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Adrian D. Best, BDSc, MB, ChB, BTh, MDS, FRACDS, R.K. De Silva, BDS,
FDSRCPS, FFDRCSI, FDSRCS, W.M. Thomson, BSc, BDS, MComDent, MA, PhD,
Darryl C. Tong, BDS, MB, ChB, MSD, PhD, FFDRCSI, FDSRCS, FACOMS, FACS,
MRSNZ, Claire M. Cameron, BSc, DipGrad, MSc, PhD, Harsha L. De Silva, BDS,
MS, FDSRCS, FFDRCS
PII: S0278-2391(17)30504-9
DOI: 10.1016/j.joms.2017.04.045
Reference: YJOMS 57798
Please cite this article as: Best AD, De Silva RK, Thomson WM, Tong DC, Cameron CM, De Silva
HL, The efficacy of codeine when added to paracetamol (acetaminophen) and ibuprofen for relief of
postoperative pain after surgical removal of impacted third molars: a double-blind randomised control
trial, Journal of Oral and Maxillofacial Surgery (2017), doi: 10.1016/j.joms.2017.04.045.
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The efficacy of codeine when added MANUSCRIPT
to paracetamol (acetaminophen) and ibuprofen for relief
Adrian D. Best, BDSc, MB, ChB, BTh, MDS, FRACDS,1 R. K. De Silva, BDS, FDSRCPS, FFDRCSI,
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FDSRCS,2 W. M. Thomson, BSc, BDS, MComDent, MA, PhD,3 Darryl C. Tong, BDS, MB, ChB, MSD,
PhD, FFDRCSI, FDSRCS, FACOMS, FACS, MRSNZ,4 Claire M. Cameron, BSc, DipGrad, MSc, PhD,5
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Harsha L. De Silva, BDS, MS, FDSRCS, FFDRCS.6
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1. Former Oral and Maxillofacial Surgery Registrar, University of Otago, New Zealand.
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2. Associate Professor, Oral and Maxillofacial Surgeon, University of Otago, New Zealand.
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3. Professor, Dental Epidemiologist, University of Otago, New Zealand.
Email: adrianucx@gmail.com
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KEYWORDS: Dental. Pain. Wisdom MANUSCRIPT
teeth. Third molars. Postoperative. Analgesia. Non-
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Abstract
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Background: The use of opioids in combination with nonopioids is common practice for
acute pain management after third molar surgery. One such combination is
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paracetamol/ibuprofen/codeine. We assessed the efficacy of codeine when added to a
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paracetamol/ibuprofen regimen for pain relief following third molar surgery.
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Methods: This study was a randomised, double-blind, placebo-controlled trial conducted
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in patients undergoing the surgical removal of at least one impacted mandibular third
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molar requiring bone removal. Participants were randomly allocated to either a control
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Postoperative pain was assessed using visual analogue scales every 3 hours (while
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awake) for the first 48 hours following surgery. Pain was globally assessed using a
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Results: There were 131 participants (36% male), with 67 in the control group and 64 in
the intervention group. Baseline characteristics were similar for both groups. Data were
analysed using a modified intention-to-treat analysis and, for this, a linear mixed model
was used. The model showed that the baseline VAS score was associated with the
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subsequent VAS scores and that, MANUSCRIPT
with each 3hr period, the VAS score increased by an
average of 0.08. The treatment effect was not statistically significant, indicating there
was no difference in recorded pain levels between the two groups over the first 48 hours
following mandibular third molar surgery. Similarly, the two groups did not differ in
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Conclusion: Codeine 60mg added to a paracetamol 1000mg/ibuprofen 400mg regimen
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does not improve analgesia following third molar surgery.
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Introduction
Despite major advances being made in pain management, acute postoperative pain remains an
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important clinical problem following third molar surgery. Patients undergoing outpatient
severe intensity, even when given optimal doses of oral opioid and or nonopioid analgesics.1-7
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Using opioids in combination with nonopioids is a common strategy for managing acute pain
following third molar surgery. The rationale for this is that combinations of opioid and
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paracetamol (acetaminophen) are relatively safe and effective analgesics with minimal adverse
effects when prescribed and used correctly. By contrast, codeine (a weak opioid) has the
potential for significant adverse effects such as nausea, vomiting, constipation, sedation,
dizziness, seizures, respiratory ACCEPTED MANUSCRIPT
depression and even addiction. Moreover, some people are
unable to convert codeine into morphine, the agent responsible for codeine’s analgesic effect.8 9
following third molar surgery. However, is it a necessary analgesic in this context? It may be
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beneficial to patients if it could be demonstrated that codeine is not needed. We investigated
the hypothesis that the addition of codeine 60mg 6 hourly to a regimen of paracetamol
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1000mg 6 hourly and ibuprofen 400mg 8 hourly does not improve analgesia following
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mandibular third molar surgery involving bone removal.
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Methods
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This study was approved by the Health and Disability Ethics Committee, New Zealand (ethics
committee reference number: 13/STH/35). It was also approved by the University of Otago
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Human Ethics Committee, New Zealand (ethics committee reference number: 13/080).
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The study was a double-blind randomised control trial conducted at the University of Otago,
New Zealand. Recruitment, surgery and follow-up took place between November 2013 and
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September 2014.
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We included adults requiring the removal of at least one mandibular third molar for which
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bone removal was expected, with or without removal of one or more upper third molars.
Anticipated bone removal was considered necessary to ensure adequate postoperative pain
intensity among participants. All participants had to be medically fit for third molar surgery
requiring a medication with analgesic properties which was not able to be ceased prior to and
for the duration of the study; needed to drive a motor vehicle or operate machinery within 48
hours following surgery; had a history of NSAID-sensitive asthma, peptic ulceration, bleeding
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lactose intolerance, respiratory depression, chronic obstructive pulmonary disease, opioid
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phenylketonuria, myasthenia gravis, glaucoma, osteoporosis, or psychosis, or were currently
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pregnant or breastfeeding; were taking an anticoagulant, hepatic enzyme inducer, or central
nervous system depressant; were suffering from systemic viral, bacterial or fungal infection; or
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if the clinician deemed for any other reason that participation in the study might be
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contraindicated.
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Having obtained informed written consent for participation and surgery, participant
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characteristics at baseline were obtained, including: mean age; sex; ethnicity; highest
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education level attained; current smoking status; the short-form Oral Health Impact Profile
(OHIP-14)10; Locker’s global oral health item11; the Dental Anxiety Scale (DAS)12; history of
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third molar pain; the type and number of mandibular impactions; and, the number of
mandibular and maxillary third molars to be removed. Any active pericoronitis associated
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with third molars intended for removal was treated and resolved prior to surgery.
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We assigned participants randomly to either the control group or the intervention group.
Block randomisation13 was the method used to generate the random allocation sequence. The
reason for this choice was to ensure balanced randomisation (that is, groups of approximately
equal number) right throughout the course of the study. The biostatistician involved in this
study generated this sequence. Implementation of the random allocation sequence was
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delegated to the hospital pharmacist, the only MANUSCRIPT
nonblinded person involved in the study. Based
off-site at the Dunedin Public Hospital, this individual was the only person in possession of the
random allocation sequence. Accordingly, as and when participants were recruited, the
pharmacist was asked to assign participants to their groups by simply progressing down the
allocation sequence. Each participant was given a randomisation number by the pharmacist.
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Participants allocated to the control group received paracetamol 1000mg plus a placebo orally
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6 hourly, and ibuprofen 400mg orally 8 hourly, commencing immediately postoperatively and
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continuing for at least the 48-hour duration of the study. The placebo was a gluten-free,
artificial sweetener containing aspartame, and it was similar to a codeine tablet in appearance.
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Participants in the intervention group received the identical regimen to the control group
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except that the placebo had been replaced by codeine 60mg. All participants were operated on
by the same surgeon, who used a standardised surgical technique. All participants required
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bone removal with a drill for at least one mandibular third molar. All surgical procedures were
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carried out under aseptic conditions, intravenous sedation with midazolam (titrated dose) and
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dexamethasone 8mg, and with mepivacaine 2% (1:100 000 adrenaline) local anaesthetic for
blocks and infiltration. Additionally, all participants were asked to use 0.2% chlorhexidine
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mouthwash three times daily for one week, commencing the day after surgery.
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If participants required additional postoperative pain relief, the oral and maxillofacial surgery
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team responsible for the study was available 24 hours a day via its on-call service through
Outcome variables
Postoperative pain was primarily measured using a non-graduated 100mm visual analogue
scale (VAS), labelled “no pain” at the left pole and “worst pain imaginable” at the right pole.
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Each participant made a baseline MANUSCRIPT
postoperative VAS measurement, followed by multiple
postoperative VAS measurements recorded at home every 3 hours, while awake, for the first
Postoperative pain was also assessed using a postoperative questionnaire completed during a
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review appointment with the surgeon on the third day following surgery. This comprised a
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prescribed treatment schedule, and whether rescue analgesia or other medical intervention
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had been necessary. One item exploring the participant’s overall perception of postoperative
pain used a verbal rating scale, with the response options of no pain, mild pain, moderate pain,
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severe pain, or excruciating pain/agony.
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Data upon which to undertake a power analysis for the current study were scarce. However,
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for an anticipated effect size of 0.5, an α value of 0.05 and a power of 0.8 to detect a difference,
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Statistical analyses
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The VAS data were analysed using an intention-to-treat approach because this gives a more
intention-to-treat approach was used because one participant was missing all VAS data
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subsequent to the baseline VAS and so was left out of the analysis. A linear mixed model (with
Results
A total of 150 patients were assessed for eligibility to participate in the study (Figure 1). Of
these, 19 did not meet the eligibility criteria and were excluded. All remaining 131 patients
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(87.3%) consented to participate and so were MANUSCRIPT
enrolled in the study and subsequently allocated
randomly to either the control group or the intervention group. The random allocation process
yielded 67 participants in the control group, all of whom received their allocated control
regimen, and 64 participants in the intervention group, all of whom received their allocated
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the control group discontinued their prescribed treatment: 1 did not adhere to the treatment
schedule, and 2 required rescue medication. Similarly, 2 participants in the intervention group
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discontinued their prescribed treatment: 1 did not adhere to the treatment schedule, and 1
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required rescue medication. These participants were not excluded from the data analysis. All
67 participants in the control group were included for analysis, but only 63 of the 64
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participants from the intervention group were included for analysis, since the excluded
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participant did not submit any VAS data at all.
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Baseline data
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The two groups were similar at baseline for age, sex, ethnicity, education level, smoking status,
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mean OHIP-14 score, impact prevalence, and DAS data (Table 1). They were also similar in
their third molar pain at baseline prior to surgery (Table 2), the type and number of
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mandibular third molar impactions, and the total number of mandibular and maxillary third
Figure 2 shows the mean VAS score at each time point for both groups. There does not appear
score as the dependent variable and the baseline VAS, intervention, time and an intervention-
by-time interaction term. Akaike’s Information Criterion (AIC) was used to determine whether
the interaction term was required in the model. The assumptions of the model were checked
and were found to be adequately met. The interaction term was found to be not required, and
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so it was omitted from the model.
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The linear mixed model showed that the baseline VAS score was associated with the
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subsequent VAS scores and that, as time passed, the VAS score increased (Table 4). With each
3hr period, the VAS score increased by an average of 0.08. The treatment effect was not
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significant, indicating no difference in recorded pain levels between the control and the
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intervention group. The control group and the intervention group did not differ in their pain
Analysis of the verbal rating scale for global postoperative pain, in which the five categories of
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this rating scale were treated as an ordinal variable, demonstrated no statistically significant
difference between the control and intervention groups in overall postoperative pain
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experienced over the first 48 hours following third molar surgery (Table 5). To confirm this,
the rating scale was additionally treated as a continuous variable and the means were
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compared. Once again, there was no significant difference between the two groups (p=0.16).
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Adverse events
During the follow-up period, 12 of the 67 control participants (18%) and 4 of the 64
intervention participants (6%) claimed that their prescribed treatment schedule did not
provide sufficient pain relief for the first 48 hours following third molar surgery. Of these, 2
participants from the control group resorted to rescue medication, with both claiming that the
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alternative medication provided MANUSCRIPT
sufficient pain relief. Similarly, 1 participant from the
intervention group resorted to rescue medication but found no additional pain relief from the
alternative medication. Finally, no participant from the control group reported visiting a
medical practitioner for postoperative pain, whereas 2 participants from the intervention
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Discussion
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This study confirmed the hypothesis that the addition of codeine 60mg 6 hourly to a regimen of
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paracetamol 1000mg 6 hourly and ibuprofen 400mg 8 hourly does not improve analgesia
following mandibular third molar surgery involving bone removal. The finding is consistent
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with previous evidence showing that codeine-containing regimens are of no greater efficacy
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than other postoperative analgesia regimens for third molar surgery.1 5 14-21
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Codeine is a weak opioid with questionable analgesic benefit. It is associated with potential
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adverse effects including nausea, vomiting, constipation, sedation, dizziness, seizures, and
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unable to convert codeine into morphine for effective analgesia.8 9 Codeine also has the
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potential for substance abuse and addiction in susceptible individuals.22 Opioid use, misuse
and addiction is on the rise, and opioid addiction has reached epidemic proportions in many
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countries including the USA, Canada, various European nations, Australia, New Zealand, and
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South Asia.23 24 These issues ought to prompt a warning for clinicians on the prescription of
codeine for patients. There are safer, more effective analgesics available.
To our knowledge, this study is the first to evaluate pain relief following third molar surgery by
1000mg/ibuprofen 400mg/codeine 60mg. The main strength of the study was that
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participants were both randomly allocatedMANUSCRIPT
and blinded for the intervention, and all
investigators were blinded. Additional strengths included its multi-dosing protocol, 48-hour
Missing VAS information was a limitation. Participant sleep periods are a plausible explanation
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for the majority of these missing data. A second (and arguably minor) explanation for some of
the missing VAS data could be unintentional non-adherence by participants. This issue may
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have been improved by a simpler study protocol for VAS data collection, such as standardising
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the time of surgery and postoperative VAS recordings. For example, all operations commence
at 9am with postoperative VAS recordings at 12pm, 3pm, 6pm, and 9pm on the day of surgery,
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9am, 12pm, 3pm, 6pm, 9pm the following day, and 9am and 12pm the next day. Another
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limitation was that the sample mainly comprised young adults. This was unavoidable because
the greatest need for third molar surgery is among people in their late teenage years and early
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twenties. A third limitation was the study duration. While its 48-hour duration is longer than
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many comparable studies and hence may be considered a strength, 48 hours may equally be
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viewed as a limitation because pain after third molar surgery often continues after the second
day. Nevertheless, a 48-hour duration was decided on because it is clinically relevant, and a
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study of longer duration is likely to have resulted in poorer adherence to data collection.7 A
displaced tooth) which may contribute to pain in the postoperative period. Finally, the study
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may have been more robust if medication side-effects, length of surgery, and potential
In conclusion, this study has shown that codeine does not provide better analgesia following
Dentists, oral surgeons, and oral and maxillofacial surgeons should be discouraged from using
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codeine after third molar surgery MANUSCRIPT
because there are safer, more effective alternatives for pain
relief. Such a recommendation may meet some opposition from clinicians who routinely
prescribe codeine and who have anecdotal evidence to the contrary. However, we assert a
movement away from codeine for postoperative pain management in third molar surgery is in
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Funding and treatment fees
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All consumable expenses (such as medications, surgical materials, cannulas), surgical
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equipment, sedation equipment, and University staff required for this study were funded
completely by the University of Otago. Patient payment for the surgical removal of their third
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molars under intravenous sedation followed the standard fee policy set by the School of
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Dentistry, University of Otago.
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Conflicts of interest
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The authors declare that there were no conflicts of interest in relation to this study. No
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individual had a financial or personal relationship with any party or product that could bias
this research.
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Additional contributions
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We thank Andria McGhie, the clinical trials pharmacist at Dunedin Public Hospital, for
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assigning participants to their groups and for preparing and dispensing the medications used
in this study. A word of appreciation is also reserved for all auxiliary staff involved in this
research (dental assistants, registered nurses, receptionists, and administrators) who work in
the Department of Oral Diagnostic and Surgical Sciences at the University of Otago.
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10 Slade GD: Derivation ACCEPTED
and validationMANUSCRIPT
of a short-form oral health impact profile.
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12 Corah NL: Development of a dental anxiety scale. J Dent Res 48:596, 1969.
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model. Clin J Pain 29:492-98, 2013.
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tablets for relief of postoperative pain after removal of impacted third molars. Br J Oral
18 Lysell L, Anzen B: Pain control after third molar surgery: a comparative study of
16:151-60, 1992.
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19 Forbes JA, Kehm CJ, Grodin MANUSCRIPT
CD, Beaver WT: Evaluation of ketorolac, ibuprofen,
20 Habib S, Matthews RW, Scully C, Levers BGH, Shepherd JP: A study of the comparative
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postoperative pain by preoperative administration of ibuprofen in comparison to
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Table 1: Participant characteristics at baseline,MANUSCRIPT
by group (brackets contain percentages unless
otherwise indicated).
Sex
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Number of males 22 (32.8) 25 (39.1)
Number of females 45 (67.2) 39 (60.9)
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Ethnicity
Pakeha 44 (65.7) 42 (65.6)
Other 23 (34.3) 22 (34.4)
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Highest education level attained
Secondary 15 (22.4) 14 (21.9)
Tertiary 52 (77.6) 50 (78.1)
OHIP-14a at baseline
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DASb at baseline
Mean DAS (SD) 8.9 (3.4) 9.0 (3.5)c
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Dental anxiety
Dentally anxious 13 (19.4) 11 (17.5)c
Not dentally anxious 54 (80.6) 52 (82.5)
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Third molar pain in last 4 weeks
Always 5 (7.5) 4 (6.3)
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Often 13 (19.4) 17 (26.6)
Sometimes 12 (17.9) 13 (20.3)
Occasionally 15 (22.4) 14 (21.9)
Never 22 (32.8) 16 (25.0)
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Mean preoperative VASa (SD) 3.6 (8.3) 6.3 (14.2)
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aVAS = visual analogue scale (range of possible scores, 0-100mm)
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Table 3: Type and number of mandibular MANUSCRIPT
impactions, and number of mandibular and
maxillary third molars removed, by group (brackets contain percentages).
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Vertical 30 (24.2) 21 (18.3)
Horizontal 30 (24.2) 21 (18.3)
Transverse 1 (0.8) 0 (0.0)
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Inverted 0 (0.0) 0 (0.0)
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1 mandibular only 5 (7.5) 5 (7.8)
1 mandibular + 1 maxillary 2 (3.0) 6 (9.4)
1 mandibular + 2 maxillary 3 (4.5) 2 (3.1)
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2 mandibular only 12 (17.9) 16 (25.0)
2 mandibular + 1 maxillary 11 (16.4) 9 (14.1)
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2 mandibular + 2 maxillary 34 (50.7) 26 (40.6)
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Table 4: Linear mixed model. ACCEPTED MANUSCRIPT
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aVAS = visual analogue scale (range of possible scores, 0-100mm)
bSE = standard error
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cCI = confidence interval
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Table 5: Global pain level over the MANUSCRIPT
first 48 hours following third molar surgery, by group
(brackets contain percentages).
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Severe 5 (7.5) 3 (4.7)
Excruciating (agony) 1 (1.5) 1 (1.6)
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