Acute Pain: Overcoming Extended Release Naltrexone

I don't usually report on animal trial but this is an important topic without a lot of published data.

What do we do when an extended-release naltrexone patient has an acute painful episode?


Pharmacol Biochem Behav. 2008 Jun;89(4):515-22
Overriding the blockade of antinociceptive actions of opioids in rats treated with extended-release naltrexone.
Dean RL, Todtenkopf MS, Deaver DR, Arastu MF, Dong N, Reitano K, O'Driscoll K, Kriksciukaite K, Gastfriend DR.
Department of Life Sciences and Toxicology, Alkermes, Inc., 88 Sidney St., Cambridge, MA 02139, USA. reggie.dean@alkermes.com
PMID: 18342360

The authors compared treating acute pain in rats treated with XR-NTX or placebo on the 'hot plate test' with morphine, fentanyl, and hydrocodone. They defined 100% Maximum Response Latency as when the rats would not lick the heated paw for 60 sec.  In rats who hadn't received naltrexone this took 15 mg/kg for morphine, 0.1 mg/kg for fentanyl or 8 mg/kg for hydrocodone.  Pretty high doses. Recall our usual starting dose of fentanyl in humans is 100 mcg = 0.1 mg (not per kg). 

Since the study was performed at Alkermes lab, I assume the XR-NTX used was the same as Vivitrol.  The rat dose of naltrexone was 50 mg/kg, compared to the 380 mg in the human dose, approximately 5 mg/kg in a 70 kg patient.

Pain relief with morphine was limited by a maximal dose of 90 mg/kg due to solubility problems. This dose produced a MRL of only 36% on day 4 and 46% on day 19. On day 39, a morphine dose of 45 mg/kg  produced 100% MRL.  

Fentanyl produced 100% response at a dose of 2.0 mg/kg on days 4 and 19. This is 20 times the dose required in rats who had not received naltrexone.  After 39 days 0.5 mg/kg allowed a full response, still 5 x the baseline dose.

Hydrocodone gave 69% MRL on day 4, 80% on day 19 at 80 mg/kg, 10 x the baseline dose. At 39 days, of 24 mg/kg (3 x the baseline dose) allowed 75% of MRL.

What can we conclude? Well, this is a rat study and the doses of both XR-NTX and opiate pain medicines were higher per kg than we use in humans. But the following facts stand out

1. Fentanyl may allow more complete pain relief in XR-NTX treated patients than morphine or hydrocodone.
2. Doses of fentanyl for maximal effect were 20 x normal.  At this dose pain relief appeared equal to rats who hadn't been treated with naltrexone.  Morphine at 6 x normal and hydrocodone at 10 x normal did not allow pain relief equal to non naltrexone treated rats.

So if our XR-NTX patients have acute pain requiring opioid treatment: use high affinity opiates (fentanyl and maybe hydromorphone) and be prepared to use a lot