Circadian differences in the individual sensitivity to opiate overdose.

OBJECTIVE: The aim of the present study was to test whether circadian differences in the response to opiates exist in humans and, if so, whether they are synchronized with the well-known circadian variations in overdose frequency. DESIGN: Daily variations in opiate overdose frequency, total amount of naloxone necessary to treat the comatose state, and frequency of hospitalization were examined in pure, nonlethal, consecutive cases of opiate (presumably intravenous heroin) overdoses. Furthermore, daily variations in the frequency of lethal overdoses were examined in all cases observed during the same period. SETTING: An 8-yr prospective, observational study in the city and suburban area of Ferrara, Italy. PATIENTS: A total of 518 consecutive cases of nonlethal opiate overdoses in 327 different patients, plus 110 consecutive cases of lethal opiate overdoses with precise or presumptive time of death. RESULTS: Analysis of the circadian distribution of nonlethal overdoses showed a significant peak in the afternoon to early evening. Analysis of the distribution of the hourly average amount of naloxone used to rescue patients from coma showed an opposite circadian variation, with a significant peak in the early morning. The hospitalization risk was also significantly higher from 3:00 to 8:59 am. However, in a subset of representative cases, plasma morphine concentrations did not change significantly in different hours of the day. Analysis of circadian distribution of lethal overdoses showed a significant peak in the evening hours. The death risk (calculated as the percentage of lethal events in the total number of intoxications within a given time frame) was significantly higher from 3:00 to 8:59 am. CONCLUSION: The present data provide evidence for the existence of circadian variations in the individual sensitivity to opiate overdose