Pain relief following stimulation of the periaqueductal gray matter (PAG) or periventricular gray matter (PVG) in man has been ascribed to stimulation-induced release of endogenous
opioid substances. Forty-five patients were studied and followed for at least 1 year after placement of chronic stimulating
electrodes in the PAG or PVG to determine if
pain relief due to stimulation could be ascribed to an endogenous
opioid mechanism. Three criteria were assessed: the development of tolerance to stimulation; the possibility of cross-tolerance to
morphine; and reversibility of stimulation-induced
pain relief by the
opiate antagonist
naloxone. Sixteen patients (35.6%) developed tolerance to stimulation, that is, they obtained progressively less effective
pain relief. Twelve (44.4%) of 27 patients undergoing stimulation of the thalamic sensory relay nuclei for treatment of
chronic pain (a presumably non-
opioid mechanism) also developed tolerance.
Morphine sulfate was administered in a blind, placebo-controlled protocol to 10 patients who had become tolerant to PAG-PVG stimulation and none showed evidence of cross-tolerance. Fifteen of 19 patients, already tolerant to
morphine at the time of PAG-PVG
electrode implantation, experienced excellent
pain relief by stimulation, also indicating a lack of cross-tolerance. Twenty-two patients who experienced excellent
pain relief from chronic PAG-PVG stimulation received intravenous
naloxone in a double-blind, placebo-controlled protocol.
Pain intensity as assessed by the visual analog scale was increased to the same degree by both placebo and
naloxone. Eight patients showed no increase in
pain intensity with either placebo or
naloxone. Although tolerance to PAG-PVG stimulation developed in these patients, the frequency of tolerance was similar to that seen in patients undergoing thalamic sensory nuclear stimulation. Since the latter technique presumably relieves
pain by a non-
opioid mechanism, the development of tolerance to PAG-PVG stimulation does not, in itself, confirm an
opioid mechanism. Cross-tolerance between PAG-PVG stimulation and
morphine was not seen and cross-tolerance to PAG-PVG stimulation in patients already tolerant to
morphine was rare. The
pain-relieving effect of PAG-PVG stimulation was reversed to an approximately equal degree by
naloxone and placebo. The authors do not believe that, in most patients,
pain relief elicited by PAG-PVG stimulation depends on an endogenous
opioid mechanism. It appears that other, non-
opioid mechanisms are primarily responsible for such
pain relief.