Methadone antinociception is dependent on peripheral opioid receptors

J Pain. 2009 Apr;10(4):369-79. doi: 10.1016/j.jpain.2008.09.011.


Morphine and methadone are both high-affinity, potent mu-opioid peptide (MOP) receptor analgesics. In this report, we compared the antinociceptive potencies of these 2 drugs when administered subcutaneously (s.c.), intrathecally (i.t.), or intracerebroventricularly (i.c.v.) in both rat and mouse, using the tail-flick assay. We found that both morphine and methadone were potently antinociceptive when the drugs were administered s.c., showing comparable AD50 values in both species. However, the antinociception produced by methadone, when it was administered centrally, was much weaker than that produced by centrally administered morphine. Specifically, the AD50 value for methadone antinociception was more than 30-fold higher at both the i.t. and i.c.v. sites in mouse and not measurable in rat. Naloxone methiodide (NLX-M), a peripherally restricted antagonist, was used to further examine the relative contribution of central versus peripheral sites to morphine and methadone antinociception. NLX-M, when administered s.c., blocked the antinociceptive effect of either systemically or centrally administered methadone but had little effect on the antinociception produced by centrally administered morphine. Furthermore, centrally administered NLX-M significantly blocked antinociception produced by centrally administered morphine but not that produced by centrally administered methadone. Together, these results suggest that methadone antinociception is significantly dependent on an action of the drug at peripheral sites and could provide novel insight into the neural mechanisms that distinguish morphine versus methadone antinociception.

Perspective: Methadone is often used as an alternative for pain management. The present study shows that a peripheral action plays a crucial role in methadone antinociception. This finding could have significant clinical relevance for the use of methadone versus morphine for the treatment of certain types of pain.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Drug Administration Routes
  • Injections, Intraventricular
  • Injections, Spinal
  • Injections, Subcutaneous
  • Male
  • Methadone / administration & dosage*
  • Methadone / pharmacology*
  • Mice
  • Morphine / administration & dosage*
  • Morphine / pharmacology*
  • Naloxone / administration & dosage
  • Naloxone / analogs & derivatives
  • Naloxone / pharmacology
  • Narcotic Antagonists*
  • Pain / drug therapy
  • Pain / physiopathology
  • Pain Measurement / methods
  • Quaternary Ammonium Compounds / administration & dosage
  • Quaternary Ammonium Compounds / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid / agonists*
  • Species Specificity


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Quaternary Ammonium Compounds
  • Receptors, Opioid
  • Naloxone
  • N-methylnaloxone
  • Morphine
  • Methadone