Drug Use in Acute Pain Management - Final 010708

Malaysian 5th Vital Sign Implementation: 2008-2010
Drugs in Acute Pain

Management
1
5 Vital Sign: Doctors’ training module: Pharmacology
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Analgesics
 Non Opioids
Paracetamol
NSAIDS
COX 2 inhibitors
 Opioids
Weak
Strong
 Naloxone
2
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Non-opioid analgesics
 Acetaminophen (Paracetamol)
 Non-steroidal anti inflammatory
drugs (NSAIDS)
 COX 2 inhibitors
3
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Acetaminophen - Paracetamol
 Weak inhibitor of both COX1 & COX 2

 Analgesic and anti-pyretic but no anti-
inflammatory activity
 Orally - peak plasma concentrations in
30-60 minutes
 Metabolized in the liver
 Half life 3-4 hours
4
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Acetaminophen – Paracetamol (cont.)
 Commonly used dose (adults) is 1

gram 6 hourly, but can be used up to 4
hourly i.e. maxiumum of 6 grams/day
 At therapeutic doses - few and
uncommon side effects
 Toxic doses (2-3 X maximum
therapeutic dose) - fatal hepatotoxicity
5
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NSAIDS
 Effects
 Anti-inflammatory
 Analgesic
 Anti-pyretic
 Anti-platelet
6
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Mode of Action
 Act by inhibiting prostaglandin
biosynthesis
 Involved in conversion of
arachidonic acid to prostaglandin
 Irreversibly blocks the enzyme
cyclo-oxygenase (COX)
7
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Cyclooxygenase Pathways
Arachidonic (-) Glucocorticoids

(block mRNA
acid expression)
(-) (-)
COX-1 NSAIDs COX-2
Coxibs
Normal Normal
Inducible
constituent constituent
 gastric cytoprotection  inflammation  brain
 renal sodium / water  pain  kidney
balance  fever  endothelium
 platelet aggregation  ovary
 uterus
9
Diagram based on information in Lipsky PE et al., J Rheumatol, 1998;
and Smith WL, Dewitt DL, Adv Immunol, 1996
NSAIDS & COX2 INHIBITORS:
EXAMPLES
NSAIDS COX 2 INHIBITORS
 Diclofenac (Voltaren)  Celecoxib (Celebrex)
 Mefenamic Acid (Ponstan)  Etoricoxib (Arcoxia)
 Ibuprofen ( Brufen)  Parecoxib (Dynastat)
 Naproxen (Naprosyn,
Synflex)
 Ketoprofen (Orudis,
Oruvail)
 Ketorolac (Toradol)
 Meloxicam ( Mobic)
10
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NSAIDs /COX 2 Inhibitors
 Route of administration
 Oral / Parenteral
 Effective for mild to moderate pain
 “Opioid-sparing” effect when used in
combination with strong opioids – a lower
dosage of opioid is required to achieve
comfort
 Treatment of other associated symptoms
i.e. Inflammation and fever
11
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NSAIDS – limitations (1)
 Ceiling effect to analgesia
 Adverse effects
 Gastric ulceration
 Reduction in renal blood flow
 Platelet inhibition
 Allergic reactions
 Bronchospasm
 Cross allergy is common
12
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NSAIDS – limitations (2)
 Gastritis and functional
thrombocytopenia are common
with therapeutic doses
 Precautions – prolonged use can
lead to
 Renal failure
 Increased risk of myocardial infarct
and stroke
13
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OPIOIDS
 Drugs (natural or synthetic ) with
morphine-like properties and which
act through the opioid receptors.
5th Vital Sign: Doctors’ training module: Pharmacology

Commonly used opioids
 Weak opioids  Strong opioids

 Dihydrocodeine  Morphine
(DF118)  Oxycodone
 Tramadol  Fentanyl
 Pethidine
 Partial agonist
 Nalbuphine
15
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Pharmacokinetics
Definition
What happens to drugs in the body
Components
Plasma level in relation to dose given
The dosing interval
Route of administration
16
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 Aim for analgesia
- Plasma levels to fall in the “analgesic corridor”
=> comfortable
- Below level → pain
- Above level → side effects
- Difficult to predict
=> titration of analgesia
- Using: PCA,
Range of doses &
dosing intervals
17
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PHARMACOKINETICS
IM or SC MORPHINE
“Analgesic corridor”
• Onset 30 min (slow)

• Duration of action 3-4 h
=> same for IM & SC

PHARMACOKINETICS
IV MORPHINE
• Onset faster (3-5 mins);

higher peak plasma
levels
• Duration of action same
as IM, i.e. 3-4 hours
• Bolus required before
starting infusion; if not,
adequate plasma levels
not achieved for many
hours
Pharmacokinetics
PCA / small frequent boluses
 Good quality analgesia

 Well within the
analgesic corridor
less risk of toxicity

PHARMACOKINETICS
IV MORPHINE
• Onset faster (3-5 mins);

higher peak plasma
levels
• Duration of action same
as IM, i.e. 3-4 hours
• Bolus required before
starting infusion; if not,
adequate plasma levels
not achieved for many
hours
- When the level of morphine is below the
analgesic corridor (especially if the dosing
interval is too long)
=> patient experiences pain
- If a higher dose is given to prolong the
duration above the analgesic corridor
=> more side effects or complications
CONCLUSION:
The best way is to give smaller doses of
morphine more frequently
22
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Pharmacokinetics
PCA / small frequent boluses
 Good quality analgesia

 Well within the
analgesic corridor
less risk of toxicity

Morphine
 Potent analgesic agent:

The Gold Standard for all analgesics
 Acts on mu and kappa opioid receptors in
brain and spinal cord
 Used for moderate to severe pain
 The first choice of strong opioid for acute
pain and for severe cancer pain
24
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 Pharmacokinetics :
 Bioavailability of oral route is 30% due to
first pass metabolism in the liver
 Converted to morphine-6-glucuronide
(active metabolite) and morphine-3-
glucuronide in liver
 Excreted through the kidney
 Elimination half life is 3-4 hours
 Peak analgesic effect
 IM / SC : 30-60 minutes
 IV : 5 minutes
25
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Morphine: Adverse effects
 Side effects the same as for all opioids:

 Nausea and vomiting
 Respiratory depression
 Sedation
 Constipation / Reduced GIT motility
 Dizziness
 Pruritus
 Reduce dose in renal and hepatic
impairment
26
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Morphine and other opioids:
Tolerance and Addiction?
 Tolerance is a physiological phenomenon where
increasing doses of a drug are required to produce the
same pharmacological effect, or where the same dose
produces less effect.
 Addiction is associated with a psychological

dependence on the drug, craving for the drug when it is
not available, and drug-seeking behaviour including
cheating, lying and stealing to obtain the drug.
27
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Tolerance and Addiction?
 Addiction does NOT occur if morphine is used
for the relief of pain (acute pain or cancer pain)
 Patient on PCA will reduce the dose of morphine
once the wound heals and pain decreases
 In patients with cancer pain who are on morphine,
requirement for higher doses is usually due to
disease progression
 Tolerance is usually not a problem when used in
the short term for the management of acute
pain
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Withdrawal
 However, patients who are on long term
opioids, even when taken for pain, will
experience withdrawal symptoms (e.g.
increased pain, abdominal cramps, sweating,
diarrhoea, agitation)
29

Morphine Pain Protocol
 Used for rapid control of severe pain

 Route: IV
 Morphine dilution: 10 mg in 10 mls
(1mg/ml)
 Monitoring (every 5 minutes)
 Pain score
 Sedation score
 Respiratory rate
30
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Morphine
Pain Protocol
Adapted from the Acute
Pain Service, Royal
Adelaide Hospital ,
South Australia

Morphine
Pain Protocol
Adapted from the Acute
Pain Service, Royal
Adelaide Hospital ,
South Australia
FOR NURSES
WHO ARE
TRAINED
AND
ACCREDITED

Other opioids
33
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Dihydrocodeine (DF118)
 Natural opioid  Side effects
 Only oral form is available in  Constipation
Malaysia: 30 mg tab
 Worst constipating effect
 Converted to morphine in the compared to other
liver opioids
 Used for mild to moderate pain
 Dose:
 Tab 30mg-60mg 6hrly (max
360mg/day)
 Onset:
 15 to 30 min (peak 1h)
 Duration: 4-6hr
34
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Pethidine
 Dose: 1-2mg/kg  Metabolised in liver to
(usually 50 – 100 mg 4 H) Norpethidine which has a
 Route: iv /im /sc hallucinogenic and convulsant
effect
 Peak analgesic effect :  Elimination half life is 2.4-7
 IM : 20-30 minutes hours
 IV : 5 -10 minute  Norpethidine has a long half
 Side Effects are the same as life (12 hours) and
for all opioids hallucinogenic effects outlast
 Nausea/vomiting the analgesic effects of
 Sedation pethidine
 Respiratory depression
 Constipation / Ileus
NOT recommended for use in chronic or cancer

pain management 35

Fentanyl
 Highly selective mu agonist Pharmacokinetics :
 50-80 times more potent  Metabolized rapidly in liver to
than morphine (10 mg norfentanyl
morphine = 100 mcg  Elimination half life is 1.5-6
fentanyl) hours
 Cardiovascularly stable but  Short duration of action is due
may cause bradycardia of to redistribution rather than
vagal origin metabolism
 Potent respiratory  Peak analgesic effect :
depressant
 IV : 3 minutes
 For acute pain, the IV form is
used (not transdermal)  Duration of action :
 Indicated when rapid pain  IV : 30-60 minutes
relief is required for short
periods of time, e.g. burns
dressing Available in transdermal patches but these are
NOT suitable for management of acute pain 36

Nalbuphine
 Partial Agonist: therefore, has a  Side effects are the same as
ceiling effect for all opioids
 10 mg nalbuphine = 10 mg  Thought to be safer because
morphine of lower risk of respiratory
 Route of administration: IV or IM depression due to ceiling effect
 Onset: 2-3 min  Will act as an opioid
 Duration: 3-6hr ANTAGONIST in the
 Indication: moderate to severe presence of a full agonist
pain like morphine
 Commonly used in Emergency
Department
Do not use on patients who are already
on strong opioids (morphine or fentanyl)
37

Oxycodone
 Synthetic opioid  Side effects are the same
 Currently only the as for all opioids
sustained release form is  Dose adjustment
available in Malaysia required in renal and
(Oxycontin) hepatic Insufficiency
 Indicated for the relief of  Used as an alternative to
moderate to severe pain morphine in “Opioid
 Dose: 10 - 20mg 12 hrly rotation”
 Onset: 30 min
 Duration of action: 12
hours
38

Tramadol
 Synthetic weak opioid  Dose adjustment required
 Also increases the levels of in renal and hepatic
noradrenaline (NA) and Insufficiency
serotonin (5HT) in the CNS  Side effect same as for all
 Used for the relief of moderate opioids
to moderately severe pain  Also has effects on CVS due
 Dose: 50-100mg 6-8hrly to NA/5HT
(max 400 mg/day)  May interact with drugs like
 Most common use is oral but Amitriptyline, Carbamazepine,
also available in injection Digioxin, MAOI, SSRI,
(IV/SC/IM) Warfarin
 IV should be given as slow  Available combined with
bolus paracetamol (ULTRACET)
 Onset: 30 min to 1h (peak 2-3h) which has Acetaminophen
 Duration: 4-6hr 325mg and Tramadol 37.5mg
39
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 NALOXONE
 Pure opioid antagonist
 Used in diagnosis and treatment of opioid
overdose
 Give IV (diluted) or IM
 Half-life 45 – 60 minutes
40
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OPIOIDS:TRADE NAMES AND DOSE EQUIVALENTS
EQUIVALENT
OPIOID TRADE NAME DURATION OF MORPHINE OPIOID
ACTION (HRS) DOSE (MG) CLASS
IM/IV PO
MORPHINE MORPHINE 10 20 AGONIST

SULPHATE 3-4
DIHYDRO DF118 AGONIST

CODEINE 4-6 60
TRAMADOL TRAMAL 100 100 AGONIST

6-8
FENTANYL DUROGESIC 0.1 AGONIST
1-2
PETHIDINE PETHIDINE 100 AGONIST
3-4
OXYCODONE OXYCONTIN 10 AGONIST
(SR) 8 - 12
NALBUPHINE NUBAIN 10 PARTIAL

4-6 AGONIST
NALOXONE NARCAN ANTAGONIST
1 – 1.5 41

ANALGESIC LADDER:
ACUTE PAIN MANAGEMENT
42
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LIST OF ANALGESIC DRUGS
DRUG FORMULATION AVAILABLE DOSAGE
Paracetamol Tablet 500mg, 500 mg – 1gm qid
Suspension 500mg/5ml,
Suppositories
NSAID
Diclofenac Tablet 50mg & 25mg, Oral: 50mg tds,
Suppositories 12.5mg, 25mg, (50mg & Sup: 50mg-100mg stat
100mg)* Topical: PRN
Gel
Mefenamic Acid (Ponstan) Capsule 250mg 250 mg – 500mg tds

Ibuprofen ( Brufen) Tablet 200mg & 400mg* 200 mg – 400 mg tds
Naproxen (Naprosyn, Tablet 250mg, 550mg 500mg-550 mg bd
Synflex)
Ketoprofen (Orudis, Capsule 100mg *, Injection 100mg, Oral: 100mg daily, IV: 100mg bd
Oruvail) Patch 30mg, Gel Patch: 30mg - 60mg bd, Topical: PRN
Ketorolac (Toradol) Injection 30mg/ml 10mg - 20 mg bd max 3 days
Meloxicam ( Mobic) Tab 7.5mg Daily or bd
COX 2 inhibitors
Celecoxib Capsule 200 mg 200 mg bd (max 1 week)
Celecoxib Capsule 200 mg 200 mg bd (max 1 week)
Etoricoxib Tablet 90 mg & 120 mg 120 mg daily (max 1 week)
Parecoxib Injection 20 mg/ml 40 mg bd ( 20 mg bd for elderly) max for 2 days
WEAK OPIOID
Tramadol Capsule 50mg, Injection 50mg/ml 50mg -100mg tds or qid (max 400mg/day)
Dihydrocodeine (DF118) Tablet 30 mg 30mg-60mg qid (max 360mg/day)
STRONG OPIOID
Nalbuphine (Nubain) Injection 10mg/ml Stat dose only: 10mg (equivalent to Morphine
10mg). Do not use in patients on regular
Morphine/ Pethidine/ Fentanyl.
Morphine Tablet SR 10mg,30mg SR and Aqueous to be used for cancer pain
Aqueous 10mg / 5ml IV and Subcut :
Injection 10 mg/ml, < 65yrs : 5mg -10mg 3-4hrly
> 65yrs : 2.5mg -5mg 3-4hrly
Reduce dose in renal and hepatic impairment
Fentanyl Injection 50 mcg/ml, IV only to be prescribed by APS team.

Patch 25 mcg, 50 mcg Patch to be used in cancer pain; NOT in Acute
Pain
Pethidine Injection 50mg/ml,100mg/2ml IV and Subcut :
< 65yrs : 50mg -100mg 3-4hrly
> 65yrs : 25mg -50mg 3-4hrly
Reduce dose in renal and hepatic impairment.
Use not encouraged because of Norpethidine
toxicity and high risk of addiction.
Oxycodone ( Oxycontin) Tablet SR 10mg & 20mg Mainly used for cancer pain
MANAGEMENT
OF SIDE EFFECTS
45
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NAUSEA AND VOMITING
 Nausea and vomiting is a common side effect but
should not be a reason for withholding opioids in
patients with severe pain
 Drugs used to treat nausea and vomiting:

 Metoclopramide 10-20 mg stat and 6 hourly
 Ondansetron 8 mg IV stat and 8H if necessary
 Granisetron 2 mg IV stat and 8H if necessary
 Haloperidol 1 mg BD IV or 1.5 mg BD oral
 Dexamethasone 4 mg IV stat

46
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RESPIRATORY DEPRESSION
 May occur with overdose of opioids.
 Very uncommon
 Always associated with sedation
 Risk of respiratory depression is minimal if strong opioids
are titrated to effect and are only used to relieve pain
(i.e. not to help patients to sleep or to calm down
agitated patients).
 Risk of respiratory depression is also minimal in patients
on chronic opioid use (e.g. patients on morphine for
cancer pain).
47
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RESPIRATORY DEPRESSION:
Management
1. Confirm Diagnosis:
 Respiratory Rate <8/minute AND Sedation Score
= 2 (difficult to arouse)
 OR Sedation Score = 3 (unarousable)
 Pin-point pupils
48
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Sedation Score
0 = none (patient is alert)

1 = mild (patient is sometimes drowsy)
2 = moderate (patient is often drowsy but
easily arousable)
3 = unarousable
S = patient is asleep, easily arousable

RESPIRATORY DEPRESSION:
Management
2. Administer oxygen – face mask or nasal prongs
3. Stimulate the patient – tell him/her to breathe
4. Dilute Naloxone 0.4 mg in 4 mls
 give 0.1 mg (1 ml) every 1-2 minutes until the patient
wakes up or Respiratory Rate > 10
5. Monitor RR, Sed Score Hrly X 4 hrs.
 Give another dose of naloxone if resp dep recurs and
refer the patient to the ICU / HDU for close monitoring
(patient may require a naloxone infusion)
50
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Key points:
 For Pain as the 5th Vital Sign to have an

impact in improving pain management in
our hospitals, doctors should understand
all the analgesic medications available and
know how and when to use them
 Important points to note on the
pharmacology of drugs are
 Onset and duration of action (so you know how
often to prescribe the drug)
 Side effects (so you can anticipate and treat SE)
51
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Key points:
 During and after administration of

analgesic medication, we must monitor:
Pain score
 Sedation score, Respiratory rate
** Aim is to achieve reasonable pain relief

without unacceptable side effects
52
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53
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Malaysian 5th Vital Sign Implementation: 2008-2010
Drugs in Acute Pain

Management
54

Drug Use in Acute Pain Management - Final 010708

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Drug Use in Acute Pain Management - Final 010708

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Malaysian 5th Vital Sign Implementation: 2008-2010

Drugs in Acute Pain

 Weak inhibitor of both COX1 & COX 2

 Commonly used dose (adults) is 1

Arachidonic (-) Glucocorticoids

5th Vital Sign: Doctors’ training module: Pharmacology

 Weak opioids  Strong opioids

• Onset 30 min (slow)

5th Vital Sign: Doctors’ training module: Pharmacology

• Onset faster (3-5 mins);

 Good quality analgesia

5th Vital Sign: Doctors’ training module: Pharmacology

• Onset faster (3-5 mins);

 Good quality analgesia

5th Vital Sign: Doctors’ training module: Pharmacology

 Potent analgesic agent:

 Side effects the same as for all opioids:

 Addiction is associated with a psychological

5th Vital Sign: Doctors’ training module: Pharmacology

 Used for rapid control of severe pain

5th Vital Sign: Doctors’ training module: Pharmacology

5th Vital Sign: Doctors’ training module: Pharmacology

NOT recommended for use in chronic or cancer

5th Vital Sign: Doctors’ training module: Pharmacology

5th Vital Sign: Doctors’ training module: Pharmacology

5th Vital Sign: Doctors’ training module: Pharmacology

5th Vital Sign: Doctors’ training module: Pharmacology

MORPHINE MORPHINE 10 20 AGONIST

DIHYDRO DF118 AGONIST

TRAMADOL TRAMAL 100 100 AGONIST

NALBUPHINE NUBAIN 10 PARTIAL

5th Vital Sign: Doctors’ training module: Pharmacology

Mefenamic Acid (Ponstan) Capsule 250mg 250 mg – 500mg tds

Fentanyl Injection 50 mcg/ml, IV only to be prescribed by APS team.

 Drugs used to treat nausea and vomiting:

0 = none (patient is alert)

S = patient is asleep, easily arousable

 For Pain as the 5th Vital Sign to have an

 During and after administration of

** Aim is to achieve reasonable pain relief

Drugs in Acute Pain

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