BACKGROUND & AIM: Globally, more than 100 000 people die annually from opioid overdose. Although strongly implicated in heroin overdose deaths, acute opioid-induced respiratory depression is poorly understood, and few laboratory studies have been completed in human subjects. It is an area of undone science. Using a human laboratory overdose model, our research question was: what is the strength of the association between increasing dose of diamorphine and degree of respiratory depression in people prescribed injectable diamorphine for heroin use disorder?

DESIGN: Single-blind, Phase IV, non-randomised, dose-escalation clinical trial. Setting was King's Clinical Research Facility, London, UK.

PARTICIPANTS: Four participants prescribed injectable diamorphine as treatment for heroin use disorder [all male, median (range) age 63 (59-72)].

INTERVENTIONS: The following dosing schedule was implemented (as a % of participant's usual prescribed diamorphine dose): visit 1-100%; visit 2-110%; visit 3-120%; visit 4-100%. Usual dose: 97.5 mg (30 mg-200 mg).

MEASUREMENTS: Physiological measures included: pulse oximetry (SpO%), end-tidal CO (ETCO%), transcutaneous CO, respiratory rate and parasternal electromyography to measure neural respiratory drive index (NRDI). Recordings were made continuously from 3 mins pre-dose to 60 mins post-dose.

FINDINGS: Respiratory measures from baseline to post-dose across all dose sessions had ranges of: 89.7%-99.5% SpO%; 4.8%-7.7% ETCO%; 5.2-13.4 breaths/minute respiratory rate; 51.2 min-165.9 min NRDI across all participants. All diamorphine doses caused some reduction in respiratory function. There was no clear difference between diamorphine dose and the degree of respiratory depression, based on descriptive analyses.

CONCLUSIONS: A dose-escalation clinical trial of people prescribed injectable diamorphine for heroin addiction found that the degree of respiratory depression caused by diamorphine does not appear to be dose dependent; however, the changes seen at diamorphine doses to which participants were accustomed suggest that participants had only partial tolerance to the respiratory depressant effect of diamorphine.