1
Intrathecal orphenadrine elicits spinal block in the rat
Yu-Wen Chen1,2,, Ph.D., Jann-Inn Tzeng3,4, M.S., M.D., Yu-Chung Chen5, M.S.,
Ching-Hsia Hung6,*, Ph.D., Jhi-Joung Wang2, M.D., Ph.D.
1
Department of Physical Therapy, China Medical University, Taichung, Taiwan
2
Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
3
Department of Food Sciences and Technology, Chia Nan University of Pharmacy
and Science, Jen-Te, Tainan City, Taiwan
4
Department of Anesthesiology, Chi-Mei Medical Center, Yong Kang, Tainan City,
Taiwan
Division of Physical Therapy, Department of Physical Medicine and Rehabilitation,
Cheng Hsin General Hospital, Taipei, Taiwan
6
Institute & Department of Physical Therapy, National Cheng Kung University,
Tainan, Taiwan
5
Ching-Hsia Hung and Yu-Chung Chen contributed equally to this work.
Conflicts of interest: There is no conflict of interests for all authors.
*Corresponding author:
Ching-Hsia Hung, Ph.D.
National Cheng Kung University,
Institute & Department of Physical Therapy,
No.1, University Road, Tainan City 701, Taiwan
Phone: 886-6-2353535 ext 5939
FAX: 886-6-2370411
Email: chhung@mail.ncku.edu.tw
2
ABSTRACT
The purpose of this study was to estimate the local anesthetic effect of orphenadrine,
an anti-muscarinic agent, on spinal anesthesia and its comparison with lidocaine, a
common local anesthetic. After rats were injected intrathecally, the spinal block of
orphenadrine and lidocaine were constructed in a dosage-dependent fashion. The
potency and duration of spinal anesthesia with orphenadrine were compared with that
of lidocaine. We demonstrated that orphenadrine and lidocaine elicited
dose-dependent spinal blockades in motor function, proprioception, and nociception.
On a 50% effective dose (ED50) basis, the rank of potency in motor function,
proprioception, and nociception was orphenadrine > lidocaine (P < 0.01 for the
differences). At equianesthetic doses (ED25, ED50, ED75), the block duration caused
by orphenadrine was greater than that caused by lidocaine (P < 0.01 for the
differences). Orphenadrine, but not lidocaine, exhibited longer duration of sensory
block than that of motor block at equipotent doses. The preclinical data revealed that
orphenadrine with a more sensory-selective action over motor blockade had more
potent and longer spinal blockades when compared with lidocaine.
Keywords: orphenadrine; lidocaine; spinal anesthesia; motor function, proprioception,
nociception
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1. Introduction
Orphenadrine was introduced into the market as an agent for the treatment of
Parkinson’s disease or some of the troublesome symptoms of the disease, especially
the involuntary resting tremor (Sweeney, 1995). Additionally, orphenadrine is a
multitarget inhibitor, including N-methyl-D-aspartate (NMDA), muscarinic and
histaminic receptors, as well as the norepinephrine reuptake system (Darwish et al.,
2012). Orphenadrine was also used as an analgesic both alone and in association with
nonsteroidal anti-inflammatory medications (Hunskaar and Donnell, 1991). New
evidence showed that there was an improvement in the visual analogue scale (VAS)
score between the day of inclusion and before drug infusions of 19% for
diclofenac+orphenadrine in chronic low back pain patients on chronic opioid
treatment (Wetzel et al., 2014). To date, the detailed molecular mechanism by which
orphenadrine induces analgesia is still unknown. The hypothesis of blockade of the
voltage-gated sodium channels was acceptable as a strong contributor to the analgesic
action of orphenadrine (Desaphy et al., 2009).
Blockade of voltage-gated sodium channels (Desaphy et al., 2009), which is one
of the major mechanisms of local anesthesia, produces spinal anesthesia, peripheral
nerve block, and infiltrative cutaneous analgesia (Borgeat and Aguirre, 2010; Vegh et
al., 2006). It has been known that orphenadrine with stronger anticholinergic property,
4
a histamine H1 receptor antagonist, is structurally related to diphenhydramine.
Diphenhydramine has the local anesthetic properties (Chen et al., 2013; Hung et al.,
2011b; Pavlidakey et al., 2009; Suffridge et al., 2009). Because orphenadrine blocked
voltage-gated sodium channels, we presumed that orphenadrine may elicit spinal
anesthesia.
To the best of our knowledge, no study of orphenadrine on spinal anesthesia has
been reported to date. Local anesthetics are frequently administered intrathecally for
various procedures or pathologies. Spinal anesthesia is a relatively simple technique,
which brings competent surgical conditions by the injection of a small amount of
local anesthetic with easy landmarks, giving a wide popularity to this practice (Chen
et al., 2012b; Vandermeersch et al., 1991). The aim of this study was to estimate the
spinal anesthesia following intrathecal injections of orphenadrine by testing motor
function, proprioception, and nociception in rats. Lidocaine, a known local anesthetic,
was used as control.
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2. Materials and methods
2.1.Animals
The experimental protocols were approved via the Institutional Animal Care and
Use Committee of National Cheng Kung University (Tainan, Taiwan) and conformed
to the recommendations and policies of the International Association for the Study of
Pain (IASP). Male Sprague-Dawley rats, each weighing 298 to 352 g, were purchased
from National Cheng Kung University and kept in the animal housing facilities at
National Cheng Kung University, with controlled humidity (approximately 50%
relative humidity), room temperature (22C), and a 12-hour (6:00 AM to 6:00 PM)
light/dark cycle.
2.2.Drugs
Orphenadrine HCl and lidocaine HCl monohydrate were purchased from
Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). All drugs in stock were freshly
prepared in 5% dextrose as solution before intrathecal injections. After injections, the
low pH of these plain solutions (range, 5.5–6.7) is likely to be buffered quickly by the
cerebral spinal fluid (pH 7.4).
2.3.Experimental groups
Three specific experiments were tested. In experiment 1, spinal anesthesia with
orphenadrine (0.20, 0.38, 0.75, 1.00 µmol) and lidocaine (0.50, 0.75, 1.50, 2.50 µmol)
6
in a dosage-dependent fashion were evaluated (n=8 rats for each dose of each drug).
In experiment 2, the %MPE, duration, area under the curves (AUCs) of the spinal
blockades by orphenadrine (1 µmol), lidocaine (2.5 µmol), and vehicle (5% dextrose)
was performed (n=8 rats for each dose of each drug). In experiment 3, on an
equipotent basis (ED25, ED50 and ED75), the duration of orphenadrine on spinal
anesthesia was compared with that of lidocaine (n=8 rats for each dose of each drug).
2.4.Intrathecal drug administration
All animals were injected intrathecally once in this study. Lumbar puncture was
done on conscious rats. Before intrathecal injection, local anesthesia was given.
Following an optimal flexion of the rat lumbar spine under prone position, each 50-µl
of 0.5% lidocaine was injected into the right- and left-side of paraspinal space (0.5 cm
in depth) which was 0.5 cm away from the mid-point of the longitudinal line of L4–
L5 intervertebral space (Leung et al., 2014; Leung et al., 2013b). Two minutes later, a
27-gauge needle attached to a 50-µl syringe (Hamilton, Reno, Nevada) was inserted
into the mid-line of the L4–L5 intervertebral space until a tail-flick indicated entrance
into the spinal space. Fifty microliters of drug were injected and the rat was observed
for the development of spinal anesthesia, indicated by paralysis of both hind limbs.
Rats, which exhibited unilateral blockade, were excluded from the experiment and
sacrificed by using an over dose of isoflurane.
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2.5.Neurobehavioral evaluation
For consistency, an experienced investigator who was blinded to the drugs
injected was responsible for neurobehavioral evaluations. After intrathecal injection,
three neurobehavioral examinations, which consisted of evaluations of motor,
proprioception, and nociception, were conducted (Chen et al., 2011b; Hung et al.,
2011a). Rats were assessed before medication and at 1, 3, 5, 7, 10, 15 and 20 min
afterwards, then again at 10-min interval until 1 h and at 15 min interval until 2 h. The
magnitude of spinal blockade in motor function, proprioception, and nociception was
described as the percent of possible effect (% PE). The maximum blockade in a time
course of spinal anesthesia with drugs was described as the percent of maximal
possible effect (% MPE).
In brief, motor function was assessed through measuring 'the extensor postural
thrust' of the right hind limb of each rat. The extensor thrust was measured as the
gram force, which resisted contacting the platform through the rat heel applied to a
digital platform balance (Mettler Toledo, PB 1502-S, Switzerland). The reduction in
the force, representing decreased extensor muscle tone, was considered as a deficit of
motor function and expressed as a percent of the control force. The preinjection
control value was considered as 0% motor block or 0% MPE. A force less than 20 g
(also referred to as the weight of the 'flaccid limb') was interpreted as the absence of
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extensor postural thrust or a 100% motor block or 100% MPE (Chen et al., 2012b, c).
Nociception was evaluated through the withdrawal reflex or vocalization evoked
through pinching a skin fold over each rat's back at 1 cm from the proximal part of the
tail, the lateral metatarsus of bilateral hind limbs, and the dorsal part of the mid-tail.
At each testing time, only one pinch was given to each of the four testing sites, and
the time interval between stimulations at different sites was around 2 s. The
nociceptive blockade was graded as 4 (normal or 0% MPE), 3 (25% MPE), 2 (50%
MPE), 1 (75% MPE), and 0 (absent or 100% MPE) (Chen et al., 2011a; Chen et al.,
2012a).
Proprioception evaluation was based on the resting posture and postural reactions
(‘tactile placing’ and ‘hopping’). Hopping response was performed through lifting the
front half of the animal off the ground and lifting one hind limb at a time off the
ground so that the animal was standing on just one limb. Then, the animal was moved
laterally, which normally caused a prompt hopping response with the weight-bearing
limb in the direction of movement to prevent the animal from falling. A
predominantly motor impairment exhibited a prompt but weaker than normal response.
Conversely, with a predominantly proprioceptive blockade, delayed hopping was
followed by greater lateral hops to prevent falling over or, in this case of complete
block, no hopping at all. The functional deficit was graded as 3 (normal or 0% MPE),
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2 (slightly impaired), 1 (severely impaired), and 0 (completely impaired or 100%
MPE) (Hung et al., 2011b; Leung et al., 2013a).
2.6.Effective doses (EDs)
After intrathecally injecting the rats with four different doses of each drug, the
dose—response curve was constructed. The curve was then fitted by using a SAS
Nonlinear (NLIN) Procedures (SAS Institute Inc., Carey, NC), and the value of 50%
effective dose (ED50), defined as a dose that elicited 50% spinal blockade, were
obtained (Chen et al., 2011c; Minkin and Kundhal, 1999). The ED25 or ED75 of drug
was obtained through the same curve-fitting (SAS NLIN Procedures) which was used
to derive the ED50 (Hung et al., 2014; Hung et al., 2012). The full recovery time,
defined as the interval from drug injection to full recovery (0% MPE).The AUCs of
spinal blockades of drugs were calculated by using Kinetica v 2.0.1 (MicroPharm
International, USA) (Chen et al., 2011b).
2.7.Statistical analysis
Values are presented as means ± S.E.M. or ED50 values with 95% confidence
interval (95% CI). Data were evaluated by either 1-way (experiments 1 and 2) or
2-way (experiment 3) analysis of variance (ANOVA) followed by pairwise Tukey's
honest significance difference (HSD) test. A statistical software, SPSS for Windows
(version 17.0, SPSS, Inc, Chicago, IL, USA), was used, and a P value less than 0.05
10
was considered statistically significant.
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3. Results
3.1.The spinal blockade of orphenadrine
Orphenadrine, as well as local anesthetic lidocaine exhibited a
dose-dependent local anesthetic effect as spinal anesthesia in rats (Fig. 1). The ED25s,
ED50s, and ED75s of drugs are shown in Table 1. On an ED50 basis, the ranks of
potencies in motor function, proprioception, and nociception were orphenadrine >
lidocaine (P < 0.01; Table 1). Additionally, the sensory/nociceptive blockade (ED50)
was more potent than the motor blockade (ED50) for orphenadrine but lidocaine (P <
0.05; Table 1).
3.2.The spinal block effect of equipotent orphenadrine and lidocaine
Intrathecal injection of 5% dextrose (vehicle) elicited no spinal anesthesia (Fig.
2). At a given dose of 1 μmol, orphenadrine produced 100, 100, and 100% of
blockades (% MPE) in motor function, proprioception, and nociception with duration
of action of about 40, 51, and 99 min, respectively (Fig. 2 and Table 2). Lidocaine at
2.5 μmol displayed 100, 100, and 100% of blockades in motor function,
proprioception, and nociception with duration of action of about 25, 29, and 33 min,
respectively (Fig. 2 and Table 2).
3.3.The complete block time, time to full recovery, and AUCs of orphenadrine and
lidocaine on spinal anesthesia
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The complete block time, time to full recovery, and AUCs of spinal anesthesia
with orphenadrine are significantly greater than those of lidocaine in Table 2.
Furthermore, orphenadrine also produced longer duration of sensory blockade than
that of motor blockade (Table 2). On an equipotent basis (ED25, ED50, ED75), the
spinal blockades of motor, proprioception and nociception caused by orphenadrine
were longer than those caused by lidocaine (Fig. 3).
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4. Discussion
In this study we demonstrated that intrathecal orphenadrine produced spinal
anesthesia that was more potent than that produced by lidocaine. Orphenadrine, but
not lidocaine, elicited greater sensory/nociceptive blockade than motor blockade. At
equianesthetic doses, the duration of spinal anesthesia with orphenadrine was greater
than that with lidocaine.
The local anesthetic drugs produce neural blockade through inhibiting the Na+
currents in the nervous tissues through the voltage-gated Na+ channels (Fozzard et al.,
2005). Because orphenadrine inhibited tetrodotoxin (TTX)-resistant sodium currents
(Desaphy et al., 2009), intrathecal orphenadrine blocked motor, sensory, and
proprioceptive functions, suggesting that orphenadrine has the characteristics of a
local anesthetic. Furthermore, we demonstrated that orphenadrine and lidocaine
exhibited dose-dependent spinal anesthesia, whereas orphenadrine was almost
2.1-folds higher potency than did lidocaine on spinal anesthesia.
We also noticed that the sensory/nociceptive blockade in orphenadrine was
almost 1.4-folds higher potency (ED50) than the motor blockade. Clinically, local
anesthetics have mostly been used to assist with complete blockage of pain and not to
augment potency. In addition, orphenadrine displayed a longer duration of sensory
blockade than that of motor blockade (Table 2). Our results supported the
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experimental data by providing strong evidence that orphenadrine had a significant
block of Nav1.7, Nav1.8, and Nav1.9 channels, which were critical for experiencing
pain sensations (Desaphy et al., 2009).
On an equal-potent basis, spinal block duration of orphenadrine was greater
than that of lidocaine (Table 2). Surgery through injecting long-lasting local
anesthetics is frequently performed (Job et al., 1979). There are few cases where
ultrashort spinal anesthesia is needed, and for these they use lidocaine or
2-chloroprocaine clinically. For this reason, we also examined orphenadrine and
lidocaine at equianesthetic doses (ED25, ED50, ED75). Our results showed that the
duration of spinal blockade caused by orphenadrine was longer than that caused by
lidocaine on an equipotent basis (Fig. 3). The administration of local anesthetics (i.e.,
orphenadrine) for surgery or postoperative pain control may be worth investigated in
the future.
Orphenadrine is structurally related to diphenhydramine, which shows the local
anesthetic properties (Chen et al., 2013; Hung et al., 2011b; Pavlidakey et al., 2009;
Suffridge et al., 2009). The previous and present studies demonstrated that
orphenadrine was more potent at producing spinal anesthesia than diphenhydramine
(Hung et al., 2011b). Our study still shows some limitations. We did not estimate
whether orphenadrine elicited neurotoxicity, however, it is noteworthy that in
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neurobehavioral studies we detected no apparent side effects after drug injection.
Histologic experiments must be performed in the future before the possible use of
orphenadrine as spinal analgesic in humans.
In conclusion, the preclinical data reported that orphenadrine produced a
dose-dependent local anesthetic effect on spinal anesthesia and had more potent and
longer spinal block duration than lidocaine. Furthermore, orphenadrine, but not
lidocaine elicited predominantly nociceptive-specific blockades. The neural block
potential by orphenadrine is worth studying in the further.
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Acknowledgements
This work was supported by the National Science Council of Taiwan (NSC
100-2314-B-039-017-MY3 and NSC 101-2314-B-006-037-MY3) and was supported
in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center
of Excellence (DOH102-TD-B-111-004). No author has any conflict of interest
related to the content of this paper.
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Table 1. The 25% effective doses (ED25s), ED50s, and ED75s of orphenadrine and lidocaine on spinal anesthesia in rats
ED50 (95% CI)
Motor
Proprioception
Mean
Nociception
ED25
ED50
ED75
Orphenadrine
0.65 (0.59–0.72)
0.50 (0.41–0.61)
0.48 (0.42–0.55)
0.32
0.54
0.76
Lidocaine
1.23 (1.13–1.36)
1.20 (1.13–1.29)
1.10 (0.99–1.25)
0.77
1.18
1.65
The EDs of drugs (μmol) were obtained from Figure 1. CI = confidence interval. The potencies of drugs (ED50s) in motor, proprioception,
and nociception were orphenadrine > lidocaine (P<0.01, for each comparison) by using 1-way ANOVA followed by pairwise Tukey’s HSD
test.
23
Table 2. The percent of maximal possible effect (%MPE), duration, area under the curves (AUCs) of drugs on spinal anesthesia in rats
Duration (min)
%MPE
Complete blockade time
Motor
Orphenadrine
Lidocaine
Proprioception
Orphenadrine
Lidocaine
Nociception
Orphenadrine
Lidocaine
AUCs (%MPE x min)
Time to full recovery
100 ± 0
12 ± 2b
40 ± 5a
2418 ± 388a
100 ± 0
7±2
27 ± 2
1310 ± 130
100 ± 0
100 ± 0
19 ± 4b
8±2
51 ± 7b
28 ± 2
3123 ± 536b
1403 ± 96
100 ± 0
100 ± 0
21 ± 3a,d
9±2
99 ± 4c,f
31 ± 2
5760 ± 331c,f
1473 ± 155
Spinal anesthesia (means  S.E.M.) with orphenadrine at 1 μmol and lidocaine at 2.5 μmol (n = 8 in each group). Of note, all of the rats in
the orphenadrine and lidocaine groups exhibited complete blockade (100%MPE) of any function tested. Symbols (a, b, c) indicate P < 0.05,
P < 0.01, P < 0.001 when orphenadrine compared with lidocaine; Symbols (d, e, f) indicate P < 0.05, P < 0.01, P < 0.001 when nociception
compared with motor function.
%MPE (maximal possible effect)
24
100
Motor
Orphenadrine
Lidocaine
80
60
40
20
0
%MPE (maximal possible effect)
0.1
100
1
Proprioception
80
60
40
20
0
%MPE (maximal possible effect)
0.1
100
1
Nociception
80
60
40
20
0
0.1
1
Dose ( mol )
Fig. 1.
25
Motor
%PE (possible effect)
100
Orphenadrine
Lidocaine
5% dextrose
80
60
40
20
0
0
15
30
45
60
75
90
105
120
30
45
60
75
90
105
120
30
45
60
75
90
105
120
Proprioception
%PE (possible effect)
100
80
60
40
20
0
0
15
Nociception
%PE (possible effect)
100
80
60
40
20
0
0
15
Time (min)
Fig. 2.
26
Full Recovery Time (min)
35
Motor
Orphenadrine
Lidocaine
28
21
14
7
0
25
Full Recovery Time (min)
35
50
75
50
75
50
75
Proprioception
28
21
14
7
0
25
Full Recovery Time (min)
35
Nociception
28
21
14
7
0
25
ED ( effective dose )
Fig. 3.
27
Figure Legends
Fig. 1. The dose—response curves of drugs (μmol) on spinal blockades of motor,
proprioception, and nociception (% MPE) in rats (n = 8 at each testing point) in rats.
Data are means ± S.E.M. %MPE = percent of maximal possible effect.
Fig. 2. The time courses of orphenadrine (1 μmol) and lidocaine (2.5 μmol) on spinal
blockades of motor, proprioception, and nociception in rats. Values are expressed as
means ± S.E.M. Each testing point of the time course study contained eight rats.
Fig. 3. Full recovery time (duration) of action of orphenadrine and lidocaine on spinal
blockades of motor, proprioception, and nociception at doses of ED25, ED50, and ED75
in rats (n = 8 at each testing point). Values are expressed as means ± S.E.M.