Opioid Pharmacology: How to choose and how to use

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Opioid Pharmacology How to choose and how to use

• Romayne Gallagher MD, CCFP
• Division of Palliative
• Providence Health Care

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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

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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

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Oxycodone
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All animals received same mg/kg dose
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Distinguishing Characteristics

• Pharmacokinetics
• Half life
• Metabolism
• Pharmacodynamics
• Potency
• Most have one or two peculiarities

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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

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Morphine

• natural opioid
• Widely available in multiple forms oral pill and
  liquid, pills, parenteral
• Used to be considered gold standard
• Hydrophilic

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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

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Codeine, morphine, hydromorphone metabolism
Glucuronidation 10 of codeine becomes
morphine Morphine and hydromorphone are both
glucuronated to active metabolites.
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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?

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Opioid 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

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Management of OIN

• Rehydration
• Treat concurrent causes of delirium e.g. UTI,
  pneumonia
• Reduce dose if pain controlled
• Switch to a different opioid

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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

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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

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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

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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

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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

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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

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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

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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

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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?

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Opioids of choice in frail elderly and renal
failure

• Hydromorphone
• Oxycodone
• Fentanyl
• Methadone

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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

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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

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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

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Respiratory Depression

• Visual analogue scale shows significant reduction
  in dyspnea plt.001
• Significant reduction in respiratory rate plt.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

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Opioid Side Effects

• Nausea
• Metoclopramide 10mg qid
• If doesnt resolve in a week switch opioid
• Itch
• Histamine release not allergy
• Antihistamine until it subsides

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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

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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

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Equianalgesic conversion

• Morphine 10mg
• Tylenol 3 2 tablets
• Codeine 60mg
• Hydromorphone 2mg
• Oxycodone 5-7.5mg
• Methadone 1mg (not q4hr)
• variable ratio

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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

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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

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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

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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

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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

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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

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Case 7

• 57 year old woman with advanced COPD
• Moderate to severe dyspnea with minimal exertion
• eGFR 55
• Opioid long acting morphine

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Questions??