Morphine Overdose in a Renal Failure Patient

Dr. Eddie Chen, DO, RPh

56 yo AAF presented to a long term acute care facility for recovery of sepsis. She has dysphagia and is on a continuous PEG tube feeding. She has been suffering from sharp pain secondary to multiple stage III-IV decubitus ulcers. The patient also has another type of pain which she describes as burning, throbbing from her toes up to her knees. Currently she is very uncomfortable and states her pain is at least 8-9/10.

PMH: MVA one year ago which left her quadriplegic, DM 2, ESRD on HD on MWF

Pain medications: Duragesic 75mcg/hr patch Q 3 d, and Dilaudid 2 mg IV Q 3 hr PRN breakthrough pain

What to do to control the pain?
Increase the dose of the pain medications, this is a no-brainer, but how to do it exactly. Duragesic patch was increased to 100 mcg/hr, and her Dilaudid was discontinued, but replaced with Roxanol 20mg/ml, 1.5 ml sublingually Q 3 hr as needed for pain. She was also placed on 100 mg of Neurontin TID via PEG tube.

What happened?
Her pain gradually decreased. On day 3, patient was very difficult to arouse in dialysis, and her blood pressure fell below 80 systolically. Patient responded to one ampoule of Narcan IV and IV normal saline boluses.

What do you think is going on?
Most likely, she developed symptoms secondary to a morphine overdose.

But she is having HD, isn't she? Is morphine removed during dialysis?
Yes, MS is removed during HD but not its metabolites, and this is what causes problems.
Morphine is 90 % metabolized by the liver with a significant first pass effect on oral administration. Urinary excretion accounts for the remaining 10%. Approximately 70 percent of morphine are conjugated with glucuronates. There are 2 major glucuronides forms - M3G and M6G (the major MS metabolites).

Major Metabolites of Morphine:
-Morphine-3-Glucuronide (M3G) has a nearly 300 fold lower affinity to the Mu receptors compared to morphine, however it has been postulated that it may act as an antagonist of opioid receptors at high concentrations. There has also showed that it may have neuroexcitatory effects, with myoclonus and allodynia seen after large dose systemic morphine were given.

-Morphine-6-Glucuronide (M6G) has a nearly 100 fold higher affinity to the Mu receptors compared to morphine. It is more selective to the Mu2 receptors, which will bring less nausea and vomiting, sedation, and decrease the risk of pulmonary depression. M6G is currently going through phase III trials for post-operative pain.

These glucuronides are excreted by the renal tubules. Thus the glucuronides do not get excreted and accumulate in the presence of renal failure and cause opiod toxicity.

But the question remains, can the glucuronides be cleared by dialysis?
No. In a small study in CRI patients, 8 patient non-dialysis group and 9 patient dialysis group had assays drawn after they received morphine 0.1mg/kg IV infusion. The dialysis group had dialysis approximately 2-4 hours post morphine infusion. In both groups, the glucuronide levels remained almost equally high, while the free morphine levels were not measurable (Osborn et al).

Though it was not a large multicenter trial, the study shows that the glucuronides do not clear after dialysis, while free morphine does. Thus the glucuronide metabolites will accumulate during routine administration of morphine in both of these patient populations and possibly cause opiate toxicity.

Final diagnosis: Morphine overdose due to MS administration in a patient with ESRD

What did we learn from this case?
Morphine should not be used for treatment of pain in renal failure patients on a routine basis, regardless of dialysis. MS can be cautiously given for treatment of acute pain.

In renal failure patients, try to use opiates not significantly excreted by the kidneys, e. g. fentanyl, hydromorphone, or oxycodone.

References:
Osborne RJ, Joel SP, Slevin ML. Morphine intoxication in renal failure: the role of morphine-6-glucuronide. Br Med J (Clin Res Ed). 1986 Jun 14;292(6535):1548-9.

Janicki P. Pharmacology of Morphine Metabolites. Current Pain and Headache Reports 1997 1:264-270.

Hemstapat K, Monteith G, Smith D, Smith M. Morphine-3-Glucuronide’s Neuro-Excitatory Effects are Mediated via Indirect Activation of N-Methyl-d-Aspartic Acid Receptors: Mechanistic Studies in Embryonic Cultured Hippocampal Neurones. Anesth Analg 2003;97: 494-505.

Osborne R, Joel S, Grebenik K, Trew D, Slevin M. The Pharmacokinetics of Morphine and Morphine Glucuronides in Kidney Failure. Clin Pharmacol Ther 1993;54: 158-67.

Created: 03/14/2005