Use of Very-Low-Dose Methadone and Haloperidol for Pain Control in Palliative Care Patients: Are the Sigma-1 Receptors Involved?

Dear Editor:

In the February issue of the Journal of Palliative Medicine, Salpeter and collaborators reported an excellent pain control of palliative care patients who were converted from another opiate to an association of a very-low-dose of methadone (median daily dose, 5 mg) and a low dose of haloperidol (median daily dose, 1.5 mg). ¹ The authors suggest that their results can be explained by the modulation of the opioid effect through the action of both drugs at NMDA-receptors; however, we think that there is a third player involved: the sigma-1 receptors.

Haloperidol and its main metabolite, reduced haloperidol, have a much greater affinity for sigma-1 receptors than for NMDA receptors (nM versus mM affinity) ² and produce a very long lasting blockade of sigma-1 receptors in rodents. ³ This effect is also relevant in human beings, since a dose of 3 mg of haloperidol occupies more than 80% of sigma-1 receptors (but less that 65% D₂ receptors) in the brain of healthy subjects. ⁴ Furthermore, an antagonism of sigma-1 receptors underlies the antinociceptive effect of haloperidol and its metabolites in mice. ² Therefore, haloperidol and its main metabolite behave as sigma-1 receptor antagonists and this effect is functionally relevant.

It was recently reported that sigma-1 receptor antagonists remove the binding of sigma-1 receptors to the NR1 subunits of NMDA receptors, which prevent the ability of these receptors to restrain opioid-induced antinociception. ⁵ In agreement with this, sigma-1 receptor antagonism restores morphine antinociception in tolerant mice. ⁶ Moreover, sigma-1 receptor antagonists potentiate opioid-induced antinociception but not opioid-induced side effects (such as inhibition of intestinal transit and others) in mice.^6,7

For these reasons we think that the marked potentiation by haloperidol of methadone-induced analgesia, but not of its side effects, that the Salpeter et al. report results ¹ is probably due to the blockade of sigma-1 receptors by haloperidol and its metabolites. This might open the possibility of the introduction of sigma-1 receptor antagonists in the clinical practice as opioid adjuvants.