Do the interactions between buprenorphine and benzodiazepines promote prolonged opioid dependence?

[Speaker] Antoine P. Coquerel:1,2,3,4
[Co-author] Ozlem Yildirim:1,2, Sonia Haddad:1,2, Lin Lin Ma:1,2, Remy Morello:5
1:Medical Pharmacology, University of Caen - Normandie. 14032 Caen, France, 2:UMR INSERM u1075 - Universite de Caen - Normandie, 14032 Caen, France, 3:Centre Regional de Pharmacovigilance, Av. Cote de Nacre. 14033 Caen, France, 4:Departement d ePharmacologie. CHU de Caen. 14033 Caen cedex 9, France, 5:Unite de biostatistiques. Depertement de recherche clinqiue. 14033. Caen, France

Background: Buprenorphine (BPN) is a high affinity opiate with partial agonist µ, and delta and kappa antagonist properties. The high-dosage form (BPN-HD) is the most prescribed opioid substitution treatment (OST) in France since 1996 in spite of many misuses with benzodiazepines (BZD) and especially Clorazepate (CRZ). Prior we found: (i) in the rats, acute or chronic administrations of BPN+CRZ induced strong changes in µ binding with reduced µ down regulation with strong desensitizations. Conversely delta and kappa receptors fluctuated little. (ii) in mice BPN induced anxiogenic effects that are reversed by CRZ in a dose-dependent manner. (iii) with the so-called "place preference" (PP) all the BZDs studied induced a PP by association to BPN while BPN alone did not. Aim: with BPN + BZD we studied (1) acute mortality induced by BPN associated to various BZD (2) changes in BZD binding (3) correlation between µ-binding changes and black-and-white box (BWB) test. Methods: experiments were done with Swiss mice. (1) acute lethality: CRZ, Diazepam, Flunitrazepam and Midazolam [MAZ]) were injected IP at different doses, looking for additive or synergistic effects (isobolography). Binding with 3H-flunitrazepam(2) and the µ ligand 3H-dermorphin(3) were analyzed with a Beta-imager (Biospace-Lab, Paris). (3) Correlations between binding and behavior changes were tested with Pearson / Spearman tests and principal component analysis. Results: (1) the acute lethality slopes tended to decrease and deaths are later, but we observed a synergistic effect with CRZ + BPN and MAZ + BPN. (2) the BZD binding is modified after treatments with BZDs but also with BPN alone and with BPN+BZD. The intensity of changes depends on the anatomical regions considered. (3) Behavior changes with BWB are correlated to the variations of the µ binding. Discussion: BPN has been popularized as OST because its acute toxicity is lower than methadone or illicit opiates. Conversely, its antagonistic kappa effect induces anxiety which causes a demand of BZD. Conclusion: BZD and µ binding changes confirmed the association maintained a higher fraction of receptors and an appetence for the association with vital risks.
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