Deep brain stimulation for the relief of chronic pain.

Deep brain stimulation analgesia is an effective method of treating otherwise intractable chronic pain, with few side-effects, and long-term good or better results in 50% to 80% of patients, depending on etiology and stimulation site. In general, the best results are in deafferentation pain with internal capsule stimulation and somatic pain with periventricular stimulation.

Zinc suppression of free radicals induced in cultures of rat hepatocytes by iron, t-butyl hydroperoxide, and 3-methylindole.

The effect of zinc on lipid peroxidation initiated by either ferric-nitrilotriacetate, t-butyl hydroperoxide, or 3-methylindole was studied using primary monolayer cultures of rat liver parenchymal cells. The malondialdehyde content of the cells and culture medium was used to estimate the extent of lipid peroxidation. As the zinc concentration of the culture medium was increased from 1 to 48 microM, peroxidation was diminished. Cellular zinc and metallothionein levels were proportionally increased by supplemental zinc. Zinc supplementation of the medium inhibited NADPH-cytochrome c reductase activity and stimulated glutathione peroxidase activity. The uptake of iron into the hepatocytes was significantly reduced as the level of zinc was raised, suggesting that zinc antagonizes uptake of chelated iron into isolated hepatocytes and in this way blocks iron-induced peroxidation. Furthermore, induction of metallothionein synthesis by zinc may contribute to the reduction in free radicals. Spectra from electron spin resonance studies, using phenylbutylnitrone as a spin-trapping reagent, demonstrated that free radical production was inversely related to the zinc concentration of the culture medium. Spin trap data suggest that metallothionein added to lysed cells in vitro decreases free radical production. Studies using the spin trap, 3,3,5,5-tetramethylpyrroline-N-oxide indicated that cumulatively the predominant radical present in the cultures was a phenyl radical with hydroperoxide or methylindole. Collectively, our data demonstrate that zinc inhibits free radical production and lipid peroxidation in cultured hepatocytes. The mode of action of zinc could occur via free radical scavenging by zinc-induced metallothionein and/or by processes related to cytochrome P-450 and glutathione peroxidase, since these were also found to be sensitive to zinc supplementation levels of the culture medium.

Autopsy analysis of the safety, efficacy and cartography of electrical stimulation of the central gray in humans.

Electrical brain stimulation is effective in controlling certain intractable chronic pain syndromes in humans, but the specific target site(s) for stimulation producing a maximal analgesic effect is (are) not well defined. This prospective study correlates the clinical results of chronic stimulation of the periaqueductal gray (PAG) and periventricular gray (PVG) matter in humans with the anatomic site of electrode placement as determined at autopsy, and documents the histologic reactions to electrode implantation and electrical stimulation of the area. Seven patients underwent electrode implantation to control their chronic pain; two had electrodes implanted bilaterally. All patients obtained complete analgesia with stimulation, although 3 subsequently found the stimulation to have diminished efficacy. The opiate antagonist naloxone reversed the analgesia in the 4 patients so tested. All 7 patients later died of causes unrelated to electrode implantation or stimulation. Postmortem analysis showed that, for 6 of the 9 electrodes implanted, the electrode tip was located in the ventrolateral PAG at the level of the posterior commissure; the other 3 electrodes were found in the white matter adjacent to the PAG. No evidence of gliosis or parenchymal reaction was observed along the tracts and tips of the electrodes. The results indicate that the ventrolateral PAG and PVG matter at the level of the posterior commissure is the optimal site for therapeutic electrical brain stimulation for opiate-responsive pain in humans.

Appearance of beta-endorphin-like immunoreactivity in human ventricular cerebrospinal fluid upon analgesic electrical stimulation.

beta-Endorphin-like immunoreactivity in human ventricular cerebrospinal fluid was measured with a specific radioimmunoassay. The subjects were undergoing a surgical procedure for relief of chronic intractable pain. This procedure involved the focal stimulation of a medial thalamic site adjacent to the wall of the third ventricle. Samples were collected before and during the analgesic stimulation. No beta-endorphin-like immunoreactivity could be detected prior to stimulation, suggesting that baseline levels are below 25 fmol/ml of cerebrospinal fluid. Electrical stimulation led to substantial increases (13- to 20-fold) in immunoreactive material in every subject. These results suggest that beta-endorphin-like material can be released into the ventricular system and may contribute to the pain blockade that results from periventricular stimulation.

Long term results of periventricular gray self-stimulation.

Thirty patients were operated upon, with chronic implantation of self-stimulating devices for stimulation of the posterior periventricular gray matter for pain control. Three patients required removal of the electrodes because of failure of adequate pain control during the period of percutaneous testing, and five patients report on long term follow-up that they have had no pain relief with stimulation, and have discontinued it. Four patients describe minor relief of pain, and 18 patients report significant relief of pain with stimulation. Therefore, 18 patients, or 66% of the 27 patients having implantation, are considered to have had successful operations, and 12 of the patients are considered failures. Stimulation for brief periods of time, such as 5 to 30 minutes every 2 to 12 hours has been found adequate for control of chronic pain with minimal side effects and a low complication rate.

Pain reduction by electrical brain stimulation in man. Part 2: Chronic self-administration in the periventricular gray matter.

Electrical stimulation of the periventricular gray matter is an effective means of relieving several types of pain without destruction of neural tissue. The effects are long lasting, often bilateral, and with judicious use do not appear subject to adaptation. However, sustained uninterrupted stimulation for several hours does lead to a reversible decrease in effectiveness. Side effects from stimulation are minimal and cause little or no untoward emotional changes. The results are discussed in terms of activation of an endogenous pain inhibitory mechanism that involves naturally occurring opiate-like factors such as the enkephalins and endorphins.

Pain reduction by electrical brain stimulation in man. Part 1: Acute administration in periaqueductal and periventricular sites.

Acute studies performed in five patients indicate that electrical stimulation of the brain could be a powerful tool for the reduction or control of intractable pain. While chronic or spontaneous pain could be relieved by stimulation of the periaqueductal gray matter, the accompanying side effects render it impossible to stimulate this site regularly. On the other hand, stimulation of medial thalamic sites, particularly medial to the nucleus parafascicularis, yielded good relief of chronic pain at parameters which did not cause many undesirable side effects. The same parameters also produced inhibition of acute pain in two of the five patients.