by dr maria

1. American Journal of Emergency Medicine (2007) 25, 385 – 390
www.elsevier.com/locate/ajem
Original Contribution
Management of severe acute pain in emergency settings:
ketamine reduces morphine consumptionB
Michel Galinski MDa,*, Francois Dolveck MDb, Xavier Combes MDe,
¸
Veronique Limoges MD , Nadia Smail MD, PhDd, Veronique Pommier MDc,
´ c !!
´
b a
Francois Templier MD , Jean Catineau MD ,
¸
Frederic Lapostolle MDa, Frederic Adnet MD, PhDa
´ ´ ´ ´
a
Samu 93-EA 3409 Avicenne Hospital, 93009 Bobigny Cedex, France
b
Samu 92-Raymond Poincare Hospital, 92100 Garches, France
´
c
Emergency Department-Smur 77, Meaux’s Hospital, 77100 Meaux, France
d
Samu 31-Purpan Hospital, 31000 Toulouses, France
e
´
Samu 94-Henri Mondor Hospital, 94000 Creteil, France
Received 1 July 2006; revised 1 November 2006; accepted 2 November 2006
Abstract
Objective: The aim of the study was to compare in emergency settings 2 analgesic regimens, morphine
with ketamine (K group) or morphine with placebo (P group), for severe acute pain in trauma patients.
Methods: This was a prospective, multicenter, randomized, double-blind, clinical trial. Seventy-three
trauma patients with a severe acute pain defined as a visual analog scale (VAS) score of at least 60/100
were enrolled. Patients in the K group received 0.2 mg d kgÀ1 of intravenous ketamine over 10 minutes,
and patients in the P group received isotonic sodium chloride solution. In both groups, patients were
given an initial intravenous morphine injection of 0.1 mg d kgÀ1, followed by 3 mg every 5 minutes.
Efficient analgesia was defined as a VAS score not exceeding 30/100. The primary end points were
morphine consumption and VAS at 30 minutes (T30).
Results: At T30, morphine consumption was significantly lower in the K group vs the P group, with
0.149 mg d kgÀ1 (0.132-0.165) and 0.202 mg d kgÀ1 (0.181-0.223), respectively ( P b .001). The VAS
score at T30 did not differ significantly between the 2 groups, with 34.1 (25.6-42.6) in the K group and
39.5 (32.4-46.6) in the P group ( P = not significant).
Conclusion: Ketamine was able to provide a morphine-sparing effect.
D 2007 Elsevier Inc. All rights reserved.
1. Introduction
Presented at the European Society of Anaesthesiology Congress in
Madrid, Spain, June 3-6, 2006.
B Morphine titration infusion usually provides rapid and
Support was provided solely by institutional and/or departmental
sources. effective analgesia in severe acute pain [1]. However,
* Corresponding author. Tel.: +33 1 48 96 44 55; fax: +33 1 48 96 44 45. adverse effects sometimes occur and may require discon-
E-mail address: michel.galinski@avc.ap-hop-paris.fr (M. Galinski). tinuation of morphine titration before sufficient pain relief is
0735-6757/$ – see front matter D 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajem.2006.11.016

2. 386 M. Galinski et al.
obtained [2]. The combination of nonopioid analgesics with randomly allocated to receive either morphine and ket-
morphine provides a morphine-sparing effect and should amine (K group) or morphine and placebo (P group).
decrease toxicity. This concept is the basis of multimodal Patients were eligible for inclusion if they presented a
analgesia [3]. trauma with a severe acute pain defined as a visual analog
Small doses of ketamine possess N-methyl-d-aspartate scale (VAS) score of at least 60/100; were aged between
(NMDA) receptor noncompetitive antagonist properties 18 and 70 years; and were without acute respiratory,
through a magnesium-dependent channel blockade [4]. hemodynamic, or neurologic compromise (respiratory
Several studies demonstrated that it improves opioid distress signs, systolic blood pressure V90 mm Hg,
analgesia in postoperative settings [5,6]. Glasgow Coma Score b15). Exclusion criteria included
Potentiation between opioids and ketamine was demon- the presence of a psychiatric history; chronic respiratory,
strated in animal studies [7] and was suggested in a renal, or hepatic failure; known ketamine sensitivity;
volunteer study [8], whereas another report favored only known opioid allergies; treatment of chronic pain or
an additive association [9]. Furthermore, ketamine attenu- treatment with opioids; incapacity to understand the VAS;
ates the development of acute analgesic tolerance to opioids pregnancy; or indication for local or regional analgesia.
in rats [10] and suppresses the rebound hyperalgesia Patients who had already received an opioid analgesic
observed after opioid exposure in volunteers [11]. A recent (either by self-administration or by another attending
study demonstrated that the combined administration of physician) were also excluded.
small-dose ketamine and morphine promptly and satis- Intravenous morphine was given and titrated according to
factorily resolved pain that was unresponsive to intra- the VAS pain score. Ketamine and placebo were adminis-
venous (IV) morphine alone [12]. In emergency settings, a tered from syringes of similar appearances prepared by a
0.1-mg d kgÀ1 dose of IV morphine was not effective for nurse anesthetist who was otherwise not involved in the
controlling severe acute pain in most patients [13]. There is study. The dilution of ketamine was 1 mg d mLÀ1. An
evidence to suggest that the lack of effectiveness of independent physician-observer blinded to the analgesic
morphine is due to the activation of NMDA receptors; and treatment group did all assessments of patients. The first
if these are not effectively inhibited in time, the process may volume administered was 0.2 mL d kgÀ1 (ie, 0.2 mg d kgÀ1)
evolve into a complex change in neural plasticity, resulting of ketamine (Ketamine; Panpharma, France) in the K group
in central sensitization [14]. To our knowledge, there is no or 0.2 mL d kgÀ1 of placebo in the P group given over
study assessing the interest of the morphine and ketamine 10 minutes with 0.1 mg d kgÀ1 of morphine, followed by
association for trauma patients with severe acute pain in additional doses of 3 mg every 5 minutes until pain relief
emergency settings. was obtained as defined by a VAS score not exceeding
We tested the hypothesis that the combination of small- 30/100. The study protocol is shown in Fig. 1.
dose ketamine and morphine would promptly reduce pain The end points of the study were the VAS and the
perception and morphine consumption compared with morphine consumption at 30 minutes (T30).
morphine alone in trauma patients with severe acute pain The VAS used was a 100-mm ruler and a marker that
in emergency settings. the patient moves to the point indicating his or her pain
intensity. The VAS was presented as a horizontal line
on which the patient’s pain intensity was represented by a
2. Materials and methods point between the extremes of bno pain at allQ and bworst
pain imaginable.Q
We performed a prospective, multicenter, randomized, Patients were asked to assess the intensity of their pain
double-blind, controlled study. The trial was coordinated by by providing a VAS score on inclusion (VAS [T0]) and then
the Avicenne University Hospital (Bobigny, France). Five every 5 minutes until arrival at hospital.
emergency departments using mobile intensive care units All VAS scores were recorded at T0, T15, and T30.
previously described [15] were involved in this study. Thirty minutes after the first injection, overall patients’ and
Mobile intensive care units are staffed by an attending investigators’ satisfaction regarding analgesia (pain relief
emergency physician, a nurse anesthetist, and an emergency classified as excellent, good, mild, or weak) was recorded.
medical technician. The safety evaluation included monitoring of the blood
The Human Subjects Committee of the Robert Ballanger pressure, heart rate, respiratory rate, and oxygen saturation
Hospital (Aulnay, France) approved this study, and all by pulse oximetry, as well as sedation level using the
patients provided written informed consent. Patients were Ramsay score ranging from 1 to 6 [16] (1, anxious and
recruited between January 01, 2003, and January 31, 2005. agitated or restless; 2, cooperative, oriented, and tranquil;
A table of random numbers determined the randomiza- 3, responds to command only; 4, brisk response to light
tion sequence, using a restricted randomization scheme to glabellar tap; 5, sluggish response to light glabellar tap; 6, no
ensure roughly equal numbers in each group. Group response to glabellar tap). Sedation was defined as a Ramsay
assignments were sealed in opaque envelopes and opened score of greater than 2. The presence of hallucination,
sequentially by the investigators. Eligible patients were dysphoria, weakness sensation, diplopia, nausea, vomiting,

3. Management of severe acute pain in emergency settings 387
Fig. 1 The study protocol involving administration of ketamine vs placebo.
dizziness, itching, and bradypnea was likewise recorded. score not exceeding 30/100, and standard deviation was
These data were recorded at T0 and T30. estimated to be approximately 15/100 [17]. To reach a
VAS difference of more than 13/100 [18] in favor of the
2.1. Statistical analysis ketamine group, the appropriate sample size using an
a error of .05 and a b error of .10 was calculated with
The Wilcoxon test was used for quantitative nonpara- the formula of Casagrande et al [19]. A minimum of
metric variables such as VAS, the Student t test for 29 patients for each group should be included to see a
parametric quantitative variables, and the v 2 test for difference of 13 mm between groups. We chose to include
qualitative variables. The aim of pain relief was a VAS 30 patients in each group to increase the power of this

4. 388 M. Galinski et al.
Table 1 Baseline characteristics of patients from groups K
and P
Characteristics K group P group P
(n = 33) (n = 32)
Age (y, mean F SD) 35 F 13 40 F 14 .3
Sex ratio (male-female) 25:8 23:9 .6
BMI (kg d mÀ2, mean F SD) 25 F 4 25 F 4 .8
Etiology of trauma (n [%]) .14
Suspicion of bone fracture 19 (58) 24 (75)
Burns 2 (6) 2 (6)
Others 12 (36) 6 (19)
BMI indicates body mass index.
Fig. 2 The effect of morphine with and without ketamine on the
variation of the VAS score at T0, T15, and T30: DVAS (VAS [T0]
À VAS [Tx]) (mean F 95% confidence interval). There was no
study. Statistical analysis was performed using Statview difference between the 2 groups.
Software (StatView version 5; Abacus Concepts, SAS
Institute, Berkeley, Calif). A P value of less than .05 was
considered statistically significant. significantly fewer morphine boluses in the K group than
those in the P group (Table 2).
The VAS score was not significantly different between
3. Results groups K and P at T0 and T30 (Table 2). Evolution of
3.1. Patient characteristics the VAS score variation (DVAS [Tx], defined as VAS
[T0] À AS [Tx]) was not significantly different between
Between January 01, 2004, and June 30, 2005, seventy- the groups (Fig. 2). At T30, 20 patients (61%) of the
three patients were enrolled in the study (Fig. 1). Seven K group had a VAS score not exceeding 30/100 vs
patients (5 in the K group and 2 in the P group) were 13 patients (41%) of the P group, representing a nonsignif-
withdrawn from the analysis because of incomplete data or icant difference ( P = .2).
disrespect of study protocol. One patient was excluded
because of an anaphylactoid reaction after antibiotic 3.3. Secondary outcome
injection in the P group. Thus, data from 65 patients were Satisfaction of patients was not significantly different
completed and analyzed, 33 in the K group and 32 in between the 2 groups. There were no differences between
the P group. groups with regard to blood pressure, heart rate, respiratory
Baseline characteristics were similar between the rate, or oxygen saturation at T0 and T30 (Table 3). The
2 groups (Table 1). incidence of neuropsychological adverse effects was signif-
3.2. Primary outcome icantly greater in the K group, with hallucinations (n = 4),
dizziness (n = 6), diplopia (n = 2), and dysphoria (n = 6),
At T30, morphine consumption was significantly lower whereas there was only 1 case of dysphoria in the P group.
in the K group than that in the P group, corresponding to Some patients had 2 or more symptoms.
Table 2 Comparison of morphine requirements, number of morphine boluses, VAS, and patient satisfaction between groups K and P
K group P group P
(n = 33) (n = 32)
Morphine requirements (mg d kgÀ1, mean [95% CI])
T0 0.099 (0.097-0.102) 0.096 (0.0917-0.100) .2
T30 0.149 (0.132-0.165) 0.202 (0.181-0.223) b.001
No. of morphine boluses (median [interquartile range]) 1.0 (0.0-2.0) 2.3 (1.8-3.8) b.0001
VAS (mean [95% CI])
T0 80.4 (75.6-85.2) 80.7 (75.8-85.6) NS
T30 34.1 (25.6-42.6) 39.5 (32.4-46.6) NS
Patient satisfaction
T30 (n [%]), excellent or good 18 (56) 22 (69) 0.3
NS indicates not significant; CI, confidence interval.

5. Management of severe acute pain in emergency settings 389
Table 3 Comparison between groups K and P for clinical
results were similar whatever their designs, namely, that
parameters and adverse effects small-dose ketamine reduced morphine requirements and
pain intensity [5,6,12]. Weinbroum [12] evaluated the
Parameters K group P group P
effects of postoperative coadministration of small doses of
(n = 33) (n = 32)
ketamine (0.250 mg d kgÀ1) and morphine on pain intensity
Heart rate in surgical patients who complained of pain of at least 6/10
(beats/min, mean F SD)
on a VAS despite more than 0.1 mg d kgÀ1 of IV morphine
T0 87 F 15 81 F 18 .3
T30 82 F 14 78 F 15 .5
administration within 30 minutes. This study demonstrated
Systolic blood pressure that a single dose of 0.250 mg d kgÀ1 of ketamine plus
(mm Hg, mean F SD) 0.015 mg d kgÀ1 of morphine provided analgesia in 68% of
T0 139 F 17 139 F 21 .9 patients compared with only 3.5% of patients who received
T30 136 F 20 133 F 20 .5 0.030 mg d kgÀ1 of morphine with saline. Pain intensity
Respiratory rate was still lower in the former group 2 hours after.
(breaths/min, mean F SD) The idea of combining opiates and NMDA receptor
T0 20 19 .6 antagonists is based on numerous experimental data
T30 18 17 .5 suggesting different and complementary mechanisms of
Pulse oximetry action for these 2 classes of analgesic agents [21,22].
(%, mean F SD)
Morphine acts at both the spinal and supraspinal levels. The
T0 99 F 2 99 F 1 .8
T30 99 F 1 98 F 2 .2
spinal action is well documented [23]. It is generally
No. of patients with 7 (21) 2 (6) .2 accepted that opioids reduce the spinal transmission of
Ramsay score z3 (n [%]) nociceptive signals predominantly at presynaptic sites
Adverse effects (n [%]) (ie, reduction in transmitter release from afferent C fibers),
Nausea and vomiting 8 (6) 4 (6) NS although a postsynaptic inhibition of spinal dorsal horn
Neuropsychological 12 (36) 1 (3) .002 nociceptive neurons has also been demonstrated. In contrast,
Itching 1 (3) 1 (3) NS NMDA receptor antagonists preferentially act postsynapti-
Bradypnea 0 1 (3) NS cally by reducing the hyperexcitability (ie, central sensiti-
zation) of spinal nociceptive neurons [21,24]. Thus, the
reduction in nociceptive inputs associated with the reduction
The level of sedation, nausea, vomiting, and itching did in postsynaptic neuronal hyperexcitability may explain the
not differ between the 2 groups (Table 3). synergistic interaction of the 2 drugs [8]. Bossard et al [8]
analyzed the effects of morphine, ketamine, and their
combination on electrophysiological recordings of the
4. Discussion nociceptive flexion RIII reflex in 12 healthy volunteers.
The stimulus response curve of the nociceptive RIII reflex
In trauma patients with severe acute pain, we found that was significantly reduced after injection of a combination of
the association of low-dose ketamine with morphine ketamine and morphine, and they concluded there was a
reduced morphine requirements by approximately 26% synergistic interaction between the 2 drugs. However, we
within 30 minutes. However, pain intensity measured on a found that there were significantly more adverse effects
VAS at T30 was not different between the 2 groups. To our with ketamine. Analgesic doses of 0.150 to 0.500 mg d kgÀ1
knowledge, this is the first study that associated morphine of ketamine have been reported to produce dose- or plasma
with low-dose ketamine for trauma patients with severe concentration–dependent cognitive, perceptual, and mood
acute pain in emergency settings. disturbances, as well as psychotomimetic adverse effects
Gurnani et al [20] studied low-dose ketamine in patients [25,26]. This could be a limitation to the use of ketamine in
with acute pain after musculoskeletal trauma in emergency such settings, especially if the benefit regarding pain is poor.
settings. However, in this study, patients initially received In our study, all adverse effects were weak and brief because
0.250 mg d kgÀ1 of IV ketamine, followed by a constant-rate no one needed treatment and patients’ satisfaction was not
infusion of subcutaneous ketamine (0.100 mg d kgÀ1 d hÀ1) different between the 2 groups. In a review article about
without morphine, whereas the control group received IV perioperative ketamine for acute postoperative pain, Bell
injections of morphine (0.1 mg d kgÀ1 every 4 hours). They et al [27] found that the occurrence of adverse effects was
found that the onset of analgesia was slower in the morphine similar in ketamine- and placebo-treated groups. Especially,
group and that analgesia was more intense in the ketamine 21 of 37 trials specifically stated that there were no
group [20]. Furthermore, the rate of patients requiring psychotomimetic adverse effects. However, in an experi-
supplementary analgesia was lower in the ketamine group. mental study on 12 healthy volunteers, Bossard et al found
However, these patients did not have severe pain. many psychosensory effects (8-10/12 volunteers) after the
Most studies about small doses of ketamine in painful administration of ketamine, morphine, or their combination,
patients were performed in postoperative settings. Their but the incidence was similar between groups.

6. 390 M. Galinski et al.
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