Methadone and buprenorphine are the two main opioid substitution treatments for heroin dependence currently offered in Australia. A number of publications have implicated buprenorphine as being potentially dangerous in combination with benzodiazepines but no comparison has been made to the relative dangers of benzodiazepines combined with buprenorphine or methadone. The effect of i.v. methadone and buprenorphine on respiration was investigated by evaluating arterial blood pCO2, pO2 and pH, and measuring respiratory rate in rats. Measurements were taken at 0, 15, 30, 60, 120, 180 and 240 min after i.v. administration of methadone or buprenorphine. Effects on respiration were greatest 15 min after i.v. drug administration. The effect of methadone and buprenorphine on respiration was compared with and without diazepam pretreatment (20 mg/kg). Buprenorphine alone exhibited a bell shaped dose response inhibition of respiration; however the plateau of the dose response inhibition on respiration was lost when administered in combination with diazepam. Methadone showed a dose-dependent inhibitory effect on respiration, which was potentiated with diazepam pretreatment. While the effect of diazepam pretreatment was the abolishment of the protective bell shaped dose response effect on respiration, the effect of buprenorphine and diazepam was not greater than methadone and diazepam.