N 20,264 and W I N 20,740 have not been carried out.
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MOLECULAR MODIFICATION IN DRUG DESIGN
W I N 20,740 occupies an intermediate position. Analgesic studies were initiated at doses of 2 mg. (9) (doses were not related to body weight). At this dose, both marked analgesia and some psychotomimetic effects were observed. In subsequent groups of patients the dose was reduced. It was found that doses as low as 0.25 mg. produced analgesia equivalent to morphine, and psychotomimetic effects were not observed in any patient given less than 1.0 mg. In contrast to W I N 29M, W I N 20,740 produced strong analgesia in low dose, psychotomimetic effects in high dose; the opposite was true of W I N 29M. From this comparison, it would seem that potent narcotic antagonism in the animal and potent analgesia in man are associated with some psychotomimetic effects in man, whereas potent analgesia without potent narcotic antagonism is relatively free of psychotomimetic effects, at least in the dose ranges studied. A n interesting contrast to support this formulation is provided by N-methallylnormorphine, a compound we studied previously in doses up to 20 mg. per kg. ( I I ) . This compound produced neither analgesia nor psychotomimetic effects in man, but was a potent narcotic antagonist in both animals and man. It would seem then that potent narcotic antagonism in animals is not necessarily associated with either analgesia or psychotomimetic effects in man, suggesting again that both potent antagonism in animals and potent analgesia in man are necessary for psychotomimetic activity. To date all compounds shown to be strong narcotic antagonists in animals have proved to be strong narcotic antagonists in man. For interest, we have included in Table II the results of our studies of the respiratory depressant activity of these compounds in man. We have not studied S K F 10,047 or W I N 29M for this parameter, since analgesia equivalent to morphine was not obtained. The other compounds were studied at doses approximately equal to morphine in analgesia. The data on W I N 20,740 were obtained by Lasagna et ah (9). All compounds produced respiratory depression equal to that produced by 10 mg. per kg. of morphine and this respiratory depressant activity was independent of the potency of the compound as a narcotic antagonist or its psychotomimetic activity. It was related to analgesia. Despite the similarity to morphine, some preliminary observations from large intravenous doses of narcotic antagonists indicate that the slope of the dose effect curve for respiratory depression by narcotic antagonists is much less than that for morphine. Possibly the maximal respiratory effect of narcotic antagonists may not be respiratory arrest, as is true with morphine-like compounds. The parent compound, phenazocine, produced more respiratory depression than morphine in doses which produce equal analgesia. Further Studies with W I N 20,228. The subjective effects produced by W I N 20,228 were studied in preoperative symptom-free patients at 10, 20, and 40 mg. per 70 kg. (7). These effects were strikingly similar to those of morphine and included dizziness, grogginess, difficulty in concentration, sleepiness, nausea, and vomiting. The incidence and severity of the effects produced by 20 mg. per 70 kg. of W I N 20,228 were almost identical to those of 10 mg. per 70 kg. of morphine. Those of 40 mg. per 70 kg. of W I N 20,228 were somewhat more marked than morphine. The only suggestion of any psychotomimetic effects from W I N 20,228 was the single report of one patient that she experienced "crazy thoughts" after the 20 mg. per 70 kg. dose.
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We attempted to antagonize the respiratory depression of morphine by W I N 20,228. We were able to demonstrate slight antagonism in seven subjects. It was more significant, however, that W I N 20,228 did not add to the respiratory depression of morphine. To study the circulatory effects of W I N 20,228, we administered total doses of 3 to 6 mg. per kg. of W I N 20,228 to three patients in small intravenous increments and compared this to the effects of 1 mg. per kg. of morphine administered under identical circumstances in other patients. Progressive respiratory depression was observed at these large doses, manifested primarily by an increase in the alveolar p C 0 . However, in contrast to morphine, tachycardia and hypertension were produced when the dose of W I N 20,228 exceeded 2 mg. per kg. As noted above, these large doses produced psychic effects indistinguishable from morphine. Two patients who received 2.5 and 3.1 mg. per kg. of W I N 20,228 intravenously in small increments were then given nalorphine or levallorphan. In neither patient was the respiratory depression of W I N 20,228 antagonized by these potent narcotic antagonists. Addiction Liability. The addiction liability of W I N 20,228 was studied by Fraser and Rosenberg (3) at the Addiction Research Center at Lexington, Ky. The compound was administered both subcutaneously and intravenously to nontolerant postaddicts, who reported that the subjective effects were not morphine-like. When substituted for morphine in morphine-dependent subjects, W I N 20,228 did not suppress the abstinence syndrome of morphine. Chronic administration of W I N 20,228 was disliked by postaddicts. One subject who continued taking the compound for 25 days exhibited a mild abstinence syndrome, but no physical dependence could be demonstrated when nalorphine was administered. These effects were considerably different from those associated with morphine and it was concluded that W I N 20,228 had minimal addiction liability. These same investigators studied W I N 20,740 in a similar manner and concluded that it too had little or no addiction liability (2). In nontolerant postaddicts, W I N 20,740 produced less euphoria than morphine. It precipitated an abstinence syndrome in morphine-dependent subjects and acute withdrawal after 25 days' administration of W I N 20,740 resulted in a mild atypical abstinence syndrome in four subjects. The inability to demonstrate a narcotic-type addiction liability for W I N 20,228 and W I N 20,740, and the previously reported failure to demonstrate this for nalorphine (4), strongly suggest that compounds shown to produce narcotic antagonism in animals will prove to be nonaddicting in studies in man. A l l three of these compounds are therefore potent nonaddicting analgesics. 2
Discussion If the results reported here can be confirmed by others, a clinically useful nonaddicting potent analgesic will have been attained. More significantly, the means by which other similar compounds may be identified in this and other chemical groups will now be apparent. Having thus far dissociated addiction liability and psychotomimetic activity from potent analgesia, it may now be
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MOLECULAR MODIFICATION IN DRUG DESIGN
possible in the continued search to extend this dissociation of potent analgesia from nausea and vomiting, constipation, or respiratory depression. On the other hand, radical new departures may be required for this further dissociation. The achievement of a nonaddicting potent analgesic and possibly a mor phine substitute does not have great significance for the general problem of narcotic addiction. It would contribute something, however. The availability of such a compound would eliminate the small number of "medical addicts" whose initial addiction results from the chronic treatment of a painful disease with narcotics and the small amount of narcotics for medical use whichfindsits way into illicit channels by theft or deceit. Much more importantly, it would permit physicians to treat pain adequately and eliminate the terrible decisions of whether to risk addiction in relieving the pain of a patient with chronic disease or to prolong suffering. On the other hand, the compounds studied to date do not represent a panacea. They still possess their other unpleasant side actions, as do morphine and other potent narcotics. The availability of this type of drug would also eliminate the tedious and expensive accounting of all supplies and administrations of narcotics, now mandatory in physicians' offices and hospitals, and by distributors, manufac turers, and the Federal Government. Finally and probably most important can be the contribution made by such drugs in further pharmacological research. Contrasting compounds such as morphine and W I N 20,228, which are so similar except for their addiction liability, may provide another tool as valuable as nalorphine for further explora tion of the problems of analgesia, physical dependence, tolerance, and the relationship between molecular modification and drug action.
Literature Cited (1) Archer, S., Harris, L. S., Albertson, N. F., Tullar, B . F., Pierson, A. K., ADVAN. C H E M . SER., No. 45, 162 (1964). (2) Fraser, H . F., Rosenberg, D. Ε., Biochemistry and Pharmacology, 2nd Interna tional Pharmacological Meeting, Prague, August 1963. (3) Fraser, H. F., Rosenberg, D. Ε., J. Pharmacol. Exptl. Therap.,143, 149 (1964). (4) Isbell, H., Federation Proc. 15, 442 (1956). (5) Keats, A. S., Telford, J., J. Pharmacol. Exptl. Therap. 117, 190 (1956). (6) Ibid., 119, 370 (1957). (7) Ibid., 143, 157 (1964). (8) Lasagna, L., Beecher, Η. K., Ibid., 112, 356 (1954). (9) Lasagna, L., DeKornfeld, T. J., Federation Proc. 22, 248 (1963). (10) May, E. L., Fry, Ε. M., J. Org. Chem. 22, 1366 (1957). (11) Telford, J., Papadopoulos, C. N., Keats, A. S., J. Pharmacol. Exptl. Therap. 133, 106 (1961). RECEIVED December 9, 1963. Investigations supported by a grant awarded by the Committee on Drug Addiction and Narcotics, National Academy of Sciences, Na tional Research Council, from funds contributed by a group of interested pharmaceuti cal manufacturers.
