The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between‐raters and within‐raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between‐raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance‐corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between‐raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within‐raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between‐raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between‐raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance. Clinical Pharmacology and Therapeutics (1981) 30, 239–245; doi:

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1. In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O‐demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.

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Much of the history of pharmacology and therapeutics involves finding new uses for old drugs. The latest rediscovery is that of psychedelic drugs. Since they can cause profound distortions of perception and were once used as part of religious ceremonies, such research may seem unusual at this time.

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The debate on the legalization of heroin has focussed attention on the broader issue of pain management of cancer. Clinicians in palliative care should be aware that poor pain management is related primarily to lack of knowledge, appropriate skills and attitudes, and health care resources. The availability of heroin will not improve these. The need is for research about pain and alternative drugs and dosage forms and the variables affecting efficacy. Professional and public education about pain management is essential.