PERT Program

Tip of the Month: August 2005


USE OF NALOXONE FOR RELIEF OF CONSTIPATION


Q. I have a patient for whom we have tried multiple agents for his constipation, none of which has been highly effective. Last week the ARNP ordered oral naloxone (Narcan). Can you tell me more about the use of naloxone for constipation?

A. Opioid-induced constipation is a frequent and bothersome adverse effect for many palliative care and hospice patients. It occurs as a result of the stimulation of opioid receptors in the gastrointestinal tract that cause delayed gastric emptying, a slowing of gastrointestinal transit time, and an increase in anal sphincter tone.1 Clinical treatment of constipation commonly requires multiple agents, and while numerous laxatives have been shown to be effective, not one single agent has been found to work in all patients.2

Opioid antagonists compete with both endogenous and exogenous opioids at μ-receptor sites. Pure antagonists, when administered systemically, reverse both the central and peripheral effects of opioids.3 Naloxone (Narcan) is a powerful opioid antagonist that affects opioid receptors both inside and outside of the central nervous system. Systemic naloxone has a rapid onset of action (typically within 2 minutes) and a serum half-life of approximately 1 hour.1 The most common indication for use is the reversal of opioid-induced respiratory depression and opioid overdose. Full doses of systemically administered naloxone will precipitate acute withdrawal in physically dependent patients.

Although the primary effect of naloxone is centrally mediated opioid antagonism, peripheral effects have also been observed.1 When given orally, hepatic metabolism limits systemic bioavailability (less than 3%), allowing for selective blocking of intestinal opioid receptors without blocking the desired systemic effects.2 It is believed that because oral naloxone appears in such small amounts in the systemic circulation, the primary effects are related to antagonism of opioid receptors in the gastrointestinal tract. There have been a number of studies, albeit with small samples, that have examined the use of oral naloxone for treatment of opioid-related constipation. The majority of these studies concluded that oral naloxone could be effective in relieving opioid-induced constipation.4-9

The literature is inconsistent in terms of how to determine the appropriate dose. A study by Robinson et al10 found no efficacy with doses between 0.4 mg and 4 mg, suggesting that oral doses below 2 to 4 mg are usually not effective.3 Other studies have advocated dosing based on pre-existing morphine dose, expressed as a percentage of daily morphine.2 In this same study, the researchers stated that doses of less than 10% of the daily morphine dosage may be ineffective, and that most patients have a favorable response to a naloxone dose equivalent to approximately 20% of the total daily morphine dosage, with doses ranging from 0.5% to 60%.4 It is important to remember that any dose may occasionally produce systemic adverse effects, but this appears to be a rare phenomenon that can be overcome by increasing the morphine dose.11 The overall recommendation when using oral naloxone is to start with low doses independent of pre-existing morphine usage. It appears that the total dose may be less critical than the dosing interval. At least one study recommended three doses per day, 4 hours apart, to reflect the plasma halflife of naloxone.3 In theory, it is believed that the dosing intervals are less likely to overtax the first-pass effect in the liver that could result in systemic adverse effects.

Although it is not the gold standard of treatment for opioid-induced constipation, oral naloxone can be an effective treatment alternative. The limited data available are not consistent in dosing recommendations other than to suggest starting at lower doses with every 4-hour dosing interval. While systemic naloxone has very few (if any) indications in hospice and palliative care, oral naloxone may be of benefit for opioid-induced constipation refractory to other treatments.



References

  1. Friedman JD, Dello Buono FA. Opioid antagonists in the treatment of opioidinduced constipation and pruritus. Ann Pharmacother. 2001;35(1):85-91.
  2. Choi YS, Billings JA. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage. 2002;24(1):71-90.
  3. Meissner W, Schmidt U, Hartmann M, Kath R, Reinhart K. Oral naloxone reverses opioid-associated constipation. Pain. 2000;84(1):105-109.
  4. Sykes NP. An investigation of the ability of oral naloxone to correct opioidrelated constipation in patients with advanced cancer. Palliat Med. 1996; 10(2):135-144.
  5. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage. 2002;23(1):48-53.
  6. Yuan CS, Foss JF, O'Connor M, Osinski J, Roizen MF, Moss J. Effects of intravenous methylnaltrexone on opioidinduced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study. Pain. 1999;83(3):631-635.
  7. Yuan CS, Foss JF, O'Connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA. 2000;283 (3):367-372.
  8. Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, et al. Treatment of opioidinduced constipation with oral naloxone: a pilot study. Clin Pharmacol Ther. 1992; 52(1):90-95.
  9. Hawkes ND, Richardson C, Evans BK, Rhodes J, Lewis SJ, Thomas GA. Effect of an enteric-release formulation of naloxone on intestinal transit in volunteers taking codeine. Aliment Pharmacol Ther. 2001;15(5):625-630.
  10. Robinson BA, Johansson L, Shaw J. Oral naloxone in opioid-associated constipation. Lancet. 1991;338(8766):581-582.
  11. Meissner W, Ullrich K. Re: naloxone, constipation and analgesia. J Pain Symptom Manage. 2002;24(3):276-277; author reply 277-279.


This month's tip was written by Darrell A. Owens, PhD, RN, CHPN, a Palliative Care Specialist at the University of Washington at Harborview Medical Center, Seattle, and a member of the Editorial Advisory Board, Journal of Hospice and Palliative Nursing. This article originally appeared in the Journal of Hospice and Palliative Nursing (Vol. 7, No. 4, July/August 2005), the official journal of the Hospice and Palliative Nursing Association.