Blackwell Publishing IncMalden, USAPMEPain Medicine1526-2375American Academy of Pain Medicine? 200672166169Case
ReportKetamine–Morphine–Bupivacaine for Cancer PainSen et al.
PA I N M E D I C I N E
Volume 7 • Number 2 • 2006
Beneficial Effect of Low-Dose Ketamine Addition to Epidural
Administration of Morphine–Bupivacaine Mixture for Cancer Pain in
Two Cases
Selda Sen, MD,* Osman N. Aydin, MD,† and Kutlay Aydin, MD‡
Departments of *Anesthesiology and Reanimation, †Algology and ‡Anesthesiology, State Hospital Anesthesiology and
Reanimation Clinic, Adnan Menderes University, Medical Faculty, Aydin, Turkey
ABSTRACT
ABSTRACT
Key Words. Terminal Cancer Pain; Neuropathic Pain; Ketamine; Bupivacaine; Morphine; Epidural
Analgesia; Quality of Life
Introduction
Report of Cases
L
Case 1
A 41-year-old man with colon cancer and skeletal
metastases was hospitalized due to increasing pain.
The pain was localized on the right hip and it was
radiating to both legs. The pain was described as
a constant, stinging, burning, and icy sensation on
movement increased to 90 on the (0–100) visual
analog scale (VAS) of pain intensity. He was unable
to find a comfortable position in the bed and had
not slept for days. Magnetic resonance imaging
showed metastases to vertebrae with spinal cord
compression from T12 to L1. Prior to admission,
the patient was treated with combined oral morphine SR 90 mg/day, tramadol 200 mg/day,
naproxen Na 3.3 g/day, and amitriptyline 50 mg/
day. Unfortunately, he did not perceive any benefit
and suffered from serious adverse effects such as
sedation, constipation, and nausea/vomiting. We
stopped oral medication and inserted an epidural
port catheter (Periplant-Braun) at T9−10 followed
by bolus dosing of combined solution consisting
of bupivacaine (1 mg/mL), morphine HCl (1 mg/
mL), and ketamine (1 mg/mL). This solution was
started 2 mL twice daily via epidural route. The
patient obtained adequate pain relief (VAS 90–30)
ong-term opioid therapy is commonly
administered for the management of severe
cancer pain. Increasing doses of opioids are
titrated against effects until analgesia is achieved
or intolerable adverse effects occur [1]. Clinical
reports indicate that ketamine in low doses as an
adjuvant to opioid treatment may improve analgesia with tolerable adverse effects. The studies suggest that epidurally administered ketamine can be
helpful in alleviating severe pain and restoring
quality of life when more conservative measures
fail [2,3]. In the present case reports, patients suffering from terminal cancer pain were given epidural pain therapy with morphine–bupivacaine
combined with low-dose ketamine because of
inadequacy or severe adverse effects of systemic
opioid therapy.
Reprint requests to: Dr. Selda Sen, MD, Adnan Menderes
University Medical Faculty, Anesthesiology and Reanimation Department, 09100 Aydin, Turkey. Tel: 90-2564441256-358; Fax: 90-256214-6495; E-mail: drseldasen@
yahoo.com.
© American Academy of Pain Medicine 1526-2375/06/$15.00/166 166–169
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on September 30, 2016
Two patients experiencing cancer pain with neuropathic components were treated with epidural
administration of a mixture of ketamine (1 mg/mL) + morphine (1 mg/mL) + bupivacaine (1 mg/
mL) injected daily by epidural port. No serious adverse effect was observed throughout the therapy.
The patients were mostly pain-free and have gotten better quality of life during 110- and 48-day
follow-up when the therapy was given by epidural route. Low doses of epidural ketamine added to
morphine and bupivacaine increase the mean duration of satisfactory analgesia without severe
adverse effects and restore quality of life when traditional therapy fails.
Ketamine–Morphine–Bupivacaine for Cancer Pain
and resumed walking with a dose of 3 mL three
times daily. No serious adverse effects were
observed throughout the therapy. The dose of
solution was titrated according to pain severity and
a last dose was 4 mL every 3 hours in a day. After
his wife learned how to administer the solution
from epidural port, he was discharged from the
hospital. The pain team of the hospital supported
the patient at home. During 110 days of survival,
he was mostly pain-free for a better quality of life
such as being able to go out with his family and
friends.
Discussion
Pain affects many patients with malignant disease,
and the prevalence of severe pain increases in the
advanced stages of the condition. Morphine has
long been used as the gold standard for the treatment of severe cancer pain. However, its side
effects, particularly sedation, nausea/vomiting,
cognitive impairment, and myoclonus at high
doses encouraged the use of adjuvant drugs [4].
The systemic absorption of morphine after
intrathecal or epidural administration is very slow,
resulting in long duration of analgesia and low
plasma concentrations, while lipid-soluble opioids
are rapidly absorbed into the circulation and redistributed to the brain. Fentanyl analogs often produce minor reductions in blood pressure, and
occasionally severe hypotension by centrally mediated reduction in systemic vascular resistance. The
serotonin syndrome may result from coadministration of pethidine, dextromethorphan, pentazocine or tramadol with monoamine oxidase
inhibitors, or selective serotonin reuptake inhibitors [5]. Pethidine (meperidine) causes histamine
release and myocardial depression, while the fentanyl analogs do not [6]. Epidural local anesthetics
may be added to opioids, but the doses should be
limited to the intensity of side effects (e.g., sensory
and motor block, and hemodynamic instability).
Other possible alternative analgesic drugs are ketamine, alpha-2 agonists, cholinergic, or GABAergic drugs [7,8]. The N-methyl-D-aspartate
receptor (NMDA) antagonist ketamine can be
used at low doses for the management of refractory and neuropathic cancer pain [4,9–11].
Opioids activate the pain facilitator system via
activation of the NMDA receptors, which may
produce hyperalgesia/allodynia. Indeed, NMDA
antagonists have been demonstrated to be particularly effective in reducing persistent pain associated with central sensitization [12]. Ketamine has
recently been shown in a rat model to prevent
fentanyl-induced hyperalgesia and subsequent
acute morphine tolerance [13]. It has been suggested that pharmacological tolerance to opioids
may develop early, but it is not clear how often it
is a clinical problem in cancer patients. It may be
difficult in this patient population to distinguish
between tolerance and disease progression, both
of which require an increase in opioids doses [3].
Bell et al. [3] evaluated the effects of ketamine in
improvement of analgesia due to opioids in various reports. The most commonly used opioid was
morphine, but in some cases, ketamine was given
as an adjunct to fentanyl, hydromorphone,
diamorphine, or combinations of these opioids.
Ketamine was also used as the sole analgesic. Sixteen publications reported dramatic relief of
refractory cancer pain with ketamine, including
“complete relief of pain,” “complete cessation of
pain,” “no pain,” and dramatic reduction in VAS
scores. The route of ketamine administration
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on September 30, 2016
Case 2
A 63-year-old man with lung cancer and vertebral
metastases was transferred from a local hospital
due to increased pain. The pain was localized on
the left hip and was radiating to the left leg and
was described as a constant, stinging, and burning
sensation with exacerbation on movement. The
intensity of pain was 90 on the VAS and he was
confined to bed because of pain. Prior to referral
to our pain clinic, the patient was given fentanyl
transdermal patch (Duragesic®, Johnson-Cilag,
Berse, Belgium) 100 µg/hour and combined oral
tramadol 200 mg/day, naproxen 2 g/day, and amitriptylin 50 mg/day. Despite receiving this combined therapy, he suffered from pain and serious
adverse effects such as nausea/vomiting and sedation. We inserted an epidural port catheter
(Periplant-Braun) at T8−9 and administered the
combined solution (same solution as case 1) epidurally. This solution was started 2 mL, twice a
day. The intensity of pain was decreased (VAS
decreased from 90 to 30) without adverse effects
when the doses increased to 3 mL every 8 hours.
He was discharged from the hospital with the epidural port catheter and supported at home by the
pain team of hospital. The doses of solution were
titrated according to pain severity and a last dose
was 3 mL every 2 hours in a day. During 45-day
follow-up, he was free of pain and serious adverse
effects while living at home with his family for a
better quality of life in his last days. He died at
home on the 48th day of epidural therapy.
167
168
receptor. The analgesic effects of ketamine are not
mediated via µ opioid receptors in the central
nervous system. The antinociceptive action of
ketamine may involve descending inhibitory
monoaminergic pain pathways [17]. Although ketamine has been reported to interact with opioid
receptors, the affinity for opioid receptors may be
10,000-fold weaker than that of morphine. Pharmacokinetic studies of extradural ketamine and
morphine in dogs showed that 30 minutes after
extradural injection, the concentration ratio of
cerebrospinal fluid and plasma was approximately
0.5 and 40, respectively. Therefore, it seems
unlikely that extradural ketamine produces analgesia via opioid receptor occupation in the spinal
cord and that effective (at the opioid receptor)
extradural doses of ketamine are likely to produce
not only spinal but also systemic effects [17,18].
Clinically, subarachnoid ketamine without preservative is a safe and effective anesthetic and has
shown no significant neurotoxic effects in swine.
Benzethonium chloride alone produces moderate
neurotoxic effects whereas ketamine with preservative produces only minimal changes [19]. We
applied ketamine via epidural route and we did
not encounter any neurotoxicity in our two
patients.
Chia et al. [18] suggested that adding ketamine
to morphine, bupivacaine, and epidural analgesia
improved both dynamic and static pain scores in
patients undergoing major intrathoracic and intraabdominal surgery. They also reported no adverse
effects from the addition of 0.4 mg/mL ketamine
to the epidural solution. The analgesia improved
with the addition of ketamine should not be
surprising because ketamine has been shown to
extend the duration of local anesthetics greatly and
to enhance the activity of epidural morphine. Furthermore, ketamine may act to potentiate the analgesic effect of bupivacaine, as well as morphine,
and to reduce its consumption [18]. Gantenbein
et al. [20] demonstrated that ketamine might
inhibit the metabolism of bupivacaine.
Wu et al. [21] suggested that the combination
of low doses of ketamine + morphine + bupivacaine with continuous epidural analgesia
effectively suppresses all possible nociceptor transduction pathways, preventing central sensitization
and improving postoperative pain management.
Continuous epidural analgesia with bupivacaine
blocks the sensory input of surgical stimuli. Morphine activates the opioid receptors and suppresses
the initial response of dorsal horn nociceptive
neurons and C-fiber stimulation. Ketamine via
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on September 30, 2016
included oral, intramuscular bolus and infusion,
intravenous bolus and infusion, epidural bolus
and intrathecal injection. Ketamine in low doses
(e.g., 1 mg/kg/24 h as subcutaneous infusion) has
been suggested to reverse or partially reverse opioid tolerance [3]. However, there is little case
report-based evidence to support this practice
[9–11].
Mercadante and colleagues [1] evaluated the
efficacy of ketamine in potentiating morphine
analgesia in 10 cancer patients with severe pain
refractory to morphine treatment. They found
that ketamine combined with morphine significantly reduced pain in majority of patients for
whom morphine alone was ineffective.
Clark and Kalan [14] also described a case of a
terminal cancer patient on extremely large doses
of opioids who experienced dramatic pain relief on
adjuvant treatment with ketamine. One wonders
whether such low doses of ketamine can be
expected to produce such effective analgesia, or is
ketamine reducing morphine tolerance? Perhaps
both effects apply.
Lauretti et al. [7] reported that epidural
NMDA receptor antagonists such as ketamine
provided analgesia without associated respiratory
depression or cardiovascular stimulation in 48 terminal cancer patients. The development of morphine tolerance may involve the activation of
NMDA receptors and nitric oxide production.
During chronic pain processing, there is increased
glutamate and aspartate release in the spinal dorsal
horn and increased synthesis of neurokininin in
sensory ganglion cells. Also, there is an increase in
their transport and release in the spinal cord that
will mediate central sensitization and “wind-up.”
This state of hyperexcitability may continue after
cessation of the peripheral input and can be
regarded as temporal summation of NMDA
receptor-mediated excitatory postsynaptic potentials [7,15].
Ketamine’s neuropharmacology is complex.
The compound interacts with multiple binding
sites, including NMDA and non-NMDA
glutamate receptors, nicotinic and muscarinic
cholinergic and monoaminergic and opioid receptors. NMDA receptors are, among many other
functions, involved in the so-called wind-up
phenomenon, which plays a major role in the
development of chronic pain [16].
Ketamine has been reported to interact with mu
(µ), delta (δ), and kappa (κ) opioid receptors. Several studies have suggested that ketamine may be
an antagonist at µ receptors and an agonist at κ
Sen et al.
Ketamine–Morphine–Bupivacaine for Cancer Pain
References
1 Mercadante S, Villari P, Ferrera P. Burst ketamine
to reverse opioids tolerance in cancer pain. J Pain
Symptom Manage 2003;25:302–5.
2 Lloyd-Williams M. Ketamine for cancer pain. J Pain
Symptom Manage 2000;19:79–80.
3 Bell RF, Ecccleston C, Kalso E. Ketamine as
adjuvant to opioids for cancer pain. A qualitative
systematic review. J Pain Symptom Manage 2003;
26:867–73.
4 Ahmedzai S. New approaches to pain control in
patients with cancer. Eur J Cancer 1997;33:8–14.
5 Ener RA, Meglathery SB, Van Decker WA, Gallagher RM. Serotonin syndrome and other serotonergic disorders. Pain Med 2003;4(1):63–74.
6 Bowdle TA. Adverse effects of opioid agonists and
agonist-antagonists in anaesthesia. Drug Saf
1998;19:173–89.
7 Lauretti GR, Gomes JMA, Reis MP, Pereira NL.
Low does of epidural ketamine or neostigmin, but
not midazolam; improve morphine analgesia in epidural terminal cancer pain therapy. J Clin Anaesth
1999;11:663–8.
8 Exner HJ, Peters J, Eikermann M. Epidural analgesia at the end of life: Facing empirical contraindications. Anesth Analg 2003;97:1740–2.
9 McQueen AL, Baroletti SA. Adjuvant ketamine
analgesia for the management of cancer pain. Ann
Pharmacother 2002;36:1614–9.
10 Fine PG. Low dose ketamine in the management of
opioid resistant terminal cancer pain. J Pain Symptom Manage 1999;17:296–300.
11 Kannan TR, Saxena A, Bhatnagar S, Barry A. Oral
ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. J Pain Symptom
Manage 2002;23:60–5.
12 Yang CP, Yeh CC, Wong CS, Wu CT. Local
anaesthetic switching for intrathecal tachyphylaxis
in cancer patients with pain. Anesth Analg 2004;
98:557–8.
13 Larcher A, Laulin JP, Celerier E, Le Moal M,
Simonnet G. Acute tolerance associated with single
opiate administration: Involvement of N-methyl-Daspartate-dependent pain facilatotory systems. Neuroscience 1998;84:583–9.
14 Clark JL, Kalan GE. Effective treatment of severe
cancer pain of the head using low dose ketamine in
an opioids-tolerant patient. J Pain Symptom Manage 1995;10:310–4.
15 Guirimand F, Dupont X, Braseur L, Chauvin M,
Bouhassira D. The effects of ketamine on the temporal summation (wind-up) of the RIII nociceptive
flexion reflex and pain in humans. Anesth Analg
2000;90:408–14.
16 Kohrs R, Durieux M. Ketamine: Teaching old drug
new tricks. Anesth Analg 1998;87:1186–93.
17 Hirota K, Lambert DG. Ketamine: Its mechanism
(s) of action and unusual clinical uses. Br J Anaesth
1996;77:441–4.
18 Chia Y, Liu Y, Liu YC, Chang HC, Wong CS.
Adding ketamine in a multimodal patientcontrolled epidural regimen reduces postoperative
pain and analgesic consumption. Anesth Analg
1998;86:1245–9.
19 Errando CL, Sifre C, Moliner S, et al. Subarachnoid
ketamine in swine––Pathological findings after
repeated doses: Acute toxicity study. Reg Anesth
Pain Med 1999;24:146–52.
20 Gantenbein M, Abat C, Attolini L, et al. Ketamine
effects on bupivacaine local anaesthetic activity and
pharmacokinetics of bupivacaine in mice. Life Sci
1997;61:2027–33.
21 Wu CT, Yeh CC, Yu MM, et al. Preincisional
epidural ketamine, morphine and bupivacaine
combined with epidural and general anaesthesia
provides pre-emptive analgesia for upper abdominal
surgery. Acta Anaesthesiol Scand 2000;44:63–8.
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on September 30, 2016
the NMDA receptors affects the potentiated
responses from repeated surgical stimulation.
The incidence of morphine–ketamineassociated side effects, such as sedation, pruritus,
nausea/vomiting, and hallucination was low in our
two patients. The reason for the lower incidence
of analgesic-related side effects might be lower
doses of the individual medications in the multimodal regimen, compared with previous studies.
We have reported two cases with severe cancer
pain, which was relieved by long-lasting epidural
infusion of local anesthetics combined with opioids and ketamine. In addition to pain relief, we did
not encounter any serious side effects such as
unconsciousness. Cancer pain can be controlled by
epidural ketamine infusion, which also produces
synergistic analgesic effect and reduces opioids
tolerance. It might be useful to reconsider institutional pain management standards when unbearable pain occurs in patients with limited life
expectancy.
169