Comparing low-dose intravenous ketamine-midazolam with intravenous morphine with respect to pain control in patients with closed limb fracture

Omid Ahmadi, Mehdi Nasr Isfahani, Awat Feizi, Omid Ahmadi, Mehdi Nasr Isfahani, Awat Feizi

Abstract

Background: We assessed the effects of low-dose IV ketamine-midazolam versus morphine on pain control in patients with closed limb fracture(s); and also compared the incidence of adverse events (cardio-pulmonary) between two groups.

Materials and methods: This prospective, single-blind, non-inferiority trial randomized consecutive emergency department (ED) patients aged 18-60 years to two groups: Receiving 300-500 mcg/kg ketamine plus 0.03 mg/kg midazolam, or 0.05-0.1 mg/kg morphine. Visual analogue score (VAS) and adverse events were verified during an interval of 30 minutes.

Results: Two hundred and thirty - six patients were selected, among whom 207 were males (87.3%). The average age was 29 ± 2, (range, 18-60 years). The VAS score at T30 (i.e., 30 minutes after initial analgesic dose) was significantly decreased compared with VAS score at T0, in both groups. No statistically significant difference, however, was observed between the two groups (-6.1 ± 1.1 versus -6.2 ± 1.0; P = 0.16). With regard to systolic blood pressure and respiratory rate, however, a meaningful difference was noted between the two groups (1.5 ± 6.4 versus -2.1 ± 6.6; P = 0.000 for SBP, and -0.2 ± 1.1 versus -1.1 ± 6.1; P = 0.048 for RR).

Conclusion: Low-dose intravenous ketamine plus midazolam has the same analgesic effects as morphine on pain control in trauma patients with closed limb fracture(s), in addition to less respiratory adverse events.

Keywords: Closed limb fracture; ketamine; midazolam; morphine.

Conflict of interest statement

Conflict of Interest: None declared.

Figures

Figure 1
Figure 1
The consort flow diagram

References

    1. Green SM, Rothrock SG, Harris T. Intravenous ketamine for pediatric sedation in the emergency department: Safety profile with 156 cases. Acad Emerg Med. 1998;5:971–6.
    1. Allerton J. Prehospital use of ketamine in mountain rescue. Emerg Med J. 2009;26:760–1.
    1. Harley JA, Sullivan AF, Dickenson AH. Evidence for N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res. 1990;518:218–22.
    1. Besson JM, Chaouch A. Peripheral and spinal mechanisms of nociception. Physiol Rev. 1987;67:67–186.
    1. Presson J, Scheinin H, Hellström G, Björkman S, Götharson E, Gustafsson LL. Ketamine antagonises alfentanil-induced hypoventilation in healthy male volunteers. Acta Anaesth Scand. 1999;43:744–52.
    1. Pierrefiche O, Foutz AS, Denavit-Saubié M. Pneumotaxic mechanisms in the non-human primate: Effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine. Neurosci Lett. 1990;119:90–3.
    1. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain: A quantitative and qualitative review (Cochrane review) Acta Anaesthesiol Scand. 2005;49:1405–28.
    1. Geisslinger G, Hering W, Thomann P, Knoll R, Kamp HD, Brune K. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereo selective analytical method. Br J Anaesth. 1993;70:666–71.
    1. Snapinn SM. Noninferiority trials. Curr Cont Trials Cardiovasc Med. 2000;1:19–21.
    1. Webb AR, Skinner BS, Leong S, Kolawole H, Crofts T, Taverner M, et al. The addition of a small-dose ketamine infusion to tramadol for postoperative analgesia: A double-blinded, placebo-controlled, randomized trial after abdominal surgery. Anesth Anal. 2007;104:912–17.
    1. Sumida T, Tagami M, Ide Y, Nagase M, Sekiyama H, Hanaoka K. The effects of intravenously (IV) administered midazolam on noxiously evoked activity of spinal wide dy- namic range (WDR) neurons were investigated in de- cerebrate, spinal-cord-transected cats. Anesth Analg. 1995;80:58–63.
    1. Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology. 1990;73:273–7.
    1. Lester L, Braude DA, Niles C, Crandall CS. Low-dose ketamine for analgesia in the ED, a retrospective case series. Am J Emerg Med. 2010;28:820–7.
    1. Mao J, Price DD, Mayer DJ. Experimental mononeuropathy reduces the antinociceptive effects of morphine: Implications for common intracellular mechanisms involved in morphine tolerance and hyperalgesia. Pain. 1995;61:353–64.
    1. Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthsiol Scand. 1997;41:1124–32.
    1. Javery KB, Ussery TW, Steger HG, Colclough GW. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth. 1996;43:212–5.
    1. Chia YY, Liu K, Liu YC, Chang HC, Wong CS. Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic concentration. Anesth Analg. 1998;86:1245–9.
    1. Wong CS, Liaw WJ, Tung CS. Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth. 1996;21:534–41.
    1. Kochs E, Scharein E, Möllenberg O, Bromm B, Schulte am Esch J. Analgesic efficacy of low-dose ketamine somatosensory-evoked responses in relation to subjective pain rating. Anesthesiology. 1996;85:304–14.
    1. Maurset A, Skoglund LA, Hustveit O, Øye L. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain. 1989;36:37–41.
    1. Sener S, Eken C, Schultz CH, Serinken M, Ozsarac M. Ketamine With and Without Midazolam for Emergency Department Sedation in Adults: A Randomized Controlled Trial. Ann emerg Med. 2011;57:109–14.
    1. Dich-Nielsen JO, Svendsen LB, Berthelsen P. Intramuscular low-dose ketamine versus pethidine for postoperative pain treatment after thoracic surgery. Acta Anaesthesiol Scand. 1992;36:583–7.
    1. Carstensen M, Møller AM. Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: A qualitative review of randomized trials. Br J Anaest. 2010;104:401–6.
    1. Gharaei B, Jafari A, Aghamohammadi H, Kamranmanesh M, Poorzamani M, Elyassi H, et al. Opioid-Sparing Effect of Preemptive Bolus Low-Dose Ketamine for Moderate Sedation in Opioid Abusers Undergoing Extracorporeal Shock Wave Lithotripsy: A Randomized Clinical Trial. Anesth Analg. 2013;116:75–80.
    1. Galinski M, Dolveck F, Combes X, Limoges V, Smaïl N, Pommier V, et al. Management of severe acute pain in emergency settings: Ketamine reduce morphine consumption. Am J Emerg Med. 2007;25:385–90.
    1. Bounes V, Charpentier S, Houze-Cerfon CH, Bellard C, Ducassé JL. Is there an ideal morphine dose for prehospital treatment of severe acute pain? A randomized, double-blind comparison of 2 doses. Am J Emerg Med. 2008;26:148–54.
    1. Sener S, Eken C, Schultz CH, Serinken M, Ozsarac M. Ketamine with and without midazolam for emergency department sedation in adults: A randomized controlled trial. Ann Emerg Med. 2011;57:109–14.
    1. Arroyo-Novoa CM, Figueroa-Ramos MI, Miaskowski C, Padilla G, Paul SM, Rodríguez-Ortiz P, et al. Efficacy of small doses of ketamine with morphine to decrease procedural pain responses during open wound care. Clin J Pain. 2011;27:561–6.
    1. Atangana R, Ngowe Ngowe M, Binam F, Sosso MA. Morphine versus morphine-ketamine association in the management of post operative pain in thoracic surgery. Acta Anaesth. 2007;58:125–7.
    1. Suppa E, Valente A, Catarci S, Zanfini BA, Draisci G. A study of low-dose S-ketamine infusion as “preventive” pain treatment for cesarean section with spinal anesthesia: Benefits and side effects. Minerva Anestesiol. 2012;78:774–81.
    1. Temple R, Ellenberg SS. Placebo-controlled trials and active control trials in the evaluation of new treatments. Ann Intern Med. 2000;133:455–70.
    1. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: A review of current techniques and outcomes. Pain. 1999;82:111–25.

Source: PubMed

3
Tilaa