We appreciate Forget et al.,1  Ingrande and Drummond,2  and Fettiplace and Gitman3  for their interest in our work.4  As noticed by the authors, we chose to not administer a nonsteroidal anti-inflammatory drug to facilitate the recruitment of patients in the study. However, we agree that nonsteroidal anti-inflammatory drugs should be administered whenever possible. We also chose to not administer regional anesthesia in patients included in the Postoperative and Opioid-free Anesthesia (POFA) study because they were already receiving intravenous lidocaine. Another study replacing intravenous lidocaine by regional anesthesia would, of course, be of interest. It was perhaps not clearly stated in our article, but the dosage of dexmedetomidine was adapted not according to the Analgesia Nociception Index but rather according to the patient’s heart rate. This was decided in the original design5  because of the lack of validation of the Analgesia Nociception Index during opioid-free anesthesia. Concerning the doses of dexmedetomidine, 14.3% of the patients received a dose higher than 1.4 µg · kg–1 · h–1 and not 21% as stated by the simulation made by the authors. Moreover, as also already stated, complications were analyzed according the dosage of dexmedetomidine (lower or higher than the median value of the whole population: 0.9 µg · kg–1 · h–1), and no differences were observed, including for bradycardia. To answer to the authors’ critics, we also performed a complementary analysis of the primary endpoint in the subgroup of the patients who received dexmedetomidine with a dosage within the predefined range (0.4 to 1.4 µg · kg–1 · h–1). The results were similar with the occurrence of the composite primary endpoint being 64% in the opioid-based anesthesia group and 77% in the opioid-free anesthesia group and occurrence of hypoxemia being 61% and 74%, respectively. Finally, we wonder what is the “responsible opioid-free anesthesia practice” proposed by the authors. So far, no study has been published on the optimal dosage of dexmedetomidine during opioid-free anesthesia or on an evidence-based opioid-free regimen.

We fundamentally agree with Ingrande and Drummond’s2  statement on the need to study the nature of the interactions between all the analgesics we are using in daily practice. We also agree that there is no well-characterized, evidence-based opioid-free regimen, and there is an urgent need to study the implications of the actual opioid-free anesthesia trend among anesthesiologists. Our study was an attempt to further study these drug-to-drug interactions.

We agree on the risk associated with intravenous lidocaine, as noted by Fettiplace and Gitman.3  However, in our study, the case presented was not a case of local anesthetic systemic toxicity. The patient experienced a severe bradycardia and asystolia after an overdosage of dexmedetomidine as a result of an overestimation of the patient’s weight. Intravenous intralipids were systematically administered because the patient received intravenous lidocaine. However, the post hoc analysis of the case concluded that it was an overdosage of dexmedetomidine and not the consequences of local anesthetic systemic toxicity.

Dr. Beloeil reports receiving fees as a speaker (AbbVie [Lake Bluff, Illinois], Aspen [Durban, South Africa]) and as member of an expert board (Orion Pharma, Espoo, Finland). The other authors declare no competing interests.

1.
Forget
P
,
Mulier
J
,
Lavand’homme
P
,
De Baerdemaeker
L
,
Pelosi
P
,
de Boer
HD
:
Opioid-free anesthesia: Comment.
Anesthesiology
2021
;
135
:
751
3
2.
Ingrande
J
,
Drummond
JC
:
Opioid-free anesthesia: Comment.
Anesthesiology
2021
;
135
:
753
4
3.
Fettiplace
MR
,
Gitman
M
:
Opioid-free anesthesia: Comment.
Anesthesiology
2021
;
135
:
755
6
4.
Beloeil
H
,
Garot
M
,
Lebuffe
G
,
Gerbaud
A
,
Bila
J
,
Cuvillon
P
,
Dubout
E
,
Oger
S
,
Nadaud
J
,
Becret
A
,
Coullier
N
,
Lecoeur
S
,
Fayon
J
,
Godet
T
,
Mazerolles
M
,
Atallah
F
,
Sigaut
S
,
Choinier
PM
,
Asehnoune
K
,
Roquilly
A
,
Chanques
G
,
Esvan
M
,
Futier
E
,
Laviolle
B
;
POFA Study Group; SFAR Research Network
:
Balanced opioid-free anesthesia with dexmedetomidine versus balanced anesthesia with remifentanil for major or intermediate noncardiac surgery.
Anesthesiology
2021
;
134
:
541
51
5.
Beloeil
H
,
Laviolle
B
,
Menard
C
,
Paugam-Burtz
C
,
Garot
M
,
Asehnoune
K
,
Minville
V
,
Cuvillon
P
,
Oger
S
,
Nadaud
J
,
Lecoeur
S
,
Chanques
G
,
Futier
E
;
SFAR research network
:
POFA trial study protocol: A multicentre, double-blind, randomised, controlled clinical trial comparing opioid-free versus opioid anaesthesia on postoperative opioid-related adverse events after major or intermediate non-cardiac surgery.
BMJ Open
2018
;
8
:
e020873