Opioid-induced Pruritus
Pruritus is a recognised adverse reaction in patients receiving IV and intraspinal opioids. How should this reaction be treated & is it a contraindication to future management with opioids?
02/05/01
Searched by: Liam Kavanagh, Pharmacy
References searched:
Medline
Embase
ANDIN
Iowa Drug Information Service
Summary
The Adverse Drug Reaction (ADR) Committee at RCH has received several reports of pruritus following opioid administration, however it is highly likely that there is a significant under-reporting. The literature indicates pruritus occurring in 13% of patients following IV opioid administration1, 20-80% of patients receiving intrathecal opioids & 20-93% of patients receiving epidural opioids2. The ADR committee attempted to determine the appropriate action to take in such circumstances.
Cause
The mechanism by which opioids cause pruritus is unclear. Many substances induce pruritus by causing a release of histamine from mast cells into the skin. Although opioids release histamine from mast cells systemically, this does not appear to be the underlying mechanism as the effect occurs about 3 hours after spinal or epidural administration occurs. Pruritus also occurs with fentanyl, which does not cause histamine release.
The most likely cause is via a direct central effect. Opioid receptors are found throughout the brain and spinal cord. High concentrations of opioid receptors are found in the substantia gelatinosa, an area within the spinal cord which is the primary site of action of intraspinal opioids. It is hypothesized that opioid-induced pruritus occurs secondary to direct opioid receptor binding in the spinal cord and brain or via neurotransmission stemming from opioid receptor binding.1,2 This is supported by the fact that opioid antagonists eg naloxone, reverse this effect.
Treatment
All data regarding the use of antihistamines indicates they are not particularly effective.1,2,3,4,5 Changing to an opioid with less histamine-releasing properties (i.e. hydromorphone, oxymorphone & fentanyl) does occasionally provide relief1 but does not reliably relieve pruritus. Substitution of epidural buprenorphine (partial agonist) in combination with bupivacaine, for morphine relieved severe, unremitting pruritus in a single reported case. 6
In adults, a dose of naltrexone 6mg orally decreased itch caused by epidural morphine without affecting analgesia but a dose of 9mg was associated with a shorter duration of analgesia. 6 Methylnaltrexone, a peripheral opioid antagonist (with orphan drug status) has been used at a dose of 19.2 mg/kg orally in a study of 10 patients and was shown to significantly reduce itch.3 The addition of a methyl group to naltrexone decreases the lipophilicity and limits its passage across the blood-brain barrier without compromising centrally mediated pain control.
Propofol has been used in adults at subhypnotic doses i.e. 10mg bolus or 0.3mcg/kg/min by infusion. It is believed to act by inhibition of ventral and dorsal spinal routes. Overall, it has a success rate of 80% in relieving pruritus induced by epidural morphine for 3 to 6 hours when given as bolus injection, with the added advantage of reducing postoperative pain.2
Ondansetron has been used to treat pruritus in patients with cholestatic diseases where endogenous opioid levels are increased. There are numerous case reports of successful use in opioid induced pruritus. In four patients where perioperative administration of opioids caused itch, ondansetron 4mg IV was administered. Pruritus resolved within a few minutes in 3 of these patients, whilst in the other there was a slight reduction in symptoms. 6 Another study showed repeated doses of ondansetron reduce the incidence of itch by 33% after subarachnoid morphine. 7
Naloxone appears to be the most reliable and cost-effective form of treatment. In one of the only paediatric studies of opioid induced pruritus, 30 patients were given a 2 - 5 mcg/kg/hr continuous infusion, 63% of patients experienced a complete response, whilst 37% experienced a partial response. Naloxone may decrease the duration of effective analgesia and requires an increase in opioid dose, yet this only occurred in 23% of patients.1
Conclusion
Although opioid induced pruritus may be severe, and in some cases, more debilitating than the pain requiring analgesia, it is not a contraindication for further opioid treatment. Change of opioid, site of administration or the use of naloxone or ondansetron appear to be the most suitable forms of management.
References:
Vrchoticky T. Naloxone for the treatment of narcotic induced pruritus. The Journal of Pediatric Pharmacy Practice 2000; 5: 92-6.
Kam P,Tan K. Pruritus-itching for a cause and relief? Anaesthesia 1996; 51: 1133 - 8.
Dello Buono F, Friedman J. Opioid antagonists in the treatment of opioid-induced constipation and pruritus. The Annals of Pharmacotherapy 2001; 35: 85 - 90.
Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and hydromorphone hydrochloride. Journal of Pain and Symptom Management 1999; 17: 70 - 72.
Dukes M. Meylers side effects of drugs. Elsevier, Holland, 1996; 13th edition: 164 - 171.
Goldberg M, Larijani G, Rogers K. Treatment of opioid-induced pruritus with ondansetron: report of four patients. Pharmacotherapy 1996; 16: 958-960.
Dimitriou V, Voyagis G. Opioid-induced pruritus: repeated vs single dose ondansetron administration in preventing pruritus after intrathecal morphine. British Journal of Anaesthesia 1999; 83: 822.
David F. McAuley, Pharm D.
GlobalRPh Inc.
In mild cases of pruritus, nonspecific measures can be used to control the symptoms such as emollients and warm baths.1,9 However, these measures often fail in moderate to severe cases of pruritis. One option for moderate to severe cases are the opioid antagonists such as intravenous naloxone (0.2 µg/kg per min for 24 hours) or oral naltrexone (50 mg daily). The use of an opiate antagonist is often associated with substantial relief of cholestatic pruritus.1,7 In one controlled, crossover trial of 29 patients, for example, naloxone led to a 27 percent reduction in scratching activity and to a significant reduction in the perception of pruritus.
Even though naloxone may be effective in reducing pruritis, there are three major limitations for long-term use: 1) Naloxone has a short half-life and therefore requires frequent dosing. 2) Naloxone also has a significant first-pass metabolism and must be given parenterally (not orally bioavailable). 3) Potential tachyphylaxis with long-term treatment.
There is more literature out there- my preference is Ondansetron 4mg tid. Costly, but not a reversing agent like Naltrexone.
