opioid pharmacology: how to choose and how to use€¦ · ppt file · web view ·...
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Opioid Pharmacology: How to choose and how to use
Romayne Gallagher MD, CCFPDivision 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 NeurotoxicityOpioid Induced Neurotoxicity• Definition
– Neuroexcitability manifested by agitation, confusion, myoclonus, hallucinations and rarely seizures
• Predisposing Factors:– 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*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
• 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
• 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
• 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 25-
50% - potential greater sensitivity to new opioid
• Prescribe new opioid with adequate breakthrough dose
• Reassess and titrate to target dose
Equianalgesic conversion
• Morphine 10mg• Tylenol #3 2 tablets• Codeine 60mg• Hydromorphone 2mg• Oxycodone 5-7.5mg• Methadone 1mg (not q4hr)
» variable ratio
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
• 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 non-opioids): 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??