Cronicon O P EN A C C ESS EC DENTAL SCIENCE

Research Article

Postoperative Healing Assessment Using Cannabinoids in Oral Surgery

Algirdas Puisys1*, Viktorija Auzbikaviciute1, Ricardas Kubilius3, Rokas Linkevicius3, Dainius Razukevicius3 and
Tomas Linkevicius2
1
Vilnius Implantology Center Clinic (Private Practice), Vilnius, Lithuania
2
Institute of Odontology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
3
Department of Oral and Maxillofacial Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania

*Corresponding Author: Algirdas Puisys, Vilnius Implantology Center Clinic (Private Practice), Vilnius, Lithuania.

Received: February 01, 2019; Published: March 11, 2019

Abstract
Objective: To ascertain and compare postoperative healing appearance after third-molar extraction when using antibiotics versus
cannabinoids.
Materials and Methods: Sixty randomly selected patients were included in the study and performed teeth removal followed the
needed protocols. Post-operative healing assessment were divided into two groups: thirty patients were instructed to use antibiotics
intraorally while another group used system of phytocannabinoid-cannabidiol substance intra- and extraorally. All research partici-
pants were followed daily for seven days. Objective intraoral estimation along with patients and doctor’s overall satisfaction of the
healing process were recorded.
Results: Observations of the pain, swelling, tolerance and overall assessment had no significant difference comparing two post-
healing medications when only significant factor was time duration after surgery (p < .0001). Additionally, five patients who used
phytocannabinoid-cannabidiol substance were followed until the tenth day when alveolitis presence fully disappeared.
Conclusions: Antibiotics and phytocannabinoids shows the same implication regard to swelling, pain intensity, patient’s and doctor’s
tolerance, overall assessment and similar results to alveolitis appearance which should be more explored in the further research.
Practical Implications: The study revealed that cannabinoids have a positive potential to be used in dental clinic practice for oral
diseases and wound healing prophylaxis.

Keywords: Cannabinoids; Cannabidiol; Postoperative Healing; Pain Management

Introduction
Third-molar tooth extraction for various reasons is a standard surgical procedure performed in daily dental practice, which can cause
multiple complications [1]. To prevent undesirable consequences, antibiotic therapy is universally acceptable protocol against infections
caused by clinically relevant bacteria [2]. Frequent use of antibiotics become a public health problem globally due to its multidrug resis-
tance in methicillin-resistant Staphylococcus aureus strains and other pathogenic bacteria [3]. This issue has enormous clinical implica-
tions which induced researchers to find alternatives for antibiotics replacement. Cannabinoids for medical purposes might be one of the
options which have to be more explored.

The plant Cannabis Sativa produces more than 421 chemical compounds, including about 80 terpeno-phenol compounds named phy-
tocannabinoids which have not been detected in any other plant and exhibit a wide range of biological activity [4-7]. It can be administered
topically, orally or sublingually; can be supplied in herbal form, extracted naturally from the plant, gained by isomerization of cannabidiol,

Citation: Algirdas Puisys., et al. “Postoperative Healing Assessment Using Cannabinoids in Oral Surgery”. EC Dental Science 18.4 (2019):
569-575.
Postoperative Healing Assessment Using Cannabinoids in Oral Surgery

570

or manufactured synthetically [8]. Cannabinoids and cannabinoid receptors are potential targets for reducing pain and inflammation [9].
The most common cannabinoids are ∆9-Tetrahydrocannabinol (THC), Cannabidiol (CBD), Cannabigerol (CBG), Cannabichromene (CBC),
and Cannabinol (CBN) [10,11]. CBD, structurally similar to THC, is a non-psychoactive cannabinoid, which has positive potential for the
treatment of neuropathic pain, multiple sclerosis and inflammation [12]. Evidence shows that CBD acts as an immunomodulator [4] and
exhibits a wide range of anti-inflammatory properties including the inhibition of IL-6 and the activation of anti-inflammatory pathways in
microglial cells [13]. CBD has been shown to induce apoptosis of microglial cells through lipid raft involvement [14]. Cannabinoid recep-
tors (CB1 and CB2) are located throughout the body in the central and peripheral nervous system [15]. Endocannabinoid system is active
peripherally where receptor CB1 stimulation reduces pain, inflammation and hyperalgesia. Receptor type 2 has been localized primarily
to cells of the immune system [16], mainly expressed on monocytes, T-cells, macrophages and B-cells. These observations lead to the hy-
pothesis that cannabinoids can partially replace antibiotics regarding inflammation reduction and pain control.

Purpose of the Study

The purpose of this in vivo study is to ascertain and compare postoperative healing appearance after third-molar extraction when
using antibiotics versus cannabinoids.

Materials and Methods

The study was conducted among randomly selected patients in Vilnius Implantology Center Clinic (Vilnius, Lithuania) who had indica-
tions for mandibular third molar extraction. Inclusion criteria were: (i) generally healthy patient, (ii) no medical contraindication for oral
surgery, (iii) partially or fully impacted mandibular wisdom teeth, (iv) no signs of inflammation. Exclusion criteria: (i) poor oral hygiene,
(ii) smoking, (iv) diabetes, (v) the use of bisphosphonates or any other medications which can affect healing, (vi) alcoholism.

In total, 60 patients were selected for the clinical study who met the previously mentioned criteria. All participants received similar
protocol for third-molar extraction, which has been approved by the Bioethics commission of the Lithuanian University of Health Science,
No. BEC-LSMU(R)-05. During surgery procedure, two incisions were made for mucoperiosteal flap elevation under inferior alveolar nerve
block anesthesia (4% articaine solution with vasoconstrictor epinephrine (1:100 000) (Ubistesin forte, 3M ESPE)). Bone resection and
odontotomy were performed to ensure enough exposure and safe extraction of the third-moral if needed. Alveolar socket following tooth
extraction was cleaned, and a blood clot was formed. After tooth removal mucoperiosteal flap was sutured with 4-0 PGA resorbable sutur-
ing material (Assucril, Switzerland).

Subsequently, all 60 patients who received the same surgical protocol were divided into two groups regarding different postoperative
medications: one group received antibiotics amoxicillin 500 mg three times daily for 7 days; another group-system of phytocannabinoids-
cannabidiol in gel form (Phytocannabinoid oil Paste 4200, SatiMed, Lithuania, www.satimed.eu) for 7 days. Both medications have been
used intraorally. Previous group of patients used phytocannabinoids-cannabidiol together with extraoral oil gel in the affected area (SA-
TIVERA Deep Tissue Oleogel 600, SatiMed, Lithuania, www.satimed.eu). All participants were instructed to rinse 0,12% chlorhexidine/
digluconate (Perio-aid; Dentaid, Spain) solution twice a day for a week as well as informed about personal care requirements.

All 60 patients were invited to the clinic daily for seven days to record patient’s satisfaction and doctor’s overview of the healing
process after surgery. The data was collected by questionnaire of closed-ended questions with one possible answer or Likert’s scale. The
purpose of the questionnaire was to measure pain intensity (1- none; 4- severe); swelling (1- none; 4- severe); presence of alveolitis (yes;
no); patient’s tolerance (1- very well tolerated; 4- not tolerated at all); doctor’s tolerance (1- very well tolerated; 4- not tolerated at all); pa-
tient’s overall assessment (1- very satisfied; 4- not satisfied at all) and doctor’s overall assessment (1- very satisfied, 4- not satisfied at all).

The descriptive statistics (mean ± SD/mode) and histogram for each follow-up day were presented for doctor’s tolerance and overall
assessment of the treatment satisfaction and pain, swelling and alveolitis assessments, respectively. The mean differences of pain, swelling
and patient’s overall assessment of the treatment satisfaction during 7 days follow-up period between treatment groups were assessed

Citation: Algirdas Puisys., et al. “Postoperative Healing Assessment Using Cannabinoids in Oral Surgery”. EC Dental Science 18.4 (2019):
569-575.
Postoperative Healing Assessment Using Cannabinoids in Oral Surgery

571

with two-way repeated measures ANOVA. Additionally, two-way ANOVA was performed for alveolitis and patient’s tolerance assessment
for each follow-up day. A two-tailed p-value less than 0.05 considered to be significant. Statistical analysis was performed using SAS 9.2.
Results
All sixty randomly selected patients who were included in the study had not missed any daily check-ups for seven days. Statistical
analysis was measured regarding collected data and assessed by dividing into fields: clinical evaluation (swelling intensity, alveolitis pres-
ence) and overall estimation (pain control, tolerance and overall assessment) approach.

Pain control

The collected data revealed that there is no correlation between pain presence and medication type, specifically, antibiotics or cannabi-
noids. As can be seen in figure 1, the statistically significant result was measured only in the term of time (p < 0,001) when the long period
after surgery shows a lower presence of pain. Comparison of the different treatment groups with time and medication had no significant
difference (p 0,9929) regarding the pain control.

Figure 1: Pain presence using different medications after surgery (1 - none; 4 - severe).

Swelling intensity

As well as presence of pain, swelling intensity using different medications after surgery revealed similar results. Only time after sur-
gery (p < 0,0001) has a positive correlation with swelling intensity (Figure 2).

Figure 2: Swelling intensity using different medications after surgery (1 - none; 4 - severe).

Citation: Algirdas Puisys., et al. “Postoperative Healing Assessment Using Cannabinoids in Oral Surgery”. EC Dental Science 18.4 (2019):
569-575.
Postoperative Healing Assessment Using Cannabinoids in Oral Surgery

572

Alveolitis presence

By measuring alveolitis in the first week after surgery positive recordings were measured in both antibiotic and cannabinoid groups
(Figure 3). It was noticed that at the 6rd day patients who used antibiotics had not any presence of alveolitis while at the same day three
patients from 30 who used cannabinoids still had the appearance of alveolitis. In the last day of recordings, the previous number got up
to 5. These patients were followed until none of them present complications and had no complains. After ten days any patient had not
alveolitis appearance. Significant results were observed by comparing alveolitis appearance and time duration after surgery (Table 1).
Independent variables of general mode (p 0,0471) and medication type (p 0,0388) were estimated.

Figure 3: Alveolitis appearance using different medications after surgery.

Dependent variables (p < 0,05)

Alveolitis appearance
Independent variables 1 day 2 day 3 day 4 day 5 day 6 day 7 day
General model 0.6477 0.6477 0.6589 0.6589 0.6589 0.3462 0.0471
Medication type 0.7573 0.7573 0.9969 0.9969 0.9969 0.1141 0.0388

Table 1: Comparison of alveolitis appearance and days after surgery.

Tolerance

Distribution of doctor’s tolerance for each day after surgery in the scale from 1 to 4 was assessed. It was noticed that the doctor’s
tolerance does not exceed average 1.3 point (max standard deviation (SD) ± 0.66; mode 1) for both medications (Table 2). No significant
difference was measured regarding medication and time after treatment according to the tolerance of the doctor.

Table 3 indicates the results of the patient’s tolerance according to the day after surgery. A significant difference was measured on the
3rd day (p < 0.0467) of the general model.

Citation: Algirdas Puisys., et al. “Postoperative Healing Assessment Using Cannabinoids in Oral Surgery”. EC Dental Science 18.4 (2019):
569-575.
Postoperative Healing Assessment Using Cannabinoids in Oral Surgery

573

Time Antibiotics Cannabinoids

(±SD/Mode) (±SD/Mode)
1 day 1.3 ± 0.60/1 1.3 ± 0.61/1
2 day 1.3 ± 0.64/1 1.3 ± 0.65/1
3 day 1.3 ± 0.65/1 1.3 ± 0.66/1
4 day 1.3 ± 0.64/1 1.3 ± 0.65/1
5 day 1.3 ± 0.64/1 1.3 ± 0.65/1
6 day 1.3 ± 0.64/1 1.3 ± 0.65/1
7 day 1.3 ± 0.64/1 1.3 ± 0.65/1

Table 2: Distribution of doctor’s tolerance for each day after surgery in the scale from (1 - very well tolerated; 4 - not tolerated at all).

Dependent variables (p < 0,05)

Patient’s tolerance
Independent variables 1 day 2 day 3 day 4 day 5 day 6 day 7 day
General model 0.5434 0.1884 0.0467 0.1659 0.7824 0.7824 0.4312
Medication type 0.5277 0.6845 0.8536 0.7308 0.6894 0.6894 0.6910

Table 3: Comparison of patient’s tolerance and days after surgery.

Overall assessment

The purpose of the overall assessment criteria is to evaluate patient’s and doctor’s satisfaction with the treatment and post-healing
period after surgery. As can be seen from table 4 doctor’s overall assessment during the week does not exceed average 1.7 point in the
scale of 4 points. From the 5 - 7-day patients who have taken cannabinoids were noted as the best satisfying healing result comparing with
antibiotics-1.5 point (Mode 1; SD ± 0.57).

Time Antibiotics (±SD/ Cannabinoids (±SD/

Mode) Mode)
1 day 1.7 ± 0.70/2 1.6 ± 0.57/2
2 day 1.7 ± 0.70/2 1.6 ± 0.57/2
3 day 1.7 ± 0.70/2 1.6 ± 0.57/2
4 day 1.7 ± 0.61/2 1.6 ± 0.57/2
5 day 1.6 ± 0.61/2 1.5 ± 0.57/1
6 day 1.6 ± 0.56/2 1.5 ± 0.57/1
7 day 1.6 ± 0.56/2 1.5 ± 0.57/1

Table 4: Distribution of doctor’s overall assessment for each day after surgery in the scale from
(1 - very satisfied; 4 - not satisfied at all).

Citation: Algirdas Puisys., et al. “Postoperative Healing Assessment Using Cannabinoids in Oral Surgery”. EC Dental Science 18.4 (2019):
569-575.
Postoperative Healing Assessment Using Cannabinoids in Oral Surgery

574

Taking a note into patient’s satisfaction during post-healing period it was noticed that type of medication has no significant difference
regarding overall assessment when only significant criteria is time (Table 5).

Patient’s overall assessment average differences P

Time 0.0238
Time and Medication 0.8675

Table 5: Patients overall assessment differences between treatment groups.

With a few exceptions, the results showed that medications, particularly, antibiotics or cannabinoids, does not have significant differ-
ence (p > 0.05) regarding successful healing. The study revealed that those criteria such as pain, swelling or patient’s overall assessment
are mainly related to time duration after surgery, and both medication expose similar implications.

Discussion
Planned comparison of antibiotics and cannabinoids revealed that both medications have a positive outcome after third-molar sur-
gery, and therefore, our hypothesis can be confirmed. These results might be promising by reducing the use of antibiotics and replacing
them by cannabinoids thus leading to lower growth of multidrug resistance caused by pathogenic bacteria.

To our knowledge, no similar in vivo research exists addressing the question of phytocannabinoids potential to replace the antibiotics
after oral surgeries. For this reason, we can only compare the studies related with cannabinoids in general approach. Angel A Izoo., et
al. arranged and submitted an overview of different types of cannabinoids with different pharmacological actions [17]. In the article is
mentioned, that cannabinoids, particularly cannabidiol, has the affect as an anxiolytic, analgesic, anti-inflammatory, antiepileptic, neuro-
protective, vasorelaxant, antispasmodic, anti-ischemic, bone-stimulant and etc. This data positively correlates with our results regarding
analgesic, anti-inflammatory response. Observations discussed in the article might lead to the new potential therapeutic interest includ-
ing not only CBD but other types of cannabinoids as well.

Although the research has reached its aims, there are several limitations. To have a better overview of the efficiency of cannabinoids
and antibiotics, it is recommended to add a control group based on placebo approach. By adding previously mentioned group clinical
evaluation, as well as overall estimation, could be accurately assessed.

Furthermore, for even higher statistically significant results there is obvious need to add the larger number of patients as a sample size
in the study thus providing researchers for reducing the probability of an error and achieving promising significant differences.

In this clinical study, it was estimated the presence of alveolitis which was recorded in the both groups of patients. Because patients
were selected with both partially and fully impacted third-molar teeth it may be assumed that different primary clinical situations lead to
a broader range of surgery techniques with its different possible complications.

Given the positive primary results of antibiotics and cannabinoids implications after third-molar surgery, the future direction of CBD
researches should be improved by adding a placebo group, expanding sample size as well as equalizing the initial clinical situations.

Conclusions
This research underlined the importance of medications replacement thus reducing the use of antibiotics after third-moral surger-
ies. It was found that antibiotics and phytocannabinoids (CBD and others) have the same or similar implication regarding swelling, pain
intensity, alveolitis presence and patient’s and doctor’s tolerance as well as overall assessment. Despite some limitations, we believe this
study might be a starting point for new clinical studies according to the use of cannabinoids in dental practice.

Citation: Algirdas Puisys., et al. “Postoperative Healing Assessment Using Cannabinoids in Oral Surgery”. EC Dental Science 18.4 (2019):
569-575.
Postoperative Healing Assessment Using Cannabinoids in Oral Surgery

575

Bibliography
1. Zeitler Dl. “Prophylactic antibiotics for third molar surgery”. Journal of Oral and Maxillofacial Surgery 53.1 (1995): 61-64.

2. Giovanni Appendino., et al. “Antibacterial Cannabinoids from Cannabis satiWa: A Structure-Activity Study”. Journal of Natural Prod-
ucts 71.8 (2008): 1427-1430.

3. Lin J., et al. “Mechanisms of antibiotic resistance”. Frontiers in Microbiology 6 (2015): 34.

4. Mechoulam R., et al. “Cannabidiol recent advances”. Chemistry and Biodiversity 4.8 (2007): 1678-1692.

5. Pertwee RG. “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabi-
diol and delta9-tetrahydrocannabivarin”. British Journal of Pharmacology 153.2 (2008): 199-215.

6. Turner CE. “Constituents of Cannabis sativa L. XVII. A review of the natural constituents”. Journal of Natural Products 43.2 (1980):
169-234.

7. Mechoulam R and Hanus L. “A historical overview of chemical research on cannabinoids”. Chemistry and Physics of Lipids 108.1-2
(2000): 1-13.

8. Hazekamp A., et al. “The medicinal use of cannabis and cannabinoids-an international cross-sectional survey on administration
forms”. Journal of Psychoactive Drugs 45.3 (2013): 199-210.

9. Clayton N., et al. “CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain”. Pain 96.3 (2002): 253-260.

10. Mechoulam R., et al. “Recent advances in the chemistry and biochemistry of cannabis”. Chemical Reviews 76.1 (1976): 75-112.

11. Elsohly MA and Slade D. “Chemical constituents of marijuana: the complex mixture of natural cannabinoids”. Life Sciences 78 (2005):
539-548.

12. Mechoulam R and Hanus L. “Cannabidiol: An overview of some chemical and pharmacological aspects. Part I: Chemical aspects”.
Chemistry and Physics of Lipids 121.1-2 (2002): 35-43.

13. Kozela E., et al. “Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like
disease in C57BL/6 mice”. British Journal of Pharmacology 163.7 (2011): 1507-1519.

14. Wu HY., et al. “Cannabidiol induced apoptosis in murine microglial cells through lipid raft”. Glia 60.7 (2012): 1182-1190.

15. Martin WJ., et al. “Cannabinoids are anti-allodynic in rats with persistent inflammation”. Pain 82.2 (1999): 199-205.

16. Cabral GA and Staab A. “Effects on the immune system”. Handbook of Experimental Pharmacology 168 (2005): 385-423.

17. Izzo AA., et al. “Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb”. Trends in Pharmacologi-
cal Sciences 30.12 (2009): 609.

Volume 18 Issue 4 April 2019

© All rights reserved by Algirdas Puisys., et al.

Citation: Algirdas Puisys., et al. “Postoperative Healing Assessment Using Cannabinoids in Oral Surgery”. EC Dental Science 18.4 (2019):
569-575.