1 Bruno Mégarbane, MD, PhD Department of toxicological and medical critical care, Lariboisière Hospital, INSERM U705, Paris-Diderot University Paris, France [email protected]Respiratory toxicity of maintenance therapy in drug addicts: contribution of animal models Prescription opioids : first cause of toxic death in the US Jones CM. JAMA 2013 National Center for Health Statistics, 2010 Increase in prescription opioid-related fatalities Häkkinen M. Forensic Sci Int 2012 Boyer EW. NEJM 2012 Opioid overdose All opioids produce a similar toxidrome in excessive dosing; Supportive care One antidote: Naloxone however, pattern of opioid abuse is various and changing Physiological regulation of ventilation All μ-receptor agonist cause a dose-dependent depression of respiration: - Reduction in the brainstem sensitivity to CO 2 - Increase in the apneic threshold - Decrease of the hypoxic drive to respiration - Abolishment of carotid body chemoreception - Depression of pontine & medullary centres involved in rhythmic respiration - Characterized by a dose-related, naloxone-reversible depression of the resting ventilation with a proportional reduction in Tidal volume, decreased PaO 2 , and arterial pH along with increased PaCO 2 . - Respiratory depression generally attributed to interactions with mu2- and delta-OR, whereas kappa-OR seem not involved. - Possible deleterious role of combination to psychotropic drugs. What do we know about opioid effects on respiration?
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Bruno Mégarbane, MD, PhD
Department of toxicological and medical critical care, Lariboisière
Co-administration of methadone + diazepam increases inspiratory time (p<0,001), without significant alteration of any other parameter
Methadone + BZD combination
(A)
(B)
Methadone concentrations in combination with diazepam
Co-administration of methadone and diazepam results in a significant increase
in AUC of R-methadone (active) concentrations over 240 min (p<0,05).
Methadone + BZD combination
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Methadone-induced respiratory effects
Methadone administration results in TI increase and at elevated doses in respiratory depression characterized by an additive TE increase associated with respiratory acidosis and hypoxemia.
Methadone-induced hypoxemia is caused by mu-opioid-receptors and modulated by kappa-opioid-receptors.
Methadone-induced increase in TE is caused by mu1- and delta-opioid receptors while increase in TI is caused by mu-opioid-receptors.
Co-administration of diazepam + methadone is not responsible for additional respiratory depression in comparison to methadone alone, despite significant metabolic interaction between the drugs.
Summary
Buprenorphine-related respiratory
effects: mechanisms of toxicity and
role of the interaction with BZD ?
Pharmacological properties of buprenorphine
High-degree of safety
Cowan A. Br J Pharmacol 1977 Walsh SL. Clin Pharmacol Ther 1994
BUP = a thebain-derived agent, with a high liposolubility, agonist-
antagonist properties, high affinity and long acting activity
Role of CYP3A induction on BUP–induced respiratory effects (2)
Role of co-ingestions
nsVm
nsTe
Ti
nsnsVt
Fr
Ttot
WT / KOS / PSC833N-BUP 1 mg/kg
nsnsVm
Te
nsTi
nsnsVt
Fr
Ttot
WT / KOS / PSC833Bup 10 mg/kg
nsVm
nsTe
Ti
nsnsVt
Fr
Ttot
WT / KOS / PSC833N-BUP 1 mg/kg
nsnsVm
Te
nsTi
nsnsVt
Fr
Ttot
WT / KOS / PSC833Bup 10 mg/kg
Role of P-gp in BUP/N-BUP toxicity in FVB mice
AlHaddad H. Crit Care Med 2012
Mechanism of BUP toxicity
P-glycoprotein
BUP: not a substrate
N-BUP: substrate
N-BUP transport
through the BBB
remains debated
?
Role of P-gp in BUP/N-BUP toxicity in FVB mice
Mechanism of BUP toxicity
? 0
5
10
15
20
25
30
35
Control PSC833 mdr1a,1b,bcrp(-/-)
[3H
]-B
up
ren
orp
hin
e K
in(µ
L/s/
g)
0
2
4
6
8
10
Control PSC833 mdr1a,1b,bcrp(-/-)
[3H
]-N
orb
up
ren
orp
hin
e K
in(µ
L/s/
g)
******
In situ brain perfusion
Endothelial cell
BLOOD
BRAIN
Mechanisms of toxicity: Protective role of P-gp at the BBB
BUP
Pharmacological effect
N-BUP
Alhaddad H. Crit Care Med 2012 Alhaddad H. Toxicology 2013
Central respiratory toxicity
Pharmacologic or
Genetic
P-gp inhibition
Conclusions
Experimental studies allow the study of opioid-related respiratory toxicity. They confirm the deleterious interaction between BUP/methadone and BZD and allow to suggest hypotheses regarding the mechanism of interaction. Clinical monitoring of practice and consumption of psychotropic drugs in drug users as well as acquisition of new experimental data may allow to better understand the mechanisms of toxicity. Improvement in safety of maintenance therapies require a better integration of pre-clinical and clinical data of toxicity.