Orally administered clonidine significantly reduces pain during injection of propofol{dagger}

T. Yoshikawa1,2,3, Z. Wajima2, A. Ogura4, T. Inoue2 and R. Ogawa4

1Department of Anaesthesia, Hakujikai Memorial Hospital, 5-11-1 Shikahama, Adachi-ku, Tokyo 123-0864, Japan. 2Department of Anaesthesia, Chiba Hokusoh Hospital, Nippon Medical School, Chiba, Japan. 3Department of Anaesthesiology, Tokyo Jikeikai Medical School, Tokyo, Japan. 4Department of Anaesthesiology, Nippon Medical School, Tokyo, Japan*Corresponding author

{dagger}This work was carried out at Chiba Hokusoh Hospital, Nippon Medical School, 1715 Kamakasi Inba-mura, Inba-gun, Chiba 270–1694, Japan.

Accepted for publication: January 29, 2001


    Abstract
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 Abstract
 Introduction
 Methods and results
 Comments
 References
 
We examined the analgesic effects of orally administered clonidine on pain induced by injection of propofol (Diprivan; 2,6-diisopropyl phenol). Female patients (n=81) were randomly allocated to one of two groups: oral clonidine (5.5 µg kg1) followed by i.v. propofol and a control group given placebo followed by i.v. propofol. The median pain score in the group receiving clonidine, using a four-point scale (0=no pain, 1=minimal pain, 2=moderate pain, 3=severe pain) was 1 (0–2), significantly lower than in the control group [2 (1–3), median (25–75 percentiles), P<0.001].

Br J Anaesth 2001; 86: 874–6

Keywords: sympathetic nervous system, clonidine; anaesthetics i.v., propofol


    Introduction
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 Abstract
 Introduction
 Methods and results
 Comments
 References
 
Clonidine is an {alpha}2 adrenergic agonist with analgesic and sedative properties. It also reduces the total requirement for propofol for general anaesthesia. Because of these characteristics, we examined the effects of clonidine premedication on pain associated with propofol injection.


    Methods and results
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 Abstract
 Introduction
 Methods and results
 Comments
 References
 
The institutional ethics committee (Research Ethics Committee, Nippon Medical School) approved this study and each patient gave signed informed consent before enrolment. Eighty-one female patients (ASA physical status I or II, aged 30–60 yr) undergoing elective gynaecological laparotomy were allocated randomly to one of two groups. No patient received premedication apart from placebo or clonidine. Patients taking sedatives or analgesic agents and those with neurological or cardiovascular diseases were excluded from the study.

An 18-gauge Teflon cannula (Insyte-W Vialon E; Becton Dickinson, Franklin Lakes, NJ, USA) was inserted into the cephalic vein of the non-dominant hand, without infiltration of local anaesthetic, about 180 min before the induction of anaesthesia when the patient was still in the ward on the day of surgery. The cannula was used for i.v. infusion of Ringer’s lactate solution.

Non-invasive systolic arterial blood pressure (ni-SBP), non-invasive diastolic arterial blood pressure (ni-DBP) and heart rate were recorded in the ward about 120 min before transferring the patient to the operating theatre and before administration of oral clonidine or placebo. Measurements were repeated in the operating theatre before induction of anaesthesia.

Patients in the clonidine group (n=41) were given powdered clonidine 5.5 µg kg–1 orally 120 min before induction of anaesthesia. Propofol 2.5 mg kg–1 was given into the cannula at induction of anaesthesia. Control patients (n=40) were given placebo (cornstarch 5.5 µg kg–1) orally 120 min before induction of anaesthesia. Propofol was then administered as described for the clonidine group.

Propofol was kept in an incubator at 20–23°C until immediately before administration. It was infused through a three-way tap directly connected to the i.v. cannula, with the i.v. infusion line closed, using an electrically powered syringe pump (Graseby Anaesthesia Pump 3500; Graseby Medical, Hertfordshire, UK). The infusion rate was 3 mg kg–1 min–1 and the total amount infused was 2.5 mg kg–1. Before administration of propofol, the patient was requested to rate immediately any sensation of pain during injection as either none (0), mild (1), moderate (2) or severe (3), similar to the method used in previous studies.1 2 3 A blinded anaesthetist recorded the reported degree of pain. The maximum degree of pain reported before the patient fell asleep was recorded as the pain score (pain score) for that patient. We also recorded the interval before pain was experienced. If there was no pain, this interval was recorded as 50 s, representing the total time required for injecting the propofol.

After induction of anaesthesia, the lungs were ventilated mechanically with 30–50% oxygen in air through an endotracheal tube, in combination with epidural anaesthesia and continuous i.v. propofol.

Power calculation indicated that recruitment of 40 patients in each group would be sufficient to demonstrate a reduction of pain score of 1 at a level of significance of P=0.05 and power of 99.3%. Statistical analysis was carried out using SPSS version 10.0 and SamplePower J version 1.0 (SPSS, Chicago, IL, USA), on a Toshiba DynaBook Satellite 2520 computer running the Microsoft J Windows 98 operating system.

Differences in continuous variables between groups were statistically evaluated with the unpaired t-test, ASA status with the {chi}2 test and pain score with the Mann–Whitney U-test. The relationship between pain score and time to pain was analysed with Spearman’s rank correction coefficient, excluding patients with a pain score of 0 because there were no patients with a pain score of 0 in the control group. A P value of <0.05 was regarded as significant.

There were no significant differences in patient characteristics between the control and clonidine groups. Median pain score in the clonidine group was 1 (0–2), significantly lower than the score of 2 (1–3) in control patients (P<0.001) (Table 1).


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Table 1 Characteristics and pain scores of clonidine-treated and control groups. The number of patients with each pain score is shown. Pain score in each group is given as median and 25th and 75th percentiles. ni-SBP=non-invasive systolic arterial blood pressure; ni-DBP=non-invasive diastolic arterial blood pressure. Continuous variables are expressed as mean (SD); n.s.=not significant. *P<0.05 compared with values measured in the ward
 
There was no significant relationship between the pain score and time to pain. In the clonidine-treated group, ni-DBP and heart rate were significantly lower in the operating theatre than in the ward (P<0.05). In the control group, there were no significant changes in ni-SBP, ni-DBP or heart rate (Table 1). None of the patients developed profound hypotension or bradycardia that required treatment (data not shown).


    Comments
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 Abstract
 Introduction
 Methods and results
 Comments
 References
 
The incidence of injection pain on propofol injection is 25–100%.2 The mechanism responsible for the pain is unknown, but activation of the kinin cascade system has been suggested.4 Several approaches have been used to reduce injection pain. Among these, the most popular is the use of lidocaine either by mixing lidocaine with propofol or by pretreatment with a bolus injection of lidocaine. The former technique seems to be more effective than the latter.4

Previous studies have demonstrated that oral clonidine administered before anaesthesia increases the analgesic effects of opioids after operation5 6 and reduces anaesthetic7 and/or opioid requirement8 9 during the peri-operative period, and that clonidine attenuates the haemodynamic responses to noxious stimuli such as tracheal intubation.8 10 Because of these beneficial properties, clonidine is a useful premedication. Our results demonstrate the efficacy of oral clonidine for pain on injection of propofol.


    Acknowledgements
 
We wish to thank Professor Dr Yoshikiyo Amaki, Department of Anaesthesiology, Tokyo Jikeikai Medical School, and Dr Nobuo Nishimura, President of the Gerontological Medicine Institute, Hakujikai Memorial Hospital.


    References
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 Abstract
 Introduction
 Methods and results
 Comments
 References
 
1 Nathanson MH, Gajraj NM, Russell JA. Prevention of pain on injection of propofol: a comparison of lidocaine with alfentanil. Anesth Analg 1996; 82: 469–71[Abstract]

2 Yokota S, Komatsu T, Komura Y, et al. Pretreatment with topical 60% lidocaine tape reduces pain on injection of propofol. Anesth Analg 1997; 85: 672–74[Abstract]

3 Iwama H, Nakane M, Ohmori S, et al. Nafamostat mesilate, a kallikrein inhibitor, prevents pain on injection with propofol. Br J Anaesth 1998; 81: 963–4[Abstract/Free Full Text]

4 Scott RPF, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988; 43: 492–4[ISI][Medline]

5 Goyagi T, Nishikawa T. Oral clonidine premedication enhances the quality of postoperative analgesia by intrathecal morphine. Anesth Analg 1996; 82: 1192–6[Abstract]

6 Park J, Forrest J, Kolesar R, et al. Oral clonidine reduces postoperative PCA morphine requirements. Can J Anaesth 1996; 43: 900–6[Abstract]

7 Bloor BC, Flacke WE. Reduction in halothane anesthetic requirement by clonidine, an alpha-adrenergic agonist. Anesth Analg 1982; 61: 741–5[Abstract]

8 Ghignone M, Quintin L, Duke PC, Kehler CH, Calvillo O. Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation. Anesthesiology 1986; 64: 36–42[ISI][Medline]

9 Flacke JW, Bloor BC, Flacke WE, et al. Reduced narcotic requirement by clonidine with improved hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery. Anesthesiology 1987; 67: 11–9[ISI][Medline]

10 Lauruto CE, Baughman VL, Becker CL, De Silva TW, Carranza CJ. The effectiveness of oral clonidine as a sedative/anxiolytic and as a drug to blunt the hemodynamic responses to laryngoscopy. Can J Anaesth 1991; 3: 186–93[ISI]