中 國 醫 藥 大 學
專題研究計畫成果報告
計畫名稱：右美沙芬與右啡烷結合 clonidine 應用於
大鼠浸潤性皮膚止痛效果評估
計畫編號： CMU99-大專-38
執行期限： 2010 年 8 月 1 日至 2011 年 2 月 28 日
單位名稱：物理治療學系
主持人：陳郁文
中 華 民 國 100 年 3 月 1 日
Manuscript Draft Manuscript Number:
Title: Clonidine as adjuvant for oxybuprocaine or dextrorphan has a significant peripheral action in intensifying and prolonging the local anaesthetic effect on infiltrative cutaneous analgesia
Article Type: Reports of Original Investigations Corresponding Author: Ching-Hsia Hung Corresponding Author's Institution: First Author: Yu-Wen Chen, Ph.D.
Order of Authors: Yu-Wen Chen, Ph.D.;Yung-Tsung Li;Yu-Chung Chen;Ching-Hsia Hung;Meng-I Hsueh Abstract: Purpose The aim of the study was to evaluate co-administration of clonidine with
oxybuprocaine or dextrorphan on infiltrative cutaneous analgesia and to see whether it could have a peripheral action in enhancing duration of local anaesthesia.
Methods Cutaneous analgesia was evaluated by a block of the cutaneous trunci muscle reflex, which is characterized by reflex movement of the skin over the back produced by twitches of lateral
thoracispinal muscles in response to local dorsal cutaneous noxious pinprick. The analgesic effect of the addition of clonidine with oxybuprocaine and dextrorphan for subcutaneous injection was evaluated. Oxybuprocaine, a common used local anaesthetic, was used as control.
Results On an ED50 basis, the rank of drug potency was oxybuprocaine > dextrorphan. Mixtures of clonidine with oxybuprocaine or dextrorphan (ED50 or ED95) extended the duration of drug action and increased the potency of cutaneous analgesia. Clonidine at the dose of 0.12 µmol did not produce cutaneous analgesia.
Conclusions Oxybuprocaine showed more potent cutaneous analgesia than dextrorphan.
Co-administration of oxybuprocaine or dextrorphan with clonidine increased the potency and duration on cutaneous analgesia in rats.
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Clonidine as adjuvant for oxybuprocaine or dextrorphan has a
significant peripheral action in intensifying and prolonging the
local anaesthetic effect on infiltrative cutaneous analgesia
Yu-Wen Chen, Ph.D.,1,2 Yung-Tsung Li, M.S.,1 Yu-Chung Chen, M.S.,3 Ching-Hsia
Hung, Ph.D.,4,* Meng-I Hsueh, M.S.1
1
Department of Physical Therapy, China Medical University, Taichung, Taiwan 2 Graduate Institute of Neural and Cognitive Sciences, China Medical University,
Taichung, Taiwan
3
Division of Physical Therapy, Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan
4
Institute & Department of Physical Therapy, National Cheng Kung University, Tainan, Taiwan
Funding: The financial support was provided by the National Science Council of Taiwan (NSC 98-2314-B-006-017-MY3; NSC 99-2314-B-039-013-MY3).
Conflicts of interest: There is no conflict of interests for all authors.
Short heading (40 characters or less): clonidine enhances dextrorphan and oxybuprocaine
Summary: Clonidine enhances and prolongs dextrorphan and oxybuprocaine cutaneous analgesia.
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*Address correspondence and reprint requests to: Ching-Hsia Hung, PhD, Department of Physical Therapy, National Cheng Kung University, No.1 Ta-Hsueh Road, Tainan, Taiwan
Tel: 886-6-2353535 ext 5939 Fax: 886-6-2370411
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Abstract
Purpose The aim of the study was to evaluate co-administration of clonidine with
oxybuprocaine or dextrorphan on infiltrative cutaneous analgesia and to see whether it
could have a peripheral action in enhancing duration of local anaesthesia.
Methods Cutaneous analgesia was evaluated by a block of the cutaneous trunci
muscle reflex, which is characterized by reflex movement of the skin over the back
produced by twitches of lateral thoracispinal muscles in response to local dorsal
cutaneous noxious pinprick. The analgesic effect of the addition of clonidine with
oxybuprocaine and dextrorphan for subcutaneous injection was evaluated.
Oxybuprocaine, a common used local anaesthetic, was used as control.
Results On an ED50 basis, the rank of drug potency was oxybuprocaine >
dextrorphan. Mixtures of clonidine with oxybuprocaine or dextrorphan (ED50 or ED95)
extended the duration of drug action and increased the potency of cutaneous analgesia.
Clonidine at the dose of 0.12 µmol did not produce cutaneous analgesia.
Conclusions Oxybuprocaine showed more potent cutaneous analgesia than
dextrorphan. Co-administration of oxybuprocaine or dextrorphan with clonidine
increased the potency and duration on cutaneous analgesia in rats.
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Introduction
Oxybuprocaine (benoxinate) produces the dose-related cutaneous analgesia1 and
spinal anaesthesia2 in rats. At equipotent doses, systemic toxicity following
intravenous oxybuprocaine and proxymetacaine occurred later compared to
bupivacaine.1 Dextrorphan is a sodium channel blocker3 which produces dose-related
local anaesthetic effects on cutaneous analgesia,4,5 spinal or sciatic nerve blockades in
motor function, proprioception and nociception in rats.6,7 Besides, dextrorphan was
similar to bupivacaine and displayed a long-acting cutaneous analgesia.5 Previous
studies from our laboratory extend those studies by showing the addition of
epinephrine with dextrorphan administered directly to the subcutaneous region
produces the additive cutaneous analgesia.5
The addition of clonidine, an α2-adrenoreceptor agonist, to low concentration of ropivacaine or bupivacaine can extend the duration of sensory block and analgesic
time in children.8 Furthermore, clonidine added to mepivacaine selectively enhanced
sensory blockade after midhumeral block,9 and co-administration of clonidine
prolonged local anaesthetic effect of lidocaine on the forearm of volunteer subjects.10
The benefits of adding clonidine to local anaesthetics are decreasing postoperative
analgesic requirement and improving analgesic quality.11-13
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a significant peripheral action in enhancing duration of local anaesthesia.10 The aim of
the study was to evaluate co-administration of clonidine with oxybuprocaine or
dextrorphan on cutaneous analgesia and to see whether it could have a peripheral
action in enhancing duration of local anaesthesia after a single subcutaneous injection.
We suggested that the impact of adding clonidine to subcutaneous injections of
oxybuprocaine or dextrophan could enhance and prolong the local anaesthetic effects
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Methods
AnimalsMale Sprague-Dawley rats weighting 200-250 g were obtained from the National
Laboratory Animal Centre (Taipei, Taiwan) and then housed in a climate controlled
room, with food and water available ad libitum up to time of testing. The climate- controlled room was maintained at 22˚C with approximately 50% relative humidity on a 12-h light/dark cycle (6:00 AM–6:00 PM). The experimental protocols were
approved by the Animal Investigation Committee of China Medical University,
Taichung, Taiwan and conformed to the recommendations and policies of the
International Association for the Study of Pain.
Drugs
Benoxinate (oxybuprocaine) HCl, dextrorphan tartrate and clonidine HCl were
purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). All drugs were
dissolved in 0.9% NaCl (saline).
Experimental Procedures
Three experiments were carried out. In experiment 1, time courses of
oxybuprocaine (1.20, 0.60, 0.15, 0.03 µmol), dextrorphan (9.00, 6.00, 3.00, 0.60
µmol), and clonidine (0.96, 0.48, 0.24, 0.12 µmol) on cutaneous analgesia were
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duration, and area under curves (AUCs) of oxybuprocaine and dextrorphan (ED50 or
ED95) with/without clonidine were assessed on cutaneous analgesia (n = 8 rats for
each dose of each drug). In experiment 3, after the above testings, one control group
was further added into the study to rule out the possibility of systemic effect of drugs
on cutaneous analgesia. Groups (n = 8 rats for each dose of each drug) received
subcutaneous injection (the right calf of the rats) of testing drug (oxybuprocaine or
dextrorphan) with a dose of 2ED95 or clonidine with a dose of 0.96 µmol.
Subcutaneous Injection of Drug
All rats were handled daily up to 7 days to minimize the stress on the rats during
experiments and generally improve their experimental performance before
experiments.1,5 On the day before subcutaneous injections, the hair on the rats' dorsal
surface of the thoracolumbar region (10×6 cm2) was mechanically shaved. The
subcutaneous injection of drug was performed as reported previously.1,5 In brief, the
drugs in 0.6 mL were injected subcutaneously using a 30-gauge needle in
unanesthetized rats at the dorsal surface of the thoracolumbar region. After
subcutaneous injection, a circular elevation of the skin, a wheal, approximately 2 cm
in diameter occurred. The wheal was marked with ink within one minute after
injection. For consistency, one experienced investigator (Dr. Chen Y.W.) who was
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effect. The drugs were prepared and injected by another investigator (Li Y.T.).
Neurobehavioral Evaluation
Cutaneous anaesthesia was evaluated by the cutaneous trunci muscle reflex
(CTMR), characterized by the reflex movement of the skin over the back produced by
twitches of the lateral thoracospinal muscle in response to local dorsal cutaneous
stimulation after drug injections.1,5 A Von Frey filament (No.15; Somedic Sales AB,
Stockholm, Sweden), to which the cut end of an 18-gauge needle was affixed, was
used to produce the standardized nociceptive stimulus (19±1 g). After observing an
animal normal reaction to pinpricks applied outside the wheal and on the contralateral
side, we applied six pinpricks (at six different points with a frequency of 1-2 Hz)
inside the wheal and scored the number to which the rat failed to react. Cutaneous
analgesic effect of each drug was assessed quantitatively as the number of times the
pinprick failed to elicit a response, with, for example, the complete absence of six
responses was defined as complete nociceptive block (100% of possible effect; 100%
PE). The test of six pinpricks was applied 5 min before drug injection, at 0, 2 and 5
min afterwards, then again every 5 min after injection for the first 30 min, every 10
min after injection for 30-60 min, and every 15-30 min thereafter until the CTMR
fully recovered from the block. During the test, the maximum blockade in a time
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possible effect (%MPE). The duration of action of each drugs was defined as the time
from drug injection (i.e., time=0) to full recovery of CTMR (no analgesic effect was
found or 0% MPE recorded).1,5
Evaluation of 50% Effective Dose (ED50) and ED95
After subcutaneously injecting the rats with four doses of each drug (n = 8 for
each dose of each drug), dose-response curves were obtained via the % MPE for each
dose of each drug. The value of 50% or 95% effective dose (ED50 or ED95), defined as
the dose that caused 50% or 95% cutaneous analgesia, was obtained via a
computer-derived SAS NLIN analysis (SPSS for Windows, version 17.0; SAS
Institute Inc., Carey, NC).14
Statistical Analysis
Data are presented as mean SD (range) or ED50 value with 95% confidence
interval (95% CI). Data were evaluated by the Student’s t-test. A statistical software,
SPSS for Windows (version 17.0, SPSS, Inc, Chicago, IL, USA), was used, and a P
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Results
The Potency of Drugs on Cutaneous Analgesia
The structures of oxybuprocaine and dextrorphan are shown in Figure 1.
Subcutaneous injections of oxybuprocaine and dextrorphan produced dose-dependent
cutaneous analgesia in rats (Fig. 2). Clonidine alone at the doses of 0.12-0.96 µmol
showed no cutaneous analgesia (data not shown). The ED50s and ED95s of drugs
constructed from Figure 2 were demonstrated in Table 1. On an ED50 basis, the rank
of drug potency was oxybuprocaine > dextrorphan (Table 1).
Cutaneous Analgesia of Drugs at ED95 with/without Clonidine
At the dose of ED95, oxybuprocaine for 92% sensory blockade with AUC of
2394 ± 782 and dextrorphan for 88% sensory blockade with AUC of 2515 ± 551 are
displayed in Figure 2 and Table 2. Subcutaneous injection of clonidine alone at the
dose of 0.12 µmol demonstrated no cutaneous anaesthesia (Fig. 3). After drugs at the
dose of ED95 were co-injected with clonidine (0.12 µmol), oxybuprocaine and
dextrorphan caused 100% sensory blockade (100% MPE) with AUCs of 10812 ±
1727 and 8360 ± 1108, respectively (Fig. 3 and Table 2). The %MPE, duration and
AUCs of drugs at the dose of ED95 with clonidine were greater (P<0.05) than drugs
without clonidine in Table 2.
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When drugs at the dose of ED50 were co-injected with clonidine (0.12 µmol),
complete sensory blockade (100% MPE) in the oxybuprocaine (8 of 8 rats) group
occurred, but not in the dextrorphan (5 of 8 rats) group. Compared with drugs at the
dose of ED50 alone, drugs (ED50) co-injected with 0.12 µmol clonidine, the AUCs
were increased in oxybuprocaine group from 699 ± 142 to 7401 ± 561 (P<0.001 and
in dextrorphan group from 916 ± 361 to 4821 ± 590 (P<0.001), respectively.
One Control Group
Neither the calf subcutaneous injection of clonidine (0.96 µmol) nor calf
subcutaneous injections of oxybuprocaine and dextrorphan (2ED95) demonstrated
cutaneous analgesia on the back of the rat, loss of motor activity or sedation (data not
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Conclusions
In this report we showed for the first time that oxybuprocaine was a more potent
local anaesthetic on cutaneous analgesia that dextrorphan. Clonidine dramatically
enhances and prolongs the sensory blocking effect of oxybuprocaine and dextrorphan
on cutaneous analgesia in rats. Subcutaneous injection of clonidine (0.96-0.12 µmol)
produces no cutaneous analgesia.
The clinical relevance of this prolonged sensory blockade, though useful in
certain situations, may be limited overall, when considering the higher incidence of
motor blockade caused by clonidine.15 Both of motor blockade following central
neuraxial block and also of sedative effects of clonidine should be limited. Given
these dose-limiting central side effects, clonidine may be beneficial to apply
peripherally. Therefore, this study evaluated the cutaneous analgesic effect of local
anaesthetics combined with clonidine. In this study, we found that co-administration
of clonidine with oxybuprocaine or dextrorphan enhanced the duration and prolonged
the cutaneous analgesia in rats. Because we have already known that clonidine
prolonges the local anaesthetic duration of lidocaine and bupivacaine,10,16 it is also not
surprising that clonidine prolongs the cutaneous analgesic duration of oxybuprocaine
and dextrorphan, two local anaesthetics.1, 2, 4, 5
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tactile hypersensitivity 24–34 h after clonidine administration in rats.17 Clonidine
hydrochloride (0.1 mg/kg, i.p.) did not affect the tactile allodynia and mechanical
hyperalgesia induced from orthotropic inoculation with melanoma into the hind paw
of mice.18 These experiments used higher doses of clonidine. Typically, these were
selected from published articles as the highest doses that were used to study
antinociception or drug tolerance.17,18 Our study displayed that the low dose of
clonidine (0.12-0.96 µmol; 0.14-1.14 mg/kg), an α2-adrenoreceptor agonist, did not
produce cutaneous analgesia. However, both scientific and clinical studies have also
provided evidence for the mechanism of action of clonidine as a local anaesthetic
additive, as well as suggesting local anaesthetic-like properties of clonidine itself.19,20
It may be explained that α1-adrenoceptor agonists (e.g. epinephrine and
phenylephrine) at low doses between 3.5 рmol – 1.0 µmol can mainly act by mixed subtypes of α1-adrenoceptor to induce the local anaesthetic activity.21
To rule out the possibility of systemic analgesic effect of drugs (oxybuprocaine,
dextrorphan, and clonidine), one control group was used. subcutaneous injection (the
right calf of the rats) of testing drug We demonstrated subcutaneous injections of a
large dose of drugs into the right calf of the rats did not produce cutaneous analgesia.
In addition, after observing an animal normal reaction to pinpricks applied outside the
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scored the number to which the rat failed to react. These results support our finding
that the cutaneous analgesic effect of clonidine with oxybuprocaine and dextrorphan
were due to their local action on the skin. Our study agrees with those results, which
showed that clonidine (0.01 mg) has significant peripheral action in enhancing local
anaesthesia duration on subcutaneous co-infiltration with lidocaine.10
In this study, duration (AUC) of drugs (oxybuprocaine and dextrorphan) at the
dose of ED95 with clonidine was approximately 4.5- and 3.3-folds greater than drugs
without clonidine, respectively. We also evaluated the local anaesthetic at the dose of
ED50 with/without clonidine. Results demonstrated that clonidine as an adjuvant for
oxybuprocaine and dextrorphan increased the potency of the local anaesthetic effect
on cutaneous analgesia. Adding clonidine rather than increasing doses of drugs may
be an option to increase the cutaneous analgesic effect of drugs. In addition, duration
(AUC) of drugs (oxybuprocaine and dextrorphan) at the dose of ED50 with clonidine
was almost 10.6- and 5.3-folds greater than drugs without clonidine, respectively.
Coadministration of oxybuprocaine with clonidine extended the longer duration on
infiltrative cutaneous analgesia than dextrorphan. Mixtures of local anaesthetics (e.g.
oxybuprocaine or dextrorphan) and clonidine might be practiced on infiltration
anaesthesia of skin incision sites for the surgery and postoperative pain relief, but this
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Cutaneous anaesthesia using local anaesthetics is an acceptable option for
surgical anaesthesia and management of postoperative pain because it is relatively
free of adverse effects.22 Oxybuprocaine and dextrorphan had a local anaesthetic
effect on cutaneous analgesia.1,5 This study demonstrated that oxybuprocaine showed
more potent cutaneous analgesia that dextrorphan. We also displayed that
oxybuprocaine or dextrorphan with clonidine prolonged the duration and enhanced
the potency of cutaneous analgesia. It has been mentioned that clonidine, clinically
added to preparations of local anaesthetics, prolonged the duration of action via three
possible mechanisms. First, clonidine may cause local vasoconstriction, thus
decreasing local anaesthetic spread and removal around nerves.23 Secondly, clonidine blocked C and Aδ fibres as a consequence of an increase in K+
conductance in
isolated neurons, thus intensifying local anaesthetic conduction block.19 Thirdly,
spinal clonidine combined with local anaesthetics or used in peripheral nerve
blockades intensifies and prolongs anaesthesia.23,24
Dextrorphan with epinephrine produced an additive effect on infiltrative
cutaneous analgesia,5 but the cutaneous analgesic effect of adding clonidine to
dextrorphan showed a synergistic effect (Fig. 3). The previous study indicated that
epinephrine mainly acts through mixed subtypes of α1-adrenoceptor to induce
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α2-adrenoceptor might interact and contribute the cutaneous analgesia. The structure of oxybuprocaine is similar to cocaine, the origin structure of most local anaesthetics,
and both of them contain an ester-linkage structure. However, the structure of
dextrorphan is different from that of oxybuprocaine in Figure 1. Coadministration of
oxubuprocaine, a topical anaesthetic, with clonidine produced a synergistic effect on
cutaneous analgesia. This result is in agreement on the benefits of adding clonidine to
dextrorphan and oxybuprocaine for infiltration.
We concluded that oxybuprocaine produced more potent cutaneous analgesia
than dextrorphan. Addition of clonidine to oxybuprocaine or dextrorphan has a
significant peripheral action in intensifying and prolonging the local anaesthetic effect
Acknowledgements
This work was supported by the National Science Council of Taiwan (NSC
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Table 1. The 50% effective doses (ED50s) and ED95s of oxybuprocaine and
dextrorphan on infiltrative cutaneous analgesia.
Drug ED50s ( 95% CI ) ED95s
Oxybuprocaine 0.23 (0.19 – 0.28) 1.29
Dextrorphan 2.47 (2.03 – 3.00) 8.45
ED50s of drugs ( μmol ) were obtained from Figure 2. CI = confidence interval.
Potencies of drugs ( ED50s ) were oxybuprocaine > dextrorphan (P<0.01, for each
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Table 2. The %MPE, duration and AUCs of oxybuprocaine and dextrorphan on infiltrative cutaneous analgesia.
%MPE
Duration (min)
AUCs (%MPEmin) Complete blockade Full Recovery
OX ED50 50 ± 9 0 25 ± 2 713 ± 142 OX ED50 + CL 100 ± 0*** 38.5 ± 6.5*** 104 ± 10*** 7401 ± 561*** DX ED50 50 ± 13 0 37 ± 9 916 ± 361 DX ED50 + CL 93 ± 9*** 2.1 ± 2.7* 97 ± 8*** 4821 ± 590*** OX ED95 92 ± 9 2.9 ± 3.9 50 ± 10 2494 ± 782 OX ED95 + CL 100 ± 0** 70.5 ± 22.5*** 155 ± 25*** 10812 ± 1727*** DX ED95 88 ± 12 0.3 ± 0.5 57 ± 11 2515 ± 551 DX ED95 + CL 100 ± 0** 44.8 ± 13.3*** 127 ± 16*** 8360 ± 1108*** CL 0 0 0 0
Percent of maximum possible effect (%MPE), duration of drug action, area under curves (AUCs) for cutaneoud analgesia (mean SD) for oxybuprocaine or dextrorphan with/without clonidine (n = 8 in all groups). Symbols (*,**,***) indicate P < 0.05, P < 0.01, P < 0.001 when drug alone compared with drug in the presence of clonidine, respectively. OX, oxybuprocaine; DX, dextrorphan; CL, clonidine 0.12 µmol.
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Legends to figures
Figure 1. The chemical structure of oxybuprocaine and dextrorphan.
Figure 2. Time courses (four doses in each group) of oxybuprocaine and dextrorphan
performed on infiltrative cutaneous analgesia in rats. Drugs were tested and results presented as dose-dependent curves, respectively. Values are expressed as mean SD; n = 8 rats for each dose of each drug.
Figure 3. The addition of clonidine (CL) with oxybuprocaine or dextrorphan (ED50 or
ED95) and clonidine alone on infiltrative cutaneous analgesia in rats. Clonidine at the
dose of 0.12 µmol produces no cutaneous analgesia. Values are expressed as mean SD; n = 8 rats for each dose of each drug. ED50 or ED95 means 50% or 95% effective
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Oxybuprocaine
Dextrorphan
O O N CH3 CH3 H2N O CH3 HO NCH3Fig. 1.
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Fig. 2.
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