Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses

Systemic dextromethorphan and dextrorphan are less toxic than bupivacaine at equianesthetic doses in the rat

Yu-Wen Chen

, PhD, Jhi-Joung Wang

, MD, PhD, Tzu-Ying Liu

, MS, Yu-Chung Chen

, MS, Ching-Hsia Hung

*, PhD

1 Department of Physical Therapy, China Medical University, Taichung, Taiwan 2 Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan 3 Institute & Department of Physical Therapy, National Cheng Kung University,

Tainan, Taiwan

4 Division of Physical Therapy, Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan

Y.W. Chen and Y.C. Chen equally contributed to this study.

Funding: The financial support was provided by the Cheng Hsin General Hospital (99-35) and the China Medical University (CMU96-099) of Taiwan.

Conflicts of interest: There is no conflict of interests for all authors.

Short heading (40 characters or less); Dextromethorphan or dextrorphan is less toxic.

Summary: Dextromethorphan and dextrorphan produce cutaneous anesthesia.

Dextromethorphan and dextrorphan were less likely to induce systemic toxicity when

compared to bupivacaine. There is a trend in slower decrease of such parameters

(mean arterial blood pressure, heart rate, cardiac output, and stroke volume) in the

dextromethorphan and dextrorphan groups.

*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

E-mail: chhung@mail.ncku.edu.tw

Abstract

Purpose Dextrorphan, a major metabolite of dextromethorphan, produces the

duration of spinal and cutaneous anesthesia similar to bupivacaine, and the suitability

of dextrorphan for clinical use is worth further investigation. The purpose of this

study was to test the central nervous system and cardiovascular toxicity of

bupivacaine, dextromethorphan, and dextrorphan.

Methods First, equipotent doses were determined for cutaneous analgesia on the rat

back by determination of dose–response curves for dextromethorphan, dextrorphan

and bupivacaine (n = 8 rats at each testing point). Then, during continuous

intravenous infusion of equipotent doses of bupivacaine, dextromethorphan,

dextrorphan and saline (n = 8 rats in each group except saline group, n =7 rats), we

observed the time to seizure, apnea and complete cardiac arrest. Mean arterial blood

pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (CO) were

also monitored.

Results Bupivacaine, dextromethorphan, and dextrorphan produced

dose–dependent cutaneous anesthesia. A longer infusion of equipotent infusion doses

was required to produce seizures in the dextrometorphan group (10.6±1.3 min) than in

the bupivacaine group (7.6±2.1 min) (P = 0.005). Dextrorphan did not produce any

seizures. Time to apnea and complete cardiac arrest was shorter in the bupivacaine

group than in the dextrorphan (P < 0.001 between bupivacaine and dextrorphan) and

dextrometorphan groups (P = 0.001 between bupivacaine and dextrometorphan). The

decline curve in MAP, HR, CO, and SV was slower in the dextromethorphan and

dextrorphan groups compared with the bupivacaine group (P < 0.001 between

bupivacaine and dextromethorphan or dextrorphan).

Conclusions Dextromethrophan and dextrorphan were similar to bupivacaine at

producing durations of cutaneous anesthesia but were less likely than bupivacaine to

induce central nervous system and cardiovascular toxicity.

Key Words: cutaneous anesthesia, systemic toxicity, dextromethorphan, dextrorphan,

bupivacaine

Introduction

Dextromethorphan, an antitussive drug, has been used for more than 50 yr

clinically, and is primarily metabolized by O-demethylation to dextrorphan in human

liver.

Recently, an experiment demonstrated that dextromethorphan and dextrorphan

are sodium channel blockers

that produce dose-related local anesthetic effects on

spinal and sciatic nerves, causing decreased motor function, proprioception and

nociception in rats.

Moreover, dextromethorphan and dextrorphan are potent local

anesthetics with 2.4- and 1.9-folds higher systemic safety indices (50% lethal

doses/50% effective doses) than lidocaine on infiltrative cutaneous anesthesia.

The

local anesthetic durations of dextromethorphan and dextrorphan on cutaneous

anesthesia

and sciatic nerve blockade

are longer than that of lidocaine, but the

spinal blockade caused by dextrorphan was similar in duration to bupivacaine,

a

long-acting local anesthetic. Thus, the suitability of these drugs as clinical local

anesthetics is worth further evaluation.

Despite physical or chemical differences, local anesthetics all have central

nervous system (CNS) toxicity and cardiovascular (CV) toxicity.

Although some

may have less toxicity to the CNS or CV system, however, the differences are minor.

This may be explained by their similar structures.

Before dextromethorphan and

dextrorphan, two potentially novel local anesthetics, are used in clinical practice, the

toxicity of these drugs should be tested. There are no studies evaluating the systemic

toxicity of dextromethorphan and dextrorphan; it is known that bupivacaine carries

significant CV toxicity.

The purpose of the study is to compare the CNS and CV toxicity of

dextromethorphan, dextrorphan and bupivacaine given as intravenous infusions, when

given in equianalgesic doses. A model of infiltrative cutaneous anesthesia was used to

determine the equivalent potencies of the drugs in non-anesthetized, spontaneously

breathing rats.

Materials and methods

Animals

Male Sprague-Dawley rats (260-310 g) were used to test cutaneous anesthesia

and systemic toxicity. They were obtained from the Animal Center of National Cheng

Kung University Medical College (Tainan, Taiwan) and housed in a climate

controlled room maintained at 21 degree C with 50% relative humidity. Lighting was

on a 12-hr light/dark cycle (light on at 6:00 AM), with food and water available ad

libitum up to time of testing. The experimental protocols were approved by the animal

investigation committee of National Cheng Kung University Medical College, Tainan,

Taiwan and conformed to the recommendations and policies of the International

Association for the Study of Pain.

Drugs

Bupivacaine HCl, dextromethorphan hydrobromide monohydrate, dextrorphan

tartrate, and sodium chloride were purchased from Sigma Chemical Co. (St. Louis,

MO). Drugs were dissolved in normal saline (0.9% NaCl).

Experimental protocol

The protocol was divided into two parts. In Part I, the effect of different doses

of bupivacaine (8.0, 6.7, 2.0, 1.25 μmol · kg

), dextromethorphan (20.0, 13.3, 5.3, 2.7

μmol · kg

), dextrorphan (40.0, 26.7, 13.1, 6.7 μmol · kg

), and saline on cutaneous

anesthesia was evaluated ((n = 8 rats for each dose of each drug) to determine the

equivalent potencies of the drugs. In Part II, time to cause toxicity (seizures, apnea

and cardiac arrest), mean arterial blood pressure (MAP), heart rate (HR), stroke

volume (SV), and cardiac output (CO) were evaluated after equipotent doses of the

drugs (bupivacaine, dextromethorphan, and dextrorphan) were infused into the rat ((n

= 8 rats for each dose of each drug). Saline group (n = 7 rats) was used as a control.

Part I - Infiltrative cutaneous anesthesia

Before subcutaneous injections, the hair on the rats' dorsal surface of the

thoracolumbar region (6×10 cm

) was mechanically shaved. Subcutaneous injections

of drugs were performed as reported previously.

In brief, the drugs, dissolved in

0.6 mL normal saline, were injected subcutaneously using a 30-gauge needle in

unanesthetized rats on the dorsal surface of the thoracolumbar region. The back of the

rat was further divided into left and right parts, either of which received one drug

injection with a washout period of 1 wk. After subcutaneous injection, a circular

elevation of the skin, a wheal, approximately 2 cm in diameter occurred. The wheal

was marked with ink within 30 seconds after injection. The cutaneous anesthetic

effects of drugs was evaluated using the cutaneous trunci muscle reflex (CTMR),

characterized by the reflex movement of the skin over the back produced by twitches

of the lateral thoracispinal muscle in response to local dorsal cutaneous stimulation.

15

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). Six pin-pricks (at six different points within each

wheal) with a frequency of 0.5-1 Hz were used in each testing. Each drug's cutaneous

analgesic effect was evaluated quantitatively as the number of times the pinprick

failed to elicit a response by the operator (Dr. Y.W. Chen). The operator did not know

what was injected. For example, the complete absence of six responses was defined as

complete nociceptive block (100% of possible effect; 100% PE). During the test, the

maximum value of %PE was presented as percent of maximum possible effect (%

MPE). Each drug’s duration of action 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).

After subcutaneously injecting the rats with four different doses of

each drug (n = 8 for each dose of each drug), time courses of cutaneous anesthesia

were constructed. We have started with the lowest doses, and then we tested larger

doses until we thought we have just the right dose. Durations of drug effect defined as

the intervals from injection to complete recovery were measured.

Part II - Cardiovascular and neurological effects

On day 1, animals were anesthetized with an intraperitoneal injection of

pentobarbital sodium (50 mg.kg

) and cannulated in the right femoral artery and vein

with polyethylene catheters (PE-50), which were filled with heparinized (30 U.mL

)

normal saline. The catheters with 18-gauge needle were then tunneled subcutaneously

and exited the skin at the midline in the posterior cervical area below the level of the

ears. The catheter was cut with 5 cm protruding from the skin and sealed by heating it

with a match and compressing it with a hemostat.

Then the animal’s trachea was

intubated (PE 200) for artificial ventilation (Small Animal Ventilator Model 683,

Harvard Apparatus, USA) at 50 breaths.min

with tidal volume of 8 mL.kg

and a

positive end expiratory pressure at 5 cmH

O. After cutting into the rat’s chest at the

third intercostal space to expose the heart, a small section (1 cm long) of the

ascending aorta was freed from connective tissue. A Transonic Flowprobe (Transonic

Systems Inc, Ithaca, NY, USA) was implanted around the root of the ascending aorta

and the connecting wire was tunneled subcutaneously and exited the skin at the

midline in the posterior area of the head.

Then, the chest was closed and the

endotracheal tube was extubated after implanting the Transonic Flowprobe. The

temperature of rat was maintained via an electric blanket until the rat was recovery.

On day 2, the animals were placed in a small cage with an open top to allow the

lines to reach the animal from the top and prevent the animal from chewing on the

lines. They were awake. The tube in the femoral artery was connected to a transducer,

and MAP and HR were recorded using a polygraph (MP36, BIOPAC Systems Inc,

Goleta, CA, USA). The tube in the right femoral vein was connected to an infusion

pump (Harvard Model 22 Infusion Pump, Harvard Apparatus Inc., Holliston, MA) for

delivery of the drugs. Another investigator (Y.C. Chen) administered the infusions,

and that the one (Dr. Y.W. Chen) doing the parameter testing was not involved in the

first experiment. Rats were used sequentially. A Transonic Flowprobe was connected

to a Transonic transit-time blood flowmeter (T403, Transonic Systems Inc, Ithaca, NY,

USA) to record the aortic blood flow. The cardiac output (CO) was calculated from

the aortic blood flow, and stroke volume (SV) was expressed as CO divided by

HR.

After infusions were begun of either 1) bupivacaine (n = 8 rats),

dextromethorphan (n = 8 rats), dextrorphan (n = 8 rats) or 2) normal saline (n = 7 rats)

in the volume of 400 μL · kg

· min

(the same volume given to the animals in the

drug group), the onset time of seizure, respiratory arrest, time to cause complete

cardiac arrest, MAP, HR, CO, and SV were evaluated. The onset time of seizure was

defined as the time when the first convulsion occurred.

Respiratory arrest time

was defined as the time point when there was apnea for 15 s by observation of chest

movement. The time to cause complete cardiac arrest was marked by observing a

decrease in HR to 0 bpm.

Statistical analysis

Values are presented as means  SD. The differences in baseline data, %MPE,

full recovery time, AUCs, and the time to cause toxicity between medications were

evaluated using one-way analysis of variance (ANOVA) and then the pairwise

Tukey's honestly significant difference test. Analysis of variance with repeated measures followed by Duncan’s multiple-range test was used for post hoc multiple

comparisons of means on MAP, HR, CO, and SV. SPSS for Windows (version 15.0)

was used for all statistical analyses. Statistical significance was set at P < 0.05.

Results

Infiltrative Cutaneous Anesthesia

The baseline data of body weight, MAP, HR, CO, and SV showed no significant

differences among groups (Table 1). After rats were injected with four different doses

of each drug (n=8 for each dose of each drug) subcutaneously, the local anesthetic

effects of cutaneous anesthesia of these drugs (Fig. 1) were constructed. The saline

group demonstrated no cutaneous anesthesia. The 100% blockades (% MPE), full

recovery time, and AUCs (Table 2) of cutaneous anesthesia between bupivacaine at 8 μmol · kg

, dextromethorphan at 20 μmol · kg

, and dextrorphan at 40 μmol · kg

were not significantly different.

Systemic Toxicity

The time required to cause seizures was longer in the dextromethorphan group

(10.6±1.3 min) than in the bupivacaine (7.6±2.1 min) group (Fig. 2) after the

intravenous administration of equipotent analgesic doses (P = 0.005 for the

difference). All animals in the saline and dextrorphan groups had no seizure response

during the infusion period. After the intravenous infusion of equipotent analgesic

doses, the time required to cause the respiratory arrest and complete cardiac arrest

were longer in the dextromethorphan (12.9±2.6, P = 0.001; 13.1±2.6 min, P = 0.001)

and dextrorphan (13.3±1.0, P < 0.001; 14.0±1.0 min, P < 0.001) groups than in the

bupivacaine (8.8±2.1 and 9.0±2.1 min) group (Fig. 2).

There were no differences in baseline data for body weight, MAP, HR, CO, and

SV between groups (Table 1). There is a trend in slower decrease of such parameters

(MAP, HR, CO, and SV) before CV collapse in the dextromethorphan and

dextrorphan groups (Fig. 3). In this group, the MAP showed a tendency to increase

before CV collapse (Fig. 3). The decline curve in MAP, HR, CO, and SV was slower

in the dextromethorphan (P < 0.001) or dextrorphan (P < 0.001) group compared with

the bupivacaine group (Fig. 3). However, the decline in MAP, HR, CO, and SV was

not different between dextromethorphan and dextrorphan groups (Fig. 3).

Discussion

This study demonstrates that bupivacaine, dextromethorphan, and dextrorphan

produce cutaneous anesthesia. At equipotent doses, dextromethorphan and

dextrorphan do not elicit systemic toxicity as quickly as bupivacaine.

Dextromethorphan and the active metabolic compound, dextrorphan, are Na

channel blockers.

They both produce spinal anesthesia,

sciatic nerve blockade,

and

infiltrative cutaneous anesthesia

in rats. We found that dextromethorphan and

dextrorphan as local anesthetics are more potent than lidocaine,

and the spinal

blockades caused by dextrorphan were similar to bupivacaine.

These findings

suggest that there may be a great potential for the use of dextromethorphan and

dextrorphan as local anesthetics in the clinical setting, provided that the CNS and CV

toxicity is investigated.

Though local anesthetics for cutaneous anesthesia is an acceptable option for

management of surgical anesthesia or postoperative pain,

accidental intravascular

injection of local anesthetics carries the risk of CNS and CV toxicity.

Using one

animal model of local anesthesia, we performed the local anesthetic effects of

infiltrative cutaneous analgesia of dextromethorphan, dextrorphan, and bupivacaine to

determine the equipotent analgesic doses of these drugs. We have started with the

lowest doses, and then we tested larger doses until we thought we have just the right

dose. Because dextromethorphan at 20 μmol · kg

, dextrorphan at 40 μmol · kg

, and bupivacaine at 8 μmol · kg

produced similar blockade of cutaneous anesthesia (Table

2), we chose these doses as the equipotent analgesic dose of each drug. In this case,

we were satisfied that for the largest doses given, the areas under the curve (AUC)

were essentially the same. The limitations of such a technique are that these doses

gave 100% maximal response, and errors can be generated if 100% responses are

considered when trying to determine equipotent analgesic doses.

At equipotent analgesic doses, we showed that infusion of dextromethorphan or

dextrorphan produced a delayed onset of CNS and CV toxicity when compared with

bupivacaine. Of note, we observed that dextrorphan produced no seizures. In both the

dextromethorphan and bupivacaine groups, seizures were observed before respiratory

and cardiac arrest. Although we did not know why dextrorphan produced no seizures,

this was worth investigating in the future. These results may indicate that

dextromethorphan and dextrorphan may feature a safer systemic toxicity profile than

bupivacaine. However, the differences in CNS and CV toxicity between

dextrometrophan, dextrorphan and bupivacaine are not very large. Differences of

25-30% in the time required to produce CNS or CV toxicity were found between

drugs, and this depends entirely on the exact determination of equipotent analgesic

doses, which might be off considering the way we did it. In addition, there might be

species differences.

Many neural blockade techniques have been associated with CNS and CV

toxicity caused by systemically absorbed local anesthetic.

The incidence of

systemic toxicity from local anesthetics appears to be decreasing with the use of safer

local anesthetics

and widespread introduction of procedural safety.

Since

dextromethorphan and dextrorphan are better tolerated systemically than bupivacaine

in this animal model, they may have an opportunity to be used as local anesthetics

clinically. However, this study is a cumulative dose design. That is, we administer an

infusion and determine the time taken to observe the side effect in question. The

underlying assumption here is that redistribution and metabolism of the drug may be

negligible during the infusion period. Nevertheless, local anesthetics are not supposed

to have the bioavailability when given subcutaneous as compared to intravenous. And

the resorption from the subcutaneous tissues is not supposed to be 100% as supposed

by the methodology presented in this manuscript. It would have been more clinically

relevant to apply a ratio between the subcutaneous dose and the intravenous dose

given as an infusion, and it was worth studying in the future.

In the recent study, we demonstrated that intravenous bupivacaine caused CV

and CNS toxicity in rats, and the toxicity of bupivacaine has been demonstrated a

long time ago

. Ropivacaine, which has less CV toxicity than bupivacaine,

was later introduced into clinical practice.

However, ropivacaine is at least 40%

less potent than bupivacaine.

We did not compare the toxicity of dextromethorphan

and dextrorphan with that of ropivacaine, and these proposals certainly await future

investigation.

This is the first investigation to determine the toxic profile of dextromethorphan

and dextrorphan, using selected surrogate parameters. During the infusion period,

MAP, HR, and CO decreased, and therefore the values of SV decreased in

bupivacaine, dextromethorphan, and dextrorphan groups. Previous studies also

demonstrated that bupivacaine administered as rapid infusions declined the value of

MAP and HR in rats.

We also found that MAP increased in bupivacaine group

before death. This could be because of hypercarbia and hypoxia caused by respiratory

depression secondary to CNS toxicity.

The decline curve in MAP, HR, CO and SV

of dextromethorphan or dextrorphan was slower than that of bupivacaine on

equipotent doses. This demonstrated that dextromethorphan and dextrorphan were

better tolerated than bupivacaine. We chose the animal model with the spontaneously

breathing rats, a clinical scenario when local anesthesia is performed on humans.

In this study, we did not evaluate whether dextormethorphan or dextrorphan had

direct nerve toxicity; however, it is noteworthy that in our previous neurobehavioral

studies we detected no apparent side effects or behavioral abnormalities after

subcutaneous,

sciatic notch,

or intrathecal

drug injection. Whether local tissue

injury to nerves occurs after dextromethorphan or dextrorphan injection is an

important issue that needs further investigation.

In conclusion, intravenous equipotent analgesic doses of dextromethorphan or

dextrorphan are better tolerated to produce central nervous system and cardiovascular

system toxicity than bupivacaine.

Acknowledgements

The authors gratefully acknowledge the financial support provided for this study

by the Cheng Hsin General Hospital (99-35) and the China Medical University

(CMU96-099) of Taiwan.

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Table 1. Baseline data of systemic toxicity measurement

Parameters\Drug Control (n=7) Bupivacaine (n=8) Dextromethorphan (n=8) Dextrorphan (n=8)

Body weight (g) 266±17 265±10 269±19 272±21

MAP (mmHg) 107±9 101±15 101±12 103±16

HR (bpm) 482±39 468±36 484±27 456±20

CO (mL•min-1) 64±6 58±8 58±14 58±13

SV (mL•beat-1) 0.14±0.01 0.14±0.02 0.13±0.02 0.14±0.02

There were not significantly different among the groups for baseline data. MAP = mean arterial blood pressure; HR =

heart rate; CO = cardiac output; SV = stroke volume. Data are presented as means ± SD.

Table 2. The %MPE, full recovery time, and AUCs of bupivacaine at 8 μmol · kg

, dextromethorphan at 20 μmol · kg

, and dextrorphan at 40 μmol · kg

%MPE Full Recovery Time (min) AUCs (%min)

Bupivacaine 100 ± 0 101 ± 19 6970 ± 1555

Dextromethorphan 100 ± 0 123 ± 25 6559 ± 1462

Dextrorphan 100 ± 0 114 ± 32 6550 ± 1883

Percent of maximum possible effect (%MPE), duration of drug action, area under curves (AUCs) (means  SD) for

bupivacaine (n = 8 rats), dextromethorphan (n = 8 rats), and dextrorphan (n = 8 rats). The %MPE, full recovery time,

and AUCs between drugs were not significantly different.

Legends to figures

Fig. 1. Time courses of bupivacaine, dextromethorphan, and dextrorphan on

cutaneous anesthesia in rats (n = 8 at each testing point). Saline group produced no cutaneous anesthesia. Values are expressed as means  SD.

Fig. 2. Time to cause toxicity of bupivacaine at 8 μmol · kg

, dextromethorphan at 20 μmol · kg

, and dextrorphan at 40 μmol · kg

at the onset of seizure, respiratory arrest,

and time to cause complete cardiac arrest. In the saline group (n=7), we did not detect

(ND) toxicity symptoms, and no seizures were noted in the dextrorphan group.

Symbols (

,

) indicate P = 0.005 or P = 0.001 for dextromethorphan compared with

bupivacaine, respectively. Symbols (

) indicate P < 0.001 for dextrorphan compared

with bupivacaine. There was not significantly different between dextromethorphan

and dextrorphan. Data are presented as means ± SD.

Fig. 3. Mean arterial blood pressure (MAP), heart rate (HR), cardiac output (CO), and

stroke volume (SV) change during infusion of either 1) bupivacaine (n = 8) at 8 μmol · kg

· min

, dextromethorphan (n = 8) at 20 μmol · kg

· min

or dextrorphan

(n = 8) at 40 μmol · kg

· min

or 2) normal saline (n = 7) in the volume of 400 μL ·

kg

· min

(the same volume given to the animals in the drug group) as infusion; 0

min is the start of infusion. Infusion was stopped when the test animals went into

cardiac arrest. Symbols (

,

) indicate P < 0.001 for dextromethorphan or dextrorphan

compared with bupivacaine, respectively. There was no significantly different

between dextromethorphan and dextrorphan. Data are presented as means ± SD.