Drug interactions in palliative care patients

Palliative care physicians need to understand drug biotransformation for many reasons, says Thomas Strouse, MD, UCLA School of Medicine. Here’s why:

--Most analgesics are metabolized by hepatic enzyme systems.

--Many palliative care patients will be receiving disease-modifying therapies.

--There’s significant potential for pharmacokinetic (PK) and pharmacodynamic (PD) interactions between analgesics and other prescribed agents.

--There’s a growing database regarding genotype/phenotype and disease-related drug reactions.

Strouse, speaking at the 6th Annual Supportive Oncology Conference in Chicago, noted that there are several factors affecting biotransformation of drugs, including genetic variations (P450 polymorphisms, fast/slow acetylation); the environment (other drugs, toxins); physiology (organ injury and other dysfunction and other variables); P-glycoprotein and conjugation effects of disease states/drugs/mutations.

Some patients are more at risk for drug-drug interactions and they tend to have these common characteristics: advanced age, acute organ dysfunction, polypharmacy (too many cooks in the kitchen), having many starts/stops of prescription drugs, acute physiological changes, such as fever, and using herbal and nutriceutical treatments.

“Opioids themselves have no effect on the metabolism of the other drugs people are taking. The other agents act on them. I tell my patients that opioids are often the safest molecules we have, ” Strouse said.

There are significant diet/herbal drug interactions for opioids:

--Grapefruit juice inhibits P450 isoenzymes 3A3/4 (increased substrate levels)

--Hypericum (St. John’s Wort) induces P450 3A3/4 (decreased substrate levels)

--Alcohol/tobacco (pan inducers) can alter the drug’s effectiveness when people abruptly stop or abruptly resume smoking or drinking.

Strouse divided opioids into two broad categories, according to the way they are metabolized: morphine, hydromorphone and oxymorphone metabolize similarly and the second group contains tramadol, codeine, hydrocodone, oxycodone, fentanyl and methadone.

Methadone is a special case, he says, because it is a low-cost synthetic opioid with semi-unique analgesic properties. It has multiple, inactive metabolites formed mainly by N-demethylation via P450 3A3/4. The most commonly reported clinical events relate to loss of methadone analgesic effect when 3A3/4 inducers (barbiturates, verapamil, protease inhibitors) have been added.

Methadone pharmacokinetics are tricky, Strouse says, because:

--Methadone may inhibit its own metabolism

--After repeated dosing, increased (induced) methadone clearance may not significantly reduce bioavailability.

--Methadone may inhibit CNS P-glycoprotein (motors that clear drugs out of cells), reducing its neuronal clearance and potentiating its analgesic effects despite lower serum levels

Strouse gave these practical strategies when adding a potent P450 modulator to a P450 Opioid, noting that explaining their effects is important in educating the patient.

For inhibitors:

--The new medicine may enhance the effectiveness of your pain medication

--You may not need to take your pain medication as often

--Your pain medicine may seem stronger or work better

For inducers:

-- The new medicine may reduce the effectiveness of your pain medicine

-- You may need to take your pain medicine more frequently

-- Your pain medicine may not seem to work as well or as quickly.