respiratory toxicity of maintenance therapy in drug ...€¦ · [email protected]...

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 CO2

- 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 PaO2, and

arterial pH along with increased PaCO2.

- 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?

2

Maintenance treatments

Methadone Buprenorphine

PD Full OR agonist Partial OR agonist

Route oral sublingual

Daily dose Variable (5-120 mg) 8-16 mg

Bioavailability 80% 75%

Liver metabolism CYP 2B6, 2C19, 3A4, 2C9, 2D6

CYP 3A4

Metabolite CDDP (inactive) N-BUP (active)

Elimination Urine > feces Feces > urine

Half-life ~25 h ~5 h

Oral long-acting opioid agonists used to avoid withdrawal and compulsive search

for heroin and allow social and professional insertion of heroin addicts

Emmanuelli J. Addiction 2005

Arrests for heroin sales Opioid-related deaths

Opioid-related deaths since marketing of maintenance treatments in France

Overdoses with maintenance treatments

Heroin Buprenorphine Methadone p

(N = 26) (N = 39) (N = 19) Suicide 12% 18% 58% 0.0007 Co-ingestions 73% 95% 89% 0.04

Glasgow Coma Score 5 [3 - 9] 7 [4 - 10] 4 [3 - 10] 0.1 Respiratory rate 10 [6 - 13] 12 [8 - 15] 10 [6 - 13] 0.4 SpO2 (%) 82 [64 - 95] 94 [87 - 98] 91 [82 - 97] 0.05

pH 7.29 [7.17-7.34] 7.35 [7.24-7.38] 7.33 [7.23-7.42] 0.07 PaCO2 (mmHg) 51 [45 - 55] 50 [45 - 66] 50 [36 - 57] 0.7

Mechanical ventilation 46% 41% 47% 0.6

Response to naloxone 81% 0% 71% <0.0001 Response to flumazenil 0% 87% 60% 0.02

Mégarbane B. JSAT 2010

Whole-body plethysmography

Experimental model to study opioid-related respiratory effects in Sprague Dawley rat

VT

TTOT

TI TE

Arterial blood gases

Methadone-related respiratory toxicity:

interest of concentration/effect

relationships and role of BZD combination

Methadone dose/effect relationships (1)

Methadone-related respiratory depression

contr

ol

1.5

mg/k

g

5 m

g/kg

15 m

g/kg

-1000

-800

-600

-400

-200

0

200

400

***§§

AU

C o

f P

aO

2

(arb

itra

y u

nit

s)

contr

ol

1.5

mg/k

g

5 m

g/kg

15 m

g/kg

0

200

400

600 *

AU

C

of

Pa

CO

2

(arb

itra

ry u

nits)

contr

ol

1.5

mg/k

g

5 m

g/kg

15 m

g/kg

-40

-30

-20

-10

0

10

**§

AU

C o

f a

rte

ria

l p

H

(arb

itra

ry u

nit

s)

contr

ol

1.5

mg/k

g

5 m

g/kg

15 m

g/kg

-1000

-500

0

500

AU

C o

f [H

CO

3- ]

(arb

itra

ry u

nit

s)

Methadone versus control: *P < 0.05, **P < 0.01, and ***P < 0.001; other doses of methadone versus 1.5 mg/kg methadone:

§P < 0.05, §§P < 0.01, and §§§P < 0.001. (N=8)

(LD50 = 18 mg/kg) Doses: 1.5 mg/kg; 5 mg/kg; 15 mg/kg IP

Chevillard L. Addiction Biol 2009

3

solv

ent

1.5

mg/k

g

5 m

g/kg

15 m

g/kg

0

20

40

60***

§§§

###

AU

C o

f in

sp

irato

ry

tim

e

(arb

itra

ry u

nit

s)

solv

ent

1.5

mg/k

g

5 m

g/kg

15 m

g/kg

0

20

40

60

80

100

120

140

160

**§§##

AU

C o

f exp

irato

ry

tim

e

(arb

itra

ry u

nit

s)

solv

ent

1.5

mg/k

g

5 m

g/kg

15 m

g/kg-100000

-50000

0

50000

100000

AU

C o

f tid

al

vo

lum

e

(arb

itra

ry u

nit

s)

solv

ent

1.5

mg/k

g

5 m

g/kg

15 m

g/kg

-4.0×10 7

-3.0×10 7

-2.0×10 7

-1.0×10 7

0

*

AU

C o

f m

inu

te

ven

tila

tio

n

(arb

itra

ry u

nit

s)

Methadone dose/effect relationships (2)


Relationships between methadone-related respiratory effects as a function of plasma R-methadone enantiomer concentrations

Plasma R-Methadone Concentration (g/mL)

0.01 0.1 1

Pa

O2 (

kP

a)

4

6

8

10

12

14

16

18


0.01 0.1 1

Pa

CO

2 (

kP

a)

2

4

6

8

10

12

14

16


0.01 0.1 1

Ti (

sec

)

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45


0.01 0.1 1

Te (

se

c)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

EC50=1.14 µg/ml EC50=3.35 µg/ml

EC50=0.501 µg/ml EC50=4.83 µg/ml

Toxicity

Death


Respiratory effects of methadone

15 mg/kg methadone

i.v.-NLZ +

methadone

s.c.-NLZ +

methadone

s.c.-NAT +

methadone

s.c.-nor-BNI +

methadone

PaO2 Complete reversion

NS NS Worsening

PaCO2 Complete reversion

Complete reversion

NS NS

pH Complete reversion

Complete Reversion

NS Worsening

Temperature Complete reversion

Complete reversion

NS NS

VE Complete reversion

Complete reversion

NS NS

f Complete reversion

Complete reversion

NS NS

TTOT Complete reversion

Complete reversion

NS NS

TI Partial

reversion Partial

reversion NS NS

TE Complete reversion

Complete reversion

Complete reversion

NS

VT NS NS NS NS NS

in vitro inhibition of methadone metabolism with diazepam

in vitro co-incubation of methadone + diazepam with microsomes results in

significant inhibition of methadone metabolism (p<0.01),

with IC50 of ~ 25 µmol/L

Chevillard L. Drug Alcohol Dep 2013

Methadone + BZD combination

Respiratory effects of methadone (5 mg/kg) + diazepam (20 mg/kg) combination

Arterial blood gases Plethysmography

Co-administration of methadone + diazepam increases inspiratory time (p<0,001), without significant alteration of any other parameter


(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).


4

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

Dahan A. Br J Anesthesiol 2005

« Ceiling effect »

Fentanyl Buprenorphine

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

BUPRENORPHINE

LEVOMEPROMAZINE

BROMAZEPAM

PARACETAMOL

CODEINE

METHADONE

CYAMEMAZINE (toxique et létal)

MEPROBAMATE (létal)l

PHENOBARBITAL (létal)

COCAINE (letal)

PROPOXYPHENE (létal)

ALCOOL sup 0.3 g/l

PATHOLOGIE IMPORTANTE

CONTEXTE JUDICIAIRE

MORPHINE

ACEPROMETAZINE (létal)

HEROINE (létal)

PETHIDINE

ALIMEMAZINE

CLOMIPRAMINE (létal)

AUTRES DROGUES ASSOCIEES A TAUX NON TOXIQUE

5

3

0

4 4

3

1 1

0

1

2

8

5

1 1

5

44

11

5

22

55

3

8

4

6

7

2

3

5

3

Pirnay S. Addiction 2004

BUP = cause of death in 4/34

Is high-dosage buprenorphine toxic ?

Asphyxic syndrome

Intravenous misuse Association with benzodiazepines

Mechanisms of death ?

Kintz P. Forensic Sci Int 2001

0 20 40 60 80 100 120 140 160 180 200

24

26

28

30

Time (minutes)

Lack of effect of single high doses of buprenorphine on arterial blood gases in the rat

BUP toxicity

Gueye et al, Tox Science 2001

Opioid effects on ventilation

Morphine: 80 mg/kg; Fentanyl: 1.7 mg/kg;

Methadone: 15 mg/kg; Buprenorphine: 160 mg/kg (80% LD50ip)

NS NS NS NS BUP 160 mg/kg

NS Methadone 15 mg/kg

Fentanyl 1.7 mg/kg

NS NS Morphine 80 mg/kg

TE TI [HCO3-] pH PaO2 PaCO2

The 4 tested opioids induced a decrease in PaO2 and an increase in TI

while only methadone, fentanyl, and morphine resulted in an increase in PaCO2 and arterial pH. Furthermore, only fentanyl and methadone increased TE.

In contrast, BUP demonstrated limited effects on ventilation.

Chevillard L. Toxicol Lett 2009

BUP toxicity

5

Role of norbuprenorphine

Major toxicity: LD50 = 10 mg/kg

Immediate and prolonged respiratory depression

Immediate production following IV BUP administration

Question: why is BUP safe in vivo?

Mégarbane B. Toxicol Appl Pharmacol 2005

BUP toxicity

Mégarbane B. Toxicol Appl Pharmacol 2005

BUP protects and reverses NBUP respiratory effects

BUP toxicity

Mechanisms of interaction between BUP and N-BUP to explain the absence of in vivo BUP

deleterious respiratory effects

Reversion Prevention

Respiratory Depression



Mégarbane B.Toxicol Review 2005

BUP toxicity

Comparison of DL50 according to the opioid and in association with flunitrazépam

61.1 ± 21.9

60.3 ± 21.3 Morphine

12.4 ± 1.8

23.8 ± 5.2 Methadone

40.4 ± 11.0

230.6 ± 49.3 Buprenorphine

LD50 opioid + flunitrazepam

LD50

Opioid alone

Opioid*

* Up and down method of Bruce

Borron SW. Hum Exp Toxicol 2002

BUP / BZD interaction

Buprenorphine (30 mg/kg IV) ± Midazolam (160 mg/kg IP)

Gueye P. Toxicol Sci, 2001

Marked and sustained respiratory depression induced by BUP + BZD


Effect of rat pretreatment with flunitrazepam (40 mg/kg) on plasma kinetics of buprénorphine (30 mg/kg)

PK interaction in the blood compartment?

Mégarbane B. Toxicol Lett 2005


6

Brain microdialysis technique in rats

a

. Patsalos PN. Br J Pharmacol 1995

Effect of rat pretreamtent with flunitrazépam (40 mg/kg) on the brain distribution of buprenorphine (30 mg/kg)

Interaction in BUP distribution in the brain?

Mégarbane B. Toxicol Lett 2005


Effect of rat pretreatment with buprenorphine (30 mg/kg) on the plasma kinetics of flunitrazépam (40 mg/kg)

Flunitrazepam time-course Desmethylflunitrazepam time-course

-35 -30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30

1000

2000

3000

4000

5000

FNZ (N = 5)

BUP + FNZ (N = 5)

50 100 150 200

Co

ncen

trati

on

pla

sm

ati

qu

e d

e F

NZ

(n

g/m

l)

-35 -30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30 35

500

1000

FNZ (N=5)

BUP + FNZ (N=5)

50 100 150 200

Co

ncen

trati

on

pla

sm

ati

qu

e d

e D

MF

NZ

(n

g/m

l)

Kinetic interaction within the blood compartment?

Pirnay S. Toxicol Sci 2008


DZP BUP DZP/BUP

VM → → ↓↓↓ PaCO2 → ↑ ↑↑↑

VT ↓ → ↓↓↓

f ↑ → →

TI → ↑↑↑ ↑↑↑ TE

↓↓↓ ↓↓↓ ↓↓↓

Mechanisms of respiratory depression

Vodovar D. Unpublished data


Benzodiazepines :

- Alteration of Upper Airways Dilators (GABA A)

hypopnea, obstructive apnea

- Diaphragmatic dysfunction

The combination of effects

may result in respiratory

depression and death

Hypothesis: PD interaction with addition of different physiological effects

Opioids - Decrease of the ventilatory response to

Inspiratory load Hypoxia Hypercapnia

Increase of the workload of breathing

Depression of the ventilation centres

Mégarbane B. Forensic Int Sci 2011


Treatment using subcutaneous 100 mg/kg dexamethasone on day1, day2, and day3

Expression of CYP3A isoenzymes using Western blott

Hreiche R. Toxicol Appl Pharmacol 2006

Role of CYP3A induction on BUP–induced respiratory effects (1)

Role of co-ingestions

7

NS NS HCO3-

NS NS PaO2

NS NS PaCO2

NS NS Arterial pH

Arterial blood gases

NS *** NS TI/TTOT Ratio NS NS NS Total time NS NS NS Temps Expiratoiry NS *** NS

Temps Inspiratoiry

NS *** NS VT/TI Ratio NS NS NS Minute volume NS NS NS Tidal volume NS NS NS

Fréquence Respiratory

HM + BUP vs

DEX + BUP

HM + TW vs

HM + BUP

HM + TW vs

DEX + TW

Plethysmography

Is there a role in vivo for N-BUP

in BUP toxicity?

Hreiche R. Toxicol Appl Pharmacol 2006

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.

respiratory toxicity of maintenance therapy in drug ...€¦ · [email protected]...

Documents