A Single Small Dose of Postoperative Ketamine Provides

Rapid and Sustained Improvement in Morphine Analgesia in

the Presence of Morphine-Resistant Pain
Avi A. Weinbroum,

MD

Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center, and the Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel

It is a common clinical observation that postoperative

pain may be resistant to morphine. The analgesic potentials of ketamine have also been well documented. In
this study, we evaluated the effects of postoperative coadministration of small doses of ketamine and morphine on pain intensity, Spo2, and subjectively rated
variables in surgical patients who underwent standardized general anesthesia and complained of pain (6 of
10 on a visual analog scale [VAS]) despite 0.1 mg/kg
of IV morphine administration within 30 min. Patients
randomly received up to three boluses of 30 g/kg of
morphine plus saline (MS; n 114) or 15 g/kg of morphine plus 250 g/kg of ketamine (MK; n 131) within
10 min in a double-blinded manner. The MS groups

he common occurrence of surgical patients perceiving pain intensively, despite the postoperative administration of ample amounts of IV morphine, suggests a failure of sustained effectiveness.
Large opioid dosages were shown to be hazardous to
the awakening patient because of potential respiratory
and hemodynamic depression. Supplementation with
rescue analgesics can compensate for the unsatisfactory effect of the primary antinociceptive drug, but
they too might evoke adverse effects. There is evidence to suggest that the lack of effectiveness of postoperatively administered morphine is due to the activation of the N-methyl-d-aspartate (NMDA) receptors
(1). If not effectively inhibited in time, the process may
evolve into a complex change in neural plasticity,
resulting in central sensitization and severe pain (1).
Insofar as surgery and opioids share NMDA receptor
activation, adequate blockade of these receptors before
Accepted for publication November 6, 2002.
Address correspondence and reprint requests to Avi A.
Weinbroum, MD, Post-Anesthesia Care Unit, Tel Aviv Sourasky
Medical Center, Weizman St., Tel-Aviv 64239, Israel. Address e-mail
to draviw@tasmc.health.gov.il.
DOI: 10.1213/01.ANE.0000048088.17761.B4
2003 by the International Anesthesia Research Society
0003-2999/03

pain VAS scores were 5.5 1.18 and 3.8 0.9 after 10
and 120 min, respectively, after 2.52 0.56 injections,
versus the MK groups VAS scores of 2.94 1.28 and
1.47 0.65, respectively (P 0.001), after 1.35 0.56
injections (P 0.001). The 10-min level of wakefulness
(110 VAS) in the MS group was significantly (P
0.001) less (6.1 1.5) than the MK groups (8.37 1.19).
Spo2 decreased by 0.26% in the MS group but increased
by 1.71% in the MK patients at the 10-min time point (P
0.001). Thirty MS versus nine MK patients (P 0.001)
experienced nausea/vomiting; nine MK patients sustained a 2-min light-headed sensation, and one patient
had a weird dream after the second drug injection.
(Anesth Analg 2003;96:789 95)

incision (as shown by dextromethorphan) (2) might benefit the patient by evoking attenuation of pain and secondary hyperalgesia, morphine consumption-sparing effect, and amelioration of several subjective variables.
Ketamine, a noncompetitive NMDA receptor antagonist
like dextromethorphan, was recently shown to enhance
opioid-induced antinociception (1). Furthermore, animal
studies have indicated that ketamine reduces hyperalgesia and prevents the induction of opioid tolerance (3,4).
Similarly to dextromethorphan (3), a marked decrease in
opioid consumption and in pain intensity accompanied
continuous IV infusion (5,6) or epidural (7,8) coadministration of ketamine and opioids.
Because analgesic doses of ketamine alone (500 g/
kg) have been reported to produce dose-dependent antinociception (4,9), associated, however, with cognitive
and mood disturbances (10 12), it was hypothesized
that the combined administration of small-dose ketamine and morphine (MK) would promptly reduce pain
perception even in patients who already had severe pain
that was nonresponsive to morphine, reduce morphine
requirements, ameliorate wakefulness and feelings of
well-being, and, at the same time, minimize ketamineand morphine-related side effects.
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Methods
Patients with ASA physical status I to III, scheduled for
elective surgery from January to March 2002, were recruited for this randomized, double-blinded study. They
gave written, informed consent approved by our human
studies committee before undergoing abdominal general
surgery, orthopedic surgery (knee replacement and disk
surgery were excluded), or transthoracic lung biopsy or
wedge resection under general anesthesia during the
morning prime shift. Exclusion criteria included morbid
obesity; disturbances of the central nervous system;
chemical substance abuse; chronic pain; cardiovascular,
hepatic, renal, or psychiatric diseases; age younger than
18 yr; and noncoherence.
General anesthesia was administered by the same
team and consisted of IV sodium thiopental
23 mg/kg for induction, rocuronium infusion to facilitate tracheal intubation and obtain muscle relaxation, fentanyl 23 g/kg for intraoperative analgesia,
and nitrous oxide/oxygen (2:1 L) enriched with isoflurane as deemed necessary by the attending anesthesiologist. All patients had volume-controlled ventilation. Neuromuscular relaxation was not reversed
pharmacologically at the end of surgery: complete and
normal recovery of neuromuscular activity was based
on normal train-of-four and clinical criteria (ability to
lift the head for 10 s, satisfactory hand-grasp strength,
adequacy of respiratory rate, and normal ETco2) (2).
No regional anesthesia was used in any of the
patients.
While recovering in the postanesthesia care unit
(PACU), all patients routinely received morphine IV
(per patient request) consisting of 2-mg increments
every 4 5 min until pain was relieved. Patients who
were given at least 100 g/kg of morphine within a
25- to 30-min period but still complained of pain (6
of 10 on a visual analog scale [VAS; see below]), whom
the attending physician found in an acceptable cognitive state (15 in the Mini-Mental State Examination
[MMSE]; see below), or who rated themselves not
sedated (5 of 10 on a VAS) were randomly enrolled
into one of the two treatment protocols on alternate
days. A cutoff score of 6 of 10 on a pain VAS was
chosen on the basis of previous experience in acute
pain control, where a 4 of 10 VAS expressed sustained
but not severe pain (2,13). Drug injections consisted of
30 g/kg of morphine plus saline (group MS) or 15
g/kg of morphine plus 250 g/kg of ketamine
(group MK). Patients were given up to three such IV
boluses either until the pain VAS was 4 of 10 or
10 min had passed. An anesthesiologist who did not
participate in the study prepared the separate syringes. If pain was not attenuated with either regimen,
a rescue dose of IM diclofenac 75 mg was given. The
effect of a subanesthetic dose of ketamine plus saline

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was not tested for ethical reasons (ineffectiveness per

se) (14).
Before starting treatment, the attending physician
evaluated the patients cognitive state by using the
MMSE (from 0 to 30) (15,16) or a sedation scale. The
attending nurse, who was blinded to the drug assignment, assessed the variables listed below for each
patient during his or her entire stay in the PACU. VAS
scores were assessed by using the 10-cm chiroscience
pain gauge every 5 min for the first hour and every
15 min afterward.
1. Subjective pain intensity was graded on a selfrating VAS, graded as no pain 0 and by
worst possible pain 10.
2. The patients subjective level of wakefulness was
assessed by a self-rated VAS from 1 heavily
sedated to 10 fully awake.
3. Subjective feelings of well-being were recorded
by a VAS of 1 sad and gloomy to 10 happy
and content.
If patients were asleep, they were awakened to obtain their rating; the data of a patient unable to cooperate were excluded from the study from that time
onward.
Vital signs included noninvasive blood pressure, a
five-lead electrocardiogram, respiratory rate, and fingertip pulse-derived oxygen saturation (Spo2) (Cardiocap; Datex, Helsinki, Finland) on air. An Spo2derived value of 92% under 40% oxygen by face mask
was the lower limit for inclusion in the study. Untoward effects (e.g., nausea, vomiting, or any distress)
were recorded by the nurse and treated if deemed
necessary by the attending physician, who was also
blinded to group assignment (e.g., metoclopramide
10 mg IV for nausea or vomiting). The patients were
kept for observation for an additional hour after the
end of the 1-h study period; on-ward diclofenac use
and side effects were later recorded.
The analyses were performed at the Statistical Laboratory of the School of Mathematics, Tel-Aviv University, by using the SPSS Release for Windows, Version 9 (SPSS Inc., Chicago, IL). The demographic data
(age and weight) and background characteristics
(amounts of morphine used before test drug administration, MMSE, VAS scores, and vital signs) of the two
study groups were compared by using Students
t-test. Sex and group distribution of the type of procedure and the incidence of the side effects were analyzed with the Pearson 2 test. The numbers of injections of the test drugs between the groups and among
the surgical subgroups were evaluated with the 2
test; the mean number of injections per group was
assessed with Students t-test. All physiological variables during the observation period in the PACU were
analyzed with one-way analysis of variance with repeated measures. Analyses of PACU and on-ward use

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of diclofenac and the use of metoclopramide were

performed with Fishers exact test. All values are expressed as mean sd, with significance defined as
P 0.05.

Results
During the study period, two-hundred-forty-five
(22%) (114 MS and 131 MK recipients) of 1088 eligible
surgical patients fulfilled study entry criteria. The demographic and surgical data were similar between the
two study groups (Table 1). All baseline vital signs,
patients self-rated pain-intensity scores, and levels of
wakefulness and feeling before the study were similar,
as were the MMSE scores (Figs. 13, Table 2) and the
amounts of morphine used (data not shown).
The amounts of analgesics that were requested by
the patients to alleviate pain were found to be associated with the drug regimen. They were significantly (P
0.001) less for the MK compared with the MS subjects, with the former sufficing with 35% of the total
amount of morphine used by the latter (Table 2). In
addition, the MS patients received almost twofold the
number of injections (P 0.001) and threefold the
diclofenac (P 0.002) administered to the MK patients
for pain control. Furthermore, whereas 63 of the 114
MS patients received 3 injections, 89 of the 131 MK
patients requested only 1 injection (Table 2). The numbers of injections within the surgical subgroups
showed the same trend as for the entire cohort (data
not shown). Finally, a similar number of patients in
each group used the rescue drug in the ward during
the following 24 h (Table 2).
The subjectively evaluated pain intensity during the
2-h PACU stay was significantly lower for the MK
patients compared with their MS counterparts (P
0.001) despite the larger amounts of morphine administered to the latter group. There was an immediate
(10 min) significant decline in pain intensity in the
MK patients, compared with only a slight attenuation
in the VAS of the MS groups (P 0.01). Additionally,
there was evidence of a drug time interaction (P
0.001), indicating that the initial antinociceptive effect
of MK continued over time (Fig. 1).
The patients subjectively rated wakefulness and
feelings of well-being (Fig. 2, top and bottom) and
indicated that the administration of MK was associated with better scores (P 0.001) than those with MS.
Although the levels of the two variables in the MK
group improved significantly within the first 10 min of
treatment (P 0.01), the MS patients scores deteriorated somewhat. Improvement in these two self-rated
variables in the MK patients continued over time,
indicating an overall (drug time effect; P 0.001)
better and sustained effect of MK on each variable
throughout the observation period compared with

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MS. MMSE scores at 30 min after the injections were

much better in the MK than in the MS patients (Table
2), as they were at the end of the observation period
(data not shown).
Respiratory rates and Spo2 levels also appeared to
be affected differently by the two drug protocols. Respiratory rates in the MK patients increased more than
the MS patients during the initial 10-min period of
drug administration (P 0.05; drug effect); they then
stabilized, indicating more efficient respiration in the
MK group (P 0.001, drug time effect; Fig. 3).
Fingertip oximetry on air was also maintained better
in the MK than in the MS individuals (P 0.001): it
increased in the former within the first 15 min after
drug administration and reached a maximal gain of
2.47%, whereas Spo2 levels in the MS patients decreased by 0.26% (P 0.01; drug effect). Spo2 started
to increase in the MS patients only 25 min after study
onset but lagged behind the MK groups oximetry
values (P 0.001; drug time effect). Thirty minutes
after the drug injections, the heart rate, blood pressure, and ETco2 in the MK patients were similar to the
preoperative values; the MS patients required almost
60 min to reach such levels (data not shown).
The MS group had significantly more side effects (P
0.001) than the MK group (Table 2); all were short
lived. Forty-two incidences (a rate of 38%) of postoperative nausea and/or vomiting (PONV) were recorded among the MS patients both in the PACU and
on the ward, compared with 16 (12%) among the MK
patients (P 0.001). The rate of metoclopramide use
was 5:1.1 (P 0.01) in the MS and the MK patients,
respectively. Nine MK patients versus no MS patients
(P 0.001) described a sensation of light-headedness,
which lasted 12 min after a second injection of MK; it
disappeared spontaneously. At no time did patients
report hallucinations; one patient described an unpleasant dream immediately after the second dose of
MK. None of these ketamine-attributable symptoms
recurred in the 24-h follow-up period.
None of the patients in either group was kept in the
PACU for more than the protocol period, and all were
discharged to the ward in accordance with PACU
regulations. All of the study patients were discharged
home uneventfully in accordance with departmental
discharge policies.

Discussion
This study demonstrated that IV administration of a
combined small dose of MK promptly and satisfactorily resolved pain that had been unresponsive to IV
morphine, whereas a threefold dose of MS only partially attenuated it. Pain intensity was still less in the

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Table 1. Patient Demographic and Surgical Data (mean sd)

Variable

MS (n 114)

MK (n 131)

P value

Age (yr)
Weight (kg)
Male/female
Surgery type (GS/ORT/THX)
Duration of surgery (min)

53 19
69 15
60/54
43/49/22
101 37

53 20
67 12
72/59
55/57/19
95 22

0.9
0.1
0.51
0.35
0.3

MS morphine plus saline; MK morphine plus ketamine; GS general surgery; ORT orthopedic procedures; THX transthoracic lung biopsy or wedge
resection.

Figure 1. Self-rated (by a 0 10 visual analog scale [VAS]) pain

intensity (mean sd). *P 0.001 between the groups (by analysis
of variance).

Figure 2. Self-rated levels (by a 0 10 visual analog scale [VAS]) of

awakening (top) and feelings of well-being (bottom) (mean sd). *P
0.001 between the groups (by analysis of variance).

former group after two hours. A single dose of 250

g/kg of ketamine plus 15 g/kg of morphine provided antinociception in 89 of the 131 MK patients,
compared with only 4 of the 114 MS patients who
received morphine 30 g/kg with saline. Sixty-three
MS patients needed the maximal three injections compared with only five in the former group; diclofenac
was used threefold more by MS patients than MK
patients during their stay in the PACU. Additionally,

Figure 3. Nurse-assessed respiratory rate (top) and fingertipderived arterial blood saturation on air (Spo2) (bottom) (mean
sd). *P 0.001 between the groups (by analysis of variance).

whereas hemodynamic and respiratory variables remained depressed in the MS group for 30 minutes,
ketamine coadministration was associated with an immediate increase in Spo2, which remained higher than
in the MS group throughout the observation period.
These objective effects were associated with an increased self-rated level of wakefulness, better feelings
of well-being and a better cognitive state, minimal
incidence of PONV, and negligible ketamine-related
side effects.
If given alone, ketamine at small doses (250 g/kg
IV) might produce subanalgesia that would last a few
minutes during the large plasma concentrations, immediately after injection. Whereas the plasma half-life
of ketamine is 15 minutes, the analgesic effect of our
MK was clearly evident throughout the 120-minute
observation period, i.e., more than seven plasma halflives and twice that which was reported earlier (5,17).
The dose and drug combination used in this study
allowed for an immediate and short-lasting reduction
in pain and in morphine consumption. In a recent
study by Guignard et al. (18), the desfluraneremifentanil anesthesia that was supplemented with
small-dose ketamine led to a morphine-sparing effect
persisting up to 24 hours, much longer than the pharmacological actions of ketamine alone. On the basis of

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Table 2. Immediate and Late Postoperative Analgesic Consumption and Incidence of Side Effects (Mean sd or
Absolute Numbers)
Variable

MS (n 114)

MK (n 131)

P value

Pretreatment morphine use (mg)

Totala morphine use (mg/kg)
Number of injections
Distribution of injections (1/2/3)b
Pretreatment MMSE
30-min MMSE
Diclofenac use in PACU
Diclofenac use in ward
Side effects in PACU
PONV
Light-headed sensation
Bad dreams
Hallucinations
Side effects in ward
PONV
Light-headed sensation
Bad dreams
Hallucinations

7.8 2.1
1.21
2.52 0.56
4/47/63
16.6 1.2
19.3 2.4
17
70

7.52 2.7
0.42
1.35 0.56
89/37/5
16.3 1.9
27.1 1.7
5
76

0.07
0.001
0.001
0.001
0.1
0.001
0.002
0.2

30
0
0
0

9
9
1
0

0.001
0.001
0.24

12
0
0
0

7
0
0
0

0.15

MS morphine plus saline; MK morphine plus ketamine; MMSE Mini-Mental State Examination; PACU postanesthesia care unit; PONV
postoperative nausea and vomiting.
a
The total amount of morphine administered before and during the study period.
b
The number of patients who received one, two, or three injections in each study group.

these and other data, it cannot be concluded that the

extent to which adding small-dose ketamine to a general anesthetic or opioid regimen attenuates postoperative pain is based only on the duration of action of
the selected analgesics, but rather on some yet-to-beevaluated long-lasting effects of ketamine.
Ketamine may produce antinociception through
various mechanisms of action: interaction with spinal
receptors, NMDA receptor antagonism, and activation of the descending pain inhibitory monoaminergic
pathways (19), which is expressed by 2-adrenoceptors
at the spinal level (20). The affinity of ketamine for
NMDA receptors is more than an order of magnitude
higher than that for receptors (21) and is several-fold
higher than that for the monoamine transporter sites or
other non-NMDA receptors (i.e., the receptor) (22).
This would suggest that small doses of the drug, as used
herein or elsewhere (17), could interact more selectively
with NMDA receptors rather than with the receptor
and explains its effective antinociception. Indeed, antinociception generated by IV ketamine 300 g/kg in humans was not reversed by naloxone (21), which suggests
that the -receptor agonistic activity was not involved
in pain control. Nevertheless, although morphine
and other opioids produce antinociception through
-receptor agonist activity and the activation of monoaminergic descending pathways at the spinal level (20),
they also activate NMDA receptors, resulting in hyperalgesia and the development of tolerance to opioids (1).
Thus, if this was the type of tolerance or resistance involved in the sustained and severe postoperative pain in
our patients, then it could theoretically be overcome by

small doses of MK either via central desensitization or

via antagonization of NMDA activity.
A MEDLINE search revealed that these findings of
prompt abolition of pain resistance to morphine by
one bolus injection of MK in 65% of the treated
patients had not been reported. The remarkable rapid
and sustained effect of ketamine is more than additive
when the total doses of morphine in both groups are
compared (1:13), supporting the contention of an interaction of ketamine with NMDA receptors that
could have been activated by either or both of the
perioperative nociceptive inputs and by the administration of morphine. Previous studies of my group
(2,13) showed that the concomitant use of morphine
with dextromethorphan, a noncompetitive NMDA antagonist, generated an 50% reduction of the consumption of postoperative morphine, further supporting such a mechanism of action.
Ketamine infusion (100 500 g/kg) (23) or a bolus
injection of (S)-ketamine (50 200 g/kg) (9,22) produced drowsiness. In this study, wakefulness was increased in the MK group. The former findings can be
attributed to ketamines being administered by infusion, and its rapid decay of the plasma concentration after the bolus injection(s) did not evoke sedation
(17). Finally, sedation had also been less in the
dextromethorphan-treated morphine-administered patients compared with those who were given placebo plus
morphine in my groups previous studies (2,17).
Heart rate and blood pressure are negatively affected by large morphine doses given within a short
lapse of time, but, most importantly, respiratory rate,

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patency of the upper airway, oxygenation, and adequate

ventilation may drastically worsen because of the increased sedation and the patients loss of lucidity. Such
precarious situations were observed in several MS patients, in whom no vital signs were ameliorated even
when pain was partly controlled, presumably because of
the large morphine consumption.
The concomitant administration of small-dose MK
improved the Spo2 level, the clinically most reliable
and rapid indicator (510 seconds) of adequate respiration. This could be because less pain would enable
the patient to breathe more deeply, cough better, and
maintain adequate minute ventilation with only negligible upper-airway obstruction compared with
heavily sedated postoperative patients. Because MS
did not control pain as did MK, saturation in the
former remained lower as well. In addition, ketamine
characteristically increases respiratory muscle tone
(24), which could have also contributed to airway
patency and better Spo2, even though a subanesthetic
dose of ketamine was applied. All the abovementioned reasons could also have contributed to the
maintenance of a normal respiratory rate in the MK
group (25).
The negligible incidence of PONV in the MK group
appears to be related to the smaller dose of morphine
consumed by the MK group. Although it is true that
PONV is a multifactorial phenomenon, the threefold
amount of morphine consumed in the MS group was
probably a causative factor. Short-lived hallucinations
are the most common side effects of ketamine: the one
case of an unpleasant dream in the current cohort is
much less than previously reported (16), possibly because of the smaller total dose of ketamine. White (26)
had reported that more than one third of the patients
may experience unpleasant dreams or acute
psychosis-like symptoms that may or may not be associated with hallucinations on emergence when anesthetic doses (13 mg/kg) of ketamine are administered IV. Subanesthetic doses of ketamine impaired
some cognitive function, such as attention, free recall,
and recognition memory, in healthy human volunteers (9,11,23), and larger doses could alter mood
states and produce dose-related impairment of sensory perception or the process of sensory integration
(11,23). There were no changes in cognition, perception, or mood swings in any of our patients even
24 hours after ketamine administration. This may be
because the dose used in this study was in between
the ones used in the above-mentioned studies and
because the plasma ketamine concentration could be
expected to decline rapidly because of its short plasma
half-life.
In conclusion, the postoperative administration of
concomitant small doses of MK provided rapid and
sustained improvement in pain control; better than
that obtained by morphine alone in patients who had

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received morphine earlier. There was minimal risk for

ketamine-associated side effects, a better level of blood
oxygen saturation, greater wakefulness, and negligible PONV incidence. Large-scale studies are still warranted to confirm these promising results.
Esther Eshkol is thanked for editorial assistance and Dr. Nissim
Marouani for intellectual input. The author also wishes to express
his gratitude to the nursing staff of the PACU for their conscientious
contribution, without which this work would not have been
possible.

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