Eur J Anaesthesiol 2019; 36:8–15

ORIGINAL ARTICLE

Low-dose ketamine infusion reduces postoperative

hydromorphone requirements in opioid-tolerant patients
following spinal fusion
A randomised controlled trial
Kirsten Boenigk, Ghislaine C. Echevarria, Emmanuel Nisimov, Annelise E. von Bergen Granell,
Downloaded from https://journals.lww.com/ejanaesthesiology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3c9CHBlrWfCo30ygl/zhIHTKbZFcAx2VAK+KLlUj41Qc= on 01/31/2019

Germaine E. Cuff, Jing Wang and Arthur Atchabahian

BACKGROUND The current opioid epidemic highlights the
urgent need for effective adjuvant therapies to complement
postoperative opioid analgesia. Intra-operative ketamine infu-
sion has been shown to reduce postoperative opioid con-
sumption and improve pain control in opioid-tolerant patients
after spinal fusion surgery. Its efficacy for opioid-naı̈ve
patients, however, remains controversial.
OBJECTIVE We hypothesised that low-dose ketamine infu-
sion after major spinal surgery reduces opioid requirements
in opioid-tolerant patients, but not in opioid-naı̈ve patients.
DESIGN Randomised placebo-controlled study.
SETTING Single-centre, tertiary care hospital, November
2012 until November 2014.
PATIENTS A total of 129 patients were classified as either
opioid-tolerant (daily use of opioid medications during 2
weeks preceding the surgery) or opioid-naı̈ve group, then
randomised to receive either ketamine or placebo; there
were thus four groups of patients. All patients received
intravenous hydromorphone patient-controlled analgesia
postoperatively.
INTERVENTION Patients in the ketamine groups received a
ketamine infusion (bolus 0.2 mg kg1 over 30 min followed
by 0.12 mg kg1 h1 for 24 h). Patients in the placebo groups
received 0.9% saline.
MAIN OUTCOME MEASURES The primary outcome was
opioid consumption during the first 24 h postoperatively. The
secondary outcome was numerical pain scores during the
first 24 h and central nervous system side effects.
RESULTS Postoperative hydromorphone consumption was
significantly reduced in the opioid-tolerant ketamine group,
compared with the opioid-tolerant placebo group [0.007
(95% CI 0.006 to 0.008) versus 0.011 (95% CI 0.010 to
0.011) mg kg1 h1, Bonferroni corrected P < 0.001]. There
was no difference in hydromorphone use between the opi-
oid-naı̈ve groups (0.004 and 0.005 mg kg1 h1 in the opi-
oid-naı̈ve ketamine and placebo group, respectively,
P ¼ 0.118). Pain scores did not differ significantly between
the opioid-tolerant ketamine group and the opioid-naı̈ve
groups. There was no significant difference in side effects
among groups.
CONCLUSION Postoperative low-dose ketamine infusion
reduces opioid requirements for the first 24 h following spinal
fusion surgery in opioid-tolerant, but not in opioid-naı̈ve
patients.
TRIAL REGISTRATION NCT03274453 with clinicaltrials.
gov.
Published online 14 August 2018

This article is accompanied by the following Invited Commentary:

Mion G. Ketamine stakes in 2018. Right doses, good choices. Eur J Anaesthesiol 2019; 36:1–3.

From the Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University, New York, New York, USA (KB, GCE, EN, AEvBG, GEC, JW, AA)
Correspondence to Arthur Atchabahian, MD, Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University School of Medicine, 301 East
17th Street – Room C2-222, New York, NY 10003, USA
Tel: +1 212 598 6085; fax: +1 212 598 6163; e-mail: arthur.atchabahian@gmail.com

0265-0215 Copyright ß 2018 European Society of Anaesthesiology. All rights reserved. DOI:10.1097/EJA.0000000000000877

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.


Introduction
Postoperative pain management in chronic pain patients
remains a clinical challenge. In the context of the current
opioid epidemic, alternative nonopioid strategies are
urgently needed to complement traditional opioid anal-
gesia in the postoperative period. Spinal fusion patients
often suffer from chronic pain and opioid tolerance,
which makes postoperative pain control difficult. Opioid
side effects such as nausea and sedation impede recovery.
Chronic pain in spinal surgery patients is often of
multifactorial origin.
There is evidence that opioid tolerance can occur in the
dorsal root ganglion via N-methyl-D-aspartate (NMDA)
receptor activation.1,2 Increased synaptic transmission,
or synaptic plasticity, from the dorsal horn neurones that
carry the peripheral pain information to the spinal dorsal
horn neurones can occur in the chronic pain state, and
this form of plasticity has been referred to as central
sensitisation.3,4 Central sensitisation has been shown to be
dependent on NMDA receptor activation. Both short-term
and long-term administration of opioids cause acute opi-
oid-induced hyperalgesia.3 Ketamine, a noncompetitive
NMDA receptor antagonist, has been hypothesised to
counter opioid tolerance and NMDA receptor-mediated
central sensitisation.5,6 In addition, ketamine has been
shown to function as an additive or complementary anal-
gesic when used in combination with opioids in patients
who display opioid tolerance.7–9
Clinical studies have demonstrated reduced postoperative
opioid requirements and improved pain control with sub-
anaesthetic intra-operative ketamine infusions in opioid-
tolerant patients.8,9 In opioid-naı̈ve patients, however, the
benefits of intra-operative and postoperative use of keta-
mine were less convincing.10 Therefore, clinical studies
are needed to clarify the benefit of ketamine in postoper-
ative pain control for opioid-tolerant versus opioid-naı̈ve
patients. Ketamine is currently not approved by the Food
and Drug Administration to reduce opioid requirements.
The aims of our study were to examine whether postoper-
ative ketamine infusion would reduce postoperative
hydromorphone consumption in opioid-tolerant patients
to a greater degree than it did in opioid-naı̈ve patients, and
whether ketamine would improve pain control in opioid-
tolerant patients to a different degree than in opioid-naı̈ve
patients. The primary outcome was 24-h postoperative
hydromorphone consumption and the secondary outcome
was numerical pain scores for the first 24 h. Potential side
effects were also recorded and analysed as additional
secondary outcome measures.
Methods
This prospective, randomised, double-blind, placebo-
controlled, four-arm parallel, single-centre study received
ethical approval (IRB number S12-02202) from the New
York University Institutional Review Board, New York,
Eur J Anaesthesiol 2019; 36:8–15
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Low-dose ketamine for opioid-tolerant spinal fusion patients 9
United States on 8 October 2012. The study was regis-
tered as NCT03274453 with clinicaltrials.gov.
The study was performed at the NYU Hospital for Joint
Diseases, NYU Langone Medical Center, during the
period from November 2012 to November 2014. All
patients gave written informed consent before participat-
ing in the study.
Patients aged 16 to 75, ASA physical status 1 to 3,
scheduled for elective lumbar fusion surgery at two or
more levels under general anaesthesia, were prospec-
tively studied. We defined opioid-tolerant as the daily
use of opioid pain medication (oxycodone, morphine,
hydromorphone, fentanyl, methadone or tramadol) dur-
ing the 2 weeks before surgery. Patients who did not fulfil
that criterion were deemed to be opioid-naı̈ve. Exclusion
criteria were poorly controlled hypertension, severe car-
diac or pulmonary disease, elevated intraocular pressure,
severe hepatic or renal dysfunction, pregnancy, a history
of psychiatric disorder, inability to speak English, inabil-
ity to understand the numerical pain scale or to operate
the patient-controlled analgesia (PCA) pump, and known
allergy to ketamine or hydromorphone.
Patients were allocated to the opioid-naı̈ve or opioid-
tolerant arms as defined above, and subsequently ran-
domised into two groups, for a total of four groups: opioid-
naı̈ve ketamine, opioid-naı̈ve placebo, opioid-tolerant
ketamine and opioid-tolerant placebo. Patients in each
group were randomised to receive either a ketamine
infusion [ketamine bolus 0.2 mg kg1 over 30 min, started
on arrival in the postanaesthesia care unit (PACU), fol-
lowed by a fixed-rate infusion of 0.12 mg kg1 h1 for
24 h], or placebo (identical volume/rate of 0.9% saline).
Randomisation within each group was performed by the
study coordinator using a computer-generated random
number list in a 1 : 1 ratio. Study medication and placebo
were produced according to the randomisation list in
identical and consecutively numbered 250-ml bags.
The pharmacist was not involved in patient care. Infor-
mation about treatment was concealed but available for
unblinding in case of acute complications. During the
entire study period, investigators performing the
postoperative assessments, medical staff (nurse, anaes-
thetist and surgeon) and subjects were blinded to
group allocation.
In all patients, general anaesthesia was induced with
propofol based on patient weight. Rocuronium 0.6 to
1.2 mg kg1 was used to facilitate tracheal intubation.
Anaesthesia was maintained with propofol (variable rate
to maintain bispectral index at a level acceptable for
surgical anaesthesia), desflurane less than 1.5% in a
mixture of air and oxygen, and fentanyl, sufentanil,
hydromorphone or morphine at the discretion of the
anaesthetic staff. Blood pressure was maintained within
 10 Boenigk et al.
20% of baseline and hypotension was treated at the
discretion of the anaesthetic staff with 0.9%
sodium chloride solution, hetastarch, ephedrine and
phenylephrine intravenously.
Most patients received 1 g of intravenous paracetamol at
the end of surgery (Table 2). NSAIDs were not used in
the immediate peri-operative period because of the sur-
geons’ concern that they might impede bone healing
and fusion.
In all patients, postoperative pain treatment during the
first 24 h consisted of standard care of intravenous PCA
with hydromorphone (0.2-mg dose, lockout time 6 min,
maximum rate 2 mg h1), started on arrival in PACU. Pre-
operatively, the patients were educated by the nursing
staff in the use of the PCA pump and the numerical pain
scale (NPS; 0 ¼ no pain, 10 ¼ worst imaginable pain).
Rescue medication of intravenous hydromorphone 0.2
to 0.3 mg as needed was administered by a nurse with the
goal to reduce the NPS to less than 4. Opioid pain
medication was restricted to hydromorphone to allow
for valid comparison between the groups. After 24 h,
PCA was discontinued and all patients were treated
according to the surgical department’s standard regimen.
Diazepam 2 mg was administered intravenously if
needed for severe muscle spasms.
Moderate-to-severe nausea or vomiting was treated
with intravenous ondansetron 4 mg. If ondansetron was
ineffective, intravenous metoclopramide 10 mg was
administered.
All postoperative assessments were performed by the
study investigators or trained nurses blinded to group
allocation. Cumulative hydromorphone consumption was
calculated from 0 to 24 h postoperatively. NPS was
recorded at arrival in PACU, every 30 min during the
first 2 h, and then every 2 h on the ward during the first
24 h after surgery while patients were awake.
The primary outcome was cumulative hydromorphone
consumption during the first 24 h after surgery. Secondary
outcome was NPS in the same time period. We also
recorded central nervous system adverse events during
the same period.
Statistical analysis
In the study by Subramaniam et al.,10 the mean 24-h
cumulative hydromorphone dose used by opioid-depen-
dent patients undergoing major spinal surgery was
19.4 mg, with a SD of 13.6 mg. Based on this, 45 patients
per group would be needed to detect a 30% reduction in
cumulative hydromorphone use in the opioid-tolerant
group treated with ketamine and at least 50% reduction
in the opioid-naı̈ve groups (as per Gottschalk et al.11),
with a power of 80% and a of 0.05. We planned to enrol 50
subjects per arm to allow for possible dropouts. An
interim analysis using the O’Brien–Fleming stopping
Eur J Anaesthesiol 2019; 36:8–15
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boundaries was planned after 50% of the patients in
the opioid-tolerant group were enrolled.12
We tested normality using the Shapiro–Wilk test and Q–
Q plots. Continuous data were compared using one-way
analysis of variance (ANOVA) or the Kruskal–Wallis H
test, as appropriate. The x2 test and Fisher’s exact test
were used for inferences on proportions. A linear mixed
model was used to analyse the effect of ketamine on
cumulative hydromorphone consumption over time
between groups, to accommodate an unbalanced design
(unequal number of subject per group), and missing data
in the repeated-measures design (missing at random).
The covariance structure was chosen based on the Akaike
information criteria and the Bayesian information criteria.
In the presence of a significant interaction term or main
effect, post hoc analyses using Bonferroni correction for
multiple comparisons was used. Since postoperative pain
scores did not follow a multivariate normal distribution,
the analysis was performed using a rank-based repeated
measures ANOVA adjusted for baseline score (immedi-
ately before starting the placebo/ketamine infusion).13
Data are expressed as mean  SEM or median [IQR],
unless stated otherwise. A two-sided P value of less than
0.05 was considered significant. All analyses were per-
formed with STATA/SE version 14.1 (StataCorp LP,
College Station, Texas, USA) and R software version
3.3.2 (R Foundation, Vienna, Austria), according to the
intention-to-treat principle.
Results
A total of 249 patients were assessed for eligibility from
November 2012 to November 2014. Of these, 129
patients were prospectively allocated randomly to groups
(Fig. 1), but only 122 received the intended study inter-
vention. Of those patients who received the study drug,
11 were excluded from the analysis due to incomplete
clinical data (data inaccessible after new Electronic
Health Record system implementation).
The study was stopped after the interim analysis of the
primary outcome variable showed a highly statistically
significant effect on the 24-h cumulative hydromorphone
use between groups (n¼111, P < 0.001; O’Brien–Flem-
ing efficacy boundary P ¼ 0.005).
Baseline characteristics and intra-operative data are
shown in Tables 1 and 2, respectively. One patient in
each group had only one level fused despite having been
initially scheduled for two. Opioid-tolerant placebo
patients had a higher BMI than those in the opioid-
tolerant ketamine group (post hoc analysis using Dunn’s
pairwise comparison). Differences in pre-operative pain
scores and opioid use, using morphine equivalents, were
significant, as expected, between opioid-naı̈ve and opi-
oid-tolerant groups. When comparing only the two opi-
oid-tolerant groups, the pain scores were significantly
different, with the tolerant-placebo group reporting
 Low-dose ketamine for opioid-tolerant spinal fusion patients 11

Fig. 1

Assessed for eligibility

(n = 241)

Excluded (n = 112)
• Not meeting inclusion criteria (n = 99)
• Declined to participate (n = 13)
• Other reasons (n = 0)

Allocated (n = 129)

Allocation

Naïve placebo (n = 38)
Received allocated intervention (n = 36)
Did not receive allocated
intervention (n = 2)
- haemodynamically unstable (n = 1)
- kept intubated at end of surgery (n = 1)
Naïve ketamine group (n = 30)
Received allocated intervention (n = 29)
Did not receive allocated intervention
- surgery cancelled (n = 1)
Tolerant placebo group (n = 32)
Received allocated intervention (n = 32)
Did not receive allocated
intervention (n = 0)
Tolerant ketamine group (n = 29)
Received allocated intervention (n = 26)
Did not receive allocated intervention
(n = 3)
- kept intubated at end of surgery (n = 3)

Follow-up

Lost to follow-up (n = 2) Lost to follow-up (n = 5) Lost to follow-up (n = 4) Lost to follow-up (n = 1)

- incomplete data* (n = 2) - incomplete data* (n = 5) - incomplete data* (n = 4) - incomplete data* (n = 1)

Analysis

Analysed (n = 34) Analysed (n = 24) Analysed (n = 28) Analysed (n = 25)

* Incomplete data : unable to retrieve data due to change in the Electronic Health Record system.

Study flow-chart.

higher scores, but the difference in pre-operative opioid
use did not reach statistical significance.
The time course of the postoperative cumulative hydro-
morphone consumption is shown in Fig. 2. Based on the
analysis, the ‘group’  ‘time’ interaction was statistically
significant (P < 0.001), indicating that the effect of
‘group’ was not the same across all levels of ‘time’
(repeated measures). The contrast analysis of ‘group’ -
 ‘time’ (effects for group at each level of time) showed
that the cumulative hydromorphone use (per kg)
between the opioid-tolerant ketamine and opioid-toler-
ant placebo group became significantly different after
16 h of ketamine infusion (Bonferroni corrected
P ¼ 0.003), a difference that persisted until the end of
the study. No difference was seen between the opioid-
naı̈ve ketamine and placebo groups, or between the opi-
oid-tolerant ketamine and opioid-naı̈ve placebo groups.
Moreover, treating ‘time’ as a continuous variable, the
rate of change (slope) in the cumulative hydromorphone
use per hour was calculated. The rate of hydromorphone
use was 0.004 (95% CI 0.003 to 0.005) and 0.005 (95% CI
0.004 to 0.006) mg kg1 h1 in the opioid-naı̈ve ketamine
and placebo group, respectively (Bonferroni corrected
P ¼ 0.118). The opioid-tolerant ketamine group used
hydromorphone at a rate of 0.007 (95% CI 0.006 to
0.008) mg kg1 h1, which was significantly less than

Table 1 Baseline characteristics

Naı̈ve placebo, nU34 Naı̈ve ketamine, nU24 Tolerant placebo, nU28 Tolerant ketamine, nU25 P
Sex (m/f) 15/19 11/13 14/14 13/12 0.929
Age (years) 56 [45 to 60] 53 [47 to 57] 57 [46 to 61] 55.5 [49 to 63.5] 0.732
Weight (kg) 83 [66.5 to 98.4] 83.9 [66 to 94] 92 [76.7 to 106] 70.3 [61.1 to 87.3] 0.072
Height (cm) 170.2 [161.3 to 178.9] 172.7 [160 to 180.3] 170.2 [160 to 176] 169.1 [161.3 to 175.3] 0.914
BMI (kg m2) 29.9 [24.9 to 33.8] 28.6 [23.3 to 31.2] 31.0 [27.5 to 35.5]a 25.7 [22.3 to 30.5] 0.048a
ASA physical 3/25/6 3/18/3 0/20/8 0/20/5 0.295
status, 1/2/3

a
Data are presented as number or median [IQR]. Tolerant placebo patients had a higher BMI than those in the tolerant ketamine group (post hoc analysis using Dunn’s
pairwise comparison).

Eur J Anaesthesiol 2019; 36:8–15

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 12 Boenigk et al.

Table 2 Anaesthetic characteristics and postoperative care data

Naı̈ve placebo, nU34 Naı̈ve ketamine, nU24 Tolerant placebo, nU28 Tolerant ketamine, nU25 P
Surgical duration (min) 312 [264 to 407] 250 [214 to 355] 355 [292 to 465] 364.5 [239.5 to 418] 0.058
Number of spinal segments 2 [1 to 3] 1 [1 to 2] 2 [1 to 4] 2 [1.5 to 3.5] 0.339
operated
Intra-operative i.v. paracetamol 17/17 16/8 22/6 15/10 0.133
(Y/N)
Intra-operative morphine 1.0 [0.9 to 1.5] 1.1 [0.7 to 1.4] 1.5 [0.9 to 2.0] 1.5 [0.9 to 2.0] 0.128
equivalent (mg kg1)
PACU stay (min) 241 [188 to 354] 197 [161 to 249] 210 [169 to 270] 219.5 [168 to 234] 0.277
Total postoperative 0.13 [0.06 to 0.18] 0.09 [0.05 to 0.15] 0.27 [0.20 to 0.37]a 0.19 [0.16 to 0.24] <0.001
hydromorphone (mg kg1)
Length of hospital stay (days) 3 [3 to 5] 3 [3 to 5] 5 [3 to 6] 4 [3 to 5.5] 0.090

a
Values are number or median [IQR]. i.v., intravenous; PACU, postanaesthesia care unit. Opioid-tolerant placebo group statistically significant compared with all other
groups (post hoc analysis using Dunn’s pairwise comparison).

the rate used by the opioid-tolerant placebo group (‘group’  ‘time’ interaction P ¼ 0.192). There were no
[0.011 mg kg1 h1 (95% CI 0.010 to 0.011), Bonferroni significant differences in side effects among groups
corrected P < 0.001]. (Table 3).
Figure 3 shows the postoperative pain scores in each
group. The analysis, adjusted for baseline pain score, Discussion
showed that only the main effect of ‘group’ was statisti- We found that postoperative ketamine infusion signifi-
cally significant (‘group’ P < 0.001, ‘time’ P ¼ 0.495). The cantly reduces the hydromorphone requirement specifi-
post hoc analysis using Bonferroni correction for the main cally for the opioid-tolerant patients after spinal surgery.
effect ‘group’ showed that the pain scores in the opioid- The opioid-tolerant ketamine group used hydromor-
tolerant placebo group were always higher in magnitude phone at a rate of 0.007 mg kg1 h1, a rate significantly
compared with the other three groups, but the study lower than that used by the opioid-tolerant placebo group
intervention did not affect the postoperative pain profile (0.011 mg kg1 h1) suggesting a strong opioid sparing

Fig. 2

0.4
Cumulative hydroxymorphone consumption (mg kg–1)

Naive ketamine
Naive placebo ***
Tolerant ketamine
0.3 Tolerant placebo

0.2

0.1

0.0

1h 2h 3h 4h 6h 8h 10h 12h 16h 20h 22h 24h

Time

Postoperative cumulative hydromorphone consumption in each group, expressed as mg kg1. Values are shown as mean  SEM. Group  time
interaction P less than 0.001. Post hoc analysis of the interaction showed that cumulative hydromorphone use between the opioid-tolerant
ketamine and opioid-tolerant placebo group became significantly different after 16 h.

Eur J Anaesthesiol 2019; 36:8–15

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 Low-dose ketamine for opioid-tolerant spinal fusion patients 13

Fig. 3

10

8
Numerical pain score

6
Naive ketamine
Naive placebo
Tolerant ketamine
4 Tolerant placebo

0h (arrival) 1h 2h 3h 4h 6h 8h 10h 12h 16h 20h 22h 24h

Time

Postoperative pain scores in each group. Values are shown as mean  SEM. Pain in the opioid-tolerant placebo group was always higher in
magnitude compared with the other three groups, but the study intervention did not affect the postoperative pain profile (main effect of ‘group’
P < 0.001, ‘time’ P ¼ 0.495 and group  time interaction P ¼ 0.192).

effect. However, the hydromorphone consumption of the
opioid-naı̈ve group who were randomised to receive
ketamine was not statistically different from that of the
opioid-naı̈ve group who received placebo. Hydromor-
phone requirement in the opioid-tolerant group on keta-
mine did not differ significantly from that in both opioid-
naı̈ve groups. The postoperative ketamine administration
seemed to readjust pain medication requirements of
opioid-tolerant patients to a range comparable with that
of opioid-naı̈ve patients. The interventions did not affect
the pain score behaviour among groups, even though pain
scores were always highest in the opioid-tolerant placebo
group. One possible reason for a lack of difference in pain
scores may be that patients on PCA self-adjust to a
comfortable level of pain.
Although opioid-related side effects did not differ among
groups, we still believe that these findings are interesting.
This study was conceived as a proof of concept, to
demonstrate the efficacy of ketamine in reducing opioid
requirements in opioid-tolerant patients. Indeed, reduc-
ing the dose of opioid taken without reducing side effects
might not seem like a worthy outcome, but it might lead
to less opioid-related pain sensitisation, lower long-term
opioid use and lower rates of chronic pain and
opioid addiction.
Intra-operative ketamine administration for postoperative
pain has been shown to be beneficial in opioid-tolerant
patients.8,9 In a review of clinical trials and meta-analyses,
Jouguelet-Lacoste et al.14 showed a reduction in opioid

Table 3 Central nervous system side effects

Naı̈ve placebo, nU34 Naı̈ve ketamine, nU24 Tolerant placebo, nU28 Tolerant ketamine, nU25 P
Headache 0 0 0 1 0.431
Confusion 1 0 1 0 1.000
Anxiety 0 1 0 0 0.431
Excessive sedation 0 0 0 1 0.431
Blurred vision 0 1 0 1 0.245

Values are numbers.

Eur J Anaesthesiol 2019; 36:8–15

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 14 Boenigk et al.
consumption by 40%. The primary endpoint of the major-
ity of the studies included in this meta-analysis was opioid
consumption (24 out of 39 studies), whereas the secondary
endpoint was most frequently reduction in pain scores (10
out of 39 studies). Our review of the literature demon-
strated several difficulties in evaluating the usefulness of
ketamine as an adjunct to postoperative pain medication,
for example heterogeneity in operative procedures (inten-
sity of pain depending on the surgery, somatic versus
visceral pain), in patient populations (chronic pain patients
versus patients who do not suffer from chronic pain), in the
divergent modes of ketamine administration (bolus versus
infusion, intra-operative versus postoperative versus a
combination of intra-operative and postoperative infusion)
and finally in differences in concomitantly administered
pain medications (including both opioids and nono-
pioids).10,14–16 Our study was designed to address some
of these difficulties by recruiting from a relatively homo-
geneous surgical population and using a standardised
analgesic protocol. We chose not to use ketamine intra-
operatively as we feared that it would lead to very different
doses of intra-operative opioids used, and thus muddle the
result. Also, surgical procedures of different length could
have led to vastly different total doses of ketamine
being administered.
We hypothesised that several mechanisms in the gener-
ation of postoperative pain determine how well opioids
and ketamine work in the treatment of this pain. Chronic
pain leads to changes in pain processing. These changes
manifest as peripheral and spinal central sensitisation, as
well as disrupted cortical and subcortical processes in the
brain.17–21 Furthermore, chronic pain is known to be
associated with a host of psychosocial comorbidities such
as anxiety and depression.2,22 Opioids are usually pre-
scribed for chronic pain. Chronic opioid use can result in
tolerance and dependence2 as well as hyperalgesia.1 Even
acute opioid administration can alter spinal and periph-
eral nociceptive processing, resulting in opioid-induced
hyperalgesia within a short time period.3,4,23 These
mechanisms of tolerance and sensitisation can rapidly
reduce the opioid benefit for pain control. Central sensi-
tisation and tolerance, meanwhile, are in part mediated in
the dorsal horn neurones as well as in the cortex by
NMDA receptor signalling, and NMDA receptors can
be antagonised by ketamine.24–27 More recently, keta-
mine has also been shown to improve mood, and it is
currently being investigated for use in depression. The
postoperative period can be accompanied by a depressed
mood, and ketamine has been shown in animal studies to
improve mood in the postoperative setting.28 One target
for its mood-enhancing properties lies in the prefrontal
cortex.29 Thus, ketamine may also be able to relieve the
affective component of pain independent from its mod-
ulation of the nociceptive transmission pathway. Our
opioid-tolerant chronic pain patients did benefit substan-
tially more from postoperative low-dose ketamine
Eur J Anaesthesiol 2019; 36:8–15
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
infusion than did opioid-naı̈ve patients who had no
significant pre-operative pain. There are several possible
reasons for this selective effect of ketamine analgesia.
First, ketamine could antagonise NMDA receptors in the
spine and brain to decrease opioid tolerance and chronic
pain. Second, ketamine infusion could provide additional
relief of the aversive component of pain as well as an
improvement in mood via its activity in the prefrontal
cortex and associated areas.
It is important to differentiate between benefits from
ketamine because of its action in reversing the effects of
chronic pain and opioid tolerance on one hand and its
benefits due to a preventive effect against acute opioid
induced hyperalgesia on the other hand. Two other
studies have examined the use of ketamine in opioid-
tolerant patients. Loftus et al.8 studied effects of intra-
operative ketamine administration exclusively in opioid-
tolerant patients and found a 37% reduction in opioid
consumption during the initial 48-h postoperative period
and a 71% reduction at 6 weeks after surgery. They also
found reductions in pain scores 48 h and 6 weeks after
surgery. The authors hypothesise that the improved pain
control at 6 weeks was due to a reduction of central
sensitisation due to NMDA receptor antagonism and
to improved acute pain control in the immediate postop-
erative period. Problems with this study included a lack
of standardisation in the opioid regimen: different opioid
classes were administered. Nielsen et al.9 found compa-
rable results in opioid-tolerant patients. Both groups also
noticed an increased benefit for patients who had been on
substantial amounts of pre-operative opioids, over 40 mg
daily in the Loftus study and over 36-mg morphine
equivalent daily in the Nielsen study. Unlike these
authors, we administered ketamine in the postoperative
period, but our results show a similar reduction in opioid
requirements. Our data suggest that a successful analge-
sic intervention in chronic-pain/opioid-tolerant patients
does not necessarily need to be implemented prior to the
surgical insult.
A problem which we encountered in our patient selection
was that our opioid-naı̈ve patients more frequently were
younger and did not suffer from chronic pain because
they presented for surgery for scoliosis correction, while
the opioid-tolerant patients had often suffered from
chronic back pain with concomitant psychological effects
and expectations of pain medication. Another shortcom-
ing of our study is that we did not precisely quantify the
amount of pre-operative opioid medication taken by the
patients, so we are unable to confirm Loftus’ and Niel-
sen’s observations that the benefit of ketamine increases
with the amount of pre-operatively administered opioids.
Finally, our study was not designed for a follow-up over a
long time period. It would be interesting to determine
whether opioid-naı̈ve patients derive any benefit from
ketamine in the longer postoperative term, such as a
reduction in the risk of developing chronic pain.

In conclusion, our study shows that low-dose ketamine
infusion postoperatively reduces postoperative opioid
requirements and pain in opioid-tolerant patients who
used opioids pre-operatively, but that it is of less benefit
for opioid-naı̈ve patients in the immediate postoperative
period. It is unclear whether other adjuvants, such as
gabapentinoids, would have a similar effect or possibly
potentiate the effect of ketamine. In the context of the
current opioid epidemic, such investigations on nono-
pioid analgesic strategies will have a large impact on
postoperative care and public health.
Acknowledgements relating to this article
Assistance with the study: we thank James McKeever, Emily Siu
and Randy Cuevas.
Financial support and sponsorship: this work was supported by the
Department of Anesthesiology, Perioperative Care and Pain Medi-
cine, New York University School of Medicine, New York,
NY, USA.
Conflicts of interest: AA has received consulting fees from Pacira
and Trevena and speaker fees from B Braun.
Presentation: preliminary data from this study were presented in
part at the International Anesthesia Research Society annual meet-
ing, 17 to 20 May 2014, Montreal, Canada, and at the European
Society of Anaesthesiology Euroanaesthesia meeting, 30 May to 2
June 2015, Berlin, Germany.
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