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Table of Contents   
ORIGINAL RESEARCH  
Year : 2012  |  Volume : 23  |  Issue : 2  |  Page : 295-296
Effect of a combination of oral midazolam and low-dose ketamine on anxiety, pain, swelling, and comfort during and after surgical extractions of mandibular third molars


1 Department of Dental Surgery, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh, India
2 Department of Anesthesia, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh, India

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Date of Submission02-Apr-2011
Date of Decision20-Aug-2011
Date of Acceptance08-Dec-2011
Date of Web Publication3-Sep-2012
 

   Abstract 

Purpose: To assess the clinical efficacy of a combination of oral midazolam plus low-dose ketamine for reducing anxiety during surgery and in preventing postoperative pain and swelling after the surgical extraction of third molars.
Materials and Methods: Thirty patients requiring bilateral surgical extraction of mandibular third molars were included in this study. Prior to extraction of the tooth on the right side, a combination of oral midazolam and low-dose ketamine was given to the patient, while this protocol was not followed for extraction of the tooth on the left side. Anxiety levels were checked before surgery. The postoperative pain and swelling and patient's comfort with and without the premedication were compared.
Results: Facial swelling on the postoperative days was lower on the right side than on the left. Pain scores at 30 minutes and 24 hours after surgery were significantly higher on the left side. Also, anxiety during the surgery was less and comfort levels were higher postoperatively when the combination of oral midazolam plus low-dose ketamine was used.
Conclusions: Premedication with midazolam plus low-dose ketamine prior to surgical extraction of third molars can provide the patient with a comfortable procedure and good postoperative analgesia, with less swelling and significantly less pain.

Keywords: Anxiety, low-dose ketamine, oral midazolam, pain, swelling, third molar extraction

How to cite this article:
Gupta R, Sharma K, Dhiman UK. Effect of a combination of oral midazolam and low-dose ketamine on anxiety, pain, swelling, and comfort during and after surgical extractions of mandibular third molars. Indian J Dent Res 2012;23:295-6

How to cite this URL:
Gupta R, Sharma K, Dhiman UK. Effect of a combination of oral midazolam and low-dose ketamine on anxiety, pain, swelling, and comfort during and after surgical extractions of mandibular third molars. Indian J Dent Res [serial online] 2012 [cited 2021 Oct 28];23:295-6. Available from: https://www.ijdr.in/text.asp?2012/23/2/295/100460
Fear of the dentist and dental procedures is a common and potentially distressing problem, both for patient and for the dentist. People are sufficiently fearful of dentist to avoid or delay consultation, which often results in increased severity of their problem. In the attempt to reduce the discomfort associated with oral surgery, a number of drugs have been used. Ketamine is a well-known general anesthetic and short-acting analgesic that has been in use for almost three decades. The recent discovery of the N-methyl-d-aspartate (NMDA) receptor (Foster and Fagg, 1987) [1] and its links to pain processing and spinal neural plasticity triggered renewed interest in ketamine as a potential antihyperalgesic agent (Wilcox, 1991), [1] given its actions as a noncompetitive NMDA-receptor antagonist.

NMDA receptors participate in the development and maintenance of what can be called 'pathologic pain' after tissue injury, that is, increased pain perception as a result of pain sensitization, which is in part due to synaptic plasticity. [2] Ketamine binds noncompetitively to the phencyclidine-binding site of NMDA [3] receptors but also modifies them via allosteric mechanisms. [4] When studied at subanesthetic doses, its analgesic efficacy correlates well with its inhibitory action on NMDA receptor-mediated pain facilitation [3] and the decrease in activity of brain structures that respond to noxious stimuli. [5] A ketamine-induced decrease in pain signaling systems may represent a common mechanism underlying reduced pain sensitization and opiate tolerance phenomena [6] [Figure 1]. Ketamine therefore is potentially promising in several perioperative strategies to prevent pathologic pain.
Figure 1: Action of ketamine[5]

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Its usefulness, however, has been limited by its undesirable psychic emergence effects whether given intramuscularly, intravenously, or orally. These side effects are dose dependent and can be minimized by starting ketamine at low doses, titrating upwards slowly, and giving a benzodiazepine concurrently. [7]

Medication with oral midazolam for obtaining anxiolysis and sedation is a common practice. Also, midazolam and ketamine have similar pharmacodynamics after oral administration, [8] and thus the use of a combination of these drugs is logical. The use of this combination for oral administration was first described by Lin et al. [9] in 1993.

Aims and objectives

  • To assess the clinical efficacy of a combination of oral midazolam plus low-dose ketamine for reducing anxiety during surgery and increasing the comfort level of the patient.
  • To assess the effect of the combination of oral midazolam and low-dose ketamine for prevention of postoperative pain and swelling after the surgical extraction of third molars.


Review of literature

Many studies have been conducted to study the effect of midazolam and low-dose ketamine. Lin et al. [9] studied and compared the effects of the combination of oral midazolam and oral ketamine with that of oral midazolam or oral ketamine used alone. They found that with the combination there was faster onset time (vs both groups), less oral secretions (vs ketamine), and faster recovery (vs midazolam). Schmida et al. [1] concluded that ketamine may provide the clinician with a tool to improve postoperative pain management and to reduce opioid-related adverse effects. Darlong et al. [10] found that the combination of oral ketamine and midazolam has minimal side effects and provides faster onset of action and more rapid recovery than ketamine or midazolam alone for premedication in children prior to elective ophthalmic surgery. Funk et al. [8] concluded that adding low-dose ketamine to oral midazolam increases the success of premedication to greater than 90% without increasing side effects or prolonging recovery.

According to Young and Kendall, [11] tolerance to local anesthetic injection was better in children receiving ketamine and midazolam with behavioral changes like agiatation etc. noted in the first 2 weeks. Ghai et al. [12] concluded that oral midazolam alone and a combination of midazolam with ketamine provide equally effective anxiolysis and separation characteristics. However, the combination provided more children in an awake, calm, and quiet state who could be separated easily from parents.

On the other hand, Sherwin et al. [13] studied recovery agitation after ketamine sedation in children in the emergency setting. They observed that the degree of recovery agitation after ketamine sedation is significantly related to the degree of preprocedure agitation. They concluded that use of adjunctive benzodiazepines in pediatric ketamine sedation is unnecessary.


   Materials and Methods Top


Thirty patients with bilateral symmetrically impacted mandibular third molars were selected from the outpatient department. The required surgery included simple elevation, without or with minimal bone removal. Thus, these patients were able to act as their own controls. The patients' ages ranged from 25 years to 40 years. None of the patients had any medical illnesses and none of them were taking any medication that could influence the surgical procedure or postoperative wound healing. Informed medical consent was obtained from all patients. The two teeth were removed in two separate sessions 6 weeks apart. About 30-45 minutes prior to extraction of the right side tooth, a combination of oral midazolam (0.25 mg/ kg) and low-dose ketamine (5 mg/kg) was given to the patient mixed in ORS-L juice (Juggat pharma.). For exrtraction on the left side, the juice was given without adding any drug.

The anxiety levels were checked before taking the patient into the operatory. The patients were asked to rate their dental fear on Gatchel's 10-point fear scale, [14] where a score of 1 indicates no dental fear, a score of 5 indicates moderate fear, and a score of 10 indicates extreme fear. A score of 8 or greater is considered to indicate a significant degree of anxiety.

Also, prior to surgery, cheek dimensions were measured using a measuring tape according to the method described by Neupert and colleagues. [15] The linear dimensions from the angle of the mandible (gonium) to the tragus and the gonium to the pogonion (middle point of the chin) were measured and recorded.

The surgical extraction was then carried out. Postoperative pain and swelling and patient's comfort were recorded. Postoperative pain was assessed using the universal pain assessment tool [Figure 2]. The first pain assessment was carried out 30 minutes post surgery, prior to patients receiving any postoperative analgesia. A further assessment of pain was carried out 24 hours after surgery.
Figure 2: Universal pain assessment tool

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The dimensions of the cheek were re-measured using the same method and compared with the patient's previous readings to assess the degree of swelling. The patient was also questioned regarding his comfort level with the procedure, i.e., whether he/she was more comfortable during the right side or left side extraction and tooth which he/she felt was more conveniently and easily extracted.

Both sides (treated and control) were compared by calculating the means and standard deviations of the measurements. The Student's t test was used to assess any difference between the means. The level of significance adopted was 5%.


   Results Top


Preoperative anxiety levels were checked using Gatchel's 10-point fear scale. The Student's t test (7.05) revealed significantly lower anxiety levels on the right side (i.e., after administration of drugs) than on the left side [Table 1] and [Table 2].
Table 1: Anxiety scores before surgery

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Table 2: Comparison of the mean anxiety scores

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Postoperative pain intensity was measured using the universal pain assessment tool 30 minutes after surgery. The Student's t test (9.46) revealed significantly lower (P=.033) pain levels on the right side than on the left side [Table 3] and [Table 4]. Similarly, 24 hours after surgery, the Student's t test (7.61) revealed significantly lower (P=.008) pain levels on the right side [Table 5] and [Table 6].
Table 3: Pain scores 30 minutes postoperatively

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Table 4: Comparison of mean pain scores 30 minutes after surgery

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Table 5: Pain scores 24 hours post surgery

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Table 6: Comparison of mean pain scores 24 hours after surgery

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Postoperative swelling was checked 24 hours after surgery using a method described by Neupert and colleagues. Out of 30 patients, only 5 patients showed slight swelling on the right side, whereas 12 patients showed swelling on the left side. Also, the patients found the surgery on the right side more comfortable.

Thus, it was proved that facial swelling on postoperative days was lower with the use of the combination of midazolam and low-dose ketamine. Pain scores, both 30 minutes and 24 hours postoperatively were significantly higher on the left side. The anxiety was less during the surgery and comfort levels were higher postoperatively when the combination of midazolam and low-dose ketamine was used.


   Discussion Top


The key to good oral health is prevention - stopping problems before they arise. Unfortunately, people who suffer from dental anxiety fail to visit the dentist in time. Surgical removal of an impacted third molar often involves pain and swelling during the postoperative period.

Hashem et al. [16] investigated pain and anxiety during the circum-operative period of implant placement and confirmed that dental surgery could lead to a high level of anxiety, with a peak immediately before the oper­ation.

Pain and swelling originate in an inflammatory process initiated by surgical trauma. Acute pain following body surface surgery is accentuated by substances such as bradykinin and prostaglandins, which are released during tissue damage. Bradykinin is considered to sensitize nociceptors and this activity is accelerated by the presence of prostaglandins.

The addition of ketamine to local anesthetic or other analgesics improves or prolongs pain relief. Ketamine binds noncompetitively to the phencyclidine binding site of NMDA receptors but also modifies them via allosteric mechanisms. When studied at subanesthetic doses, its analgesic efficacy correlates well with its inhibitory action on NMDA receptor-mediated pain facilitation and the decrease in activity of brain structures that respond to noxious stimuli.

The major problem limiting the widespread clinical use of ketamine in pain management is the frequent (5%-35%) incidence of disturbing psychotomimetic side effects. [17] Combination with a minor tranquilizer seems to be the logical answer to this problem, and such a combination could at the same time broaden the pharmacodynamic profile.

Midazolam meets all the criteria of a good premedication drug, i.e., it has rapid onset of action, short duration of action, lack of significant side effects, and no interference with vital signs in doses less than 0.5 mg/kg. [18] However, good results are seen in only 60%-80% of patients. [19] Ketamine has excellent analgesic properties but it has been reported to be associated with apnea and psychologic side effects. On the other hand, midazolam, a benzodiazepine, is effective for sedation and relief of anxiety but has little or no analgesic activity. Hence, these two drugs were used in combination.

Literature review suggests that the effective oral dose of ketamine may be lower than the parenteral dose. [20] It has been also suggested that oral ketamine should produce less side effects because of the different pharmacodynamics of its metabolite norketamine. [21]

This study was carried out to assess the clinical efficacy of a combination of oral midazolam and low-dose ketamine for the prevention of postoperative pain and swelling after surgical extraction of third molars. It was found that facial swelling on postoperative days was lower on the right side (i.e., when the combination of drugs was used) than on the left side. Pain scores at 30 minutes and 24 hours after surgery were significantly higher on the left side. Also, the anxiety was less during the surgery and comfort levels were higher postoperatively after using the oral midazolam plus low-dose ketamine combination. In addition, either no side effects or only minimal drug-related side effects (dizziness, sedation, and dry mouth) were encountered, which was mainly because the doses of the drugs could be reduced when they were used in combination.


   Summary and Conclusion Top


Within the limitations of this study, we conclude that premedication with the combination of midazolam and low-dose ketamine during surgical extraction of third molars can provide less anxiety preoperatively, a comfortable procedure, and less swelling and significantly less pain postoperatively.

 
   References Top

1.Schmida RL, Sandler AN, Katza J. Use and efficacy of low dose ketamine in the management of acute post-operative pain: A review of current techniques and outcomes. Pain 1999;82:111-25.  Back to cited text no. 1
    
2.Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D- aspartate receptors in pain: A review. Anesth Analg 2003;97:1108-16.  Back to cited text no. 2
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3.Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: Evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 1992;260:1209-13.  Back to cited text no. 3
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4.Orser BA, Pennefather PS, MacDonald JF. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology 1997;86:903-17.  Back to cited text no. 4
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5.Langso JW, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V, et al. Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 2003;99:614-23.  Back to cited text no. 5
    
6.Himmelseher S, Durieux M. Ketamine for perioperative pain management. Anesthesiology 2005;102:211-20.  Back to cited text no. 6
    
7.Clark J, Kalan G. Effective treatment of severe cancer pain of the head using low dose ketamine in an opoid tolerant patient. J Pain Symptom Manage 1995;10:310-4.  Back to cited text no. 7
    
8.Funk W, Jakob W, Riedl T, Taeger K. Oral preanaesthetic medication for children: Double blind, randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth 2000;84:335-40.  Back to cited text no. 8
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9.Lin YC, Moynihan EJ, Hackel A. A comparison of oral midazolam, oral ketamine and oral midazolam combined with ketamine as a preanaesthetic medication for pediatric outpatients. Anesthesiology 1993;70:A1177.  Back to cited text no. 9
    
10.Darlong V, Shende D, Subramanyam MS, Sunder R, Naik A. Oral ketamine or midazolam or low dose combination for premedication in children. Anaesth Intensive Care 2004;32:246-9.  Back to cited text no. 10
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11.Younge PA, Kendall JM. Sedation for children requiring wound repair: A randomized controlled double blind comparison of oral midazolam and oral ketamine. Emerg Med J 2001;18:30-3.  Back to cited text no. 11
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12.Ghai B, Grandhe RP, Kumar A, Chari P. Comparitive evaluation of midazolam and ketamine with midazolam alone as oral premedication. Pediatr Anesth 2005;15:554-9.  Back to cited text no. 12
    
13.Sherwin TS, Green SM, Khan A, Chapman DS, Dannenberg B. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebo-controlled trial. Ann Emerg Med 2000;35:229-38.  Back to cited text no. 13
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14.Gatchel RJ. The prevalence of dental fear and avoidance: Expanded adult and recent adolescent surveys. J Am Dent Assoc 1989;118:591-3.  Back to cited text no. 14
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15.Neupert EA 3 rd , Lee JW, Philput CB, Gordon JR. Evaluation of dexamethasone for reduction of post surgical sequelae of third molar removal. J Oral Maxillofac Surg 1992;50:1177-83.  Back to cited text no. 15
    
16.Hashem A, Claffey N, O'Connell B. Pain and anxiety following the placement of dental implants. Int J Oral Maxillofac Implants 2006;21:943-50.  Back to cited text no. 16
    
17.White P, Way W, Trevor A. Ketamine - its pharmacology and therapeutic uses. Anaesthesiology 1982;56:119-36.  Back to cited text no. 17
    
18.Kain ZN, Mayes LC, Bell C, Weisman S, Hofstadter MB, Rimar S. Premedication in united states: A status report. Anesth Analg 1997;84:427-32.  Back to cited text no. 18
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19.Feld LH, Negus JB, White PF. Oral midazolam preanesthetic medication in pediatric outpatients. Anesthesiology 1990;73:831-4.  Back to cited text no. 19
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20.Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 1997;333:99-104.  Back to cited text no. 20
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21.Grant IS, Nimmo WS, Clements JA. Pharmacokinetics and analgesic effects of i.m. oral ketamine. Br J Anaesth 1981;53:805-9.  Back to cited text no. 21
    

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Correspondence Address:
Rubina Gupta
Department of Dental Surgery, Muzaffarnagar Medical College, Muzaffarnagar, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.100460

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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