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A subhypnotic dose of ketamine reduces pain associated with injection of propofol and rocuronium

Abduşoğlu, Mustafa N; Özkoçak, Işlı; Yurtlu, Bülent S; Hanc, Volkanı; Okyay, Rahşan D; Ayoğlu, Hilal

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European Journal of Anaesthesiology: March 2011 - Volume 28 - Issue 3 - p 229-230
doi: 10.1097/EJA.0b013e3283425603

Pain on injection of propofol during induction of anaesthesia is an unpleasant experience for patients.1 After loss of consciousness, injection of rocuronium can cause reflex withdrawal of the hand or generalised movements of the body. This withdrawal movement is probably due to pain at the site of injection.2 Many drugs have been used in attempts to prevent the pain associated with injection of propofol or rocuronium.1–3 In a previous study, we demonstrated a reduction in pain intensity on injection of propofol by pretreatment with low-dose ketamine.1 However, there have been few studies of the effect of ketamine on pain associated with injection of rocuronium.2,3 The aim of the present study was to investigate the effect of ketamine in subanaesthetic doses on pain caused by injection of propofol and rocuronium.

After obtaining the approval of the hospital ethics committee [Ethical Committee of Karaelmas University Hospital, Zonguldak, Turkey (President Associate Professor BD. Gun) on 16 April 2009, No 2009/05–15], this prospective, randomised study was conducted between 2009 and 2010 in the Department of Anaesthesiology and Reanimation in Zonguldak Karaelmas University School of Medicine. A total of 54 patients aged between 18 and 60 years and in the American Society of Anesthesiologists (ASA) risk groups I–II, scheduled for elective operations, were enrolled in the study after providing their consent. Exclusion criteria included allergy to ketamine, propofol or rocuronium; previous history of neurological disorders or trauma in the hand; high intracranial pressure; uncontrolled hypertension; heart failure; ischaemic heart disease, diabetes mellitus; neuromuscular disease; use of an analgesic drug within the last 24 h; and pregnancy. All patients were given intramuscular midazolam 0.07 mg kg−1 (Dormicum 5 mg ml−1; Roche, Fontenay-sous-Bois, France) as premedication 45 min before arrival to the operating theatre. A 10-point visual analogue scale (VAS) was used to record the patients' baseline and vascular access pain scores. The patients were allocated randomly into one of two groups, which received either 5 ml of isotonic saline 0.9% (Group S) or ketamine 0.5 mg kg−1 (50 mg ml−1, Ketalar, Pfizer, Ortaköy, Istanbul, Turkey) diluted with isotonic saline 0.9% to a volume of 5 ml (Group K). The anaesthesiologist who performed induction of anaesthesia was unaware of the contents of the study syringe. A tourniquet was placed on the proximal wrist before injection of the study substance. One minute after the administration of the study substance, the tourniquet was released and 25% of the total dose of 2.5 mg kg−1 of propofol (Propofol 1% Fresenius Kabi) was injected over a period of 20 s. Injection pain was assessed using the 10-point VAS. Following the administration of the remainder of the propofol, the pain score was recorded again, but this time using a four-point scale [0, no motion; 1, motion at the wrist only; 2, motion in one arm (elbow or shoulder) only; 3, widespread motion in one extremity]. Each patient then received rocuronium 0.6 mg kg−1 (Esmeron 10 mg ml−1; N.V. Organon, Oss, Holland) injected intravenously over a period of 5–10 s and injection pain was assessed using the same four-point scale. Statistical analysis was undertaken using SPSS (version 16.0). A value of P less than 0.05 was taken to indicate statistical significance.

There were no significant differences between the groups in respect of baseline and vascular access pain scores. The VAS scores after injection of the first 25% of the total dose of propofol were significantly lower in Group K than Group S (P < 0.001). Four-point pain scores after injection of the remainder of the propofol and on injection of rocuronium were significantly lower in Group K than Group S (P < 0.001 and P = 0.004, respectively; Fig. 1).

Fig. 1
Fig. 1

The chemical mechanism of pain associated with injection of propofol is kinin release due to direct irritation of venous endothelium (particularly, tunica media and intima).1 Saadawy et al.4 evaluated pain caused by injection of propofol after pretreatment with thiopentone, pethidine, lidocaine and ketamine (0.4 mg kg−1) and concluded that although all drugs were effective in reducing pain, ketamine administered after venous occlusion was particularly effective. Tan et al.5 showed that administration of ketamine 10 mg before injection of propofol reduced the incidence of moderate or severe pain on injection from 84% to 26%. In our study, 70.4% of patients in Group K had no pain after injection of 25% of propofol dose, this ratio was 81.5%, upon completion of total dose injection. Pretreatment with low-dose ketamine has been shown previously to reduce pain associated with injection of propofol and inflammation-related ischaemic pain.4,6 As ketamine cannot be expected to provide analgesia by central mechanisms due to the use of a tourniquet, we are of the opinion that ketamine reduces injection pain by a local effect.

The mechanism of the pain associated with injection of rocuronium is not clearly understood. Acidic (pH ≤4) and alkaline (pH ≥11) solutions with high osmolarity are known to cause injection pain.7 Rocuronium is an isotonic solution with a pH value of 4. In our study, there was no evidence of pain associated with injection in 51.9% of patients in Group K, whereas the incidence of pain in Group S was 85.1%. In a study of paediatric patients, Liou et al.2 found that pretreatment with low-dose ketamine reduced the incidence of withdrawal movements induced by the injection of rocuronium. Mahajan et al.3 showed that pretreatment with ketamine significantly reduced pain associated with the injection of rocuronium in adults. It is argued that, as a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, ketamine may reduce pain by blocking NMDA receptors in both vascular endothelium and the central nervous system. Ketamine has also been shown to have a local analgesic action when administered for intravenous regional analgesia.6 It is possible that the reduction in injection pain in this study was the result of a local peripheral action.2,3

In conclusion, we found that a subhypnotic dose of ketamine significantly decreased the pain associated with intravenous injection of propofol and rocuronium.


1 Ozkoçak I, Altunkaya H, Ozer Y, et al. Comparison of ephedrine and ketamine in prevention of injection pain and hypotension due to propofol induction. Eur J Anaesthesiol 2005; 22:44–48.
2 Liou JT, Hsu JC, Liu FC, et al. Pretreatment with small-dose ketamine reduces withdrawal movements associated with injection of rocuronium in pediatric patients. Anesth Analg 2003; 97:1294–1297.
3 Mahajan R, Batra YK, Kumar S. Pain on injection of rocuronium: influence of ketamine pretreatment. Can J Anaesth 2005; 52:111–112.
4 Saadawy I, Ertok E, Boker A. Painless injection of propofol: pretreatment with ketamine vs thiopental, meperidine, and lidocaine. Middle East J Anesthesiol 2007; 19:631–644.
5 Tan CH, Onsiong MK, Kua SW. The effect of ketamine pretreatment on propofol injection pain in 100 women. Anaesthesia 1998; 53:302–305.
6 Satsumae T, Yamaguchi H, Sakaguchi M, et al. Preoperative small-dose ketamine prevented tourniquet-induced arterial pressure increase in orthopedic patients under general anesthesia. Anesth Analg 2001; 92:1286–1289.
7 Klement W, Arndt JO. Pain on i.v. injection of some anaesthetic agents is evoked by the unphysiological osmolality or pH of their formulations. Br J Anaesth 1991; 66:189–195.
© 2011 European Society of Anaesthesiology