Drug Interactions with Patient-Controlled Analgesia

Abstract

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems. Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of alpha1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance. Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or alpha2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.

Morphine Glucuronosyltransferase Activity in Human Liver Microsomes is Inhibited by a Variety of Drugs that are Co-administered with Morphine

“…4) Morphine 3-glucuronide has no analgesic eŠects, but morphine 6-glucuronide is a more potent (20 times) analgesic than morphine itself. 5) Patients suŠering from cancer need continuous therapy with morphine. Anti-cancer drugs such as etoposide, irinotecan (its active metabolite is SN-38), and tamoxifen, are widely used for chemotherapy with morphine.…”

In Vivo Activation of Human Pregnane X Receptor Tightens the Blood-Brain Barrier to Methadone through P-Glycoprotein Up-Regulation

“…This has been observed in animals chronically exposed to certain P-glycoprotein substrates (Fromm et al, 1997;Lotsch et al, 2002), but the mechanism underlying the increase in transporter activity has not been identified. We recently detected expression of the ligand-activated, pregnane X receptor (PXR) in isolated rat brain capillaries .…”

Cardiotoxicity of Oral Methadone as an Analgesic–-Recommendations for Safe Use

“…2 Despite a moderateto-high degree of plasma protein binding and the ability of basic drugs to displace methadone from its binding sites on alpha 1 acid glycoprotein (AAG), there are no data suggesting that these protein binding displacement interactions are clinically relevant. 10,11 Another potential confounder is cocaine, a common co-drug-of-abuse in opioid abusers. This is because cocaine suppresses the delayed rectifier potassium ion channels in cardiac myocytes (HERG current where HERG = human ether-a-go-go gene) like many other torsadogenic drugs, including methadone.…”