The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery.
ABSTRACT In a randomized, double-blinded study, we evaluated the analgesic effect of ketamine in the management of pain in a surgical intensive care unit after major abdominal surgery. Patients received morphine patient-controlled analgesia with either placebo (Group M) or ketamine (Group K). Morphine was administered with initial loading doses of 2 mg until the visual analog scale (VAS) score was <30 and thereafter with bolus doses of 1 mg and a lockout time of 7 min. Ketamine was administered with an initial bolus of 0.5 mg/kg followed by a perfusion of 2 micro g x kg(-1) x min(-1) during the first 24 h and 1 micro g x kg(-1) x min(-1) during the following 24 h. The 4-h cumulative morphine doses were measured over 48 h. The VAS scores at rest and at mobilization were measured every 4 h during 48 h. A total of 101 patients were enrolled, and 93 were analyzed (41 in Group K and 52 in Group M). VAS scores at rest and at mobilization were similar. The cumulative consumption of morphine was significantly smaller in Group K (P < 0.05). We concluded that small doses of ketamine were a valuable adjunct to opioids in surgical intensive care unit patients after major abdominal surgery.
- [show abstract] [hide abstract]
ABSTRACT: Over the last several years, compelling evidence has accumulated indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. Such neuronal plastic changes may involve activation of central nervous system excitatory amino acid (EAA) receptors, subsequent intracellular cascades including protein kinase C translocation and activation as well as nitric oxide production, leading to the functional modulation of receptor-ion channel complexes. Similar EAA receptor-mediated cellular and intracellular mechanisms have now been implicated in the development of tolerance to the analgesic effects of morphine, and a site of action involved in both hyperalgesia and morphine tolerance is likely to be in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, may be interrelated by common neural substrates that interact at the level of EAA receptor activation and related intracellular events. This view is supported by recent observations showing that thermal hyperalgesia develops when animals are made tolerant to morphine antinociception and that both hyperalgesia and reduction of the antinociceptive effects of morphine occur as a consequence of peripheral nerve injury. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.Pain 10/1995; 62(3):259-74. · 5.64 Impact Factor
- Acta Anaesthesiologica Scandinavica 09/1998; 42(7):747-9. · 2.36 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Ketamine hydrochloride is a well known general anesthetic and short acting analgesic in use for almost 3 decades. The role of the NMDA receptor in the processing of nociceptive input has led naturally to renewed clinical interest in N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. This paper reviews the use and efficacy of low-dose ketamine in the management of acute postoperative pain. The literature was obtained from a computer search of the MEDLINE database from 1966 through December 1998. Studies were included for review if they were randomized, prospective, controlled, double-blind and reported pain scores. We evaluate the clinical literature and discuss the efficacy of low-dose ketamine in the management of acute postoperative pain when administered alone or in conjunction with other agents via the oral, intramuscular, subcutaneous, intravenous and intraspinal routes. Low-dose ketamine is defined as a bolus dose of less than 2 mg/g when given intramuscularly or less than 1 mg/kg when administered via the intravenous or epidural route. For continuous i.v. administration low-dose ketamine is defined as a rate of < or =20 microg/kg per min. We conclude that ketamine may provide clinicians with a tool to improve postoperative pain management and to reduce opioid related adverse effects. The evidence suggests that low-dose ketamine may play an important role in postoperative pain management when used as an adjunct to local anesthetics, opioids, or other analgesic agents. Further research is required in the following areas: (a) dose-finding studies for ketamine as an adjunct to opioids and local anesthetics (b) efficacy and optimal route of administration (c) the role of S(+)-ketamine; (d) the influence of ketamine on long-term outcome such as chronic pain (e) long-term physical and chemical stability of mixtures containing ketamine (f) spinal toxicity of ketamine and (g) effects of low-dose ketamine on cognitive and memory functioning after surgery.Pain 08/1999; 82(2):111-25. · 5.64 Impact Factor
The Effects of Small-Dose Ketamine on Morphine
Consumption in Surgical Intensive Care Unit Patients After
Major Abdominal Surgery
Nicolas Guillou, MD*, Miche `le Tanguy, MD*, Philippe Seguin, MD*, Bernard Branger, MD†,
Jean-Pierre Campion, MD‡, and Yannick Malle ´dant, MD*
*Surgical Intensive Care Unit, †Biostatistical Unit, and ‡Surgical Unit, Ho ˆpital Pontchaillou, Rennes, France
In a randomized, double-blinded study, we evaluated
the analgesic effect of ketamine in the management of
inal surgery. Patients received morphine patient-
controlled analgesia with either placebo (Group M) or
ketamine (Group K). Morphine was administered with
initial loading doses of 2 mg until the visual analog
scale (VAS) score was ?30 and thereafter with bolus
administered with an initial bolus of 0.5 mg/kg fol-
lowed by a perfusion of 2 ?g · kg?1· min?1during the
first 24 h and 1 ?g · kg?1· min?1during the following
24 h. The 4-h cumulative morphine doses were meas-
ured over 48 h. The VAS scores at rest and at mobiliza-
patients were enrolled, and 93 were analyzed (41 in
Group K and 52 in Group M). VAS scores at rest and at
mobilization were similar. The cumulative consump-
tion of morphine was significantly smaller in Group K
(P ? 0.05). We concluded that small doses of ketamine
were a valuable adjunct to opioids in surgical intensive
care unit patients after major abdominal surgery.
(Anesth Analg 2003;97:843–7)
always successful in this context. Indeed, the nociceptive
inputs of patients in the SICU have additional sources
and severities beyond those created by tissue injuries.
Pathologic pain states, mainly hyperalgesia and allo-
dynia, can be induced. As a consequence, morphine may
be less effective despite larger consumption. This toler-
ance to morphine is an early process favored by a para-
doxical nociceptive stimulation; two studies have impli-
cated N-methyl-d-aspartate (NMDA) receptors in these
The anesthetic and analgesic effects of ketamine were
first described 30 yr ago, but its use as an anesthetic has
declined. However, because of research showing that
NMDA receptors have a fundamental role as gates of
perception, ketamine was reconsidered for clinical use.
Indeed, ketamine is the most potent NMDA receptor
urgical intensive care unit (SICU) patients need
effective and sustained pain relief without signifi-
cant side effects, and IV morphine alone is not
inhibitor available, and it binds to a specific phencyclid-
ine site in the NMDA receptor-gated channel, mainly
when the channels are in the “open activated state” (3).
Because NMDA receptors are also implicated in the de-
velopment of tolerance to opioids, the vicious circle be-
tween pathologic pain and tolerance to opioids might be
stopped with ketamine (1,4). With subanesthetic doses, a
specific effect on postoperative hyperalgesia has been
hypothesized (5). Previous clinical studies that have
evaluated the use of ketamine in pain management have
been limited to patients with uncomplicated postopera-
tive courses after planned surgeries (6–15). Moreover,
the routes and timing of administration have varied, and
the results are controversial (6–15). No data are available
about the use of ketamine for pain relief in the SICU.
This prospective, randomized clinical trial was designed
to determine whether the addition of small-dose ket-
amine could reduce the consumption of morphine and
create fewer adverse effects in patients treated in the
SICU after major abdominal surgery.
The protocol was approved by the IRB for human
research of our hospital (Comite ´ Consultatif de Pro-
tection des Personnes dans la Recherche Biome ´dicale
Accepted for publication April 23, 2003.
Address correspondence and reprint requests to Yannick Malle ´-
dant, MD, Service d’Anesthe ´sie-Re ´animation Chirurgicale 1, Ho ˆpi-
tal Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes Cedex 9,
France. Address e-mail to email@example.com.
©2003 by the International Anesthesia Research Society
0003-2999/03 Anesth Analg 2003;97:843–7
de Rennes). The study was prospective, randomized,
and double-blinded and was performed on two par-
allel groups in the SICU of a university hospital. In-
formed consent was obtained from each patient.
Adults older than 18 yr were included if they were
scheduled to have major abdominal surgery and post-
operative management and ventilation in a SICU.
Pregnant women and patients who had severe cardio-
vascular disorders (ejection fraction ?30%) or renal
insufficiency (creatinine clearance ?30 mL/min), or
who were unable to understand the use of patient-
controlled analgesia (PCA), were not included.
The following data were recorded at inclusion: 1)
general characteristics (age and sex), 2) type of sur-
gery, 3) the dose of sufentanil used during surgery,
and 4) severity as assessed by the Simplified Acute
Physiology Score II. The following variables were as-
sessed: the 4-h cumulative morphine doses over the
48-h period; the visual analog scale (VAS) score (16) at
rest and at mobilization, measured by a blinded ob-
server every 4 h; and the Ramsay score for sedation.
The occurrence of side effects (nausea, hallucination,
confusion, and itching) was also measured.
After inclusion criteria were checked and informed
consent was obtained, patients were instructed before
surgery on the use of PCA and the VAS. Each patient
was premedicated with oral midazolam 90 min before
the operation. General anesthesia was induced with
propofol (2 mg/kg) or thiopental (10 mg/kg). Anes-
thesia was maintained with nitrous oxide, isoflurane,
sufentanil, and atracurium. A central venous catheter
and an arterial radial catheter were inserted. Electro-
cardiogram, pulse oximetry, capnography, arterial
blood pressure, and central venous pressure were con-
tinuously monitored. Crystalloids were infused dur-
ing the surgical procedure if the central venous pres-
sure decreased to less than 3 cm H2O, and packed red
bloods cells were administered if the patient’s hemo-
globin level decreased to less than 7.0 g/dL. At the
end of the procedure, no antagonists were used. After
the operation, patients were treated in the SICU for at
least 48 h.
On admission, when the patient was awake, the
nurse in charge of the patient’s care presented the VAS
for pain. The nurse displaced the cursor of the 100-mm
horizontal line from the point “no pain” to the point
“worst pain imaginable,” and the patient notified with
his or her head, or hand, if possible, where the nurse
should stop. The distance in millimeters was noted
between “no pain” and the point designated by the
patient. Next, participants were randomized to receive
morphine PCA with either placebo (Group M) or ket-
amine (Group K). The PCA device contained mor-
phine at a concentration of 1 mg/mL. All patients
received initial loading doses of 2 mg of morphine
until their VAS score was less than 30; they were then
allowed to have bolus doses of morphine (1 mg every
7 min) without any limitation. In Group K, ketamine
was administered separately with an initial bolus of
0.5mg/kgfollowedbyaperfusionof2?g · kg?1· min?1
during the first 24 h and 1 ?g · kg?1· min?1in the fol-
lowing 24 h. In Group M, ketamine was replaced by
saline serum and was administered under the same con-
ditions. Ketamine or placebo was administered simulta-
neously with the titration of morphine. A nurse not
involved in the care of the patients prepared the syringes
of ketamine or placebo. No additional analgesia or seda-
Data are presented as mean ? sd. Statistical analysis
was performed with SAS statistical software (SAS In-
stitute, Cary, NC). Analyses were performed with the
Mann-Whitney U-test (quantitative variables) and ?2
tests (qualitative variables). Forty patients were re-
quired in each group to detect a 25% difference in the
amount of morphine consumption at the 0.05 level of
significance with a power of 0.90. A P value ?0.05 was
considered significant. An analysis of variance (age,
pathology, intraoperative opioid amount, and sex)
was used to compare the cumulative dose of
A total of 101 patients were enrolled in the study
between March 1999 and March 2001. Eight patients
could not be studied (six patients in Group K and two
patients in Group M). Of these, four patients had
inadequate data collection, two needed emergency re-
operation, and two left the SICU before the completion
of the study. Thus, 93 patients were included in the
final results: 41 in Group K and 52 in Group M.
At baseline, there was no significant difference be-
tween the two groups in age, sex, type of operation
performed, dose of sufentanil used during the opera-
tion, or severity (Table 1). During the period of study,
despite localized differences, VAS scores were similar
at rest and at mobilization (Figs. 1 and 2), whereas
morphine consumption was significantly less at all
times in Group K (Fig. 3). Before the start of the study
(i.e., before the administration of the morphine or
ketamine), the VAS score was similar in the two
groups (point T0 of Figs. 1 and 2). It is noteworthy that
the reduction of morphine consumption was larger
during the first hours after admission to the SICU. The
mean morphine consumption at 48 h was 80 ? 37 mg
in Group M and 58 ? 35 mg in Group K, and the
difference in the cumulative consumption of mor-
phine between the two groups was 22 ? 8 mg (P ?
0.05). The mean consumption of ketamine at 48 h was
367 ? 37 mg. The Ramsay score was not different
between the two groups and was maintained between
2 and 3 during the study. The incidence of side effects
was comparable in the two groups (Table 2).
CRITICAL CARE AND TRAUMA
ANALGESIC EFFECT OF KETAMINE
GUILLOU ET AL.ANESTH ANALG
Pain management is a critical problem in SICU pa-
tients (17,18). IV PCA with morphine is convenient.
However, prolonged exposure to large doses of opi-
oids has side effects. Our study aimed to determine
whether ketamine has a significant morphine-sparing
effect. The main finding of this study was that a
small dose of ketamine in combination with mor-
phine allowed a significant reduction in morphine
consumption in SICU patients after major abdomi-
Many factors may account for this beneficial effect.
SICU patients experience prolonged noxious stimuli
caused by the inflammation reaction of damaged tis-
sues and also created by the monitoring environment,
therapeutic devices, and nursing care. In this context,
central sensitization to pain may take place despite the
use of adequate doses of opioids. The activation of
NMDA receptors, marked by the development of hy-
peralgesia and allodynia, is critical in this evolution
(1,2,19). In this context, ketamine, the most potent
NMDA receptor inhibitor, has been used in the post-
operative period. Stubhaug et al. (12) have shown that
Table 1. Demographic Data, Type of Surgery Performed, Intraoperative Dose of Sufentanil, and Severity
(n ? 41)
60 ? 16
(n ? 52)
60 ? 15
Type of surgery (%)
Intraoperative sufentanil dose (?g)*
149 ? 64
30 ? 7
144 ? 58
31 ? 8
SAPS ? Simplified Acute Physiology Score.
* Values are expressed as mean ? sd.
Figure 1. Visual analog scale score at rest during the 48-h study.
Black column ? Ketamine group; white column ? Morphine group;
ICU ? intensive care unit. *P ? 0.05.
Figure 2. Visual analog scale score at mobilization during the 48-h
study. Black column ? Ketamine group; white column ? Morphine
group; ICU ? intensive care unit. *P ? 0.05.
Figure 3. Cumulative postoperative patient-controlled analgesia
(PCA) morphine consumption. Black column ? Ketamine group;
white column ? Morphine group; ICU ? intensive care unit. * P ?
Table 2. Incidence of Side Effects in the Two Groups
(n ? 41)
(n ? 52)
CRITICAL CARE AND TRAUMAGUILLOU ET AL.
ANALGESIC EFFECT OF KETAMINE
small doses of ketamine administered before surgery
(0.5 mg/kg) and until 72 hours after surgery (2
?g · kg?1· min?1during the first 24 hours and 1
?g · kg?1· min?1thereafter) significantly reduce the
area of punctuate hyperalgesia surrounding the sur-
gical incision compared with adequate opioid treat-
ment alone. A larger consumption of morphine was
observed in the placebo group. Some authors have
found a more frequent incidence of nausea, vomiting,
and use of antiemetics in placebo groups (6,10).
However, some aspects of the use of ketamine are
controversial (5). Some authors advocate preemptive
analgesia, and in this context the objective is to pre-
vent a massive barrage of afferent impulses from
reaching the spinal cord and causing a central sensi-
tization (20). Others consider that an activated open
state of NMDA receptors is required for an optimal
effect of ketamine (3). Clinical trials can be broadly
divided into those focusing on a preemptive effect and
those using ketamine as a postoperative analgesic. In a
nondouble-blinded study performed in patients un-
dergoing abdominal surgery, these two strategies ap-
peared to lead to differences in the amount of cumu-
lative and incremental postoperative morphine, with a
40% larger opioid-sparing effect for preemptive anal-
gesia (8). However, the amount of ketamine adminis-
tered was different between the two groups (8). In our
study, ketamine was started on arrival in the SICU
and then administered as a continuous infusion over
48 hours. We found a 25% reduction in opioid con-
sumption in patients who received ketamine. A 50%
opioid-sparing effect was even reported by Adriaens-
sens et al. (6), who used a similar methodology in
patients undergoing abdominal surgery. Such a dis-
crepancy may be explained by the fact that in our
study, analgesia was started regardless of VAS score;
in Adriaenssens et al.’s (6) study, analgesia was not
administered until a VAS score of 40 was reported by
Optimal dosage is another controversial area. In
Adriaenssens et al.’s study, the infusion rate for pa-
tients allocated randomly to receive ketamine was
calculated by using a pharmacokinetic-computed sim-
ulation and was set to produce a theoretical plasma
analgesic concentration of 100 ng/mL. After the ad-
ministration of an initial loading dose, an infusion rate
of 2.5 ?g · kg?1· min?1was sustained for 48 hours.
The affinity of ketamine for NMDA receptors is more
than an order of magnitude higher than that for
?-receptors and is several-fold higher than that for
monoamine transporter sites or other non-NMDA re-
ceptors. This suggests that the smaller the dose, the
more selective the ketamine interaction with NMDA
receptors. Our dosage schedule (2 ?g · kg?1· min?1
for 24 hours and then 1 ?g · kg?1· min?1for another
24 hours) induces very small serum concentrations of
ketamine without any sign of accumulation, such as
that demonstrated by Stubhaug et al. (12). With these
very small doses (i.e., ?10 mg/h), a specific effect on
allodynia and hyperalgia is compatible with the ab-
sence of psychotic effects. In this context of very small
doses, some authors have evaluated ketamine in PCA
devices (13–15). Results are contradictory, and the
analysis of these studies is made difficult by differ-
ences in the preoperative and postoperative manage-
In our study, the profile of morphine consumption
over time was as expected, i.e., an initial 50% smaller
morphine consumption in Group K due to the initial
loading dose of ketamine and then a sustained 25% to
30% opioid-sparing effect. We were unable to demon-
strate a consistently increasing difference in morphine
consumption between the two groups. Tolerance to
opioids does not seem to be counterbalanced by
The activation of NMDA receptors in the central
nervous system is seen as a mechanism involved in
the adaptive changes underlying both tolerance to
opioids and delayed hyperalgesia. It has been sug-
gested that activation of opioid receptors leads to pro-
tein kinase C-mediated activation of NMDA receptors.
Rapid development of acute opioid tolerance is well
established in animals, and the amount of tolerance
that results from various opioids appears similar.
However, tolerance develops faster in response to
short-acting analgesics such as alfentanil or remifen-
tanil (21,22). Attenuation of the development of acute
tolerance to opioids by ketamine has received specific
attention (23). This property has been demonstrated in
clinical and experimental models when ketamine was
administered before the opioid infusion. However, in
most studies, patients received alfentanil. In our
study, because of the extensive abdominal surgery
with an immediate postoperative SICU admission,
sufentanil was administered during the surgery.
Despite a stable reduction in morphine consump-
tion, the patients in Group K showed a tendency for
less pain at rest. Ketamine produced pain relief supe-
rior to that of placebo during mobilization from the
supine to the sitting position; a significant level was
obtained three times. Whether these differences are
clinically relevant can be debated because of a low
VAS score at these times (24).
An objective of our study was to determine whether
ketamine was able to reduce the side effects of opioids,
particularly nausea. Unlike some authors who re-
ported a beneficial effect, we did not observe any
significant difference between the two analgesic regi-
mens. As demonstrated in many studies, the incidence
of psychomimetic effects and cognitive impairment
was negligible at small doses.
In conclusion, the administration of small doses of
ketamine as an adjunct to morphine may be a valuable
strategy for pain management in SICU patients. This
CRITICAL CARE AND TRAUMA
ANALGESIC EFFECT OF KETAMINE
GUILLOU ET AL.ANESTH ANALG
strategy may effectively circumvent some of the prob-
lems with the use of morphine. Moreover, in this
context, a multimodal approach to pain control could
provide increased activity against pathologic pain
states. However, further investigations are warranted
to determine the effect of ketamine on tolerance to
opioids and to confirm a sustained action in case of
prolonged exposure to opioid analgesics.
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