Table 1.

Clinical Investigations of the Interactions between Opioids and Benzodiazepines

Author(s)	Drugs and Doses	n	Outcome
Pond et al., 1982	Diazepam: ≈ 0.3 mg/kg for 9 days. Methadone: 50 mg ± 17	4	Diazepam failed to inhibit the metabolism of methadone.
Farqui et al., 1983	Diazepam: 200 μg/kg Buprenorphine: 2 μg/kg Buprenorphine: 3 μg/kg Fentanyl: 1.5 μg/kg	88	Eleven patient who had received buprenorphine suffered sudden respiratory depression requiring manual ventilation of their lungs followed by doxaprain infusion.
Preston et al., 1984	Diazepam: 20, 40mg Methadone: 50 or 60 mg (mean = 56 mg), 100%, 150% and 200% of normal dose.	5	The pupil constriction induced by diazepam + methadone combinations was greater than that induced by comparable doses of methadone alone. Diazepam 40 mg significantly increased opioid subjective effects when compared to either drug alone.
Preston et al., 1986	Diazepam: 20, 40 mg Methadone: 50 or 60 mg (mean = 56 mg), 100% and 150% of normal dose.	5	No evidence of a pharmacokinetic interaction between methadone and diazepam.
Farre et al., 1998	Flunitrazepam: 1, 2, 4 mg Triazolam: 0.5, 0.75 mg Methadone: 40-50 mg (mean= 44 mg)	10	Flunitrazepam (4 mg) produced significantly increased ratings of “high” and “euphoria,” indicating that the drug had significant abuse liability among methadone-maintenance patients.
Spiga et al., 2001	Diazepam: 0, 5, 10, or 20 mg/70 kg Methadone: 80 mg	5	The 10 and 20 mg diazepam doses significantly increased subjective reports of “good,” “like,” “strong,”, and” high.” Pretreatment with these doses significantly decreased methadone self-administration.
Lintzeris et al., 2006	Diazepam: 0, 10, 20 mg Methadone: 35–100 mg (mean = 55 mg) Buprenorphine: 6–16 mg (mean = 10.5 mg)	16	Co-administration of diazepam (10 and 20 mg) resulted in greater sedation and strength of drug effects for both methadone and buprenorphine, but had minimal impact on physiological parameters.
Lintzeris et al., 2007	Diazepam: 0, 40 mg Methadone: 50–100 mg (mean= 68.8 mg), 100% and 150% of normal dose Buprenorphine: 8–16 mg (mean= 11.1 mg), 100% and 150% of normal dose	12	Diazepam 40 mg increased the intensity of subjective drug effects (strength of drug effect, sedation) and decreased psychological performance (reaction time, DSST) for both methadone and buprenorphine (independent of the opioid dose).
Zacny et al., 2012	Alprazolam: 0.5 mg Oxycodone: 10 mg	20	The two drugs in combination produced stronger psychomotor effects and performance impairment. Yet, alprazolam did not alter abuse liability-related subjective effects of oxycodone.