Analgesia and Side Effects of Codeine Phosphate Associated with Paracetamol Versus Oxycodone After the Extraction of Mandibular Third Molars: A Randomized Double-Blind Clinical Trial Using the Split-Mouth Model

Abstract

Purpose

To assess the analgesia and side effects of 10 mg oxycodone as compared to 30 mg of codeine phosphate associated with 500 mg of paracetamol after bilateral lower third molar extraction.

Methods

This is a prospective, randomized, double-blind study applied to a sample of 16 patients. They were evaluated for seven days postoperatively, and the mean score of the visual analogue scale (VAS) of pain between test and control medications was assessed by the Wilcoxon distribution. The side effects of these medications were assessed by the Q Cochran test. A p value of < .05 was considered statistically significant.

Results

The mean score of the VAS of pain was higher in the oxycodone side, where few patients reported the use of rescue analgesic. There was no report of rescue medication in codeine phosphate associated with paracetamol side. The most common side effects reported in both groups, predominantly in patients using the oxycodone, were drowsiness, dizziness, and headache.

Conclusion

The use of codeine phosphate associated with paracetamol after the extraction of impacted mandibular third molars is a better choice than oxycodone for controlling postoperative pain.

Trial Registration Number and Date of Registration

RBR-8ntwmyq 07/07/2021.

Introduction

The extraction of impacted lower third molars is one of the most frequently performed surgical procedures by maxillofacial surgeons, yet it occupies a prominent place in relation to other oral surgeries because it is associated with feelings of fear and anxiety on the part of patients, thus requiring greater care aimed at pain control [1].

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with or similar to that associated with actual or potential tissue damage". Therefore, it is subjective in origin, influenced by biological, psychological, and social factors, in which the patient is primarily responsible for identifying its intensity and pattern [2].

Faced with this challenge, several studies have been conducted with the objective of evaluating the efficacy, safety, and acceptability of analgesics in patients undergoing lower third molar extraction [3–5]. In this context, it is possible to highlight studies evaluating multimodal analgesia characterized by the association of two or more medications that act on different pain control mechanisms, aimed at providing better analgesia and minimizing the adverse effects of the medications [6].

Among the drugs that present multimodal characteristics, the association of codeine phosphate with paracetamol stands out. This drug combines a chemical substance with a central action (codeine) with another substance with a predominantly peripheral action (paracetamol), which is indicated for the control of acute or chronic pain [7].

It is believed that weak opioids, such as codeine, may be as effective in controlling pain in lower third molar extractions as more potent opioids, such as oxycodone, in addition to causing fewer side effects. There is also considerable interest in raising awareness of the rational use of opioids in lower third molar extractions to combat the abuse of these analgesics [8]. To date, no study has been found in which the patient is his or her own control or a comparison was made of the analgesic efficacy and side effects between 30 mg of codeine phosphate in association with 500 mg of paracetamol and 10 mg of oxycodone after extractions of impacted lower third molars, which is the aim of the present study.

Material and Methods

The research was approved by the Research Ethics Committee of the Faculty of Dentistry, Federal University of Juiz de Fora, under opinion number 2,939,608, CAAE 92497218.0.0000.5147. This is a clinical, prospective, randomized, double-blind study applied to a sample of 18 patients in need of bilateral lower third molar extraction with similar bone impaction. The sampling method was of the non-casual type, for convenience, based on the patients’ search for the undergraduate clinics of the Faculty of Dentistry of the Federal University of Juiz de Fora. All patients signed the Informed Consent Form.

Patients met the following inclusion criteria: both genders, aged over 18 years; presenting similar tooth impaction; absence of systemic diseases or locoregional changes; no contraindication to the use of dexamethasone, paracetamol, codeine phosphate, or oxycodone; and no history of hypersensitivity to mepivacaine. Forms containing insufficient or inadequately filled data and patients who needed to use another medication were excluded from the initial selection.

The random sequence was generated by the Random Allocation Software 2.0 program, and randomization was organized through the aleatory number strategy using Microsoft Excel. Patients in the test group and in the control group were submitted to a unilateral tooth extraction and then inverted, guaranteeing the crossover study criteria. All patients received only an anti-inflammatory dose of 8 mg of dexamethasone orally, one hour before surgery, to control edema and trismus. Antibiotics were not prescribed pre- or postoperatively.

The dental position was evaluated with the aid of a digital orthopantomography of the jaws, classifying the teeth according to the Winter scale [9] and the Pell and Gregory scale [10]. Some transoperative data were also collected: degree of surgical difficulty according to the Pozos scale [11], the time of beginning of anesthesia, time of beginning and end of the extraction, and incidence of operative complications. Two percent mepivacaine hydrochloride was used with 1:20,000 corbadrine (Mepi-Levo 20-DFL^®) in a standardized quantity of two tubes (3.6 ml) for all procedures.

All extractions were performed by a maxillofacial surgeon at two different times with a minimum interval of 21 days. On one side, patients received 10 mg of oxycodone (control group). On the contralateral side, the patients received an association of 30 mg of codeine phosphate and 500 mg of paracetamol (test group). A 500-mg dose of paracetamol was used as rescue medication for both groups. The medications were handled in identical capsules (same color, shape, and size), stored in sealed bottles, containing 24 tablets. After unilateral extraction, the patient received bottles labeled with the letters A, B, and C, while in contralateral extraction, he or she received bottles D, E, and F (Fig. 1).

Fig. 1.

Bottles A (codeine phosphate + paracetamol), B (codeine phosphate + paracetamol), C (paracetamol), D (oxycodone), E (placebo-starch), and F (paracetamol)

Patients received the first tablet (A or D) immediately after surgery and were instructed to regularly take one tablet (B or E) at six-hour intervals, in alternation (AB or DE), until complete cessation of pain. In case the patient presented unbearable pain or unacceptable side effects, the C or F bottles that corresponded to the rescue medication were to be used. This dosage was used to equalize the administration time between the 10-mg dose of oxycodone (12–12 h) and the 30-mg dose of codeine (6–6 h), respecting the package inserts for these medications.

Subsequently, the patient was instructed to fill out the postoperative form at home with data regarding the time of end of anesthesia in soft tissue, consumption of analgesics, and the evolution of pain with the aid of a quantitative scale (Visual Analog Scale—VAS), applied immediately, 2 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h, after the end of the surgery. Daily information on possible side effects was also obtained. In the postoperative period of the second surgery, each patient chose the most comfortable surgery, taking into account pain and side effects.

Descriptive data analysis used absolute and relative frequencies, and for quantitative variables, measures of central tendency (mean, median). Minimum and maximum values of these quantitative variables were also described. The frequencies of signs and symptoms, among the drugs under test were evaluated over time by the Q Cochran test for related samples. The mean pain VAS score during the postoperative period and the number of rescue pills taken between the groups were compared using the Wilcoxon distribution. A p value of < 0.05 was considered statistically significant.

Results

Two participants were excluded from the initial selection, one for returning with a postoperative form containing insufficient data and the other for presenting alveolar infection after the second extraction. Among the 16 patients who participated in the statistical analysis, ten (62.5%) were female and six (37.5%) were male. The average age of participants was 25 years, ranging between 18 and 41 years old.

The selection of patients allowed the comprehensive pairing of sides when the Pell and Gregory classes and the Winter dental position were analyzed. A 96.9% pairing of the sides was found for the Pell and Gregory levels and the Pozos degree of surgical difficulty. All extractions required ostectomy and/or odontosection, having been classified as grade III and grade IV, according to the Pozos scale, and lasted, on average, 25.35 min on average.

Analgesic efficacy was evaluated based on the analysis of pain VAS and the need to use the rescue medication (paracetamol) during the seven-day postoperative period. Table 1 identifies an increased pain between the first and second days after the surgery in both groups. All patients received two cartridges of anesthetics, and the average duration of anesthesia in soft tissue was 3 h and 42 min, ranging between 1 h and 9 min and 5 h and 32 min.

Table 1.

Comparison of pain VAS between the test groups (codeine phosphate and paracetamol) and the control group (oxycodone) at different times during the seven-day postoperative period

Postoperative period	Groups
	Codeine phosphate and paracetamol				Oxycodone
	Median	Minimum	Maximum	N	Median	Minimum	Maximum	N
Immediately	0	0	2	16	0	0	1	16
2 h	0	0	5	16	1.5	0	8	16
24 h	1,5	0	4	16	2	0	5	16
48 h	2	0	6	16	2	0	7	16
72 h	1	0	5	16	1	0	9	16
96 h	0	0	5	16	0	0	9	16
120 h	0	0	4	16	0	0	10	16
144 h	0	0	4	16	0	0	10	16
168 h	0	0	0	16	0	0	0	16

Table 2 highlights yet another superiority of the association of codeine phosphate and paracetamol, demonstrating that there was no rescue pill consumption in this group, while there is a report of consumption of this drug at different times in the control group, albeit by a small number of patients.

Table 2.

Description of the number of patients who used rescue medication during the postoperative period between test groups (codeine phosphate and paracetamol) and the control group (oxycodone)

Postoperative period	Groups
	Codeine phosphate and paracetamol		Oxycodone
	N	%	N	%
24 h	0	0	2	12.5
48 h	0	0	1	6.2
72 h	0	0	1	6.2
96 h	0	0	0	0
120 h	0	0	2	12.5
144 h	0	0	1	6.2

Both groups reported similar side effects, with a predominance of somnolence (Table 3). Even so, there was no report of drug discontinuation in the test group or in the control group. Fifty percent of patients presented no side effects. Global satisfaction analysis showed that patients were satisfied with analgesic coverage in both groups, with 80% preference for the test group (codeine phosphate and acetaminophen).

Table 3.

Description of the number of patients who had postoperative side effects between the test groups (codeine phosphate and acetaminophen) and the control group (oxycodone)

Side effects	Groups
	Codeine phosphate and acetaminophen		Oxycodone
	N	%	N	%
Dizziness	2	12.5	6	37.5
Nausea	3	18.75	4	25
Drowsiness	8	50	5	31.25
Constipation	5	31.25	3	18.75
Headache	4	25	5	31.25

Discussion

Mandibular third molar extraction is considered as a highly qualified research model in the study of postoperative pain, with one of its advantages being it provides paired studies. In the present study, pairings above 96.9% were found in dental positions. This research model also allows a split-mouth study in which the individual is his or her own control, making the results even more reliable.

Jerjes et al. [12] argue that the surgeon’s level of experience is one of the factors capable of interfering with the incidence of complications in lower third molar extractions. Seymour et al. [13] evaluated postoperative pain in impacted third molar extractions and found a 30% increase in pain in patients whose procedure lasted more than 25 min. In the present study, an average of 25.35 min was found in the duration of each extraction, with all surgeries performed by a specialist in maxillofacial surgery with more than ten years of experience.

According to Contar et al. [14], the incidence of complications in third molar extraction ranges from 2.6 to 30.9%, being influenced by several factors, such as the patient's age and health condition, degree of dental impaction, smoking, contraceptive drug intake, quality of oral hygiene, choice of surgical technique, and the surgeon’s experience. In the present study, only one patient was excluded from the study for presenting infection in the surgical site in the immediate postoperative period, requiring the use of amoxicillin, not conforming to the aforementioned risk factors.

Long-acting local anesthetics provide greater comfort to the patient immediately after tooth extraction. Carvalho et al. [5] used 3.6 ml of 2% mepivacaine with 1:20,000 corbadrine in extraction of impacted third molars and found an average of 4 h and 12 min of soft tissue anesthesia, with patients presenting an average score of 1 point on the pain VAS ranging from 0–10 points immediately after extraction. Therefore, it was decided to adopt the same anesthetic protocol, finding an average duration of 3 h and 42 min of anesthesia in soft tissue. Pain VAS immediately after surgery had a mean score of 0, confirming the efficacy of the anesthetic protocol used in the study. Su et al. [15] also demonstrated the superior efficacy of 2% mepivacaine hydrochloride with 1:20,000 corbadrine in relation to 2% lidocaine with 1:100,000 epinephrine and in relation to 2% lidocaine with 1:50,000 epinephrine. Haas [16] also highlights the advantage of the low toxicity of mepivacaine.

Some authors have already proven the efficacy of steroidal anti-inflammatory drugs in the preoperative period of tooth extractions to prevent edema, which can be used in different dosages and administration routes [17, 18]. In the present study, an oral dose of 8 mg of dexamethasone was chosen, one hour before the surgical procedure, in agreement with Vicentini et al. [19] and Alcântara et al. [20]. Pre-emptive use of dexamethasone dilutes the effectiveness of the pain medication. To reproduce a postoperative period closer to the reality of the surgical procedure, the same dose of medication was used in all surgeries, inhibiting inconsistency during the comparison between the groups.

There was no rescue pill consumption in codeine phosphate and acetaminophen group, while there is a report of consumption of this drug at different times in the oxycodone group. Snyder et al. [21] argue that analgesic consumption is a better indicator of pain perception when compared to numerical scales. Considering the risks of self-medication and the irrational use of opioids, and based on the pharmacokinetic and pharmacodynamic knowledge of the medications, a pre-established dosage was chosen, respecting the medication package inserts. Considering that the 10-mg dosage of oxycodone must be taken every twelve hours and that the 30-mg dosage of codeine phosphate with paracetamol must be taken every six hours, it was necessary to include the placebo tablet in the control group, thus allowing the medication intervals in the test group and in the control group to be equally spaced, i.e., every six hours.

Some studies prefer to adopt the VAS to analyze the perception of pain, evaluating it at a single time or at different times during the first 24 h after surgery [22–25]. Carvalho et al. [5] emphasize that the peak of pain coincides with the maximum evolution of the edema, which may occur between 24 and 48 h. According to Mutlu et al. [26], pain after third molar extractions lasts three to four days on average, reaching a maximum after 48 h, similar to the results found in the present study.

Both groups presented excellent results in analgesic coverage, maintaining pain VAS scores between 0 and 2 throughout the postoperative period. The World Health Organization analgesic ladder classifies the codeine as a weak opioid, indicated for moderate pain, and the oxycodone as a strong opioid, indicated for severe pain [27]. In this study, the maximum pain in the oxycodone group is greater than the maximum pain in the codeine group at all postoperative moment. These findings indicate the 6-h dosing of the weak opioid is more effective than the 12-h dosing of the strong opioid. This result is consistent with the advantage of multimodal analgesia, demonstrating that the use of strong opioids for pain control in third molar extractions is not necessary.

Several studies [3–5, 18, 25, 26, 28, 29] indicate the incidence of side effects resulting from the use of opioids to control postoperative pain in third molar extractions, yet without significant harm to patients. In the present study, dizziness, nausea, constipation, headache, and drowsiness were found, both in the test group and in the control group, with no medication abandonment by any of the 16 patients.

Resnick et al. [8] emphasize that the abuse of opioids is a public health problem. Han et al. [30] noted that specialists in maxillofacial surgery are prescribing fewer opioids in third molar extractions, without impairing pain control. The authors believe that this change is due to greater awareness of the rational prescription of opioids, the discovery and proof of the analgesic efficacy of other non-opioid medications, and the preparation of organizational guidelines that govern the use of this important medication.

Conclusion

The use of 30 mg of codeine phosphate associated with 500 mg of paracetamol after the extraction of impacted mandibular third molars is a better choice than the 10 mg of oxycodone for controlling postoperative pain.

Author Contributions

MFdC: the conception and design of the study; acquisition and interpretation of data; drafting the article; revising the article critically for important intellectual content; final approval of the version to be submitted. GdMS: the conception and design of the study; interpretation of data; drafting the article; final approval of the version to be submitted. PARdC: interpretation of data; revising the article critically for important intellectual content; final approval of the version to be submitted. ICGL: analysis and interpretation of data; final approval of the version to be submitted. MdGN-H: the conception and design of the study; interpretation of data; drafting the article; final approval of the version to be submitted.

Funding

No funding was received for conducting this study.

Declarations

Conflict of Interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical Approval

The Ethics Committee of UFJF (Universidade Federal de Juiz de Fora), approved this study—Protocol nº. 2.939.608.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

The content of this paper represents original work for first publication in the Journal of Maxillofacial and Oral Surgery and it is not being considered for publication elsewhere.