Clinical trials with bupivacaine in

oral surgery

ORAL SUKGERY SERVICE, DEI’ARTMEST OF DEiYTIYTRY, BROOKE ARMY JIEDICAI~

CENTER, FORT SARI HOUSTON, TEXAS

Hupivacaine HCl is compared to
Onset, potency, and duration of
vantage of its uw is the long
wturn to full wnsation, which
Iwriod.
lidocaine with respect to clinical use in oral surgery.
anesthesia with it arc’ documented. The major ad-
duration of its anesthetic c~ffwt, 1%.ith a wry slo\I
eases thca paticwt through the early postoprratiw

S incc the widespread use of cocaine was prompted by Kohler’s demonstration

of its local anesthetic effects in 18S4, the quest for a better regional anesthetic
agent has been continued. The ideal properties of such an agent are sufficient
potency, reversibility, low degree of systemic toxicity, nonirritat,ing effects, yapid
onset, sufficient duration, stability, and capability of sterilization. When the sur-
gical demands are of short or medium duration, the currently available local
anesthetics are quite satisfactory. But none of these agents has been proved to bc
effective for prolonged procedures. Bupivacaine HCl has been shown to provide
an extended anesthetic effect, as well as a period of postanesthctic analgesia, that
could be very useful in all areas of dentistry.‘+
Bupiracaine I-ICI (1-n-butyl-DL-piperidine-2-carbosylic acid-2,6-dimethylanil-
ide hydrochloride) is a local anesthetic synthesized at AB Bofors,t by Bo AE’
Ekenstam.” It contains an amide linkage like lidocaine, but differs from mepiva-
Caine in that, a but,vl group is substituted for a methyl group (Fig. 1). The hy-
drochloridc of bupivacaine is reatlil!- soluble in water and has a high dcgrec of
stability. \Vithout epinephrinc, it can withstand repeated autoclaving.” The drug
is commercially available as Marcainct in conrentractions of 0.25 per cent, 0.5
per cent, 0.75 per cent with or without epinephrine 1 :200,000. The agent without
a vasoconstrictor has a pH of 6.0 to 6.5, and with epincphrine it has a pH of 3.5.
Animal experiments have shown that bupiracainr, although chemically related to
mepivaraine, is more like tetracaine in local anesthetic and toxicologic properties.
The acute toxicity (Ll),,,) of bupivacainc is about the same as that of tetracaine,
and approximately four times lower than that of mepivacaine. Bupivacaine and
*Chief, Oral Surgery, Gorgas Hospital, Balboa Heights, Canal Zone.
tMedica1 Research Laboratory, Miilndal, Sweden.
$Marcaine lrnnd of bupivarninr HCI, Winthrop Lnl)oratoricls, New York, N. Y.

301
302 Nespecn Oral Surg.
Septemhrr, 1976

:H&i2 -CH2 -CH3

Cl-i3

Bupivocaine HCL l

CH’YH
I2 I20
CHz CH-t

‘N’ *HCL
iHli CH3
Mepivacaine vHCL

Lidocaine HCL CH3l

Pig. 1. Chemical structures of bupivacaine, mepivacaine, and lidoeaine.

tetracaine have the same tissue toxicity, about six times higher than that of
mepivacaine. In regional block, they are approximately three times more potent
than mepivacaine.‘-” Local disturbances in nerve function were investigated in
man by Hofstrom and associates,*“, I1 who found no electroneurographic signs of
nerve damage from either extrancural or atraumatic intraneural application.
Nordqvist and Dhuner’” studied its effects on the blood and liver function of pa-
tients treated with repeated blocks; no disturbances were found.
Henn and BrattsandR point out that. bupivacaine shows a smaller degree of
cumulation than either mepivacaine or tetracaine, and that it is rapidly metabo-
lized in spite of being an amide,
Moore and associates’” reported that clinical trials with total doses of 200 mg.
without epinephrine or 250 mg. with epinephrine were safe in human beings, and
that similar doses could be repeated after 3 hours. Moore’” concluded that the
relatively long duration of action is related not to its over-all retention in the
body but rather to its binding to nerve tissue.
Feldmann and Nordenram,l in the only other clinical trial of bupivacaine in
oral surgery reported in the English literature, stated that it had the same short
onset time, high frequency of anesthesia, and low side effects as mepivacaine.
Both 0.25 per cent and 0.5 per cent bupivacaine produced considerably longer
Volume 42 Clinical trials with bupivamine 303
sumher 3

soft-tissue anesthesia than did mepivacaine, and there was a delay of postopera-
tive pain in the patients who were given bupivacaine.
Bupivacaine has been reported throughout the world in trials for (1) surgical
and obstetrical anesthesia,‘“-‘” (2) diagnostic and therapeutic blocks,20-“’ and (3)
investigative studies.‘“-‘x This study was undertaken to compare the effects of
bupivacaine and lidocaine in painful oral surgical procedures.

MATERIALS AND METHODS

In the Oral Surgery Service at Brooke Army Medical Center, Fort Sam
Houston, Texas, 262 patients were treated with the use of randomly selected
local anesthetic agents. Both inpatients and outpatients were selected for use in
the study on the basis of the clinical judgment of expected moderate to severe
postoperative pain. The patients were being treated for bony impacted third
molars, facial fractures, tori removal, multiple extractions with alveolectomies,
and arch-bar application preceding corrective surgery. All patients were told pre-
operatively that they would be questioned postoperatively concerning the dura-
tion and effectiveness of the anesthetic, and analgesic usage. They were not told
what to expect nor what agents were being tested. Two separate studies were
conducted involving 119 and 143 patients, respectively. Those selected for the
study were ASA I and ASA 11. The age range was from 16 to 65 years (mean,
26 years), and there was no sexual discrimination.
The proposed agents, bupiracaine 0.25 per cent and 0.5 per cent with or
without epinephrine 1:200,000, and lidocaine 2 per cent with or without epineph-
rim 1 :lOO,OOO were randomly selected by the dental assistant, who blindly
chose a lettered marker corresponding to one of the six agents. The operator was
not aware of the contents of the anesthetic syringe. Surgical anesthesia was ob-
tained with 1.5 t,o 2.0~C.C.injectable doses for both infiltration and block anesthc-
sia. On the day of the operation, injection time, onset, anesthetic effectiveness,
and dosage were recorded. Twenty-four hours later the patients returned for the
recording of additional subjective and objective data. They were asked how long
the anesthesia lasted, when they experienced the onset of pain, when they needed
to take an analgesic, how many doses of analgesic were used since the time of the
operation, whether the anesthesia was sufficient for the procedure, and any side
effects that they encountered. Further recordings concerning any delayed compli-
cations were made at a later date on standardized patient data sheets.
Following the preliminary study, clinical guidelines and comparison param-
eters were established. Bupivacaine 0.5 per cent and 0.25 per cent without epi-
nephrine was very difficult to use. The onset of anesthesia was often delayed be-
yond 15 minutes. Anesthetic effectiveness was very problematic. Numerous injec-
tions had to be given in order to render good surgical anesthesia; without epi-
nephrine, surgical visibility was compromised because of the lack of hemostasis.
Therefore, as a result of the findings with the first 119 patients, the agents with-
out epinephrine were omitted from the rest of the study.
In the second study, the agents were evaluated and compared by recording
four specific clinical parameters : duration, onset, first pain, and total medica-
tions.
 Oral Surg.
Septcml,cr, 19’ifi

Table I

-Mean I Standard error No. ofpatienls

Onset
Lidocaine 2 per cent 2.40 mins. 0.16
Bupivacaine 0.25 per cent 4.74 mins. 0.46 ti
Bupivacaine 0.5 per cent 4.48 mins. 0.28 60
Duration
Lidocaine 2 per cent 190.60 mins. 9.3 40
Bupivacaine 0.25 per cent 401 .O mins. 18.65 43
Bupivacaine 0.5 per cent 493.3 mins. 17.43 60
First pain
Lidocaine 2 per cent
Bupivacaine 0.25 per cent
Bupivacaine 0.5 per cent
204.9
386.5
449.0
mins.
mins.
mins.
1:
60
Total medications
Lidocaine 2 per cent 4.9 doses
Bupivacaine 0.25 per cent 3.58 doses 0.35
0.36 ti
Bupivacaine 0.5 per cent 3.02 doses 0.27 60
-111 agcwts with wsoconstrictors; lidocainc with 1 : 100,000 rpinephrine, and lmpivacaine
with 1 :i’OO,OOO epinephrine.

1.Durtrfh. This wax defined as the total time of soft-tissue anesthesia as

recorded from the patient’s remarks. The preliminary study revealed that bupi-
vacninr di(l not have an unusually long effect after infiltration. Therefore, this
parameter is specific for block type anesthesia.
2. (hset. This was defined as the earliest time after injection that the surgeon
was able to begin operating.
3. First ~Au. This was the first moment postopcrativcly that the patient felt
sufficient pain to need potent analgesics. The patients were instructed not to take
the prescribed medications prophylactically, but to wait until they were needed.
4. Total ?Jzediccltiows. This was the total usual doses of Tylenol with codeine
clisir (potent analgesics) taken within the first 21 hours. The usual dose was con-
sidercd to bc 30 mg. of eodcinc. Other analgesics, potentiators and sedatives, were
used only when this rcgimcn proved to be ineffective or when the patient required
additional support.
The second study involvcxl 143 patients. The agent,s were selected and used as
unknowns to the operator ant1 the patient. The chemical structure of each agent
is given in Fig. I.

RESULTS
The data in Table I were statistically compared via F ratio, probability of oc-
CUrrellcC, and standard t tests. One-way analysis of variance indicated a signif-
icant, difference among mean time of onset for the three agents. F ratio = 57.5,
p < 0.001. 1’ test revealed that both strengths of bupivacaine required a longer
time of onset than did lidocaine-lidocainc versus bupivacainc 0.25, t = -3.90,
p < 0.001; lidocaine versus bupivacaine 0.5, t = -3.75, p < 0.001. There was, how-
cxr, no significant diffcrcnce of onset l)ct,wecn the t,wo strengths of bupiracaine.
The mean durations were compared via a one-way analysis of variance and
showed a significant difference among the three agents (F ratio = 41.17, p <
0.001). Similarly, bupivacaine 0.5 per cent was shown to have a significantly
longer duration than bupivacaine 0.25 per cent.
 The onsets of first pain when the three medications were compared showed
significant differences (F ratio = 24.3, p CO.001). T tests showed that there was
a significant difference with both concentrations of bupivacaine when compared
to lidocainc (lidocainc versus bupivacaine 0.25 per cent, t = -6.45, p < 0.001;
lidocaine versus bupivacaine 0.5 per cent, t = -9.31, p < 0.001). There was also
a significant difference between bupivacainc 0.25 per cent and bupivacainc 0.5
per cent (p < 0.02).
The postoperative analgesics showed significant differences among the three
agents (F’ ratio = 8.758, p < 0.001). T tests showed that a greater number of
postoperative medications v,‘as required with lidocainc than with either of the
two strengths of bupivacaine (p < 0.001)) but there was no significant difference
l)etweeu the two strengths of bupivacaine.
Many of the patients who were given Iidocaine reported moderate to severe
postoperative pain immediately at the end of the period of anesthesia. This in-
tense pain was often uncontrolled for a varying period of time before analgesics
became effective. The patients who received bupivacaine found that, when the
ancsthctic cff’ect, tlissipatcd, there was a gradual onset of discomfort. This pain
was expericncccl on an average of 14 minutes before the end of the period of
anrsthcsia with bupivacainc 0.25 per cent, and 35 minutes with bupivacainc 0.5
per cent. With lidocaine, the first pain was noticed 15 minutes after the end of
the period of anesthesia. h’umcrous patients who had been given the bupivacaine
ancsthct,ics reported that they went home, fell asleep, and did not awaken until
early the nest morning, and t,hat they had had no sudden onset of pain. The pa-
tients who were anesthetized for a long period of time did not report any specific
side offccts from the long duration, except a concern for eventual dissipation of
t,he anesthesia. Eight patients with bupfacaine 0.5 per cent espericnced a dura-
tion of anesthesia beyond 30 hours, whereas only one patient with bupivacaine
0.25 per cent had the same experience. The longest, duration of anesthesia ex-
perienced with lidocaine was 6 hours. Only four of sixty patients who had been
given bupivacaine 0.5 per cent experienced uncontrolled early pain, whereas
twelve of forty patients who had been given lidocaine experienced a period of
uncontrolled pain. In two patients who were given lidocaine, it was difficult or
nearly impossible to attain good surgical anesthesia; and there were three pa-
tients who were given bupivacaine 0.25 per cent, and two who received bupiva-
cainc 0.5 per cent, who had questionable anesthesia. No unusual side effects were
noticed with either lidocainc or bupivacaine.

DISCUSSION
The major clinical problem associated with bupivacaine and its use is its
pa.ckaging. Rupivacaine is ava.ilable only in multiple-dose vials and must be
drawn into disposable syringes before injection. Otherwise, it apears to be a safe
local agent that is quite effective for long, extended periods of anesthetization. Its
period of effectiveness is improved by a slow, gradual return to sensation, even
in the cast of very painful operations. The patients require less analgesic support
during their early postoperative period and tolerate the long duration of anesthe-
sia without complication.
306 Nespeca Oral Surg.
September, 1976

SUMMARY
Bupivacaine KC1 is compared to lidocaine in clinical use in oral surgery. On-
set, potency, and duration of anesthesia with it are documented. The major ad-
vantage of its use is the long duration of its anesthetic effect, with a very slow
return to full sensation, which eases the patient through the early postoperative
period. The study was undertaken with double-blind controls, and the data were
significant to a variety of statistical analyses.
I wish to thank John A. Coventry, Major, MSC, Health Care Administration Division,
Academy of Health Sciences, Fort Sam Houston, Texas, for his assistance in research design
and statistical analysis.

REFERENCES
1. Feldman, C., and Nordenram, A.: Marcaine in Oral Surgery (A Clinical Comparative Study
With Carbocaine), Acta Anaesthesiol. Stand. Suppl. 25: 409, 1966.
2. Dhuner, K. G.: Clinical Experience With Marcaine (LAC-43). A New Local Anesthetic,
Acta Anaesthesiol. Stand. Suppl. 23: 395, 1966.
3. Moore, D. C., et al.: Bupivacaine for Peripheral Nerve Block: A Comparison With Mepiva-
Caine, Lidocaine, and Tetracaine, Anesthesiology 32: 460, 1970.
4. Swerdlow, M., and Jones, R.: The Duration of Action of Bupivacaine, Prilocaine, and
Lianocaine. Br. J. Anaesth. 42: 335. 1970.
5. Ecenstam,‘Bo AF: The Effect of the Structural Variation on the Local Analgesic Prop-
erties of the Most Commonly Used Groups of Substances, Acta Anaesthesiol. Stand.
Suppl. 25: 10, 1966.
6. Korkeila, J. : LAC-43. Clinical Experiences With a New Long-acting Local Anaesthetic
Agent in Epidural Anesthesia, Acta Anaesthesiol. Stand. Suppl. 23: 453, 1966.
7. Widman, B. : Clinical Trial of a New Local Anesthetic (LAC-43) With the Aid of the
Pin-prick and Ninhydrin Methods of Finger Blocks, Acta Anaesthesiol. ‘&and. 8: 219, 1964.
8. Henn, F., and Brattsand, R.: Some Pharmacological and Toxicological Properties of a
New Long-acting Local Anesthesia, LAG-43, in Comparison With Mepivacaine and Tetra-
Caine, Acta Anaesthesiol. Stand. Suppl. 21: 9, 1966.
9. Fortuna, A. : Further Experiments With LAC-43 in Peridural Block, Acta Anaesthesiol.
Stand. Suppl. 23: 402, 1966.
10. Hofstrom, B., Wennberg, A., and Widen, L.: Late Disturbances in Nerve Function After
Block With Local Anesthetic Agents : An Electroneuralgraphic Study, Acta Anaesthesiol.
Stand. 10: 111, 1966.
11. Telivuo, L. : Effects of Intra-arterial Mepivacaine and Bupivacaine on Neuromuscular
Transmission in Man, Acta Anaesthesiol. S&d. 11: 327, 1967.-
12. Nordqvist, P., and Dhuner, K. G.: Blood and Liver Function During Local Anesthesia
With Marcaine, Acta Anaesthesiol. Scand. Suppl. 23: 414, 1966.
13. Moore, D. C., Bridenbaugh, L. D., Bridenbaugh, P. O., and Tucker, G. T.: Bupivacaine, A
Review of 2,077 Cases, J. A. M. A. 214: 713, 1960.
14. Moore, D. C., et al.: Bupivacaine Hydrochloride. A Summary of Investigational Use in
3,274 Cases, Anesth. Analg. 50: 856, 1971.
15. Moore, D. C., et al.: Bupivacaine Hydrochloride: Laboratory and Clinical Studies, Anes-
thesiology 32: 78, 1970.
16. Watt, M. J.. Ross. D. M.. and Atkinson, R. S.: A Clinical Trial of Bupivacaine, & Anaesthesia
23: i, 1968.’ ’ ’
17. Beazley, J. M., Taylor, G., and Reynolds, F.: Placental Transfer of Bupivacaine After
Paracervical Block, Obstet. Gynecol. 39: 2, 1972.
18. Ekblom, L., and Widman, B.: LAC-43 and Tetracaine in Spinal Anesthesia, Acta Anaes-
thesiol. &and. Suppl 23: 419, 1966.
19. Herbing, B. G.: A Comparative Study of LAC-43, Mepivacaine, and Tetracaine in Caudal
Anaesthesia, Acta Anaesthesiol. &and. Suppl. 21: 45, 1966.
20. Bonica, J. J. : Clinical Investigation of Local Anesthetics, Anesthesiology 18: 110, 1957.
21. Hollmen, A. : Bxillary Plexus Block (A Double Blind Study of 59 Cases Using Mepivacaine
and LAC-43), Acta Anaesthesiol. &and. Suppl. 21: 53, 1966.
22. Ekblom, L., and Widman, B.: A Comparison of the Properties of LAC-43, Prilocaine and
Mepivacaine in Extradural Anaesthesia, Acta Anaesthesiol. Stand. Suppl. 21: 33, 1966.
Bromage, P. R.: Extradural Analgesia for Pain Relief, Br. J. Anaesth. 39: 721, 1967.
2”:: Spence, A. A., and Smith, G. : Postoperative Analgesia and Lung Function : A Comparison
of Morphine With Extradural Block, Br. J. Anaesth. 43: 144, 1971.
25. Waters, H. R., Rosen, N., and Perkins, D. H.: Extradural Blockade With Bupivacaine,
Anaesthesia 25: 184-190. 1970.
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26. Mather, L. E., Long, G. H., and Thomas, J.: The Intravenous Toxicity and Clearance of
Rupivacaine in Man, Clin. Pharmacol. Ther. 12: 935, 1971.
27. Rubin, A. P., and Lawson, D. F.: A Controlled Trial of Bupivacaine (A Comparison With
Lignocaine), Anaesthesia 23: 327, 1968.
28. Watt, M. J., et al.: A Double Rlmd Trial of Bupivacaine and Lignocaine, Anaesthesia 23:
331, 1968.

Beprint requests to :
Major John A. Nespeca
Chief, Oral Surgery
Gorgas Hospital
Box “0”
Balboa Heights, Canal Zone