Opiates in advanced renal failure

I was taught the rule of 6's when it came to using opiates in dialysis patients:

• they're metabolized by hepatic glucuronidase to 6-glucurinides (e.g. morphine 6 glucuronide or M6G)
• these metabolites are renally excreted, increasing the half-life to 6 times that of the parent compound in ESRD
• peak toxicity may not occur for over 6 hours (or at 6 am while you're on call) as M6G occurs in both hydrophilic and lipophilic forms, and it takes time for the latter to cross the blood-brain barrier and acculmulate in the CSF. Opiate toxicity should be your first thought in any hypoventilating dialysis patient.

The worst offenders are codeine and morphine, and to a lesser extent oxycodone and hydromorphone. Not all opiates behave like this though, and the following three are probably safest:

• Fentanyl has no active metabolites and appears to be well tolerated.
• Tramadol is a non-narcotic analgesic with some effects at the mu opioid receptor. It's usual half-life is 5 hours, increasing to ten in ESRD. Max. dose of 50mg bid. Watch out for serotonin syndrome with SSRI's
• Methadone does not appear to accumulate at all in renal failure, as observed in drug addicts with CKD and ESRD, and appears safe to use.

Finally, the same pharmokinetic properties that render these 3 agents "safe" in ESRD also make them un-dialyzable, so they should be up-titrated cautiously.