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BMC Oral Health
BMC Oral Health
BMC Oral Health
1472-6831
BioMed Central London

39232703
4787
10.1186/s12903-024-04787-5
Research
Analgesic effect of ultrasound-guided extraoral mandibular nerve block compared to intraoral conductive block of the inferior alveolar nerve after lower third molar alveolectomy: a clinical prospective study
Martinus Marija 1
Mihaljevic Slobodan 2
Reiner Kresimir 2
Verzak Zeljko 3
Panic Monika Kocman 1
Strahija Aleksandra 4
Gluncic Vicko 5
Lukic Ivan Kresimir 6
Lukic Anita lukic.anita@yahoo.com

178
1 grid.490560.e 0000 0004 0366 9711 Department of Anesthesiology, Reanimatology, and Intensive Medicine, Varazdin General Hospital, 1 I. Mestrovica Street, Varazdin, 42000 Croatia
2 https://ror.org/00r9vb833 grid.412688.1 0000 0004 0397 9648 Clinic of Anesthesiology, Reanimatology, Intensive Care and Pain Therapy, University Clinical Hospital Centre Zagreb, Zagreb, Croatia
3 https://ror.org/00mv6sv71 grid.4808.4 0000 0001 0657 4636 University of Zagreb School of Dental Medicine, Zagreb, Croatia
4 https://ror.org/0518jvn15 grid.476280.f Department Otorhinolaryngology, Varazdin General Hospital, Varazdin, Croatia
5 https://ror.org/036vtmj33 grid.413330.6 0000 0004 0435 6194 Department of Anesthesia, Advocate Illinois Masonic Medical Center, Ilinois, USA
6 https://ror.org/022991v89 grid.440823.9 0000 0004 0546 7013 Catholic University of Croatia, Zagreb, Croatia
7 https://ror.org/01afbkc02 grid.502995.2 0000 0004 4651 2415 University North, Varazdin, Croatia
8 Bjelovar University of Applied Sciences, Bjelovar, Croatia
4 9 2024
4 9 2024
2024
24 104122 6 2024
20 8 2024
© The Author(s) 2024
2024
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Background

The analgesia after lower third molar alveolectomy is based on the use of non-steroidal anti-inflammatory drugs (NSAIDs) that have significant risks, and are contraindicated in the third trimester of pregnancy. Aiming to reduce NSAIDs use after this surgery, we quantified analgesic effects of ultrasound (US)-guided extraoral mandibular nerve block.

Methods

Thirty-six patients were equally allocated to the experimental or control group, based on their willingness to receive experimental US-guided extraoral mandibular nerve block for postoperative analgesia. The experimental block applied prior to lower third molar alveolectomy, was followed by standard intraoral inferior alveolar nerve block. In the control group, patients received only intraoral block of inferior alveolar nerve. All patients reported pain level (visual analogue scale, VAS) right after the application of blocks. The next day, patients reported duration of pain-free time and the use of analgesic.

Results

The US-guided extraoral mandibular nerve block prolonged the pain-free time to 8 h (vs. 4 in control group, P < 0.001) and reduced NSAIDs use (12 patients needed analgesic in experimental vs. 17 patients in control group, P = 0.038). The application of experimental block was less painful (VAS = 2) than the application of intraoral inferior alveolar nerve block (VAS = 4, P = 0.011). In 8/18 patients in the experimental group US-guided extraoral mandibular nerve block solely achieved adequate surgical anesthesia.

Conclusion

US-guided extraoral mandibular nerve block prolonged pain-free period and reduced the use of NSAIDs after lower third molar alveolectomy, thus proving to be successful analgesia method for this dental surgery.

Clinical trial registration

https://classic.clinicaltrials.gov/ct2/show/NCT06009302, identification number: NCT06009302, date of registration: 18/08/2023.

Keywords

Dental anesthesia
Inferior alveolar nerve
Regional anesthesia
Ultrasound
Tooth
Impacted
Mandibular nerve
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pmcBackground

Eruption of third molars is often absent, leaving them impacted and making their surgical extraction one of the most common dental operations. Along with swelling and trismus, usual complication after molar extraction is pain, with the peak intensity 6–8 h after the procedure [1–3].

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most often prescribed analgesics after surgical extraction of third molars. However, cyclooxygenase (COX) inhibitors are associated with gastrointestinal disorders and platelet dysfunction (both even in acute use), and liver and kidney damage [4]. Fewer gastrointestinal side effects occur with selective COX-2 inhibitors, but they increase risk of thromboembolic events, including myocardial infarction and stroke [5].

Additionally, NSAIDs might inhibit osteoblast differentiation and enhance osteoclast activity (even in usual perioperative doses of e.g. 2 mg/kg/day of diclofenac, during several days) [6], thereby interfering with bone healing after alveotomy. Furthermore, the use of NSAIDs is contraindicated in the first and second trimesters of pregnancy since their use is associated with higher risks for major congenital malformations, and third trimester of pregnancy due to the risk of obliteration of the ductus arteriosus [7]. Having all the above in mind, to reduce side effects and treatment complications, NSAIDs should be used in the lowest effective dose and for the shortest possible time. Another available analgesic is paracetamol, but the possible hepatotoxic effect of paracetamol should also be taken into account [8]. However, to reduce deleterious side-effects of both NSAIDs and paracetamol, patients are often advised to combine NSAIDS and paracetamol to reduce the dose of both, since they act synergistically [4]. On the other hand, opioids, are not the first line of pain treatment after alveotomy, due to high incidence of side effects [4].

Similarly, although corticosteroids are sometimes used perioperatively in maxillofacial surgery due to their analgesic effects combined with decreased swelling, their use is linked to the hyperglycaemia and the increased risk of infection and bleeding [9].

An additional problem are patient’s comorbidities, especially in the elderly. Namely, they regularly use different pharmaceuticals for their cardiovascular and musculoskeletal diseases, which increase the risk of postoperative bleeding. Examples include directly acting oral anticoagulants (NOACs: enoxaparin, dalteparin, dabigatran, edoxaban, rivaroxaban.), coumarin antithrombotic drugs (warfarin), antiplatelet drugs (acetylsalicylic acid, clopidogrel.), antidepressants, and NSAIDs [10]. In addition, some herbal preparations (i.e. curcuma) [11] and oral supplements, e.g. glucosamine sulfate, often used in arthropathy, affect the interactions of the above drugs, further increasing the risk of bleeding, especially in combination with antithrombotic agents, such as NSAIDs [12].

Thus, to delay the onset of pain and to reduce the use of NSAIDs, some other method of analgesia, or anesthesia, should be employed, and the use of several other agents were investigated already, such as ketamine and melatonin. While pre-emptive low-dose ketamine combined with local anesthesia previously showed decreased pain and swelling within the first 24 h after lower third molar surgery, the authors of meta-analysis done in 2020 emphasized the further studies are needed to eliminated possible confounding factors (such as dose of ketamine and the route of ketamine administration) [13]. Additional problems with ketamine are that ketamine is usually approved for induction and maintenance of general anesthesia, but not for treatment of pain [14], and that its parenteral application requires the employment of standard anesthesia monitoring, since it is general anesthetic that could induce respiratory and hemodynamic complications [15]. Another investigated agent was melatonin, which was found to reduce pain and swelling and improved the maximum mouth opening due to its anti-inflammatory effects, when melatonin gel was packed into socket the after removing the impacted third molar [16]. However, in some countries melatonin is considered a dietary supplement, but not a drug [17, 18].

On the other hand, one of alternative strategies to delay the onset of pain and to reduce the use of NSAIDs could be regional analgesia, which is routinely used for pain relief after numerous surgical procedures. While the possibility of using an ultrasound block of the mandibular nerve for analgesia after the extraction of lower third molars has not yet been investigated, previous studies and reports of analgesia after other orofacial surgeries or for certain orofacial conditions suggest that such a block could be effective [19–23].

That prompted us to investigate whether analgesic effects of ultrasound (US) guided extraoral mandibular nerve block for analgesia after the extraction of lower third molars would be sufficient to reduce the use of NSAIDs and the associated risks.

Methods

This prospective clinical study was approved by Ethics committee of Varazdin General Hospital, Varazdin, Croatia (Approval Number: 02/1–91/107–2022), as well as The Ethical board of The University of Zagreb School of Dental Medicine, Zagreb, Croatia (Approval Number: 05-PA-30-18-5/2023), and it was done in accordance with the Declaration of Helsinki. The study was registered in clinicaltrials.gov database (NCT06009302, registered on 18/08/2023), and subject enrolment took place from 1 September, 2023 to 31 December, 2023.

Subjects

We included patients aged 18 to 65 years who underwent extraction of lower third molars, classified radiologically as horizontally positioned lower third molars in the Department of Otorhinolaringology, Varazdin General Hospital, Varazdin Croatia.

We choose horizontally positioned lower third molars (according to Winter’s classification) [24] because this type of patients are the most frequently sent by primary dentist to our hospital. Furthermore, as this type of impaction needs alveotomy and third molars need to be sectioned before extraction (decoronation followed by the division of the roots which are delivered separately) which increases surgical complexity and potential pain level. If third molars are vertically positioned they can erupt into the mouth and they can be removed without alveotomy.

Other inclusion criteria were American Society of Anesthesia (ASA) I or II status, meaning that they have none or mild, well regulated, systemic disease [25]. The exclusion criteria were diabetes (due to lower susceptibility to local anesthetics) [26], allergy to local anesthetics, infection at the punction site, parotitis, serious liver disease, the use of group III antiarrhythmic drugs (i.e. amiodarone), the use of anticoagulants, the use of antithrombotic drugs, lactation, and preventive use of analgesics before the surgery. Patients with an allergy to penicillin were also excluded, since all the patients received antibiotic prophylaxis (amoxicillin 875 mg with clavulanic acid 125 mg, every 12 h for 7 days), as per oral surgeon’s order.

Patient allocation

We presented the study to all the patients coming for the extractions for lower third molars in Varazdin General Hospital, and invited them to enroll. If patients agreed to US-guided mandibular nerve block, they were allocated to experimental group and signed the respective informed consent (Fig. 1.). If a patient did not agree to US-guided mandibular nerve block, but agreed to be contacted for follow up after 24 h, he/she was allocated to the control group and signed the respective informed consent (Fig. 1.).

Fig. 1 Patient flow-chard in the study comparing US-guided mandibular nerve block (experimental) with intraoral inferior alveolar nerve block (control)

Patients coming for the extractions for lower third molar were asked to join the study until desired number of participants was reached in both groups.

Sample size calculation

To the best of our knowledge, there were no similar studies comparing conductive nerve anesthesia (standard anesthesia for the extractions of lower third molars) and any kind of regional anesthesia, we based our calculation on the following: (a) the study comparing the effect of anesthetics with and without the addition of dexamethasone in inferior alveolar nerve block; [21] and (b) the study describing the use of trigeminal nerve block for analgesia following facio-maxillary surgeries [23].

Using the variables reported previously (the time to the first analgesic used after the mandibular nerve block, pain level at that time, the number of analgesic doses during the first 24 h) [21], we would need six to twelve subjects per group (depending on the variable). When we used the pain level after the trigeminal nerve block for analgesia following facio-maxillary surgeries [23], the result was 17 subjects per group. Both calculations were performed with the significance level of 0.05, power of 80%, and with a group size ratio of 1:1.

As those studies used different blocks and were methodologically different to ours, we decided to include 18 patients per group, i.e. one patient more than the largest calculated size.

Anesthetic blocks

In the control group the patients received only the standard intraoral conductive block of inferior alveolar nerve. In the experimental group the patients received the extraoral US-guided mandibular nerve block before the surgery (for postoperative analgesia), followed by standard intraoral conductive block of the inferior alveolar nerve.

Intraoral conductive block of the inferior alveolar nerve

With the patient in supine position and mouth open widely, the inferior alveolar, lingual, and buccal nerves were anesthetized using intraoral approach, described by New York School of Regional Anesthesia [27]. We used premixed combination of 40 mg/ml articaine (4%) and epinephrine 1/100 000 (0.01 mg/ml) (Ubistesin forte, 3 M Deutschland GmbH, Neuss, Germany), starting with 2 × 1.7 ml. If the adequate anesthesia was not achieved, an additional volume of anesthetic was applied as required.

For inferior alveolar and lingual nerve anesthesia a needle was inserted between pterygomandibular raphae and coronoid notch, 6–10 mm above the occlusal plane. After the contact with the bone, a needle was retracted for 1 mm, and ¾ of anesthetic volume was deposited for alveolar nerve anesthesia. Following this, lingual nerve was anesthetized by instillation of the remaining volume during the needle withdrawal [27].

After that, the buccal nerve was anesthetized by the insertion of needle in the tissue just distal and buccal to the last molar tooth. The needle is advanced to the bone, and with the syringe in parallel with the occlusal plane local anesthetic solution was instilled [27].

The efficiency of anesthesia was tested 10 min after the block by the pin prick test of gingiva (pricking the gingiva with a dental probe) for testing inferior alveolar nerve anesthesia. For the assessment of lingual nerve anesthesia half of the tongue on the side of extraction was tested with probe, while the assessment of buccal nerve anesthesia was done by probing the tissues adjacent to the tooth to be extracted.

The numbness reaching the median line (lateral half of lover lip) was considered adequate for inferior alveolar nerve anesthesia, while no pain reported on probing the ipsilateral side of tongue and tissue adjacent to targeted tooth was considered adequate for lingual and buccal nerve anesthesia, respectively.

US guided mandibular nerve block

The block was conducted before the surgery, using an US device (Noblus ultrasound diagnostic scanner, 2019, Hitachi, Ltd.) and a linear probe (8–15 MHz) protected with sterile nylon translucent sleeve. The patient was in a supine position, head facing to the contralateral side (Fig. 2.A.), and with semi-opened mouth. Following the disinfection of the puncture site, the US probe was placed transversally onto the zygomatic arch at the top of the mandibular fossa, right anteriorly and inferiorly to the auricular tragus (Fig. 2.B.). Sliding distally until the pterygomandibular space was visualized (Fig. 2.C.), the mandibular nerve and the maxillary artery were visualized and (at the depth of two to four cm, Fig. 3.A) confirmed by color Doppler [28]. Using the “out of plane” technique, the needle (pencil point, 22G and 5 cm long) was advanced between the coronoid and condylar processes of mandible (Fig. 3.A, B), and the space around maxillary artery was infiltrated with 2.5 ml of 0.75% ropivacaine (total of 18.75 mg), after a negative aspiration (Fig. 2.C, 3.A-C). Our choice was ropivacaine since ubistezin, the typical choice for the alveolar nerve block, has been associated with ischemia of a large facial region [29]. Namely, epinephrin contained in ubistezin may lead to vasoconstriction of the maxillary artery.

Fig. 2 Patient positioning (A, B) and ultrasound visualisation (C) of pterigoamdibular space for US-guided mandibular nerve block

Abbreviations: COR – coronary processus of mandible; CON – condilary processus of mandible

Markings: solid white arrow – points to the needle penetrating skin perpendiculary; * - pterygomandibular space; solid white line – represents needle penetrating skin and masseter muscle perpendiculary, above the level of mandibular processes; dashed white line – represent the needle under the level of mandibular processes

Fig. 3 Anatomy relevant for US-guided mandibular nerve block: Magnetic resonance angiography (A) and intraoperative view (B)

Abbreviations: COR – coronary processus of mandible; CON – condilary processus of mandible

Markings: * - pterygomandibular space; solid white line – represents needle penetrating skin and masseter muscle perpendiculary, above the level of mandibular processes; dashed white line – represent the needle under the level of mandibular processes; solid white arrow – points to the maxillary artery

After that, the standard intraoral inferior alveolar nerve block was conducted, as in the control group, but with one difference: the volume of anesthetic (ubistezin) was titrated to achieve adequate anesthesia. The efficiency of anesthesia was tested 10 min after the intraoral inferior alveolar nerve block by the pin prick test of gingiva and probing the tongue and tissue adjacent to targeted tooth, as in the control group. Since in some cases adequate anesthesia was reached with the US-guided mandibular nerve block only, the intraoral inferior alveolar nerve block was omitted, to avoid applying additional (unnecessary) volume of anesthetics.

The pain level during the performance of the block was assessed on a 0 to 10 visual analogue scale (VAS) [30].

Follow up

Twenty four hours following the surgery all patients received a message (by e-mail or SMS, depending on their preference) containing four questions evaluating the effects of anesthetic/analgesic blocks and the use of rescue analgesics:

time to cessation of lower lip numbness,

time to pain onset (if any),

have they took an (rescue) analgesic (and which one) – if they had taken any rescue analgesic,

the pain level on the VAS scale [30] at the time when they took an analgesic – if they had taken any rescue analgesic.

The patients were supposed to send back their answers to the investigators, and all participants did so. The rescue analgesics the patients took were ibuprofen 400 or 600 mg, paracetamol 1 g, or naproxen 550 mg, as patients reported. We did not advise them in advance which rescue analgesics to take, since primary objective of this study was investigating the pain-free period after US-guided mandibular block as analgesic method (as discussed below). Therefore, we did not feel that it was important what that type of postoperative rescue analgesic patients took after analgesic effect of our US-guided mandibular block weaned off.

In addition, the patients were advised to report any side effects and/or complications.

Investigated outcomes

The primary outcomes of this study were the duration of pain-free time and the need for rescue analgesic. The secondary outcomes included: anesthetic volume needed to achieve adequate anesthesia, pain during the block application (VAS score), duration of the numbness of the lower lip, VAS score at the time of taking a rescue analgesic, and side effect/complications (of both blocks).

Statistical methods

Patients’ characteristics are summarized using median, range, and interquartile range (IQR) (due to the non-normal distribution). The continuous numerical variables were analyzed using the Mann-Whitney’s test for independent samples, while categorical variables were compared using the χ2-test. The sample size calculation and all analyses were performed using MedCalc 20.305 (MedCalc Software Ltd, Ostend, Belgium). P values less than 0.05 were considered statistically significant.

Results

Both groups consisted of seven male and eleven female patients. Median age of patients in the control group (29 years, range 19–64, IQR 12) was similar to the age of the patients in the experimental group (28 years, 21–48, 10) (P = 0.788). In addition, the patients didn’t differ in ASA status (P = 0.486): there were 11 patient of ASA I and 7 patients of ASA I status in the control group, and 13 patients of ASA I and 5 patients of ASA II status in the experimental group.

Primary outcomes

Our primary aim was to investigate the duration of analgesia after the operation, especially the duration of pain free time and the need for rescue analgesic.

The patients in the experimental group reported more pain-free hours (8 h) than the patients in the control group (4 h), P < 0.001 (Table 1.). In addition, almost a quarter of patients in the experimental group (4/18) didn’t experience pain during the entire 24-hour follow-up period.

Table 1 Analgesia features in US-guided mandibular nerve block (experimental) compared to intraoral inferior alveolar nerve block (control)

Analgesia features	Group, N (Median, range, IQR*) (09% confidence interval for median)	P	
Control (N = 18)	Experimental (N = 18)	
Volume of local anesthetic needed for intraoral inferior alveolar nerve block (ml)	3.4, 3.4-6.0, 0 (3.0 to 4.8)	1.7, 0–4.0, 3.4 † (4.6 to 7.8)	< 0.001	
Pain intensity during the intraoral inferior alveolar nerve block (VAS‡)	4, 1–10, 3 (3,0 to 5,6)	1, 0–6, 3 † (0.0 to 2.6)	< 0.001	
Pain intensity during the block application (VAS‡)	4, 1–10, 3 § (3.0 to 5.6)	2, 1–5, 3 II (1.0 to 4.0)	0.011	
Time to cessation of numbness of lower lip (hours)	4, 2–24, 2 (3.0 to 4.8)	7, 3–24, 4 (4.6 to 7.8)	0.002	
Time to pain onset (hours)	4, 1–9, 2 (2. 7 to 5.0)	8, 4–24, 7 ¶ (5. 7 to 10.9)	< 0.001	
Pain intensity when taking the analgesic (VAS†)	4, 3–5, 1 (3.0 to 4.0)	4, 3–5, 1 (3.0 to 4.0)	0.597	
No. of patients who needed rescue analgesic	12	17	0,038	
* IQR – interquartile range

† in 8 patients intraoral inferior alveolar nerve block was not needed because US-guided mandibular block provided adequate anesthesia for the procedure

‡ VAS – visual analogue scale for pain intensity measurement

§ US-guided mandibular block

II intraoral inferior alveolar nerve block

¶ four patients didn’t experience pain during the 24 h follow up period

As for the per-oral analgesic supplementation, fewer patients in the experimental group needed analgesics than in the control group (67% vs. 94%, respectively; P = 0.038), Table 1.

Secondary outcomes

The anesthetic volume needed to achieve anesthesia was significantly lower in the experimental group: median volume of 1.7 ml vs. 3.4 ml in the control group (P < 0.001; Table 1). In addition, the US-guided mandibular nerve block alone achieved adequate anesthesia needed for the procedure in eight cases in the experimental group and no supplementation with inferior alveolar nerve block was needed (Table 1.).

Regarding the pain during the block application, the patients in the experimental group, who received US-guided mandibular block before inferior alveolar nerve block, reported significantly lower level of pain experienced during the performance of inferior alveolar nerve block (median VAS score 2) than the patients in the control group (median VAS score 4), P < 0.001 (Table 1.). Furthermore, the VAS scores for the application of US-guided mandibular block in the experimental group were significantly lower (median 2) than those for the application of inferior alveolar nerve block in the control group (median 4), P = 0.011.

The numbness of the lower lip lasted about two-fold longer in the experimental group: median 7 h compared to 4 h in the control group, P = 0.002 (Table 1.).

In five patients the pain occurred before cessation of lower lip numbness: three of those were in the control and two in the experimental group (and these two patients needed the supplementation of US-guided block with intraoral inferior alveolar nerve block).

However, although fewer patients in the experimental group needed analgesics than in the control group, the pain level at the moment of taking a rescue analgesic was similar in both groups (median VAS score 4 in both; P = 0.597).

Side effects of anesthetic blocks

Right after the US-guided mandibular nerve block was performed, one patient developed Horner’s syndrome, which was considered a complication of the procedure and it resolved by the end of the surgery. Other patient from the same group reported feeling of pressure at the puncture site (side effect), which diminished spontaneously over the next few weeks.

Discussion

Regional anesthesia and analgesia, as an example of an alternative to NSAIDs after orofacial surgeries or conditions have been tried out before: for instance, gnathoplasty, trismus, orofacial carcinoma surgery [19–23]. However, our study expands that body of work by showing that regional analgesia, i.e. US-guided extraoral mandibular nerve block can be used for the management of postoperative pain after surgical extraction of third molars. Not only that the pain-free time after the extraction was longer when the extraoral mandibular nerve block was applied, it actually covered the first 6-postoperative hours when the pain reaches it’s peak [1–3]. Since the most painful postoperative time was bridged and the time to use of first analgesics was prolonged, fewer patients required analgesics. In addition, a quarter of the patients who received extraoral mandibular nerve block experienced no pain at all, while there were no such patients in the control group. All these results show that the extraoral mandibular nerve block successively controlled postoperative pain after the extraction of lower third molars, reducing the use of NSAIDs.

In addition, the standard intraoral inferior alveolar nerve block was not even needed in some cases. Namely, since this method was not described before, we did not think that it would be possible that extraoral mandibular nerve block would achieve adequate surgical anesthesia, so we planned it to be a method for postoperative analgesia only, while standard infraoral nerve block was given for anesthesia. However, to our surprise, in almost half of the patients US-guided extraoral mandibular nerve block achieved surgical anesthesia, so ad hoc decision was made not to proceed with the planned infraoral nerve block, to avoid applying an additional volume of local anesthetics.

We believe that surgical level of anesthesia was enabled by the US visualization of the mandibular nerve and focused application of anesthetics in the close vicinity of the nerve. In that way, we avoided larger anesthetic volumes anesthetic (e.g. one patient in the control group required a total of 7.8 ml of anesthetic during the intraoral inferior alveolar nerve block, which means that he needed additional top-up of 4.4 ml to initially planned 2 × 1.7 ml), thereby further reducing the risk of possible side effects.

A possible reason why this patient needed such a large anesthetic volume could be an aberrant localization of the inferior alveolar nerve [31–33]. As anatomical variations can not be foreseen or detected without imaging, a top-up of local anesthetic is required to achieve sufficient anesthesia by a wider distribution of larger volume of anesthetic. Thus, employing an imaging method, such as ultrasound, enables a precise localization of the target structure and the consequent reduction of the anesthetic volume. Subsequently, analgesia would be prolonged, and the use of analgesics for pain relief would be mitigated, along with the reduced incidence of their side effects and complications.

An additional advantage of US visualization of anatomic structures is focused analgesia in the area of the target nerve, so that the anesthesia of the whole face could be avoided along with its concomitant side effects. For example, sensory and motor dysfunction of the trigeminal nerve may lead to problems with biting, chewing, equalization of air pressure in the tympanic cavity, and entry of food into the nasopharynx during swallowing, all of which were described when anesthesia was performed without direct visualization of neurovascular structures [19–23].

It is worth noticing an unexpected advantage of US-guided extraoral mandibular nerve block: although we had had concerns that patients would report higher level of pain when the block was applied by deep facial puncture, US-guided extraoral approach was associated with lower VAS scores than the intraoral block. We believe that this finding might be explained by the morphology of orofacial structures. During the intraoral inferior alveolar nerve block the volume of local anesthetic is forced in the almost nonexistent space between the gingiva and periosteum. In contrast, during the US-guided extraoral mandibular nerve block the volume of local anesthetic is applied in the pterygomandibular space which contains anatomical structures that could be compressed and/or pushed aside (fat tissue and venous plexus), so that the distension of tissues and consequent pain are avoided.

Our results also led us to hypothesize that US-guided extraoral mandibular nerve block could be used as a standalone anesthetic method. Since US-guided extraoral mandibular nerve block was solely sufficient in almost half of the participants in the experimental group it is possible that this block could be used as sole technique for anesthesia, but probably with slightly larger volume of local anesthetics.

Although this study shoved advantages of US-guided extraoral mandibular nerve block, one could argue that there are disadvantages of this technique regarding the need for additional equipment. It is true that obtaining an US machine is needed, as well as learning a new technique. However, as it was seen with introducing a nitrous oxygen for analgesia and anxiolysis for dental procedures, dentists are opened to learning and mastering of new techniques, even if it includes completely new concepts and application of drugs that puts them out of their usual practices and possibly out of their comfort zone. Despite the fact that special equipment and education is needed for the use of nitrous oxygen and the fact that its use could be associated with serious complications, nitrous oxygen inhalation in dentistry is now accepted world widely [34] and used for sedation in many dental in practices for various dental and dental surgery procedures, and it was even stated by a dental office that “nitrous oxide’s role in dentistry cannot be overstated.” [35] Hence, we don’t see introducing of US-guided extraoral mandibular nerve block in dental practice as a problem, but rather as an opportunity for providing an additional level of care oriented towards a particular patient having in mind his/hers specific comorbidities and needs.

We also need to acknowledge possible limitations of our work. One is the design of the study, which is uncommon for clinical trials. Namely, although the initial design of our study envisaged the inclusion of only those patients who consented both to participate and to be randomly allocated to study or control group, we could not collect sufficient number of such patients due to the reluctance/refusal of patients to receive the face puncture needed for US-guided mandibular nerve block. Another design-related limitation is the lack of masking. We are aware that the use of a placebo in the control group (e.g., the volume of saline in the control group equal to the volume of local anesthetic in the study group) would had been optimal, we could not do that for the same reason that we could not do randomization. Therefore, we opted for the aforementioned design. Additionally, the authors who did statistical analysis and the majority of data interpretation, were not aware of group allocation (they were “blinded”), since they were not included in data acquisition and they received coded data only. However, since our results are strongly convincing and since the statistical difference of the primary outcome (time to pain onset) was highly significant (P < 0.001), which proved sufficient power of the study, we believed that similar results would be achieved with the study that includes random allocation of patients to study and control group, and with the use of placebo in the control group.

The second limitation is that we used Winter’s classification [24], which describes angulation of molars only, but not other characteristics of impaction. If we used some other classification that takes into consideration possible difficulties during molar extraction, such as Pederson’s classification [24], we could have investigated pain-free period regarding the difficulty of surgical procedure depending on complexity of impaction.

The last limitation is a possible bias of the patients in the experimental group. Namely, it is known that the pain perception is influenced by the psychological structure of the person [36–39]. Also, it has been shown that more adventurous persons are more willing to embrace new experiences, so they might also be more open to experimental techniques and chose the experimental group. Since such personality traits are associated with better pain tolerance [40], it is possible that VAS scores in the experimental group were influenced by personality traits of the subjects.

Conclusion

Despite the limitations, this study clearly demonstrated that US-guided extraoral mandibular nerve block prolonged the pain-free time after the extraction of lower third molars. Also, the US-guided extraoral mandibular nerve block reduced the need for rescue NSAID analgesics, which could mitigats the risks associated with the use of NSAIDs.

Author contributions

Marija Marinus – conception and design of the study, data acquisition and interpretation, manuscript drafting and final approval. Slobodan Mihaljevic – conception and design of the study, overseeing, manuscript final approval. Kresimir Reiner – conception and design of the study, manuscript final approval. Zeljko Verzak – conception and design of the study, overseeing, manuscript final approval. Monika Kocman Panic – conception and design of the study, manuscript final approval. Aleksandra Strahija – data acquisition, manuscript final approval. Vicko Gluncic – manuscript drafting and final approval. Ivan Kresimir Lukic – conception and design of the study, data interpretation, manuscript drafting and final approval. Anita Lukic – conception and design of the study, data interpretation, statistical analyses, manuscript drafting and final approval.

Funding

The authors have no sources of funding to declare for this manuscript.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Huma ethics and Consent to participate

This study was approved by Ethics committee of Varazdin General Hospital, Varazdin, Croatia (No. 02/1–91/107–2022), as well as The Ethical board of The University of Zagreb School of Dental Medicine, Zagreb, Croatia (No. 05-11-30-18-5/2023), and it was done in accordance with the Declaration of Helsinki.

Patient consents

All participants signed informed consent form to clinical trial.

Consent for publication

The person whose face is partially visible at the photo that shows the placement ultrasound probe signed additional consent form allowing the authors to use the photo of his face in the publication.

Consent for publication

The authors declare that they have no competing interests.

Abbreviations

NSAID Non–steroidal anti–inflammatory drugs

VAS Visual analogue scale

COX Cyclooxygenase

ASA American Society of Anesthesia

IQR Interquarile range

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Khorshidi Khiavi R Pourallahverdi M Pourallahverdi A Ghorani Khiavi S Ghertasi Oskouei S Mokhtari H Pain control following impacted third molar surgery with bupivacaine irrigation of tooth socket: a prospective study J Dent Res Dent Clin Dent Prospects 2010 4 105 9 10.5681/joddd.2010.027 23346335
Khorshidi Khiavi R, Pourallahverdi M, Pourallahverdi A, Ghorani Khiavi S, Ghertasi Oskouei S, Mokhtari H. Pain control following impacted third molar surgery with bupivacaine irrigation of tooth socket: a prospective study. J Dent Res Dent Clin Dent Prospects. 2010;4:105–9. 10.5681/joddd.2010.02723346335 10.5681/joddd.2010.027
2. Nørholt SE Aagaard E Svensson P Sindet-Pedersen S Evaluation of trismus, bite force, and pressure algometry after third molar surgery: a placebo-controlled study of ibuprofen J Oral Maxillofac Surg 1998 56 420 9 10.1016/s0278-2391(98)90705-4 9541340
Nørholt SE, Aagaard E, Svensson P, Sindet-Pedersen S. Evaluation of trismus, bite force, and pressure algometry after third molar surgery: a placebo-controlled study of ibuprofen. J Oral Maxillofac Surg. 1998;56:420–9. 10.1016/s0278-2391(98)90705-49541340 10.1016/s0278-2391(98)90705-4
3. Fisher SE Frame JW Rout PG McEntegart DJ Factors affecting the onset and severity of pain following the surgical removal of unilateral impacted mandibular third molar teeth Br Dent J 1988 164 351 4 10.1038/sj.bdj.4806453 3165011
Fisher SE, Frame JW, Rout PG, McEntegart DJ. Factors affecting the onset and severity of pain following the surgical removal of unilateral impacted mandibular third molar teeth. Br Dent J. 1988;164:351–4. 10.1038/sj.bdj.48064533165011 10.1038/sj.bdj.4806453
4. Hernández-Viana S Silva-Gómez N Galvis-Pareja DA Martínez-Pabón MC The use of analgesics and anti-inflammatories in an oral surgery service in Medellín, Colombia, 2013–2015 Rev Fac Odontol Univ Antioq 2019 30 154 68 10.17533/udea.rfo.v30n2a3
Hernández-Viana S, Silva-Gómez N, Galvis-Pareja DA, Martínez-Pabón MC. The use of analgesics and anti-inflammatories in an oral surgery service in Medellín, Colombia, 2013–2015. Rev Fac Odontol Univ Antioq. 2019;30:154–68. 10.17533/udea.rfo.v30n2a310.17533/udea.rfo.v30n2a3
5. Martínez-González J Badimon L Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks Curr Pharm Des 2007 13 2215 27 10.2174/138161207781368774 17691994
Martínez-González J, Badimon L. Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks. Curr Pharm Des. 2007;13:2215–27. 10.2174/13816120778136877417691994 10.2174/138161207781368774
6. Etikala A, Tattan M, Askar H, Wang HL. Effects of NSAIDs on Periodontal and Dental Implant Therapy. Compend Contin Educ Dent. 2019;40:e1-e9. PMID: 30767546.
7. Koren G Florescu A Costei AM Boskovic R Moretti ME Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis Ann Pharmacother 2006 40 824 9 10.1345/aph.1G428 16638921
Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME. Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother. 2006;40:824–9. 10.1345/aph.1G42816638921 10.1345/aph.1G428
8. Coticosteroides. In: Schug SA, Palmer GM, Scott DA, Alcock MM, Halliwell R, Mott JF, editors. Acute Pain Management: Scientific Evidence (5th edition). APM: SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. pp 214-7.
9. Piccinin E Ducheix S Peres C Arconzo M Vegliante MC Ferretta A PGC-1β induces susceptibility to Acetaminophen-Driven Acute Liver failure Sci Rep 2019 9 16821 10.1038/s41598-019-53015-6 31727907
Piccinin E, Ducheix S, Peres C, Arconzo M, Vegliante MC, Ferretta A, et al. PGC-1β induces susceptibility to Acetaminophen-Driven Acute Liver failure. Sci Rep. 2019;9:16821. 10.1038/s41598-019-53015-631727907 10.1038/s41598-019-53015-6
10. Teoh L Moses G McCullough MJ A review of drugs that contribute to bleeding risk in general dental practice Aust Dent J 2020 65 118 30 10.1111/adj.12751 32064612
Teoh L, Moses G, McCullough MJ. A review of drugs that contribute to bleeding risk in general dental practice. Aust Dent J. 2020;65:118–30. 10.1111/adj.1275132064612 10.1111/adj.12751
11. Keihanian F Saeidinia A Bagheri RK Johnston TP Sahebkar A Curcumin, hemostasis, thrombosis, and coagulation J Cell Physiol 2018 33 4497 511 10.1002/jcp.26249
Keihanian F, Saeidinia A, Bagheri RK, Johnston TP, Sahebkar A. Curcumin, hemostasis, thrombosis, and coagulation. J Cell Physiol. 2018;33:4497–511. 10.1002/jcp.2624910.1002/jcp.26249
12. Knudsen JF Sokol GH Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database Pharmacotherapy 2008 28 540 8 10.1592/phco.28.4.540 18363538
Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database. Pharmacotherapy. 2008;28:540–8. 10.1592/phco.28.4.54018363538 10.1592/phco.28.4.540
13. Refahee SM Al-Moraissi AE Alkhutari ASY Pre-emptive low-dose ketamine with local anesthesia reduces postoperative morbidity after third molar surgery: a systematic review and meta-analysis J Oral Res 2020 9 259 70 10.17126/joralres.2020.067
Refahee SM, Al-Moraissi AE, Alkhutari ASY. Pre-emptive low-dose ketamine with local anesthesia reduces postoperative morbidity after third molar surgery: a systematic review and meta-analysis. J Oral Res. 2020;9:259–70. 10.17126/joralres.2020.06710.17126/joralres.2020.067
14. US Food & Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/understanding-current-use-ketamine-emerging-areas-therapeutic-interest-06272024 (2024) (accessed 11 August 2024).
15. US Food & Drug Administration. FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine (2023) (accessed 11 August 2024).
16. Refahee SM Aboulmagd I Ragab R Abdel Aziz O Ahmed WAEA Shabaan AA The effect of local melatonin application following the removal of an impacted mandibular third molar J Oral Maxillofac Surg 2023 81 622 31 10.1016/j.joms.2023.01.010 36796435
Refahee SM, Aboulmagd I, Ragab R, Abdel Aziz O, Ahmed WAEA, Shabaan AA. The effect of local melatonin application following the removal of an impacted mandibular third molar. J Oral Maxillofac Surg. 2023;81:622–31. 10.1016/j.joms.2023.01.01036796435 10.1016/j.joms.2023.01.010
17. Savage RA, Zafar N, Yohannan S et al. August. Melatonin. [Updated 2024 Feb 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK534823/ (accessed 11 2024).
18. National Center for Complementar and Integrative Health. Melatonin: What You Need To Know. https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know#:~:text=Melatonin%20is%20regulated%20as%20a,the%2Dcounter%20drug%20would%20be (2024) (accessed 11 August 2024).
19. Kumita S Murouchi T Arakawa J Ultrasound-guided maxillary and inferior alveolar nerve blocks for postoperative analgesia in gnathoplasty Asian J Anesthesiol 2017 55 89 90 10.1016/j.aja.2017.11.001 29198931
Kumita S, Murouchi T, Arakawa J. Ultrasound-guided maxillary and inferior alveolar nerve blocks for postoperative analgesia in gnathoplasty. Asian J Anesthesiol. 2017;55:89–90. 10.1016/j.aja.2017.11.00129198931 10.1016/j.aja.2017.11.001
20. Kojima Y Sendo R Ohno S Sugimura M Ultrasound-guided inferior alveolar nerve block for trismus during dental treatment: a case report JA Clin Rep 2020 6 94 10.1186/s40981-020-00400-0 33269430
Kojima Y, Sendo R, Ohno S, Sugimura M. Ultrasound-guided inferior alveolar nerve block for trismus during dental treatment: a case report. JA Clin Rep. 2020;6:94. 10.1186/s40981-020-00400-033269430 10.1186/s40981-020-00400-0
21. Stojanović S Burić N Tijanić M Todorović K Burić K Burić N The Assessment of prolonged inferior alveolar nerve blockade for postoperative analgesia in Mandibular Third Molar surgery by a Perineural Addition of Dexamethasone to 0.5% ropivacaine: a randomized comparison study Int J Environ Res Public Health 2022 19 1324 10.3390/ijerph19031324 35162346
Stojanović S, Burić N, Tijanić M, Todorović K, Burić K, Burić N, et al. The Assessment of prolonged inferior alveolar nerve blockade for postoperative analgesia in Mandibular Third Molar surgery by a Perineural Addition of Dexamethasone to 0.5% ropivacaine: a randomized comparison study. Int J Environ Res Public Health. 2022;19:1324. 10.3390/ijerph1903132435162346 10.3390/ijerph19031324
22. Plantevin F Pascal J Morel J Roussier M Charier D Prades JM Effect of mandibular nerve block on postoperative analgesia in patients undergoing oropharyngeal carcinoma surgery under general anesthesia Br J Anesth 2007 99 708 12 10.1093/bja/aem242
Plantevin F, Pascal J, Morel J, Roussier M, Charier D, Prades JM, et al. Effect of mandibular nerve block on postoperative analgesia in patients undergoing oropharyngeal carcinoma surgery under general anesthesia. Br J Anesth. 2007;99:708–12. 10.1093/bja/aem24210.1093/bja/aem242
23. Kumar A Sinha C Kumar A Kumari P Mukul SK Ultrasound-guided trigeminal nerve block and its comparison with conventional analgesics in patients undergoing faciomaxillary surgery: Randomised control trial Indian J Anesth 2018 62 871 5 10.4103/ija.IJA_256_18
Kumar A, Sinha C, Kumar A, Kumari P, Mukul SK. Ultrasound-guided trigeminal nerve block and its comparison with conventional analgesics in patients undergoing faciomaxillary surgery: Randomised control trial. Indian J Anesth. 2018;62:871–5. 10.4103/ija.IJA_256_1810.4103/ija.IJA_256_18
24. Jaroń A Trybek G The pattern of Mandibular Third Molar Impaction and Assessment of surgery difficulty: a retrospective study of radiographs in East Baltic Population Int J Environ Res Public Health 2021 18 6016 10.3390/ijerph18116016 34205078
Jaroń A, Trybek G. The pattern of Mandibular Third Molar Impaction and Assessment of surgery difficulty: a retrospective study of radiographs in East Baltic Population. Int J Environ Res Public Health. 2021;18:6016. 10.3390/ijerph1811601634205078 10.3390/ijerph18116016
25. American Society of Anesthesiologists. Statement on ASA Physical Status Classification System [online]. 2020. https://www.asahq.org/standards-and-practice-parameters/statement-on-asa-physical-status-classification-system (last accessed 1 April, 2024).
26. Ten Hoope W Hollmann MW de Bruin K Verberne HJ Verkerk AO Tan HL Pharmacodynamics and pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy Anesthesiology 2018 128 609 19 10.1097/ALN.0000000000002035 29251644
Ten Hoope W, Hollmann MW, de Bruin K, Verberne HJ, Verkerk AO, Tan HL, et al. Pharmacodynamics and pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy. Anesthesiology. 2018;128:609–19. 10.1097/ALN.000000000000203529251644 10.1097/ALN.0000000000002035
27. New York School of Regional Anesthesia. Oral & Maxillofacial Regional Anesthesia https://www.nysora.com/techniques/head-and-neck-blocks/oral-maxillofacial-regional-anesthesia/ (accessed 11 August 2024).
28. Chang KV Lin CS Lin CP Wu WT Özçakar L Recognition of the lateral pterygoid muscle and plate during Ultrasound-guided trigeminal nerve block J Clin Diagn Res 2017 11 UL01 2 10.7860/JCDR/2017/27724.9932 28658882
Chang KV, Lin CS, Lin CP, Wu WT, Özçakar L. Recognition of the lateral pterygoid muscle and plate during Ultrasound-guided trigeminal nerve block. J Clin Diagn Res. 2017;11:UL01–2. 10.7860/JCDR/2017/27724.993228658882 10.7860/JCDR/2017/27724.9932
29. Ulutürk H Eberlikose G Özcan G Yilmaz D Rare cutaneous Ischaemia and Pain during Infiltrative Anesthesia for Dental surgery: Case Reports and Literature Review J Clin Diagn Res 2020 14 ZD01 4 10.7860/JCDR/2020/43030.13519
Ulutürk H, Eberlikose G, Özcan G, Yilmaz D. Rare cutaneous Ischaemia and Pain during Infiltrative Anesthesia for Dental surgery: Case Reports and Literature Review. J Clin Diagn Res. 2020;14:ZD01–4. 10.7860/JCDR/2020/43030.1351910.7860/JCDR/2020/43030.13519
30. Delgado DA Lambert BS Boutris N McCulloch PC Robbins AB Moreno MR Validation of Digital Visual Analog Scale Pain Scoring with a traditional paper-based Visual Analog Scale in adults J Am Acad Orthop Surg Glob Res Rev 2018 2 e088 10.5435/JAAOSGlobal-D-17-00088 30211382
Delgado DA, Lambert BS, Boutris N, McCulloch PC, Robbins AB, Moreno MR, et al. Validation of Digital Visual Analog Scale Pain Scoring with a traditional paper-based Visual Analog Scale in adults. J Am Acad Orthop Surg Glob Res Rev. 2018;2:e088. 10.5435/JAAOSGlobal-D-17-0008830211382 10.5435/JAAOSGlobal-D-17-00088
31. Thotakura B Rajendran SS Gnanasundaram V Subramaniam A Variations in the posterior division branches of the mandibular nerve in human cadavers Singap Med J 2013 54 149 51 10.11622/smedj.2013051
Thotakura B, Rajendran SS, Gnanasundaram V, Subramaniam A. Variations in the posterior division branches of the mandibular nerve in human cadavers. Singap Med J. 2013;54:149–51. 10.11622/smedj.201305110.11622/smedj.2013051
32. Siessere S Hallak Regalo SC Semprini M Honorato De Oliveira R Vitti M Mizusaki Iyomasa M Anatomical variations of the mandibular nerve and its branches correlated to clinical situations Minerva Stomatol 2009 58 209 15 19436250
Siessere S, Hallak Regalo SC, Semprini M, Honorato De Oliveira R, Vitti M, Mizusaki Iyomasa M, et al. Anatomical variations of the mandibular nerve and its branches correlated to clinical situations. Minerva Stomatol. 2009;58:209–15. PMID: 19436250.19436250
33. Kim SY Hu KS Chung IH Lee EW Kim HJ Topographic anatomy of the lingual nerve and variations in communication pattern of the mandibular nerve branches Surg Radiol Anat 2004 26 128 35 10.1007/s00276-003-0179-x 14586562
Kim SY, Hu KS, Chung IH, Lee EW, Kim HJ. Topographic anatomy of the lingual nerve and variations in communication pattern of the mandibular nerve branches. Surg Radiol Anat. 2004;26:128–35. 10.1007/s00276-003-0179-x14586562 10.1007/s00276-003-0179-x
34. Khinda V Rao D Sodhi SPS Nitrous Oxide Inhalation Sedation Rapid Analgesia in Dentistry: an overview of technique, objectives, indications, advantages, monitoring, and Safety Profile Int J Clin Pediatr Dent 2023 16 131 8 10.5005/jp-journals-10005-1807 37020786
Khinda V, Rao D, Sodhi SPS. Nitrous Oxide Inhalation Sedation Rapid Analgesia in Dentistry: an overview of technique, objectives, indications, advantages, monitoring, and Safety Profile. Int J Clin Pediatr Dent. 2023;16:131–8. 10.5005/jp-journals-10005-180737020786 10.5005/jp-journals-10005-1807
35. Atrium Dental. Understanding Nitrous Oxide in Dentistry: A Safe and Effective Sedation Method. https://atriumdental.net/nitrous-oxide/ (2024) (accessed 11 August 2024).
36. Conrad R Schilling G Bausch C Nadstawek J Wartenberg HC Wegener I Temperament and character personality profiles and personality disorders in chronic pain patients Pain 2007 133 197 209 10.1016/j.pain.2007.07.024 17964076
Conrad R, Schilling G, Bausch C, Nadstawek J, Wartenberg HC, Wegener I, et al. Temperament and character personality profiles and personality disorders in chronic pain patients. Pain. 2007;133:197–209. 10.1016/j.pain.2007.07.02417964076 10.1016/j.pain.2007.07.024
37. Grouper H Eisenberg E Pud D More insight on the role of personality traits and sensitivity to Experimental Pain J Pain Res 2021 14 1837 44 10.2147/JPR.S309729 34168491
Grouper H, Eisenberg E, Pud D. More insight on the role of personality traits and sensitivity to Experimental Pain. J Pain Res. 2021;14:1837–44. 10.2147/JPR.S30972934168491 10.2147/JPR.S309729
38. Cosio D. The Perseverance Loop: The Psychology of Pain and Factors in Pain Perception. [online]. Pract Pain Manag. 2020;20. www.medcentral.com/behavioral-mental/cbt/perseverance-loop-psychology-pain-factors-pain-perception (accessed 1 April 2024).
39. McGrath PA Psychological aspects of pain perception Arch Oral Biol 1994 39 s55 62 10.1016/0003-9969(94)90189-9
McGrath PA. Psychological aspects of pain perception. Arch Oral Biol. 1994;39:s55–62. 10.1016/0003-9969(94)90189-910.1016/0003-9969(94)90189-9
40. Miller PK Van Der Zee S Elliott D Pain Culture and pedagogy: a preliminary investigation of attitudes towards reasonable Pain Tolerance in the grassroots Reproduction of a culture of risk Psychol Rep 2022 125 1086 102 10.1177/0033294120988096 33573499
Miller PK, Van Der Zee S, Elliott D, Pain. Culture and pedagogy: a preliminary investigation of attitudes towards reasonable Pain Tolerance in the grassroots Reproduction of a culture of risk. Psychol Rep. 2022;125:1086–102. 10.1177/003329412098809633573499 10.1177/0033294120988096
