1. Opioid Pharmacology: How to choose and how to use
Romayne Gallagher MD, CCFP
Division of Palliative
Providence Health Care

2. 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

3. 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

4. Oxycodone

5. All animals received same mg/kg dose

6. Distinguishing Characteristics
Pharmacokinetics
Half life
Metabolism
Pharmacodynamics
Potency
Most have one or two peculiarities

7. 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

8. Morphine “natural opioid”
Widely available in multiple forms: oral pill and liquid, pills, parenteral
Used to be considered “gold standard”
Hydrophilic

9. 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

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

11. 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?

12. 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

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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Tramadol Weak opioid – mu receptor agonist
Also inhibits reuptake of serotonin and noradrenalin
Requires metabolism to become analgesic
Maximal dose mg day
Useful for moderate pain

21. 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

22. 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?

23. Opioids of choice in frail elderly and renal failure
Hydromorphone
Oxycodone
Fentanyl
Methadone

24. 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

25. 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

26. 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

27. 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 = to p= 0.686
Opioids work through reduction of respiratory rate and workload
Clemens et al J. Palliative Medicine 2008

28. Opioid Side Effects Nausea Itch Metoclopramide 10mg qid
If doesn’t resolve in a week switch opioid
Itch
Histamine release – not allergy
Antihistamine until it subsides

29. 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

30. 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

31. Equianalgesic conversion
Morphine 10mg
Tylenol #3 2 tablets
Codeine 60mg
Hydromorphone 2mg
Oxycodone mg
Methadone 1mg (not q4hr)
variable ratio

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. Case 7 57 year old woman with advanced COPD
Moderate to severe dyspnea with minimal exertion
eGFR = 55
Opioid: long acting morphine