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??