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APPENDIX B. 1 PANEL ON DRUGS FOR RELIEF OF PAIN Statement Concerning the Package Inserts Used for Drugs for Relief of Pain (1.) Evidence for General Analgesic Effect. It is the recommendation of the Panel that, when a drug has been shown to be an effective analgesic in several different kinds of clinical pain, by suitably controlled trials using modern criteria, such a drug be entitled to consideration as an "all-purpose analgesic" unless special considerations indicate that this is not appropriate. In such cases, it would seem desirable to allow the drug to be marketed for the relief of most kinds of pain, thus avoiding the necessity for list- ing specific conditions. (2.) Analgesic Mixtures. There is increasing evidence, which has accumulated particularly within the past few years, that it is not always easy to predict the effects of adding one drug to another. Thus, drugs may merely summate in their activities, antagonize each other, or produce true potentiation. Since adequate trials on the relative efficacy of single drugs and mixtures are usually unavailable, it is hard for the Panel to be both fair and scientific in the evaluation of many of the mixtures which it has been asked to review. Furthermore, some ingredients appear to have been added to these mixtures on the basis of a rationale that is not evident to the Panel. On other occasions, the rationale seems evident, but the reason for the particular doses chosen (especially those which seem homeopathic) is not clear. In addition to the well-known objections that fixed-ratio mixtures do not allow flexibility in the doses of individual ingredients, one can object to many analgesic mixtures because they contribute little addi- tional therapeutic benefit while increasing the risks of side effects, allergic sensitization, etc. One can perhaps justify the use of some of these mixtures when pain is present with some other symptom, such as a stuffy nose, and both symptoms can be handled reasonably well by the mixture. However, to promote such a mixture as an all-purpose remedy for all kinds of pain, including those which cannot possibly be aided by one or more of the ingredients, is, in the view of the Panel, to encourage bad therapeutics. (3.) Semantic Confusion. The words "synergism" and "potentiation" are subject to multiple inter- pretations, even among professional pharmacologists. It would seem desirable to avoid their use, focusing instead on a description of what actually was achieved in the clinical setting. The word "potency" also 105
has different meanings to different persons. If one is talking simply about milligram pctency, this is actually a trivial matter in the clin- ical setting and, therefore, the term "potency" should probably be avoided. (4.) Irrelevant Information. Many package inserts contain material of no relevance to most practi- tioners. For example, the animal data are often not helpful, and are not always clearly identifiable as such. This material often seems to be used as a substitute for clinical data. Also irrelevant and not particularly helpful to the reader is a long list of clinical testi- monials, only some of which bear on the points at issue, and most of which are uninterpretable because of defects in clinical design. (5.) Drug Dependence and Abuse. The following statement is proposed to bring uniformity to the claims made concerning the dependence-producing properties of narcotic anal- gesics and preparations containing narcotic analgesics. It is recog- nized that many of the claims concerning a lesser dependence-producing liability of specific narcotic analgesics reflect the fact that the particular agents are not conmonly abused. However, i t must also be recognized that the actual abuse rates do not accurately reflect dependence-producing potential. It is known that agents and prepar- ations that have not been commonly a.b used in some social settings at some times, have been extensively abused in other settings at other times. One of the major purposes of the existing laws and regulations con- cerning narcotic analgesics is to prevent abuse. Therefore, all agents that have been shown to produce morphine-like physiologic and subject- ive changes when administered chronically, that will produce morphine- like dependence, or that will substitute for morphine in morphine-de- pendent subjects, shall carry the following recommended warning: "(Name of agent) can produce dependence of the morphine type and there- fore has the potential for being abused." The only exceptions to this recommendation are substances specifically exempted from bearing the label ''Warning -- may be habit forming" re- quired by federal law or regulation. (6.) Rigid Dose Recommendations. The Panel believes that doctors should not be bound legally by dose recommendations in package inserts. These recommendations represent advice as to the dose at which most patients can be started, and the range at which the needs of most patients can be met. However, it is good practice to manipulate the dose in the event of a therapeutic failure, or in the event of untoward effects. Furthermore, tolerance
to a drug may develop, and may require an increase in dose. It is the Panel's observation that some of the recommended doses are too low. (7.) Deficiencies of Methodology. There is a need for additional methodology for the study of pain. Thus, for example, there is a paucity of information available on the compara- tive effects of analgesics given repeatedly to patients with chronic pain. The result with single doses may or may not be transferable to such situations. Another area of deficiency is the evaluation of topical ointments that produce obvious sensations of cooling or warmth. Such limitations in methodology should be kept in mind by the Food and Drug Administration when evaluating data on drugs, both old and new. 107
