Is There a Better or a Best Opioid

Is There a Better or a Best Opioid? S. Lawrence Librach MD, CCFP, FCFP Professor, Family & Community Medicine Sun Life Financial Chair in Bioethics

The Simple Answer It depends!

Pharmacogenetics & Role in Opioid Selection • Increasing evidence that perception of pain & response to analgesics especially opioids have genetic components ØPain thresholds & processing ØDrug pharmacokinetics & pharmacodynamics • Single nucleotide polymorphism in a number of genes may be responsible for individual variation

Pharmacogenetics & Role in Opioid Pharmacokinetics • Metabolism of opioids mostly dependent on 2 pathways ØCytochrome P 450 2 D 6 & 3 A enzymes (CYT) ØUridine-diphosphoglucuronosyltransferase (UGT) Øe. g. codeine • Ultrarapid metabolizers in children responsible for caution re: use in children • Poor metabolizers have functionally impaired CYP 2 D 6 (7 -10% Caucasians, 3% Blacks, 1% Asians) limited effect because cannot convert to morphine

Pharmacogenetics & Role in Opioid Receptors • Opioid receptors mu, delta, kappa & “orphan receptor” ORL 1 have all been found to have genetic variants • For mu receptors ØDifferent binding to receptors ØReceptor density, location, dimers ØAddiction ØRequire more opioid for same effect • No clear info re: impact on or receptors

Pharmacogenetics & Multidrug Resistance-1 Gene (MDR-1) • MDR-1 limits GI absorption & excretion via liver, kidneys or GI tract ØCertain genotypes associated with increased adverse effects ØORLs associated with better response

Pharmacogenetic Testing • The next horizon • As genome testing becomes less expensive may be a factor in the future

Opioid Metabolism • Clearance of metabolites an issue with morphine, hydromorphone, oxycodone as metabolites can build up in renal failure • Hepatic failure requires adjustment of all opioids

Opioid Pharmacokinetics Opioid Terminal Half-Life Oral Bioavailabilty Active Metabolites Morphine 2– 4 10 – 50 M 6 G, M 3 G Meperidine 3– 4 20 Normeperidine Methadone 6 – 150 60 – 90 None known Fentanyl 3– 7 <2 None known Codeine 3– 4 40 -50 Morphine Oxycodone 2– 6 40 – 60 Oxymorphone Hydromorphone 2– 4 35 – 50 H 3 G

Lipid Solubility of Some Common Opioid Drugs DRUG HEPTANE - BUFFER PARTITION COEFFICIENT • Morphine • 000001 • Hydromorphone • 00001 • Fentanyl • 196 • Methadone • 446

Opioids Tolerance & Hyperalgesia • Experience with chronic administration of opioids in cancer or other illnesses has shown us that analgesia is not always maintained • OT defined as reduction in response to same dose of opioid after repeated exposure or when doses required to achieve same effect

Opioids & Tolerance • Clearly seen in animal models fairly early on • Clinical trials are difficult to do especially in cancer pain • Certain effects of opioids like respiratory depression, nausea, sedation are often tolerated quickly but analgesic tolerance may not be seen or diagnosed

Opioid Tolerance & Clinical Relevance • Not clear but some interesting possibilities to consider • If pain is even in presence of disease , need to consider tolerance ØMay justify opioid rotation more frequently • Should every patient we treat have a cocktail of opioids plus co-analgesics? • Need studies

Poor Choices for Opioids • Pethidine (meperidine) ØPoor oral absorption ØMetabolite toxicity • Pentazocine • Dextropropoxyphene • Tramadol ØFor severe pain

Pain Severity • Start with strong opioids in moderate to severe pain ØLittle to gain by starting with weak drugs

Type of Pain • All opioids effective in neuropathic pain ØMethadone may have an advantage • All opioids similarly effective in inflammatory (nociceptive pain)

Adverse Effects • No evidence that any opioid better than another for adverse effects ØHowever, some patients report differences

Physician Factors • • • Experience “my favourite opioid is…. . ” Fear or ignorance

Opioid Availability • Menu should be full of choices

Dr. Larry Librach Temmy Latner Centre for Palliative Care 20

Costs • Sustained release drugs may not be necessary • Affordability for patients • Affordability for the system Øe. g. transmucosal fentanyl products

Special Issues • Drug interactions ØAdditive effects ØCYP 450 inhibition • e. g. tramadol, methadone, fentanyl • Universal precautions for opioids

Summary • Really is no one best opioid • Need more than morphine in your formulary as tolerance may be an issue