Ropivacaine: The new local anesthetic

Seminars in ANESTHESIA Vol 15, No 1

March 1996

Ropivacaine: The N e w Local Anesthetic George S. Leisure and Cosmo A. DiFazio

EGIONAL anesthesia involves the use of a local anesthetic strategically placed along the neural access to produce surgical anesthesia, postoperative analgesia, or analgesia for acute and chronic pain management. In the last half of the twentieth century, new amide-based local anesthetic drugs with a reasonable onset time and with intermediate or long duration of action have been prepared. At present, bupivacaine is the most widely used long-acting local anesthetic drug. However, while it has multiple desirable characteristics, there have been some problems associated with its toxicity when large doses are administered intravenously. For example, concern about cardiac toxicity for long-acting local anesthetics such as bupivacaine developed after numerous reports of cardiac arrest that were followed by difficult and often unsuccessful resuscitation subsequent to the unintended intravascular injection of a large amount of drug or caused by the premature release of a tourniquet after intravenous regional anesthesia with bupivacaine. 1'2 Pregnant patients seem to have a greater risk of cardiotoxicity when this inadvertent large dose ofbupivacaine is administered, as indicated by the high frequency of bupivacaine cardiotoxicity in this group. Animal studies also indicated that cardiac toxicity of drugs such as bupivacaine is accentuated with pregnancy.3'4 When the newer amide local anesthetic drugs have been prepared, some of these drugs may have chiral forms ie, enantiomers caused by stereoisomerism, and these isomers can be associated with different duration of action and toxicity profiles. Such stereoisomerism occurs when an asymmetric carbon is present in the molecule,

R

Seminars in Anesthesia, Vo115, No 1 (March), 1996: pp 1-9

namely when a carbon atom is present with four different substituent groups. Enantiomers are currently indicated as S and R isomers instead of the old notation of L and D, and the optical rotation is designated (+) or (-). When present in the local anesthetic chemical structure, the asymmetric carbon atom is illustrated (Fig l). This article reviews the specific isomer drug ropivacaine, a long-acting local anesthetic, and primarily emphasizes comparisons with the commonly used, long-acting local anesthetic agent bupivacaine. Although these two drugs are structurally very similar, ropivacaine differs chemically from bupivacaine in the alkyl group substituted on the piperidine nitrogen (Fig l) and in being a pure enantiomer, namely the S ( - ) isomer. Conversely, bupivacaine is an equal mixture of the S ( - ) and R (+) isomers and thus is a racemic mixture. The complete chemical name of ropivacaine is S (-)-l-propyl-2',6'-pipecoloxylidide. The enantiomerically pure ropivacaine has many of the desirable local anesthetic effects seen with bupivacaine and has been found to be superior to bupivacaine in safety. The safety difference between these two drugs is well demonstrated in cardiotoxicity studies in animals and is particularly accentuated in pregnant animals and in in vitro studies in cardiac tissue from From the Department of Anesthesiology, Universityof Virginia Health Sciences Center, Charlottesville, VA. Address reprint requests to George S. Leisure, MD, Department of Anesthesiology, University of Virginia Health Sciences Center, Box 238, Charlottesville, VA 22908. Copyright 9 1996 by W.B. Saunders Company 0277-0326/96/1501-000455.00/0

1

LEISURE AND DIFAZIO

2 A - Esters

B - Amides

Group 1 0 H N ]7-''~ II /CzHs 2 ~ ' ~ . ~ - - C-- O-- CH=-- CHz-- NN

Group 2 CH3 0 N ~

-- C -- CHz --N\

C2Hs

CtH5

CH3

Procaine

Lidocoine

Mepivacaine CH3 0 C4He N--~ *N

CH3 0 CzH~

CI

CH3

2- Chloroprocoine

H9C4\ / N " ~ H

\czH 5

Tetracaine

Bupivacaine

Prilocaine

0i C--O--CHz - - CH,-- N/c~H5

ClH3 *N

c.3 o ~CH

3

CzH5

Etidocoine

pregnant animals. As a local anesthetic, several of the areas of superiority for ropivacaine compared with bupivacaine have been identified, including a lower potential to produce motor blockade, a dose response superiority for duration of infiltration anesthesia, and a higher dose requirement to produce toxicity such as seizures or cardiotoxicity. LOCAL ANESTHETIC AND TOXIC EFFECTS OF THE ROPIVACAINE ISOMERS

Historically, when the enantiomers of local anesthetics have been assessed and differences between the R and S forms are present, the S form has consistently been observed to be either more potent or less toxic than its R form (Table 1). For ropivacaine, both the S ( - ) and R (+) forms as well as the racemic mixture have local anesthetic activity which is produced at the sodium channel, the site of action for other local anesthetic drugs. Subsequent activity and toxicity investigations document the superiority of the S ( - ) isomer ropivacaine over the R (+) form. For example, in producing peripheral nerve blocks in guinea pigs, onset time of sciatic nerve blockade was similar for the isomers and decreased with increasing concentration for the isomers. However, the duration of anesthesia differed significantly for t~ae isomers. At concentrations of 0.5% and 0.75% the S ( - ) ropivacaine gives motor and sensory sciatic nerve blockade that was 30% to 50% longer than that produced by its R (+) isomer. With 1% solution, the differences between

C3H7

CsH,

N__~N~

('N'~CHa ')-- N--CO"--BDO"~"~" N\/CzH,

CH3 R0pivacaine

Fig 1. Chemical structure of local anesthetics. The asymmetric carbon atom when present in structure is highlighted.

the isomers for sensory blockade was no longer statistically significant, although ropivacaine was still longer acting. In the case of infiltration anesthesia, a profound difference in the duration of action between the isomers was observed. Ropivacaine at 0.25% and 0.5% in guinea pigs had a duration of anesthesia that was 4 to 8 times longer than its R (+) isomer. When toxicity was assessed, no difference in acute toxicity was seen, ie, the intravenously administered lethal doses for the two isomers were similar. However, when the drugs were administered subcutaneously, as in infiltration anesthesia, a major difference between the doses needed to produced toxicity was present. The dose needed for toxicity for ropivacaine was approximately 50% greater than that for the R (+) isomer. When the intravenous toxicity of the two isomers were compared with that of bupivacaine, both isomers were found to be 40% to 50% less toxic than bupivacaine and the ropivacaine dose required to produce toxicity after

Table 1.

Anesthetic Duration and Toxicity of Local Anesthetic Isomers

Drug Etidocaine Mepivacaine Bupivacaine Ropivacaine

Duration S= S> S> S>

R R R R

Toxicity S S S S

= = < <

R R R R

ROPIVACAINE" THE NEW LOCAL ANESTHETIC

administration by infiltration was more than two times that needed for bupivacaine toxicity. In other animals studies, spinal anesthesia was evaluated in mice and onset time decreased and duration of anesthesia increased with the use of increasing concentrations of drug from 0.25% to 1%. Ropivacaine and the R (+) isomer both have a short and similar duration of spinal anesthesia in this concentration range. In summary, these studies strongly support the safety of ropivacaine, the pure S ( - ) isomer, and are consistent with the observations made with other local anesthetics that, when differences are present, the S (-) form is less toxic and/or has a longer duration of action than the R (+) form. PRECLINICAL ASSESSMENT OF ROPIVACAINE

The in vitro testing of ropivacaine conduction anesthesia shows an excellent motor sensory profile for ropivacaine. These findings have been reported in three separate studies. In a frog sciatic nerve study, it was found that ropivacaine and bupivacaine were equipotent in the concentration range evaluated (l to 100 ~tM). However, in isolated vagus and phrenic nerve preparations with separation of A-beta, A-delta, and C fibers, 5 ropivacaine was found to produce a profound and rapid block of both A-delta and C fibers, and appeared to be twice as potent as bupivacaine in blocking these fibers. At high concentrations, ropivacaine and bupivacaine had similar activity in blocking C fibers while ropivacaine produced a more profound block of A-delta fibers. Because A-delta and C fibers are active in pain transmission, the sensitivity of these fibers to ropivacaine indicate that this drug should be an improvement over bupivacaine in blocking pain impulses. The depressant effects on motor fibers was significantly less (approximately 16%) with ropivacaine than with similar concentrations of bupivacaine in a third study.6 In this study, no apparent differences in the blockade of sensory C fibers was seen. These in vitro studies indicate that ropivacaine is comparable to or slightly more potent than bupivacaine in blocking sensory fibers and is less active in blocking motor fibers. With bupivacaine recognized as having the best motor sensory separation of the currently available local anesthetics, these studies indicate that ropivacaine is at least comparable to and probably su-

3

perior to bupivacaine in the separation of these effects. Ropivacaine also has been used in multiple preclinical studies evaluating a variety of block techniques. In peripheral nerve blocks, including brachial plexus blockade, most of these studies show that the concentration of ropivacaine of 0.5% to 1% produces effective sensory and motor anesthesia. Neither an increase in the concentration of ropivacaine above 0.75% nor adding epinephrine significantly improved the duration of motor or sensory anesthesia in these peripheral blocks. When central neural blockade such as epidural anesthesia was evaluated, the epidural administration of 0.75% ropivacaine and bupivacaine produced similar onset times for sensory and motor anesthesia and a similar duration of sensory blockade. Duration of motor anesthesia tended to be shorter with ropivacaine, but differences were not statistically significant (Fig 2). The arterial blood concentrations seen in dog epidural studies were related to the total dose administered. In summarizing the multiple species evaluated, it seems that the onset times of epidural anesthesia with ropivacaine and bupivacaine are similar. The concentration required to produce complete motor blockade with epidural anesthesia for ropivacaine appeared to be 0.75% to 1% and 0.75% for bupivacaine, respectively. Duration of sensory anesthesia with epidural administration seemed to be comparable for equal concentrations of ropivacaine and bupivacaine. When infiltration anesthesia has been evaluated in a variety of animals, ropivacaine was markedly superior to bupivacaine in producing sustained cutaneous anesthesia at all concentrations. The duration of sensory anesthesia produced with the least effective ropivacaine concentration (0.25%) far exceeded that produced by the highest bupivacaine concentration (0.75%) (Fig 3). In addition, the duration of blockade increased as the concentration of ropivacaine was increased, and the addition of epinephrine further increased the duration of infiltration anesthesia produced by ropivacaine. In Fig 3, it is apparent that when similar concentrations of ropivacaine and bupivacaine are used, ropivacaine produced anesthesia that was 2 to 3 times longer than with bupivacaine.

4

LEISURE AND DIFAZIO 10'I"

,L

8"

3 ~^ 9 EPINEPHRINE SOLUTION Q PLAIN SOLUTION f-I X + S.E.M., N = 6

7"

N=5

_z ~ tu

6"

Z5.

ROPIVACAINE BUPIVACAINEROPIVACAINEBUPIVACAINE 1.00% 0.75% ! .00% 0.75*/.

BUPIVACAINEROPlVACAINEROPIVACAINE BUPIVACAINE 0.75% 1.00% 1.00% 0.75%

CONCENTRATION

CONCENTRATION

IN VIVO CENTRAL NERVOUS SYSTEM EFFECTS The doses required for ropivacaine and bupivacaine to produce seizures has been established using intravenous infusion techniques.7'8 In sheep studies, where both pregnant and nonpregnant animals have been evaluated, it is apparent that ropivacaine is less toxic than bupivacaine in producing seizures (Table 2). The dose required to produce seizures in nonpregnant animals for ropivacaine is approximately 11/2 to 2 times that needed for bupivacaine and in pregnant sheep the ropivacaine dose is approximately 1I/2 to 3

INFILTRATION ANESTHESIA 300-j 240- I "1-

"~ = o =

0.25%

0.55%

0.75%

Fig 3. The duration of complete sensory block with infiltration of ropivacaine or bupivacaine in the concentrations shown. Ropivacaine is shown in solid bars while bupivacaine is in hatched bars.

Fig 2. Onset and duration of motor block after 1% ropivacaine and 0 . 7 5 % bupivacaine both with and without epinephrine.

times the dose of bupivacaine (Table 3). Extrapolating the data to humans suggests that ropivacaine is potentially a much safer drug in the care of obstetric patients. When drugs used to protect or abort seizures produced by local anesthetics were evaluated in animals, both diazepam and midazolam administration in large doses resulted in the complete abolition of seizures produced by ropivacaine. Protection against seizures by these drugs at high doses occurred even when the dose ofropivacaine administered was 3 times the seizure threshold dose. When small doses of diazepam were administered, the duration of seizures was reduced but seizures were not eliminated. When thiopental was used, the duration of seizures after a ropivacaine seizure dose decreased by more than 40%. Similar findings were observed when midazolam or diazepam was used to treat seizures caused by bupivacaine. In summary, when ropivacaine and bupivacaine were administered to either pregnant or nonpregnant sheep, ropivacaine was consistently less toxic and the dose required to produce seizures is greater than that needed for bupivacaine. Moreover, it seems that both diazepam and midazolam are able at the upper dosage range, to provide complete protection from ropivacaine seizures and lethality resulting from seizures whereas at small doses of the protective drug, the duration of seizures can be markedly shortened.

ROPIVACAINE: THE NEW LOCAL ANESTHETIC Table 2.

5

Effect of Pregnancy on Sheep Seizure (CN5) and Cardiac Arrest (CV) Doses CNS

CV

Nonpregnant

Pregnant

Nonpregnant

Pregnant

6.1

5.9

11.3

12.4

6.1

7.5

11.6

12.9

2.7 4.6

1.9 5.0

8.9 8.9

5.1 8.5

Ropivacaine Bupivacaine

NOTE. Doses in mg/kg. Abbreviations: CNS, central nervous system; CV, cardiovascular.

CARDIOTOXICITY Cardiotoxicity during regional anesthesia seldom occurs secondary to the absorption of the local anesthetic drug because the dose of drug used for anesthesia should produce blood levels that are no more than one half to two thirds those which produce central nervous system excitation. Furthermore, because the blood level of drug which produces seizures is generally considerably lower than that which produces cardiotoxicity, absorption should be an unlikely causative factor in cardiotoxicity. On the other hand, the cardiotoxic effects can occur when large doses of local anesthetic drugs are inadvertently administered intravenously. At least 69 cases of cardiac arrest have occurred secondary to inadvertent intravenous bupivacaine administration. Albright and Marx ''2 pointed out that when drugs such as bupivacaine produced cardiac arrest, patients were difficult to resuscitate, the resuscitation was frequently prolonged, and in many cases was unsuccessful. In contrast, a cardiac arrest produced by other local anesthetics such as lidocaine or mepivacaine was responsive to resuscitation. When the cardiotoxic effects of ropivacaine and

Table 3.

bupivacaine overdoses were assessed, ropivacaine was noted to be a safer drug than the widely used bupivacaine. The following specific areas for improved cardiac safety for ropivacaine over bupivacaine in animals and in vitro studies have been identified: 1. Ropivacaine is much less likely to produce dangerous arrhythmias such as ventricular tachycardia and ventricular fibrillation than bupivacaine as drug levels increase. 7 2. Resuscitation of the heart after deliberate overdoses of ropivacaine that result in a cardiac arrest can be achieved with drugs and electrical pacing. In contrast, when bupivacaine causes a cardiac arrest, the heart is more difficult to resuscitate and electrical pacing is not always successful. 9

3. The cardiotoxic risks with ropivacaine are not increased in pregnant animals in contrast to the cardiotoxicity of bupivacaine, which may be increased with pregnancy, m.,,

Physiochemical Properties of Local Anesthetics

Agent

Molecular Weight (Base)

pKa (25~

Partition Coefficient*

Percent Protein Binding t

Lidocaine Mepivacaine Bupivacaine Etidocaine Ropivacaine

234 246 288 276 274

7.9 7.6 8. I 7.7 8.0

2.9 0.8 27.5 141.0 6.1

64.3 77.5 95.6 94 94

* Partition coefficient determined for n-heptane/pH 7.4 buffer. t Amide protein binding determined at plasma concentration of 2/zg/mL.

6

The relative cardiotoxic effects of ropivacaine and bupivacaine were assessed in rat and rabbit Langendorff beating heart preparations. 9 Two major points are evident from these studies. (1) When relatively high concentrations of ropivacaine and bupivacaine were used (11 to 13 ~tg/ mL) the following changes were noted for ropivacaine and bupivacaine: heartrate decreased 35% and 43% respectively while the QRS duration (believed to be a prodromal change for ventricular arrhythmias) increased 13% and 69% respectively. (2) In the rabbit heart Langendorff study, a major difference was apparent in the ability to pace the heart in the presence of increased concentrations of these local anesthetics. When ropivacaine was present in a 1 or 6 #g/mL concentration, all hearts could be paced atrially. When the ropivacaine concentration was increased to 13/~g/mL, three of the five hearts failed to be paced atrially but all could be paced ventricularly. In contrast, when bupivacaine was used, all hearts could be paced at a concentration of 1 #g/mL, however, when the concentration was increased to 6 ~tg/mL, three of the six failed atrial pacing and one of the three hearts that failed atrial pacing also could not be paced using a ventricular pacing stimulus. At the highest concentration ofbupivacaine (13/zg/mL) all hearts failed atrial pacing and five of the six also failed ventricular pacing. These Langendorff heart studies clearly indicate that ropivacaine has less cardiotoxic potential than bupivacaine and overdoses should be less difficult to resuscitate than bupivacaine. In order to ascertain safety and clinical usefulness of ropivacaine, the drug was administered intravenously in volunteers and evaluated in a number of clinical studies. When ropivacaine or bupivacaine was administered by slow intravenous infusion to volunteers, 12ropivacaine was observed to be better tolerated in doses up to 150 mg. On average, the doses associated with the onset of symptoms of early central nervous system effects of local anesthetics, such as circumoral numbness and ringing in the ears occurred with ropivacaine doses were approximately 1.3 times greater than with bupivacaine. In a subsequent study, with intravenous doses of up to 250 mg of ropivacaine or bupivacaine, ropivacaine was also noted to have less arrhythmogenic potential and produced

LEISURE AND D)FAZIO

much less QRS prolongation than a comparable dose of bupivacaine. Both studies speak to a greater safety margin with ropivacaine. A short overview of some of the clinical studies documenting the pharmacology and clinical usefulness ofropivacaine are summarized in the following.

Pharmacokinetics of Ropivacaine Ropivacaine is essentially completely absorbed from all neural sites of injection and is rapidly distributed to organs with high perfusion such as the heart, brain, lung, and liver. Plasma protein binding in man of 90% to 95% has been observed with ropivacaine. It has a similar pKa to that of bupivacaine, but the lipid solubility of ropivacaine is approximately half that of bupivacaine. Ropivacaine has a large volume of distribution which is similar to that ofbupivacaine. However, the clearance of ropivacaine is 30% greater than the clearance of bupivacaine, thus reducing the potential for accumulation and toxicity with continuous administration, la The comparative local anesthetic pharmacokinetic parameters are summarized in Table 3. The principal metabolite of ropivacaine is 3hydroxy-ropivacaine which is produced in the liver by oxidative metabolism. 14 (Fig 4) This metabolite is conjugated and excreted in both urine and bile. In in vitro studies using liver micro-

ROPIVACAINE METABOLISM

--CO" Clh

/

/ ,"o

in vitro

NH.CO~

CH3

PPX

HI

Ropivacaine

I

C~I.I7

\ in vivo

\

~

CH3

o

NH.CO~.

I r H~ 3 Hydroxy Ropivacaine

Fig 4. The in vitro and in vivo metabolism of ropivacaine.

ROPIVACAINE: THE NEW LOCAL ANESTHETIC

somes obtained from animal species and man, the PPX metabolite, which is formed by the dealkylation ofropivacaine, is the principal metabolite. (Fig 4)

Epidural Analgesia in Labor A number of clinical studies have documented the effectiveness ofropivacaine epidural analgesia for labor pain. In over 90% of patients, ropivacaine 0.25% provided good or excellent pain relief, a result similar to the effect seen with bupivacaine 0.25%. Analgesia with ropivacaine develops 11 to 18 minutes after initial injection and is equally effective in primigravida and multigravida patients. In addition, the time to delivery and mode of delivery were the same in both drug treatment groups. In general, ropivacaine was less likely to produce motor blockade than bupivacaine and ropivacaine was associated with a lower incidence of instrumental deliveries.IS

Postoperative Epidural Analgesia Multicenter clinical studies using continuous postoperative epidural infusions have been carried out. The patients involved had upper abdominal, lower abdominal, or orthopedic procedures. A constant epidural infusion rate of l0 mL/hr was used and patients received zero, (normal saline), 1, 2, or 3 mg/mL (0.1%, 0.2%, or 0.3%) ropivacaine. In two studies, ropivacaine 2 mg/mL (0.2%) was infused at 6, 8, 10, 12, or 14 mL/hr and supplemental morphine patient-controlled analgesia (PCA) was used to achieve postoperative pain relief. In all studies, the spread of both sensory and motor block was dependent on concentration and dose of ropivacaine administered. The greater the dose of drug, the larger the number of dermatomes blocked and the greater the duration of block. In the constant volume (10 mL/hr) studies, ropivacaine produced doserelated pain relief that was superior to PCA morphine alone. However, a concentration of ropivacaine 2 mg/mL (0.2%) was required to provide effective pain relief during coughing. In the varied infusion rate studies, patients receiving 0.2% ropivacaine used approximately two thirds less PCA morphine than controls. The higher concentration of ropivacaine was minimally different than the 0.2% ropivacaine. The great majority of patients receiving either 0.2% or 0.3% ropivacaine rated the effects on postoperative analgesia as

7

good or excellent. In conclusion, ropivacaine 2 mg/mL (0.2%) infused between 6 and 10 mL/hr and administered in combination with small doses of PCA morphine, provides good postoperative analgesia with minimal motor blockade of the lower extremities. ,6

Epidural Anesthesiafor Surgery Ropivacaine has been evaluated for epidural anesthesia in orthopedic, urologic, and obstetric (Cesarean section) surgery by Wildsmith ~7where 0.5%, 0.75%, and 1.0% ropivacaine was compared with bupivacaine. Duration of sensory block for ropivacaine was observed to be dose (concentration and volume) related and compared with bupivacaine, the onset of sensory block was similar with all concentrations of both drugs. However, duration of sensory block with ropivacaine in general was slightly shorter than equivalent concentrations of bupivacaine. The rate of onset, frequency, and duration of motor block were also dose and concentration related. Summarizing these findings, ropivacaine produces motor blockade that is less intense, has a somewhat longer onset time, and has a shorter duration of action than the same concentration of bupivacaine. 18 (Table 4) Both ropivacaine and bupivacaine produced satisfactory conditions for surgery in a high proportion of patients receiving a 20 mL epidural injection. The 5 mg/mL (0.5%) concentration of both drugs was less effective than higher concentrations for orthopedic surgery. Larger volumes and higher concentrations of ropivacaine up to 1% clearly have been shown in dose/response studies to produce more intense sensory and motor blockade for hip surgery. 19

Brachial Plexus Anesthesia Double-blind control studies of brachial plexus block have been performed using both subclavian and axillary approaches with equal concentrations of 0.25% and 0.5% ropivacaine and bupivacaine. Ropivacaine 0.5% administered by the subclavian route provided adequate sensory block for surgery in 92% and muscle relaxation in 100% of patients. However, sensory and motor block were adequate in only 64% of patients if the 0.25% concentration ofropivacaine was used. In the axillary approach, the use of 0.5% also seems to be needed to provide more intense sensory and mo-

LEISURE A N D

Table 4.

DIFAZIO

Sensory and Motor Anesthesia With Ropivacaine and Bupivacaine Ropivocaine

Group Sensory Block Level 1 No. Onset(min) Duration (min) T6 No. Onset (rain) Duration (min) M o t o r Block Level 1 No. Onset (min) Duration (min) Level 2 No. Onset (min) Duration (min)

Bupivacaine

0.5%

0.75%

1.0%

0.5%

0.75%

22 8 (4) 210 (53)

22 8 (9) 272 (96)

22 6 (3) 322 (84)

22 6 (5) 266 (100)

22 6 (5) 324 (83)

11 20(10) 161 (50)

12 12 (5) 192 (92)

13 23(15) 153 (61)

13 12 129

(7) (55)

15 18(13) 179 (89)

10 20 (19) 148 (62)

6 26 (25) 190 (85)

3 14 (7) 240 (97)

6 !6 194

(9) (56)

3 12 (5) 263 (80)

5 39 (16) 120 (50)

6 44 (28) 140 (82)

6 39 (44) 189 (74)

9 26 156

(15) (59)

6 21 (9) 217 (69)

NOTE. Numbers of patients (n 22) achieving sensory block and mean (standard deviation) onset and duration times at T6. Numbers of patients achieving level 1 motor block and mean (standard deviation) onset and duration times. Lower limb motor block was recorded using a modified Bromage scale (1 = inability to raise leg, able to flex knees; 2 = inability to flex knees, able to flex ankles). 4 =

tor block. This concentration is faster in onset and has a longer duration of action than the 0.25% ropivacaine solution. There were no consistent differences seen between bupivacaine 0.5% and ropivacaine 0.5% for brachial plexus blocks. The addition of epinephrine to solutions of ropivacaine does not seem to alter the onset or duration of sensory or motor block with brachial plexus anesthesia.19

Subarachnoid The use of 3 m L of ropivacaine 0.5% or 0.75% in the subarachnoid space has been evaluated in order to assess the safety of ropivacaine that might be inadvertently administered into the subarachnoid space. Duration of sensory and motor block was greater with use of the higher (22.5 mg) ropivacaine dose, but the onset and extent of block were similar with the 15 mg and 22.5 mg doses. Satisfactory sensory and motor block for surgery was achieved in 85% and 95% respectively of patients receiving 0.75% ropivacaine and 60% and 84% respectively with ropivacaine 0.5%.

Safety Profile An improved safety profile compared with bupivacaine has been shown with ropivacaine in multiple animal species as well as in humans. In animals, doses needed to produce seizures and cardiotoxicity are consistently up to 1.5 to 2 times greater than the doses ofbupivacaine required to produce these same effects. Ropivacaine has also been shown with increasing drug doses to produce a lower incidence ofventricular tachycardia than bupivacaine. In cases of deliberately induced cardiotoxicity, ropivacaine is associated with better reversibility by drugs and/or by electrical atrial or ventricular pacing. Finally, the cardiotoxic risks of ropivacaine are not increased by pregnancy. The analysis of adverse events associated with ropivacaine in human studies supports its safety. Pruritus, headache, abnormal hearing, nausea, vomiting, hypotension, anemia, dysuria, fever, back pain, chills, dizziness, skin rashes, and bradycardia all have been reported. However, the profile of events was similar for ropivacaine and bupivacaine. There was a statistically significant

ROPIVACAINE: THE NEW LOCAL ANESTHETIC greater i n c i d e n c e o f b r a d y c a r d i a after b o t h test a n d m a i n doses o f b u p i v a c a i n e c o m p a r e d with ropivacaine. H y p o t e n s i o n was a relatively c o m m o n adverse event, o c c u r r i n g in a b o u t 37% o f cases with r o p i v a c a i n e with the m a j o r i t y occurring after epidural anesthesia. This is a recognized effect o f e p i d u r a l anesthesia, a n d was p r o d u c e d as frequently with b u p i v a c a i n e . R o p i v a c a i n e seems to be safe for l a b o r epidural analgesia as well as for C e s a r e a n section anesthesia. M o s t adverse events t h a t were seen such as p o o r progression o f labor, fetal b r a d y c a r d i a , a n d fetal distress were c o n s i d e r e d to be related to obstetric factors. There was a n equal frequency o f adverse events with b o t h r o p i v a c a i n e a n d b u pivacaine. N e o n a t a l fever was seen m o r e often after higher doses o f ropivacaine. T h e relevance o f this finding is unclear. T h e r e were n o differences in A p g a r o r N e u r o l o g i c a n d A d a p t i v e Capacity Scores between infants whose m o t h e r s received r o p i v a c a i n e o r b u p i v a c a i n e . CONCLUSION R o p i v a c a i n e is an effective local anesthetic that shows superiority to o t h e r available long-acting local anesthetics in four areas: I. A n i m p r o v e d safety profile is s h o w n in a n i m a l e x p e r i m e n t s . Doses n e e d e d to p r o d u c e toxicity are consistently u p to 1.5 to 2 t i m e s larger with r o p i v a c a i n e t h a n with b u p i v a c a i n e . 2. R o p i v a c a i n e i n d u c e d c a r d i o t o x i c i t y is n o t increased in p r e g n a n c y . 3. C a r d i a c arrest is m o r e easily reversed in studies o f r o p i v a c a i n e overdoses t h a n with b u p i v a c a i n e overdoses. 4. R o p i v a c a i n e shows an i m p r o v e d m o t o r sensory s e p a r a t i o n o f local anesthetic effects t h a t s h o u l d be o f great value in p r o v i d i n g p a i n relief using e p i d u r a l infusions. Use o f this new d r u g in t h e clinical setting will still require that the usual m o n i t o r i n g a n d safety p r e c a u t i o n s be t a k e n a n d careful dose selection with d i v i d e d a d m i n i s t r a t i o n o f doses used to avoid p o t e n t i a l toxicity. T h e large n u m b e r o f areas o f i m p r o v e d safety o f this long-acting local anesthetic should m a k e r o p i v a c a i n e a well received new local anesthetic drug.

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