ANALGESIC EFFECT OF CODEINE PLUS BROMOCRIPTINE DURING SIMPLE TEETH EXTRACTION AND MINOR ORAL SOFT TISSUE SURGERY

A. H. Fakhraee DMD*, H. H. Mazandarany DMD*, M. R. Zarrindast PhD* **

*Department of Oral and Maxillofacial Surgery, School of Dental Medicine, and **Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

  • Abstract

    Objective-In this study, the effect of codeine alone and in combination with D2 dopamine agonist bromocriptine in pain sensation during simple tooth extraction or minor oral soft tissue surgery has been examined.
    Method-Patients (121 male and 91 female) who were undergoing one of the above procedures, were included in this double-blind study. They were given randomly one of the following medications: Codeine (10-20 mg), bromocriptine (2.5-5 mg) in different combinations controlled by a placebo and a dental lidocaine cartridge group. The medication was given 20 minutes before the procedure and the patients subsequently recorded their pain intensity on a scale of 0-3.
    Results-ANOVA showed significant difference between placebo group and cases who received the combination of bromocriptine and codeine (with certain dosages), but the analgesic effect was significantly lower than the lidocaine group (p<0.05).
    Discussion-Patients who received bromocriptine 5 mg plus codeine (10 or 20 mg) had a better effective response than those receiving either of the components alone or placebo. It appears that D2 activation potentiates the response induced by the opioid agonist codeine.

    Keywords • Bromocriptine • codeine • analgesic • teeth extraction • surgery

    •

    Introduction

    It is generally accepted that neurotransmitter systems are involved in the modulation of nociceptive responses. There is considerable evidence to suggest that the brain dopaminergic mechanism is involved in the modulation of nociception 1,2. It has been shown that activation of dopaminergic systems pharmacologically may increase the stimulus-produced analgesia 3 . Electrical stimulation of substantia nigra also elicits stimulus-induced analgesia in rats 4, while lesions of the nigrostriatal pathway 5 and injection of the neurotoxin 6-hydroxydopamine 6 abolishs morphine-induced analgesia. The results for effects of dopaminergic agents on antinociception are conflicting. Dopamine agonists such as D-amphetamine, cocaine and apomorphine consistently produce analgesia in the formalin test. 7-10 Although, some researchers have suggested that dopaminergic agonists, such as apomorphine 11 and bromocriptine 2 increase the efficacy of morphine antinociception, while others have reported the opposite effects. 6,12 Morphine has been also shown to stimulate dopamine synthesis. 13

    The existence of two dopamine receptor subtypes, D1 and D2 in the brain is well established. The D1 receptor being positively linked to adenyl cyclase and D2 receptor being negatively linked or uncoupled to this enzyme. 14,15 Gene cloning studies have split these further into subgroups. 16,17 The D1 family now includes D1 and D5, while D2 family has been split into D2, D3 and D4. Previously we reported that two different D1 and D2 dopamine receptor subtypes may decrease or increase morphine-induced antinociception in tail-flick test respectively 18. In this study, the effect of codeine alone or in combination with D2 dopamine agonist bromocriptine in patients pain sensation during teeth extraction or minor oral soft tissue surgery has been examined.

    Materials and Methods

    Subjects

    Male or female volunteer patients referred to the school of dental medicine entered this study. They had either of the two procedures: (1) anterior teeth extraction or (2) oral soft tissue surgery (e. g. excisional and incisional biopsies, frenectomy, removal of epulis fissuratum and nevus). Patients were excluded from the study who: were under age 18 or over age 75, were pregnant or admitted the possibility of an undiagnosed pregnancy, had cardiovascular disease or were medically compromised. The patients who could not tolerate pain (Male=16, Female=11, Addict=2), or unable to communicate adequately with study personnel (Male=1) were also excluded from the study. Finally 121 male and 91 female patients were included in this study.

    Study design

    This study was conducted with the double-blind method with random allocation of one capsule containing one of the following medications to the patients. 1. placebo (lactose), 2. codeine (10 or 20 mg), 3. bromocriptine (2.5 or 5 mg), 4. codeine (10 mg) + bromocriptine (2.5 mg), 5. codeine (10 mg) + bromocriptine (5 mg), 6. codeine (20 mg) + bromocriptine (2.5 mg), 7. codeine (20 mg ) + bromocriptine (5 mg), and 8. dental cartridge of lidocaine containing 36 mg of lidocaine plus 0.018 mg of epinephrine. All the drugs were administered orally except of lidocaine which was injected.

    Patients were instructed to take the medication orally 20 min before tooth extraction or oral soft tissue surgery. Lidocaine was also injected 20 min before the tooth extraction or the surgery. Patients recorded their pain intensity on a four-point scale (0=none, 1=slight, 2=moderate, 3=severe).

    Statistical Analysis

    Data were expressed as the meanąSEM of mean. ANOVA followed by Newman-Keuls test were used for analysis of the data. Differences between means were considered statistically significant if p<0.05.

    Results

    Subject sample of 121 men and 91 women, ranging in age from 18 to 73 (meanąSEM = 42.8ą0.9) were enrolled and received medication. Tables 1 and 2 shows these data by treatment group, as well as the number of patients in each treatment group. To evaluate the analgesic activity of codeine, bromocriptine or codeine plus bromocriptine, the pain intensity, during tooth extraction or soft tissue surgery was utilized. Table 1 indicates effects of the drugs in tooth extraction. ANOVA showed significant difference between the results obtained from placebo, codeine or codeine plus bromocriptine [F (9, 82)=11.5, p<0.0001]. Further analysis showed that combinations of codeine and bromocriptine induced analgesic effects, however, the induced responses were significantly less than lidocaine administration. No significant changes were found, when mean blood pressure of the patients before and after the drugs administration were compared. Table 2 shows the response of single administration of codeine, bromocriptine or combination of the two drugs during minor oral soft tissue surgery. ANOVA also showed difference between the data obtained by the drugs [F (9,82)=12.0, p<0.0001]. Analysis indicates that the analgesic effect induced by combination of two drugs is much higher than each of them. In these patients the drugs administration did not alter the mean blood pressure.

    A male patient (age=45) that received the combination of codeine (10 mg) plus bromocriptine (2.5 mg) reported vomiting 30 min after tooth extraction. The mean blood pressure of the patient was not altered before (105 mmHg) and after (100 mmHg) tooth extraction. A female patient (age=35) receiving the combination of codeine (10 mg) plus bromocriptine (5 mg), reported drowsiness and flushing 1 hour after excisional biopsy. The mean blood pressure before and after surgery were 113.7 and 96.7 mmHg respectively.

    Discussion

    The effects of D1 and D2 dopamine agonists and antagonists alone and in combination with morphine have been previously investigated in different animal models 18,19. In the present study, the effect of dopamine agonist bromocriptine on analgesia induced by codeine has been shown. Codeine 20-22 and codeine in combination with other drugs are extensively used as dental analgesics. 23,24 Although codeine may induce analgesia, its abuse potential and side effects such as drowsiness, gastrointestinal upset and constipation precludes its satisfactory application. The aim of this study was to find a codeine combination, which would; (a) reduce codeine dose in order to avoid its side effects, (b) prepare a combination with more effective analgesic effect.

    The ergot derivative bromocriptine is classified as a D2 agonist with some very weak antagonist activity at D1 receptors. 14,25,26 It is widely used for the treatment of Parkinson’s disease. 27 Although it is a dopamine agonist, it does not act in the same way as the dopamine agonist apomorphine, and has been shown to be inactive in the absence of endogenous dopamine. 27 Bromocriptine has been used in severe cyclical breast pain. 28 The results of our present study demonstrate that oral administration of low dose codeine plus bromocriptine provide greater pain relief during tooth extraction or minor oral soft tissue surgery. Patients who received bromocriptine 5 mg plus codeine (10 or 20 mg) had a better response than those receiving either of the components alone or placebo. Our present data also support previous results 18,19 that dopamine agents are able to alter opioid induced antinociception in experimental animals. Therefore in agreement with our previous results, it appears that D2 activation potentiate the response induced by the opioid agonist codeine. The hypothesis can be supported by the results indicating that the D2 dopamine receptor agonist quinpirole increased morphine induced antinociception in the tail-flick 18 and the both phases of formalin 19 tests. Quinpirole by itself could induce antinociception.

    Bromocriptine like other dopamine receptor agonists, produces biphasic effects on locomotor activity in rodents. Low doses produce only depression, while higher doses produce depression which can last for many hours, followed by locomotor activation. The depression is due to the stimulation of dopamine autoreceptors reducing synaptic dopamine concentrations. 27 Wether the response of the drug is due to post-synaptic D2 dopamine receptor or due to autoreceptors should be investigated.

    In order to show whether combinations of both drugs alter blood pressure as a side effect, effects of codeine and bromocriptine alone and in combination, on blood pressure has been also analized. Analysis showed that there was no difference between the blood pressure of the patients before and after oral administration of the drugs.

    In addition to its effect on pain during tooth extraction and oral soft tissue surgery, codeine plus bromocriptine may be used as an analgesic for after surgery.

    Acknowledgments

    The authors wish to thank Dr. M Sahebgharani for his assistance in preparing this manuscript.

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