science
Narcotic antagonists fight addiction, abuse Research progress involves
a nonaddicting antagonist that could also be used to relieve pain. The first narcotic antagonist, N-allylnorcodeine, was synthesized in 1914 for counteracting morphine overdose. In 1940 nalorphine, a stronger antagonist that also had strong pain-killing properties, was synthesized. Unfortunately, it produced unpleasant feelings of disorientation, hallucinations, and other side effects and could not be used for purposes other than the treatment of narcotic overdose. Merck sells nalorphine for this purpose as Nalline. Another antagonist, levallorphan (L-iV-allyl-3-hydroxymorphinan), was synthesized in 1951 and is sold today as an antidote for narcotic overdose by Hoffmann-La Roche. In the 1950's when work on nalorphine and levallorphan was being carried out, scientists were not thinking in terms of applying narcotic antagonists directly toward the treatment of addiction because narcotic addiction and abuse were not serious problems at that time. The narcotic antagonists evaluated in man for analgesia all appeared to have some potential for hallucinogenic action. The more potent antagonists such as cyclazocine and cyclorphan are the most hallucinogenic. A major breakthrough in the search for a nonaddicting narcotic antagonist came in 1960 when Dr. Mozes Judah Lewenstein synthesized naloxone (Nallylnoroxymorphone, A^-allyl-7,8-dihydro-14-hydroxynormorphinone). In 1961 Dr. Harold Blumberg and his associates at Endo Laboratories, now a subsidiary of Du Pont, discovered that naloxone is a potent narcotic antagonist in animals, about 10 to 20 times as active as nalorphine. Later, other scientists showed that naloxone is a potent narcotic antagonist in man.
treatment of addicts, longer lasting and potent nonaddictive antagonists, long-acting dosage forms Nationwide the number of drug addicts has increased more than fivefold in little more than a decade. Yet during the same decade, progress in the battle against drug abuse has seemed painfully slow at times. One major setback was the recent discovery by public health officials that oral methadone, widely used to treat heroin addicts, can be processed for intravenous injection by addicts who often prefer it to heroin. Now scientists think they have found a weapon better than methadone to successfully combat narcotic addiction and drug abuse: nonaddicting narcotic antagonists. Latest research on nonaddicting narcotic antagonists was highlighted by scientists late last month at the American Chemical Society's 13th National Medicinal Chemistry Symposium in Iowa City. Attendees at the meeting were told of progress in several areas, including: • Treatment of drug addicts with nonaddicting narcotic antagonists. • Research on several new narcotic antagonists that are longer lasting and more potent than naloxone. • Development of long-acting dosage forms for narcotic antagonists. Research on narcotic antagonists is not new, but early studies were done primarily with the view in mind of developing a substitute for morphine—
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C&EN July 3, 1972
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Unlike previous antagonists, naloxone not only counteracts the effects of narcotics, but also counteracts agonist actions or side effects of narcotic antagonist analgesics. And it has little or no analgesic action of its own. It is effective in counteracting various narcotics, but is ineffective against depressants such as barbiturates. Its principal commercial use has been as an antidote for overdose of narcotics. Endo, which developed naloxone during the 1960's, sells it for this purpose as Narcan. The reason for naloxone's limited commercial use to date lies in its short duration of action. Naloxone can counteract narcotic depression within a minute or two when given intravenously —but only for two to four hours. Large oral doses of 1 to 3 grams are required to get even 24-hour protection. Duration of blocking action of narcotic antagonists is of paramount importance in treatment of addicts because patients must come to a hospital to receive their doses. (Many addicts cannot be relied upon to come every day.) So the search for a longer-lasting nonaddicting antagonist has continued with several laboratories working to synthesize new compounds. Dr. Blumberg's laboratories at Endo have developed several new compounds chemically related to naloxone. One compound, synthesized in 1963, is Ncyclopropylmethylnoroxymorphone or what Endo calls EN-1639. EN-1639 has limited effectiveness as an analgesic, but it is about twice as active and longer acting than naloxone as a narcotic antagonist when injected in animals. By oral administration EN-1639 appears to be about eight times as active as naloxone and about three times as long acting in producing narcotic block-
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Drug addiction programs get big boost from Government The problem of abuse and misuse of drugs is not a new one, says Dr. Robert Rees, consultant to the Special Action Office on Drug Abuse Prevention (SAODAP). After all, drugs have been used for "recreational" and other non medical purposes for centuries. But the problem has become much more com plex and widespread in the U.S. in re cent years as drugs designed for bene ficial purposes are being abused and misused by what appears to be an in creasingly large number of people. Getting a hold on the number of peo ple with drug problems is difficult, however. Different groups use a variety of drugs in a number of distinct patterns and each pattern of use represents a different set of risks to the user and to society, Dr. Rees says. Probably the most serious risk group in terms of both society and the individual are heroin users. Yet com plete or reliable statistics on the num ber of heroin addicts are virtually non existent, says a SAODAP spokesman. SAODAP's best estimate is that there were between 300,000 and 360,000 heroin addicts in the U.S. in 1971. This is about a five- or sixfold increase in the number of heroin addicts from 1960. The Federal Government has be come increasingly involved in the preage in animals, Dr. Blumberg says. Preliminary studies carried out in man at the U.S. Addiction Research Center in Lexington, Ky., by Dr. Donald R. Jasinski, Dr. W. R. Martin, and col leagues also indicate that EN-1639 is more potent and longer acting than naloxone in narcotic blocking effect with less agonistic activity (and less effective) than cyclazocine. Another compound being studied by scientists at the Addiction Research Center is L-l-N-cyclopropylmethyl-3,14dihydroxymorphinan, which is synthe sized by Bristol Laboratories of Canada, Ltd., and is called levo-BC-2605. Still another compound, a derivative of oripavine (M-5050), has been synthesized in the laboratories of Reckitt and Cole man and has been shown to be a potent antagonist with low agonist activity. Research is also under way at Hoff mann-La Roche by Dr. E. Mohacsi and his colleagues on new metabolites of levallorphan. Meanwhile, some progress has been made in extending the blocking action of naloxone. A team of psychiatrists at the New York Medical College and Metropolitan Hospital Center recently has been able to prolong the blocking action of naloxone for up to 72 hours without harmful effects to 13 volunteer test subjects. Dr. Robert H. Levine, Dr. Arthur Zaks, Dr. Max Fink, and Dr. Alfred Freedman used a suspension of naloxone pamoate, a partially soluble salt with a timed-release action. How ever, for a drug to be useful in addiction
vention of drug abuse from a number of different angles. To cut down illegal drug traffic into the U.S., President Nixon last year formed a Cabinet Com mittee on International Narcotics Con trol. A notable recent example of the success of this program is the bilateral agreement with the government of Turkey to stop Turkish farmers from growing the opium poppy. The Government has also concen trated efforts on beefing up its en forcement arm—the Bureau of Nar cotics and Dangerous Drugs (BNDD) in the Justice Department. BNDD's budget increased from $14.4 million in fiscal 1968 to more than $65 million in fiscal 1971. The money has enabled the bureau to increase its staff of en forcement officers and to buy sophisti cated new equipment for detection of drugs being smuggled into the country. In one of the most significant moves, President Nixon created by executive order on June 17, 1971, the Special Ac tion Office for Drug Abuse Prevention under the directorship of Dr. Jerome Jaffe. SAODAP coordinates the efforts of 13 federal agencies that have deal ings in the drug area. SAODAP's prime function is to focus the resources of the Federal Government on the national problems of drug abuse education,
treatment, it should be able to last for a month or even longer, the psychiatrists say. Such a method for administering nar cotic antagonists to deliver continuous dosage over a prolonged period, perhaps as long as several months, has been developed by Dr. Seymour Yolles, Dr. David Blake, Dr. John Eldridge, and James Woodland at the department of chemistry, University of Delaware, Newark. In principle, Dr. Yolles ex plains, the method consists of incorpo rating the narcotic antagonist as homo geneously as possible in a plastic matrix (preferably biodegradable), shaping the mixture into a film, microsphere, or fiber, and inserting the blend into the body tissue by surgery or hypodermic injection. The antagonist migrates con tinuously from the interior of the struc ture to the outer surface where it is swept away by the body fluid surround ing the structure. The advantages of the method are that it doesn't require the continuing cooperation of the patient after the device is implanted and it minimizes the time required of skilled personnel in administering the drug to the patient. Dr. Yolles and colleagues have in fact demonstrated the feasibility of the method in rats using cyclazocine-polyethylene in film form and cyclazocinepoly(lactic acid) blends in film form and small particle form. Polylactide has the advantage that it is biodegrad able and doesn't require surgical re moval when the dose is complete.
training, treatment, rehabilitation, and research. In the research area SAODAP has been directed to encour age and promote by grants, contracts, and other means expanded research programs to create, develop, and test several types of substances, including: • Nonaddictive synthetic analgesics to replace opium and its derivatives in medical use. • Long-lasting nonaddictive blocking or antagonistic drugs for treatment of heroin addiction. • Detoxification agents that will ease the physical effects of withdrawal from heroin addiction. Although SAODAP has no funds of its own to speak of for support of basic re search in the field of narcotic addiction, overall federal support of basic re search, particularly in developing non addictive antagonists, has increased greatly. In fiscal 1971 the Federal Gov ernment spent only $16.6 million for support of basic research, coordination, and evaluation. In fiscal 1972 this was increased to $56.1 million, and $70.6 million is proposed for fiscal 1973. Overall, the Federal Government has in creased the amount of money allotted for its entire drug abuse prevention program from $77.1 million in fiscal 1969 to $594.2 million in fiscal 1973.
Potentially, naloxone could be used in "depot injections" such as this. Another use for naloxone in drug addic tion therapy is seen by Dr. Anthony W. Pircio of Bristol Laboratories, Syracuse, N.Y., who says current studies indicate it may be the ideal agent for combating the abuse of legitimate drugs such as methadone and paregoric. When legiti mate drugs treated with naloxone are processed for attempted abuse by in jection, the naloxone immediately works to block narcotic effects and in addicts feelings of withdrawal are experienced. The idea is that if an addict knows that his methadone contains naloxone, he will not risk processing it for injection since it could lead to severe withdrawal symptoms.
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July 3, 1972 C&EN
15
