Medicina (Kaunas) 2006; 42(8) 625
KLINIKINIAI TYRIMAI

Effects of ketamine on precipitated opiate withdrawal

Tomas Jovaiša, Giedrius Laurinėnas, Saulius Vosylius, Jūratė Šipylaitė,
Robertas Badaras, Juozas Ivaškevičius
Clinic of Anesthesiology and Intensive Care, Vilnius University, Lithuania

Key words: ketamine, opiate withdrawal, anesthesia, opiate antagonists, cortisol.

Summary: Objective. N-methyl-D-aspartate antagonists were shown to be effective in
suppressing the symptoms of opiate withdrawal. Intravenous anesthetic, ketamine, is the most
potent N-methyl-D-aspartate antagonist available in clinical practice. The present study was
designed to evaluate the effects of subanesthetic ketamine infusion, as little human data are available on ketamine in precipitated opiate withdrawal.
Materials and methods. A total of 58 opiate-dependent patients were enrolled in a randomized,
placebo-controlled, double-blind study. Patients underwent rapid opiate antagonist induction
under general anesthesia. Prior to opiate antagonist induction patients were given either placebo
(normal saline) or subanesthetic ketamine infusion of 0.5 mg/kg/h. Further evaluations were
divided into three phases: anesthetic, early postanesthetic (48 hours), and remote at 4 months
after procedure. Cardiovascular, respiratory, renal, and gastrointestinal responses to opiate
antagonist induction weremonitored during anesthesia phase. Changes in plasma cortisol concentrations
were measured as stress-response markers. Evaluations during early postanesthetic phase
were based on Subjective and Objective Opiate Withdrawal Scales. Remote effects were assessed
according to questionnaire based on Addiction Severity Index.
Results. Altogether, 50 patients were included in the final analysis. Ketamine group presented
better control of withdrawal symptoms, which lasted beyond ketamine infusion itself. Significant
differences between Ketamine and Control groups were noted in anesthetic and early postanesthetic
phases. There were no differences in effects on outcome after 4 months.
Conclusion. In this study, subanesthetic ketamine infusion was an effective adjuvant in the
correction of acute precipitated opiate withdrawal although it had no long-term effects on treatment
of opiate dependence.

Introduction
A number of recent publications support the hypothesis
thatN-methyl-D-aspartate (NMDA) antagonists
attenuate the signs of opiate withdrawal and diminish
progression or reverses existing opiate tolerance. Majority
of these facts are shown on animal studies and
experimental data using selective NMDA antagonists
or clinically available substances (1–3). NMDA antagonists
are shown to have an effect on opiate-induced
behavioral changes in animal models (4, 5). Existing
human data obtained fromstudies with clinically available
NMDA antagonists, memantine and dextromethorphan,
also prove the beneficial effects (6, 7).
Ketamine is another clinically available NMDA
antagonist. A recent study found that electroencephalographic
changes during rapid opiate detoxification
are reversed by ketamine (8). Animal studies
show that ketamine not only suppresses opiate withdrawal
symptoms but also produces different andmore
extensive effects when compared to other anesthetic
agents (9, 10). The use of ketamine in treatment of
opiate withdrawal is limited mainly because of psychotropic
effects and abuse potential (11). Considering
this, we decided to evaluate the effects of ketamine
during rapid opiate antagonist induction (RAI) under
general anesthesia. In anesthesia community, RAI is
regarded as a controversial procedure because of pronounced
stress response effects, possible pulmonary,
cardiovascular, and other complications (12–14). But
if performed by experienced team in well-equipped
facilities, it presents the safe and acceptable model
for evaluation of ketamine effects (15–18). At this
stage, the effects and safety of ketamine anesthesia
should be primarily questioned. Although initially
designed to explore this issue only, the study was
prolonged beyond the hospital period to evaluate the
possible long-term effects.

Materials and methods
The study was approved by the National Bioethics
Committee of Lithuania and theNationalDrug Control
Agency. Each patient gave written informed consent
at the beginning of the study. The study ran over the
period of 18 months and took place at the Vilnius University
Emergency Hospital, Lithuania.
Patients’groups. Atotal of 58 patients were enrolled
in the study. Inclusion criteria were opiate dependence
according to the 10th Revision of International
Classification of Diseases (ICD-10) and 4th edition
of Diagnostic and StatisticalManual ofMentalDisorders
(DSMIV), the duration of substance abuse more
than one year, age of 18–35 years, no or minor comorbidities,
grade I–II according to physical status classification
system of American Society of Anesthesiologists.
We excluded patients with a current history
of long acting opiate or polysubstance abuse, acute
medical or surgical condition, and pregnancy. In the
later phase, patients that required less than 30 mg of
morphine during stabilization phase were excluded
from final analysis. Patients were randomly assigned
toKetamine or Control group on the day of procedure.
Study plan. A randomized, placebo-controlled,
double-blind study was performed. Patients were
admitted to the hospital two days before the anesthesia
for morphine stabilization. Intramuscular morphine
hydrochloride was administered at doses of 5–10 mg
as needed, based on Subjective and Objective Opiate
Withdrawal Scales (SOWS and OOWS).
General anesthesia was induced uniformly at 9:00
a.m. on the in-patient day 3. A strict timing has been
urged due to circadian rhythm in plasma cortisol
concentration. A separate anesthetic chart and the set
of algorithms were developed for uniform management
of cardiovascular, respiratory, or muscle relaxant-
related issues. The same RAI protocol was used
as previously published (16). Withdrawal severity
during anesthesia was measured according to Wang
modified scale (OOWS-A) (19). Measurements were
made every 10 minutes and summed up at the end of
each hour following opiate antagonist induction. Anesthesia
medications, interventions, and monitors are
shown in Table 1.
Patients were required to have an aftercare plan
before RAI. Following discharge from the hospital,
patients entered the aftercare program of their choice:
either abstinence-based, naltrexone-supported outpatient
counseling or residential rehabilitation programs.
All patients were contacted after 4 months to fill in
the questionnaire based on Addiction Severity Index.
Questionnaire focused on health and socio-legal issues:
remote anesthesia complications, changes in
health status, new onset of psychopathology or compulsive
behavior, initiation and retention in naltrexone
maintenance or rehabilitation program, changes in
social life, family relations, and legal status. Retention
in treatment and abstinence were confirmed by urine
toxicology tests.
Statistical methods. Data are presented as means±
standard deviation (SD). Statistical analyses were
performed using “Microsoft Excel” and “SPSS for
Windows” software. The Student’s t-test was used to
assess the difference between group means. The paired
samples t-test was used to compare plasma cortisol
concentration at baseline and following time points.
The chi-square method was used to compare nonparametric
values. A p-value of <0.05 was considered
statistically significant.

Results
Complete profiles were obtained for 50 patients.
Eight patients were excluded because of failure to
comply with study protocol and incomplete data collection.
Outcome data four months after the procedure
were obtained for 45 patients. Five sets of blood samples
were excluded due to processing-related issues.
Patients’ characteristics. Demographic and clinical
characteristics of 50 patients were comparable.
Randomization resulted in very similar and equal distribution
of main patients’ characteristics (Table 2).
Anesthesia phase. Ketamine infusion significantly
suppressed the expression of precipitated opiate withdrawal
and prevented significant rise in cardiovascular,
respiratory, and neuroendocrine response. The
majority of recorded variables followed the same
pattern, as differences between two groups were more
pronounced during the acute phase of opiate antagonist
induction.
Differences in cardiovascular response were more
pronounced during the first two hours after opiate
antagonist induction. Ketamine infusion resulted in
more stable hemodynamic profile (Table 3). Mean
arterial pressure and heart rate during the peak response
to opiate antagonist induction and throug-

Table 1. Anesthesia medications, interventions, and monitors. Timing of cortisol samples
Medication Intervention/Monitor Cortisol samples
Preanesthesia
Clonidine 5 mg/kg, orally 1st sample – baseline level
Octreotide 100 mg, IV infusion
Heparin 5000 U, IV
Induction of anesthesia
Preoxygenation Standard anesthesia monitoring
Propofol 2.5 mg/kg (Datex-Engstrom AS/3)
Lidocaine 1.5 mg/kg Endotracheal intubation
Pipecuronium 0.1 mg/kg Insertion of oro-gastric tube
Maintenance of anesthesia
Isoflurane ³0.8 MAC in oxygen/air* Anesthetic gas analyzer
Pipecuronium as needed Myoneural block monitor
Ketamine or placebo**
Opiate antagonist induction
Naloxone 1.6 mg, IV 2nd sample – 20 minutes
Naloxone 0.8 mg/h, IV infusion after naloxone bolus
Naltrexone 100 mg, via oro-gastric tube
Emergence from anesthesia
Reversal of myoneural blockade Tracheal extubation 3rd sample – at the end of
Transfer to postanesthesia anesthesia phase
care unit
48-hour postanesthesia phase
Clonidine 2 mg/kg, orally, twice daily Subjective and Objective Opiate 4th sample – following
Carbamazepine 200 mg, orally as needed Withdrawal Scales morning after RAI at
Clonazepam 2 mg, orally at night 8 a.m.
Naloxone challenge test 1.2 mg, IV
* adjusted if cardiovascular response exceeded 30% of the baseline values. Minute ventilation was targeted
to maintain the constant etCO2 at the level of 5%;
** started 5 minutes before the opiate antagonist induction, initial 0.5 mg kg–1 bolus, followed by infusion of
0.5 mg kg–1 h–1.
Table 2. Patients’ characteristics
Characteristic
Ketamine group Control group
(n=22) (n=28)
Age (years) 22.7±3.0 23.4±3.1
Weight (kg) 71.8±8.2 67.7±11.1
Sex (female/male) 2/20 5/23
Morphine stabilization dose (mg) 57.7±16.4 54.6±15.8
History of opiate abuse (years) 3.7±2.0 4.2±1.9
Number of previous medical detoxifications 2.2±2.1 2.4±2.3
Data are presented as mean±SD and total number for sex. Differences between groups are not significant
for all variables, p>0.1.
hout the procedure were lower in Ketamine group
(Fig. 1).
The peak rise in the requirement of respiratory
minute volume following opiate antagonist induction
was lower in Ketamine group. Differences between
mean baseline volume and mean peak volume were
0.712±0.6 and 1.486±0.7 l in Ketamine and Control
groups, respectively (p<0.001).
Effects of ketamine on precipitated opiate withdrawal
Medicina (Kaunas) 2006; 42(8)

Table 3. Cardiovascular response during rapid opiate antagonist induction under general anesthesia
Variable Control Ketamine 95% confidence interval n=28 n=22 of the difference p
Mean arterial pressure
Baseline 71.6±10.9 69.6±5.2 –3.2; 7.04 0.450
Peak 96.6±13.8 79.4±10.8 9.9; 24.4 <0.001
1st hour 86.5±10.9 74.2±7.9 6.7; 17.9 <0.001
2nd hour 83.5±10.7 76.2±7.3 1.9; 12.6 0.009
3rd hour 82.2±10.4 79.2±7.3 –2.3; 8.3 0.255
Heart rate
Baseline 69.1±15.5 64.3±9.7 –2.9; 12.4 0.216
Peak 95.5±12.8 75.6±13.0 12.5; 27.3 <0.001
1st hour 86.5±12.9 71.6±10.5 8.1; 21.7 <0.001
2nd hour 88.6±12.1 74.6±11.8 7.1; 20.8 <0.001
3rd hour 87.6±11.5 77.9±11.4 3.2; 16.3 0.005
Data are presented as mean±SD. Baseline – time point following induction of general anesthesia when
hemodynamically steady state is achieved. Peak – single reading representing the maximum increase of the
variable following opiate antagonist induction.
Fig. 1. Cardiovascular response during rapid antagonist induction
Bars show means of mean arterial pressure (MAP), lines show means of heart rate (HR).
* difference between groups significant for MAP and HR, p<0.01;
** difference between groups significant for HR only, p<0.05.
Baseline Peak 1st hour 2nd hour 3rd hour
100
90
80
70
60
100
90
80
70
60
MAP, mmHg
HR, b/min
Ketamine
Control
Tomas Jovaiša, Giedrius Laurinėnas, Saulius Vosylius et al.
Medicina (Kaunas) 2006; 42(8)
629
There were no significant changes or differences
between groups in hourly urine output and gastrointestinal
reaction.
Opiate withdrawal scores on OOWS-A scale were
significantly higher in Control group, despite significantly
higher mean hourly minimum alveolar concentration
(MAC) of isoflurane (Fig. 2 and 3).
Baseline cortisol levels were comparable between
groups. Mean concentrations for Ketamine and Control
groups were 496±120 and 468±160 nmol/l, respectively
(p>0.5). During general anesthesia phase,
ketamine infusion significantly suppressed cortisol
level even after opiate antagonist induction. Concentration
decreased by 165±125 nmol/l when compared
to baseline in Ketamine group (p<0.05); no significant
changes were found in Control group – 62±92
nmol/l (p>0.1). A significant increase in morning cortisol
levels was noted in both groups on the following
day: 154±141 nmol/l for Ketamine group (p<0.05)
and 302±210 nmol/l for Control group (p<0.001). The
extent of increase was significantly higher in Control
group patients compared to Ketamine group (p<0.05)
(Fig. 4).
Early postanesthetic phase. Patients in Ketamine
group required significantly less additional carbamazepine
and clonazepam to maintain the same level of
opiate withdrawal symptoms during the first 48 hours
following RAI. Mean total clonazepamdose was 5.0±
2.7 and 8.6±3.7 mg for Ketamine and Control groups,
respectively (p<0.001). Mean total carbamazepine
dosewas 473±335 and 957±423 mg (p<0.001). There
were no significant differences in SOWS and OOWS
scores on days 3 to 5 (p>0.1). Naloxone challenge
test was negative in all cases. There were no complications
related to anesthesia phase or opiate antagonist
induction.
Outcome results after four months. Five patients
were lost to follow-up. Altogether, 13 out of 21 pa-
Fig. 2. Severity of opiate withdrawal during anesthesia phase according to Objective Opiate
Withdrawal Scale (OOWS-A) score
Bars show means of hourly OOWS-A score, error bars show standard deviation.
* difference between groups significant for hourly OOWS-A score, p<0.05.
1st hour 2nd hour 3rd hour
100
75
50
25
OOWS-A, score
Ketamine
Control
0
Effects of ketamine on precipitated opiate withdrawal

Patients in Ketamine group and 19 out of 24 patients in
Control group entered outpatient counseling programs;
other patients entered residential rehabilitation
programs. Difference between groups is statistically
insignificant. The patients in Ketamine and Control
groups were opiate free on average for 9.4±6.6 and
8.0±7.0 weeks, respectively (p>0.05). The summary
of outcome data is presented in Fig. 5. Differences
between groups are statistically insignificant. No
remote complications related to RAI were reported.
Four patients were admitted to hospital in a 4-month
period for trauma, acute pancreatitis, and ulcerative
colitis. One more patient returned to regular opiate
use, developed injection-related sepsis, and later died
in hospital.

Discussion
This is the first randomized, placebo-controlled,
double-blind trial evaluating effects of subanesthetic
infusion of ketamine during RAI. Our data support
the hypothesis that NMDA antagonists may selectively
interfere with expression of opiate withdrawal.
Although it is known that different doses of ketamine
may produce different effects (9, 10), but there are
few studies indicating the target infusion rate or dose.
Doses of 1.5 mg/kg and higher were used in the studies
mentioned above. The protocol of our studywas aimed
at maintaining equianesthetic conditions during opiate
antagonist induction. None of routinely used methods
for monitoring or assessing the depth of anesthesia
are suitable for ketamine-induced general anesthesia
(20, 21). This makes it impossible to compare it with
other anesthetic agents (mainly gamma-aminobutyric
acid (GABA)-acting) without questioning the comparability
of anesthetic protocols. We chose subanesthetic
infusion of 0.5 mg/kg/h as it is likely to produce
NMDA antagonistic effects and have minimal effect
on overall depth of anesthesia. Ketamine, as a single
agent, administered at infusion rates of 0.3 and 0.5
mg/kg/h was used in the studies evaluating neuroen-
Baseline 1st hour 2nd hour 3rd hour
1.2
1.0
0.8
Isoflurane MAC
Ketamine
Control
0
Fig. 3. Minimum alveolar concentration (MAC) of isoflurane during anesthesia phase
Bars show mean minimum alveolar concentrations of isoflurane, error bars show SD.
* difference between groups significant, p<0.05.

Fig. 4. Trends of plasma cortisol levels during the first 24 hours following rapid opiate antagonist
induction
Bars show means and error bars show SD. OA – opiate antagonist.
* a statistically significant difference as compared to baseline for Ketamine group only; p<0.05;
† and ‡ – a statistically significant difference as compared to baseline for both groups; p<0.05.
Fig. 5. Summary of outcome at 4 months following rapid opiate antagonist induction
25 50 75
g Reported social g / family life
Reported health
Retention in
aftercare
Complete
Control
Ketamine
0 25 50 75
Reported social/family life
improvement
Reported health
improvement
Retention in
aftercare program
Complete abstinence
Patients, %
Effects of ketamine on precipitated opiate withdrawal
Medicina (Kaunas) 2006; 42(8)
baseline oa end_ga 24 h
]
X
]
X
] X
]
X
]
]
]
]
X
X
X
X
p g Ketamine
*
‡
†
1000
750
500
Cortisol concentration, nmol/l
Control
250
Baseline OA induction End of EAI Next morning
632
docrine response (22). It was shown that this dose
regimen did not induce general anesthesia and complex
hallucinations.
In the number of analyzed variables, we noticed
the same pattern – more significant differences between
Ketamine and Control groups during the acute
phase of RAI and minor or no differences at the end
of procedure. This trend may be attributable directly
to changes in plasma ketamine concentration – peak
of concentration following bolus and later steady state
following continuous infusion. To some extent, this
pattern may be caused by non-NMDA-mediated
activation of hypothalamo-pituitary-adrenal axis.
Many neurons express simultaneously two or more
isotypes of glutamate receptors, so pharmacological
modulation of more than one receptor may be necessary
to abolish completely neuroendocrine response
(23).
Ketamine is the only anesthetic which stimulates
the cardiovascular system, and even a dose of 0.5 mg/
kg can cause this effect. It causes an increase in plasma
concentrations of catecholamines and cortisol as well
(22). Contrary to basic pharmacodynamics of ketamine,
in this study ketamine infusion resulted in lowered
blood pressure, heart rate, and cortisol levels. We
can hypothesize that in precipitated opiate withdrawal,
NMDA blockade produced by ketamine outweighs
the stimulant effects of ketamine.
Known effects of ketamine on respiratory system
are minimal; the only clinically important feature is
bronchodilation. Ketamine neither suppresses the
respiratory minute volume nor alters the respiratory
response to an increase in carbon dioxide. Opiate
antagonist induction is shown to increase ventilatory
requirement (24). Considering the above facts, lower
peak respiratory minute volume in Ketamine group is
more likely to be due to more effective suppression
of opiate withdrawal rather than anesthetic effects of
ketamine.
In this study, differences in cardiovascular and
respiratory response between groups are attributable
solely to ketamine infusion. There is no doubt that
higher dose of other general anesthetic agents may
suppress these responses, but this study demonstrates
that NMDA receptor antagonist may result in very
specific effects, at least comparable to those ofGABAacting
anesthetic agents. Isoflurane MAC was significantly
higher in Control group as a result of more
pronounced withdrawal symptoms during the anesthetic
phase. Even if we speculate that difference in
MAC was attributable to different depth of anesthesia
because of ketamine, then isoflurane and ketamine
mixture may be regarded as more effective, considering
significant differences in OOWS-A scores.
More importantly, this study demonstrates the preemptive
effect of ketamine. Lower doses of clonazepamand
carbamazepine on days 3–5 and significantly
lower concentration of cortisol 24 hours after procedure
represent the lower intensity in the residual symptoms
of opiate withdrawal. This effect cannot be attributed
to any of the residual effects of anesthetic, and
it demonstrates complex processes underlying interference
with opiate withdrawal. It is generally accepted
that opiate withdrawal induces a significant rise
in plasma and salivary cortisol levels. This effect may
last for weeks after detoxification (25). Neurobehavioral
effects of addiction and withdrawal may correlate
to neuroendocrine changes (26). Modulation of
this response during rapid opiate antagonist induction
may be promising, but clinical significance of this
effect remains unclear, as the differences in long-term
outcome results were insignificant. Similar outcome
results were published in a recent Cochrane review
(27).
This dose of ketamine may be used in other protocols
of RAI under anesthesia or deep sedation. It may
also offer some advantages in cases of polysubstance
abuse when tolerance to GABA-acting substances is
very likely. Nevertheless, contraindications should
include cases of concomitant cocaine intake and alcohol
withdrawal.
Considering the recent publication by E. Freye and
colleagues (8) and available animal model data, this
trial adds to growing body of evidence that ketamine
may be a promising adjuvant in RAI. Further studies
are needed for a better understanding of ketamine
effects on opiate withdrawal.
Conclusion
In this study, subanesthetic ketamine infusion was
an effective adjuvant in the correction of acute precipitated
opiate withdrawal although it had no long-term
effects on treatment of opiate dependence.
Acknowledgements
The authors would like to thank Lithuanian AIDS
Center for support performing laboratory analysis in
this study.

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Ketamino įtaka sukeltai opioidinei abstinencijai
Tomas Jovaiša, Giedrius Laurinėnas, Saulius Vosylius, Jūratė Šipylaitė,
Robertas Badaras, Juozas Ivaškevičius
Vilniaus universiteto Anesteziologijos ir reanimatologijos klinika
Raktažodžiai: ketaminas, opioidinė abstinencija, anestezija, opioidų antagonistai, kortizolis.
Santrauka. N-metil,D-aspartato receptorių antagonistai slopina opioidinės abstinencijos simptomus. Į veną
vartojamas anestetikas ketaminas yra stipriausias N-metil,D-aspartato receptorių antagonistas, net anestezijos
nesukeliančios ketamino dozės veikia gliutamato receptorius.
Tyrimo tikslas. Įvertinti subanestetinės ketamino infuzijos sukeliamus poveikius, nes klinikinių duomenų
apie ketaminą, vartojamą opioidinei abstinencijos būklei gydyti, yra labai mažai.
Metodai. Prospektyviajame, atsitiktinių imčių, dvigubai koduotame tyrime dalyvavo 58 tiriamieji. Ketamino
poveikiai tirti atliekant opioidų antagonistų ankstyvąją indukciją bendrosios anestezijos metu. Prieš opioidų
antagonistų indukciją pacientams buvo skiriama pastovi ketamino infuzija 0,5 mg/kg/val. arba placebo
(fiziologinis tirpalas). Tyrimas suskirstytas į tris fazes: anesteziją, ankstyvąjį laikotarpį po anestezijos (48
valandos) ir vėlyvąjį laikotarpį. Anestezijos metu buvo stebimi širdies ir kraujagyslių, kvėpavimo sistemų,
inkstų ir virškinamojo trakto funkcijų pokyčiai. Atsakui į stresą vertinti buvo tiriama kortizolio koncentracija.
Vėlyvieji rezultatai buvo vertinami po keturių mėnesių remiantis priklausomybės sunkumo indeksu, pagrįstu
klausimynu.
Rezultatai. 50 pacientų duomenys įtraukti į tolesnę analizę. Ketamino infuzija veiksmingiau slopino
opioidinės abstinencijos simptomus, šis poveikis užfiksuotas ir pabaigus infuziją. Reikšmingų skirtumų nustatyta
tarp tiriamosios ir kontrolinės grupių anestezijos metu ir ankstyvuoju laikotarpiu po anestezijos. Reikšmingo
skirtumo tarp tiriamosios ir kontrolinės grupių po keturių mėnesių nenustatyta.
Išvada. Papildoma subanestetinė ketamino infuzija padeda efektyviau koreguoti sukeltos opioidinės
abstinencijos simptomus, tačiau neturi įtakos vėlesniems opioidinės priklausomybės gydymo rezultatams.
Adresas susirašinėti: T. Jovaiša, Vilniaus universitetoAnesteziologijos ir reanimatologijos klinika, Šiltnamių 29,
04130 Vilnius. El. paštas: tjovaisa@yahoo.co.uk
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Correspondence to T. Jovaiša, Clinic ofAnesthesiology and Intensive Care, Vilnius University, Šiltnamių 29,
04130Vilnius, Lithuania. E-mail: tjovaisa@yahoo.co.uk