Synthetic Narcotics

In contrast to pharmaceutical products derived directly or indirectly from narcotics of natural origin, synthetic narcotics are produced entirely within the laboratory. A continuing search for a product that will retain the analgesic properties of morphine, without the consequent dangers of tolerance and dependence, has yet to yield a drug that is not susceptible to abuse. The two that are most widely available synthetics are meperidine and methadone. We will also discuss the fentanyls, which area large class of synthetic opiates.

MEPERIDINE (pethidine).- The first synthetic narcotic, produced originally a generation ago, meperidine is chemically dissimilar to morphine but resembles it in its analgesic potency. It is probably the most widely used drug for the relief of moderate to severe pain. Available in pure form as well as in products containing other medicinal ingredients, it is administered either orally or by injection, the latter method being the most widely abused. Tolerance and dependence develop with chronic use, and large doses can result in convulsions. Demerol is a commercial name for pethidine.

METHADONE AND RELATED DRUGS.- Methadone is widely used in the treatment of narcotic addicts. The effects of methadone differ from morphine-based drugs in that they have a longer duration of action, lasting up to 24 hours, thereby permitting administration only once a day in heroin detoxification and maintenance programs. Moreover, methadone is almost as effective when administered orally as it is by injection. But tolerance and dependence may develop, and withdrawal symptoms, though they develop more slowly and are less severe, are more prolonged. Ironically, methadone, designed to control narcotic addiction, has emerged in some metropolitan areas as a major cause of overdose deaths.

Closely related chemically to methadone is the synthetic compound levo-alpha-acetylmethadol (LAAM), which has an even longer duration of action (from 48 to 72 hours), permitting a further reduction in clinic visits and the elimination of take-home medication. Recently, LAAM has been approved for the treatment of narcotic addicts by the Federal Food and Drug Administration.

Another close relative of methadone is propoxyphene, first marketed in 1957 under the trade name of Darvon for the relief of mild to moderate pain. Less dependence-producing than the opiates, it is also less effective as an analgesic.

Fentanyl Analogues

The fentanyls represent a large class of synthetic opiates having powerful analgesic and anesthetic effects. They act via mechanisms similar to that of morphine. The prototypical drug in this class is fentanyl which has a clinical potency of 50 to 100 times that of morphine. Certain members of this class have important application in human and veterinary medicine. Other substances within this class are of interest primarily because of their clandestine synthesis and subsequent abuse on the street.

In the United States four fentanyls are approved for marketing. These drugs include fentanyl citrate inself, alfentanil hydrocholride, sufentanil citrate, and carfentanil citrate. The first three drugs are approved for use in human medical practice. The fourth, carfentanil citrate, is approved for use in veterinary medicine. Fentanyl, alfentanil, sufentanil and carfentanil are all considered to have a high abuse potential and are in Schedule II of the FCSA.

Of the four drugs, only fentanyl has been clandestinely synthesized and abused out on the street using common, commercially available chemicals and simple laboratory equipment. The biological effects of the fentanyls are indistinguishable from those of heroin with the exception that the fentanyls may be hundreds of times more potent. There are hundreds of fentanyl analogues, with each differing only in potency and duration of action. The high potency, thence low dosage required for producing effect, and the multiplicity of active, structural analogues possible, make it difficult to detect the fentanyls in the illicit traffic. To date, over 12 different clandestinely

produced fentanyl analogues have been identified in the U.S. illicit drug traffic. Over 100 deaths have been attributed to the abuse of these drugs. Although the clandestine synthesis, distribution, and abuse of the fentanyls have been confined to the United States up to this time, their extremely high potency and relative ease of synthesis make them serious drug abuse threats internationally.

PHARMACOLOGICAL EFFECTS.- Fantanyls produce pharmacological effects characteristic of opiates. They produce all the effects of heroin including analgesia, euphoria, pinpoint pupils, and respiratory depression. Due to their high lipid solubility, fentanyls, regardless of route of administration, reach the brain quickly, thus providing for a very fast onset of action. The fast onset of action is considered a highly desirable trait by heroin users. Fentanyl users report experiencing the first desirable trait by heroin users. Fentanyl users report experiencing the first effects within 90 seconds after intravenous administration and by 2 minutes they are in a relaxed, euphoric state. In nontolerant individuals, spontaneous breathing can stop at this time, and overdose deaths are likely to occur very rapidly with these drugs.

The duration of the pharmacological effects will vary depending upon the fentanyl analogue used. Opiatelike effects can persist for as little as 5 minutes, as in the case with alfentanil, or last for one-half hour as in the case for fentanyl. 3-mathylfantanyl has a duration of action of about 4 hours which is similar to that of heroin.