[su_button url=”http://www.dentalmedjournal.it/files/2017/09/JDM_2017_003_INT@083-089.pdf” target=”blank” style=”flat” background=”#bd1221″ size=”5″]Download PDF[/su_button]
L. Viganò1, C. Casu2, F. Argenta3
1 School of Dentistry, University of Milan, professor at the course on diagnostic imaging and radiotreatment, Milan, Italy
2 Private practice, Cagliari (Italy)
3 Private practice, Milan (Italy)
Bromelain is known for its anti-inflammatory and anti-edematous action. Its anti-inflammatory effect is due to the local proteolytic (protein-digesting) action and the interaction with lipoxygenases. It also reduces the plasma kininogen concentration inhibiting the formation of vasoactive peptides that cause inflammation, edema and pain. Its action is enhanced by being combined with other active ingredients of natural origin such as curcumin, quercetin and Malva Sylvestris. The aim of this study is to evaluate the anti-inflammatory and analgesic effect of Bromelain (Pineapple extract) as an active ingredient to be taken orally in the pre and postoperative stages of oral surgery.
Materials and methods
For this prospective and controlled study, 300 oral surgery patients were selected, 150 of whom treated with bromelain and 150 solely with paracetamol and codeine. The types of oral surgery include the placement of implants (up to 3 implants), extraction of partially or totally impacted molars, lateral maxillary sinus lift and enucleation of odontogenic cysts. These patients were observed during the post-operative period of 7 to 15 days. The evaluation considered inflammation, pain, swelling and possible difficulty in opening the mouth, and also the need for further analgesics in addition to the base protocol. All the patients were given a questionnaire to fill for a subjective evaluation of the pain and quality of life. Only those who returned the fully completed questionnaires were recruited for the research. The ultimate size of the sample is 106 patients.
In the test group (bromelain and analgesic), inflammation, edema and trismus were statistically better than in the group that only received analgesics. These figures related to implantology and oral surgery. The main effect of Bromelain seems to be in its anti-edematous effect. The pharmaceutical preparation tested also contains curcumin, quercetin and Malva Sylvestris that increase its effect.
The product tested proved useful for lessening the inflammation symptoms. It is not intended to replace the conventionally used analgesics but is to be administered together with them to increase the anti-edematous effect and thus improve patients comfort.
Anti-edematous effect; Bromelain, Oral surgery.
Oral surgery includes a variety of surgical operations that all have similar post-operative symptoms of different levels of severity depending on the nature of the surgery and the indi-vidual situation of patients. Characteristics of post-surgical clinical situation are inflamma-tion, oedema, pain, trismus and risk of infection at the site of the surgery (1, 2). These symp-toms can generally be reduced by carefully managing the surgical site and the stages of sur-gery and also by using anti-inflammatory drugs (3-8).
A number of scientific findings suggest that the response to surgery or trauma is inflamma-tion and, as in all inflammatory processes, it manifests itself in a succession of known stages of symptoms.
There are currently numerous active ingredients that are effective for reducing these symp-toms. Known and clearly effective is the action of bromelain, an enzyme group extracted from the stalk of Ananas comosus (9, 10). It is indicated in cases of inflammation and/or oe-dema of soft tissues, it has an anti-inflammatory effect due to the local proteolytic action and, by its interaction with lipoxygenases, results in an increase in the formation of plasmin that has a fibrinolytic action i.e. ability to break down the fibrin and prevent or reduce the for-mation of a localised edema (11). It reduces the synthesis of pro-inflammatory prostaglan-dins and stimulates the formation of prostaglandin E2 which inhibits inflammation (12). Bromelain has been shown to reduce plasma kininogen concentration, inhibiting the for-mation of quinines, which may produce vasoactive peptides that cause inflammation, edema and pain.
A recent double-blind study has shown bromelain’s ability to reduce post-surgical dental edema and pain, reporting that its effect is significantly greater than that of placebo: edema in patients treated with bromelain reduced in 3-4 days, while the time taken for reducing the post-surgical edema in the patients treated with a placebo was 7 days, and the bromelain-treated patients had 5 days of pain compared to 8 days for the placebo group. Orally-administered bromelain therefore produced positive results in reducing edema, inflamma-tion, healing time and post-surgical pain (10). In the specific case of surgery in the oral cavity, it is advisable to begin treatment with bromelain in the days before surgery and continue it afterwards.
Bromelain can be combined with other active ingredients of natural origin such as curcumin, quercetin and Malva Sylvestris. Curcumin is extracted from the Curcuma Longa rhizome and has a proven anti-inflammatory and anti-edematous action, but is of limited therapeutic effi-cacy owing to its reduced bioavailability and absorption, and its high plasma clearance. The metabolic profile, and thus the efficacy of this active ingredient, is improved by using phyto-some complexes that protect the extract from proteolytic degradation, increasing its cellular absorption and thus improving the therapeutic efficacy (13). Quercetin is a flavonoid with an antinociceptive and antioxidant action able to suppress cytokines and restore the oxidative balance. This helps to reduce inflammation pain (14, 15). Lastly, Malva Sylvestris, known and already used for its anti-inflammatory, antibacterial and disinfectant action, is very use-ful in the post-surgical period for preventing the onset of infectious complications (16).
Starting from these scientific findings, this study has been carried out to evaluate the efficacy of the above active ingredients administered in a food supplement in gastro-resistant tablets indicated for post-surgical inflammatory conditions.
Aim of the study
The primary objective of this study is to evaluate the progression of pain, swelling and trismus symptoms during the 15 days after surgery.
The secondary objective is to verify the improvement in the quality of life perceived by patients during their daily activities in the days following surgery and the speed with which any swelling reduced.
Materials and methods
In the study were included patients requiring one or more dental extractions under local anaesthesia, one or more implant placements (up to a maximum of three), or minor oral surgery (dental extraction, including partially or totally impacted third molars) or maxillary sinus lift. Exclusion criteria were known or suspected allergies to one or more of the active ingredients used in the trial, pregnant or breast-feeding women, patients receiving anticoagulant drugs, patients with gastric/duodenal ulcer or gastritis and children aged under 12 (Table 1). Based on these criteria, 300 patients were selected, of which 106 were evaluated for all the above-listed parameters. Many of the subjects recruited for the study did not provide one or more items of information required for the study protocol.
Dosage and duration of treatment
The drugs administered and dosage were selected by the clinician so as to equally and randomly distribute the patients between a test group and a control group.
The test group was prescribed Foredem + paracetamol and codeine as follows.
• Pre-surgery: 1 bromelain 200 mg tablet (Foredem) 3 times daily for 3 days;
• Post-surgery: 1 bromelain tablet (Foredem) 3 times daily for 7 days and 1 paracetamol and codeine tablet (1000 mg) every 8 hours for a total of 3 tablets.
The control group was only prescribed paracetamol + codeine at a dosage of 1 tablet pre-surgery and 1 tablet every 8 hours for a total of 3 tablets.
The efficacy of the two types of treatment was evaluated 7 days and 15 days after surgery by assessing the following parameters: pain, feeling of tightness linked to swelling, trismus (reduction of the interincisal opening less than 38 mm), quality of life perceived by patients regarding their daily activities, speed of reduction of any swelling.
The tolerability of the two treatments was evaluated based on the occurrence of adverse events.
The stages of experimentation were divided as follows: after a clinical examination the surgery was scheduled, the pharmaceutical treatment was prescribed and a form handed over to collect data useful for carrying out the experimentation.
The first check-up examination took place seven days after surgery and the second check-up 15 days after surgery. In the second examination, the patients were asked whether they had regularly taken the drugs and they were asked for the data collection form given to them at the first appointment.
Examination for recruitment to the study_D0 (screening and start of treatment).
– Clinical history and evaluation.
– Scheduling of surgery.
– Treatment prescription.
Check-up 7 days after surgery.
– Interview about regularly taking the treatment.
– Evaluation of clinical symptoms.
– Noting of any adverse events related to the treatment
Patients were asked to fill in the questionnaire (Figure 1) and to give their opinion about the pain perceived in a visual analogue scale (VAS), a verbal rating scale (VRS), a numeric rating scale (NRS) and a questionnaire on their health SF 16 standard V1.
VAS (Visual analogue scale) is a 10 cm straight line with two ends that correspond to “no pain” and “maximum possible pain (or otherwise the maximum ever experienced)” (Figure 2). It is a unidimensional tool that quantifies what the patient subjectively perceives as pain or as relief in the complex of his physical, psychological and spiritual variables without distinguishing which of these components has a greater role.
If intending to evaluate the pain or relief in a period of time, the question could be: “Think about the pain and the relief from pain that you may have felt in this last week. For each of the two (pain/relief), mark a point between the two extremes of the line which best corresponds to your situation”. The scale can also be used to quantify the pain in the actual moment of examining the patient. The difficulty for some patients to understand the maximum pain possible can be made easier by asking them to remember the “strongest ever” pain they have had in their lives (maximum pain). The measurement is in millimetres.
The simple verbal scale VRS (Verbal rating scale), also unidimensional, is again on a 10 cm line where the choice is facilitated (but also influenced) by the presence of adjectives to quantify the pain (Figure 3). Satisfactory results are obtained when there are at least six levels of intensity. The possible questions to ask a patient are: “How much pain have you experienced in the last 4 weeks?” or “How much pain are you in right now?”
The NRS (Numeric rating scale) is based on the same principle as the previous scales but shows numerical values from 0 (no pain) to 10 (maximum pain) (Figure 4).
When considering the results obtained from these three scales, it is essential to not only evaluate the intensity of pain but also the subjective level of suffering by the patient. This is the product between pain (understood as intensity and duration) and a coefficient that represents the sum of all the variables that increase such pain (anxiety, depression, context, other pathologies, etc.).
The data must therefore be integrated together by the physician, recognising which of them act to decrease the pain threshold (to remove them) and those that raise it (to introduce them or increase them in the treatment program), with the aim of obtaining a real evaluation of the severity of the patient’s pain.
Questionnaire on the state of health SF 12 Standard V1
The patient is asked to fill the health questionnaire to evaluate his/her personal perception of his/her general health conditions. The patient is asked to answer sixteen questions about what he thinks of his/her health.
The questionnaire is presented to the patient in this way: “The purpose of this questionnaire is to evaluate what you think about your health. The information collected will make it possible to always keep updated on how you feel and how well you are able to carry out your usual activities”.
Of the 106 patients selected, 44 had undergone implant surgery, 56 had undergone dental extraction, 3 had undergone surgery for lateral maxillary sinus lift and 3 had surgical enucleation of odontogenic cysts.
Among those whose treatment consisted of inserting one or more osseointegrated dental implants (Table 2), in 23 test patients and in 21 control patients, the post-surgery pain perceived was very mild or not perceived at all. In detail, according to the VAS, 17 test patients felt no pain at all, 2 perceived a mild amount and 4 had moderate pain. Among controls, 10 felt no pain, 9 had slight pain and 2 had moderate pain. None of the patients from either group had intense pain. According to the VRS, 8 test patients reported having no pain, 10 complained of having very mild pain, 2 slight and 3 moderate. Among the control patients, 7 had no pain, 8 perceived a very mild amount and 6 perceived a moderate amount of pain. None experienced intense pain. In the NRS, 17 test patients had pain level at 1, 6 perceived it at level 2 and no-one at level 3; among the control patients, 12 perceived pain at level 1, 6 at level 2 and 3 at level 3.
As regards swelling, only a few patients had this symptom: 15 test patients and 10 control patients stated having no post-surgery pain, 7 test and 4 control patients perceived a mild amount and 1 test and 7 control patients perceived pain clearly.
Most of the test and control patients had no trismus problems, but 4 test patients and 9 control patients had a mild amount of trismus.
Among the 28 test and 28 control patients undergoing dental extraction (Table 3), there was generally no post-surgery pain perceived. In detail, in the VAS, 25 test patients felt no pain at all, 2 perceived a mild amount and 1 had intense pain; 22 control patients had no pain, 3 perceived a mild amount, 2 a moderate amount and 1 had intense pain. In the VRS, 21 test patients stated having no pain, 5 perceived mild pain and 2 had moderate pain; 14 control patients stated having had no pain, 8 had mild pain and 6 had a moderate amount. None experienced intense pain. On the NRS, 24 test patients had pain at level 1, 4 perceived it at level 2 and no-one at level 3; among the control patients, 21 perceived pain at level 1, 4 perceived it at level 2 and 3 at level 3.
As regards the feeling of tightness linked to swelling, 22 test patients did not have this symptom while 6 stated having a mild amount; among the control patients, only 9 stated having no swelling, 16 perceived a slight swelling and 3 clearly perceived swelling.
Twenty-six test patients had no trismus effect and 2 of them had a mild amount; in the control patients, 1 had a slight amount of trismus, but it was absent from 17 control patients.
Among those who received lateral maxillary sinus lift surgery (Table 4), the post-surgery pain perceived by 1 test and 2 control patients was at medium-high levels. In detail, according to the VAS, the test patient experienced intense pain while the two control patients had mild pain. On the VRS, the pain was moderate for the test patient while, for the control patients, the pain perceived was moderate and very mild respectively. On the NRS, the test patient had pain at level 3, while the control patients had pain at level 2. Swelling, visible in the test patient, was only slight in the two control patients. None of the patients, either test or control, experienced trismus.
One test patient and 2 control patients who had undergone enucleation of odontogenic cysts (Table 5) perceived generally mild pain post-surgery. In detail, according to VAS, the test patient had no pain while the two control patients experienced a high level of pain and no pain respectively. On the VRS, the pain was mild for the test patient, while for the two control patients it was respectively moderate and absent. On the NRS, the test patient perceived pain at level 1, and the pain perceived by the control patients was at levels 1 and 2. Swelling was visible in the test patient, and slight in one of the control patients and visible in the other. The test patient had a slight amount of trismus, while it was was absent in one of the control patients and only slight in the other.
Evaluating the questionnaires, it emerged that the general conditions of all patients were excellent or good on average. No patient started out with a negative general physical condition.
From a recent review by Cochrane it has emerged that even a single oral administration of analgesic after surgery can have side effects, even very serious although not very frequent. This work examined 39 previous reviews of the literature on the subject, with 41 types of analgesic and anti-inflammatory drugs investigated. The total number of patients in this study exceeds 39,000 and each type of drug was compared with a placebo. The results reveal a greater tendency for adverse events to develop by administering conventional anti-inflammatory drugs with the addition of opiates, which also includes the paracetamol and codeine combination (17). Scientific attention is shifting towards a greater use of natural supplements and ingredients free of side effects.
For instance, a study examined the effect of a green tea mouthwash, compared with placebo, on patients whose third molars had been extracted. This was a randomised clinical trial with 44 patients undergoing bilateral third molar extraction. During the first surgery, a green tea mouthwash was used in the post-operative stage, and a placebo was used after the second surgery. The results showed significantly better post-surgical progress in the first group (18).
Further interesting data are from a Brazilian study on acupuncture: 24 patients split into two groups had extraction of their third molars. The first group had an acupuncture session within 24 hours of surgery and the other group did not. Results showed a greater reduction in symptoms in the first group (19).
The limits to the study were in the sample being small and there being no comparison with a placebo, but nonetheless these are interesting preliminary data.
Our approach was to use a natural supplement and to evaluate its effectiveness not just for dental extractions but also in oral surgery such as implants, cyst removal, maxillary sinus lift. Bromelain, taken orally, proved to be very effective for reducing the number of patients with post-surgery edema and for accelerating its re-absorption when present (20), for reducing inflammation and post-surgical pain (10). In this study, its combination with other active ingredients of natural origin such as the anti-inflammatory and anti-edematous curcumin, antinociceptive and antioxidant quercetin, and anti-inflammatory, antibacterial and disinfectant Malva Sylvestris, definitely increased the anti-inflammatory and pain relief properties of the product.
When comparing the data regarding implantology and dental extraction – which, in this study, proved to be the most significant data because of involving the highest number of patients – the anti-edematous, pain relief and anti-trismus effect of bromelain is confirmed, and appears more marked as regards dental extraction than with implantology. Administering the compound more effectively reduces post-surgical swelling, edema and pain than the codeine/paracetamol combination, but does not eliminate these symptoms in all patients. It is especially effective in the case of dental extraction. As regards surgery for maxillary sinus lift and enucleation of odontogenic cysts, the data in our possession involve too few patients to allow an objective evaluation of this product.
Thanks to its innovative, complete and synergetic formulation consisting of bromelain, highly bio-available curcumin, quercetin and Malva sylvestris, the food supplement tested proves useful for lessening the inflammatory symptoms in patients undergoing oral surgery, with consequent reduction in patient recovery time. It is to be remembered that it is not intended for bromelain to replace analgesics conventionally used.
1. McGrath C, Comfort MB, Lo EC, Luo Y. Changes in life quality following third molar surgery-the immediate postoperative period. Br Dent J 2003;194:265-8.
2. Oginni FO, Ugboko VI, Assam E, Ogunbodede EO. Postoperative complaints following impacted mandibular third molar surgery in Ile-Ife, Nigeria. SADJ 2002;57:264-8.
3. Kirtiloğlu T, Bulut E, Sümer M, Cengiz I. Comparison of 2 flap designs in the periodontal healing of second molars after fully impacted mandibular third molar ex-tractions. J Oral Maxillofac Surg 2007;65:2206-10.
4. Kim HR, Choi BH, Engelke W, Serrano D, Xuan F, Mo DY. A comparative study on the extractions of partially impacted mandibular third molars with or without a buccal flap: a prospective study. J Oral Maxillofac Surg 2011; 69:966-70.
5. Freudlsperger C, Deiss T, Bodem J, Engel M, Hoffmann J. Influence of lower third molar anatomic position on postoperative inflammatory complications. J Oral Maxillofac Surg 2012;70:1280-5.
6. Goyal M, Marya K, Jhamb A, Chawla S, Sonoo PR, Singh V et al. Comparative evaluation of surgical outcome after removal of impacted mandibular third molars using a Piezotome or a conventional handpiece: a prospective study. Br J Oral Maxillofac Surg 2012 ;50:556-61.
7. Barone A, Marconcini S, Giacomelli L, Rispoli L, Calvo JL, Covani U. A random-ized clinical evaluation of ultrasound bone surgery versus traditional rotary instru-ments in lower third molar extraction. J Oral Maxillofac Surg 2010;68:330-6.
8. Osunde OD, Saheeb BD, Adebola RA. Comparative study of effect of single and multiple suture techniques on inflammatory complications after third molar sur-gery. J Oral Maxillofac Surg 2011;69:971-6.
9. Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evid Based Complement Alternat Med 2004;1:251-7.
10. MacKay D, Miller AL. Nutritional support for wound healing. Altern Med Rev 2003;8:359-77.
11. Taussig SJ. The mechanism of the physiological action of bromelain. Med Hypoth-eses 1980;6:99-104.
12. Inchingolo, del Carmen de la Barrera-Núñez, Gaspani L, Limiroli E, Ferrario P, Bianchi M. In vivo and in vitro effects of bromelain on PGE2 and SP concentrations in the inflammatory exudate in rats. Pharmacology 2002;65:83-86.
13. Maroon JC et al. Natural anti-inflammatory agents for pain relief. Surg Neurol Int 2010; 1: 80.
Nagpal M, Sood S. Role of curcumin in systemic and oral health: An overview. J Nat Sc Biol Med 2013;4:3-7.
14. Corega C, Vaida L, Festila DG, Rigoni G, Albanese M, D’Agostino A et al. The benefits of Quercitin for dentistry and maxillofacial surgery: a systematic review. Minerva stomatologica 2014 Jan; 14.
15. Leena Sankari S, Aravindha Babu N, Vidya Rani, Priyadharsini C, Masthan KMK. Flavonoids – Clinical effects and applications in dentistry: A review. J Phar-macy And Bioallied Sciences 2014 Jul; 6(Suppl 1): S26–S29.
16. Benso B, Franchin M, Massarioli AP, Paschoal JAR, Alencar SM, Franco GCN et al. Anti-Inflammatory, Anti-Osteoclastogenic and Antioxidant Effects of Malva sylvestris Extract and Fractions: In Vitro and In Vivo Studies. PLoS ONE 2016; 11(9): e0162728.
17. Moore RA, Derry S, Aldington D, Wiffen PJ. Adverse events associated with sin-gle dose oral analgesics for acute postoperative pain in adults – an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2015; 10. Art. No.: CD011407.
18. Majid Eshghpour, Hamed Mortazavi, Naser Mohammadzadeh Rezaei, AmirHos-sein Nejat. Effectiveness of green tea mouthwash in postoperative pain control fol-lowing surgical removal of impacted third molars: double blind randomized clinical trial. Eshghpour et al. DARU Journal of Pharmaceutical Sciences 2013; 21(1): 59.
19. Tavares MG, Machado AP, Motta BG, Borsatto MC, Rosa AL, Xavier SP. Elec-tro-acupuncture efficacy on pain control after mandibular third molar surgery. Braz Dent J 2007; 18(2): 158-162.
20. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001;58:1234-45.