Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure
Authors: Halbsguth Ulrike , Rentsch Katharina M. , Eich‐Höchli Dominique , Diterich Isabel , Fattinger Karin 
Published: August 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Venosclerosis prevents many opioid addicts in heroin substitution programmes from injecting intravenously, which makes consideration of other routes of administration necessary.

• Even high doses of oral diacetylmorphine are completely converted to morphine presystemically.

• Morphine bioavailability in heroin addicts after high‐dose oral diacetylmorphine administration is considerably higher than expected based on prior data obtained with relatively low oral diacetylmorphine or morphine doses in healthy subjects or patients receiving treatment for pain (64–72%vs.20–25%).

WHAT THIS STUDY ADDS

• Morphine influx into systemic circulation is more rapid after oral diacetylmorphine than after oral morphine, resulting in earlier and more than double maximal concentrations.

• In opioid‐dependent people, bioavailability of morphine from oral doses of diacetylmorphine is also 37% higher than that of oral morphine.

• Morphine bioavailability is two and 1.5 times higher in chronic users than in opioid‐naive subjects after low oral doses of diacetylmorphine or morphine, respectively.

• Oral absorption of morphine from diacetylmorphine is dose dependent, i.e. bioavailability increases with diacetylmorphine dose.

AIMS

In the Swiss heroin substitution trials, patients are treated with self‐administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high‐dose oral diacetylmorphine is considerably higher than would be predicted from low‐dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose.

METHODS

Opioid‐naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium‐labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose.

RESULTS

The maximum plasma concentration (Cmax) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 µmol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 µmol).

CONCLUSIONS

Oral absorption of opioids is substance‐, dose‐ and patient collective‐dependent, suggesting that there may be a saturation of first‐pass processes, the exact mechanism of which is not yet understood.