Transcript What is pain?

OVERVIEW and UPDATE
Analgesia
Dr Rebekah Moles
Outline
• What are the different types of pain?
• How should opioids be used in the treatment of pain?
• New opioid related drugs
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What is pain?
• Pain has been defined formally as:
“an unpleasant sensory and emotional process which we
primarily associate with tissue damage or describe in
terms of such damage.”
• Note: The inability to communicate, in no way negates
the possibility that an individual is experiencing pain
and is need of appropriate pain relieving treatment
Pain Classification
– Acute pain: short duration, cause often identifiable eg
myocardial infarction, burn, appendicitis and kidney
stones
– Chronic pain: persists after healing is expected to be
complete; caused by chronic disease; acute
exacerbations can occur; management often difficult
• Cancer
• Non-cancer (eg. arthritis, low back pain)
Classification of Pain
• Physical causes
– Nociceptive: activation of afferent fibres due to tissue
injury or inflammation
• Somatic eg skin & superficial structures
• Visceral eg deeper structures – liver, pancreas
– Neuropathic: nerve damage or nerve compression
• Peripheral eg sciatica
• Central eg post herpetic neuralgia
– Mixed nociceptive/neuropathic
• Brachial plexus lesion (deep somatic pain and neuropathic
components
Factors contributing to suffering
Neural pain pathways
Nociceptors in skin
Sensory afferent fibres
http://www.georgiapainphysicians.com/downloads/m1_slides/4.%20Spinal%20cord%20junctions.jpg
Detection in the CNS
http://www.georgiapainphysicians.com/downloads/m1_slides/4.%20Spinal%20cord%20junctions.jpg
World Health Organization (WHO)
Analgesic Ladder
Step 1- Mild Pain
• Non-narcotic medication
Paracetamol
NSAID
Step 2- Moderate Pain
• Add an opioid for moderate pain
Paracetamol/Codeine
World Health Organization (WHO)
Analgesic Ladder
Step 3- Severe Pain
• Strong opioid
Morphine
Long-acting opioid such as MS
Contin
Note: All residents on around the clock opioids
should be started on prophylactic bowel
medications to prevent constipation
Pain types & typical response
(Adapted from AMH)
Nociceptive
Neuropathic
Inflammatory
Paracetamol
Effective, regular
use at max
doses
Less effective
Opiods
Effective
NSAIDs
Effective
Often less
effective when
used alone
May be effective
in short term
Effective
analgesia; no
antiinflamm
effect
May be effective
initially; dose
dependent
Effective
antidepressants
&
anticonvulsants
? – sedative –
useful nocte
Most effective
May be effective
as adjunct
Opioids - Mechanism of action
• Activation of peripheral nociceptive fibers causes
release of substance P and other pain-signaling
neurotransmitters from nerve terminals in the dorsal
horn of the spinal cord
• Release of pain-signaling neurotransmitters is
regulated by endogenous endorphins or by
exogenous opioid agonists by acting presynaptically
to inhibit substance P release, causing analgesia
Opioids – Mode of Action
• Opioid receptors are classified into:
– Mu: analgesia, respiratory depression and constipation
(All)
– Kappa: analgesia (mainly in the spinal cord), miosis,
dysphoria and respiratory depression (Heroin, Pethidine.
Buprenorphine = Kappa antag)
– All these receptor sites antagonised by naloxone
The family of opioids
Similarities - mainly m
receptor agonists 1. analgesia  sleep
2. respiratory depression
3. nausea and vomiting
4.  gastrokinesis
5. reversed by naloxone
Differences 1. potency
2. pharmacokinetics
3. cost - availability
4. applications (?)
5. drug interactions (?)
Equianalgesic Table
PO/PR (mg)
Analgesic
SC/IV/IM (mg)
30
Morphine
10
6–8
Hydromorphone
1.5
15
Oxycodone
20
Methadone
10
100-150
Tramadol
180-240
Codeine
Dosing Information
Norspan
5
10
20
Morphine
(oral / day)
20
40
80
Oxycodone
(oral / day)
15
30
60
• No more than 2 patches (MAX 2x20) to be used at once
• May require other SA drugs for 72hrs on initiation
• No other analgesics for 24hr when discontinued
Dosing information - Durogesic
Codeine
• 7-10% population lack CYP2D6 liver enzyme:
– Codeine cannot be metabolized and therefore will
not be effective
• Doses less than 30mg are most likely sub
therapeutic.
• Doses more than 60mg will not provide
further benefit at 2D6 will be saturated at that
dose
Opioid Therapy in Pain Related to
Medical Illness
Opioid therapy is the mainstay approach for
•
•
•
•
Acute pain
Cancer pain
AIDS pain
Pain in advanced illnesses
But under treatment is a major problem
Opioid Responsiveness
• Opioid dose titration over time is critical to
successful opioid therapy
• Goal: Increase dose until pain relief is adequate or
intolerable and unmanageable side effects occur
• No maximal or “correct” dose
• Responsiveness of an individual patient to a specific
drug cannot be determined unless dose was
increased to treatment-limiting toxicity
Addiction
• Rare when opioids given for pain control
– Less than 1%
– A study of 11,882 patients, no episode of
addiction
Porter and Jick, NEJM 302: 123, 1980
Breakthrough Pain
• Incident pain – which occurs with or following
physical activity,
• End-of-dose failure – which occurs in the time
before you are supposed to take your next
dose of medication
• Spontaneous breakthrough pain – which
occurs without predictable cause or frequency
Advances in opioid treatment
Medication Safety
As the Director of Pharmacy at the Royal Parade
Hospital you have been asked to undertake a
root cause analysis for a medication error that
occurred on Ward 6W
MS Contin 60 mg was administered to a patient
instead of Oxycontin 60 mg
©Pharmaceutical Society of Australia
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Oxycodone Sustained Release
Oxycodone (Oxycontin)
• New strengths: 15 mg and 30 mg
• Potential for confusing with MS Contin (morphine)
which also has 15 mg and 30 mg strengths
• Oxycontin 15 mg: grey
• MS Contin 15 mg: light green
• Oxycontin 30 mg: brown
• MS Contin 30 mg: purple
©Pharmaceutical Society of Australia
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Oxycontin vs MS Contin *
5 mg
5mg
10 mg
15 mg
30 mg
60 mg
100 mg
200 mg
©Pharmaceutical Society of Australia
28
Hydromorphone sustained release
(Jurnista)
• Sustained release hydromorphone tablets in 8
mg, 16 mg, 32 mg & 64 mg strengths
• Palladone XL withdrawn because of dose
dumping when taken with alcohol
• Immediate release (Dilaudid) in 2 mg, 4 mg and
8mg available
• For disabling pain not responding to non-narcotic
analgesics
©Pharmaceutical Society of Australia
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Hydromorphone
Dose:
• Opioid naïve patients should be commenced on an
immediate release product
• Oral hydromorphone is estimated to be around 5 times
as potent as morphine
• 32 mg hydromorphone extended release = 160 mg oral
morphine
• If switching to hydromorphone from another opioid,
switch between 1/3 and ½ of the equianalgesic total
daily dose to allow for incomplete cross tolerance
©Pharmaceutical Society of Australia
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Hydromorphone
Role in therapy:
• Allows doctors more options when managing
moderate to severe chronic pain
• Reduce frequency of medication
administration
• High risk of dependence and potential for
abuse
©Pharmaceutical Society of Australia
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Hydromorphone
Practice points:
• Jurnista should only be taken ONCE a day at the
same time
• Sustained release formulation should be swallowed
whole
• Ensure patients do not double up on chronic narcotic
analgesics if switching over to new drug
• Breakthrough analgesia may be required
• Food has minimal effect on medication
©Pharmaceutical Society of Australia
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Methylnaltrexone bromide
(Relistor 12mg/0.6mL)
Class:
• selective μ opioid receptor antagonist
Indication:
• opiate induced constipation in advanced illness
Mechanism of action:
• blockage of μ receptors leading to reversal of
peripheral effects from opiate analgesics
©Pharmaceutical Society of Australia
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Methylnaltrexone bromide
Dose:
• Injected subcutaneously every SECOND day
• Dosage based on weight
–
–
–
0.15 mg/kg if under 38 kg or over 114 kg
0.4 ml (8 mg) if between 38 – 62 kg
0.6 ml (12mg) if between 62 –114 kg
• Halve dose if CrCl < 30 mL/min
Contraindication and precautions:
• GI obstruction
• Severe renal or liver impairment
©Pharmaceutical Society of Australia
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Methylnaltrexone bromide
Adverse effects:
• Abdominal pain
• Diarrhoea
• Nausea
• Flatulence
• Dizziness
©Pharmaceutical Society of Australia
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Methylnaltrexone bromide
Clinical evidence – pivotal studies to date:
Portenoy (2008)
• Dose ranging study
• 4 groups: 1 mg, 5 mg, 12.5 mg and 20 mg methylnaltrexone
given on days 1, 3 and 5
• Primary endpoint: laxation within 4 hours of first dose
• 5 mg, 12.5 mg and 20 mg group: 11/23 responded 
commercial dose
• Followed by open label phase where 18 out of 33 continued
 similar results
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Methylnaltrexone bromide
Thomas(2008)
• 2 groups: placebo and methylnaltrexone (0.15 mg/kg)
• Outcomes were:
– laxation within 4 hours of first dose
– laxation within 4 hours after four subsequent doses
• 48% of treatment group compared to 15% in placebo
group had laxation response within 4 hours of 1st dose (p <
0.001)
• Half of treatment group who had laxation response had it
within 30 minutes of dose
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Methylnaltrexone bromide
Role in therapy:
• Useful if not responding to traditional laxatives
• Targeted therapy: does not induce withdrawal or
interfere with pain management
• No severe side effects
• Quick action
• Studies in specific patient groups only
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Methylnaltrexone bromide
Practice Points:
• Administered subcutaneously
• Dose is based on patient weight-check calculations
• It is injected into the upper arm, thigh or abdomen
• Site should be rotated, and areas with scars should be avoided
• Bowel motion expected in ~ 30 minutes
• Most common side effect is abdominal pain
• No effect on analgesia expected
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Rodney
Rodney presents a script for Durotram XR 200 mg for
dispensing
His history shows that he was previously taking Zydol
SR 100 mg twice daily for several months
It has been six days since the last dispensing of his
Zydol SR 100 mg
Rodney tells you he was told to start the Durotram XR
He has had his morning Zydol SR tablet
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Tramadol Once Daily
(Durotram)
• Tramadol hydrochloride now available in once daily
dosing (Durotram XR)
• 100 mg, 200 mg & 300 mg tablets
• PBS listing and indication- pain where aspirin and/or
paracetamol alone are inappropriate or have failed
• Releases 25% of dose within 2 hours of consumption
• Remainder is released from the core at a constant
rate over 24 hours.
©Pharmaceutical Society of Australia
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Tramadol Once Daily
Role in Therapy?
•
Similar efficacy to twice daily tramadol
•
Not useful for acute/breakthrough pain
•
Most common side effects:
•
•
– dizziness or vertigo (10% to 26%)
– drowsiness (7% to 30%)
– constipation (10% to 34%)
– nausea (11% to 33%)
Dizziness and vertigo less common with the extended release product
than sustained release (26% v 37% p = 0.017)
Drowsiness is more common with extended release product than
sustained release (30% v 21% p = 0.047)
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Tramadol Once Daily
Dose:
• 200mg daily is recommended ‘starting dose’
when switching from regular immediate release
tramadol
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Tramadol Once Daily
Dose:
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Tramadol Once Daily
Practice points:
• Ensure patient is not confused with change of
formulation
• Remind patient that it is only ONCE daily (at the
same time each day)
• Sustained release formulation should not be broken,
crushed or chewed
• They may be more drowsy on this formulation
• Be aware of drug interactions
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Tapentadol
Class:
• A novel μ opioid receptor agonist and noradrenaline
reuptake inhibitor
Indication*:
• For relief of moderate to severe acute pain in
patients > 18 years (approval in US)
Mechanism of action:
• Opioid receptor effects combined with noradrenaline
reuptake inhibition activates descending pain
inhibitory pathways
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Tapentadol
Dose:
• 50 mg –100 mg every 4 – 6 hours
• Maximum daily dose: 600 mg/day
• Daily dose on the first day may be increased up to
700 mg
Contraindications & precautions:
• Impaired pulmonary function
• Paralytic ileus
• Concomitant use with MAOI
• CNS effects
• Abuse potential
• Use in epilepsy
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Tapentadol
Adverse effects:
• Nausea
• Dizziness
• Vomiting
• Somnolence
• Itch
• Constipation
• Euphoria
• ‘Feeling drunk’
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Tapentadol
Clinical evidence - pivotal studies to date:
Stegmann (2008)
• Tapentadol 50 mg or 100 mg, oxycodone 10 mg (immediate
release) or placebo every four to six hours
• Primary outcome was to measure pain intensity, pain relief
and time course of analgesia (SPI-24)
• Both tapentadol and oxycodone provided greater analgesia
over placebo
• 100 mg tapentadol more effective than 10 mg oxycodone (p =
0.0455) but greater dizziness & somnolence
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Tapentadol
Hartrick (2009)
• Trial of tapentadol in joint replacement
• Tapentadol 50 mg, tapentadol 75 mg, oxycodone 10 mg and
placebo every four to six hours
• Outcomes measured were sum of pain intensity difference
(SPID) over five days
• All treatment groups reported improved pain relief compared
to placebo (p < 0.001)
• Nausea/vomiting and constipation lower in the tapentadol
group
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Tapentadol
Role in therapy:
• Acute pain relief
• Much lower potential for serotonin syndrome
compared with tramadol
• Equivalence with opioids unknown
• Role in severe pain or chronic pain yet to be
established
• ?Better side effect profile than oxycodone
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Key Steps to Improving Treatment
in Chronic Pain
• Step 1: Administer medications routinely, not
prn
• Step 2: Use the least invasive route of
administration first
• Step 3: Begin with low dose-Titrate up
• Step 4: Monitor & document effectiveness of
medication daily
• Step 5: Reassess and adjust dose frequently
to optimize pain relief while monitoring and
managing side effects
Questions?
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