Do low levels of beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study.

OBJECTIVE: Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF). DESIGN: Cross-sectional, comparative, observational study. SUBJECTS: Patients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included. METHODS: Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit. RESULTS: We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs. rs = 0.574, P = 0.032). CONCLUSIONS: Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

Glial cell line-derived neurotrophic factor is increased in cerebrospinal fluid but decreased in blood during long-term pain.

Glial cell line-derived neurotrophic factor (GDNF) is involved in inflammation and pain, roles which remain to be delineated clinically. We aimed to evaluate the role of central nervous and peripheral GDNF in long-term pain patients and in controls by analysing intrathecal and blood concentrations of GDNF. Simultaneous measurements of pro-inflammatory cytokines IL-1beta, TNF-alpha and IL-6, anti-inflammatory cytokine IL-10 and chemokine IL-8 served to define inflammatory responses. Generally, blood levels of GDNF were higher than corresponding intrathecal levels. Pain was associated with levels of GDNF that were increased intrathecally, but decreased in blood. IL-8 was uniformly higher in pain patients.

Intracerebroventricular morphine for refractory cancer pain: transitioning to the home setting.

Refractory cancer pain may be effectively controlled by titrating intracerebroventricular (ICV) preservative-free opioid. In this case report, a continuous infusion of ICV morphine permitted our patient with lung cancer and painful spinal metastases to be discharged to home hospice with family. The approach exploits the high potency of morphine injected into cerebrospinal fluid (CSF). Sterile, injectable, preservative-free morphine is directly infused into CSF through a subcutaneous Ommaya reservoir placed under the scalp by a neurosurgeon, with an attached catheter passed through a burr hole in the skull with its tip in a cerebral ventricle. Although investigators have described home care of patients receiving intraspinal analgesics, no report describes the process of transitioning the patient receiving continuous ICV morphine infusion to the home setting.

Acute response to intracisternal bupivacaine in patients with refractory pain of the head and neck.

Continuous intracisternal infusion of bupivacaine for the management of intractable pain of the head and neck is effective in controlling pain in this patient group. With the catheter tip being located at the height of the C1 vertebral body, autonomic regulatory information may also be influenced by the infusion of bupivacaine. By combining direct sampling of cerebrospinal fluid (CSF), via a percutaneously placed catheter in the cisterna magna, with a noradrenaline and adrenaline isotope dilution method for examining sympathetic and adrenal medullary activity, we were able to quantify the release of brain neurotransmitters and examine efferent sympathetic nervous outflow in patients following intracisternal administration of bupivacaine. Despite severe pain, sympathetic and adrenal medullary activities were well within normal range (4.2 +/- 0.6 and 0.7 +/- 0.2 nmol min(-1), respectively, mean +/-S.E.M.). Intracisternal bupivacaine administration caused an almost instantaneous elevation in mean arterial blood pressure, increasing by 17 +/- 7 mmHg after 10 min (P < 0.01). Heart rate increased in parallel (17 +/- 5 beats min(-1)), and these changes coincided with an increase in sympathetic nervous activity, peaking with an approximately 50% increase over resting level 10 min after injection (P < 0.01). CSF levels of GABA were reduced following bupivacaine (P < 0.05). CSF catecholamines and serotonin, and EEG, remained unaffected. These results show that acutely administered bupivacaine in the cisterna magna of chronic pain sufferers leads to an activation of the sympathetic nervous system. The results suggest that the haemodynamic consequences occur as a result of interference with the neuronal circuitry in the brainstem. Although these effects are transient, they warrant caution at the induction of intracisternal local anaesthesia.

Loss of intrathecal morphine analgesia in terminal cancer patients is associated with high levels of excitatory amino acids in the CSF.

PURPOSE: To examine excitatory amino acid (EAA) levels in the cerebrospinal fluid (CSF) of patients on long-term morphine treatment for terminal cancer pain relief and to correlate these with morphine's analgesic effect. METHODS: Fourteen terminal cancer patients suffering severe pain and requiring long-term opioid treatment for pain relief were included. An intrathecal (IT) catheter was implanted at the L(3-4)/L(4-5) level and advanced 10 cm in a cephalad direction. IT morphine injection was started at 100 microgram q 12 hr with a daily incremental dose of 50 microgram until the effective dose was reached. The CSF was sampled (2 mL) as follows: 1) before the first IT morphine injection, 2) when the effective dose of morphine was reached, 3) when loss of morphine's analgesic effect at the effective dose (pain visual analogue scale > 5), and 4) after consecutive increases of the morphine dose (50 microgram, IT, daily) for satisfactory pain relief and up to double the effective dose. The concentrations of glutamate and aspartate in the CSF were determined. RESULTS: CSF levels of glutamate and aspartate at the effective dose of morphine were lower than the baseline levels and increased when pain intensity increased and when morphine's analgesic effect was lost. CONCLUSION: Long-term IT morphine administration was accompanied by an increase of EAA level in the CSF that was associated with a loss of morphine's analgesic effect.

Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia.

UNLABELLED: BACKGROUND AND OBJECTIVES The goal of this study was to evaluate the analgesic effects of intrathecal versus epidural methylprednisolone acetate (MPA) in patients with intractable postherpetic neuralgia (PHN). METHODS: We studied 25 patients with a duration of PHN of more than 1 year. The patients were randomly allocated to one of two groups: an intrathecal group (n = 13) and an epidural group (n = 12). Sixty milligrams of MPA was administered either into the intrathecal or the epidural space four times at 1-week intervals depending on the treatment group. Continuous and lancinating pain and allodynia were evaluated by a physician unaware of group assignment with a 10-cm visual analogue scale before treatment, at the end of treatment, and 1 and 24 weeks after treatment. In addition, cerebrospinal fluid (CSF) was obtained for measurement of interleukin (IL)-1beta, -6, and -8 and tumor necrosis factor-alpha before and 1 week after treatment. RESULTS: We found marked alleviation of continuous and lancinating pain and allodynia in the intrathecal group (P < .001). The improvements were much greater in the intrathecal group than in the epidural group at all time points after the end of treatment (P < .005). IL-8 in the CSF decreased significantly in the intrathecal group as compared to the epidural group at the l-week time point (P < .01), whereas the other cytokines were undetectable. CONCLUSIONS: Our results suggest the effectiveness of intrathecal as compared to epidural MPA for relieving the pain and allodynia associated with PHN. Also, our findings, together with the decrease in IL-8, may indicate that intrathecal MPA improves analgesia by decreasing an ongoing inflammatory reaction in the CSF.

Release of beta-endorphin and methionine-enkephalin into cerebrospinal fluid during deep brain stimulation for chronic pain. Effects of stimulation locus and site of sampling.

The authors systematically studied the release of the endogenous opioid peptides beta-endorphin and methionine (met)-enkephalin into the cerebrospinal fluid (CSF) during deep brain stimulation in patients suffering from otherwise intractable chronic pain. Nine patients were included in the study; six had stimulation electrodes placed in both the periventricular gray matter (PVG) and the thalamic nucleus ventralis posterolateralis (VLP) and three in the PVG only. Immunoreactivity of beta-endorphin and met-enkephalin (beta-EPir and MEir, respectively) was measured by radioimmunoassays in ventricular and lumbar CSF samples obtained before, during, and after stimulation. Prestimulation concentrations of beta-EPir and MEir were lower in ventricular than in lumbar CSF (6.6 +/- 0.5 vs. 13.7 +/- 1.0 pmol/liter, p = 0.0001, for beta-EPir; 33.6 +/- 5.1 vs. 48.3 +/- 3.2 pmol/liter, p < 0.05, for MEir). Ventricular CSF concentrations of both beta-EPir and MEir increased significantly during PVG stimulation, whereas VPL stimulation was without effect. No changes were seen in lumbar CSF levels of the peptides during stimulation in either site. A significant inverse relationship was found between the "during:before stimulation" ratios of visual analog scale ratings and beta-EPir levels during PVG stimulation. The beta-EPir and MEir concentration during:before stimulation ratios were positively correlated, whereas no correlation was present in prestimulation samples from ventricular or lumbar CSF. High-performance liquid chromatography of ventricular CSF pools obtained during PVG stimulation revealed that major portions of beta-EPir and MEir eluted as synthetic beta-endorphin and met-enkephalin, respectively, thus documenting the release of beta-endorphin and met-enkephalin into ventricular CSF during PVG stimulation. The finding of a direct relationship between beta-EPir release and pain alleviation may suggest a role for beta-endorphin in the analgesic mechanism of PVG stimulation.

The distribution of medication along the spinal canal after chronic intrathecal administration.

Chronic intrathecal drug infusion for the treatment of neurological diseases, such as spasticity and chronic pain, has become an accepted method of therapy in recent years. Concurrent pharmacokinetic studies have shown that the cisternal cerebrospinal fluid (CSF) drug level is considerably lower than the lumbar CSF level during continuous infusion into the lumbar subarachnoid space. One factor that makes analysis of this decline in drug level difficult to quantify is that it is only feasible to sample CSF at the two extremes of the spinal subarachnoid space. Using a radionuclide technique, we have examined the distribution along the spinal canal of a hydrophilic compound, indium-111 diethylenetriamine pentaacetic acid, that was delivered over 72 hours into the lumbar subarachnoid space in five patients with implanted drug pumps. Over a 20-cm distance of the thoracic cord, radionuclide counts decreased gradually so that the indium-111 diethylenetriamine pentaacetic acid concentration surrounding the cord at the T2 vertebral level was 43% of that at the T12 level in four patients. Therefore, it appears that even with a hydrophilic compound, which minimizes spinal cord capillary losses, there is still a considerable reduction of CSF drug concentration along the spinal canal. The clinical implication of this gradual decline in drug level is that for intrathecal infusion of relatively hydrophilic compounds there may not be any advantage in placing the catheter tip at more rostral locations, such as at the midthoracic or cervical cord.

Effects of dorsal root entry zone lesions on CSF and plasma neuropeptides and catecholamines.

Effects of dorsal root entry zone lesions (DREZLs) on cerebrospinal fluid (CSF) and plasma concentrations of neuropeptides, catecholamines, and cyclic nucleotides were studied in 9 patients with intractable chronic pain. Contents of beta-endorphin-like-material in CSF decreased in all patients 12-17 days following DREZLs during which complete to good pain relief was achieved. Contents of beta-endorphin-like-material in CSF increased again about one month after DREZLs in two and remained unchanged in one of three patients tested, who complained of partial reappearance of pain. Contents of beta-endorphin-like-materials in plasma showed no significant changes after DREZLs. Substance P, noradrenaline, adrenaline, and cyclic nucleotide levels in both CSF and plasma were variable among the subjects and did not change significantly following the operations. Thus, the results suggest that production of beta-endorphin-like-material in the central nervous system is decreased by DREZL, though the increase in its turn-over might not be neglected. The mechanisms of the decrease in contents of beta-endorphin-like-material in CSF after DREZLs were discussed in terms of our current knowledge of pain and pain inhibitory systems.

[Cerebrospinal fluid beta-endorphin in chronic pain in man]. / Bêta-endorphine du liquide céphalo-rachidien et douleurs chroniques chez l'homme.

Concentrations of beta-endorphin in the cerebrospinal fluid were measured in 21 painless subjects and 37 patients with chronic pain. Statistical analysis of the results showed no significant difference between the two groups. This lack of correlation between beta-endorphin concentrations in the CSF and the presence of chronic pain highlights the difficulties and limitations encountered when trying to determine the role of endogenous opioid systems with this method.

Substance P in CSF of patients with chronic pain syndromes.

Immunoreactive substance P was determined in lumbar CSF of 35 healthy volunteers and 60 patients with chronic pain syndromes of at least 6 months duration. No significant relationships were found between substance P levels and age, sex or body height. Substance P levels were lower in chronic pain patients, with either neurogenic (n = 23) or idiopathic pain (n = 37) syndromes, than in the healthy volunteers. Substance P levels were especially low in patients with neurogenic pain with lesions involving the extremities and in those with polyneuropathy, while patients with central pain or pain of the head or face had higher values. Substance P levels were related to depressive symptomatology as determined by means of visual analogue scales and to stable personality traits as determined by means of the Karolinska Scales of Personality (KSP). The most consistent (and inverse) relationship was found between substance P levels and the symptom 'inner tension' and between substance P levels and the personality trait 'psychic anxiety.'

CSF and plasma morphine concentrations in cancer patients during chronic epidural morphine therapy and its relation to pain relief.

Seventeen patients with advanced cancer pain, treated with chronic epidural morphine, were studied. Minimum plasma and CSF morphine concentrations (CSSmin) were determined at pharmacokinetic steady state. A linear relationship was found between epidural morphine dose and concentrations obtained in plasma (r = 0.92) as well as CSF (r = 0.90). The line for best fit was much steeper for CSF than for plasma. The CSF/plasma concentration gradient of morphine at CSSmin was 132 +/- 31 (mean +/- S.E.M.). Large interindividual variations of morphine concentrations in CSF were found. It is suggested that the variations are due to substantial differences in transdural morphine diffusion between individuals. No correlation was found between pain relief, evaluated with a visual analog scale, and CSF morphine concentrations at pharmacokinetic steady state, when calculated in 9 patients. Mean duration of treatment was 104 days (range 14-366) and the daily dose was increased from 18 +/- 2 to 87 +/- 31 mg/day (mean +/- S.E.M.). A total of 39 epidural catheters were inserted in 14 patients. The catheters were patent for 2-223 days with a mean of 38 days. When re-examined later during treatment, 2 out of 8 patients demonstrated decreased CSF morphine concentrations in spite of increased doses given. One patient with extremely high dose demand is reported on separately and data supporting the concept of a combined spinal and systemic brain morphine effect in such cases are presented. Side effects were not a major problem but the possibility of infectious complications should be considered during chronic epidural morphine therapy.

A specific radioimmunoassay for [Leu] and [Met]enkephalin applied to a HPLC separation of human CSF.

Highly specific antisera have been raised to [Leu]enkephalin and applied in a radioimmunoassay that is sufficiently sensitive and precise for the measurement of enkephalin pentapeptides in body fluids. Extraction of CSF by Sep-pak cartridges, followed by reverse-phase HPLC to separate [Leu] and [Met]enkephalin prior to assay, has assessed their concentrations as 59-170 pmol/l and 0.5-30 pmol/l, respectively, in three patients with chronic pain. The reproducibility of the HPLC separation step was checked by adding to the sample a synthetic analogue of very low cross-reactivity in UV detectable quantities. The assay procedure described is generally applicable to the assessment of [Leu] and [Met]enkephalin concentrations in CSF.

Simultaneous determination of radio-immunoassayable methionine-enkephalin and radioreceptor-active opiate peptides in CSF of chronic pain suffering and non suffering patients.

Radio-immunoassayable methionine-enkephalin (ME) and radioreceptor-active opiate peptide levels (OP) were determined in CSF from patients, both with and without chronic pain, under investigation for vertebral disk disease. This study showed: that there was no direct correlation between ME and OP levels in CSF; OP levels were negatively correlated with the ME/OP ratio; migraine patients had higher levels of ME; ME concentrations were reduced in patients receiving anti-inflammatory drugs (nonsteroidal): patients with chronic pain (non migraine, no anti-inflammatory drug therapy) had lower ME levels than patients without pain. The data are discussed in relation to animal models of chronic pain.

[beta-Endorphin and monoamine metabolite concentrations in patients with intractable pain--changes before and after deep brain or spinal dorsal column stimulation].

Baseline concentrations of beta-endorphin (beta-EP) and monoamine metabolites (MHPG: 3-methoxy-4-hydroxy-phenylglycol, HVA: homovanillic acid, 5-HIAA: 5-hydroxyindoleacetic acid) in lumbar CSF (LCSF) and ventricular CSF (VCSF) were measured in 18 patients with intractable pain; 10 with deafferented pain and 8 with peripheral pain. Control values were obtained from 37 individuals of various ages. Changes in the concentrations of these substances were determined before and after giving stimulations (2-5 V, 0.2-0.5 msec, 40-50 Hz, 20-sec duration) to 6 patients through electrodes implanted in deep brain structures (DBS; posterior limb of the internal capsule in 5 patients and rostral mesencephalic lemniscus medialis in one patient), and to 2 other patients through electrodes implanted in the spinal dorsal column (DCS). The control value of beta-EP in LCSF was 57.6 +/- 24.7 pg/ml, which was not significantly different from that of VCSF. Great variation in the individual control LCSF beta-EP concentrations was found, but it was not related to differences in age. The mean baseline LCSF beta-EP concentration was significantly higher (p less than 0.05) than the control in the patients with deaffernted pain before stimulation. One of the monoamine-metabolites, MHPG, showed higher level in the patients with peripheral pain (p less than 0.01). The LCSF beta-EP concentration was not affected by deep brain stimulation, but was increased by dorsal column stimulation. In one patient with excellent pain relief by stimulation of the posterior limb of the internal capsule, the LCSF HVA and 5-HIAA concentrations were conspicuously increased.(ABSTRACT TRUNCATED AT 250 WORDS)

[Thalamic relay nucleus stimulation for relief of intractable pain. Clinical results and beta-endorphin immunoreactivity in cerebrospinal fluid].

Chronic implantation of a stimulating electrode in the thalamic relay nucleus (11 cases), in the periaqueductal gray (1 case) and in the internal capsule (2 cases) was performed in fourteen cases which suffered from intractable pain. All these cases could get pain relief at least initial two months. Ventricular fluids were collected before and after stimulation with optimal combination of parameters, and measurements of beta-endorphin were performed by radio-immunoassay. Intrathecal morphine (1mg) injection was performed in eight cases. Cerebrospinal fluids were collected by lumbar tap before and 24 hours after morphine injection. beta-endorphin immunoreactivity was measured by the same method. Pain relief was judged to be excellent if the patient so claimed, and if he discontinued analgesics. Pain relief was thought to be good when it was not completely controllable by stimulation but was sufficiently improved that the patient could do without analgesics. It was thought to be fair when patient could not discontinue analgesics, and poor when patient could not get pain relief. We usually attempt to prevent the stimulation-tolerance by administration of the monoamine precursors , i.e., 1-dopa and 1-tryptophan, on the basis of the experimental observation reported previously. In somatogenic pain patients, the thalamic relay nucleus stimulation was performed in 7 cases (excellent; 3, good; 1, fair; 3) and the periaqueductal gray stimulation in one case (good).(ABSTRACT TRUNCATED AT 250 WORDS)

Endorphin levels in cerebrospinal fluid of patients with postoperative and chronic pain.

The authors measured endorphin levels in the cerebrospinal fluid (CSF) of 12 patients with chronic pain due to lumbar disc syndrome and eight patients with acute postoperative pain. These were compared with CSF endorphin levels in 20 control patients with no history of pain. Endorphins were extracted by adsorption to a synthetic resin (Amberlite XAD-2), eluted with methanol, and assayed using the electrically stimulated mouse vas deferens. Results were expressed as methionine-enkephalin (Met-E) equivalents, which was the standard in the bioassay. The CSF endorphin level was 0.42 +/- 0.07 pmol/ml (mean +/- SE) in the postoperative group, 1.44 +/- 0.2 pmol/ml in the chronic pain group, and 4.36 +/- 0.89 pmol/ml in the control group. CSF endorphin levels in the two pain groups differed significantly from both the control group and each other. These results suggest a correlation between pain levels and endorphin concentration in the CSF; however, in the acute postoperative pain group the influence of other factors such as anesthesia or surgical stress cannot be evaluated.

Increase of beta-endorphin in cerebrospinal fluid after removal of ACTH-secreting pituitary adenoma.

beta-Endorphin and methionine(met)-enkephalin in cerebrospinal fluid (CSF) were measured before and after removal of an adrenocorticotropic hormone-(ACTH)-secreting adenoma in Cushing's disease by a sensitive radioimmunoassay and a radio-receptor assay, respectively. After tumor resection, the level of ACTH in plasma markedly decreased from 82.6 +/- 22.7 pg/ml to 16.7 +/- 4.1 pg/ml (mean +/- S.E., n = 4). It was found that the level of beta-endorphin in CSF significantly increases from 32.0 +/- 4.5 pg/ml to 61.8 +/- 10.7 pg/ml (P less than 0.05) after tumor resection, while the level of metenkephalin in CSF remained unaltered. This result suggests that hypophysectomy induces an increase of beta-endorphin in CSF.