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Department of Anaesthesia

University of Cape Town


Lecture 13
Peri-operative Pain Management

This chapter will serve to give you an understanding of all types of pain. Anaesthetists manage intra-
operative pain as part of the triad of anaesthesia, and we prescribe medication to control post-
operative pain. Anaesthetists are also involved in the management of chronic pain; however this is a
subject of a textbook on its own! Our aim of this lecture is to provide you with a basic review of pain
physiology, but more importantly to give you an approach to acute post-operative pain management
as a junior doctor.

Definitions
Pain
Unpleasant sensory and emotional experience associated with actual or potential tissue damage
or described in terms of such damage (IASP International Association for the Study of Pain).
Nociception
The detection, transduction and transmission of a noxious stimulus, associated with tissue
damage and

/

or inflammation.
The word pain is derived from poena the Latin word for punishment! Pain is the perception of
nociception that occurs in the brain and is determined by memory, emotion, interpretation and genetic
influence. Perception of nociception implies a subjective experience and no actual tissue damage
needs to be present.

Classification
Acute Pain
This implies recent onset and of a short duration less than 6 weeks. It is associated with trauma,
surgery or acute Illness limited to the area of damage or disease; and resolves with healing. Acute
pain includes post-operative pain.
Chronic Pain
Pain that persists beyond the usual course of an acute illness or injury (usually beyond 3 months)
outlasting the potential for healing. Chronic pain can also be AIDS-related or due to terminal
cancer.

Pain mechanism

Potentially harmful thermal, chemical or mechanical stimuli activate free nerve endings called
nociceptors. If the required activation threshold is reached (depending on the intensity of the
stimulus and the type of nerve fibre), depolarisation results in the propagation of an impulse from the
nociceptors to the dorsal horn of the spinal cord. A- (delta) fibres transmit a sharp, well
localised pain, followed by a dull, persistent pain via C-fibres. The release of inflammatory
mediators (K
+
, serotonin, substance P, histamine, cytokines, nitric oxide, and prostaglandins) lowers
the firing threshold of receptors in the injured area, resulting in a zone of primary hyperalgesia.
Hyperalgesia is an increased sensitivity to pain. The 1
st
order neuron synapses with 2
nd
order
neurons in the dorsal horn of the spinal cord. The impulse then crosses the midline and ascends
via the anterior and lateral spinothalamic tracts to the thalamus, where the axons synapse with 3
rd

order neurons. These send axonal projections to the sensory cortex most importantly; and also to
Peri-operative pain management

13 - 2
the limbic system, cerebellum, peri-aqueductal grey matter (PAG) and reticular formation (RF).
Various excitatory (glutamate, substance P, and neurokinin A + B) and inhibitory (GABA and
glycine) neurotransmitters play a role in these pathways.
Descending inhibition is a means of decreasing the pain stimulus. The most important site of pain
modulation is in the dorsal horn where the 1
st
and 2
nd
order neurons synapse. Efferent neurons in
the brainstem send impulses to the outer layers of the dorsal horn, where the release of
neurotransmitter substances (endorphins, enkephalins, noradrenaline, serotonin and GABA)
dampen the nociceptive transmission by making the post-synaptic membrane more difficult to
depolarise or by impairing the release of nociceptive neurotransmitters.
As the inflammatory process subsides and healing occurs, the nervous system returns to a resting
state. In chronic pain, an excited, sensitised state persists beyond the healing period.

Pharmacological management of pain
80 % of GP-visits are prompted by pain of one sort or another. You must have a sound knowledge of
analgesic options for your patients. Treatment depends on the aetiology of the pain. The World
Health Organization (WHO) suggests a step-wise approach when treating pain. Mild pain should be
treated with simple analgesics which include Paracetamol, non-steroidal anti-inflammatories (NSAIDS)
and Codeine (a weak opiate). With moderate pain, a higher dose of Codeine can be introduced or
Tramadol. With severe pain the stronger opioids are used, e.g. Morphine and Fentanyl. An
understanding of the patients psycho-social background can aid your approach to the management
of pain in a particular patient.
The approach to peri-operative pain management is slightly different and although the WHO step-wise
approach may be followed, it does not comprehensively cover the treatment of surgical pain. There
are also several additional drugs and modalities available to anaesthetists.

Drugs used in the management of peri-operative pain
A multi-modal approach is important and based on the knowledge that there are many different
receptors and transmitters involved in nociception. Using several different classes of drugs to act at
different points in the pain pathway will give more effective analgesia, and the synergistic actions of
the different classes will reduce total doses and side effects.
Classes of Drugs
Simple analgesics Local anaesthetics
Paracetamol Bupivacaine and Lignocaine
NSAIDs (Non-steroidal anti-inflammatories) Hypnotic agents
Diclofenac (Voltaren

)
Indomethacin (Indocid

)
Ibuprofen (Brufen

)
Celecoxib(Celebrex

)
IV: Parecoxib (Rayzon

), Ketorolac
N
2
O
Ketamine
Opiates Secondary analgesics (chronic pain)
Codeine
Tramadol
Morphine
Pethidine
Fentanyl, Sufentanil and Alfentanil
Remifentanil
Tricyclic antidepressants and SSRIs
Anti-convulsants
Gabapentin

2
-agonists: Clonidine, Dexmedetomidine
Steroids
Psychology

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13 - 3
Simple analgesics
Paracetamol
Paracetamol is termed a simple analgesic, although its exact site and mechanism of action is
unknown. It is thought to act centrally and peripherally, and it has an anti-prostaglandin effect via a
COX-3 enzyme. It has mild analgesic properties, but this does not mean that it is not effective in the
treatment of intra- and post-operative pain. It is very efficacious and can be used alone for minor
surgery or in conjunction with the other stronger analgesics for major surgery. It is felt that the
maximum analgesic effect of Paracetamol is greater than any of the other non-opioid analgesics,
i.e. NSAIDs. It has no anti-inflammatory properties; however it does have anti-pyretic properties.
Paracetamol is a safe drug and only has side effects in overdose, in terms of potential fulminant
hepatic necrosis and failure. Paracetamol overdose is a medical emergency and should be treated
rapidly, and N-acetylcysteine is given as an infusion to protect from the development of liver damage.
Dose:
Adults: 1 g orally

/

rectally 6-hourly. Maximum 6 g in 24 hours.
Children: 15 mg kg
-1
6-hourly. Do not exceed 90 mg kg
-1
day
-1
. 60 mg kg
-1
day
-1
in neonates due
to liver immaturity.
Onset of action following oral or rectal administration is 30 minutes. Duration of action is 2


5 hours.
In 2005, the intravenous form of Paracetamol was released, called Perfalgan

. It is a welcome
addition to the anaesthetists armamentarium in the treatment of peri-operative pain; and it is more
effective than the oral or rectal route due to its improved bio-availability and faster onset time of 5


10
minutes. 1 g IV is equivalent to 10 mg IM Morphine. It is particularly useful if the patient is nil per os,
and if sedating opiates should be avoided. It is available in most provinces in the state sector for use
in the first 24


48 hours post-operatively. Dose: 1 g IV 6-hourly (4 doses) for adults and 15 mg kg
-1
IV
6-hourly for children to a maximum of 60 mg kg
-1
day
-1
. Dose in neonates is reduced to 7,5 mg kg
-1

due to liver immaturity.

NSAIDs
NSAIDS inhibit cyclo-oxygenase (COX), thereby inhibiting the production of prostaglandins and
thromboxanes from membrane phospholipids.
Membrane Phospholipids
Arachidonic Acid
Cyclic Endoperoxidaes
Thromboxane
PGI
2
PGE
2,
PGF
2,
PGD
2
PLA
2
COX
Platelets
Endothelium
Widespread

Aspirin binds irreversibly to COX. NSAIDs cause reversible enzyme inhibition. They have an
antipyretic action via inhibition of central prostaglandins. The inhibition of thromboxane production
results in reduced platelet aggregation and risks of bleeding. There are 3 types of COX enzymes,
COX-1 and COX-2 are important here. The role of COX-3 is yet to be fully elucidated. COX-1 is
constitutive and helps maintain normal physiology with important roles in renal blood flow,
haemostatic function, and mucosal integrity. COX-2 is inducible and is expressed in response to
tissue damage. NSAIDS are classified as non-selective (inhibiting both COX 1 and COX 2) and
selective COX-2 inhibitors. Important side-effects include gastric irritation, bronchospasm, renal
dysfunction, platelet dysfunction, hepatotoxicity, and myocardial infarction. NSAIDS can be given
orally, rectally, intravenously and intramuscularly and due to their anti-inflammatory action they
are useful in the treatment of musculoskeletal pain.

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13 - 4
Commonly used NSAIDs
Aspirin
10


15 mg kg
-1
for analgesia.
Children can develop Reyes syndrome.
We do not use aspirin for intra- and post- operative pain relief; it is included here for completeness
sake, as it is a commonly used NSAID.
Non-selective NSAIDs
Ibuprofen (Brufen

)
Adult: 200


400 mg orally 8-hourly.
Children: 5


10 mg kg
-1
orally 8-hourly.
Ibuprofen has the lowest incidence of side effects of these NSAIDS.
Diclofenac (Voltaren

)
Adult: 50 mg orally 8


12-hourly with a maximum dose of 150 mg daily.
Children: 1 mg kg
-1
orally or 1


2 mg kg
-1
rectally 8-hourly.
Indomethacin (Indocid

)
Adults: 25


50mg orally 8-hourly; 100 mg 12-hourly rectally.
Children: 0,5


1 mg kg
-1
8-hourly.
Indomethacin has the most potent anti-inflammatory effect, however the least analgesic effect.
Onset of action for Ibuprofen, Diclofenac and Indomethacin is approximately 30


60 minutes after
oral or rectal administration. Duration of action is 6


8 hours.
Ketorolac (Toradol

)
Adults: 10mg orally 4


6-hourly (0,2 mg kg
-1
). Max. = 90 mg day
-1
.
0,6 mg kg
-1
IM stat then 0,2


0,4 mg kg
-1
6-hourly.

Ketorolac is indicated for short-term management of moderate to severe acute pain requiring
analgesia at the opioid level, and therefore it is opiate-sparing (you need less opiate). Onset of
action orally is 30


60 minutes; IM 10 minutes and IV 5 minutes. Duration of action is 6


8 hours.

COX-2 Selective
Celecoxib (Celebrex

)
Adults: 100 mg orally 12-hourly or 200 mg daily
Indicated for acute pain of moderate to severe nature.
Onset of action orally is 30


60 minutes and duration 10


12 hours.
Parecoxib (Rayzon

)
Adults: 40 mg IV or IM followed by 20


40 mg 6


12-hourly. Max. = 80 mg day
-1
.
Onset of action is 5 minutes IV and 30 minutes IM. Duration of action 8


10 hours.
The COX-2 selective agents have been associated with an increased risk of myocardial infarction
with high doses and prolonged use. They are contra-indicated in high-risk patients.

Opiates
Opiates act centrally and peripherally on -, and receptors, which are found in peripheral and
central neurons. Endogenous agonists are endorphins and enkephalins. Endogenous agonists
and opiates act by reducing neuronal cell excitability. Stimulation of these receptors results in
analgesia, drowsiness, change in mood, nausea, bradycardia, respiratory depression, miosis, pruritis
and inhibition of gut motility with constipation. They are selective for pain and they do not interfere
with other sensory modalities. The patient may still have pain, but feels more comfortable.
Common side effects include nausea and vomiting, itching, constipation, and urinary retention. More
serious but less commonly reduced level of consciousness, respiratory depression and muscle rigidity
can occur. Patients can develop tolerance to opiates, requiring more to achieve the same effect.
They can become physically and psychologically dependant (resulting in withdrawal symptoms if the
opiate is discontinued). This is not a problem in the treatment of acute pain, and do not withhold
opiates on the false assumption that you may induce addiction. You are treating very real pain.
Opiates can be given intravenously, orally, intramuscularly, transdermally, and into the epidural and
intrathecal spaces. Opiates form the mainstay of peri-operative analgesia for severe pain.

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13 - 5
Commonly used opiates:
Codeine
Adults: 30


60 mg orally 4


6-hourly.
Available as a tablet and syrup in South Africa.
Panadeine

is a combination tablet with Paracetamol 500 mg and Codeine 8 mg.


10 % of the drug is metabolised to Morphine. Cytochrome P
450
polymorphism results in poor
metabolism in certain individuals, resulting in less pain relief.

Tramadol (Tramal

)
Adults: 50


100 mg orally and IV 4


6-hourly. Max. = 600 mg day
-1
.
Children: 1


2 mg kg
-1
4


6-hourly.
Onset of action orally is 30


60 minutes and 5


10 minutes IV. Duration of action is 2


5 hours. It
is an agonist at the opioid receptors. It also has an additional mechanism of action where it
inhibits the re-uptake of NA (Noradrenaline) and 5-HT (5-hydroxytrytamine or serotonin) at the pre-
synaptic nerve endings; and stimulates pre-synaptic 5-HT release. This is particularly important in
the descending inhibitory pathways. It produces less constipation and respiratory depression, but
more nausea. Drug interactions with SSRIs and Noradrenaline re-uptake inhibitors can result in
seizures and the serotonin syndrome.
Tramacet is a combination tablet with 325 mg Paracetamol and 37,5 mg Tramadol. It is a very
effective oral analgesic for moderate to severe post-operative pain. The reduced dose of Tramadol
lowers the incidence of post-operative nausea and vomiting.
Pethidine
Adults: 25


50 mg IV and 25


100 mg 4-hourly IM.
Children: 0,5


1 mg kg
-1
IV 4-hourly
Pethidine was originally designed as an anti-cholinergic agent and can produce a dry mouth and
tachycardia. Convulsions, hyperpyrexia, coma and a labile circulation can occur if it is
administered with monoamine oxidase inhibitors (MAOIs). Pethidine readily crosses the placenta
due to its lipid solubility, following its metabolism. Norpethidine, its metabolite, will accumulate in
the foetus, because it is less lipid soluble. Norpethidine is also thought to be responsible for
inducing seizure-activity. It is not a very good analgesic. It tends to have dissociative effects
where the patient feels spaced out but still experiences the pain. It is not commonly used for peri-
operative analgesia. It is still used regularly in obstetrics, perhaps on an historical basis. Morphine
is more potent and a superior analgesic.
Morphine
Adults + Children: 0,1


0,2 mg kg
-1
4


6-hourly IV and IM.
Oral dose is double the parenteral dose.
In adults, Morphine is titrated to effect intraop with boluses of 1


5mg IV.
Epidural and spinal administration enhances the analgesic effect of the local anaesthetics;
however this can predispose to delayed respiratory depression. Patients must be monitored in
high-care.
IV infusions of Morphine are infrequently used in the ward. They are reserved for the ICU or high-
care setting where the patient can be monitored for respiratory depression.
PCA (patient-controlled analgesia): 50 mg Morphine in 50 ml normal saline in an infusion pump.
Each time the patient presses a button a 1


2 ml bolus will be delivered IV. There is a 5


8
minute lockout time where no further dose can be administered even if the button is pressed. This
is a safety feature to prevent overdose. No background infusion is usually given. PCAs can be
used for opiates other than Morphine, e.g. Pethidine.
Fentanyl
Adults + Children: 1


2 g kg
-1
IV
Epidural and Spinal administration is common.
Fentanyl is more potent than Morphine and 600 times more lipid soluble than Morphine, therefore it
does not cause delayed respiratory depression when given into the epidural or spinal space. It is
less likely to cause histamine release. High doses can cause chest wall rigidity and bradycardia.
Apart from its analgesic effects, it is used at the induction of the anaesthetic with the IV induction
agent. This is termed co-induction, and the aim is to reduce the dose of the induction agent with
the synergistic effect of opiates. Fentanyl also depresses the laryngeal reflexes which is useful
when placing an LMA or ETT. Onset of action is quick at 3


4 minutes and it has a short duration
of action of 30


40 minutes, but can be up to 6 hours with a high dose.
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13 - 6
Sufentanil and Alfentanil
These are also synthetic opiates and short-acting when given as boluses. They can be given as
infusions. They are cardiovascularly stable. They are also used in co-induction, and to depress
laryngeal reflexes. Alfentanil particularly is useful at inhibiting the increased HR and BP seen with
the stimulation of laryngoscopy and intubation known as the intubation response.

Remifentanil
Infusion: 0,05


0,5 g kg
-1
min
-1
.
Remifentanil is an ultra-short acting opiate due to rapid metabolism by non-specific plasma and
tissue esterases. This is beneficial as it is not dependent on liver metabolism or renal excretion for
elimination. It is excellent at controlling the heart and blood pressure response with the intubation
response and during the stimulating periods of surgery. Hypotension, bradycardia, chest wall
rigidity and respiratory depression can occur. Additional long-acting analgesia for post-op pain
relief should be given 15


20 minutes before the termination of a case.
Naloxone: Opiate ANTAGONIST (Narcan)
Naloxone is an opioid antagonist at , and receptors. 1


4 g kg
-1
is given for opiate overdose.
The ampoules are 0,4 mg in 1 ml. Dilute with 9 ml normal saline into a 10 ml syringe and then you
have 40 g ml
-1
. It is antanalgesic and can also cause hypertension, arrhythmias and pulmonary
oedema.

Local anaesthetics
Local anaesthetics reversibly block the transmission of nociceptive impulses in a nerve by acting on
the Na
+
Channels. They can be injected at the surgical site, along the course of a nerve, or centrally in
the subarachnoid or epidural space. The commonly use local anaesthetics are Lignocaine and
Bupivacaine. Bupivacaine is usually the agent of choice due to its longer duration of action.
Regional anaesthesia in the form of peripheral nerve blocks and neuraxial blocks (spinals, caudals
and epidurals), is a very useful and effective technique in the multi-modal approach to anaesthesia.
Often the use of these blocks negates the need for opiates as the post-operative analgesia is so
effective. Even if regional blocks are not possible, do not forget the simple technique of asking the
surgeon to infiltrate local anaesthesia around the incision site as this will help with pain relief post-
operatively.

Hypnotic agents
Ketamine
Ketamine antagonises glutamate at the NMDA receptors; and it is an agonist at and opiate-
receptors, but an antagonist at -receptors. It produces dissociative anaesthesia. Indirect
sympathetic stimulation results in hypertension and tachycardia. It also produces bronchodilatation
and the airway is often maintained. Salivation and emergence phenomena are a problem. However,
it is a very potent analgesic even at sub-anaesthetic doses; and it is the only IV induction agent that
has any real analgesic effects.
Analgesic dose: 0,2


0,5 mg kg
-1
IV. 2


4 mg kg
-1
IM. Infusion 4 g kg
-1
min
-1
. 5 mg kg
-1
oral.
Induction dose: 1


2 mg kg
-1
IV. 5


10 mg kg
-1
IM. Infusion 10


40 g kg
-1
min
-1
.

2
agonists
Clonidine is an -agonist with a high affinity to
2
-receptors. Its analgesic action is in the spinal cord,
where it augments endogenous opiate release and modulates the descending noradrenergic
pathways. It can be given IV or intrathecal, but hypotension remains a problem.
Dexmedetomidine was released in 2005, and it has an even higher affinity to
2
-receptors with similar
effects to clonidine. It is given as an infusion. It has analgesic, anxiolytic and sedative effects without
causing respiratory depression, and only mild hypotension.

Multi-modal approach to post operative pain

Post operative analgesia has multiple benefits: Patient comfort and satisfaction; plus adequate
breathing and coughing, decreasing the incidence of post-operative lung infections as patients are
able to clear their secretions. Early mobilisation due to good analgesia reduces the incidence of deep
venous thrombosis and leads to an earlier discharge home. Limiting the stress response with good
analgesia also reduces the incidence of acute coronary events.
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13 - 7
The multi-modal approach can start pre-operatively with the concept of pre-emptive analgesia.
You pre-empt the pain by giving the analgesic with the premed or induction before the pain even
starts. This is thought to reduce the pain experienced and reduce the stress response. The benefit is
that the analgesia is working by the time most normal duration surgeries are complete. A good option
is to administer Paracetamol as part of the premed.
Intra-operatively a combination of a regional technique, an opioid and an anti-inflammatory agent is
often helpful. For minor procedures, local infiltration intra-operatively, and oral Paracetamol and
codeine post-operatively are often sufficient. For major procedures, intravenous opioids are added to
the simple analgesics and NSAIDs intra-operatively. Opiates can be given as IV boluses, as an
infusion intra-op; or as a PCA (Patient Controlled Analgesia) or IM post-op. Sometimes a Morphine
infusion is used post-op, but the patient must be in a monitored area to detect respiratory depression.
The IV route is preferred for all analgesics intra-operatively, and the intramuscular (IM) route is used
only post-operatively.
Remember Paracetamol and NSAIDS are still effective in major surgery and although you cannot
administer them orally as per the usual route; you can give them rectally or the more preferred route
IV, if these preparations are available. For example, IV Paracetamol (Perfalgan) and IV NSAIDs
(Ketorolac and Parecoxib) are very beneficial if used alongside the opiates.
In upper GI and thoracic surgery, epidural pain relief provides excellent analgesia. Local anaesthetic
opiates via the epidural can be continued for 24


48 hours. The patient must be monitored in a high-
care setting or ICU, or in a ward where the staff have been trained to deal with the problems with
epidurals.
Post-operatively, you should prescribe strong analgesia for the first few days alongside the simple
analgesics and NSAIDs; and as the patients pain subsides you can reduce the amount of analgesia.
A common prescription for post-operative pain in an adult would include the following:
Morphine 5


10 mg IM 4


6-hourly.
Tramadol 50


100 mg PO 4


6-hourly (do not prescribe both Morphine and Tramadol as both
are opiates, and increases respiratory depression).
Paracetamol 1 g PO

/

PR 6-hourly, or
A combination tablet: Panadeine 2 tablets 6-hourly.
NSAID e.g. Ibuprofen 400 mg PO 8-hrly or Diclofenac (Voltaren) 100 mg PR 12-hourly.
Remember to prescribe an anti-emetic with opiates: Prochlorperazine (Stemetil) 12,5 mg IM 8-
hourly or Ondansetron (Zofran) 4mg IV

/

IM 8-hourly.
Ultimately the choice of analgesics should be tailored to the patients underlying medical and surgical
conditions. For example, avoid NSAIDs in patients with peptic ulcer disease, renal failure and
asthmatics. Avoid Paracetamol in patients with liver dysfunction. And avoid opiates in patients at risk
of respiratory depression, e.g. neonates, obstructive sleep apnoea.

Chronic Pain
Chronic pain is very difficult to treat. A biopsychosocial approach is essential and often involves a
multidisciplinary team. The WHO analgesic step ladder is followed, but the tricyclic anti-depressants
(TCAs) are often added early on. Anti-convulsants are moderately successful in certain pain
condition, e.g. Carbamazepine in trigeminal neuralgia. Psychological support and therapy (e.g.
cognitive behaviour therapy) is important. The patient has to gain insight into his pain and must be
taught to manage his pain in order to remain as functional as possible. Physiotherapy plays a major
role. Patient education and exercise aims at improving posture and functioning. Physios also employ
techniques such as dry needling and transcutaneous electrical nerve stimulation (TENS). Diagnostic
and therapeutic regional blocks are often performed, but are of limited long-term value.
Radiofrequency ablation of nerves provides relatively longer pain relief, sometimes longer than 6
months. Implanted devices such as spinal dorsal column stimulators and epidural Morphine pumps
are also used.


Peri-operative pain management

13 - 8
Notes: