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The
persistence of pain after surgery has become a major concern due to its
variable debilitating consequences. Epidural analgesia is widely used for
postoperative pain in a variety of surgical procedures and recognized to
provide excellent quality of analgesia when compared with systemic opioid use.
Midazolam
belongs to benzodiazepine/type Gamma-aminobutyric acid (GABA)-A which produces
an analgesic action through GABA-A receptor complex; it can be used as a
promising adjuvant in postoperative epidural analgesia.
In 2013,
researchers have conducted the prospective study to compare the effectiveness
of 2 mg Midazolam as an adjuvant in combination with 0.5% Bupivacaine and 5 mg
Morphine as an intermittent bolus of epidural for postoperative analgesia after
an elective lower limb orthopedic surgery. It showed a satisfying prolonged
analgesia duration (up to 23.04 h) compared to bupivacaine with pethidine or
morphine alone. It also exhibited better pain control without any significant
drowsiness effect, nausea/vomiting and pruritus.
This case
report described a 20 year old male who underwent mayor orthopedic surgery due
to comminutive open fracture of the right tibia and fibular bone. He has
achieved a satisfying postoperative pain scale after having a 12 hourly
intermittent bolus of Epidural with 1 mg preservative-free of midazolam as an
adjuvant of 0.1% plain Levobupivacaine, 1 mg morphine and 30 mcg clonidine for
treating his ten days of persistent postoperative pain condition. For the last
five days of his hospital stays after the adjuvant therapy has been given, it
was successfully produced bearable pain (at rest and a light degree of
mobilization) without any significant undesirable side effect recorded.
Keywords: Persistent postoperative pain, Midazolam
adjuvant, Intermittent epidural bolus
INTRODUCTION
The Persistent
Postoperative Pain (PPP) reflects an evolving complex constellation of
processes involving several neurotransmitters, modulators and immune system at
peripheral, spinal and cerebral levels. Normally, acute surgical pain in most
patients declines over the first few days after surgery. Unfortunately, in a
proportion of patients, the pain can persist and become chronic, severe and
long-lasting disabilities. The consequences of PPP can be variable and
significant, not only in terms of suffering and reducing quality of life (QoL)
but also the subsequent cost to the health care and social support [1-3].
Genetic factors appear to account as one of the risk factors for the transition
from acute pain to PPP and have contributed to a significant degree of
inter-individual pain sensitivity and treatment response. Phenotypes variants
in pain perception and modulation together with genetic variation during drug
uptake, transport, action at the effector site and during the metabolism and
excretion, plays a role in perpetuating postoperative pain. Poor metabolism
showed in a frequency of about 7-10% in Caucasian populations. Moreover, 3-5%
of them are ultra-rapid metabolizer, in whom the therapeutic effect cannot be
obtained with conventional dose only [1].
There is no
definition of persistent or Chronic Post-Surgical pain (CPSP) that
distinguishes its mechanism from acute pain. Its definition for chronicity
relates only with the time duration, which
International Association for
the Study of
Postoperative pain is a potent trigger for
the stress response; it has resulted from not only local tissue injury but also
from sensitization of central nervous system which creates pain from a wider
area (secondary hyperalgesia).
Secondary hyperalgesia is thought to be a
basis for chronic postoperative pain which has many mechanisms related to
memory at supraspinal sites. It is defined as mechanical hypersensitivity in
uninjured tissue surrounding the wound, amplifies postoperative pain and
contributes to chronic pain [1,2,5].
In human pain research, the anterior
cingulate cortex of the brain has been implicated in a number of persistent or
chronic pain syndromes. The thalamus is frequently activated as well in the
process. The potentiation of anterior cingulate cortex neuronal activity
induced by thalamic bursting suggests that short-term synaptic plasticity
enable the processing of nociceptive information from the medial thalamus. This
variability of temporary response is particularly important in pain because it
maintains the response which supports cortical integration and memory formation
related to noxious events. Moreover, these modifications of cingulate synapses
appear to regulate afferent signals associated with persistent peripheral
noxious stimulation that may be important in the transition from acute to
chronic pain [1].
Some meta-analysis studies have shown that
epidural analgesia is recognized to provide excellent quality of analgesia for
each postoperative day, for all types of surgeries and all types of pain
assessment methods. It showed a relative lower complication rate, more superior
to parenteral opioids following upper abdominal, thoracic, pelvic and lower
extremities orthopedic procedures [6-10]. In the study conducted by Kaynar et
al. [9] showed that intermittent bolus of the epidural catheter has a wider
spread of sensory analgesia compared to the continuous epidural infusion (CEI),
which probably contributes to the better quality of the nerve block in the
clinical setting.
Despite the advantages in intermittent
epidural boluses in managing persistent postoperative pain, a higher dose of
local anesthetics is required for effective epidural analgesia when it is used
alone. It may be associated with its limited duration of action and
dose-dependent deleterious adverse effects on the cardiac and central nervous
system. To decrease these “dose-dependent” side effects and prolong the
duration of analgesia of local anesthetics, opioids are commonly added [10-15].
However, since epidural opioids may be associated with distressing side effects
for instance nausea, vomiting, pruritus, urinary retention and respiratory
distress, therefore, the non-opioid drugs like midazolam, clonidine and others,
have been investigated as the promising adjuvants to epidural local
anesthetics. Potential advantages of these agents include a reduction in the
dose of individual drugs, opioid requirements and opioid-related side effects
[10].
Midazolam, a water-soluble
benzodiazepine/type Gamma-aminobutyric acid (GABA)-A produces an analgesia
action through GABA-A receptor complex and reducing the excitability of the
spinal cord. Midazolam can be used as an ideal epidural and intrathecal
analgesic for persistent postoperative pain due to its widespread availability,
low cost and excellent patient tolerance [6].
Intrathecal (preservative-free) midazolam
produces spinally mediated analgesia by the effect in the type
benzodiazepine/GABA-A receptors which distributed in a consistently similar
fashion in the gray matter of the cervical, lumbar and sacral regions within
lamina II of the dorsal horn human spinal cord. This region plays a prominent
role in processing nociceptive and thermoceptive stimulation along with a possible
role in pain modulation [14,16-18]. The GABA-A receptors and the GABAergic
system have been proposed to play an important role in the presynaptic
inhibition of primary afferents nervous system. GABA binding results in a
change of receptor configuration, opening an ion channel which allows an influx
of chloride ions down their electrochemical gradient into the cell. This
results in hyperpolarization of the neuron and reduces action potential
propagation and by reducing the glutamate release in the spinal cord. Thus, it
modulates gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter
in the brain [17-19]. The intrathecal midazolam is also been shown to act at
opioid receptors which may potentiate the anti-nociceptive effect of morphine-like
agents by acting as a direct agonist at kappa (κ) and delta (δ) opioid receptor
site in the spinal cord [7,11]. The epidural midazolam also exerts antiemetic
action through an unknown mechanism. It is probably due to glycine mimetic
inhibitory effect, enhancement of the inhibitory effect of GABA, inhibition of
dopamine release, and augmentation of adenosine-mediated inhibition of dopamine
in the chemoreceptor trigger zone [20-22]. The incidence of neurological
symptoms after intrathecal midazolam was uncommon (1.8%) and differed from
placebo (odds ratio 1.2, 95% CI 0.22 to 6.68, p=0.84) [7]. Although, concerns
with the possibility of epidural midazolam toxic effects, particularly in
neonates continue to persist. Recently available evidence suggests that a small
diluted dose of less than 1 mg/mL preservative-free midazolam (Dormicum®
F, Hoffmann-La Roche Ltd., Basel, Switzerland) or Midazolam Torrex, Torrex
Chiesi Pharma GmbH, Vienna, Austria) shows no neurotoxicity [13]. Previous
studies have found that epidural midazolam in a dose of 50 mcg/kg diluted in 10
mL of saline co-administered with local anesthetics has been shown to be
effective in providing prolonged postoperative analgesia without significant
adverse effect in adults undergoing orthopedic, urological, lower abdominal
surgeries, cesarean sections and children undergoing the urologic procedure
[12,13]. In 2005, Agrawal et al conducted a study on postoperative pain relief
following intrathecal administration of 1 mg preservative-free midazolam with bupivacaine
in patients scheduled for elective lower abdominal, lower limb orthopedic
procedure and endoscopic urological surgeries. Time to the first rescue
analgesic in patients who received bupivacaine alone was significantly earlier
than the patient who received bupivacaine and midazolam combination (4 ± 3.5 h
vs. 17.6 ± 8.87 h, p<0.0001). They concluded that intrathecal midazolam and
bupivacaine provides a longer duration of postoperative analgesia as compared
to intrathecal bupivacaine alone without extending the time for dermatomal
regression [14,16].
CASE REPORT
DISCUSSION
In recent days,
despite extensive progress in our understanding of pain physiology and
availability of multiple analgesic drugs and techniques, relieving persistent postoperative
pain specifically movement-associated pain remains unsatisfactory and becomes a
challenge in one-third of the patients. The concept of multimodal or balanced
analgesia Offers more advantage by creating additive or synergistic effects of
combining multiple technique and medications [2,3,20]. Epidural analgesia is
widely used for postoperative pain in a variety of surgical procedures and
recognized to provide excellent quality of analgesia when compared with
systemic opioids [6]. Recently, midazolam use has been extended to the epidural
and intrathecal route with considerable success as an adjuvant to decrease
“dose-dependent” side effect of local anesthetics. It also minimizes opioids
associated-distressing potential effect when it is used as the regiment of
postoperative epidural analgesia [9,10].
The comparison
between literature reviews and current evidence or studies support with the
application of this case are shown in Table 1.
CONCLUSION
The addition of
preservative-free midazolam (Dormicum®) to the intermittent bolus
epidural seems to be a promising adjuvant to persistent postoperative pain. Since
midazolam is also favored with its widespread availability, low cost and
excellent patient tolerance, it would be an ideal analgesic approach for
persistent postoperative pain. There was no significant adverse effect
(neurotoxicity, sedation effect, hypotension, respiratory depression,
nausea/vomiting, motor and sensory deficits, bowel and bladder dysfunction) of
midazolam use has been observed in this orthopedic surgery. This is in
accordance with the outcome of previous studies which showed that the potential
neurotoxicity of Midazolam can be avoided if the dosage is kept within the
safety range.
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