Clinical Research
Gender Differences in Analgesia for Endodontic Pain
Jeffrey L. Ryan, DDS, MS,* Badri Jureidini, DDS, MS, James S. Hodges, PhD,
Michael Baisden, DDS,* James Q. Swift, DDS, and Walter R. Bowles, DDS, MS*
Abstract
The purpose of this prospective clinical trial was to
investigate the analgesic efficacy of three oral medica-
tion groups on postoperative endodontic pain in male
and female dental patients, with an emphasis on an-
algesic differences between the sexes. Forty-three pa-
tients were administered ibuprofen 600 mg, placebo, or
pentazocine 50 mg/0.5 mg naloxone in a randomized,
double-blinded manner. Beginning immediately after
endodontic treatment, patients took the assigned med-
ication every 6 hours for 24 hours and recorded their
degree of discomfort on a 100-mm visual analog scale.
Statistical analysis of the data showed that ibuprofen
600 mg provided statistically significantly greater an-
algesia than placebo at 6 and 12 hours (P 0.0014
and 0.0024), and pentazocine/naloxone provided sta-
tistically significantly greater analgesia than placebo at
12 hours (P 0.0084). Sex-dependent differences were
noted within the pentazocine/naloxone group, which
showed significantly greater analgesia in females com-
pared with males (P 0.007). (J Endod 2008;34:
552556)
Key Words
Analgesia, pentazocine, sex
From the *Division of Endodontics, University of Minne-
sota School of Dentistry, Minneapolis, Minnesota; Private
Practice, Edina, Minnesota; Division of Biostatistics, Univer-
sity of Minnesota, Minneapolis, Minnesota; and Division of
Oral and Maxillofacial Surgery, University of Minnesota School
of Dentistry, Minneapolis, Minnesota.
Address requests for reprints to Dr Walter R. Bowles, 8-166
Moos Tower, 515 Delaware St SE, Minneapolis, MN 55455.
E-mail address: bowle001@umn.edu.
0099-2399/$0 - see front matter
Copyright 2008 by the American Association of
Endodontists.
doi:10.1016/j.joen.2008.01.021
552 Ryan et al.
E pidemiologic studies have shown that odontalgia affects 12% to 14% of the North
American population (1, 2). A strategic approach to manage odontalgia involves an
accurate diagnosis, definitive dental treatment, (ie, root canal treatment, extraction,
and incision for drainage), and, finally, anti-inflammatory/analgesic drugs (3). Despite
advances in endodontic therapy and an increase in knowledge of pulpal and perira-
dicular inflammation, studies have shown that up to 43% of patients report pain of
varying degree after root canal treatment (4).
It is well known that prostaglandins play a critical role in the pathogenesis of pulpal
and periradicular disease (57). Nonsteroidal anti-inflammatory drugs (NSAIDs) are
commonly used to control prostaglandin-induced inflammation, and ibuprofen is gen-
erally considered the prototype of NSAIDs because of its efficacy and safety profile (8).
Ibuprofens effectiveness in providing analgesia has been repeatedly shown for dental
procedures such as third molar extractions, surgical and nonsurgical root canal treat-
ment, biopsy, and deep gingival curettage (9 11).
For the NSAID-sensitive patient or for the management of moderate to severe
dental pain, NSAIDs alone may not be an effective analgesic choice. Prolonged pulpal
and periradicular tissue damage can result in the release of inflammatory mediators as
well as neural input centrally, producing sensitization (7). Pain treatment in these
circumstances may benefit from opioid analgesics, which can be combined with NSAIDs
or acetaminophen to manage the pain more effectively (3, 12).
Talwin NX (pentazocine 50 mg naloxone 0.5 mg) (Sanofi Winthrop, Morris-
ville, PA) is an opioid analgesic that was synthesized in 1959 in an attempt to create a
potent analgesic with weak addiction potential. Pentazocines analgesic efficacy has
been shown in a variety of clinical models (1315) and its use in dentistry for
moderate to severe pain has received previous attention (16). Pentazocine acts as
a -opioid receptor agonist and a partial -opioid receptor agonist, with mixed
agonist-antagonist properties at the -opioid receptor. Because of its broad spec-
trum of activity, pentazocine is thought to have relatively little opioid dependence
and abuse potential (17), little respiratory depression after higher/repeated doses
(18), and possibly moderate anti-inflammatory effects (19).
Although root canal treatment is often successful, 12% of patients may con-
tinue to report pain after successful root canal treatment (20). In Polycarpous
study (20), factors associated with persistent postoperative pain were preoperative
pain, female sex, and a history of painful treatment in the orofacial region or
previous chronic pain experience. Sex has been suggested to play a role in other
pain studies. For example, in the endodontic literature, women have been shown to
experience higher levels of postoperative pain compared with men (21, 22). Phar-
macologically, Gear et al. (23) showed in an oral surgical model that intravenous
pentazocine produced significantly greater analgesia in females compared with
males at 3 hours postoperatively. These findings suggest that the patients sex may
contribute to pain perception and the pharmacodynamics of the analgesic, which
could aid the clinician in customizing an effective pain management regimen for
each individual patient.
Currently, few studies exist in the endodontic literature showing differences in
analgesia between the sexes. Because a significant percentage of patients appear to
experience posttreatment endodontic pain, further research in this area is warranted.
Therefore, the purpose of this clinical trial was to investigate the analgesic efficacy of
three oral medication groups on postoperative endodontic pain in male and female
patients, with an emphasis on analgesic differences between the sexes.
JOE Volume 34, Number 5, May 2008

TABLE 1. Demographic Data
Group n Sex (F:M)
Placebo 14 8:6
Ibuprofen 15 7:8
Talwin 14 8:6
F, female; M, male; IRP, irreversible pulpitis; APP, acute periradicular periodontitis; APA, acute periradicular abscess.
Materials and Methods
The appropriate human subjects institutional review board ap-
proved the protocol for this study. Potential subjects for this study in-
cluded healthy adults with a preoperative visual analog scale (VAS)
discomfort score greater than or equal to 30 mm out of 100 mm. All
patients exhibited pulpal symptoms consistent with irreversible pulpitis
or pulpal necrosis, with a periradicular diagnosis of normal, acute
periradicular periodontitis, chronic periradicular periodontitis, or
acute periradicular abscess. Patient demographics/characteristics are
shown in Table 1.
Patients were excluded who had documented allergies or intoler-
ance to any of the proposed test medications or placebo, patients who
were pregnant, patients currently taking pain medication for a condition
other than odontalgia, and patients who were unwilling/unable to be
followed for 24 hours.
Endodontic treatment was provided by graduate endodontic resi-
dents or by undergraduate dental students under the supervision of
residents or faculty members at the University of Minnesota School of
Dentistry. Each potential study participant completed a baseline
100-mm VAS to establish whether their preoperative spontaneous pain
met the previously discussed inclusion threshold of 30 mm. Forty-
eight eligible patients signed the consent form, which outlined the pro-
cedures and possible risks of the study. Before the initiation of end-
odontic treatment, demographic data were recorded.
Once baseline data were gathered and the consent form signed,
appropriate emergency endodontic treatment was initiated. Local anes-
thesia was obtained, and the tooth was isolated with a rubber dam,
followed by access preparation, identification, and instrumentation of
all canals. No long-acting local anesthetics were used, and no significant
differences in amounts of local anesthetics were noted. The minimum
instrumentation that was considered acceptable for inclusion into this
study was to at least a size #25 file to within 0.5 to 1 mm of the radio-
graphic apex. Half-strength (3%) or full-strength (6%) sodium hypo-
chlorite was used for intracanal irrigation. If endodontic treatment was
not completed and a second appointment was necessary, teeth were
temporized by using cotton pellet and Cavit (3M, St Paul, MN.), with or
without intracanal calcium hydroxide (Calasept; Nordiska Dental AB,
Ridgefield, CT). If endodontic treatment was completed, the teeth were
obturated with gutta-percha and ZOE sealer (Roth 801; Roth Interna-
tional, Chicago, IL) followed by a temporary or definitive restoration.
On completion of the endodontic treatment, the patient was given
a packet containing a prescription bottle of the pain medication in blue
gelatin capsules containing placebo (lactose powder; Humco, Texar-
kana, TX), 600 mg ibuprofen (Interpharm Inc, Commack, NY), or 50
mg pentazocine/0.5 mg naloxone (Talwin NX; Sanofi Winthrop), along
with forms and follow-up pain scales to be completed to evaluate spon-
taneous pain levels over the next 24 hours.
After treatment completion, the patient was given the first capsule
of the assigned medication to take immediately. The patient then com-
pleted the first of five pain questionnaires. Patients took one capsule of
the assigned medication every 6 hours (time 0 immediate posttreat-
ment and at 6 hours, 12 hours, 18 hours, and 24 hours after treatment),
for a total of 5 capsules. Patients also completed one questionnaire for
JOE Volume 34, Number 5, May 2008
Clinical Research
IRP Necrosis Normal Periradicular APP APA
7 7 0 9 5
9 6 2 11 2
8 6 0 9 5
the level of spontaneous tooth pain after each capsule at each time point.
Patients returned the questionnaires in the prestamped, self-addressed
envelope.
Statistical Analysis
Baseline comparisons used either t tests (age, initial VAS) or Pear-
son chi-square tests (sex, preoperative pulpal diagnosis, and preoper-
ative periradicular diagnosis).
To compare the treatment groups without considering patient sex
or initial VAS, a repeated-measures analysis of variance (ANOVA) was
used in which the random effect was subject and the fixed effects were
drug group, time (0, 6, 12, 18, and 24 hours), and their interaction.
To compare the treatment groups while also considering sex, a
mixed linear model was used, a generalization of a repeated-measures
ANOVA, in which the fixed effects were drug group, sex, time, and their
interactions. To compare the treatment groups while also considering
initial VAS, the same analysis was used except that initial VAS was treated
as a continuous measure.
All treatment-group comparisons were analyzed with the JMP sys-
tem (version 6.0; SAS Institute, Inc, Cary, NC) using the restricted-
likelihood method with variance components constrained to be non-
negative.
Results
A total of 48 patients enrolled in this clinical trial. Five patients
were unable to complete the study: two because of inadequate pain
control from the trial medication and who took the escape medication
within 6 to 12 hours of treatment and three because they could not be
reached after the 24-hour trial period. Therefore, data from 43 patients
were available for analysis. The medication groups were similar for the
distribution of preoperative pulpal diagnosis and preoperative perira-
dicular diagnosis with no significant differences between groups (P
0.857 and P 0.231, respectively).
We compared the effect of the three medications on pain measure-
ments at various time points (0, 6, 12, 18, and 24 hours). In the manner
of ANOVA, this was examined in terms of the group-by-time interaction.
The group-by-time interaction addresses the question of whether the
differences between the drugs change over time. This was statistically
significant, with P 0.037. Patients taking ibuprofen had consistently
lower pain than patients taking pentazocine/naloxone or placebo
(Fig. 1), although this did not test significantly different from pentazo-
cine/naloxone at any time point or averaged over all five time points.
TABLE 2. Comparison of Three Medication Groups at Each Time Point
Time P Value
0h 0.97
6h 0.006
12 h 0.005
18 h 0.33
24 h 0.28
Groups differed significantly at 6 hours for ibuprofen versus placebo and at 12 hours for ibuprofen or
pentazocine versus placebo.
Gender Differences in Analgesia for Endodontic Pain 553
Clinical Research
80 Placebo 60
Ibuprofen
Placebo
70 Pentazocine/Naloxone 50 Ibuprofen
Pentazocine/naloxone
60 40

VAS
50
30
VAS Score

40
20
30
* 10
20
* * 0
10 Female Male

0 Figure 3. Adjusted VAS averages: group-by-sex interaction. Although patients

Pre-Treatment 0 hr 6 hr 12 hr 18 hr 24 hr
Time
Figure 1. Group-by-time interaction: average VAS measurements for each pa-
tient group at individual time points. 0 hr scores indicate pain level immedi-
ately after completion of endodontic procedure. Patients and dentists were
blinded as to medication. Patients took the assigned medication immediately
after completion of endodontic treatment and ever 6 hours thereafter for 24
hours. Pain scales were completed at each time point. Pain levels were signifi-
cantly decreased at 6 hours in the ibuprofen group (P 0.0014) and at 12
hours in both the ibuprofen and pentazocine/naloxone groups (P 0.0024
and 0.0084, respectively) compared with placebo-treated patients.
Because the group-by-time interaction was significant, separate
tests were done comparing the medication groups at each time point.
The groups differed significantly at 6 and 12 hours (Table 2), with P
0.006 and P 0.005, respectively. Post hoc tests using pairwise com-
parisons specifically determined which pairs of medication groups dif-
fered significantly from each other. At 6 hours, ibuprofen had signifi-
cantly lower pain than placebo (P 0.0014), and at 12 hours both
ibuprofen and pentazocine/naloxone had lower pain than placebo (P
0.0024 and 0.0084, respectively) but did not test different from each
other.
90
Male
80
Female
70
within either the placebo and ibuprofen groups showed similar pain levels
whether they were male or female, patients within the pentazocine/naloxone
group did not. Male patients within this latter group showed significantly higher
average postoperative pain scores than female patients receiving the same drug
with overall average postoperative pain of 38.4 (male) versus 11.2 (female).
Next we evaluated whether gender of the patient was associated
with treatment effects. Considering all medication groups, men had
higher pain scores than women, by 8 points on average (data not
shown), but this was not statistically significant (P 0.18). The group-
by-sex interaction, which addresses the question of whether the sexes
differ in their VAS measurements averaged over the five time periods,
was also not statistically significant (P 0.074).
However, an interesting finding occurred within the pentazocine/
naloxone group of patients when we analyzed the five time periods for
each gender with the addition of pretreatment VAS as a covariate (Figure
2). Of the patients taking pentazocine/naloxone, men had consistently
higher post-operative pain levels than women, and this difference was
statistically significant (P 0.007). As shown in Figure 3 below, men
and women demonstrated very similar average VAS measurements in
the ibuprofen and placebo groups over the five time periods, whereas
male patients had higher average pain scores with pentazocine/nalox-
one when compared to female patients in this group (38.4 vs 11.2).
As seen earlier in Figure 2, the pre-treatment pain scores for male
patients within the pentazocine/naloxone group were slightly higher

60
VAS Score

50

40

30

20

10

0
Pre-Treatment 0 hr 6 hr 12 hr 18 hr 24 hr
Time

Figure 2. Pentazocine/naloxone: sex-by-time interaction. For female endodon-

tic pain patients taking pentazocine/naloxone, pain levels consistently remain
low and flat over time. For male endodontic pain patients in this drug group,
pain levels remain elevated from 6 to 24 hours compared with female VAS
scores. Of the patients taking pentazocine/naloxone, with the addition of initial
VAS score as a covariate, men had consistently higher pain levels than women,
and this difference was statistically significant (P 0.007). Error bars
standard error of the mean (SEM), n 14.
Figure 4. For the pentazocine/naloxone group of patients, the overall reduction
of pretreatment pain was greater in female endodontic pain patients. The re-
duction in pretreatment pain was calculated for each patient based on the
following formula: ([pretreatment VAS score postoperative VAS score]/pre-
treatment VAS score) 100 at each time point and averaged over the 24-hour
period. This calculation was completed to account for the difference seen with
male and female pretreatment VAS scores in this group of patients.

554 Ryan et al. JOE Volume 34, Number 5, May 2008


than for the female patients. To adjust for this difference, we examined
the reduction in pretreatment pain using the formula [pre-treatment
VAS score post-operative VAS score)/pre-treatment VAS score]
100 at each time point and calculated the percent reduction in pre-
treatment pain over the 24 hours after treatment. Male patients within
this group showed a 54.8% reduction of pre-treatment pain, compared
to an 82.7% reduction in female patients (Figure 4). The ibuprofen and
placebo groups showed no significant differences in pain reduction
between males or females (Placebo group: male 50.4% vs. female
54.4%. Ibuprofen group: male 78.8% vs. female 76.8% reduction of
pre-treatment pain).
Side effects associated with the use of pentazocine/naloxone were
consistent with previous studies, with some patients reporting one or
more of the following: dizziness, light-headedness, sedation, nausea,
and emesis.
Discussion
Analgesic regimens to combat postoperative endodontic pain are
often based on the severity of the patients preoperative pain level.
Because pain can range from mild to severe, a flexible analgesic pre-
scription strategy is recommended (24). NSAIDs, such as ibuprofen,
are a popular choice among endodontists (25) and have been shown to
adequately manage mild to moderate dental pain (9, 10). When post-
operative pain becomes more severe, the addition of a centrally acting
opioid to the NSAID is often effective (3, 12). This is explained by the fact
that opioids and NSAIDs produce analgesia by different mechanisms,
and the additive effect of administering an opioid in combination with an
NSAID is often greater than the analgesia achieved by doubling the dose
of either drug administered alone (26).
In this clinical trial, 43 patients were randomized to receive one of
three medications: lactose (placebo), 600 mg ibuprofen alone, or 50
mg pentazocine/0.5 mg naloxone (Talwin NX) for 5 total doses (one
every 6 hours). An NSAID/opioid combination group was not included
in this study. The placebo was included to serve as a negative control for
the analgesic. The analgesic effects of ibuprofen alone were investigated
because of its superior anti-inflammatory properties and effectiveness
in managing dental pain (9, 10, 27). In this sense, ibuprofen served as
a quasi-positive control. Finally, pentazocine/naloxone was included to
investigate its analgesic effects, particularly with regard to different an-
algesic responses between males and females.
With these three medication groups, a consideration for not in-
cluding an NSAID/opioid combination group was the fact that a previous
clinical trial showed no statistically significant difference between pen-
tazocine/naloxone and the ibuprofen pentazocine/naloxone group at
any time period (0, 6, 12, 18, and 24 hours) (28). Furthermore, the
same authors suggested in their discussion that the addition of ibupro-
fen could have masked the female/male difference in the ibuprofen plus
pentazocine/naloxone group via its contribution to analgesia.
Although we studied pentazocine/naloxone alone as a treatment
group in the current study, we do not recommend prescribing opioid
analgesics alone for the management of postoperative endodontic pain.
This is because of the fact that the use of most opioids, including pen-
tazocine/naloxone, is generally limited by adverse side effects including
(but not limited to) nausea, emesis, dizziness, drowsiness, respiratory
depression, constipation, and neuropsychiatric effects such as halluci-
nations (13, 29, 30). Therefore, if needed for severe pain, a combina-
tion NSAID/opioid formulation is preferred because it permits the use of
a lower dose of the opioid, thereby reducing the side effects (31).
The results of this clinical trial revealed several significant findings.
Ibuprofen provided consistently greater analgesia (ie, lower pain
scores) than both pentazocine/naloxone and placebo throughout the
JOE Volume 34, Number 5, May 2008
Clinical Research
five time periods. Specifically, ibuprofen provided significantly greater
analgesia than placebo at 6 hours (P 0.0014), and both ibuprofen
and pentazocine/naloxone provided significantly greater analgesia than
placebo at 12 hours (P 0.0024 and 0.0084, respectively). At no point
throughout the study did ibuprofen show a statistically significant dif-
ference from pentazocine/naloxone. These findings lend further sup-
port to the use of ibuprofen for the management of postoperative dental
pain and provide evidence that it is an effective analgesic for the specific
management of endodontic pain during the first 24 hours after treat-
ment.
Perhaps the most interesting finding of the study was the statisti-
cally significant difference between men and women in analgesic re-
sponse to pentazocine/naloxone. Within the pentazocine/naloxone
group, female patients experienced significantly greater analgesia com-
pared with male patients (P 0.007). This contrasts with the analgesic
response to ibuprofen and placebo in men and women, with neither
medication group showing statistically significant differences between
the sexes.
The sex difference in response to pentazocine/naloxone reveals
several potential indications for its use in the management of postoper-
ative endodontic pain. Although the ibuprofen group showed consis-
tently lower pain levels than pentazocine/naloxone or placebo through-
out this clinical trial, many patients cannot take NSAIDs because of
intolerance or allergic/adverse reactions to this class of drugs. Further-
more, some patients cannot take acetaminophen because of liver dys-
function (ie, hepatitis and cirrhosis). For these individuals, particularly
female patients, pentazocine/naloxone could be an effective analgesic
when other nonnarcotic options are contraindicated. Although other
pain studies using different models have shown sex-dependent differ-
ences in analgesia, no studies currently exist in the endodontic literature
showing a significant difference in analgesia between the sexes. In a
series of oral surgery studies, Gear et al. (23, 32, 33) showed a more
robust analgesic response to pentazocine, butorphanol, and nalbu-
phine in women compared with men after the extraction of impacted
third molars. In a hospital emergency room study, females had better
pain scores in response to butorphanol compared with morphine at 60
minutes, whereas males responded with better pain scores in response
to morphine compared with butorphanol (34). The results of these
studies highlight sex differences in analgesia shown by -opioid recep-
tor agonists, and these findings may generally apply to this class of
opioid analgesics (33).
In an endodontic model similar to this studys, Jureidini (28)
showed no statistically significant difference between the sexes at any
time period for patients taking pentazocine/naloxone or an ibupro-
fen pentazocine/naloxone combination. However, a trend was noted
with pentazocine/naloxone alone (P 0.059) for higher analgesic
efficacy in females compared with males using the Heft-Parker pain
scale at 6 hours. The authors speculated that this trend might reach
significance if the number of subjects enrolled was larger.
When comparing the protocol of the current study to Jureidinis,
one difference that may account for the significantly greater analgesic
response to pentazocine/naloxone in women is that the dose was 50 mg
in the current study and 100 mg in Jureidinis study (28). Previous
research by Gear et al. (33) showed that a 10-mg dose of the -opioid
nalbuphine produced better analgesia in females than a 20-mg dose and
that a 5-mg dose resulted in an increase in pain in males as compared
with placebo. The authors suggested that nalbuphine possesses an an-
tianalgesic effect as well as an analgesic effect. If so, then the observed
analgesic sex difference could have resulted from differing proportions
of antianalgesic/analgesic effects in women and men, with men having a
proportionally greater analgesic effect (33).
Gender Differences in Analgesia for Endodontic Pain 555
Clinical Research
Neuropsychiatric effects, such as hallucinations, were not re-
ported in this study with 50 mg pentazocine/naloxone. In contrast,
two patients reported hallucinations in Jureidinis clinical trial with 100 mg
pentazocine/naloxone (28). Previous research has shown that neuro-
psychiatric effects are dose dependent (31), which supports the differ-
ent side effects between these two studies. Clinicians must consider the
potential for these adverse effects when prescribing pentazocine/nalox-
one as well as other opioid analgesics.
The sex-dependent difference in analgesic response is an interest-
ing physiologic phenomenon. With sex playing a role in the pharmaco-
dynamics of the analgesic, new doors are opened allowing clinicians to
tailor their pain-management strategies more to the individual patient.
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JOE Volume 34, Number 5, May 2008