Narcotics research, rehabilitation, and treatment. Hearings, Ninety ...

337be satisfactory substitutes in these higher dose ranges, such doses are not recommendedin the labeling. High doses of methadone and levorphanol are oftenassociated with an appreciable incidence of tissue irritation, and their use bythe intravenous route is not recommended. Even less experience is availableconcerning the effects of high doses of such other morphine substitutes asphenazocine and anileridine.Meperidine and its congeners are superior to morphine for use in labor anddelivery because their rapid onset and short duration of action minimizes therisk to the newborn infant. They are al.so often used postoperatively, as adjunctsto anesthesia and as analgesics in brief painful procedures. However, this sameproperty of rapid onset and short duration of action constitutes a liability whenthe physician wishes to treat persistent pain.As noted above, various of the synthetic morphine substitutes have limitationsin terms of a lack of knowledge concerning their effects in one or anotherof certain special patient groups such as children, women in early pregnancyand patients concurrently receiving certain other potent medications. For example,individuals being treated with monoamine-oxidase inhibitors have experiencedfatal reactions when given ordinary therapeutic doses of meperidine.This reaction does not seem to occur in such patients when morphine is used asan analgesic, and morphine is therefore the recommended potent analgesic in thisgroup of patients.With the exception of pentazocine, all of the potent synthetic narcotics havean abuse liability comparable to that of morphine. Indeed, meperidine has provenmuch more of an abuse problem than morphine in doctors, dentists, nurses andother paramedical personnel, probably because of a mistaken impression thatit is "safer" than morphine in this respect.As a research tool, morphine has been utilized as the standard of comparisonin virtually all of the modern controlled trials of analgesic efficacy and side effectliability involving semisynthetic and totally synthetic potent injectable analgesics.It has likewise been used at the Addiction Research Center in Lexington as thestandard for evaluating the abuse liability of these agents. These comparativestudies form the backbone of our knowledge concerning the relative therapeuticmerits and liabilities of every single potent analgesic currently available. Thecontinuing availability of morphine as a standard of comparison is absolutely essentialif the quest for more effective and safer potent analgesics is to progressTinhindered.Morphine has likewise been used as the primary tool in the vast majority ofstudies of clinical and animal pharmacology aimed at elucidating the mechanismof action of narcotic analgesics and the interaction of these substances with narcoticantagonists. Morphine is so generally accepted as the prototype potentanalgesic that teaching medical students and young physicians the pharmacologyandrational use of these drugs almost invariably involves presenting a detailedanalysis of the pharmacology and therpeutic properties of the prototype, morphine,followed by a briefer presentation of the ways in which the semisyntheticand totally synthetic potent analgesics differ from this prototype.In summary, while synthetics can be substituted for morphine in the majorityof patients requiring a potent analgesic, there is serious doubt as to the feasibilityof making such a substitution in a significant minority of such patients. In addition,the elimination of morphine would have a major adverse effect on the progressof our research in the fields of narcotics, analgesics, and drug dependence.CODEINELike morphine, codeine has been in therapeutic use for over one hundred yearsand is currently regarded as one of the basic or fundamental drugs in medicine.This agent is usually used orally and occupies a different therapeutic niche thanmorphine. Oral codeine is used in the treatment of moderate to moderately severepain and is generally considered, with the possible exception of aspirin, to be thesingle most useful mild analge.sic. Although codeine is present to a very smallextent in opium, the demand for codeine is so great that virtually all of the availablesupply is synthesized from morphine. In addition to its use as a mild analgesiccodeine finds extensive use as an antitussive.Codeine has several properties which make it uniquely valuable among the narcoticanalgesics. The drug has excellent oral efficacy, a property not shared bymost of the other narcotics. In conjunction with this, codeine has substantially