European Journal of Pharmacology 544 (2006) 10 – 16

www.elsevier.com/locate/ejphar

Dextromethorphan, 3-methoxymorphinan, and dextrorphan have local

anaesthetic effect on sciatic nerve blockade in rats
Chia-Hui Hou a,b , Jann-Inn Tzeng a,c,⁎, Yu-Wen Chen a , Ching-Nan Lin a , Mao-Tsun Lin a ,
Chieh-Hsien Tu b , Jhi-Joung Wang a
a
Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
b
Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan
c
Department of Anesthesiology, Taipei Medical University, Taipei, Taiwan
Received 28 March 2006; received in revised form 24 May 2006; accepted 9 June 2006
Available online 15 June 2006

Abstract

Dextromethorphan has been used as an antitussive for more than 40 years and is considered a drug with a good margin of safety. The aim of the
study was to evaluate whether dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan— had local anaesthetic effects.
Using a method of sciatic nerve blockade in rats, the potencies and durations of actions of dextromethorphan and its metabolites on sciatic nerve
blockades of motor function, proprioception, and nociception were evaluated. Lidocaine was used as control. We found that dextromethorphan
and its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception, and nociception.
The ranks of potencies were lidocaine > dextromethorphan > 3-methoxymorphinan > dextrorphan (P < 0.01 for each comparison). Under an equi-
potent basis, dextrorphan and 3-methoxymorphinan had durations of actions longer than that of lidocaine (P < 0.05 for each comparison). Co-
administration of dextromethorphan or its metabolites with lidocaine produced an additive effect on sciatic nerve blockades. In conclusion,
dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan— had a local anaesthetic effect on sciatic nerve blockades of
motor function, proprioception and nociception with durations of actions longer than that of lidocaine. Co-administration of dextromethorphan and
its metabolites produced an additive effect on sciatic nerve blockades.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Anaesthesia; Dextromethorphan; Dextrorphan; Local anaesthetic; 3-methoxymorphinan; Sciatic nerve

1. Introduction mate and nicotine/neuronal nicotinic receptor channels, and the

Dextromethorphan, a dextrorotatory morphinan, has been
used clinically as a cough suppressant for more than 40 years and
is considered a drug with a good margin of safety (Bem and Peck,
1992; Carlsson et al., 2005; Duedahl et al., 2006; Weinbroum et
al., 2000). Dextromethorphan was synthesized originally as a
pharmacological alternative to morphine. However, in contrast to
the levorotatory morphinans, dextromethorphan has little or no
opioid activity (Weinbroum et al., 2000). Dextromethorphan has
a complex pharmacology. In in vitro binding assays, dextro-
methorphan inhibits the N-methyl-D-aspartate (NMDA) gluta-
⁎ Corresponding author. Tel.: +886 6 2517844; fax: +886 6 2832639.
E-mail address: 400002@mail.chimei.org.tw (J.-I. Tzeng).
0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejphar.2006.06.013
voltage-gated Ca2+ and Na+ channels (Carlsson et al., 2005;
Damaj et al., 2005; Netzer et al., 1993; Trube and Netzer, 1994).
Dextromethorphan has been used as an antitussive and proposed
as a treatment for stroke, brain ischemia (Moses and Choi, 1991;
Steinberg et al., 1993), seizure disorders (Fisher et al., 1990),
morphine dependence (Glick et al., 2001; Mao et al., 1996), and
acute or neuropathic pain (Carlsson et al., 2005; Duedahl et al.,
2006; Joshi, 2005; Weinbroum et al., 2000). The NMDA receptor
antagonist effects of dextromethorphan seem to be the primary
rationale for these uses.
Although dextromethorphan has a long history of clinical
uses with a good margin of safety, the pharmacologic effects
with respect to its channel bindings were not well studied, e.g.,
the Na+ channel blockade. The Na+ channel blockade is an
essential activity of the local anaesthetics (Fozzard et al., 2005;
 C.-H. Hou et al. / European Journal of Pharmacology 544 (2006) 10–16 11

McLure and Rubin, 2005; Scholz, 2002). With this activity,
local anaesthetics produce infiltrative cutaneous analgesia,
peripheral nerve block, and spinal/epidural anaesthesia
(McLure and Rubin, 2005). Because dextromethorphan has a
Na+ channel blocking effect (Netzer et al., 1993), theoretically,
it may have a local anaesthetic effect. However, this was never
tested. The aim of the study was to evaluate whether
dextromethorphan has a local anaesthetic effect. We focused
on the sciatic nerve blockade. The potency and duration of
action of dextromethorphan on sciatic nerve blockade in rats
were evaluated. Two major metabolites of dextromethorphan —
3-methoxymorphinan and dextrorphan— (Mordecai et al.,
1995) were also studied. Lidocaine, a commonly used local
anaesthetic, was used as control. The effects of co-administra-
tion of dextromethorphan or its metabolites with lidocaine on
sciatic nerve blockade were evaluated, too.
2. Materials and methods
2.1. Animals
Experiments were performed on 200–250 g male Sprague–
Dawley rats (the National Laboratory Animal Center, Taipei,
Taiwan). Rats were housed in a climate controlled room
maintained at 21 °C with approximately 50% relative humidity.
Lighting was on a 12-h light–dark cycle (light on at 6:00 a.m.),
with food and water available ad libitum up to the time of
testing. The experiments protocols were approved by the animal
investigation committee of Chi-Mei Medical Center, Tainan,
Taiwan and conformed to the recommendations and policies of
the International Association for the Study of Pain.
tuberculin syringe (Gerner et al., 2002). Rats were then
observed for the development of sciatic nerve blockade which
was indicated primarily by the paralysis of their left hindlimbs.
The right hindlimbs severed as controls. For consistency, one
experienced investigator (Ms. Hou) who was blinded to drugs
for injections was responsible for all rat handling and behavior
evaluating. The drugs were prepared by another investigator
(Dr. Chen).
2.5. Neurobehavioral evaluations
Following injections, three neurobehavioral examinations
which consisted of evaluations of motor function, proprioception
and nociception were conducted. The detail methods for
neurobehavioral examinations of sciatic nerve blockades were
described in previous reports (Gerner et al., 2002; Sudoh et al.,
2003). In brief, the motor function was evaluated by measuring
the ‘extensor postural thrust’ of the left hindlimbs of rats on a
digital scale. The forces of the left hindlimbs to push against the
platform of the scale were measured. Rats were tested 15 min
before medication, at 5 and 10 min afterwards, and then again at
10–30 min intervals until 2.5 h. The magnitude of sciatic nerve
blockades of motor function was shown as the percentage of
possible effect (% PE). The pre-injection control value (ranging
from 240 to 260 g) was considered 0% possible effect (0% PE). A
force <20 g was considered absence of extensor postural thrust or
100% motor block or 100% PE. The maximum response of each
dose of each drug was considered the % maximum possible effect

2.2. Drugs

Dextromethorphan hydrobromide monohydrate, 3-methox-

ymorphinan HCl, dextrorphan tartrate, and lidocaine HCl were
purchased from Sigma Chemical Co. (St. Louis, MO). All drugs
were freshly prepared in 0.9% NaCl as solution before peri-
sciatic nerve injections. After injections, the low pH of these
plain solutions (ranging from 5.3 to 5.8) were likely to be
buffered quickly by the tissue fluid which had a pH of 7.4.

2.3. Experimental protocols

The study was carried out in three parts. In part 1, the

potencies of dextromethorphan, 3-methoxymorphinan, dextror-
phan, and lidocaine on sciatic nerve blockade were evaluated. In
part 2, on an equi-potent basis, the durations of their effects on
sciatic nerve blockade were evaluated. In part 3, the effects of
co-administration of dextromethorphan or its metabolites with
lidocaine on sciatic nerve blockade were evaluated.

2.4. Drug injections

Sciatic nerve blockade was performed in conscious rats.
Drugs (200 μl) were injected into the sciatic notch of the left
hindlimbs of rats with a 27-gauge needle attached to a
Fig. 1. Time courses of sciatic nerve blockades (% PE) of dextromethorphan (A)
and lidocaine (B) in rats (n = 6 in each medication). Data are means ± S.E.M. The
injected dose was 6.7 mg/kg. Neurologic evaluations of sciatic nerve blockades
were done before, and 5, 10, 20, 30, 40, 50, 60, 80, 100, and 120 min after
injection.
12 C.-H. Hou et al. / European Journal of Pharmacology 544 (2006) 10–16

Fig. 3. The duration of drugs' effects on sciatic nerve blockades of motor

Fig. 2. The dose–response curves of dextromethorphan, 3-methoxymorphinan,
dextrorphan, and lidocaine on sciatic nerve blockades of motor function,
proprioception and nociception (% MPE) in rats (n = 6 at each testing point).
Data are means ± S.E.M. and were fitted with SAS NLIN analysis.
function, proprioception and nociception (% MPE). Data are means ± S.E.M.
The doses were ED25s, ED50s, and ED75s (n = 6 rats at each testing point). The
differences in durations of drugs' effects were evaluated by a two-way ANOVA
followed by the pairwise Tukey’s HSD test. A P value less than 0.05 was
considered statistical significance.

(% MPE). The dose–response curves of drugs were constructed

using the % MPE of each dose of each drug. The proprioceptive
evaluation was based on the resting posture and postural reactions
(‘tactile placing’ and ‘hopping’). The functional deficit was
graded as 3 (normal or 0% PE), 2 (slightly impaired), 1 (severely
impaired), and 0 (completely impaired, or 100% PE). The
nociceptive reaction was evaluated by the withdrawal reflex or
vocalization elicited by the pinch of a skin fold over the back at
1 cm near the proximal part of the tail, the lateral metatarsus of the
left hindlimb, and the dorsal part of the mid-tail. The nociceptive
reaction was graded as those described in the proprioception.
In part 1, the potency study was carried out. After peri-sciatic
nerve injections of drugs with different doses (n = 6 for each
dose of each drug), the dose–response curves of drugs were
constructed. The curves were then fitted by a computer-derived

Table 1
Effective doses 50% (ED50s) of drugs with 95% confidence interval (95% CI) on sciatic nerve blockades of motor function, proprioception, and nociception in rats
Drugs Motor Proprioception Nociception Mean
ED50 (95% CI) ED50 (95% CI) ED50 (95% CI) ED50
Lidocaine (L) 2.67 (2.55–2.81) 2.57 (2.38–2.79) 2.35 (2.14–2.57) 2.53
Dextromethorphan (DM) 3.95 (3.79–4.12) 3.73 (3.49–3.98) 3.49 (3.23–3.78) 3.72
3-Methoxymorphinan (3MM) 7.40 (6.77–8.08) 6.76 (6.12–7.47) 5.89 (5.45–6.37) 6.68
Dextrorphan (DX) 14.66 (13.78–15.58) 14.52 (13.40–15.73) 13.38 (12.37–14.47) 14.19
ED50s of drugs (mg/kg) were obtained from computer-derived curve fitting by SAS NLIN analysis of the dose–response curves of drugs shown in Fig. 2. The ranks of
potencies of drugs on sciatic nerve blockades of motor function, proprioception, and nociception were L > DM > 3MM > DX, respectively (P < 0.01 for each
comparison), using a one-way ANOVA followed by the pairwise Tukey’s HSD test.
 C.-H. Hou et al. / European Journal of Pharmacology 544 (2006) 10–16 13

SAS NLIN analysis (SAS Institute Inc., North Carolina, USA),
and the values of 50% effective doses (ED50s) which were
defined as the doses that caused a 50% sciatic nerve blockade
were obtained (Minkin and Kundhal, 1999). The potencies of
drugs on sciatic nerve blockades were then compared by using
the ED50 doses.
In part 2, the duration study was carried out. As the method
for ED50, the ED25 and ED75 of drugs were also obtained from
the computer-derived curve fitting (SAS NLIN analysis). Peri-
sciatic nerve injections of drugs with doses of ED25, ED50, and
ED75 (n = 6 rats for each dose of each drug) were then
performed. On an equi-potent basis, the durations of drugs,
which were defined as the intervals from injection to complete
recovery, were measured and compared.
In part 3, the effects of co-administration of dextromethor-
phan or its metabolites with lidocaine on sciatic nerve blockades
were evaluated. Three studies were carried out. In study 1, rats
were further divided randomly into 3 groups and received
dextromethorphan (2 ED50), dextromethorphan with lidocaine
(ED50 for both drug), or lidocaine (2 ED50), respectively. In
studied 2 and 3, as the protocol in study 1, rats received 3-
methoxymorphinan and dextrorphan instead of dextromethor-
phan, respectively. The numbers of rats were six in each group
of different medications. After testing, the time courses of
drugs' effects were constructed, and the areas under the curves
(AUCs) were obtained by calculation, using the trapezoidal rule
(Ritschel and Kearns, 2004). The effects of co-administration of
dextromethorphan or its metabolites with lidocaine on sciatic
nerve blockades were then evaluated.
2.6. Statistical analysis
Data are presented as means ± S.E.M. or means with 95%
confidence interval. Before analysis, the Shapiro–Wilk test was
used to evaluate whether, theoretically, the data were normal
distributed. After testing, the majority of the data fitted the
normality assumption; therefore, the differences among data
were evaluated by the parametric tests. The differences in ED50s
between drugs were evaluated by the student t-test with
Bonferroni correction. The differences in durations between
drugs were evaluated by a two-way analysis of variance
(ANOVA) followed by the pairwise Tukey's honest significance

Fig. 4. Time curves of sciatic nerve blockades (% PE) of dextromethorphan or its metabolites with/without lidocaine in rats (n = 6 in each kind of medication). Data are
means ± S.E.M. The doses for injections were 2 ED50 for a single drug or ED50 for drugs in combination (A: dextromethorphan; B: 3-methoxymorphinan; C:
dextrorphan).
14 C.-H. Hou et al. / European Journal of Pharmacology 544 (2006) 10–16

Table 2
The effects (AUCs) of co-administration of dextromethorphan, 3-methoxymorphinan, or dextrorphan with lidocaine on sciatic nerve blockades in rats
Motor P Proprioception P Nociception P
Dextromethorphan (DM)
DM 4056 ± 212 DM > L 5498 ± 507 DM > DM + L, L 6295 ± 643 DM > DM + L, L
DM + L 3268 ± 258 3367 ± 237 4479 ± 353
Lidocaine (L) 2594 ± 284 2682 ± 204 2886 ± 164

3-Methoxymorphinan (3MM)
3MM 4559 ± 584 3MM > L 5191 ± 652 3MM > L 8026 ± 1437 3MM > L
3MM + L 3343 ± 414 3794 ± 743 4696 ± 959
Lidocaine (L) 2692 ± 248 2808 ± 218 2957 ± 253

Dextrorphan (DX)
DX 7077 ± 429 DX > DX + L, L 7357 ± 558 DX > DX + L, L 8786 ± 915 DX > DX + L, L
DX + L 3448 ± 808 3893 ± 470 6177 ± 687 DX + L > L
Lidocaine (L) 2505 ± 199 2534 ± 196 2694 ± 248
Values are means ± S.E.M. AUCs : areas under the curves. The doses for injections were 2 ED50 (double of 50% effective dose) for a single drug or ED50 for drugs in
combination. The values of AUCs were derived from Fig. 4 after calculation. The differences in AUCs among different medications (e.g., DM, DM + L, L in motor
function) were evaluated by a one-way ANOVA followed by the pairwise Tukey’s HSD test. A P value less than 0.05 was considered statistical significance.

difference (HSD) test. The differences in AUCs between
different medications were evaluated by a one-way ANOVA
followed by the pairwise Tukey's HSD test. A statistical
software, SPSS for Windows (version 10.0.7), was used. A P
value less than 0.05 was considered statistical significance.
3. Results
3.3. Duration study
The durations of drugs on sciatic nerve blockades of motor
function, proprioception, and nociception were evaluated under
a series of doses of ED25s, ED50s, and ED75s (Fig. 3). On this
basis, dextrorphan and 3-methoxymorphinan produced longer
durations of actions than did lidocaine (Fig. 3).

3.1. Time courses of sciatic nerve blockade 3.4. Co-administration of drugs with lidocaine

The time courses of sciatic nerve blockades in motor
function, proprioception, and nociception by dextromethor-
phan, 3-methoxymorphinan, dextrorphan, and lidocaine were
performed. Due to the similarities of the figures, only the figures
obtained from dextromethorphan and lidocaine at a dose of
6.7 mg/kg are shown (Fig. 1). At the given dose, dextromethor-
phan produced 71 ± 16, 78 ± 17, and 83 ± 26% of blockades (%
MPE) in motor function, proprioception, and nociception with
durations of action of about 77 ± 23, 78 ± 20, and 85 ± 27 min,
respectively. Lidocaine produced 100% of blockades in motor
function, proprioception, and nociception with durations of
action of about 63 ± 14, 73 ± 10, and 83 ± 15 min, respectively.
The effects of co-administration of dextromethorphan or its
metabolites with lidocaine on sciatic nerve blockades were
studied (Fig. 4A–C). The co-administration of dextromethor-
phan with lidocaine produced AUCs between dextromethor-
phan and lidocaine on the sciatic nerve blockades of motor
function, proprioception, and nociception (Fig. 4A; Table 2).
The co-administration of 3-methoxymorphinan or dextrorphan
with lidocaine also produced similar results (Fig. 4B and C;
Table 2). These results demonstrated that co-administration of
dextromethorphan or its metabolites with lidocaine produced
an additive effect on the sciatic nerve blockades (Tallarida,
2001).

3.2. Potency study 4. Discussion

After peri-sciatic nerve injections, the dose–response curves
of drugs in motor function, proprioception, and nociception
were constructed (Fig. 2), and the ED25s, ED50s, and ED75s of
drugs for sciatic nerve blockades were obtained (Table 1). All
drugs produced dose-related sciatic nerve blockades of motor
function, proprioception, and nociception (Fig. 2). At high dose,
all drugs produced complete sciatic nerve blockades of motor
function, proprioception, and nociception. On an ED50 basis,
the ranks of potencies of drugs on sciatic nerve blockades were
lidocaine > dextromethorphan > 3-methoxymorphinan > dextror-
phan (Fig. 2; Table 1). Also, dextromethorphan and 3-
methoxymorphinan had a more potent effect on nociception
than on motor function (p < 0.01, Table 1).
In this study, the local anaesthetic effects of dextromethor-
phan and its metabolites — 3-methoxymorphinan and dex-
trorphan — on sciatic nerve blockades of motor function,
proprioception and nociception were studied. We found that
dextromethorphan and its metabolites produced dose-related
local anaesthetic effects on sciatic nerve blockades of motor
function, proprioception and nociception. Co-administration of
dextromethorphan or its metabolites with lidocaine produced an
additive effect on the sciatic nerve blockades.
Local anaesthetics are drugs that produce neural blockade
through a direct blocking effect on the voltage-gated Na+
channels of the nervous tissues (Fozzard et al., 2005; McLure
and Rubin, 2005; Scholz, 2002). Because dextromethorphan
 C.-H. Hou et al. / European Journal of Pharmacology 544 (2006) 10–16
has a blocking effect on the voltage-gated Na+ channels (Netzer
et al., 1993), theoretically, it may have a local anaesthetic effect.
In the current study, we did find that dextromethorphan had a
local anaesthetic effect. Dextromethorphan produced a dose-
related local anaesthetic effect on the sciatic nerve blockades of
motor function, proprioception, and nociception.
In this study, we also found that co-administration of
dextromethorphan with lidocaine produced an additive effect on
the sciatic nerve blockades of motor function, proprioception
and nociception (Fig. 4A; Table 2). This meant that dextro-
methorphan exerted its effect on the sciatic nerve blockades
through a mechanism similar to that of lidocaine (Tallarida,
2001). The Na+ channel blocking effect might be the common
mechanism of their actions.
Dextromethorphan is primarily metabolized either by O-
demethylation to dextrorphan or to a lesser extent by N-methy-
lation to 3-methoxymorphinan in the liver (Mordecai et al., 1995).
Both of the metabolites are further demethylated to 3-hydro-
xymorphinan. Among these metabolites, dextrorphan was found
to have active pharmacologic actions, whereas the pharmacologic
effects of 3-methoxymorphinan and 3-hydroxymorphinan were
largely unknown (Glick et al., 2001; Kato et al., 1997; Mordecai
et al., 1995; Terada et al., 2000). As dextromethorphan, dex-
trorphan also inhibits the NMDA and nicotine/neuronal nicotinic
receptor channels, and the voltaged-gated Ca2+ and Na+ channels
(Damaj et al., 2005; Franklin and Muway, 1991; Trube and
Netzer, 1994). Beside these bindings, dextrorphan further binds
to the phencyclidine receptors and exerts phencyclidine-like
effects (Szekely et al., 1991). Because dextrorphan has a Na+
channel blocking effect (Trube and Netzer, 1994), it may have a
local anaesthetic effect. In the current study, we did find that
dextrorphan had a local anaesthetic effect on sciatic nerve
blockades of motor function, propriception and nociception.
Beside dextrorphan, 3-methoxymorphinan was also found to
have a similar local anaesthetic effect on sciatic nerve blockades.
As those found in dextromethorphan, co-administration of 3-
methoxymorphinan or dextrorphan with lidocaine produced an
additive effect on the sciatic nerve blockades (Fig. 4B and C;
Table 2). This meant that the mechanism of action of 3-
methoxymorphinan and dextrorphan on sciatic nerve blockades
was also similar to that of lidocaine. Although the activity of 3-
methoxymorphinan on the Na+ channels was not evaluated
previously, we predict that 3-methoxymorphinan may have a Na+
channel blocking effect which contributes to its local anaesthetic
effect.
In the current study, dextromethorphan and 3-methoxymorphi-
nan were found to have a more potent effect on nociception than
the effect on motor function (Table 1). This phenomenon may be
explained by the following reason (Strichartz, 1998). In peripheral
neural blockade, local anaesthetics are suspected to have a more
potent effect on nerve fibers which have a small diameter and no
myelin sheath (i.e., fibers for transmission of nociception) than on
fibers which have a large diameter and myelin sheath (i.e., motor
fibers). This may be the reason for the above finding.
In Fig. 4B, we found that the maximum effects of drug
combination (lidocaine with 3-methoxymorphinan) in motor
function and nociception did not reach 100% PE, although the
15
maximum effects of drugs alone reached 100% PE. We also
found that lidocaine had a fast onset with a relatively shorter
duration of action, whereas 3-methoxymorphinan had a slow
onset with a relatively longer duration of action. The peak effects
of these two drugs were not totally overlapped. There was a gap.
According to the trends of the curves of drug combination
(lidocaine with 3-methoxymorphinan) in motor function and
proprioception, the peak effects of these curves were suspected
to occur within this gap (between 20 and 30 min post-injection).
However, the drugs' effects within this time interval were not
detected coincidentally. Therefore, in Fig. 4B, the peak effects of
drug combination in motor function and proprioception might
not be sufficiently presented. These phenomena were also found
in Fig. 4C. Due to this reason, we used AUCs to evaluate the
effects of drug combination. We found that they had an additive
effect in comparison with drugs alone.
Peripheral neural blockade by local anaesthetics is an attractive
option for surgical anaesthesia and management of postoperative
pain (McLure and Rubin, 2005). In the current study, we found that
dextromethorphan and its two metabolites had significant effects
on the peripheral neural blockade on sciatic nerves. Dextromethor-
phan, 3-methoxymorphinan, and dextrorphan may potentially be
the novel local anaesthetics for peripheral neural blockade.
In conclusion, dextromethorphan and its metabolites — 3-
methoxymorphinan and dextrorphan — had a local anaesthetic
effect on the sciatic nerve blockades of motor function, pro-
prioception, and nociception with durations of action longer than
those of lidocaine, a commonly used local anaesthetic. When co-
administered with lidocaine, dextromethorphan and its metabo-
lites also produced an additive effect on the sciatic nerve block-
ades. Dextromethorphan, 3-methoxymorphinan, and dextrorphan
may potentially be the novel local anaesthetics for peripheral
neural blockade.
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