The Journal of Clinical

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Dental Impaction Pain Model as a Potential Tool to Evaluate Drugs With Efficacy in Neuropathic Pain
Kerstin Malmstrom, Paul Kotey, Megan McGratty, Rohini Ramakrishnan, Keith Gottesdiener, Alise Reicin and John A.
Wagner
J. Clin. Pharmacol. 2006; 46; 917
DOI: 10.1177/0091270006289847

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Dental Impaction Pain Model as a Potential
Tool to Evaluate Drugs With Efficacy in
Neuropathic Pain
Kerstin Malmstrom, PhD, Paul Kotey, PhD, Megan McGratty, RN, Rohini Ramakrishnan,
PhD, Keith Gottesdiener, MD, Alise Reicin, MD, and John A. Wagner, MD, PhD
Intravenous lidocaine, a nonspecific Na-channel blocker,
was used to assess the dental impaction model for evaluation
of neuropathic pain drugs. Sixty patients, experiencing mod-
erate or severe pain after removal of ≥ 2 third molars, were
randomized (2:2:1:1) to lidocaine (4 mg/kg; maximal dose
300 mg), oxycodone/acetaminophen (10/650 mg), placebo,
and active placebo (diphenhydramine, 50 mg). Lidocaine
provided a modest degree of pain relief. Predefined end-
points of total pain relief and sum of pain intensity at 2, 4,
and 6 hours showed numerically, not statistically signifi-
cantly, greater pain relief versus placebo. A significantly
greater effect over placebo was observed in peak effect and at
C linical studies that evaluate the efficacy of
agents for the treatment of neuropathic pain are
generally technically difficult and time-consuming.
It would be valuable to have a standardized clinical
pain model that can be readily implemented to assess
neuropathic pain. As it is believed that postsurgery
pain consists of both nociceptive and neuropathic
pain,1 the dental impaction model, a well-established,
well-validated, and extensively used postsurgery
pain model in assessing the efficacy of analgesics on
inflammatory pain,2 would be of potential value.
Third molar surgery involves considerable tissue
trauma, although the exact pathophysiological mecha-
nism through which the pain produced following
removal of impacted third molars is not yet fully
understood. The early phase of dental pain is
From the Departments of Clinical Immunology & Analgesia, Clinical
Pharmacology, and Biostatistics, Merck Research Laboratories, Rahway,
New Jersey, and Clinical Drug Metabolism, West Point, Pennsylvania.
Submitted for publication November 30, 2005; revised version accepted
April 13, 2006.
DOI: 10.1177/0091270006289847
J Clin Pharmacol 2006;46:917-924
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CLINICAL STUDIES
shorter time points (30 minutes and 1 hour), consistent with
the pharmacokinetic profile (plasma concentration of ~2
µg/mL). Oxycodone/acetaminophen provided significantly
greater analgesia versus placebo, validating study conduct,
and significantly greater pain relief was observed versus lido-
caine, which is consistent with a smaller portion of dental
extraction pain being of neuropathic origin.
Keywords: Neuropathic pain; dental impaction pain;
lidocaine; pain model
Journal of Clinical Pharmacology, 2006;46:917-924
©2006 the American College of Clinical Pharmacology
believed to be dominated by a peripheral inflamma-
tory response with sensitization of the nociceptor and
up-regulation of prostaglandin synthesis. Pain path-
ways other than the prostaglandin-mediated pathway
may be of importance (eg, direct damage to periph-
eral nerves during the surgical procedure or the
“wind-up” phenomenon related to sensitization of
neurons in the central nervous system).
The use of the dental impaction model in assess-
ing drugs with potential efficacy in the treatment of
neuropathic pain would have many advantages. For
example, (1) the subjects studied are young and
healthy adults, (2) the pain is consistent in nature
with low variability between subjects, and (3) the
magnitude of the pain is high, with both onset and
duration of pain being reproducible in most subjects
(ie, subjects generally request analgesics within 2 to
3 hours after surgery, and the principal need for anal-
gesic treatment is over the first 24 to 48 hours).
This pilot study was designed to assess the anal-
gesic effect of intravenous lidocaine, a nonspecific
Na-channel blocker, on pain following the removal of
impacted third molars. Lidocaine, when given intra-
venously, has demonstrated efficacy in the treatment
917
 MALMSTROM ET AL
of postoperative pain1,3 and in various types of neuro-
pathic pain (eg, thalamic pain, trigeminal, postampu-
tation pain).4-8 Lidocaine is known to cause noticeable
side effects; therefore, to ensure blinding, an active
placebo group (diphenhydramine, ie, an agent with-
out analgesic properties and with side effects similar
to that of lidocaine) was included in addition to a
standard placebo group.
METHODS
Study Design
This was a randomized, double-blind, placebo-
controlled, and active comparator–controlled, parallel-
group study. The study consisted of 3 visits: prestudy
visit, treatment visit (day of surgery; within 14 days of
the prestudy visit), and poststudy visit (~5 to 7 days
after treatment visit). This single-center study was
conducted at the Dental Center, PPD Development
(Austin, Tex). Protocol and consent form were
approved by the central institutional review board,
Research Consultants’ Review Committee (Austin, Tex).
All subjects gave written informed consent before any
procedures were performed.
Study Population
Eligible subjects were healthy men and women, 18 to
45 years of age, who had 2 or more third molars
to be removed, of which at least 1 was either partially
or completely embedded in mandibular bone. The
degree of impaction for each tooth that was to be
removed was evaluated using an Impaction Score;
each tooth was rated from 1 to 4 using the following
criteria: (1) erupted in tissue; (2) broken, soft tissue;
(3) partial boney impaction; and (4) full boney
impaction. Subjects with abnormal findings at the
physical examination, abnormal laboratory safety
tests, and an abnormal electrocardiogram (ECG; resting
heart rate of ≤ 45 bpm, PR interval of ≥ 200 msec, or
a QRS duration of ≥ 115 msec) at prestudy or before
dosing were excluded. Women of childbearing poten-
tial with a positive pregnancy test at the prestudy visit
or the day of surgery (dosing) were also excluded. All
women agreed to either remain abstinent or use
appropriate contraception starting at the screening visit
and through 7 days postdose. Subjects who required
treatment for any chronic condition were excluded,
whereas subjects who used analgesics (eg, aspirin,
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acetaminophen, nonsteroidal anti-inflammatory drugs
[NSAIDs], opioids) sporadically were permitted to
participate. If used, the analgesic must have been
stopped within 6 to 72 hours before the surgery,
depending on the half-life of the drug. Lidocaine
with epinephrine was the local anesthetic used in
this study; all subjects also received nitrous oxide.
The subjects remained in the clinic for at least
6 hours postdose; they were required to have normal
ECG and vital signs (blood pressure, heart rate, and
respiratory rate) before they were discharged from
the clinic.
Study Medication, Rescue Medication,
Randomization, and Blinding
Subjects who developed moderate or severe pain
within 5 hours of surgery received, in a blinded fash-
ion, intravenous lidocaine, oxycodone/acetaminophen,
active placebo (intravenous diphenhydramine and
placebo tablets), or placebo (saline and placebo tablets)
according to a computer-generated allocation sched-
ule in a ratio of 2:2:1:1. All subjects were adminis-
tered 2 tablets (taken with water) and an intravenous
(IV) bolus (over 2 minutes) followed by a continuous
infusion (over 60 minutes). The lidocaine dosing regi-
men was selected based on the maximal approved
dose (300 mg) and pharmacokinetic modeling using
a 2-compartment model9: a bolus of 1.25 mg/kg lido-
caine was estimated to result in peak plasma con-
centrations of ~2 to 3 µg/mL, and a continuous
lidocaine infusion of 2.75 mg/kg following the IV
bolus is expected to maintain the plasma lidocaine con-
centrations above 1.2 µg/mL for ~2 hours (Figure 1a).
The lidocaine group also received grossly matching
placebo tablets. The oxycodone/acetaminophen group
received 2 tablets of oxycodone/acetaminophen (10/
650 mg), a bolus, and continuous infusion of saline.
The placebo group received grossly matching placebo
tablets, as well as a bolus and continuous infusion
of saline. The active placebo group received grossly
matching placebo tablets and a bolus of 10 mg diphen-
hydramine followed by a continuous infusion of
40 mg diphenhydramine. The intravenous study drugs
were administered using a Baxter AS 50 pump.
Subjects were monitored for ECG changes via 5-lead
telemetry starting 30 minutes before dosing and
through 6 hours postdose. A physician was present
throughout the administration of study drug. To
ensure that blinding was maintained, study medica-
tion was administered by a staff member, who was
not involved in the study conduct.
 DENTAL IMPACTION PAIN MODEL

Figure 1. (A) The predicted mean plasma concentration (µg/mL) of intravenous lidocaine over the first 2 hours postdose. The mean
plasma concentration of lidocaine (µg/mL) was simulated using pharmacokinetic modeling using the 2-compartment model.9 (B) The
actual mean plasma concentration (µg/mL) of intravenous lidocaine (±SE) over the first 2 hours postdose. Plasma samples were collected
from all subjects predose, 10 minutes postdose (start of the intravenous bolus), at the completion of the continuous infusion (approxi-
mately 60 minutes postdose), and approximately 2 hours postdose.

Rescue medication (acetaminophen/hydrocodone ng/mL. Precision and accuracy were determined by

500/5 mg) was available should the subjects not
obtain pain relief from the study drug; however, the
subjects were encouraged to refrain from using res-
cue medication, if possible, until after 90 minutes
postdose, to allow the study medication to manifest
its effect.
Lidocaine Plasma Concentration
Blood samples, for the determination of lidocaine
plasma levels, were collected from all subjects before
dosing, 10 minutes after start of the intravenous
infusion, at the completion of the infusion (approxi-
mately 60 minutes postdose), and approximately 120
minutes postdose. The plasma samples were frozen
and shipped to a central laboratory for determina-
tion of lidocaine levels. Only plasma samples from
the subjects who received lidocaine were assayed.
Plasma samples collected following each lido-
caine dose were assayed for lidocaine concentra-
tions (PPD Development Middleton, Wis) and
analyzed. Analysis was accomplished using high-
performance liquid chromatography (HPLC) with
ultraviolet absorbance detection. The HPLC lido-
caine assay used prilocaine as the internal standard,
and the ultraviolet absorbance wavelength used was
210 nm. The sample preparation for liquid chro-
matography involved extraction into hexane, drying
under vacuum, and reconstitution with mobile
phase. The calibration curve ranged from 2 to 500
replicate (n = 3) analysis of quality control samples
at 3 concentrations spanning the calibration range.
Interassay accuracy (expressed as percent difference
of the mean value for each quality control from the
theoretical concentration) ranged from 1% to 33%.
Interassay precision (expressed as percent coeffi-
cient of variation) was < 20%.
Diary Card
Subjects rated the pain intensity (none, slight, mod-
erate, or severe) and the pain relief they experienced
(none, a little, some, a lot, and complete) at 12 pre-
specified time points (5, 10, 20, 30, 45, 60, and 90
minutes and 2, 3, 4, 5, and 6 hours after completion
of the bolus injection) and recorded the scores on a
diary card. At 2, 4, and 6 hours postdose, they also
rated the study medication using a scale of poor, fair,
good, very good, or excellent. The subjects also
recorded when they took rescue medication.
Efficacy Endpoints
Pain relief and pain intensity scores, respectively,
were used to calculate the overall analgesic effect:
the weighted total of pain relief scores over the first
2, 4, and 6 hours (TOPAR2, TOPAR4, and TOPAR6)
and the weighted sum of pain intensity difference
scores over the first 2, 4, and 6 hours (SPID2, SPID4,
and SPID6). TOPAR2 was the primary endpoint,

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 MALMSTROM ET AL
selected based on the estimated half-life for intra-
venous lidocaine. In addition, TOPAR4 and TOPAR6
were evaluated because the recommended dosing inter-
vals for oxycodone/acetaminophen are 4 and 6 hours.
Global evaluation at 2, 4, and 6 hours also estimated
the overall pain relief over the respective time peri-
ods. Other endpoints assessed the peak analgesic
effect: the maximum pain relief and maximum pain
intensity difference (PID) during the 6 hours post-
dose using a 0 to 4 scale and –1 to 3 scale, respec-
tively. The duration of the analgesic effect (median
time to the first dose of rescue medication) and the
percentage of subjects requesting rescue medication
were also determined.
Tolerability Assessment
On the day of dosing, the tolerability of the study
drugs was assessed by ECG (5-lead telometry),
which was started 30 minutes before the start of
infusion and for the next 6 hours. In addition, heart
rate and blood pressure were measured hourly after
infusion. Adverse experiences were reported spon-
taneously, which the investigator determined in a
blinded fashion whether it could have been caused
by the study drug.
Statistical Analyses
The efficacy analysis was a modified intention-to-treat
analysis and included all randomized subjects who
had a baseline pain intensity score and reported at least
1 postdose pain and/or pain relief assessment. All ran-
domized subjects were included in the tolerability
evaluation. TOPAR2, TOPAR4, and TOPAR6 were ana-
lyzed by using a parametric analysis of variance
(ANOVA) model. The ANOVA model, Cox propor-
tional hazards regression model, or logistic regression
model was used in the analyses of the other endpoints,
as appropriate. In each model, treatment was included
as a factor. Post hoc analyses were performed to allow
additional assessment of the treatment effect at earlier
time points using similar approaches.
RESULTS
A total of 121 subjects were screened, of which 60
subjects were randomized. The most common rea-
sons for subjects not being randomized were as fol-
lows: abnormal laboratory safety tests at screening
(n = 12), withdrawal of consent (n = 10), positive
drug screening test (n = 8), abnormal ECG (n = 7),
and not developing sufficient pain (n = 7). The
subjects were randomly allocated to receive intra-
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© 2006 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
venous lidocaine (n = 20), oxycodone/acetaminophen
(n = 20), diphenhydramine (active placebo; n = 10),
or placebo (n = 10). One subject (placebo group),
who was incorrectly randomized (reported slight
pain), was not included in the efficacy analysis. All
subjects completed the study. The subjects’ demo-
graphics, baseline characteristics, and baseline pain
intensity were similar across the 4 treatment groups
(Table I). Approximately 82% of the subjects were
women, the mean age was 23 years, and approxi-
mately 80% of the subjects reported moderate pain
at the time of randomization.
Lidocaine Versus Placebo
The concentration versus time curve of the lidocaine
plasma concentration for subjects who received
intravenous lidocaine is shown in Figure 1b. The
predose lidocaine plasma concentration was slightly
elevated (0.8 µg/mL), which was not unexpected
because all subjects received lidocaine as the local
anesthetic for the dental surgery. The observed maximal
lidocaine concentration (~2.3 µg/mL; Figure 1b) was
similar to the projected maximal concentration of
2.5 µg/mL (Figure 1a).
Intravenous lidocaine provided numerically but
not statistically greater pain relief compared with
the 2 placebo groups, as indicated by the TOPAR2,
TOPAR4, and TOPAR6 scores and the SPID2, SPID4,
and SPID6 scores (Table II, Figure 2). However, at
shorter time points (eg, 30 minutes and 1 hour post-
dose), the time periods when lidocaine plasma con-
centration was elevated (~2 µg/mL; Figure 1b), the
analgesic effect as assessed by TOPAR0.5 scores was
significantly different from both placebo and active
placebo (P ≤ .023), and TOPAR1 approached statisti-
cal significance (P ≤ .082). SPID0.5 and SPID1 scores
were significantly different from placebo (P ≤ .041)
but not active placebo (P ≤ .219; Table II). The anal-
gesic effect of lidocaine was also evidenced by the
peak analgesic effect; the peak pain relief scores
were statistically significantly greater than that of
placebo (P = .013) and active placebo (P = .029). The
peak PID score was significantly greater than that
of placebo (P = .006) but numerically greater than
that of active placebo (Table II). The global scores
for lidocaine at 2, 4, and 6 hours postdose were sim-
ilar to those of placebo. Furthermore, there was no
difference in duration of effect for lidocaine versus
placebo, as assessed by the median time to rescue
medication; median time to first dose of rescue
medication was 1.6 hours for lidocaine versus 1.2
and 1.4 hours for placebo and active placebo,
respectively.
 DENTAL IMPACTION PAIN MODEL

Table I Subjects Demographic and Baseline Characteristics

Intravenous Oxycodone/
Lidocaine Acetaminophen
Placebo Active Placebo 4 mg/kg 10/650 mg
(n = 10) (n = 10) (n = 20) (n = 20)

Gender, n (%)
Women 7 (70.0) 8 (80.0) 17 (85.0) 17 (85.0)
Men 3 (30.0) 2 (20.0) 3 (15.0) 3 (15.0)
Race, n (%)
White 7 (70.0) 8 (80.0) 12 (60.0) 14 (70.0)
Hispanic American 3 (30.0) 0 (0.0) 6 (30.0) 2 (10.0)
Others† 0 (0.0) 2 (20.0) 2 (10.0) 4 (20.0)
Age, y
Mean (SD) 22.4 (3.9) 22.5 (3.7) 22.7 (4.8) 23.1 (5.0)
Range 18.0 to 31.0 18.0 to 31.0 18.0 to 40.0 18.0 to 35.0
Duration of surgery, minutes
Mean (SD) 17.6 (6.0) 13.9 (5.2) 15.9 (7.9) 18.2 (4.8)
Range 10.0-30.0 9.0-26.0 6.0-42.0 10.0-26.0
Baseline pain intensity, n (%)
Moderate 7 (77.8) 9 (90.0) 17 (85.0) 15 (75.0)
Severe 2 (22.2) 1 (10.0) 3 (15.0) 5 (25.0)
Dose (mL) of lidocaine hydrochloride
(2%) + epinephrine (1:100,000)
used for local anesthesia
Mean (SD) 12.1 (4.3) 11.0 (4.0) 12.4 (2.7) 14.3 (3.1)
Range 5.4-18.0 7.2-18.0 9.0-18.0 7.2-18.0
Number of teeth removed
Mean (SD) 3.8 (0.6) 3.3 (1.1) 3.3 (1.0) 3.7 (0.7)
Range 2.0-4.0 2.0-5.0 2.0-5.0 2.0-4.0
Impaction score
Mean (SD) 2.4 (0.6) 1.8 (0.5) 2.2 (0.5) 2.3 (0.6)
Range 1.5-3.0 1.3-3.0 1.5-3.0 1.5-3.0
a. Includes Asian, black, and Native American.

Oxycodone/Acetaminophen Versus Placebo
The study conduct was validated by oxycodone/
acetaminophen providing statistically significantly
better analgesic effect than placebo (P < .001), as
assessed by TOPAR2, TOPAR4, and TOPAR6.
Corresponding SPID2, SPID4, and SPID6; global
evaluation at 2, 4 and 6 hours; the peak effect; and
duration of effect were also significantly greater
than placebo (Table II, Figure 2). Also, TOPAR0.5,
TOPAR1, and SPID1 for oxycodone/acetaminophen
were significantly greater than both placebo groups,
whereas SPID0.5 was only significantly greater
than placebo (Table II). Oxycodone/acetaminophen
had a greater peak effect compared with both
placebo groups (Table II). The analgesic effect for
oxycodone/acetaminophen lasted longer than that
of placebo: median time to rescue medication use for
oxycodone/acetaminophen was 3.1 hours compared
with 1.2 and 1.4 hours for placebo and active placebo,
respectively.
Oxycodone/Acetaminophen Versus Lidocaine
The analgesic effect of oxycodone/acetaminophen
was statistically significantly greater than lidocaine,
as assessed by all predefined endpoints TOPAR2,
TOPAR4, and TOPAR6 and SPID2, SPID4, and SPID6 (P
≤ .003), including peak effect (P < .05; Figure 2, Table II).
Tolerability
The percentage of subjects who reported clinical
adverse experiences was similar in all treatment
groups: 12 (60%) and 12 (60%) subjects, respectively,
in the lidocaine and oxycodone/acetaminophen
groups and 7 (70%) and 5 (50%) in the placebo and
the active placebo groups, respectively. The most

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 MALMSTROM ET AL

Table II Summary of Efficacy Endpoints: Least Squares Mean (95% Confidence Interval [CI])
Intravenous Oxycodone/
4 Lidocaine Acetaminophen
Placebo Active Placebo mg/kg 10/650 mg
(n = 9) (n = 10) (n = 20) (n = 20)

Overall analgesic effect

TOPAR0.5 0.1 (0.0, 0.3) 0.1 (0.0, 0.3) 0.4* (0.2, 0.6) 0.6** (0.4, 0.8)
TOPAR1 0.2 (0.0, 0.7) 0.3 (0.0, 0.8) 0.7‡ (0.3, 1.0) 1.8*** (0.5, 1.1)
TOPAR2 0.3 (0.0, 1.3) 0.5 (0.0, 1.4) 1.0 (0.3, 1.7) 3.3*** (2.7, 4.0)
TOPAR4 0.5 (0.0, 2.4) 0.5 (0.0, 2.3) 1.4 (0.1, 2.8) 5.1*** (3.8, 6.3)
TOPAR6 0.8 (0.0, 3.5) 0.6 (0.0, 3.2) 1.8 (0.0, 3.8) 6.8*** (4.9, 8.6)
SPID0.5 –0.1 (–0.3, 0.1) 0.0 (–0.2, 0.2) 0.2† (0.1, 0.3) 0.21† (0.1, 0.3)
SPID1 –0.3 (–0.7, 0.1) –0.1 (–0.5, 0.3) 0.1† (–0.2, 0.4) 0.7*** (0.4, 1.0)
SPID2 –0.7 (–1.4, 0.0) –0.5 (–1.2, 0.1) –0.1 (–0.6, 0.4) 1.3*** (0.8, 1.8)
SPID4 –1.6 (–3.0, –0.3) –1.5 (–2.9, 0.2) –0.7 (–1.7, 0.3) 1.5*** (0.6, 2.4)
SPID6 –2.5 (–4.6, –0.5) –2.5 (–4.5, –0.4) –1.3 (–2.8, 0.2) 1.6*** (0.2, 3.0)
Peak analgesic effect
Peak pain relief (0 to 4 scale) 0.3 (0.0, 1.0) 0.5 (0.0, 1.1) 1.3* (0.8, 1.8) 2.5*** (2.0, 2.9)
Peak PID (–1 to 3 scale) –0.1 (–0.6, 0.3) 0.2 (–0.2, 0.7) 0.6† (0.3, 1.0) 1.1**§ (0.8, 1.5)
Rescue medication use
Median time to rescue 1.2 (1.0, 1.3) 1.4 (1.3, 1.6) 1.6 (1.5, 1.7) 3.1 (2.1, 3.7)
medication use in hours (95% CI)
N (%) of patients requesting 9 (100.0) 10 (100.0) 19 (95.0) 15 (75.0)
rescue medication
*P ≤ .05 vs placebo and active placebo. **P < .001 vs placebo and active placebo. ***P < .001 vs placebo, active placebo, and lidocaine. †P ≤ .05 vs
placebo. ‡P = .082 vs placebo and active placebo. §P = .015 vs lidocaine.

common adverse experiences were nausea, alveoli-

tis, and headache (Table III).

DISCUSSION

There is a great demand for better treatment of

Figure 2. The mean pain relief scores over 6 hours postdose.
Subjects reported pain relief scores (none, some, a little, a lot, and
complete) after receiving intravenous lidocaine 4 mg/kg (n = 20;
♦—♦), oxycodone/acetaminophen 10/650 mg (n = 20; = — •– =),
placebo (saline; n = 10; –{–), or active placebo (diphenhydramine
50 mg; n = 10; –…–).
neuropathic pain, a challenging pain syndrome. The
clinical pain studies generally used for evaluating
efficacy in neuropathic pain are diabetic neuropathy
and postherpetic neuralgia, which are technically
difficult and time-consuming to conduct. To more
rapidly assess the efficacy of drugs for the treatment
of neuropathic pain, an easily employed and repro-
ducible clinical pain model would be advantageous.
Studies using the dental pain model have demon-
strated efficacy of neuropathic pain drugs. For
example, ketamine, an N-methyl-D-aspartate (NMDA)
receptor antagonist, at a low dose (0.3 mg/kg) and
pregabalin (300 mg), with a mechanism of action
that is not completely understood (believed to act via
calcium channels and/or the NMDA receptor), have
diminished postsurgery dental pain.10,11 These studies
suggest that pain associated with the removal of
impacted wisdom teeth may involve both inflammatory
and neuropathic pain. To our knowledge, it has not

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 DENTAL IMPACTION PAIN MODEL

Table III Clinical Adverse Experiences

Oxycodone/
Active Lidocaine Acetaminophen
Placebo Placebo 4 mg/kg 10/650 mg
(n = 10) (n = 10) (n = 20) (n = 20)
n (%) n (%) n (%) n (%)

Patients with one or more 7 (70.0) 5 (50.0) 12 (60.0) 12 (60.0)

adverse experience
Ventricular ectopics 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0)
Tinnitus 0 (0.0) 0 (0.0) 3 (15.0) 0 (0.0)
Nausea 1 (10.0) 0 (0.0) 4 (20.0) 11 (55.0)
Vomiting 0 (0.0) 0 (0.0) 3 (15.0) 6 (30.0)
Tiredness 0 (0.0) 1 (10.0) 1 (5.0) 0 (0.0)
Cold symptoms 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0)
Dizziness 1 (10.0) 0 (0.0) 2 (10.0) 1 (5.0)
Drowsiness 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.0)
Facial paraesthesia 1 (10.0) 0 (0.0) 0 (0.0) 0 (0.0)
Headache 1 (10.0) 3 (30.0) 4 (20.0) 1 (5.0)
Lightheadedness 0 (0.0) 1 (10.0) 4 (20.0) 4 (20.0)
Vasovagal attack 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.0)
Depression 0 (0.0) 1 (10.0) 0 (0.0) 0 (0.0)
Alveolitis 4 (40.0) 2 (20.0) 2 (10.0) 3 (15.0)
Sore throat 0 (0.0) 0 (0.0) 2 (10.0) 0 (0.0)
Diaphoresis 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.0)
Flushing 0 (0.0) 0 (0.0) 1 (5.0) 2 (10.0)

been demonstrated that an Na-channel blocker (eg,
lidocaine, mexiletine, or amitryptylline, drugs with
efficacy in neuropathic pain) would affect postdental
surgery pain.
To assess the relevance of dental impaction pain as
a model to evaluate treatments for neuropathic pain,
we performed a randomized, double-blind, double-
dummy, parallel-group study to evaluate the efficacy
of intravenous lidocaine in subjects with postsurgery
dental pain with the objective to evaluate this stan-
dardized pain model as a potential pain model for
neuropathic pain. The study showed that lidocaine
can provide a modest degree of pain relief to subjects
experiencing postsurgery dental pain over the first
hour postdose, suggesting that the dental impaction
model may be a relevant model for assessing efficacy
of neuropathic pain medications, particularly if over-
all efficacy greater than that of lidocaine is expected.
The observed pain relief with intravenous lido-
caine was modest. The most likely reason is that the
portion of neuropathic pain in postsurgery dental
pain is comparatively smaller than that observed in
other conditions such as diabetic neuropathy and
postherpetic neuralgia; however, it is conceivable
that the lidocaine dose used was not sufficiently high.
The lidocaine dose range and plasma concentration
in this study were within approved and recommended
dose range and the plasma concentration. Data from
published studies show that lidocaine at doses of 1.5
to 5.0 mg/kg is effective in the treatment of various
neuropathic pain conditions (eg, postamputation
pain, diabetic neuropathy, and postherpetic neural-
gia).4-6,8,12 Various doses and dosing regimens (eg,
bolus followed by continuous infusion or continu-
ous infusion alone) have been used. Intravenous
lidocaine administered as 3 mg/kg over 3 minutes
followed by a continuous infusion of 4 mg/kg over
60 minutes was effective in reducing neuropathic
pain, including thalamic pain, trigeminal neuralgia,
and phantom limb pain.5 Other studies showed that
an infusion of 2 mg/mL over 60 minutes, resulting in
mean serum concentrations of 2.4 µg/mL, decreased
neuropathic pain.7,13 Lidocaine, administered as a
1-mg/kg bolus followed by a 4-mg/kg infusion (plasma
levels of 2.1 ± 1.5 µg/mL), demonstrated efficacy in
the treatment of postamputation pain5. Intravenous
lidocaine at 5 mg/kg over 3 hours provided efficacy
in patients with sciatica.13 It is not evident from
the present study results whether higher lidocaine
plasma concentrations would have provided a better
response; however, 3 subjects in the lidocaine-
treated group experienced tinnitus, suggesting that

CLINICAL STUDIES 923

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© 2006 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
 MALMSTROM ET AL
lidocaine exposure was adequate. Therefore, increas-
ing lidocaine exposure may not be a feasible option
in further testing this mechanism in the dental pain
model, although other drugs (eg, gabapentin) may be
useful. Nonetheless, the results showed that lidocaine
could diminish the pain to a degree consistent with
a small portion of the pain experienced after the
extraction of impacted third molars for neuropathic
pain. It is evident that the effect occurred early and
during the time when the plasma concentration was
elevated (~2 µg/mL), that is, during the first hour.
Therefore, if the primary endpoint had been prespeci-
fied as TOPAR0.5 or TOPAR1, the study would have
demonstrated a treatment effect that was significantly
different from placebo.
In summary, this randomized, double-blind study
demonstrated that intravenous lidocaine diminished
a portion of the pain experienced after extraction of
impacted third molars during the first hour after
patients received lidocaine. In addition, an opioid-
combination drug provided superior pain relief
compared with the 2 placebo groups and was also
superior to lidocaine. The present study and the
studies using ketamine10 and pregabalin11 suggest
that pain associated with the removal of impacted
wisdom teeth may involve both inflammatory and
neuropathic pain. These studies have demonstrated
that agents that act via Na- and/or Ca-channels,
and/or NMDA receptors can modify pain associated
with extraction of impacted third molars. The
results of the present study provide additional evi-
dence that an Na-channel blocker (lidocaine) modi-
fies pain from the extraction of impacted third
molars to a modest degree, although further studies
with higher doses of lidocaine are needed to more
completely assess the use of this model for neuro-
pathic pain. Anticonvulsants other than pregabalin
and tricyclics have also demonstrated efficacy in
neuropathic pain; however, to our knowledge, they
have not been tested using the dental impaction
model. Studies using these agents would further
substantiate the use of the dental impaction pain
model in the evaluation of neuropathic pain.
924 • J Clin Pharmacol 2006;46:917-924
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© 2006 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
This study was funded by a grant from Merck & Co, Inc.
The authors wish to thank the dental surgeons Drs G. Grant and
J. Fricke for performing the dental surgeries; Dr L. W. Andrews
for safety monitoring; Mary Coe and Rachel Cox at PPD, Dental
Unit in Austin, Texas, for coordination of the study; and Anish
Mehta of Merck Research Laboratories for writing and editorial
assistance.
REFERENCES
1. Kawamata M, Tahahashi T, Kozuka Y, et al. Experimental
incision-induced pain in human skin: effect of systemic lidocaine
on flare formation and hyperalgesia. Pain. 2002;100:77-89.
2. Urquhart E. Analgesic agents and strategies in the dental pain
model. J Dent. 1994;22:336-341.
3. Cassuto J, Wallin G, Hogstrom S, Faxen A, Rimback G. Inhibition
of postoperative pain by continuous low-dose intravenous infu-
sion of lidocaine. Anest Anal. 1985;64:971-974.
4. Boas RA, Covino BG, Shahnarian A. Analgesic response to IV
lidocaine. Br J Anesth. 1982;54:501-505.
5. Wu CL, Tella P, Stassts PS, et al. Analgesic effects of intravenous
lidocaine and morphine of postamputation pain. Anesthesiology.
2002;96:841-848.
6. Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief.
Pain. 2000;87:7-17.
7. Ferrante FM, Paggioli J, Cherukuri S, Richard AG. The anal-
gesic response to intravenous lidocaine in the treatment of neu-
ropathic pain. Anesth Anal. 1996;82:91-97.
8. Wallace MS, Dyck JB, Rossi SS, Yahsh TL. Computer-controlled
lidocaine infusion for the evaluation of neuropathic pain after
peripheral nerve injury. Pain. 1996;66:69-77.
9. Koppert W, Dern SK, Sittl R, Albrecht S, Schuttler J, Schmelz
M. A new model of electrically evoked pain and hyperalgesia in
human skin. Anesthesia. 2001;95:395-402.
10. Maurset A, Skoglund LA, Hystveit O, Oye I. Comparison of
ketamine and pethidine in experimental and postoperative pain.
Pain. 1989;36:37-41.
11. Hill CM, Balkenohl M, Thomas DW, Walker R, Mathe H,
Murray G. Pregabalin in patients with postoperative dental pain.
Eur J Pain. 2001;5:119-124.
12. Wallace MS, Laitin S, Licht D, Yaksh TL. Concentration-effect
relations for intravenous lidocaine infusions in human volunteers.
Anesthesiology. 1997;86:1262-1272.
13. Medrick-Goldberg T, Lifschitz D, Pud D, Adler R, Eisenberg E.
Intravenous lidocaine, amantadine, and placebo in the treatment
of sciatica: a double-blind, randomized, controlled study. Regional
Anesth Pain Med. 1999;24:534-540.