Acute Pain

Dr Julian Murphy

Objectives
1. Acute pain mechanisms.
2. Acute pain management for cancer surgery.
3. NSAIDs.
4. Opioid Tolerance and Opioid Induced Hyperalgesia.
5. Improving perioperative analgesia.

Acute pain mechanisms.

The International Association for Study of Pain defines pain as an unpleasant sensory and
emotional experience associated with actual or potential tissue damage.
Pain is a complex perceptual experience that in addition to conveying sensory information
such as location, type, and intensity of a stimulus, also has profound affective and cognitive
features. Pain is not a stimulus. There are no pain fibers in nerves or pain pathways in the
central nervous system. Pain perception is the final product of a complex information-
processing network. It requires a functional cerebral cortex. Whether or not a particular
stimulus will be perceived as painful depends not only on the nature of the stimulus, but
also on the context within which it is experienced, memories and emotions. One has to be
conscious to experience pain.
Nociception and the perception of pain is a physiological process necessary for survival.
Pain may be characterized as inflammatory (nociceptive) or neuropathic.
Nociceptive pain is defined as noxious perception resulting from cellular damage following
surgical, traumatic, or disease related injuries. Nociceptive pain has also been termed
inflammatory pain because peripheral inflammation and inflammatory mediators play major
roles in is initiation and amplification.
Neuropathic pain is defined by the International Association for the Study of Pain as pain
initiated or caused by a pathologic lesion or dysfunction in peripheral nerves and the central
nervous system. Neuropathic pain can manifest acutely and neuropathic pain must be
considered when treating acute pain states for example post operative pain. The clear
separation between inflammatory and neuropathic pain does not exclude inflammatory
components in neuropathic pain or neuropathic components in inflammatory pain.
The realization that neuropathic pain contributes to acute pain has resulted in studies being
published where drugs such as gabapentin and pregabalin are being evaluated for
postoperative pain management.
Nociception.
The body’s perception of noxious stimuli. Nociception may be interpreted as pain in a
conscious brain (functioning cerebral cortex).
Nociceptor.

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The term nociceptor refers to the entire sensory neurone which responds to injurious or
potential injurious stimuli. The free nerve endings of nociceptors contain receptors capable
of transuding chemical, mechanical and thermal stimuli into action potentials
Nociceptive terminals innervate a wide variety of tissues and are present in both somatic
and visceral structures but, interestingly, not the brain. A-delta and C fibers are the classic
nociceptors. A-beta fibers which normally respond to light touch may respond to noxious
stimuli in the setting of peripheral and central sensitization.
Glutamate is the major excitatory neurotransmitter of nociceptors. Substance P and
calcitonin gene-related peptide are peptide transmitters of nociceptors.

Peripheral Sensitization.
Prolonged noxious stimulation can sensitize nociceptors. Sensitization refers to a decreased
threshold as well as to an increased response to noxious stimulation.
Tissue injury and inflammation lower the firing threshold of the A-delta and C nociceptive
afferents into the non-noxious range. The mechanism involves the synthesis and release of
prostaglandins, bradykinin, histamine, 5HT, ATP, K+, H+, epinephrine, norepinephrine,
substance P, cholycystokinin and calcitonin gene related peptide. These mediators make up
the Inflammatory Soup responsible for peripheral sensitization.

Central Sensitization.
When primary afferent nociceptors begin to respond to weak, normally non-painful stimuli
(peripheral sensitization), the result is allodynia and hyperalgesia. The pain is amplified
when second order and third order sensory neurons in the CNS respond to the increased
neural traffic from the periphery. This is central sensitization. These processes work in
tandem. Central sensitization may be the outcome of a large variety of molecular, cellular,
and circuit changes that occur in the CNS. If these changes are due to CNS injury, the result
is central pain. Prominent among the mechanisms that have been implicated in the
generation of central sensitization is an NMDA receptor mediated potentiation of dorsal
horn nociceptive processing. When glutamate, released from primary afferent neurons,
binds to the NMDA receptor there is an influx of calcium into the postsynaptic neurone. This
influx initiates cascades of biochemical processes, including the induction of new genes,
which contribute to the strengthening of synapses and central sensitization. Central
sensitization is triggered by impulse traffic entering the CNS from the periphery generated
by ether inflammatory or neuropathic injury.
Peripheral and central sensitization is a normal physiological processes resulting from tissue
injury, for example surgery, and usually resolves back to the base line state. The issue is
whether perioperative analgesic techniques can attenuate activation of these processes and
result in better perioperative analgesia and lessen the occurrence of persistent or even
chronic pain.

Spinal chord laminar organization.

The dorsal horn synapse is an important site for further processing and integration of the
incoming nociceptive information.

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May be the point at which nociceptive information is conducted to higher centres or it may
be the point at which nociception is inhibited by descending systems or other sensory
inputs.
Neurotransmitters:
Numerous neurotransmitters and other biochemical mediators are released in the dorsal
horn from: primary afferents, interneurones and descending fibre systems. The
neurochemistry of the dorsal horn is complicated and there are qualitative differences
between the physiolology of acute pain and that of facilitated pain states. Some of the
neurochemical mediators can be categorised as excitatory or inhibitory, although many
serve complex and mixed functions.
Examples:
a) Excitatory Neuromediators
Exciatory animo acids – glutamate and aspartate, sustance P (SP)g calcitonin gene
related peptide (CGRP),growth factor, brain–derived neurotrophic factor (BDNF)
b) Inhibitory Neuromediators
Endogenous opiods,GABA (Gamma amino butyric acid),
Glycine.

In 1954 Rexed demonstrated that the grey matter of the spinal cord could be divided into
cyto-architecturally distinct layers or laminae.
Lamina 1 (Marginal Layer):
Cells respond primary to noxious stimuli.
Lamina II (Substantia Gelatinosa)
Contain small interneurones; many respond to noxious inputs. Lamina II neurones
modulate cells of lamina I and V. Laminae 1 and 2 receive direct primary affrent input
only from small-diameter fibers.
Laminae III & IV
Cells respond to innocuous stimuli.
Examples are hair brush and tactile skin stimuli.
Lamina V
Cells respond to noxious and non noxious stimulus; as such they are wide dynamic range
cells (WDR). They also respond to noxious visceral stimuli. They receive excitatory input
from large and small diameter afferent fibers.
Lamina VI
Cells respond to joint movement as well as to cutaneous stimulation.
Wide dynamic range cells
In addition to convergence of different modalities of input, WDR neurones in lamina V
receive inputs from a relatively large area, i.e.,there is spatial convergence.
Single cells in lamina V of the dorsal horn of the spinal cord have a complex receptive field
consisting of at least two distinctive regions.
In the centre of the receptive field both innocuous and noxious stimuli are excitatory.
In the surrounding regions non noxious stimuli carried by large fibres are inhibitory.
This factor presumably accounts for the pain relieving effects of shaking one’s hand or
receiving vibrating stimuli or transcutaneous electrical nerve stimulation (TENS).

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By contrast removal of the inhibitory components of the receptive field, (e.g. after nerve
injury) might increase the response of a WDR cell to a noxious stimulus.
Pain modulation.
Segmental mechanisms: Gate control theory.
Activation of large fibres can suppress pain.The idea that the balance in activity in large and
small fibres is important is the basis of the gate control theory of pain. This theory proposed
that interneurones of the substantia gelatinosa regulate the input of large and small fibres to
lamina V cells, serving as a gating mechanism.The theory accounted for the fact that
analgesia can be produced by low-intensity stimulation of the skin or peripheral nerves
(TENS). Dorsal column electrical stimulation is also effective probably by antidromic
activation of large diameter primary afferents. It helps to shake your hand when it is burned
because this action predominantly activates large fibers.You do not shake your left foot to
block pain in your right hand; the pain control in this case is segmentally organised.
Supraspinal mechanisms (Brain stimulation produced analgesia)
There are also powerful “pain” (nociceptive) inhibitory mechanisms in the brain.Electrical
stimulation of the midbrain periaqueductal grey matter (PAG) produces analgesia in humans
and laboratory animals and also inhibits the firing of doral horn neurones that respond to
noxious stimulation. The descending control is mediated via an excitatory connection from
the PAG to serotonin (5-HT) - containg neurones of the nucleus raphe magnus of the
medulla. The 5-HT axons from the nucleus raphe magnus inhibit the firing of neurones in
laminae I & V of the dorsal horn. There are also parallel descending noradrenergic inhibitory
controls. The latter circuits may be the targets of tricyclic antidepressants in the treatment
of neuropathic pain. The PAG to the spinal cord circuits constitue the brain’s endogenous
pain control system.
Opiates, Opiods and Endorphins
The PAG and dorsal horn contain high concentrations of opioid receptors. The brain contains
endogenous opioid compounds, the endorphin peptides.The endorphins are
pharmacologically similar to morphine and may be released by “pain” and possibly by
analgesia-producing electrical brain stimulation. In fact naloxone can reverse the analgesia
produced by brain stimulation. Placebo analgesia probably involves activation of this
endogenous pain control system and can be reversed be naloxone.
Supraspinal and Spinal mechanism of morphine analgesia
Systemic morphine produces analgesia in part by binding to opiod receptors in the PAG (
bypassing the endogenous opoid peptide). This process initiates PAG descending inhibitory
control of spinal cord nociceptive transmission neurones. Opiods also act in the thalamus
and parts of the cerebral cortex, with a high dentisty of receptors in the anterior cingulate
cortex (ACC). The opiate receptorsin the ACC may be particulary important for the affective
dimention of pain.
Local injection of opiods, usually morphine, either epiduarally or intrathecally also produces
a very profound analgesia. This results in part from a post synaptic inhibition of laminae I
and V neurones and from a presynaptic block of the release of neurotransmitters (e.g.
subtance P and CGRP) from small diameter primary afferents.

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Analgesia for Cancer surgery.

Major surgery is associated with immunosuppression, which, together with the release of
cytokines, chemokines, and prostaglandins, can facilitate angiogenesis, tumor metastasis,
and tumor invasion. In particular surgery inhibits the natural killer (NK) cells, which are the
major first-line defense against the development and spread of primary tumors and the
metastatic spread of established tumors.

There is increasing evidence from experimental studies and a limited number of clinical
studies that some anaesthetics and opioids may be contributing factors to the development
of metastases after cancer surgery.
Pain, a potent stimulant of the hypothalamic-pituitary-adrenal (HPA) axis, has been
implicated in causing immunosuppression, making pain management particularly important
in cancer surgery. Pain activates the HPA axis and the sympathetic nervous system, thus
setting off a cascade of events that leads to immunosuppression. Acute pain has been
shown to suppress NK cell activity. The treatment of pain is therefore particularly important.
Unfortunately it has been established that certain opioids morphine in particular inhibit
cellular and humoral immune function in humans.
Opioids can possibly promote the dissemination of malignant cells by the following
mechanisms.
1. Stimulate angiogenesis a key factor in the growth and dissemination of cancers, in part by
activating cyclooxygenase-2, increasing production of prostaglandin E2, which promotes
angiogenesis and tumor progression.
2. Influence Immune system
a. Indirectly via the hypothalamic-pituitary-adrenal axis.
b. Directly through opioid receptors, especially µ3 receptors expressed on
immunocytes. These receptors are involved in signaling pathways that modulate
antibody production and the activity of NK cells. There is compelling evidence that
animals, including humans, synthesize morphine and related morphinan alkaloids,
and that these endogenous opioids are involved in morphinergic signaling in immune
cells. The µ3 receptors are also expressed on human cancer cell lines where they are
coupled to constitutive nitric nitric oxide release.
Opioid alkaloids such as morphine bind strongly to the µ3 receptor, whereas binding
of synthetic opioids such as fentanyl and endogenous opioid peptides is considerably
weaker.
This explains why alkaloids such as morphine are predominantly
immunosuppressive, where as endogenous opioid peptides are predominantly
immumostimulatory.

NSAIDs, especially those with COX-2 inhibitory activity, have been shown to reduce the risk
of several types of cancer, including colon, breast and prostate cancers. These studies were
related to the chronic use of NSAIDs. Forget et al. has published an article suggesting that a
single dose of an NSAID given intraoperativly may significantly reduce cancer recurrence

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after surgery. Cancer recurrence after surgery was less in the group given ketorolac (6%)
immediately before skin incision than those that did not receive ketorolac. There are
important limitations to this study. Despite these reservations the analysis of their data is
sufficiently robust that the implications of their findings cannot be ignored. Surprisingly no
association between cancer recurrence and the use of diclofenac in the postoperative
period was found. Ketorolac and diclofenac have similar have similar COX-1 and COX-2
activity so similar influence on cancer recurrence would have been expected
Increased expression of COX-2 occurs in many types of cancers and is a crucial element not
only in the pathogenesis and dissemination of tumors but also in increasing their resistance
to apoptosis, and with the generation of prostaglandins and related compounds that
support carcinogenesis.
In addition to the inhibition of COX-2 and prostaglandin synthesis by NSAIDs recent studies
have suggested that COX-independent pathways may contribute to the anticancer actions of
COX-2-selective NSAIDs.
Therefore, there are good arguments for using COX-2-specific inhibitors in anaesthesia; in
addition to providing analgesia there by reducing the amount of opioid needed for optimal
analgesia, they can contribute to minimizing the risk of tumor growth and spread.

Non-steroidal antiflammatory drug update.

NSAIDs have analgesic, antipyretic and in higher doses anti-inflammatory effects. NSAIDs
when given for postoperative pain can reduce the dose of opioid analgesia required by 20%
to 50%.
Most NSAIDs are non-selective inhibitors of the enzyme cyclo-oxygenase, inhibiting both the
cyclo-oxygenase-1 and cyclo-oxygenase- 2 iso-enzymes. Originally thought that analgesia
was related to elimination of the inflammatory process via cox-1 and cox-2 inhibition.
However NSAIDs reduce cutaneous and corneal pain induced by acidic pH in the absence of
inflammation and it has now been shown that NSAIDs inhibit the activity of acid-sensing ion
channels (ASICs) at therapeutic doses and thus produce analgesia by preventing
transduction of nociceptors by tissue acidosis. NSAIDs may inhibit ASIC channel expression.
ASIC channels are members of the sodium channel super family and are activated by
increase in extracellular acidity. Six different isoforms of the ASIC channels have been
identified and different NSAIDs may inhibit different ASIC channels.
As was pointed out in the editorial; Perioperative Analgesia: What Do We Still Know?
Postoperative administration of COX-2 inhibitors has consistently been demonstrated to
have beneficial effects in improving analgesia, reducing opioid-related side effects, and
improving quality of patient recovery in the early and intermediate postoperative period.
However, the potential for long-term clinical benefits remains to be confirmed.
There is no longer unequivocal evidence supporting the preemptive effect of NSAIDs and
COX-2 inhibitors.
The ultimate clinical effect of NSAIDs and the COX-2 inhibitors, in particular, on bone fusion,
remains unclear and further investigative work is needed in this controversial area.
The ability of a multimodal preemptive analgesic regimen to prevent the development of
chronic pain after major orthopedic surgery remains unproven.

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Dr J Murphy
2010 FCA II Refresher Course Page 6
Opioid Tolerance and Opioid-Induced hyperalgesia. (OIH)

Tolerance is a problem of desensitization of opioid antinoceceptive pathways caused by

exposure to opioids.
Mechanisms of Tolerance.
Opioid tolerance cannot be ascribed to a global down regulation of receptors. Attention has
turned to the issue of receptor trafficking and receptor-effector coupling. Work suggests
that the µ-opioid receptor and δ-opioid receptor are functionally uncoupled from second–
messenger systems after acute and chronic opioid exposure.
Phosphorylation is one of the first events in this uncoupling and the rate and degree of
phosphorylation are highly dependent on the agonist with more rapid phosphorylation
observed for high potency agonists such as remifentanil than for morphine itself.
The N-Methyl-d-Aspartate Receptor (NMDA) and Protein Kinase activation is involved in this
process.
The NMDA receptor is one of the principal excitatory receptors and is expressed throughout
the central nervous system. The postulated mechanism is that exposure to an opioid leads
to activation of the NMDA receptor which opens the NMDA pore to admit calcium. The
increased calcium ion concentration then activates Protein Kinase C, which leads to the
activation of other proteins resulting in tolerance. The simultaneous administration of an
NMDA antagonist dextromethorphan and morphine has been used in attempts to reduce
opioid tolerance in humans. A study by Galer showed no change in pain relief or morphine
consumption.
Opioid Induced Hyperalgesia is a problem of sensitization of pronociciceptive pathways
caused by exposure to opioids.
It is characterized by a paradoxical response whereby a patient receiving opioids for the
treatment of pain may actually become more sensitive to pain over time. This increased
sensitivity to pain is a new, unique entity that is distinct from the patient’s original
underlying painful condition. In clinical settings, OIH may represent one of many reasons for
declining levels of analgesia while receiving opioids. This phenomenon is thought to result
from neuroplastic changes in the central and peripheral nervous systems leading to the
sensitization of pronociceptive pathways. When treating acute pain in a patient who has
developed tolerance increased doses of opioid will be required. Increasing the dose of
opioid in a patient who has OIH may worsen the patient’s pain. In the perioperative period
exclusion of other causes of pain such as bleeding, infection and ischemia must be excluded.
Mechanistic distinction of Tolerance and Opioid Induced Hyperalgesia
Analgesic tolerance and OIH generally occur under similar circumstances and some
investigators believe that opioid tolerance and OIH are different manifestations of the same
underlying physiological changes.
Only a few clinical studies have looked at the development of tolerance and or OIH in the
acute perioperative period when high dose remifentanil has been used and the results are
contradictory.
Modulation of OIH and tolerance.
Ketamine is an uncompetitive antagonist of the phencycidine-binding site on the NMDA
receptor. Several recent studies have examined the use of ketamine in low subanaesthetic

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dose in conjunction with opioid medications in an attempt to attenuate the expression of
OIH and or tolerance.
There is some evidence to show that perioperative administration of low-dose ketamine
may modulate the expression of OIH or tolerance and that it reduces postoperative wound
hyperalgesia. These findings support the hypothesis that NMDA receptor antagonism
modulates changes in antinociceptive and pronociceptive systems. The clinical significance
of these benefits still needs to be proven.
Does tolerance develop to remifentanil infusions? A cold-water immersion test suggested
tolerance, however in a three-hour study using heat and electrical models of pain in human
volunteers did not show this. Only a few clinical studies have looked at the development of
tolerance and or OIH in the acute perioperative period. These studies suggest that when
high dose opioid techniques are used intraoperatively patients have a higher opioid
requirement postoperatively. Not all studies have reached this conclusion. These results
may seem paradoxical given the lingering belief that aggressive analgesia might actually
reduce postoperative pain and analgesic requirements. It is not resolved at this point
whether this modest to moderate post operative increase in opioid consumption resulting
from limited acute tolerance results in poorer pain control, greater frequency of opioid side
effects and poorer surgical outcomes. It should be noted that these clinical types of data
only provide indirect evidence for the development of tolerance and an alternative
explanation, (OIH) may explain observed differences in postoperative opioid consumption
and pain. Tolerance to fentanyl and remifentanil has been reported in the ICU setting where
these drugs are used for sedation particularly in pediatric patients.

Improving postoperative pain Management.

Despite advances in our understanding of the physiology of acute pain, the availability of
new drugs and techniques postoperative pain management remains a challenge in many
situations.
Multimodal Analgesia
The concept of multimodal opioid sparing analgesic techniques was introduced with the aim
of improving analgesia by combining analgesics with additive or synergistic effects. Although
only a limited number of well conducted, prospective randomized clinical trials have
demonstrated improved clinical outcomes with respect to analgesia and opioid related side
effects with multimodal compared to single therapy, meta analyses of single modality,
nonopioid analgesics have demonstrated clinically significant reduction in postoperative
nausea, vomiting and sedation. The beneficial effects of multimodal therapy with respect to
other common side effects such as bowl and bladder dysfunction and improvement in
dynamic analgesia have been less consistently reported.
Although upload-related side effects have been extensively reported in the literature, non
opioid analgesics such as acetaminophen, classic and cyclooxygenase selective nonsteriodal
antiinflammatry drugs, ketamine, and gabapentanoids have their own unique side-effect
profiles (hepato and renal toxicity, coagulation effects, confusion, sedation and dizziness),
which may be exacerbated when they are administered as a part of a multimodal regimen
after surgery. The benefit risk ratio for analgesic drug combinations is therefore dependent
on the type of surgery.

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Procedure specific protocols for analgesia need to be introduced. Recommendations for
certain procedures are available on the PROSPECT WEB site.
Studies comparing quality of postoperative analgesia with improved clinical outcomes have
been disappointing. This may be due to poor protocol design where more clinically
meaningful endpoints such as resumption of dietary intake, recovery of bowl and bladder
function and resumption of normal physical activities should be studied instead of surrogate
endpoints such as changes in pain score.
The issue regarding the relationship between the management of acute pain and the
development of chronic pain remains controversial.
The ability to identify patients with both high and low risk of developing clinically significant
pain after surgery will enhance the efficacy and safety of analgesic therapies. A recent study
identified that the most important predictors of post operative pain after ambulatory
surgery were (1) the presence of pre- operative pain, (2) patient and physician expectations
regarding the level of pain after the operation, (3) patient fear regarding the short-term
outcome of their surgery (4) age of the patient (5) hyper vigilance.
The Way Forward.
Begin implementing procedure–specific, evidenced based protocols in the perioperative
period. However these procedure specific analgesic care maps need to be combined with a
fast track recovery strategy to obtain the desired improvements in patient outcome.
Although the existing evidence in the literature fails to support the concept that
improvement in pain management automatically leads to enhanced recovery and reduced
morbidity it is clear that improvements in patient satisfaction can be constantly achieved.
More attention should be directed towards targeting nociceprors in the periphery. The
potential for clinical improvement in pain related outcomes is exciting because it is simple
and targets pain at the site of origin before centrally mediated changes occur in the spinal
cord and cerebral cortex. In the future, local applications of long acting local anaesthetic
formulations (e.g. depo-bupivacane) and topical capsaicin may eventually obviate the need
for cumbersome and expensive catheter deliver systems. The development of drugs, which
target the receptors on the peripheral nerve endings. Capsaicin produces prolonged
inhibition of C-fibers by interacting with transient receptor potential vanilloid 1 binding sites
and has recently been reported to produce sustained pain relief lasting 3-5 days after
surgery. The selective cannabinoid receptor-1 agonists may be used in the future.
Preliminary clinical data suggest that even old drugs such as glucocorticoid steroids may
provide sustained analgesia without clinically significant side effects in the peri- operative
period.
Another very important area for future research includes the need to develop a more in
depth understanding of the basis of the large individual variability in the pain response to
similar noxious surgical stimuli. In the future, an improved and individualized approach to
acute pain management may be possible if we can determine the patient’s pain threshold
before the operation. Genetic research may allow the ability to identify high vs. low pain
responders
Pharmacogenetics is an intriguing area for future investigations aimed at improving pain
management. A report has been published suggesting an association between µ-opioid
receptor gene polymorphism and the variation in morphine requirement after lower
abdominal surgery.

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Dr J Murphy
2010 FCA II Refresher Course Page 9
Other potentially important areas for future research in acute pain management relate to
the influence of age, gender and metabolic factors on patient response to analgesic
medication.
The concept of preemptive analgesia needs to be carefully reexamined because data from
randomized controlled trials have produced confusing findings. In addition information is
needed on the optimal duration of postoperative treatment.
Finally the effect of individual analgesic agents on the immune system will need to be
addressed.

Reference.

1. Editorial. Anesth Analg 2010;110:1524-26.

2. Forget P et al. Do intraoperative analgesics influence influence breast cancer
recurrence after mastectomy? A retrospective analysis. Anesth Analg
2010;110:1630-1635
3. Editorial. British Journal of Anaesthesia 2008;101 (3): 291-3
4. Gottschalk A. The role of preoperative period in recurrence after cancer surgery.
Anesth Analg 2010; 110: 1636-1643
5. White F. Perioperative analgesia: What do we still know? Anesth Analg 2009; 108:
1364 – 1367
6. Basbaum A et al. Pain: Basic mechanisms. Pain 2008 An updated review: Refresher
course syllabus: 3 – 10
7. Sinatra R et al. Acute Pain Management.2009.
8. White P et al. Improving postoperative pain management. Anesthesiology V112. No
1: 220 – 225
9. Kehlet H et al. Persistent postsurgial pain: risk factors and prevention. Lancet 2006;
367: 1618 - 1625

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Dr J Murphy
2010 FCA II Refresher Course Page 10