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Central sensitization phenomena after third molar surgery: A quantitative sensory testing study
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European Journal of Pain 12 (2008) 116–127 www.EuropeanJournalPain.com
Central sensitization phenomena after third molar surgery: A quantitative sensory testing study Gitte I. Juhl a
a,*
, Troels S. Jensen a, Sven E. Norholt b, Peter Svensson
c
Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark b Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, DK-8000 Aarhus C, Denmark c Department of Clinical Oral Physiology, School of Dentistry, University of Aarhus, DK-8000 Aarhus C, Denmark Received 6 November 2005; received in revised form 9 April 2007; accepted 10 April 2007 Available online 5 June 2007
Abstract Background: Surgical removal of third molars may carry a risk of developing persistent orofacial pain, and central sensitization appears to play an important role in the transition from acute to chronic pain. Aim: The aim of this study was to investigate sensitization (primarily central sensitization) after orofacial trauma using quantitative sensory testing (QST). Methods: A total of 32 healthy men (16 patients and 16 age-matched control subjects) underwent a battery of quantitative tests adapted to the trigeminal area at baseline and 2, 7, and 30 days following surgical removal of a lower impacted third molar. Results: Central sensitization for at least one week was indicated by significantly increased pain intensity evoked by intraoral repetitive pinprick and electrical stimulation (p < 0.05) including facilitation of temporal summation mechanisms (p < 0.05), extraoral repetitive electrical stimulation (p < 0.001), significantly more frequent aftersensation in patients (p < 0.001), extraoral hyperalgesia due to single pinprick stimulation (p < 0.05) and larger pain areas due to intranasal stimulation (p < 0.001). Peripheral sensitization was indicated by intraoral hyperalgesia due to single pinprick (p < 0.05). Conclusion: We found clear signs of sensitization of the trigeminal nociceptive system for at least one week after the surgery. Our results indicate that even a minor orofacial surgical procedure may be sufficient to evoke signs of both central and peripheral sensitization, which may play a role in the transition from acute to chronic pain in susceptible individuals. Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Human trigeminal physiology; Orofacial pain; Third molar surgery; Quantitative sensory testing; Sensitization
1. Introduction Why does acute pain become chronic? This is an important but still unsolved question. To improve chronic pain treatment or prevent chronic pain from developing, knowledge about the mechanisms responsi*
Corresponding author. Present address: Multidisciplinary Pain Center, Herlev Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. Tel.: +45 4488 4751. E-mail address: [email protected] (G.I. Juhl).
ble for the transition from acute to chronic pain is important (Woolf and Salter, 2000; Costigan and Woolf, 2000; Mantyh et al., 2002; Stubhaug, 2005). Peripheral sensitization of nociceptors and central sensitization of second order neurons in the dorsal horn or in the trigeminal nucleus are assumed to play a major role in the development of chronic pain after surgical procedures (Sessle, 2000; Jensen et al., 2001a). Tissue trauma due to surgical procedures inevitably starts an inflammatory reaction with the release of inflammatory mediators from the surroundings (Costigan and
1090-3801/$32 Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2007.04.002
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Woolf, 2000). Immediately after the tissue trauma, the production of an ‘‘inflammatory soup’’ takes place (Scholz and Woolf, 2002). This inflammatory soup is involved in the healing processes of the tissue, but at the same time it may sensitize the nociceptors in the tissue, thereby initiating a sensitization of higher order neurons as well. This may lead to hyperalgesia and allodynia: features that may serve protective functions in order to avoid further damage to the injured tissue (Sessle, 1999). In most cases the process is self-limiting, but in some cases the process may continue and produce prolonged and even chronic conditions of hyperalgesia and allodynia with or without spontaneous pain (Gottrup et al., 2006). Quantitative sensory testing (QST) can be used to assess the clinical manifestations of peripheral and central sensitization (Wilder-Smith et al., 2003; Cruccu et al., 2004) including the trigeminal area (Svensson et al., 2004). Central sensitization may be assessed by temporal summation: enhancement of pain intensity due to repetitive stimulation, increased frequency of aftersensations and increased occurrence of referred pain (Coderre and Katz, 1997; Jensen et al., 2001b). Trauma to the orofacial regions can produce sensitization peripherally and in the central nervous system. For example, Chiang et al. (2002) found central sensitization after dental trauma in rats. Moreover, we have recently provided evidence that peripheral sensitization may occur after surgical removal of third molars in healthy adults (Juhl et al., 2006). Thus, long-lasting mechanical sensitization for up to one month was present even in the absence of spontaneous pain and even after pain treatment with paracetamol for up to one week (Juhl et al., 2006). In this study, we focused on the clinical manifestations of central sensitization and for how long these may be detected using specific QST techniques after third molar surgery in humans. The subjects and surgical procedures in the present study are the same as in Juhl et al. (2006), but here we report an extensive set of novel QST findings related to central sensitization in the orofacial region, and none of the present results have been published before.
2. Materials and methods 2.1. Subjects The study was conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki and was approved by the local Ethics Committee for Aarhus County. Before signing the consent form, all subjects were informed of all study procedures by the investigator. Healthy males aged at least 18 years were eligible for the study if they were scheduled for elective removal of
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one or more third molars under local anaesthesia and at least one third molar was fully or partially impacted in the mandibular bone (patient group). A sex- and agematched group of males without prior or scheduled third molar surgery served as controls (control group). Subjects were excluded from the study for the following reasons: other painful physical conditions that might confound pain assessment, psychiatric or medical conditions that might impair communication or compliance with the study procedures, known drug abuse or contra-indications to paracetamol or local anaesthesia. Local anaesthesia (prilocaine 3% and felypressin 0.54 lg/mL) was used during standardized surgery procedures (Norholt, 1998). No subjects needed additional tranquillizers. One experienced oral surgeon (SEN) performed all surgical procedures. Postoperative pain treatment was paracetamol 0.5 g administered orally at a maximum of 8 times daily for one week. The subjects were allowed to take the paracetamol whenever it was needed, but no more than the maximum prescribed amount per day. They were allowed to take additional pain medication provided they informed the investigator. 2.2. Experimental design Sensitization can be investigated by using quantitative sensory testing (QST). Clinical manifestations of central sensitization were in this study investigated using repetitive stimulation assessing temporal summation, stimulation of adjacent areas (e.g. intranasal stimulation) and occurrence of aftersensation (Jensen and Baron, 2003). Furthermore, the skin under the lower lip at the termination of the inferior alveolar nerve (mental nerve) was stimulated. Mental nerve stimulation may provide information on: (1) possible central sensitization as the nerve is relatively protected against mechanical trauma in the bony canal; and (2) nerve involvement due to inflammatory processes in the operated area (Eliav and Gracely, 1998). Peripheral sensitization due to tissue trauma was investigated intraorally using single stimulation on the mucosa (gingiva/gum) adjacent to the lower first molar. A battery of QST techniques was used to activate different populations of nerve fibres. Thick von Frey hairs were used to stimulate Ad nerve fibres, whereas electrical stimuli bypassing the nociceptor were used to activate directly the nerve fibres (Eliav and Gracely, 1998). All orofacial QST was performed bilaterally. Tests on the extremities were used as an extra-trigeminal control. All tests were performed preoperatively (baseline) and postoperatively on days 2, 7 and 30 in the patient group. The control group underwent the same tests according to the same time schedule as the patient group. In the patient group, the contralateral side was always investigated first followed by the operated side. In the control group, the same procedure was followed:
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8 subjects were assigned to have the right side investigated first (first measurement), followed by investigation of the left side (second measurement); 8 subjects were assigned to have the left side investigated first (first measurement), followed by investigation of the right side (second measurement). The order of investigation for each subject was kept throughout the study. The same investigator (GIJ) carried out all tests.
3. Quantitative sensory tests 3.1. Single and repetitive stimulation Pinprick stimulation was evoked by applying a von Frey hair (75 g) (Fruhstorfer et al., 2001) as a single stimulation and after a period of 2 min as a repetitive stimulation for the assessment of temporal summation (5 stimuli at a rate of 2 Hz) (Gottrup et al., 2000; Baad-Hansen et al., 2003). Evoked pain intensity was scored on a numerical rating scale of 0–10 (NRS; 0 = no pain, 10 = unbearable pain). Assessment of temporal summation was performed by calculating delta values of pain intensity (delta value = evoked pain after 5 stimuli minus the value of evoked pain after one stimulus). Electrical stimulation is known to bypass the nociceptor receptor mechanism and was used for direct activation of the afferent nerve fibres (Gracely, 1999; Eliav and Gracely, 1998). Intraoral electrical pain thresholds (EPTs) in steps of 0.05–0.1 mA were assessed at the gingiva adjacent to the first molar and extraorally at the skin under the lower lip and at the extremity. The electrical stimulation was delivered from a constant current device (Aalborg University, DK) using a circular anode and cathode probe (diameters: 0.3/0.7 mm). Each stimulus lasted 0.5 ms. As soon as the EPT was reached, single stimuli with the intensity of EPT were applied to the subject, and the evoked pain was assessed on the NRS. Thereafter, a repetitive sequence of 5 stimuli was applied to the subject (computer controlled). Subjects scored the maximum evoked pain on the NRS after the 5 stimuli with the intensity of EPT. Temporal summation was calculated as described above. 3.2. Aftersensation Aftersensations, which may be consequences of central sensitization (Gottrup et al., 2003; Jensen and Baron, 2003), were reported by the subject after applying an ice cube intraorally at the buccal surface of the first molar. As soon as pain was experienced due to coldness, the stimulation was discontinued and the subject reported any occurrence of aftersensations intraorally. Aftersensations due to von Frey hair stimulation were reported as well.
3.3. Referred pain Central sensitization may involve adjacent regions, which may be sensitive when stimulated. In our study, we assessed the occurrence of referred pain by stimulating the nasal mucosa below the middle concha using a blunt wooden stick as described by Hutchins and Reynolds (1947) and Reynolds and Hutchins (1948). The stimulus was applied in the ipsilateral nasal cavity under direct vision using a 0 degree rigid nasoendoscope (AbuBakra and Jones, 2001). The subject assessed the maximum evoked pain on the NRS and mapped the area where the pain was felt on a drawing of the face. The mapped area of referred pain was subsequently calculated using a digitizer and dedicated software (Quantity; K.L.O.N.K). 3.4. Assessment of pain Stimulus-evoked pain was assessed on the NRS. Postoperative pain was also assessed on the NRS. Three times daily in the first postoperative week, and the assessments were recorded in a diary that was returned to the investigator at the end of the period. Summed pain intensity SPI2 was derived from diary recordings from the time after surgery (TO) and two days after (day 2). If pain persisted for a longer period, the patient continued the pain assessment until a pain-free condition was reached. The control group reported any presence of pain during the study to the investigator.
4. Statistics Unpaired t-test was used for comparison of age between the two groups. Baseline data from the orofacial region in the two groups were compared using two-way Analysis of Variance (ANOVA) with the factors group (control vs. patient) and side (right then left vs. left then right (i.e. first and second measurement) and control vs. operated side). Baseline data from the forearm in the two groups were compared using unpaired t-test or Mann–Whitney Rank Sum test. Separate two-way ANOVAs for each group were used to test for time effects (baseline, 2, 7 and 30 days) and for side differences (patient group: control side vs. operated side; control group: right side then left side or left side then right side). Separate one-way ANOVAs for each group were used to test for time effects at the forearm (baseline, 2, 7 and 30 days). Assessment of temporal summation was performed by using two-way ANOVAs to test for group effect and time effect at each side of delta values of pain intensity (delta value = evoked pain after 5 stimuli minus the value of evoked pain after one stimulus). To minimize baseline differences between calculated referred pain areas in the two groups, delta values were
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compared (baseline values were subtracted from the values at baseline, 2, 7 and 30 days). Two-way ANOVAs were used to test for time effects (baseline, 2, 7 and 30 days) and for group effects of baseline-corrected referred pain area. Fisher’s exact test was used for comparing the frequencies of aftersensation in the two groups. Due to not normally distributed data, the Friedman Repeated Measures Analysis of Variance on Ranks followed by multiple comparisons was used to test for time effects of postoperative pain intensity. Pearson Product Moment Correlation was used to test for correlations between Summed pain intensity (SPI2) and evoked pain intensity by von Frey hair, or between paracetamol consumption and postoperative pain intensity. Post-hoc tests were performed with Student–Newman–Keuls tests (SNK) to compensate for multiple comparisons. Missing data were not replaced. The level of significance was set at p < 0.05. Data are presented as mean values ± SEM if not otherwise specified.
5. Results A total of 32 healthy males were included: 16 patients (mean age 25.4 ± 2.6 years) with an impacted third molar and 16 control subjects (mean age 23.9 ± 2.2 years). The two groups were similar concerning demographics, including age (t-test: p = 0.082). No subject withdrew from the study. In the patient group, the impacted third molars were located as follows: 6 third molars were located on the right side and 10 third molars were located on the left side and 15 of these third molars were in a semiimpacted position (7 of these with a mildly irritated gingiva). The surgical procedures lasted 12 ± 5 min (range: 5–29 min) and the local anaesthetic volume used in the lower jaw was 3.7 ± 0.5 ml (range: 3.6–5.4 ml). Ipsilateral upper third molars were in 7 cases removed as well. There were no occurrences of serious adverse events during or after the study. Non-serious adverse events during the first postoperative week occurred in 8 patients: 4 patients experienced long-lasting bleeding (bleeding that persisted more than one day after the operation), 3 patients experienced headache, and 1 patient experienced extensive oedema (lasting for one week). In the control group there were no reports of adverse events or intake of medication.
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F = 1.02, p = 0.751) von Frey hair stimulation or for single (ANOVAs: F = 0.04, p = 0.831) or repetitive (ANOVAs: F = 0.83, p = 0.366) intraoral electrical stimulation. No significant differences between groups or sides could be detected for single (ANOVAs: F = 0.05, p = 0.826) or repetitive extraoral von Frey hair stimulation (ANOVAs: F = 1.28, p = 0.722) or single (ANOVAs: F = 0.006, p = 0.939) or repetitive (ANOVAs: F = 0.65, p = 0.423) extraoral electrical stimulation (ANOVAs: F = 1.02, p = 0.751). At baseline, no significant differences between groups could be detected for forearm von Frey hair single stimulation (Mann– Whitney: p = 0.235) or repetitive von Frey stimulation (t-test: p = 0.505) or electrical single stimulation (Mann–Whitney: p = 0.191) or electrical repetitive stimulation (Mann–Whitney: p = 0.406). 6.2. Single and repetitive von Frey hair stimulation 6.2.1. Patient group Intraorally, there was a significant side difference with increased evoked pain intensity at day 2 and day 7 on the operated side for both single (ANOVAs: F = 10.54, p = 0.006, Fig. 1B) and repetitive stimulations (ANOVAs: F = 9.83, p = 0.008, Fig. 1D). There was a tendency towards a significant effect with increased pain intensity on the operated side at day 30 for single stimulation (p = 0.078). Additionally, there was a significant interaction between time and side for repetitive stimulation with increased evoked pain intensity at day 2 on the operated side (ANOVAs: F = 5.11, p = 0.004, Fig. 1D) and likewise increased pain intensity at day 2 compared to day 30. There were no significant time effects for single (ANOVAs: F = 0.81, p = 0.498) or repetitive stimulation (ANOVAs: F = 1.65, , p = 0.193). Extraorally, there was a significant effect of single stimulation with increased evoked pain intensity on the operated side at day 2 and day 7 compared to the control side (ANOVAs: F = 5.07, p = 0.042, Fig. 1F). There was also a significant interaction between time and side with increased evoked pain intensity due to single stimulation on the operated side at day 2 compared to day 30, and a decreased pain intensity on the control side at day 30 compared to baseline (ANOVAs: F = 3.55, p = 0.02, Fig. 1F). No significant time effect (ANOVAs: F = 2.60, p = 0.07), side difference (ANOVAs: F = 3.50, p = 0.08), or interaction between time and side was found for repetitive stimulation (ANOVAs: F = 0.86, p = 0.468) (Fig. 1H).
6. Quantitative sensory testing 6.1. Single and repetitive stimulation At baseline, no significant differences between groups or sides could be detected for single (ANOVAs: F = 0.01, p = 0.908) or repetitive intraoral (ANOVAs:
6.2.2. Control group Intraorally, there was no significant time effect (ANOVAs: F = 2.65, p = 0.06), or side difference (ANOVAs: F = 0.62, p = 0.443), or interaction between time and side (ANOVAs: F = 0.60, p = 0.619) for single stimulation. There was no significant time effect (ANOVAs:
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Fig. 1. Intensity of evoked pain by von Frey hair stimulation (numeric rating scale [NRS]) at baseline (Bas), day 2 (D2), day 7 (D7), and day 30 (D30) in the two groups. Controls: Open circles – right side. Closed circles: left side. Patients: Open squares-control side. Closed squares-operated side. A,B: Intraorally evoked pain by one stimulation. C,D: Intraorally evoked pain by five stimulations. E,F: Extraorally evoked pain by one stimulation. G,H: Extraorally evoked pain by five stimulations. Evoked pain expressed as mean ± SEM. + indicates p < 0.05 compared to baseline (time effects), # p < 0.05 compared to side (side-to-side effect), *p < 0.05 compared to baseline (interactions between time and side); two-way ANOVAs.
F = 2.02, p = 0.125), or side difference (ANOVAs: F = 1.22, p = 0.286), or interaction between time and side (ANOVAs: F = 1.23, p = 0.309) for repetitive intraoral stimulations (Fig. 1A and C).
Extraorally, there was a significant time effect with decreased evoked pain intensity due to single (ANOVAs: F = 5.34, p = 0.003), or repetitive stimulations at day 7 and day 30 compared to baseline (ANOVAs:
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F = 4.21, p = 0.01) (Fig. 1E and G). There were no significant side difference (ANOVAs: F = 2.62, p = 0.126) or a significant interaction between time and side (ANOVAs: F = 0.03, p = 0.993) for extraorally evoked pain intensity due to single stimulation. There were no significant side difference (ANOVAs: F = 3.19, p = 0.094) or a significant interaction between time and side (ANOVAs: F = 0.25, p = 0.860) for extraorally evoked pain intensity due to repetitive stimulation . 6.3. Single and repetitive electrical stimulation 6.3.1. Patient group Intraorally, there was a significant side-to-side effect with increased evoked pain intensity at day 2 on the operated side compared to the control side for repetitive stimulation (ANOVAs: F = 5.73, P = 0.032, Fig. 2D). There were no significant time effect (ANOVAs: F = 0.81, p = 0.497) or interaction between time and side (ANOVAs: F = 1.81, p = 0.161) for repetitive stimulation. There was no significant time effect (ANOVAs: F = 0.45, p = 0.719), or side difference (ANOVAs: F = 0.45 p = 0.514) or interaction between time and side (ANOVAs: F = 0.40, p = 0.756) for single stimulation. Extraorally, a significant side-to-side effect with increased pain intensity on the operated side compared to the control side at day 2 and day 30 due to repetitive stimulation was observed (ANOVAs: F = 19.47, p < 0.001, Fig. 2H). Additionally, there was a tendency towards a significant effect with increased pain intensity on the operated side at day 2 due to single stimulation (ANOVAs: F = 4.50, p = 0.054, Fig. 2). No significant time effect (ANOVAs: F = 1.26, p = 0.301) or interaction between time and side (ANOVAs: F = 0.65, p = 0.588) was found for single stimulation. No significant time effect (ANOVAs: F = 1.67, p = 0.189) or interaction between time and side (ANOVAs: F = 2.18, p = 0.105) was found for repetitive extraoral stimulation. 6.3.2. Control group Intraorally, there was no significant time effect (ANOVAs: F = 0.90, p = 0.447) or side-to-side effect (ANOVAs: F = 0.08, p = 0.774) or interaction between time and side (ANOVAs: F = 0.85, p = 0.476) for single stimulation . There was no significant time effect (ANOVAs: F = 0.32, p = 0.813) or side-to-side effect (ANOVAs: F = 0.66, p = 0.429) or interaction between time and side (ANOVAs: F = 0.19, p = 0.884) for repetitive intraoral electrical stimulation (Fig. 2). Extraorally there was a significant side difference with increased evoked pain intensity on the ‘‘left side (second measurement)’’ due to repetitive stimulation at day 7 (ANOVAs: F = 15.00, p = 0.002, Fig. 2). There was no significant time effect (ANOVAs: F = 1.63, p = 0.196) or significant interaction between time and side (ANO-
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VAs: F = 2.69, p = 0.06) due to repetitive stimulation. There was no significant time (ANOVAs: F = 1.24, p = 0.946) or side-to side effect (ANOVAs: F = 0.04, p = 0.835) or interaction (ANOVAs: F = 1.72, p = 0.177) of single stimulation. 6.4. Temporal summation Comparison between groups of calculated delta values of evoked pain intensity at each side was used to assess temporal summation. Comparison was performed with the von Frey hair stimulations. Intraorally on the operated side, there was a significant interaction between group and time (ANOVAs: F = 2.71, p = 0.048, Fig. 3). Post-hoc analysis indicated that this significant finding was due to increased pain intensity on the operated side in the patient group at day 2 or day 7. Intraorally on the control side, there was no significant group effect (ANOVAs: F = 0.27, p = 0.606) or time effect (ANOVAs: F = 0.15, p = 0.933) or interaction between group and time (ANOVAs: F = 0.40, p = 0.753). 6.5. Referred pain 6.5.1. Pain intensity There were no significant findings of time (ANOVAs: F = 0.37, p = 0.773) or group effect (ANOVAs: F = 2.02, p = 0.158) or interaction between time and group (ANOVAs: F = 0.40, p = 0.752) of evoked pain intensity due to intranasal stimulation (Fig. 4). The patient perceived their pain referral and spread from the intranasal mucosa to the adjacent orofacial areas without any report of referred pain to the operated area. 6.5.2. Calculated area There was a significant group effect due to intranasal stimulation with a higher calculated area (d values) in the patient group than in the control group (ANOVAs: F = 14.92, p < 0.001, Fig. 5). There was no time effect (ANOVAs: F = 0.43, p = 0.733) or interaction between time and group (ANOVAs: F = 1.70, p = 0.171). 6.6. Aftersensations Subjects reported the occurrence of aftersensations due to application of ice or stimulation with von Frey hair. Aftersensations were more frequent in patients on the operated side than in control subjects at day 7 (Fishers exact test: p < 0.001, Table 1).
7. Postoperative pain intensity Postoperative pain was significantly higher at the day of surgery, median pain intensity 6 [25–75% range, 4–7.5, Friedman] and gradually decreased over the
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Fig. 2. Intensity of evoked pain by electrical stimulation (numeric rating scale [NRS], 0–10) at baseline (Bas), day 2 (D2), day 7 (D7), and day 30 (D30) in the two groups. Controls: Open circles – right side. Closed circles: left side. Patients: Open squares – control side. Closed squares – operated side. A,B: Intraorally evoked pain by one stimulation. C,D: Intraorally evoked pain by five stimulations. E,F: Extraorally evoked pain by one stimulation. G,H: Extraorally evoked pain by five stimulations. Evoked pain expressed as mean ± SEM. # indicates p < 0.05 compared to side (sideto-side comparison); *p < 0.05 compared to baseline (interactions between time and side); two-way ANOVAs.
following days (SNK: p < 0.001). One patient experienced shooting, unbearable pain (NRS = 10) in the ipsilateral trigeminal area during the first postoperative week. Postoperative acetaminophen (paracetamol) intake was significantly higher at the day of surgery (mean intake of tablets 5.6 ± 0.5) and gradually decreased here-
after (SNK: p < 0.001). There was a positive correlation between postoperative pain intensity and paracetamol consumption (Pearson: correlation coefficient r = 0.975, p < 0.001). Summed pain intensity SPI2 was positively correlated to intraoral repetitive von Frey stimulation pain inten-
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8. Discussion
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In this study, we have focused on the clinical manifestations and duration of central sensitization after third molar surgery in humans whereas our previously published data focused on peripheral sensitization after third molar surgery (Juhl et al., 2006). Although the subjects, the surgical procedures and some of the QST instruments in the present study are the same as in Juhl et al. (2006), the QST techniques used to measure central sensitization are completely different from those used to measure peripheral sensitization. The main new findings in this study investigating primarily central sensitization in patients undergoing third molar surgery were significant increases in evoked pain intensity intraorally and extraorally on the operated side due to repetitive stimulation with significant facilitation of temporal summation. In the patient group, we also found areas of increased orofacial pain due to intranasal stimulation, a significant occurrence of aftersensations and a positive correlation between summed pain intensity and intraoral pain intensity evoked by repetitive von Frey hair stimulation on the operated side at day 2. Furthermore, adaptation (decreased responsiveness to test stimuli) was observed in the control group to some of the tests during the one-month observation period. These findings indicate the development of central sensitization after minor orofacial surgery lasting for at least one week despite preoperative local anaesthetics and postoperative paracetamol treatment for up to one week after surgery.
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9. Methodological considerations
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Time Fig. 4. Referred pain. Intensity of evoked pain by intranasal stimulation (Numeric rating scale [NRS], 0–10) at baseline (Bas), day 2 (D2), day 7 (D7), and day 30 (D30) in the two groups. Controls: Closed circle. Patients: Closed squares. Evoked pain expressed as mean ± SEM. Two-way ANOVAs.
sity on the operated side at day 2 (Pearson: r = 0.54, p = 0.047). There was a tendency towards a positive correlation between SPI2 and intraoral single von Frey pain intensity on the operated side at day 2 (Pearson: r = 0.52, P = 0.057). There was no correlation between SPI2 and extraoral single (Pearson: r = 0.36, p = 0.208) or repetitive (Pearson: r = 0.07, p = 0.811) von Frey pain intensity at the operated side at day 2.
We chose to test the contralateral side first and then the operated side to avoid long and intense pain on the operated side, and thereby potentially influencing our measurements. In addition, this setting resembles the clinical approach to investigating pain patients where the unaffected side is normally investigated prior to the affected side. However, this procedure may have affected our results as side differences were found even in the control group. We found increased pain intensity evoked by electrical stimulation on the ‘‘left side (second measurement)’’ in the control group. Thus, the order of the measurement may affect the result. Still, side differences in the control group (only observed for electrical stimulation) were not as consistent as in the patient group. Thus, even though our procedure may have affected the results in the control group, we still suggest that the control side should be tested before the operated (affected) side. Otherwise there may be a risk to evoke severe and longer-lasting pain in the patients on the operated side that could instead interfere with the assessment of pain on the control side.
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Fig. 5. Areas of referred pain. Delta values of calculated areas (A) expressed as mean ± SEM (cm2); two-way ANOVAs.
Table 1 Number of subjects with aftersensations due to cold and/or von Frey hair stimulations
Controls Patients P-Value a
Baseline
Day 2
Day 7
Day 30
0/16 0/16 1a
0/16 3/15 0.11a
0/16 6/16 0.0002a
0/16 3/16 0.22a
Fishers exact test.
In our recent study on consequences of oral surgery, we have shown that inclusion of a control group may indirectly provide additional information on the changes that may happen in the patient group (Juhl et al., 2006). Pain conditions may due to central sensitization alter the somatosensory sensitivity on the contralateral side in patients (Jaaskelainen, 2004), thereby lowering the possibility of finding differences between the two sides in the patients. Inclusion of a control group is therefore recommended to ensure the validity of the results whenever central sensitization is investigated. Electrical stimulation did not produce consistent results, which could be explained by methodological issues. Single or repetitive stimulation was performed with electrical current equivalent to pain threshold. This procedure may have evoked less pain than required to show a robust difference. In future studies, a higher electrical stimulation may be needed. A blunt instrument was used to stimulate the nasal mucosa to avoid damage to surface. Because only mild or moderate pain was evoked, this may have resulted in less prominent findings than the original observations by Hutchins and Reynolds (1947). Nevertheless, we still
found increased areas of referred pain in the patient group compared to the control group. A more painful stimulation of the nasal mucosa would probably have resulted in the subjects withdrawing from the study because they all reported that the nasal stimulation was the most unpleasant stimulation of all the sensory modalities.
10. Sensitization in the orofacial region 10.1. Sensitization Central and peripheral sensitization involve several mechanisms. The release of inflammatory mediators after tissue trauma sensitizes Ad and C fibres peripherally and may start a central activation of different mediators including cyclo-oxygenase (cox) enzymes. Cox enzymes produce prostaglandines that increase the release of neurotransmitters, like glutamate, thereby increasing the possibility of activating the NMDA receptor (Costigan and Woolf, 2000; Ghilardi et al., 2004). Glutamate binds preferentially to the NMDA receptor, but this receptor is under normal circumstances blocked by a magnesium ion. Prolonged or more intense nociceptor activation enhances the risk of NMDA receptor activation and provides an opportunity for plasticity, temporal summation and central sensitization (Costigan and Woolf, 2000). Therefore, central sensitization is considered, in part, to be a consequence of NMDA receptor activation, and a dysfunction of the NMDA-dependent disinhibition of temporal
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summation could contribute to central sensitization (Woda et al., 2004). Other mechanisms such as activation of neurokinin-1 receptor and production of nitric oxide have been suggested to play a role as well (Woolf, 1994; Svensson et al., 2001; Jensen et al., 2001a). Thus, tissue trauma releases inflammatory mediators that may induce a neuronal inflammation without structural damage (Eliav et al., 1999). Neuronal inflammation develops after injection of complete Freund’s adjuvant (CFA) in rats (immune cells including macrophages, lymphocytes, and granulocytes were found in the nerves) and the percentage of mechanosensitive fibres increased (Eliav et al., 2001). 10.2. Oral sensitization Previously it has been shown that dental trauma in rats is associated with signs of central sensitization, critically dependent on subnuclei caudalis (Chiang et al., 2002) and oralis (Woda, 2003) of the trigeminal spinal tract nucleus. Yu et al. (1993) found that deep inputs in contrast to cutaneous inputs are especially effective in inducing neuroplastic changes in central nociceptive pathways (Yu et al., 1993). Similar to this, Kupers et al. (2004) found in a PET study of human jaw muscle pain that mechanical hyperaesthesia was associated with a unique activity in the thalamus and anterior subgenual cingulated. Thus, the development of central sensitization after a surgical procedure involving not only oral structures but also more deep structures may be due to neuronal inflammation and activation of subnuclei caudalis and thalamus. Yet, altered processing of somatosensory stimuli is unlikely to be restricted to either pure peripheral or central mechanisms, and central neuronal hyperexcitability changes may occur following peripheral sensitization (Dubner, 1992; Svensson et al., 1998; Woolf and Salter, 2000). 10.3. QST Standardized QST may help to demonstrate the clinical manifestations of central or peripheral sensitization (Eliav and Gracely, 1998; Wilder-Smith et al., 2003; Cruccu et al., 2004; Rolke, 2006; (Cruccu et al., 2004)). For example, intraoral and extraoral hyperalgesia due to repetitive stimulation may indicate central sensitization (Herrero et al., 2000; Gottrup et al., 2003). Extraoral hyperalgesia due to single stimulation may indicate a neuronal inflammation with increased mechanosensitivity at the termination of the nerve due to either central or peripheral sensitization (Eliav and Gracely, 1998). Intraoral increased pain intensity (hyperalgesia) due to single stimulation may indicate peripheral sensitization in the vicinity of the operated area.
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A series of studies have shown that increased pain following repetitive stimulation depends on central sensitization (Jensen et al., 2001b; Jensen and Baron, 2003). We observed in our study that patients experienced increased pain intraorally evoked by repetitive von Frey hair stimulation for up to one week postoperatively. Thus, activation of Ad fibres by von Frey hair supports the finding of central sensitization after third molar surgery. Electrical stimulation did not produce the same consistent results, which could be explained by low levels of evoked pain and therefore a smaller chance to find robust differences. We also observed extraoral hyperalgesia to single pinprick stimuli on the operated side in patients which supports our previous finding of extraoral hyperalgesia on the operated side due to pressure pain stimuli (Juhl et al., 2006). These findings are compatible with a sensitization that is either central or peripheral (Eliav and Gracely, 1998). In addition to central sensitization we found indications of peripheral sensitization. In patients, stimulation with von Frey hair evoked increased pain on the operated side compared to the control side for up to one week. This may indicate that Ad afferent fibres were sensitized. We failed to show increased pain evoked by single electrical stimulation either due to methodological reasons or because the nerve fibres were not adequately sensitized to cause significant findings whenever electrical stimulation was used. 10.4. Referred pain Referred pain, which was also present in the this study, is considered in part to depend on the convergence of impulses from the injured and referred regions on the same cells in the spinal cord (Coderre and Katz, 1997; Sessle, 1999; Wright, 2000). Thus, a nociceptive stimulus, like intranasal stimulation, may be perceived as arising from neighbouring regions including previous surgical areas (Falace et al., 1996). In our study, we found that intranasal stimulation in the patients produced referral and spread of pain to adjacent superficial orofacial areas, which could be explained by central sensitization of the trigeminal brainstem complex. An increased area of self-reported pain after a local injection of hypertonic saline into the orofacial muscles has previously been shown (Svensson et al., 1998). Likewise has spread of referred pain to intraoral structures after a local injection of hypertonic saline into orofacial muscles been seen (Svensson et al., 2003). Yet, no referred intraoral pain upon intranasal stimulation was found in our study. This result is in accordance with the original findings by Reynolds and Hutchins (1948) showing that dental procedures done under local anaesthesia did not result in referred pain to the orofacial area when the subjects were
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stimulated intranasally. In contrast, dental procedures done under general anaesthesia or without anaesthesia were associated with the development of referred pain elicited by intranasal pinprick stimuli to the previously treated areas (Hutchins and Reynolds, 1947). Thus, pre-treatment with local anaesthetics seems to block the nociceptive impulses for some time reducing the activation and sensitization of central neurons. 10.5. Aftersensations In the patient group, aftersensations were more frequently observed on the operated side than on the control side or in the control group. This result is in accordance with Gottrup et al. (2003) who found that aftersensation was more frequent in sensitized skin after nerve injury or capsaicin-sensitized skin than in contralateral normal skin. However, we found indications of mechanical sensitization without spontaneous pain in the patient group. The explanation for this feature may be that ongoing pain as well as mechanical hyperalgesia is dependent on separate molecular mechanisms (Gottrup et al., 2006). 10.6. Acute pain with high intensity Acute pain with high pain intensity in the early postoperative period after different surgical procedures (limb amputation, mastectomy, thoracotomy, gallbladder surgery, inguinal hernia surgery (Perkins and Kehlet, 2000) and caesarean section (Nikolajsen et al., 2004)) has been found to be a risk factor of chronic pain (Shipton and Tait, 2005). As expected, none of our patients developed chronic pain, but evidence of neuronal sensitization was still a prominent feature. Sensitization, especially central sensitization, is considered to play a significant role in the transition from acute to chronic pain (Jensen and Baron, 2003). In our study, we found a correlation between high postoperative pain intensity during the first 3 days after surgery and signs of sensitization. Reduction of postoperative pain intensity and thereby reduction of sensitization may reduce the risk for development of chronic pain. In conclusion, central and peripheral sensitization developed after third molar surgery in humans and lasted for at least one week in spite of pretreatment with local anaesthetic and postoperative administration of paracetamol. These results obtained in a human oral pain model are comparable to animal and human experimental studies demonstrating perturbed mechanosensitivity after different types of tissue trauma. Thus, even after minor orofacial surgery, sensitization can be detected, which may play a role in the transition from acute to chronic pain and point to the need for more specific pain management to prevent long-lasting sensitization and chronic pain.
Conflict of interest statement There are no conflicting interests.
Acknowledgements The present study was supported by grants from the Danish Pain Research Center, Aarhus University Hospital, Karen Elise Jensens’s Foundation, the Lundbeck Foundation and the Science Initiative of Aarhus University Hospital, Denmark.
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G.I. Juhl et al. / European Journal of Pain 12 (2008) 116–127 Herrero JF, Laird JM, Lopez-Garcia JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 2000;61:169–203. Hutchins HC, Reynolds OE. Experimental investigation of the referred pain of aerodontalgia. J Dent Res 1947;26:3–8. Jaaskelainen SK. Clinical neurophysiology and quantitative sensory testing in the investigation of orofacial pain and sensory function. J Orofac Pain 2004;18:85–107. Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 2003;102:1–8. Jensen TS, Gottrup H, Kasch H, Nikolajsen L, Terkelsen AJ, Witting N. Has basic research contributed to chronic pain treatment? Acta Anaesthesiol Scand 2001a;45:1128–35. Jensen TS, Gottrup H, Sindrup SH, Bach FW. The clinical picture of neuropathic pain. Eur J Pharmacol 2001b;429:1–11. Juhl GI, Svensson P, Norholt SE, Jensen TS. Long-lasting mechanical sensitization following third molar surgery. J Orofac Pain 2006;20: 59–73. Kupers RC, Svensson P, Jensen TS. Central representation of muscle pain and mechanical hyperesthesia in the orofacial region: a positron emission tomography study. Pain 2004;108:284–93. Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP. Molecular mechanisms of cancer pain. Nat Rev Cancer 2002;2:201–9. Nikolajsen L, Sorensen HC, Jensen TS, Kehlet H. Chronic pain following Caesarean section. Acta Anaesthesiol Scand 2004;48: 111–6. Norholt SE. Treatment of acute pain following removal of mandibular third molars. Use of the dental pain model in pharmacological research and development of a comparable animal model. Int J Oral Maxillofac Surg 1998;27(Suppl. 1):1–41. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology 2000;93: 1123–33. Reynolds OE, Hutchins HC. Reduction of central hyper-excitability following block anesthesia of peripheral nerve. Am J Physiol 1948;152:654–62. Rolke R. Quantitative sensory testing in the German Research Network on neuropathic pain (DFNS): Standardized protocol and reference values. Pain 2006;123:231–43. Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002;5(Suppl.):1062–7.
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European Journal of Pain 12 (2008) 116–127 www.EuropeanJournalPain.com
Central sensitization phenomena after third molar surgery: A quantitative sensory testing study Gitte I. Juhl a
a,*
, Troels S. Jensen a, Sven E. Norholt b, Peter Svensson
c
Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark b Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, DK-8000 Aarhus C, Denmark c Department of Clinical Oral Physiology, School of Dentistry, University of Aarhus, DK-8000 Aarhus C, Denmark Received 6 November 2005; received in revised form 9 April 2007; accepted 10 April 2007 Available online 5 June 2007
Abstract Background: Surgical removal of third molars may carry a risk of developing persistent orofacial pain, and central sensitization appears to play an important role in the transition from acute to chronic pain. Aim: The aim of this study was to investigate sensitization (primarily central sensitization) after orofacial trauma using quantitative sensory testing (QST). Methods: A total of 32 healthy men (16 patients and 16 age-matched control subjects) underwent a battery of quantitative tests adapted to the trigeminal area at baseline and 2, 7, and 30 days following surgical removal of a lower impacted third molar. Results: Central sensitization for at least one week was indicated by significantly increased pain intensity evoked by intraoral repetitive pinprick and electrical stimulation (p < 0.05) including facilitation of temporal summation mechanisms (p < 0.05), extraoral repetitive electrical stimulation (p < 0.001), significantly more frequent aftersensation in patients (p < 0.001), extraoral hyperalgesia due to single pinprick stimulation (p < 0.05) and larger pain areas due to intranasal stimulation (p < 0.001). Peripheral sensitization was indicated by intraoral hyperalgesia due to single pinprick (p < 0.05). Conclusion: We found clear signs of sensitization of the trigeminal nociceptive system for at least one week after the surgery. Our results indicate that even a minor orofacial surgical procedure may be sufficient to evoke signs of both central and peripheral sensitization, which may play a role in the transition from acute to chronic pain in susceptible individuals. Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Human trigeminal physiology; Orofacial pain; Third molar surgery; Quantitative sensory testing; Sensitization
1. Introduction Why does acute pain become chronic? This is an important but still unsolved question. To improve chronic pain treatment or prevent chronic pain from developing, knowledge about the mechanisms responsi*
Corresponding author. Present address: Multidisciplinary Pain Center, Herlev Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. Tel.: +45 4488 4751. E-mail address: [email protected] (G.I. Juhl).
ble for the transition from acute to chronic pain is important (Woolf and Salter, 2000; Costigan and Woolf, 2000; Mantyh et al., 2002; Stubhaug, 2005). Peripheral sensitization of nociceptors and central sensitization of second order neurons in the dorsal horn or in the trigeminal nucleus are assumed to play a major role in the development of chronic pain after surgical procedures (Sessle, 2000; Jensen et al., 2001a). Tissue trauma due to surgical procedures inevitably starts an inflammatory reaction with the release of inflammatory mediators from the surroundings (Costigan and
1090-3801/$32 Ó 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2007.04.002
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Woolf, 2000). Immediately after the tissue trauma, the production of an ‘‘inflammatory soup’’ takes place (Scholz and Woolf, 2002). This inflammatory soup is involved in the healing processes of the tissue, but at the same time it may sensitize the nociceptors in the tissue, thereby initiating a sensitization of higher order neurons as well. This may lead to hyperalgesia and allodynia: features that may serve protective functions in order to avoid further damage to the injured tissue (Sessle, 1999). In most cases the process is self-limiting, but in some cases the process may continue and produce prolonged and even chronic conditions of hyperalgesia and allodynia with or without spontaneous pain (Gottrup et al., 2006). Quantitative sensory testing (QST) can be used to assess the clinical manifestations of peripheral and central sensitization (Wilder-Smith et al., 2003; Cruccu et al., 2004) including the trigeminal area (Svensson et al., 2004). Central sensitization may be assessed by temporal summation: enhancement of pain intensity due to repetitive stimulation, increased frequency of aftersensations and increased occurrence of referred pain (Coderre and Katz, 1997; Jensen et al., 2001b). Trauma to the orofacial regions can produce sensitization peripherally and in the central nervous system. For example, Chiang et al. (2002) found central sensitization after dental trauma in rats. Moreover, we have recently provided evidence that peripheral sensitization may occur after surgical removal of third molars in healthy adults (Juhl et al., 2006). Thus, long-lasting mechanical sensitization for up to one month was present even in the absence of spontaneous pain and even after pain treatment with paracetamol for up to one week (Juhl et al., 2006). In this study, we focused on the clinical manifestations of central sensitization and for how long these may be detected using specific QST techniques after third molar surgery in humans. The subjects and surgical procedures in the present study are the same as in Juhl et al. (2006), but here we report an extensive set of novel QST findings related to central sensitization in the orofacial region, and none of the present results have been published before.
2. Materials and methods 2.1. Subjects The study was conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki and was approved by the local Ethics Committee for Aarhus County. Before signing the consent form, all subjects were informed of all study procedures by the investigator. Healthy males aged at least 18 years were eligible for the study if they were scheduled for elective removal of
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one or more third molars under local anaesthesia and at least one third molar was fully or partially impacted in the mandibular bone (patient group). A sex- and agematched group of males without prior or scheduled third molar surgery served as controls (control group). Subjects were excluded from the study for the following reasons: other painful physical conditions that might confound pain assessment, psychiatric or medical conditions that might impair communication or compliance with the study procedures, known drug abuse or contra-indications to paracetamol or local anaesthesia. Local anaesthesia (prilocaine 3% and felypressin 0.54 lg/mL) was used during standardized surgery procedures (Norholt, 1998). No subjects needed additional tranquillizers. One experienced oral surgeon (SEN) performed all surgical procedures. Postoperative pain treatment was paracetamol 0.5 g administered orally at a maximum of 8 times daily for one week. The subjects were allowed to take the paracetamol whenever it was needed, but no more than the maximum prescribed amount per day. They were allowed to take additional pain medication provided they informed the investigator. 2.2. Experimental design Sensitization can be investigated by using quantitative sensory testing (QST). Clinical manifestations of central sensitization were in this study investigated using repetitive stimulation assessing temporal summation, stimulation of adjacent areas (e.g. intranasal stimulation) and occurrence of aftersensation (Jensen and Baron, 2003). Furthermore, the skin under the lower lip at the termination of the inferior alveolar nerve (mental nerve) was stimulated. Mental nerve stimulation may provide information on: (1) possible central sensitization as the nerve is relatively protected against mechanical trauma in the bony canal; and (2) nerve involvement due to inflammatory processes in the operated area (Eliav and Gracely, 1998). Peripheral sensitization due to tissue trauma was investigated intraorally using single stimulation on the mucosa (gingiva/gum) adjacent to the lower first molar. A battery of QST techniques was used to activate different populations of nerve fibres. Thick von Frey hairs were used to stimulate Ad nerve fibres, whereas electrical stimuli bypassing the nociceptor were used to activate directly the nerve fibres (Eliav and Gracely, 1998). All orofacial QST was performed bilaterally. Tests on the extremities were used as an extra-trigeminal control. All tests were performed preoperatively (baseline) and postoperatively on days 2, 7 and 30 in the patient group. The control group underwent the same tests according to the same time schedule as the patient group. In the patient group, the contralateral side was always investigated first followed by the operated side. In the control group, the same procedure was followed:
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8 subjects were assigned to have the right side investigated first (first measurement), followed by investigation of the left side (second measurement); 8 subjects were assigned to have the left side investigated first (first measurement), followed by investigation of the right side (second measurement). The order of investigation for each subject was kept throughout the study. The same investigator (GIJ) carried out all tests.
3. Quantitative sensory tests 3.1. Single and repetitive stimulation Pinprick stimulation was evoked by applying a von Frey hair (75 g) (Fruhstorfer et al., 2001) as a single stimulation and after a period of 2 min as a repetitive stimulation for the assessment of temporal summation (5 stimuli at a rate of 2 Hz) (Gottrup et al., 2000; Baad-Hansen et al., 2003). Evoked pain intensity was scored on a numerical rating scale of 0–10 (NRS; 0 = no pain, 10 = unbearable pain). Assessment of temporal summation was performed by calculating delta values of pain intensity (delta value = evoked pain after 5 stimuli minus the value of evoked pain after one stimulus). Electrical stimulation is known to bypass the nociceptor receptor mechanism and was used for direct activation of the afferent nerve fibres (Gracely, 1999; Eliav and Gracely, 1998). Intraoral electrical pain thresholds (EPTs) in steps of 0.05–0.1 mA were assessed at the gingiva adjacent to the first molar and extraorally at the skin under the lower lip and at the extremity. The electrical stimulation was delivered from a constant current device (Aalborg University, DK) using a circular anode and cathode probe (diameters: 0.3/0.7 mm). Each stimulus lasted 0.5 ms. As soon as the EPT was reached, single stimuli with the intensity of EPT were applied to the subject, and the evoked pain was assessed on the NRS. Thereafter, a repetitive sequence of 5 stimuli was applied to the subject (computer controlled). Subjects scored the maximum evoked pain on the NRS after the 5 stimuli with the intensity of EPT. Temporal summation was calculated as described above. 3.2. Aftersensation Aftersensations, which may be consequences of central sensitization (Gottrup et al., 2003; Jensen and Baron, 2003), were reported by the subject after applying an ice cube intraorally at the buccal surface of the first molar. As soon as pain was experienced due to coldness, the stimulation was discontinued and the subject reported any occurrence of aftersensations intraorally. Aftersensations due to von Frey hair stimulation were reported as well.
3.3. Referred pain Central sensitization may involve adjacent regions, which may be sensitive when stimulated. In our study, we assessed the occurrence of referred pain by stimulating the nasal mucosa below the middle concha using a blunt wooden stick as described by Hutchins and Reynolds (1947) and Reynolds and Hutchins (1948). The stimulus was applied in the ipsilateral nasal cavity under direct vision using a 0 degree rigid nasoendoscope (AbuBakra and Jones, 2001). The subject assessed the maximum evoked pain on the NRS and mapped the area where the pain was felt on a drawing of the face. The mapped area of referred pain was subsequently calculated using a digitizer and dedicated software (Quantity; K.L.O.N.K). 3.4. Assessment of pain Stimulus-evoked pain was assessed on the NRS. Postoperative pain was also assessed on the NRS. Three times daily in the first postoperative week, and the assessments were recorded in a diary that was returned to the investigator at the end of the period. Summed pain intensity SPI2 was derived from diary recordings from the time after surgery (TO) and two days after (day 2). If pain persisted for a longer period, the patient continued the pain assessment until a pain-free condition was reached. The control group reported any presence of pain during the study to the investigator.
4. Statistics Unpaired t-test was used for comparison of age between the two groups. Baseline data from the orofacial region in the two groups were compared using two-way Analysis of Variance (ANOVA) with the factors group (control vs. patient) and side (right then left vs. left then right (i.e. first and second measurement) and control vs. operated side). Baseline data from the forearm in the two groups were compared using unpaired t-test or Mann–Whitney Rank Sum test. Separate two-way ANOVAs for each group were used to test for time effects (baseline, 2, 7 and 30 days) and for side differences (patient group: control side vs. operated side; control group: right side then left side or left side then right side). Separate one-way ANOVAs for each group were used to test for time effects at the forearm (baseline, 2, 7 and 30 days). Assessment of temporal summation was performed by using two-way ANOVAs to test for group effect and time effect at each side of delta values of pain intensity (delta value = evoked pain after 5 stimuli minus the value of evoked pain after one stimulus). To minimize baseline differences between calculated referred pain areas in the two groups, delta values were
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compared (baseline values were subtracted from the values at baseline, 2, 7 and 30 days). Two-way ANOVAs were used to test for time effects (baseline, 2, 7 and 30 days) and for group effects of baseline-corrected referred pain area. Fisher’s exact test was used for comparing the frequencies of aftersensation in the two groups. Due to not normally distributed data, the Friedman Repeated Measures Analysis of Variance on Ranks followed by multiple comparisons was used to test for time effects of postoperative pain intensity. Pearson Product Moment Correlation was used to test for correlations between Summed pain intensity (SPI2) and evoked pain intensity by von Frey hair, or between paracetamol consumption and postoperative pain intensity. Post-hoc tests were performed with Student–Newman–Keuls tests (SNK) to compensate for multiple comparisons. Missing data were not replaced. The level of significance was set at p < 0.05. Data are presented as mean values ± SEM if not otherwise specified.
5. Results A total of 32 healthy males were included: 16 patients (mean age 25.4 ± 2.6 years) with an impacted third molar and 16 control subjects (mean age 23.9 ± 2.2 years). The two groups were similar concerning demographics, including age (t-test: p = 0.082). No subject withdrew from the study. In the patient group, the impacted third molars were located as follows: 6 third molars were located on the right side and 10 third molars were located on the left side and 15 of these third molars were in a semiimpacted position (7 of these with a mildly irritated gingiva). The surgical procedures lasted 12 ± 5 min (range: 5–29 min) and the local anaesthetic volume used in the lower jaw was 3.7 ± 0.5 ml (range: 3.6–5.4 ml). Ipsilateral upper third molars were in 7 cases removed as well. There were no occurrences of serious adverse events during or after the study. Non-serious adverse events during the first postoperative week occurred in 8 patients: 4 patients experienced long-lasting bleeding (bleeding that persisted more than one day after the operation), 3 patients experienced headache, and 1 patient experienced extensive oedema (lasting for one week). In the control group there were no reports of adverse events or intake of medication.
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F = 1.02, p = 0.751) von Frey hair stimulation or for single (ANOVAs: F = 0.04, p = 0.831) or repetitive (ANOVAs: F = 0.83, p = 0.366) intraoral electrical stimulation. No significant differences between groups or sides could be detected for single (ANOVAs: F = 0.05, p = 0.826) or repetitive extraoral von Frey hair stimulation (ANOVAs: F = 1.28, p = 0.722) or single (ANOVAs: F = 0.006, p = 0.939) or repetitive (ANOVAs: F = 0.65, p = 0.423) extraoral electrical stimulation (ANOVAs: F = 1.02, p = 0.751). At baseline, no significant differences between groups could be detected for forearm von Frey hair single stimulation (Mann– Whitney: p = 0.235) or repetitive von Frey stimulation (t-test: p = 0.505) or electrical single stimulation (Mann–Whitney: p = 0.191) or electrical repetitive stimulation (Mann–Whitney: p = 0.406). 6.2. Single and repetitive von Frey hair stimulation 6.2.1. Patient group Intraorally, there was a significant side difference with increased evoked pain intensity at day 2 and day 7 on the operated side for both single (ANOVAs: F = 10.54, p = 0.006, Fig. 1B) and repetitive stimulations (ANOVAs: F = 9.83, p = 0.008, Fig. 1D). There was a tendency towards a significant effect with increased pain intensity on the operated side at day 30 for single stimulation (p = 0.078). Additionally, there was a significant interaction between time and side for repetitive stimulation with increased evoked pain intensity at day 2 on the operated side (ANOVAs: F = 5.11, p = 0.004, Fig. 1D) and likewise increased pain intensity at day 2 compared to day 30. There were no significant time effects for single (ANOVAs: F = 0.81, p = 0.498) or repetitive stimulation (ANOVAs: F = 1.65, , p = 0.193). Extraorally, there was a significant effect of single stimulation with increased evoked pain intensity on the operated side at day 2 and day 7 compared to the control side (ANOVAs: F = 5.07, p = 0.042, Fig. 1F). There was also a significant interaction between time and side with increased evoked pain intensity due to single stimulation on the operated side at day 2 compared to day 30, and a decreased pain intensity on the control side at day 30 compared to baseline (ANOVAs: F = 3.55, p = 0.02, Fig. 1F). No significant time effect (ANOVAs: F = 2.60, p = 0.07), side difference (ANOVAs: F = 3.50, p = 0.08), or interaction between time and side was found for repetitive stimulation (ANOVAs: F = 0.86, p = 0.468) (Fig. 1H).
6. Quantitative sensory testing 6.1. Single and repetitive stimulation At baseline, no significant differences between groups or sides could be detected for single (ANOVAs: F = 0.01, p = 0.908) or repetitive intraoral (ANOVAs:
6.2.2. Control group Intraorally, there was no significant time effect (ANOVAs: F = 2.65, p = 0.06), or side difference (ANOVAs: F = 0.62, p = 0.443), or interaction between time and side (ANOVAs: F = 0.60, p = 0.619) for single stimulation. There was no significant time effect (ANOVAs:
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Fig. 1. Intensity of evoked pain by von Frey hair stimulation (numeric rating scale [NRS]) at baseline (Bas), day 2 (D2), day 7 (D7), and day 30 (D30) in the two groups. Controls: Open circles – right side. Closed circles: left side. Patients: Open squares-control side. Closed squares-operated side. A,B: Intraorally evoked pain by one stimulation. C,D: Intraorally evoked pain by five stimulations. E,F: Extraorally evoked pain by one stimulation. G,H: Extraorally evoked pain by five stimulations. Evoked pain expressed as mean ± SEM. + indicates p < 0.05 compared to baseline (time effects), # p < 0.05 compared to side (side-to-side effect), *p < 0.05 compared to baseline (interactions between time and side); two-way ANOVAs.
F = 2.02, p = 0.125), or side difference (ANOVAs: F = 1.22, p = 0.286), or interaction between time and side (ANOVAs: F = 1.23, p = 0.309) for repetitive intraoral stimulations (Fig. 1A and C).
Extraorally, there was a significant time effect with decreased evoked pain intensity due to single (ANOVAs: F = 5.34, p = 0.003), or repetitive stimulations at day 7 and day 30 compared to baseline (ANOVAs:
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F = 4.21, p = 0.01) (Fig. 1E and G). There were no significant side difference (ANOVAs: F = 2.62, p = 0.126) or a significant interaction between time and side (ANOVAs: F = 0.03, p = 0.993) for extraorally evoked pain intensity due to single stimulation. There were no significant side difference (ANOVAs: F = 3.19, p = 0.094) or a significant interaction between time and side (ANOVAs: F = 0.25, p = 0.860) for extraorally evoked pain intensity due to repetitive stimulation . 6.3. Single and repetitive electrical stimulation 6.3.1. Patient group Intraorally, there was a significant side-to-side effect with increased evoked pain intensity at day 2 on the operated side compared to the control side for repetitive stimulation (ANOVAs: F = 5.73, P = 0.032, Fig. 2D). There were no significant time effect (ANOVAs: F = 0.81, p = 0.497) or interaction between time and side (ANOVAs: F = 1.81, p = 0.161) for repetitive stimulation. There was no significant time effect (ANOVAs: F = 0.45, p = 0.719), or side difference (ANOVAs: F = 0.45 p = 0.514) or interaction between time and side (ANOVAs: F = 0.40, p = 0.756) for single stimulation. Extraorally, a significant side-to-side effect with increased pain intensity on the operated side compared to the control side at day 2 and day 30 due to repetitive stimulation was observed (ANOVAs: F = 19.47, p < 0.001, Fig. 2H). Additionally, there was a tendency towards a significant effect with increased pain intensity on the operated side at day 2 due to single stimulation (ANOVAs: F = 4.50, p = 0.054, Fig. 2). No significant time effect (ANOVAs: F = 1.26, p = 0.301) or interaction between time and side (ANOVAs: F = 0.65, p = 0.588) was found for single stimulation. No significant time effect (ANOVAs: F = 1.67, p = 0.189) or interaction between time and side (ANOVAs: F = 2.18, p = 0.105) was found for repetitive extraoral stimulation. 6.3.2. Control group Intraorally, there was no significant time effect (ANOVAs: F = 0.90, p = 0.447) or side-to-side effect (ANOVAs: F = 0.08, p = 0.774) or interaction between time and side (ANOVAs: F = 0.85, p = 0.476) for single stimulation . There was no significant time effect (ANOVAs: F = 0.32, p = 0.813) or side-to-side effect (ANOVAs: F = 0.66, p = 0.429) or interaction between time and side (ANOVAs: F = 0.19, p = 0.884) for repetitive intraoral electrical stimulation (Fig. 2). Extraorally there was a significant side difference with increased evoked pain intensity on the ‘‘left side (second measurement)’’ due to repetitive stimulation at day 7 (ANOVAs: F = 15.00, p = 0.002, Fig. 2). There was no significant time effect (ANOVAs: F = 1.63, p = 0.196) or significant interaction between time and side (ANO-
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VAs: F = 2.69, p = 0.06) due to repetitive stimulation. There was no significant time (ANOVAs: F = 1.24, p = 0.946) or side-to side effect (ANOVAs: F = 0.04, p = 0.835) or interaction (ANOVAs: F = 1.72, p = 0.177) of single stimulation. 6.4. Temporal summation Comparison between groups of calculated delta values of evoked pain intensity at each side was used to assess temporal summation. Comparison was performed with the von Frey hair stimulations. Intraorally on the operated side, there was a significant interaction between group and time (ANOVAs: F = 2.71, p = 0.048, Fig. 3). Post-hoc analysis indicated that this significant finding was due to increased pain intensity on the operated side in the patient group at day 2 or day 7. Intraorally on the control side, there was no significant group effect (ANOVAs: F = 0.27, p = 0.606) or time effect (ANOVAs: F = 0.15, p = 0.933) or interaction between group and time (ANOVAs: F = 0.40, p = 0.753). 6.5. Referred pain 6.5.1. Pain intensity There were no significant findings of time (ANOVAs: F = 0.37, p = 0.773) or group effect (ANOVAs: F = 2.02, p = 0.158) or interaction between time and group (ANOVAs: F = 0.40, p = 0.752) of evoked pain intensity due to intranasal stimulation (Fig. 4). The patient perceived their pain referral and spread from the intranasal mucosa to the adjacent orofacial areas without any report of referred pain to the operated area. 6.5.2. Calculated area There was a significant group effect due to intranasal stimulation with a higher calculated area (d values) in the patient group than in the control group (ANOVAs: F = 14.92, p < 0.001, Fig. 5). There was no time effect (ANOVAs: F = 0.43, p = 0.733) or interaction between time and group (ANOVAs: F = 1.70, p = 0.171). 6.6. Aftersensations Subjects reported the occurrence of aftersensations due to application of ice or stimulation with von Frey hair. Aftersensations were more frequent in patients on the operated side than in control subjects at day 7 (Fishers exact test: p < 0.001, Table 1).
7. Postoperative pain intensity Postoperative pain was significantly higher at the day of surgery, median pain intensity 6 [25–75% range, 4–7.5, Friedman] and gradually decreased over the
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Fig. 2. Intensity of evoked pain by electrical stimulation (numeric rating scale [NRS], 0–10) at baseline (Bas), day 2 (D2), day 7 (D7), and day 30 (D30) in the two groups. Controls: Open circles – right side. Closed circles: left side. Patients: Open squares – control side. Closed squares – operated side. A,B: Intraorally evoked pain by one stimulation. C,D: Intraorally evoked pain by five stimulations. E,F: Extraorally evoked pain by one stimulation. G,H: Extraorally evoked pain by five stimulations. Evoked pain expressed as mean ± SEM. # indicates p < 0.05 compared to side (sideto-side comparison); *p < 0.05 compared to baseline (interactions between time and side); two-way ANOVAs.
following days (SNK: p < 0.001). One patient experienced shooting, unbearable pain (NRS = 10) in the ipsilateral trigeminal area during the first postoperative week. Postoperative acetaminophen (paracetamol) intake was significantly higher at the day of surgery (mean intake of tablets 5.6 ± 0.5) and gradually decreased here-
after (SNK: p < 0.001). There was a positive correlation between postoperative pain intensity and paracetamol consumption (Pearson: correlation coefficient r = 0.975, p < 0.001). Summed pain intensity SPI2 was positively correlated to intraoral repetitive von Frey stimulation pain inten-
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8. Discussion
Pain intensity, delta values NRS (0_10)
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Time Fig. 3. Temporal summation. Delta values of pain intensity (delta value = evoked pain intensity after 5 stimuli minus value of evoked pain intensity after one stimulation) due to von Frey stimulations. Delta values of numeric rating scale [NRS, (0–10)] at baseline (Bas), day 2 (D2), day 7 (D7), and day 30 (D30) on the operated side in the two groups. Controls: Closed circles. Patients: Closed squares. Delta values of evoked pain expressed as mean ± SEM. ¥ p < 0.05 comparison between groups and times; two-way ANOVAs.
Referred pain, intranasal stimulation
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In this study, we have focused on the clinical manifestations and duration of central sensitization after third molar surgery in humans whereas our previously published data focused on peripheral sensitization after third molar surgery (Juhl et al., 2006). Although the subjects, the surgical procedures and some of the QST instruments in the present study are the same as in Juhl et al. (2006), the QST techniques used to measure central sensitization are completely different from those used to measure peripheral sensitization. The main new findings in this study investigating primarily central sensitization in patients undergoing third molar surgery were significant increases in evoked pain intensity intraorally and extraorally on the operated side due to repetitive stimulation with significant facilitation of temporal summation. In the patient group, we also found areas of increased orofacial pain due to intranasal stimulation, a significant occurrence of aftersensations and a positive correlation between summed pain intensity and intraoral pain intensity evoked by repetitive von Frey hair stimulation on the operated side at day 2. Furthermore, adaptation (decreased responsiveness to test stimuli) was observed in the control group to some of the tests during the one-month observation period. These findings indicate the development of central sensitization after minor orofacial surgery lasting for at least one week despite preoperative local anaesthetics and postoperative paracetamol treatment for up to one week after surgery.
3
9. Methodological considerations
2
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Time Fig. 4. Referred pain. Intensity of evoked pain by intranasal stimulation (Numeric rating scale [NRS], 0–10) at baseline (Bas), day 2 (D2), day 7 (D7), and day 30 (D30) in the two groups. Controls: Closed circle. Patients: Closed squares. Evoked pain expressed as mean ± SEM. Two-way ANOVAs.
sity on the operated side at day 2 (Pearson: r = 0.54, p = 0.047). There was a tendency towards a positive correlation between SPI2 and intraoral single von Frey pain intensity on the operated side at day 2 (Pearson: r = 0.52, P = 0.057). There was no correlation between SPI2 and extraoral single (Pearson: r = 0.36, p = 0.208) or repetitive (Pearson: r = 0.07, p = 0.811) von Frey pain intensity at the operated side at day 2.
We chose to test the contralateral side first and then the operated side to avoid long and intense pain on the operated side, and thereby potentially influencing our measurements. In addition, this setting resembles the clinical approach to investigating pain patients where the unaffected side is normally investigated prior to the affected side. However, this procedure may have affected our results as side differences were found even in the control group. We found increased pain intensity evoked by electrical stimulation on the ‘‘left side (second measurement)’’ in the control group. Thus, the order of the measurement may affect the result. Still, side differences in the control group (only observed for electrical stimulation) were not as consistent as in the patient group. Thus, even though our procedure may have affected the results in the control group, we still suggest that the control side should be tested before the operated (affected) side. Otherwise there may be a risk to evoke severe and longer-lasting pain in the patients on the operated side that could instead interfere with the assessment of pain on the control side.
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Fig. 5. Areas of referred pain. Delta values of calculated areas (A) expressed as mean ± SEM (cm2); two-way ANOVAs.
Table 1 Number of subjects with aftersensations due to cold and/or von Frey hair stimulations
Controls Patients P-Value a
Baseline
Day 2
Day 7
Day 30
0/16 0/16 1a
0/16 3/15 0.11a
0/16 6/16 0.0002a
0/16 3/16 0.22a
Fishers exact test.
In our recent study on consequences of oral surgery, we have shown that inclusion of a control group may indirectly provide additional information on the changes that may happen in the patient group (Juhl et al., 2006). Pain conditions may due to central sensitization alter the somatosensory sensitivity on the contralateral side in patients (Jaaskelainen, 2004), thereby lowering the possibility of finding differences between the two sides in the patients. Inclusion of a control group is therefore recommended to ensure the validity of the results whenever central sensitization is investigated. Electrical stimulation did not produce consistent results, which could be explained by methodological issues. Single or repetitive stimulation was performed with electrical current equivalent to pain threshold. This procedure may have evoked less pain than required to show a robust difference. In future studies, a higher electrical stimulation may be needed. A blunt instrument was used to stimulate the nasal mucosa to avoid damage to surface. Because only mild or moderate pain was evoked, this may have resulted in less prominent findings than the original observations by Hutchins and Reynolds (1947). Nevertheless, we still
found increased areas of referred pain in the patient group compared to the control group. A more painful stimulation of the nasal mucosa would probably have resulted in the subjects withdrawing from the study because they all reported that the nasal stimulation was the most unpleasant stimulation of all the sensory modalities.
10. Sensitization in the orofacial region 10.1. Sensitization Central and peripheral sensitization involve several mechanisms. The release of inflammatory mediators after tissue trauma sensitizes Ad and C fibres peripherally and may start a central activation of different mediators including cyclo-oxygenase (cox) enzymes. Cox enzymes produce prostaglandines that increase the release of neurotransmitters, like glutamate, thereby increasing the possibility of activating the NMDA receptor (Costigan and Woolf, 2000; Ghilardi et al., 2004). Glutamate binds preferentially to the NMDA receptor, but this receptor is under normal circumstances blocked by a magnesium ion. Prolonged or more intense nociceptor activation enhances the risk of NMDA receptor activation and provides an opportunity for plasticity, temporal summation and central sensitization (Costigan and Woolf, 2000). Therefore, central sensitization is considered, in part, to be a consequence of NMDA receptor activation, and a dysfunction of the NMDA-dependent disinhibition of temporal
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summation could contribute to central sensitization (Woda et al., 2004). Other mechanisms such as activation of neurokinin-1 receptor and production of nitric oxide have been suggested to play a role as well (Woolf, 1994; Svensson et al., 2001; Jensen et al., 2001a). Thus, tissue trauma releases inflammatory mediators that may induce a neuronal inflammation without structural damage (Eliav et al., 1999). Neuronal inflammation develops after injection of complete Freund’s adjuvant (CFA) in rats (immune cells including macrophages, lymphocytes, and granulocytes were found in the nerves) and the percentage of mechanosensitive fibres increased (Eliav et al., 2001). 10.2. Oral sensitization Previously it has been shown that dental trauma in rats is associated with signs of central sensitization, critically dependent on subnuclei caudalis (Chiang et al., 2002) and oralis (Woda, 2003) of the trigeminal spinal tract nucleus. Yu et al. (1993) found that deep inputs in contrast to cutaneous inputs are especially effective in inducing neuroplastic changes in central nociceptive pathways (Yu et al., 1993). Similar to this, Kupers et al. (2004) found in a PET study of human jaw muscle pain that mechanical hyperaesthesia was associated with a unique activity in the thalamus and anterior subgenual cingulated. Thus, the development of central sensitization after a surgical procedure involving not only oral structures but also more deep structures may be due to neuronal inflammation and activation of subnuclei caudalis and thalamus. Yet, altered processing of somatosensory stimuli is unlikely to be restricted to either pure peripheral or central mechanisms, and central neuronal hyperexcitability changes may occur following peripheral sensitization (Dubner, 1992; Svensson et al., 1998; Woolf and Salter, 2000). 10.3. QST Standardized QST may help to demonstrate the clinical manifestations of central or peripheral sensitization (Eliav and Gracely, 1998; Wilder-Smith et al., 2003; Cruccu et al., 2004; Rolke, 2006; (Cruccu et al., 2004)). For example, intraoral and extraoral hyperalgesia due to repetitive stimulation may indicate central sensitization (Herrero et al., 2000; Gottrup et al., 2003). Extraoral hyperalgesia due to single stimulation may indicate a neuronal inflammation with increased mechanosensitivity at the termination of the nerve due to either central or peripheral sensitization (Eliav and Gracely, 1998). Intraoral increased pain intensity (hyperalgesia) due to single stimulation may indicate peripheral sensitization in the vicinity of the operated area.
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A series of studies have shown that increased pain following repetitive stimulation depends on central sensitization (Jensen et al., 2001b; Jensen and Baron, 2003). We observed in our study that patients experienced increased pain intraorally evoked by repetitive von Frey hair stimulation for up to one week postoperatively. Thus, activation of Ad fibres by von Frey hair supports the finding of central sensitization after third molar surgery. Electrical stimulation did not produce the same consistent results, which could be explained by low levels of evoked pain and therefore a smaller chance to find robust differences. We also observed extraoral hyperalgesia to single pinprick stimuli on the operated side in patients which supports our previous finding of extraoral hyperalgesia on the operated side due to pressure pain stimuli (Juhl et al., 2006). These findings are compatible with a sensitization that is either central or peripheral (Eliav and Gracely, 1998). In addition to central sensitization we found indications of peripheral sensitization. In patients, stimulation with von Frey hair evoked increased pain on the operated side compared to the control side for up to one week. This may indicate that Ad afferent fibres were sensitized. We failed to show increased pain evoked by single electrical stimulation either due to methodological reasons or because the nerve fibres were not adequately sensitized to cause significant findings whenever electrical stimulation was used. 10.4. Referred pain Referred pain, which was also present in the this study, is considered in part to depend on the convergence of impulses from the injured and referred regions on the same cells in the spinal cord (Coderre and Katz, 1997; Sessle, 1999; Wright, 2000). Thus, a nociceptive stimulus, like intranasal stimulation, may be perceived as arising from neighbouring regions including previous surgical areas (Falace et al., 1996). In our study, we found that intranasal stimulation in the patients produced referral and spread of pain to adjacent superficial orofacial areas, which could be explained by central sensitization of the trigeminal brainstem complex. An increased area of self-reported pain after a local injection of hypertonic saline into the orofacial muscles has previously been shown (Svensson et al., 1998). Likewise has spread of referred pain to intraoral structures after a local injection of hypertonic saline into orofacial muscles been seen (Svensson et al., 2003). Yet, no referred intraoral pain upon intranasal stimulation was found in our study. This result is in accordance with the original findings by Reynolds and Hutchins (1948) showing that dental procedures done under local anaesthesia did not result in referred pain to the orofacial area when the subjects were
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stimulated intranasally. In contrast, dental procedures done under general anaesthesia or without anaesthesia were associated with the development of referred pain elicited by intranasal pinprick stimuli to the previously treated areas (Hutchins and Reynolds, 1947). Thus, pre-treatment with local anaesthetics seems to block the nociceptive impulses for some time reducing the activation and sensitization of central neurons. 10.5. Aftersensations In the patient group, aftersensations were more frequently observed on the operated side than on the control side or in the control group. This result is in accordance with Gottrup et al. (2003) who found that aftersensation was more frequent in sensitized skin after nerve injury or capsaicin-sensitized skin than in contralateral normal skin. However, we found indications of mechanical sensitization without spontaneous pain in the patient group. The explanation for this feature may be that ongoing pain as well as mechanical hyperalgesia is dependent on separate molecular mechanisms (Gottrup et al., 2006). 10.6. Acute pain with high intensity Acute pain with high pain intensity in the early postoperative period after different surgical procedures (limb amputation, mastectomy, thoracotomy, gallbladder surgery, inguinal hernia surgery (Perkins and Kehlet, 2000) and caesarean section (Nikolajsen et al., 2004)) has been found to be a risk factor of chronic pain (Shipton and Tait, 2005). As expected, none of our patients developed chronic pain, but evidence of neuronal sensitization was still a prominent feature. Sensitization, especially central sensitization, is considered to play a significant role in the transition from acute to chronic pain (Jensen and Baron, 2003). In our study, we found a correlation between high postoperative pain intensity during the first 3 days after surgery and signs of sensitization. Reduction of postoperative pain intensity and thereby reduction of sensitization may reduce the risk for development of chronic pain. In conclusion, central and peripheral sensitization developed after third molar surgery in humans and lasted for at least one week in spite of pretreatment with local anaesthetic and postoperative administration of paracetamol. These results obtained in a human oral pain model are comparable to animal and human experimental studies demonstrating perturbed mechanosensitivity after different types of tissue trauma. Thus, even after minor orofacial surgery, sensitization can be detected, which may play a role in the transition from acute to chronic pain and point to the need for more specific pain management to prevent long-lasting sensitization and chronic pain.
Conflict of interest statement There are no conflicting interests.
Acknowledgements The present study was supported by grants from the Danish Pain Research Center, Aarhus University Hospital, Karen Elise Jensens’s Foundation, the Lundbeck Foundation and the Science Initiative of Aarhus University Hospital, Denmark.
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