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European Journal of Pharmacology 738 (2014) 153157

Contents lists available at ScienceDirect

European Journal of Pharmacology


journal homepage: www.elsevier.com/locate/ejphar

Pulmonary, gastrointestinal and urogenital pharmacology

Nalmefene reverses carfentanil-induced loss of righting reex


and respiratory depression in rats
Zheng Yong, Xiang Gao 1, Wentao Ma, Huajing Dong, Zehui Gong, Ruibin Su n
Beijing Institute of Pharmacology & Toxicology, 27 Taiping Road, Beijing 100850, China

art ic l e i nf o

a b s t r a c t

Article history:
Received 15 May 2014
Received in revised form
21 May 2014
Accepted 23 May 2014
Available online 2 June 2014

Reversing the respiratory depression induced by carfentanil involves intravenous administration of


naloxone or naltrexone, but this treatment has disadvantages. Hence, nding a more appropriate
treatment to counter the depressive actions of carfentanil is needed. In the present study, with the
naloxone as a control, we investigated the efcacy of nalmefene for countering the depressive actions of
carfentanil. Rats were treated successively with carfentanil (10 g/kg, i.v.) and nalmefene (9.4150.0 g/kg,
i.m.), and the duration of loss of righting reex (LORR) recorded. Respiratory parameters were measured in
free-moving rats using a whole-body plethysmograph after rats were administered carfentanil (20 g/kg,
i.v.) and nalmefene (9.4150.0 g/kg, i.m.) sequentially. The parameters of arterial blood gases were also
examined. Nalmefene (9.4150.0 g/kg, i.m.) treatment dose-dependently decreased the duration of
carfentanil-induced LORR. The respiratory rate after 60 min of nalmefene (150.0 g/kg, i.m.) treatment
increased from 34.375.3 bursts/min to 117.8718.9 bursts/min, and enhanced pause decreased from
1.170.1 to 0.470.1, and was close to those of normal rats. Furthermore, nalmefene (37.5150.0 g/kg)
treatment could enable the PaO2, SaO2 and PaCO2 to approach normal levels 10 min (15 min after
carfentanil injection) or 30 min (25 min after carfentanil injection) after injection. While, a single injection
of naloxone (150.0 g/kg, i.m.) only achieved partial remission of respiratory depression. These data
suggest that nalmefene more effectively counters the depressive actions induced by carfentanil and is a
more appropriate treatment to antagonize carfentanil toxicity compared with naloxone.
& 2014 Elsevier B.V. All rights reserved.

Keywords:
Nalmefene
Carfentanil
Loss of righting reex
Respiratory depression
Chemical compounds studied in this article:
Nalmefene (PubChem CID: 5284594)
Carfentanil (PubChem CID: 62156)

1. Introduction
Carfentanil is an analog of the synthetic opioid analgesic fentanyl.
It is one of the most potent opioids, with a quantitative potency
10,000-times that of morphine and 100-times that of fentanyl (Lust
et al., 2011). Initially, carfentanil was intended for use only as a
tranquilizing agent to rapidly incapacitate large animals for examinations and procedures by veterinarians (Ramsay et al., 1995; Shaw
et al., 1995). Nowadays, carfentanil is also used for in vivo positron
emission tomography studies of mu-opioid receptors in the laboratory and clinic (Hagelberg et al., 2012; Ly et al., 2013).
In recent years, there have been reports of humans developing
symptoms of drug toxicity induced by carfentanil (George et al.,
2010). As with other opioid analgesics, carfentanil can produce loss
of righting reex (LORR) and even induce respiratory depression
(recognized as one of the most serious adverse events) (Moresco

Corresponding author. Tel.: 86 1066931607; fax: 86 1068211656.


E-mail address: ruibinsu@126.com (R. Su).
1
This author contributed equally to this work.

http://dx.doi.org/10.1016/j.ejphar.2014.05.044
0014-2999/& 2014 Elsevier B.V. All rights reserved.

et al., 2001). Therefore, nding an appropriate treatment to


counter the depressive actions of carfentanil is needed.
Naloxone is an opioid receptor antagonist. Several studies have
shown that naloxone can reverse the respiratory depression induced
by morphine or fentanyl in an effective and rapid manner (Goodman
et al., 2007; Longnecker et al., 1973). The short elimination and
biophase equilibration half-lives (as well as rapid receptor kinetics)
of naloxone complicate the reversal of high-afnity opioids such as
carfentanil (Dahan et al., 2010). However, the duration of action of
carfentanil far exceeds that of naloxone. The course of naloxone
treatment should be kept under continued surveillance, and repeat
doses should be administered as needed (Sarton et al., 2008).
Naltrexone, as a long-acting antagonist, has also been reported
to reverse carfentanil-induced respiratory depression (Miller et al.,
1996). However, recycling of carfentanil occurs because it has
afnity for adipose tissues; it is stored there and also has a longer
half-life than that of naltrexone. Once naltrexone has been
metabolized completely and cleared from the body, carfentanil
can be released from adipose tissue and recirculate, thereby
causing a renarcotization event (Storms et al., 2006). New types
of opioid antagonist with longer durations of action and higher

154

Z. Yong et al. / European Journal of Pharmacology 738 (2014) 153157

efciency against carfentanil would be useful for avoiding such


recycling as well as for alleviating side effects.
Nalmefene is an opiate derivative similar in structure and
activity to the opiate antagonist naltrexone (Keating, 2013). The
advantages of nalmefene relative to naltrexone include: a longer
half-life; greater oral bioavailability; more competitive binding
with subtypes of opioid receptors; no observed dose-dependent
liver toxicity (Ingman et al., 2005). Nalmefene is used to completely or partially reverse the effects of narcotics and alcohol by
blocking opiate receptor sites, thereby reversing or preventing the
toxic effects of narcotics and alcohol (Soyka and Ro
sner, 2010).
In the present study, we hypothesized that nalmefene would
effectively counter the depressive actions of carfentanil. Thus, with
the naloxone as a control, we investigated the efcacy of different
doses of nalmefene for antagonizing carfentanil-induced LORR and
respiratory depression in rats.

a stable baseline was produced. They were then injected with


carfentanil (20 g/kg, i.v.) based on the preliminary result. After
10 min, rats were treated with different doses of nalmefene (9.4
150.0 g/kg, i.m.) or naloxone (150.0 g/kg, i.m.). Data for respiratory parameters were collected for an additional 60 min and
analyzed using IOX software (EMKA Technologies).
2.5. Measurement of arterial blood gases

All experiments were conducted after approval of the study


protocol by the Animal Care and Use Committee of the Beijing
Institute of Pharmacology and Toxicology (Beijing, China). The study
protocol conformed to guidelines on the ethical use of animals set by
the National Institutes of Health (Bethesda, MD, USA). All efforts were
made to minimize the number of animals used and their suffering.

To characterize the effects of nalmefene against carfentanilinduced respiratory depression of arterial blood gases, rats were
injected with carfentanil (20 g/kg, i.v.), and then, 5-min later,
given different doses of nalmefene (9.4150.0 g/kg, i.m.) or
naloxone (150.0 g/kg, i.m.). At 0, 5, 15, and 30 min after injection
with carfentanil, arterial blood samples (1.0 ml) were drawn from
the abdominal aorta with a self-lling polypropylene syringe
containing 60 IU of dry, electrolyte-balanced heparin (PICO70;
Radiometer Medical; Copenhagen, Denmark). At the point time of
0 min, rats were anesthetized by ether before acquiring arterial
blood samples. Air pockets were expelled immediately after
sampling. Thereafter, samples were mixed gently until testing on
an ABL90 Flex Blood Gas Analyzer (Radiometer Medical). The
partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2) as
well as oxygen saturation (SO2) in arterial blood were recorded
and analyzed at the corresponding time point. Five animals per
time point were used for measurement of arterial blood gases.

2.1. Animals

2.6. Statistical analysis

Experiments were completed on adult male Sprague-Dawley


rats (180220 g) provided by the Beijing Animal Center (Beijing,
China). Animals were housed ve per cage in a room maintained at
257 1 1C with an alternating 12-h lightdark cycle. Rats had free
access to water and food.

For LORR and measurement of arterial blood gases, data are the
mean 7S.E.M. They were analyzed by two-way ANOVA followed
by Dunnett's t-test for multiple comparisons. The Student's t-test
was used if two independent groups were compared. P o0.05 was
considered signicant.
For determination of respiratory parameters, data are the
mean 7S.E.M. The value from stabilized rats before carfentanil
injection was considered to be the baseline. Analysis of two-way
ANOVA was used to compare differences, followed by Bonferroni
post-tests for comparisons between individual groups. P o0.05
was considered signicant for all tests.

2. Materials and methods

2.2. Laboratory reagents


Nalmefene hydrochloride was purchased from Haisco Pharmaceutical Co., Ltd. (Sichuan, China), and naloxone from Sigma (St. Louis,
MO, USA), and dissolved in sterile physiological saline (0.9% NaCl) to
the nal concentrations used in this study. Carfentanil oxalate was
obtained from Humanwell Healthcare Group (Hubei, China) and also
dissolved in physiological saline before experimentation. Nalmefene
or naloxone was injected intramuscularly (0.5 ml/kg body weight)
and carfentanil was injected intravenously (2 ml/kg).

3. Results
3.1. Nalmefene signicantly reduced the carfentanil-induced
duration of LORR

2.3. LORR
To study the effect of nalmefene on carfentanil-induced LORR,
rats were injected with carfentanil (10 g/kg, i.v.) according the
result of our preliminary experiment. Five minutes later, rats were
injected with varying doses of nalmefene (9.4150.0 g/kg, i.m.) or
naloxone (150.0 g/kg, i.m.). The duration of LORR was recorded
individually for each rat. It was calculated by subtracting the time
of onset of LORR from the time at recovery from carfentanilinduced sleep. The righting reex was deemed to be lost if an
animal did not right itself within 15 s of being placed on its back.
2.4. Determination of respiratory parameters
The dose-dependent effect of nalmefene against carfentanilinduced respiratory depression was studied in freely moving rats.
A Whole-body Plethysmograph (EMKA Technologies, Paris, France)
was used to measure respiratory parameters, i.e., respiratory rate
and enhanced pause (an index of airway obstruction). Rats were
stabilized in the plethysmograph chamber for 3040 min until

To determine the dose-dependent effect of nalmefene on


the duration of carfentanil-induced LORR, rats were injected
with different doses of nalmefene after carfentanil treatment.
Intravenous injection of carfentanil (10.0 g/kg) induced LORR
immediately in all rats, who showed muscle rigidity (Fig. 1A).
Treatment with nalmefene (9.4150.0 g/kg, i.m.) dose-dependently decreased the duration of carfentanil-induced LORR. The
duration of LORR treated with low dose (9.4 g/kg, i.m.) and high
dose (150.0 g/kg, i.m.) nalmefene was decreased signicantly to
22.69% and 8.46% of the duration of LORR due to the injection of
saline, respectively (Fig. 1B). However, in rats treatment with
naloxone (150.0 g/kg, i.m.), the duration of LORR was decreased
to 22.96% compared to saline treatment.
3.2. Nalmefene greatly reversed carfentanil-induced drespiratory
depression
We undertook a plethysmographic study to investigate the dose
response effect of nalmefene injection after carfentanil administration

Z. Yong et al. / European Journal of Pharmacology 738 (2014) 153157

returned the parameters of arterial blood gases to almost normal


levels. Nalmefene treatment (37.5150.0 g/kg) could even enable
PaO2, SaO2 and PaCO2 to approach normal levels 10 min (15 min after
carfentanil injection) or 30 min (25 min after carfentanil injection)
after injection. While, in rats treatment with naloxone (150.0 g/kg,
i.m.), the change of arterial blood gas parameters is similar to those of
rats with nalmefene (18.8 g/kg, i.m.) treatment.

100
80

Nalmefene ( g/kg, i.m.)

40

*
18.8

37.5

4. Discussion

20

Duration of LORR (min)

120

60

0
Saline

9.4

75.0

150.0 Naloxone (150 g/kg, i.m.)

Carfentanil (10 g/kg, i.v.)

40

% of saline control

30

20

10

0
0.
15

.0
75

37

.5

0
9.
4
18
.8

155

Nalmefene ( g/kg, i.m.)


Fig. 1. (A) Effect of nalmefene or naloxone and (B) dose-related effect of nalmefene
on the duration of carfentanil-induced LORR in rats. Nalmefene or naloxone was
injected via the intramuscular route 5 min after carfentanil injection. Each column
(A) and each point (B) represent the mean and S.E.M. of 5 rats. *Po 0.01 vs
respective saline-treated rats. (n 5 for each group).

to determine its efcacy in countering respiratory depression. Carfentanil (20 g/kg) injection caused marked suppression of respiratory
rate (470% of baseline) and induced a striking increase in enhanced
pause (4300% of baseline) (Fig. 2). Specically, 10 min after administration of carfentanil, the respiratory rate decreased from
124.4714.1 bursts/min to 34.375.3 bursts/min (n5) and enhanced
pause increased from 0.370.1 to 1.170.1 (n5). Respiratory depression persisted for 1 h. Treatment with nalmefene (9.4150.0 g/kg,
i.m.) dose-dependently reversed the respiratory depression induced
by carfentanil. The respiratory rate after 60 min of nalmefene
(150.0 g/kg, i.m.) treatment increased from 34.375.3 bursts/min
(n 5) to 117.8718.9 bursts/min (n 5) and enhanced pause
decreased from 1.170.1 to 0.470.1 (n5), and these values were
close to those of normal rats. On the other hand, in rats treatment with
naloxone (150.0 g/kg, i.m.), the respiratory rate increased from
36.4711.3 bursts/min (n5) to 75.0711.1 bursts/min (n5) after
60 min of treatment, while, enhanced pause decreased from
1.370.1 to 0.770.1 (n5) after 30 min of treatment, followed by
an increase from 0.770.1 to 1.170.3 (n5) during the period of
3060 min treatment, and these values were close to those of rats
with carfentanil injection.
3.3. Nalmefene manifestly resumed arterial blood gas parameters
We studied the doseresponse effect of nalmefene treatment
upon changes in the parameters of arterial blood gases in carfentanilinjected rats. Injection of carfentanil caused a signicant reduction in
PaO2 (39.2% of 0 min) and SaO2 (25.4% of 0 min) and induced an
obvious increase in PaCO2 (252.8% of 0 min) after 5 min (Table 1).
Treatment with nalmefene (9.4150.0 g/kg, i.m.) dose-dependently

Respiratory depression is a serious complication of carfentanil


treatment. We administered nalmefene to counter the depressive
actions of carfentanil. Nalmefene signicantly reduced the duration of LORR induced by carfentanil, greatly reversed carfentanilinduce respiratory depression, and returned the parameters of
arterial blood gases to almost normal levels. Nalmefene was more
useful for reversing the depressive actions of carfentanil than
naloxone.
In animals, LORR induced by a general anesthetic is considered
to be a behavioral measure similar to a loss of consciousness
(Franks, 2008). In the present study, carfentanil induced LORR.
Carfentanil acts as an analgesic and a general anesthetic (Neumann
et al., 1980). LORR can be considered to be a severe motor effect
resulting from an anesthetic dose of carfentanil. Carfentanil-induced
LORR is modulated by activation of endogenous opioid systems in
the brain. We showed that the LORR induced by carfentanil was
antagonized by nalmefene in a dose-dependent manner. Nalmefene
was more efcient for reversing carfentanil-induced LORR in rats
than naloxone. As an opioid receptor antagonist, the reversal effect
of nalmefene can be explained by its interaction with the opioid
system in the brain (Srisurapanont and Jarusuraisin, 2002). Nalmefene resulted in very higher occupancy at mu-opioid receptors than
naloxone, and produced potent antagonism of the agonist effects of
carfentanil while precipitating LORR (Kim et al., 1997).
Respiratory depression remains the main hazard of carfentanil
because of the obvious risk of death. The effects upon respiratory
function are believed to result from the mu-opioid receptormediated inhibition of neuronal transmission in the rostrodorsal
surface of the pons, nucleus tractus solitarius, and nucleus ambiguous (Morin-Surun et al., 1984; Hurle et al., 1985). Carfentanil has
strong agonistic activity upon mu-opioid receptors. Hence, in the
present study, carfentanil injection elicited marked suppression of
respiration in rats. As an opioid receptor antagonist, nalmefene
completely reversed this effect of carfentanil. Treatment with
nalmefene dose-dependently elevated suppression of the respiratory rate, and returned the parameters of arterial blood gases to
normal levels. While, a single injection of naloxone only achieved
partial remission of respiratory depression for 30 min, which was
relative with the short elimination and rapid receptor kinetics of
naloxone (Dahan et al., 2010). The slow dissociation rate and high
occupancy level at mu-opioid receptors render nalmefene a useful
drug in the reversal of the respiratory suppression induced by
carfentanil (Kim et al., 1997).
Currently, the only treatment available to reverse the respiratory depression induced by carfentanil is direct antagonism of the
site of action of opioid effects (mu-opioid receptors) using naloxone or naltrexone given via the intravenous route (Goodman et al.,
2007; Johnstone et al., 1974). Nalmefene is a pure opioid antagonist that is structurally similar to naloxone and naltrexone.
Compared with naloxone and naltrexone, nalmefene is more
potent at the mu-receptor, and has a higher afnity for kappaand delta-opioid receptors (George et al., 2010). The duration of
reversal of fentanyl- and morphine-induced respiratory depression is dose-dependent. The plasma terminal half-life of oral
nalmefene markedly exceeds that of naltrexone (Dixon et al.,

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Z. Yong et al. / European Journal of Pharmacology 738 (2014) 153157

drug toxicity induced by carfentanil. In the present study, we


demonstrated that nalmefene was more useful for avoiding the
renarcotization event of carfentanil and alleviating its side effects
compared to naloxone.

1987; Meyer et al., 1984), and there have been no reports of


serious adverse drug reactions on hepatic or other body systems
(Ingman et al., 2005; Mason et al., 1999). Hence, nalmefene could
offer advantages over naloxone or naltrexone in treatment of the

Respiratory rate (bpm)

200

Carfentanil (20.0 g/kg)


Nalmefene (150.0 g/kg)

150

Nalmefene (75.0 g/kg)


Nalmefene (37.5 g/kg)

100

Nalmefene (18.8 g/kg)

50

Nalmefene (9.4 g/kg)


Naloxone (150.0 g/kg)

0
-20 -10

10

20

30

40

50

60

70

80

Time after carfentanil (min)

Value of enhanced pause

3.0

Carfentanil (20.0g/kg)
Nalmefene (150.0g/kg)

2.5

Nalmefene (75.0g/kg)

2.0

Nalmefene (37.5g/kg)

1.5

Nalmefene (18.8g/kg)

1.0

Nalmefene (9.4g/kg)
Naloxone (150.0g/kg)

0.5

##

0.0
-20 -10

10

20

30

40

50

60

70

80

Time after carfentanil (min)


Fig. 2. Treatment with nalmefene (9.4150.0 g/kg, i.m.) reverses carfentanil-induced respiratory depression in rats. (A) Normal respiratory rhythm of rats before carfentanil
injection. (B) Injection with carfentanil (20 g/kg, i.v.) over a short period induced profound and lethal respiratory depression. (C) Administration of nalmefene or naloxone
after carfentanil enabled recovery of respiratory rhythm. Population data showing the time course of changes in the respiratory rate (D) and enhanced pause (E) in response
to carfentanil administration and post-administration of nalmefene or naloxone. *Po 0.05, the corresponding time point of nalmefene (18.8 g/kg and 37.5 g/kg) vs
carfentanil; #Po0.05, the corresponding time point of nalmefene (75.0 g/kg and 150.0 g/kg) vs carfentanil; **Po0.05, the corresponding time point of naloxone (150.0 g/kg)
vs carfentanil; ##Po0.05, the time point of 30 min of nalmefene (18.8 g/kg and 150.0 g/kg) vs the corresponding time point of carfentanil.

Z. Yong et al. / European Journal of Pharmacology 738 (2014) 153157

157

Table 1
Treatment with nalmefene returned the changes in the parameters of arterial blood gases in carfentanil-injected rats to almost normal levels (drug doses are in g/kg).
PaO2 (mmHg)

0 min

5 min

15 min

30 min

Carfentanil 20.0
Naloxone 150.0
Nalmefene 9.4
18.8
37.5
75.0
150.0

94.9 73.60
94.2 74.39
96.0 73.20
94.3 73.81
94.4 73.94
94.17 3.62
95.9 73.40

37.2 7 14.86 a
49.3 715.95 a
36.17 16.93 a
35.47 16.52 a
43.8 7 2.00 a
35.77 16.73 a
35.07 16.14 a

31.4 7 18.23 a
72.6 7 5.81 b,c
60.5 73.75 b,c
78.4 77.09 b,c
88.17 2.84 b,c
98.2 712.34 b,c
97.4 7 14.40 b,c

48.47 5.60 a
83.2 7 5.07 b,c
69.7 7 7.06 b,c
72.5 7 12.73 b,c
94.0 7 2.41 b,c
95.9 7 8.37 b,c
97.8 710.46 b,c

PaCO2 (mmHg)
Carfentanil 20.0
Naloxone 150.0
Nalmefene 9.4
18.8
37.5
75.0
150.0

36.2 74.00
38.7 76.45
35.87 4.46
36.4 74.60
36.7 74.49
37.5 7 3.21
34.9 72.90

91.5 7 7.11 a
89.5 7 10.63 a
92.7 7 7.56 a
91.9 7 8.14 a
88.3 7 1.38 a
92.3 7 7.94 a
92.17 8.03 a

89.17 16.12 a
57.0 7 5.40 b,c
62.17 6.31 b,c
51.0 75.97 b,c
45.2 78.38 b,c
36.6 75.65 b,c
37.4 7 4.58 b,c

87.1 711.56 a
47.3 7 3.60 b,c
61.8 7 8.14 b,c
52.6 7 9.48 b,c
46.7 7 5.82 b,c
42.0 7 3.93 b,c
38.2 7 6.64 b,c

SaO2 (%)
Carfentanil 20.0
Naloxone 150.0
Nalmefene 9.4
18.8
37.5
75.0
150.0

93.7 71.33
93.2 72.35
94.17 1.22
93.7 71.54
93.4 71.21
93.5 71.34
94.17 1.31

23.8 7 10.20 a
20.8 7 4.28 a
23.3 7 11.70 a
23.0 7 11.60 a
28.2 7 3.28 a
23.2 7 11.65 a
21.5 7 10.20 a

21.2 7 11.97 a
58.3 78.60 b,c
60.6 74.92 b,c
78.2 73.59 b,c
87.8 7 4.60 b,c
90.4 73.93 b,c
91.8 7 3.68 b,c

33.478.76 a
72.8 7 18.54 b,c
68.77 14.66 b,c
81.1 77.94 b,c
90.4 7 2.89 b,c
92.4 7 2.23 b,c
93.3 7 3.36 b,c

Note: rats were injected with carfentanil (20 g/kg, i.v.) and then with nalmefene (9.4150.0 g/kg, i.m.) or naloxone (150.0 g/kg) 5-min later. At 0, 5, 15 and 30 min after
injection with carfentanil, the PaO2, PaCO2 and SaO2 of arterial blood were recorded and assessed.
a
b
c

P o0.05 relative to 0 min of the corresponding group (before carfentanil injection, n 5 per time point).
Po 0.05 relative to 5 min of the corresponding group (5 min after carfentanil injection and nalmefene or naloxone treatment, n 5, per time point).
Po 0.05 relative to the carfentanil-injection group (n 5, per time point).

In conclusion, our data suggest that nalmefene effectively


counters the depressive actions induced by carfentanil. Nalmefene
appears to be more appropriate treatment for the antagonism of
carfentanil toxicity compared with naloxone.

Acknowledgment
Funding for this study was provided by National Science and
Technology Major Projects for Major New Drugs Innovation and
Development (2013ZX09J13104-01A) in China.
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