Open Access
Issue
J Oral Med Oral Surg
Volume 26, Number 3, 2020
Article Number 27
Number of page(s) 6
Section Cas clinique / Short case report
DOI https://doi.org/10.1051/mbcb/2020018
Published online 18 June 2020

© The authors, 2020

Licence Creative Commons
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [1]. Minor oral surgeries, including dissection and detachment of periosteum, gingival mucosa, and removal of bone tissue, are procedures associated with frequent postoperative pain and its level can be high [2].

Because postoperative pain is common in those situations mentioned above it can have a significant influence on patient's recovery. The pain management can be often suboptimal and patients return home with ongoing ache. An understanding of patients attitudes, concerns, and previous experiences with postoperative pain is important for improvement of postoperative care, as it is known that adequate pain alleviation is a major element on the postoperative recovery [3].

There are important differences in acute and chronic pain as well as related treatments. Acute pain, which is a symptom, if it is not managed, can lead to chronic pain, which is a disease [4]. Effective analgesia for acute pain is one of the most important protective ways against the development of chronic pain [5].

The chemical compound called (5R)-[(1S)-1,2-Dihydroxyethyl]-3,4-dihydroxyfuran-2(5H)-one is also known as L-ascorbic acid, ascorbate or simply L-ascorbic acid and it is readily distributed in high concentrations into immune cells, has antimicrobial and natural killer cell activities, promotes lymphocyte proliferation, and is consumed quickly during infections, effects indicating a prominent role in immune system regulation [6].

Even though L-ascorbic acid is not a pain medication per se it can act as an analgesic in different medical conditions and after surgical therapy. A growing body of scientific evidence support this assertion [746].

The objective of this article is to present a case in which a patient had intense and constant pain during several weeks after oral surgery, even when different medicine prescriptions and regimens including antibiotics, non-steroidal drugs and opioids were used. Postoperative pain was only possible to be mitigated after L-ascorbic acid intake.

Observation

A 20-year-old female patient was referred to our OMFS office with severe pain in the anterior lower teeth. Patient was experiencing pain on tooth number 31 and had visited a general dentist who started treatment with tooth trepanation and root canal preparation. In spite of pulp extirpation, canal irrigation and insertion of antibiotic paste patient expressed no pain relief. After the second visit to her dentist, the referred tooth was left opened without temporary filling and patient was sent to seek oral and maxillofacial surgery specialty for subsequent treatment.

At patient's first visit to our office severe and constant pain for over one week was reported with a grade 8 in the Numerical Rating Pain Scale (NRPS) used for pain quantification.

Clinical examination showed minor swelling in the anterior lower buccal gingiva but pathological response to vitality test on tooth number 32 and extreme pain after percussion on teeth numbers 31 and 32. Periapical X-ray of the lower anterior teeth revealed apical lesion on both apices (Fig. 1).

After discussion with the patient about all possible therapeutic alternatives, surgical therapy consisting in apicoectomy was proposed. The elected surgical procedure would follow root canal treatment of teeth numbers 31 and 32. Consent form was read and signed. Prior surgery both teeth were endodontically treated.

On the day of the surgery, under local anesthesia, an incision was performed on the region of teeth numbers 31 and 32. Apices of those teeth were resected with piezosurgery (Fig. 2).

Periapical lesion was curetted and the material send for histological examination. The whole procedure was uneventful and painless. Surgical site was abundantly rinsed with Chlorhexidine solution and 0.9% saline solution. A gelatine sponge (Gelastypt® −Sanofi-Aventis, France) was inserted into bone defect and the wound primarily closed with 4.0 supramid suture. Postoperative medication consisted of Amoxicillin 1000 mg every 8 hours/daily and Metamizole (liquid form) 750 mg every 8 hours/daily for pain. Cooling pad was given to patient and she was oriented how to properly administer it.

The histological result showed normal bone tissue with no specific fibrous content.

At the next follow up, one day after the surgery, no complications were observed at the surgical site but the patient had the same severe pain (NRPS − grade 8). The pain medication was changed to Novalminsulfon and dosage increased to 750 mg taken four times/daily. Five days later, patient returned to scheduled appointment complaining of no pain relief. The NRPS numbered 8. Intraorally there were no clinical signs of exacerbated inflammation, no swelling or erythema of the mucosa. Nine days later patient visited our office without any pain relief with NRPS numbering 8. Three ml of a long-lasting local anesthetic (Bupivacaine 0.5%) was injected in the region of teeth numbers 33 to 41. Because complete absence of pain was reported around ten minutes after the local analgesic infiltration, neuropathic pain of central origin was excluded. Ibuprofen 600 mg to be taken three times/daily was prescribed as an additional pain medication in an attempt to obtain a summation effect.

One week after, Bupivacaine infiltration, patient returned. Pressure pain and percussion symptoms on surgery site were minimal but patient referred no change in the pain status, recording a NRPS grade 8. Antibiotic and analgesic therapies were continued for another week and new appointment for surgical revision was planned. At this point, patient underwent surgical revision under local anesthesia. After flap elevation, material for microbiological test and tissue probe for histological examination were taken. Prior to wound closure with 4.0 supramid suture, bone defect was curetted and copiously irrigated with 0.9% saline solution. Exacerbated inflammation, exudation or other pathological findings were not observed intraoperatively. Antibiotic was then changed to Cefuroxime 500 mg taken two times/daily and Ibuprofen 800 mg taken three times/daily. The microbiological and histological results added no important information. These exams showed only resident microorganisms which were sensible to Amoxicillin and Cefuroxime, plus normal reparative tissue.

On the next follow up, two days after surgical revision, pain was still persistent with NRPS grade 8. After injection of 3 ml of Bupivacaine 0.5% for a temporary symptomatic relief, new pain regimen was given which consisted of Tramadol 75 mg taken four times/daily. The next infiltration of Bupivacaine 0.5% was scheduled for two days later. On this next visit laser-therapy applied to surgical site was included. The laser-therapy protocol consisted of Diodlaser 810 nm with an intensity of 1.6 W and 300 J per session. On the next day the same pain treatment was performed. The patient did not report any pain reduction when laser treatment was added.

A week after surgical revision, a month after apicoectomy, and forty four days after the first surgical procedure, patient was still reported the same severe pain with NRPS grade 8. She referred pain relief for no more than three hours after taking pain medication. At this point, intake of L-ascorbic acid 1000 mg three times/daily was recommended for a period of ten days.

The next visit, forty eight hours later, patient expressed the first relative pain reduction with NRPS grade 5–6. After three more days of L-ascorbic acid intake pain improvement was significant with NRPS grading 4. Two days later, after a phone call, patient informed that she was completely pain free.

On a six months follow up patient referred no soreness at all in the surgical area.

thumbnail Fig. 1

Periapical X-ray showing preoperative lesion on the apices of teeth 31 and 32.

thumbnail Fig. 2

Postoperative X-Ray after root treatment and apicoectomy of teeth 31 and 32 performed with piezosurgery.

Comments

Potential mechanism of action

Although there is no consensus as to the analgesic mechanism by which L-ascorbic acid could be acting, there are at least three potential theories accordingly with Carr et al. [7]: (a) action as a potent antioxidant; (b) role as a cofactor for the synthesis of catecholamine neurotransmitters; and (c) potential role of L-ascorbic acid in the synthesis of amidated opioid peptides.

  • Action as a potent antioxidant − L-ascorbic acid serve as an antioxidant and scavenges reactive oxygen species and protect cells from oxidative damage. It also exhibits anti-inflammatory properties and decreases markers of inflammation such as C-reactive protein and pro-inflammatory cytokines [7]. Reactive Oxygen Species (ROS) are a number of reactive molecules and free radicals derived from molecular oxygen. They are well known for their role in mediating both physiological and pathophysiological signal transduction [8]. Based on literature data, the ROS has been elucidated as a factor in the generation of pain, especially persistent, recurrent, or neuropathic. The ascorbic acid protects the cells and tissues, including the nerves from oxidative stress and damage through scavenging a wide range of ROS [911].

  • Role as a cofactor for the synthesis of catecholamine neurotransmitters − L-ascorbic acid can be a cofactor for the synthesis of catecholamine neurotransmitters and is involved in neuromodulation. It is important for the convertion of dopamine into norepinephrine and alleviate the synthesis of dopamine. L-ascorbic acid also takes part in the biosynthesis of the serotonin. Both serotonin and norepinephrine reuptake inhibitors show efficacy in control of pain [7].

  • Potential role of L-ascorbic acid in the synthesis of amidated opioid peptides − Currently unexplored analgesic mechanism of L-ascorbic acid involves the potential role in the synthesis of amidated opioid peptides as a cofactor for the enzyme peptidylglycine α-amidating mono-oxygenase (PAM). PAM is the only known enzyme in humans capable of amidating the carboxy-terminus of peptide hormone precursors, a post-translational modification which is essential for their subsequent stability and/or biological activities. A number of amidated neuropeptides have potent opioid activity [7].

Acute and chronic pain can be debilitating for patients, particularly if not adequately alleviated by conventional analgesics. There is increasing scientific evidence indicating that L-ascorbic acid can exhibit analgesic properties in some clinical conditions, thus potentially mitigating suffering and improving patient's quality of life [7].

There are a number of studies showing the positive effects of ascorbic acid on the pain experience after different surgical procedures. In surgical patients the L-ascorbic acid requirement is increased, and the potential advantage of supplementation is to increase the plasma and tissue levels of L-ascorbic acid and thus reduce oxidative stress. Trauma and surgery are known to significantly deplete L-ascorbic acid concentrations [12].

According to Carr et al. the administration of L-ascorbic acid intraoperatively reduced postoperative pain without increased side-effects in patients undergoing uvulopalatopharyngoplasty and tonsillectomy [13]. A number of randomized controlled trials have investigated the effect of L-ascorbic acid supplementation on the incidence of complex regional pain syndrome (CRPS) in wrist and ankle surgery patients. They showed a decreased incidence of CRPS in the patients receiving L-ascorbic acid, with the doses ≥0.5 g/day being the most efficacious [14]. Based on the results of a study published in 2017, L-ascorbic acid might be associated with improvement of functional status after posterior lumbar interbody fusion (PLIF) surgery [15]. Jeon et al. reported the effect of high dose intravenous supplementation of L-ascorbic acid on postoperative pain control after laparoscopic colectomy [16]. Laflı Tunay et al. reported preoperative oral administration 2 g L-ascorbic acid led to a reduction in pain scores, total morphine consumption, supplemental analgesic requirement after major abdominal surgery compared with placebo [17].

There are certain published data for ascorbic acid used as pain modulator not only after surgeries, but also in various acute and chronic conditions and in cancer patients.

A randomized placebo-controlled crossover trial carried out with one hundred thirty three patients with osteoarthritis of the hip or knee joint showed reduced pain following consumption of 1000 mg/day calcium ascorbate (Calcium salt of ascorbic acid) for two weeks as determined by the visual analogue scale (P < 0.008). The observed decrease in pain was less than half than that reported for non-steroidal anti-inflammatory drugs [18].

Patients with painful Paget's disease of the bone were treated with high doses of ascorbic acid (3000 mg/day). Of these patients, 50% experienced reduction of pain within a period of five to seven days after commencing the vitamin therapy. In 20% of these patients the pain was completely abolished [19]. Nabzdyk et al. [advocated that L-ascorbic acid administration may have a variety of beneficial effects as reducing pain in other conditions − acute burn injury and in the treatment of cancer [20]. Two prospective studies of patients with advanced cancer who were administered high dose of L-ascorbic acid intravenously have shown significant decrease in pain (over 30%) [21,22]. Decrease in postoperative morphine consumption was also reported by other authors[13,16,23]. Even complete reduction in morphine requirement was observed in a patient with terminal cancer treated with high dosage L-ascorbic acid infusion for palliative care [24]. Cameron and Campbell published cases of complete amelioration of osseous pain in patients with bone metastases. The patients were treated orally and intravenously with L-ascorbic acid and the results advocated the use of L-ascorbic acid for improvement in pain experience [25].

Günes-Bayir et al. reported similar pain reduction results after ascorbic acid application in patients with radiotherapy-resistant bone metastases [26].

Two case reports and a cohort study from Schencking et al. described clinical improvement and relief of pain for patients with acute herpes zoster exacerbation who received L-ascorbic acid [27,28]. Double-blind placebo-controlled study revealed that the duration of pain caused by labial herpes was shortened by 51%, when patients were administered 1 g/day of L-ascorbic acid together with bioflavonoids [29]. Ascorbate treatment also resulted in a better efficacy than placebo in pain modulation in post herpetic neuralgia (PHN) and intravenous ascorbate helps relieve spontaneous pain in PHN [30,31].

Animal experiments also advocate the implementation of L-ascorbic acid. An intraperitoneal injection of Ascorbic acid (400 mg/kg), thirty minutes before morphine self-administration, produced a significant decrease in twelve days self-administration of morphine [32]. A mouse experiment demonstrated that neuropathic pain induced by peripheral injury and the acute pain response to formalin could be inhibited by a combination of Vitamin E and L-ascorbic acid. Hence, supplementation or treatment with both Vitamins might be an option for patients suffering from specific pain states [33]. Another article revealed the results of interactions between ascorbic acid and tramadol or morphine in mice. The results showed that the interaction effects on antinociception may be synergistic or additive, depending on the level of effect [34].

Chaitanya et al. concluded that L-ascorbic acid had its potential role in antinociceptive effect and postoperative pain relief [35]. In addition the authors concluded that future trials were needed to further explore the potential effect on postoperative pain following tooth extractions, treatment of oral ulcers, and the optimal doses and routes of administration. Korean authors Lee et al. reported that insufficient intake of dietary ascorbic acid was associated with increased periodontal pain and L-ascorbic acid could be beneficial for pain modulation [36]. A publication in American Journal of Dentistry reported that 4000 mg/day dosages of L-ascorbic acid is associated with rapid recovery after tooth extraction [37]. Another study presented a growing body of evidence that indicated supplemental L-ascorbic acid might be beneficial in speeding healing following tooth extraction and in reducing the likelihood of alveoalgia and other complications [38]. Chaitanya et al. determined that the method of administering 2000 mg IV L-ascorbic acid intravenously was well suited to the treatment of postoperative pain, swelling and trismus following the surgical extraction of impacted third molars [39]. A study in its summary concluded that because of the reduction in L-ascorbic acid concentration after surgery and the modest evidence for L-ascorbic acid's antinociceptive effect and role in postoperative pain relief, further clinical trials were warranted to determine its potential effect on postoperative pain, as well as its optimal doses and routes of administration [40].

L-ascorbic acid dose and its safety features

In healthy humans, circulating levels of ascorbate are typically in the range of 50–70 µmol/l, whereas levels <23 µmol/l are considered marginally deficient (or hypovitaminosis C) [41]. The optimal dose of ascorbic acid to fully saturate plasma and tissues in healthy adults is 500 mg [42]. That is more than the common recommended (60–100mg) to prevent deficiency diseases. At oral doses of 200 mg, the steady-state plasma concentrations are ≈80 µmol/l. As doses exceed 200 mg, relative absorption decreases, urine excretion increases and the fraction of bioavailable ascorbate is reduced [43].

Levine and coworkers have shown that oral L-ascorbic acid uptake becomes less efficient as the dose increases due to saturation of the transporters. Although an oral dose of 200 mg L-ascorbic acid is completely absorbed, at doses of 500 mg and 1250 mg L-ascorbic acid, <75% and <50% of the Vitamin dose is absorbed [44]. For the maximum tolerated oral dose of 3000 mg every four hours, pharmacokinetic modeling predicted peak plasma L-ascorbic acid concentrations of 220 µmol/l [45].

It seems that trauma and surgery patients need greater doses of L-ascorbic acid. Long et al. (2003) [46] demonstrated that up to 3000 mg/day ascorbate was required to restore plasma levels of critically ill patients to normal (i.e. 68 µmol/l). Generally, evidence that even doses of at 1.5 g/kg ascorbic acid as infusion exhibit a favorable safety profile and are well tolerated can be found in available scientific publications [47,48]. Based on the L-ascorbic acid levels proposed by these above mentioned studies the authors decided to prescribe 3000 mg daily for this patient, staying within a safety margin with an effective result though.

Conclusions

The practical importance and optimal efficacious doses of ascorbic acid for treating postoperative pain as a single medication and/or in combination with analgesics is unknown but even with modest effects it may be worth of further research.

Given to its potential benefits, low cost, and safety, and considering the limitation of this paper and need for further research, L-ascorbic acid supplementation could be considered by oral surgeons and general dentists as possible pain modulator after oral/dental surgical procedures.

Regarding that the ascorbic acid intake may not be the only component explaining the disappearance of the pain, the temporality of the events can bring new insights into the possible relationships between ascorbic acid and analgesia to the scientific community.

Funding

No financial interest or benefit that has arisen from the direct applications of this research.

Conflicts of interests

The authors declare that they have no conflicts of interest in relation to this article.

References

  1. Carr AC, McCall C. The role of L-ascorbic acid in the treatment of pain: new insights. J Transl Med. 2017;15 (1):77. [CrossRef] [PubMed] [Google Scholar]
  2. Fukushima R, Yamazaki E. L-ascorbic acid requirement in surgical patients. Curr Opin Clin Nutr Metab Care. 2010;13 (6):669–676. [CrossRef] [PubMed] [Google Scholar]
  3. Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can L-ascorbic acid prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am. 2007;89 (7):1424–1431. [CrossRef] [PubMed] [Google Scholar]
  4. McGreevy K, Bottros MM, Raja SN. Preventing chronic pain following acute pain: risk factors, preventive strategies, and their efficacy. Eur J Pain Suppl. 2011;5 (2):365–372. [CrossRef] [PubMed] [Google Scholar]
  5. Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019;123(2):e273–e283. [CrossRef] [PubMed] [Google Scholar]
  6. Wintergerst ES, Maggini S, Hornig DH. Immune-enhancing role of L-ascorbic acid and zinc and effect on clinical conditions. Ann Nutr Metab. 2006;50(2):85–94. [CrossRef] [PubMed] [Google Scholar]
  7. Jensen NH. Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate. A randomized, placebo-controlled cross-over trial in general practice. Ugeskr Laeger. 2003;165 (25):2563–2566. [PubMed] [Google Scholar]
  8. Basu TK, Smethurst M, Gillett MB, Donaldson D, Jordan SJ, Williams DC, et al. Ascorbic acid therapy for the relief of bone pain in Paget's disease. Acta Vitaminol Enzymol. 1978;32(1-4):45–49. [Google Scholar]
  9. Cameron E, Campbell A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact. 1974;9 (4):285–315. [CrossRef] [PubMed] [Google Scholar]
  10. Takahashi H, Mizuno H, Yanagisawa A. High-dose intravenous L-ascorbic acid improves quality of life in cancer patients. Personalized Med Universe. 2012;2 (1):49–53. [CrossRef] [Google Scholar]
  11. Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients' health-related quality of life after high dose L-ascorbic acid administration. J Korean Med Sci. 2007;22 (1):7–11. [CrossRef] [PubMed] [Google Scholar]
  12. Carr AC, Vissers MC, Cook J. Parenteral L-ascorbic acid for palliative care of terminal cancer patients. N Z Med J. 2014;127(1396):84–86. [Google Scholar]
  13. Jeon Y, Park JS, Moon S, Yeo J. Effect of intravenous high dose L-ascorbic acid on postoperative pain and morphine use after laparoscopic colectomy: a randomized controlled trial. Pain Res Manag. 2016;2016:9147279. [Google Scholar]
  14. Ayatollahi V, Dehghanpoor-Farashah S, Behdad S, Vaziribozorg S, Rabbani Anari M. Effect of intravenous L-ascorbic acid on post-operative pain in uvulopalatopharyngoplasty with tonsillectomy. Clin Otolaryngol. 2017;42(1):139–143. [CrossRef] [PubMed] [Google Scholar]
  15. Kanazi GE, El-Khatib MF, Yazbeck-Karam VG, Hanna JE, Masri B, Aouad MT. Effect of L-ascorbic acid on morphine use after laparoscopic cholecystectomy: a randomized controlled trial. Can J Anaesth. 2012;59:538–543. [Google Scholar]
  16. Schencking M, Sandholzer H, Frese T. Intravenous administration of L-ascorbic acid in the treatment of herpetic neuralgia: two case reports. Med Sci Monit. 2010;16(5):CS58–CS61. [PubMed] [Google Scholar]
  17. Laflı Tunay D, Türkeün Ilgınel M, Ünlügenç H, Tunay M, Karacaer F, Biricik E. Comparison of the effects of preoperative melatonin or L-ascorbic acid administration on postoperative analgesia. Bosn J Basic Med Sci. 2020;20(1):117–124. [PubMed] [Google Scholar]
  18. Schencking M, Vollbracht C, Weiss G, Lebert J, Biller A, Goyvaerts B, et al. Intravenous L-ascorbic acid in the treatment of shingles: results of a multicenter prospective cohort study. Med Sci Monit. 2012;18(4):CR215–CR224. [CrossRef] [PubMed] [Google Scholar]
  19. Nabzdyk CS, Bittner EA. L-ascorbic acid in the critically ill − indications and controversies. World J Crit Care Med. 2018;7(5):52–61. [PubMed] [Google Scholar]
  20. Buettner GR. The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch Biochem Biophys 1993;300 (2):535–543. [CrossRef] [PubMed] [Google Scholar]
  21. Peek DF, van Zundert J. The L-ascorbic acid controversy. Clin J Pain. 2010;26 (6):551–552; author reply 552–553. [CrossRef] [PubMed] [Google Scholar]
  22. Carr A, Frei B. Does L-ascorbic acid act as a pro-oxidant under physiological conditions? FASEB J. 1999;13(9):1007–1024. [CrossRef] [PubMed] [Google Scholar]
  23. Lee JH, Shin MS, Kim EJ, Ahn YB, Kim HD. The association of dietary L-ascorbic acid intake with periodontitis among Korean adults: results from KNHANES IV. PLoS One. 2017;12(5):e0177074. [CrossRef] [PubMed] [Google Scholar]
  24. Halberstein RA, Abrahmsohn GM; Clinical management and control of alveolalgia (“dry socket”) with L-ascorbic acid. Am J Dent. 2003;16 (3):152–154. [PubMed] [Google Scholar]
  25. Chaitanya NC, Muthukrishnan A, Krishnaprasad CMS, Sanjuprasanna G, Pillay P, Mounika B. An insight and update on the analgesic properties of L-ascorbic acid. J Pharm Bioallied Sci. 2018;10 (3):119–125. [CrossRef] [PubMed] [Google Scholar]
  26. Abrahmsohn GM, Halberstein RA, Fregeolle S. L-ascorbic acid and dental healing: testing and placebo effect. Gen Dent. 1993;41 (6):523–527. [PubMed] [Google Scholar]
  27. Talkhooncheh M, Alaei HA, Ramshini E, Shahidani S. The effect of L-ascorbic acid on morphine self-administration in rats. Adv Biomed Res. 2014;3:178. [CrossRef] [PubMed] [Google Scholar]
  28. Lu R, Kallenborn-Gerhardt W, Geisslinger G, Schmidtko A. Additive antinociceptive effects of a combination of L-ascorbic acid and Vitamin E after peripheral nerve injury. PLoS One. 2011;6 (12):e29240. [CrossRef] [PubMed] [Google Scholar]
  29. Zeraati F, Araghchian M, Farjoo MH. Ascorbic Acid interaction with analgesic effect of morphine and tramadol in mice. Anesth Pain Med. 2014;4(3):e19529. [PubMed] [Google Scholar]
  30. Hasanzadeh Kiabi F, Soleimani A, Habibi MR, Emami Zeydi A. Can L-ascorbic acid be used as an adjuvant for managing postoperative pain? A short literature review. Korean J Pain. 2013;26(2):209–210. [PubMed] [Google Scholar]
  31. Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive oxygen species in metabolic and inflammatory signaling. Circ Res. 2018;122(6):877–902. [Google Scholar]
  32. Terezhalmy GT, Bottomley WK, Pelleu GB. The use of water-soluble bioflavonoid-ascorbic acid complex in the treatment of recurrent herpes labialis. Oral Surg Oral Med Oral Pathol 1978;45:56–62. [Google Scholar]
  33. Chen JY, Chang CY, Feng PH, Chu CC, So EC, Hu ML. Plasma L-ascorbic acid is lower in postherpetic neuralgia patients and administration of L-ascorbic acid reduces spontaneous pain but not brush-evoked pain. Clin J Pain 2009;25(7):562–569. [CrossRef] [PubMed] [Google Scholar]
  34. Lee GW, Yang HS, Yeom JS, Ahn MW. The efficacy of L-ascorbic acid on postoperative outcomes after posterior lumbar interbody fusion: a randomized, placebo-controlled trial. Clin Orthop Surg. 2017;9 (3):317–324. [CrossRef] [PubMed] [Google Scholar]
  35. Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of L-ascorbic acid for healthy young women. Proc Natl Acad Sci USA 2001;98:9842–9846. [CrossRef] [Google Scholar]
  36. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. L-ascorbic acid pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533–537. [CrossRef] [PubMed] [Google Scholar]
  37. Graumlich JF, Ludden TM, Conry-Cantilena C, Cantilena LR Jr, Wang Y, Levine M. Pharmacokinetic model of ascorbic acid in healthy male volunteers during depletion and repletion. Pharm Res. 1997;14 (9):1133–1139. [CrossRef] [PubMed] [Google Scholar]
  38. Long CL, Maull KI, Krishnan RS, Laws HL, Geiger JW, Borghesi L, et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res. 2003;109(2):144–148. [CrossRef] [PubMed] [Google Scholar]
  39. Chaitanya NC, Badam R, Siva Prasad Reddy G, Alwala A, Srinivas P, Saawarn N, et al. Analgesic effect of intravenous ascorbic acid versus acelcofena post-transalveolar extraction: a case–control study. J Popul Ther Clin Pharmacol. 2019;26(2):e43–e52. [PubMed] [Google Scholar]
  40. Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: a rationale for L-ascorbic acid administration in severe sepsis and septic shock? Crit Care. 2015; 19:418. [CrossRef] [PubMed] [Google Scholar]
  41. Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, et al. L-ascorbic acid pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci USA. 1996;93 (8):3704–3709. [CrossRef] [Google Scholar]
  42. Wang F, He MM, Wang ZX, Li S, Jin Y, Ren C, et al. Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal cancer or gastric cancer. BMC Cancer. 2019;19 (1):460. [CrossRef] [PubMed] [Google Scholar]
  43. Kim MS, Kim DJ, Na CH, Shin BS. A study of intravenous administration of L-ascorbic acid in the treatment of acute herpetic pain and postherpetic neuralgia. Ann Dermatol. 2016;28 (6):677–683. [CrossRef] [PubMed] [Google Scholar]
  44. Günes-Bayir A, Kiziltan HS. Palliative L-ascorbic acid application in patients with radiotherapy-resistant bone metastases: a retrospective study. Nutr Cancer. 2015;67(6):921–925. [CrossRef] [PubMed] [Google Scholar]
  45. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97 (2):534–540. [CrossRef] [PubMed] [Google Scholar]
  46. Đanić P, Salarić I, Macan D. New findings on local tramadol use in oral surgery. Acta Stomatol Croat. 2017;51 (4):336–344. [CrossRef] [PubMed] [Google Scholar]
  47. Hanzawa A, Handa T, Kohkita Y, Ichinohe T, Fukuda KI. A comparative study of oral analgesics for postoperative pain after minor oral surgery. Anesth Prog. 2018;65 (1):24–29. [Google Scholar]
  48. Pain terms: a list with definitions and notes on usage. Recommended by the IASP Subcommittee on Taxonomy. Pain. 1979;6 (3):249. [PubMed] [Google Scholar]

All Figures

thumbnail Fig. 1

Periapical X-ray showing preoperative lesion on the apices of teeth 31 and 32.

In the text
thumbnail Fig. 2

Postoperative X-Ray after root treatment and apicoectomy of teeth 31 and 32 performed with piezosurgery.

In the text

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