Opioid Pharmacology: How to
choose and how to use
Romayne Gallagher MD, CCFP
Division of Palliative
Providence Health Care
Rules of thumb in chronic pain
• Not all pains are the same
• Not all patients have the same pain sensitivities
• Not all patients have the same pain relief from opioids
• Not all patients have the same side effects of opioids
• Not all opioids are the same
– Mercadante 2001, Pasternak 2001
Opioid Receptors
• Mu, Delta, Kappa
• All pure agonists act at Mu receptor
• Opioid receptors act on
– CNS: cortex, thalamus, periaquaductal gray,
spinal cord
– Peripheral neurons
– Inflammed tissue
– Immune cells
– Respiratory and GI tract
Oxycodone
All animals received same mg/kg dose
Distinguishing Characteristics
• Pharmacokinetics
– Half life
– Metabolism
• Pharmacodynamics
– Potency
– Most have one or two peculiarities
Codeine
• Not an analgesic unless metabolized to
morphine
• Up to 10% of population are poor
metabolizers – little or no analgesia from
codeine
• Rapid metabolizers also may have little
analgesia
• Ceiling dose: 360mg/day
Morphine
• “natural opioid”
• Widely available in multiple forms: oral pill
and liquid, pills, parenteral
• Used to be considered “gold standard”
• Hydrophilic
Hydromorphone
• Synthetic “sister” of morphine
• Potency is 5X morphine
• Widely available in multiple forms: oral pill
and liquid, pills, parenteral
• More rapid onset and shorter half life
• ?less histamine release than morphine
• hydrophilic
Codeine, morphine,
hydromorphone metabolism
Glucuronidation
10% of codeine becomes morphine
Morphine and hydromorphone are
both glucuronated to active
metabolites.
Morphine and Hydromorphone
• Metabolized to 3-glucuronide metabolites
– No analgesic properties
– CSF doses often exceed doses of parent compound
(rats)
– Cause neuroexcitation
• Smith MT Clin. Exper. Pharmacology Physiology 2000
• 6-glucuronide has analgesic properties
• Hydromorphone usually tolerated (low doses) as
has shorter half-life than morphine?
Opioid Induced Neurotoxicity
• Definition
– Neuroexcitability manifested by agitation, confusion,
myoclonus, hallucinations and rarely seizures
• Predisposing Factors:
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High opioid doses
Prolonged opioid use
Recent rapid dose escalation
Dehydration
Renal failure
Advanced age
Other psychoactive drugs
*Daeninck PJ, Bruera E. Acta Anaesthesiol Scand. 1999
Management of OIN
• Rehydration
• Treat concurrent causes of delirium e.g.
UTI, pneumonia
• Reduce dose if pain controlled
• Switch to a different opioid
Oxycodone
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Synthetic “cousin” to morphine
Potency is 1.5-2X morphine
Targets mu receptor and kappa receptors
No clinically significant active metabolites
Not available in parenteral form in Canada
Fentanyl
• Targets mu and delta receptors
• 80-100X potency of morphine
• Rapid onset and very short half-life –
needs to be delivered as parenteral
infusion or transdermal patch for constant
analgesia
• No active metabolites
• Highly lipophilic – useful in renal dialysis
Notes about the Fentanyl patch
• Takes 12 hours for onset of analgesia
• Need adequate subcutaneous tissue for
absorption
• Takes 24 hours to reach maximum effect
• Change patch every 72 hours
• Dosage change after six days on patch
• Suitable for stable pain only
Sufentanil
 10 fold more potent than fentanyl
 Lipophilic so can be absorbed through
the buccal/sublingual mucosa
 Onset is 5-10 minutes, lasts 30 minutes
 Excellent for incident pain
Methadone
• Supplied as a racemic mixture
– L methadone is mu agonist
– D methadone is NMDA receptor antagonist
• May have greater efficacy in neuropathic
pain
• Half life variable but average is 24 hours –
needs slow titration
• Highly lipophilic – good in renal dialysis
Fentanyl, oxycodone, methadone
• Metabolized by CYP3A4 and to a lesser
extent CYP2D6
• Methadone has some metabolism by up to
4 other enzymes and has ++potential
interactions with other medications
• None of these opioids have clinically
significant active metabolites
Tramadol
• Weak opioid – mu receptor agonist
• Also inhibits reuptake of serotonin and
noradrenalin
• Requires metabolism to become analgesic
• Maximal dose 400-600 mg day
• Useful for moderate pain
Buprenorphine
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Partial agonist of mu receptor
Requires metabolism to become analgesic
Slow onset, highly bound to receptor
Ceiling effect – consider as a weak opioid
Comes in patch that lasts 7 days
Useful for moderate pain
What opioid to choose?
• Age – renal clearance is lower, higher fat
to muscle ratio
• Renal Function
• What have they tried before and what was
their experience?
Opioids of choice
in frail elderly and renal failure
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Hydromorphone
Oxycodone
Fentanyl
Methadone
What route to use?
• GI tract and level of consciousness
• How rapidly you need to get pain under
control
• Cmax
– po ~ 1 hour
– sc ~ 30 minutes
– IV ~ 5-10 minutes
• This indicates how frequently you can give
breakthrough doses
Respiratory Depression
• In those who do not have pain or
respiratory symptoms it is an ongoing risk
• For those who are opioid naïve and
receive more drug than needed for pain it
is a risk – i.e. post operative
• Not an issue when opioids used
appropriately to treat pain and dyspnea
even in patients with cardiopulmonary
disease
Respiratory Depression
• Best measure is the rise in peripheral
pCO2 and peripheral pO2
• Study of patients with moderate to severe
dyspnea due to advanced cancer, ALS
• Patients administered short acting opioid
for dyspnea and parameters measured
before, 30, 60, 90, 120 mins after opioid
• Opioid naïve and opioid tolerant patients
Respiratory Depression
• Visual analogue scale shows significant
reduction in dyspnea p<.001
• Significant reduction in respiratory rate p<.002
• No significant rise in pCO2 or fall in pO2 during
any measurement p = 0.203 to p= 0.686
• Opioids work through reduction of respiratory
rate and workload
• Clemens et al J. Palliative Medicine 2008
Opioid Side Effects
• Nausea
– Metoclopramide 10mg qid
– If doesn’t resolve in a week switch opioid
• Itch
– Histamine release – not allergy
– Antihistamine until it subsides
Constipation
• Interindividual variation
• Need osmotic laxative or stimulant
• Some evidence that fentanyl patch may
result in less constipation
• PEG 3350 (Laxaday) – RCT: more
effective, better tolerated than lactulose
• No evidence to support use of docusate
Principles of opioid rotation
• Calculate the equianalgesic dose
• Reduce the dose of the new opioid by 2550% - potential greater sensitivity to new
opioid
• Prescribe new opioid with adequate
breakthrough dose
• Reassess and titrate to target dose
Equianalgesic conversion
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Morphine
Tylenol #3
Codeine
Hydromorphone
Oxycodone
Methadone
» variable ratio
10mg
2 tablets
60mg
2mg
5-7.5mg
1mg (not q4hr)
Case 1
• 62 year old man on hemodialysis with
chronic neuropathic pain secondary to
diabetes
• Opioid: fentanyl with hydromorphone
breakthrough OR methadone
• Neuropathic pain adjuvant
Case 2
• 76 year old woman with rheumatoid and
osteoarthritis
• Normal renal function
• Moderate constant joint pain
• Opioid: tramadol OR buprenorphine OR
low dose long acting oxycodone,
hydromorphone
Case 3
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89 year old man with severe osteoporosis
eGFR = 32
Mild dementia
Living in community on own
Opioid: long acting oxycodone in blister
pack OR fentanyl patch with follow up by
home care nurse
Case 4
• 94 year old woman with moderate to
severe dementia
• Resistant to care and calling out
• Known spinal stenosis
• Opioid: long acting oxycodone OR fentanyl
patch OR methadone
• Neuropathic adjuvant: SNRI or
mirtazepine
Case 5
• 54 year old man with metastatic bowel
cancer causing bowel obstruction and liver
mets
• eGFR = 40
• Opioid: hydromorphone sc infusion via
CADD pump OR methadone
Case 6
• 48 year old man with history of alcoholism
and illicit drug use
• Previous work accident resulting in
moderate to severe chronic neuropathic
pain
• Opioid(after trials of all reasonable nonopioids): fentanyl patch dispensed one at
a time with exchange
• Neuropathic pain adjuvants
Case 7
• 57 year old woman with advanced COPD
• Moderate to severe dyspnea with minimal
exertion
• eGFR = 55
• Opioid: long acting morphine
Questions??