Long acting local anesthesia and preventive analgesia—difficulty of prove on clinical trial

Owing to effective anesthetic agents and improved methods of anesthesia, nowadays, patients feel almost no pain during extractions. However, postoperative pain continues to cause discomfort and distress to many patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are often prescribed post-extraction. However, because NSAIDs may cause ulcers, they must be used with caution in patients with gastrointestinal disease. Furthermore, they cannot be administered to patients who have aspirin intolerance, which has become an issue in the recent years. The addictive nature of opioids also makes it difficult to prescribe them in sufficient doses. Therefore, alternative methods for alleviation of postoperative pain are being investigated. Animal studies have explored the use of preventive (also called pre-emptive) analgesia and have reported that adequate pre-operative analgesia can confer effective post-operative pain relief (1-4). However, results of clinical studies have been inconsistent, with some reporting that preventive analgesia was effective (5,6) but others showing negative results (7-9). The reasons for these conflicting observations may be individual differences in pain thresholds and psychological factors.

The study of Amorim et al. titled “Postoperative analgesia in extraction of impacted mandibular third molars? A randomized clinical trial” was well-designed and showed that the long-acting local anesthetic ropivacaine was effective for postoperative analgesia (10). This study used the cross-over method to compare pain following the extraction of bilateral mandibular third molars (class II-B according to Pell and Gregory’s classification) requiring bone removal under 0.75% ropivacaine or 2% lidocaine with 1:100,000 epinephrine. One of both anesthetics were administered by infiltration anesthesia, buccal nerve block, and inferior alveolar nerve block. Clinical studies that rely on self-reporting by patients often suffer from missing data. Therefore, the authors in this study made telephone calls to each patient every 30 minutes to enquire about the anesthetic effect. As a result, the data obtained were reliable. They found that the mean duration of anesthesia with 0.75% ropivacaine was 445.7±58 minutes (mean ± standard deviation), which was significantly longer than the 213.8±41 minutes with 2% lidocaine with 1:100,000 epinephrine. This is similar to the findings of Ogura et al. (11). Further, Amorim et al. found that the postoperative pain score on a visual analog scale (VAS) did not decrease significantly over 24 hours on administering 2% lidocaine with 1:100,000 epinephrine, whereas it decreased significantly within 8 hours on administering 0.75% ropivacaine. The total amount dosage and frequency of sodium dipyrone administered were also significantly lower when 0.75% ropivacaine was administered. Especially, at 72 hours, no patient took sodium dipyrone following 0.75% ropivacaine administration, unlike 20 patients who took following 2% lidocaine with 1:100,000 epinephrine administration. Therefore, the authors concluded that 0.75% ropivacaine exerts a preventive analgesic effect and diminishes pain following extraction of impacted third molars. I (KS) agree that 0.75% ropivacaine was more effective than 2% lidocaine with 1:100,000 epinephrine for post-extraction pain relief. However, it may not be possible to state categorically whether this effect is the direct result of preventive analgesia as the authors claim.

Pain stimulation decreases the threshold of peripheral neurons and causes excitation of the central nervous system. Therefore, preventive analgesia is obtained by preventing pain input to the nervous system. On the other hand, long-acting anesthetics prolong the effect of postoperative analgesia, so that the dose of analgesics can be reduced. In addition, long duration of analgesia can help the patient recover oral function, including occlusion and swallowing, quickly, and there is a possibility that there is faster resolution of inflammation and pain owing to increased blood perfusion at the wound site. In short, it cannot be denied that long-acting anesthetics may decrease the amount of required analgesics through different reasons than preventive analgesia. Accordingly, the clinical study of preventive analgesia requires comparison of the postoperative pain levels of patients who undergo painless extractions and with those who undergo extractions under inadequate anesthesia. However, such research cannot be performed for ethical reasons.

This may be what underlies the difficulty in demonstrating preventive analgesia in a clinical setting. The authors have cited a study by Johansson et al., which concluded that “Ropivacaine has a significant, dose-related pain-reducing effect in the immediate postoperative period but we could find no support for the theory that preoperative infiltration analgesia reduces long term pain” (12).

This study also discusses the vasoconstrictive action of 0.75% ropivacaine and the effect of adding epinephrine. The authors have cited past clinical studies according to which ropivacaine has vasoconstrictor properties (13,14) and epinephrine helps extend the duration time of vasodilating anesthetics like Lidocaine (15,16). On the other hand, Yamashiro et al. reported that 0.5% ropivacaine did not have a vasoconstrictive effect, and the addition of epinephrine tripled the concentration of ropivacaine in the maxillary tissue (17) in an experimental study on rats. Fujita et al. also reported that epinephrine addition had a greater effect on 0.5% ropivacaine than on 2% lidocaine in increasing the anesthetic concentration in the rat maxillary tissue (18). I believe that the cause for high postoperative bleeding following 0.75% ropivacaine administration in this study was that it did not have a vasoconstrictor effect. For these reasons, I consider that adding epinephrine to ropivacaine strengthens its anesthetic effect, provides long-lasting anesthesia, and decreases postoperative bleeding. Of course, as authors said that more clinical studies are needed about the use of ropivacaine with epinephrine in oral surgery and dentistry in general. However, I personally believe that ropivacaine with epinephrine would be a useful dental anesthetic solution.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Oral and Maxillofacial Anesthesia. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-21-14/coif). KS serves as an unpaid editorial board member of Journal of Oral and Maxillofacial Anesthesia from August 2021 to July 2023. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Bufalari A, Maggio C, Cerasoli I, et al. Preemptive carprofen for peri-operative analgesia in dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO): a prospective, randomized, blinded, placebo controlled clinical trial. Schweiz Arch Tierheilkd 2012;154:105-11. [Crossref] [PubMed]
2. Shavit Y, Weidenfeld J, DeKeyser FG, et al. Effects of surgical stress on brain prostaglandin E2 production and on the pituitary-adrenal axis: attenuation by preemptive analgesia and by central amygdala lesion. Brain Res 2005;1047:10-7. [Crossref] [PubMed]
3. Minville V, Fourcade O, Girolami JP, et al. Opioid-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine. Br J Anaesth 2010;104:231-8. [Crossref] [PubMed]
4. Nagasaka H, Nakamura S, Mizumoto Y, et al. Effects of ketamine on formalin-induced activity in the spinal dorsal horn of spinal cord-transected cats: differences in response to intravenous ketamine administered before and after formalin. Acta Anaesthesiol Scand 2000;44:953-8. [Crossref] [PubMed]
5. Lavand'homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology 2005;103:813-20. [Crossref] [PubMed]
6. Lohsiriwat V, Lert-akyamanee N, Rushatamukayanunt W. Efficacy of pre-incisional bupivacaine infiltration on postoperative pain relief after appendectomy: prospective double-blind randomized trial. World J Surg 2004;28:947-50. [Crossref] [PubMed]
7. Jung YS, Kim MK, Um YJ, et al. The effects on postoperative oral surgery pain by varying NSAID administration times: comparison on effect of preemptive analgesia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:559-63. [Crossref] [PubMed]
8. Suresh S, Barcelona SL, Young NM, et al. Does a preemptive block of the great auricular nerve improve postoperative analgesia in children undergoing tympanomastoid surgery? Anesth Analg 2004;98:330-3. [Crossref] [PubMed]
9. Ghezzi F, Cromi A, Bergamini V, et al. Preemptive port site local anesthesia in gynecologic laparoscopy: a randomized, controlled trial. J Minim Invasive Gynecol 2005;12:210-5. [Crossref] [PubMed]
10. Amorim KS, Gercina AC, Ramiro FMS, et al. Can local anesthesia with ropivacaine provide postoperative analgesia in extraction of impacted mandibular third molars? A randomized clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol 2021;131:512-8. [Crossref] [PubMed]
11. Ogura S, Shinohara K, Sunada K, et al. Randomized controlled trial comparison between ropivacaine and 2% lidocaine containing adrenalin for inferior alveolar nerve block during implant surgery. Oral Therap Pharmacol 2008;27:125-30.
12. Johansson B, Hallerbäck B, Stubberöd A, et al. Preoperative local infiltration with ropivacaine for postoperative pain relief after inguinal hernia repair. A randomised controlled trial. Eur J Surg 1997;163:371-8. [PubMed]
13. Brkovic BM, Zlatkovic M, Jovanovic D, et al. Maxillary infiltration anaesthesia by ropivacaine for upper third molar surgery. Int J Oral Maxillofac Surg 2010;39:36-41. [Crossref] [PubMed]
14. Brković B, Andrić M, Ćalasan D, et al. Efficacy and safety of 1% ropivacaine for postoperative analgesia after lower third molar surgery: a prospective, randomized, double-blinded clinical study. Clin Oral Investig 2017;21:779-85. [Crossref] [PubMed]
15. Schoenmakers KP, Fenten MG, Louwerens JW, et al. The effects of adding epinephrine to ropivacaine for popliteal nerve block on the duration of postoperative analgesia: a randomized controlled trial. BMC Anesthesiol 2015;15:100. [Crossref] [PubMed]
16. Cederholm I, Anskär S, Bengtsson M. Sensory, motor, and sympathetic block during epidural analgesia with 0.5% and 0.75% ropivacaine with and without epinephrine. Reg Anesth 1994;19:18-33. [PubMed]
17. Yamashiro M, Hashimoto S, Yasuda A, et al. Epinephrine Affects Pharmacokinetics of Ropivacaine Infiltrated Into Palate. Anesth Prog 2016;63:71-9. [Crossref] [PubMed]
18. Fujita K, Sunada K. Effect of epinephrine on the distribution of ropivacaine and lidocaine using radioactive isotopes in rat maxilla and pulp. Odontology 2021;109:168-73. [Crossref] [PubMed]