The level of an endogenous opioid (peak B endorphin) was measured in chromatographically fractionated cerebrospinal fluid (CSF) sampled from two groups of chronic pain patients before and after intrathecal saline (placebo) injection. As assessed by a verbal rating scale, one group reported no change in their level of pain (non-responders, NR; n = 6) while the other group reported complete or greater than 50% pain relief (placebo responders, PR; n = 14). We find, as has been reported previously, that initial peak B levels were lower (by 50%) in these chronic pain patients' CSF than in CSF from pain-free (PF) normal controls (P less than 0.001, t-test). Peak B levels measured from CSF of the NR group undergoing this procedure did not change (P greater than 0.4, paired t-test). In contrast, a significant 2.3-fold increase was measured in the CSF peak B level of the PR group (P less than 0.05, paired t-test). This is the first direct evidence that a CSF opioid is correlated with placebo pain relief in chronic pain patients. Peak B is a potent analgesic substance when administered by the intracerebroventricular route in mice and its level is related to the patients' pain status in a presumably causal manner.
The pain tolerance latencies of 10 chronic pain patients were evaluated by heat beam dolorimetry (stimulus intensity 15.33 mW.cm-2.sec-1) prior to and following administration of morphine by intrathecal (n = 5) or intravenous (n = 5) routes. Patients not undergoing opiate withdrawal evinced increased baseline pain tolerance latencies prior to drug administration compared with normal volunteers. Two patients undergoing the opiate withdrawal syndrome at the time of test experienced reduced pain tolerance latencies compared with normal volunteers, most probably corresponding to the hyperesthesia symptom of the syndrome. Intravenous morphine infusion (30 mg) induced a time-dependent increase in cutaneous pain tolerance with peak effect occurring 1-2 h after administration. This persisted for up to 4 h and thereafter declined. The time course of subjective pain self-report by visual pain analog scale (VPAS) measurements corresponded to the time course of increasing cutaneous pain tolerance latency assessed by dolorimetry. Pain self-reports following intrathecal morphine infusion (2.25 or 1 mg) followed a similar though slower onset to that reported by patients receiving intravenous morphine and was of lesser degree. In contrast, heat beam dolorimetric evidence of increased cutaneous pain tolerance (which was of lesser degree than following i.v. morphine) did not reach its maximum during the 4 h measuring period. A dissociation was noted therefore between the self-reported relief of endogenous pain and dolorimetrically measured cutaneous analgesia following intrathecal morphine administration. Linear regression correlation analysis characterized this phenomenon as a positive correlation between cutaneous pain tolerance and pain relief self-report following intravenous morphine infusion and a negative correlation following intrathecal administration. We propose that the phenomenon may be due to intrathecal morphine acting via two separate compartments: one spinal and one supraspinal.(ABSTRACT TRUNCATED AT 250 WORDS)
An interesting behavioral syndrome results in animals from the same or similar types of lesions that lead to deafferentation pain in humans; many neurectomized animals begin to scratch, bite, or self-mutilate their denervated limb, a phenomenon termed autotomy. The proposition that this behavior in animals is a response to the chronic pain of peripheral nerve injury has met with considerable controversy. If this issue were resolved, then a better understanding of the neurophysiology of autotomy might help elucidate the mechanisms of the human conditions. To determine the association between deafferentation and the autotomy behavior, we developed a pharmacologically induced functional deafferentation preparation using chronic perineural lidocaine infusion of the sciatic nerve. This 'chronic lidocaine' model's behavior was compared with that of the neurectomy model. While autotomy was noted in 80% of the latter group, no animal undergoing a chronic perineural infusion of lidocaine autotomized. We thus conclude that autotomy is not a response to non-painful sensory deafferentation, but rather that this behavior is a response to pain. We also studied the development of autotomy in a variety of other focal denervation preparations. On the basis of these data, we conclude that autotomy is not due to loss of sensory input on a functional basis nor to an action potential-mediated process. Rather, nerve damage which coincidentally involves sensory loss is necessary and sufficient for the development of this behavior. We suggest that interruption of a humoral feedback process homeostatically operating within the first order sensory neuron with its effect exerted post-synaptically leads to autotomy. The evidence supports the existence of a loss of a transportable, humoral autotomy inhibitory factor.
The heat beam dolorimeter (HBD) was developed to evaluate cutaneous pain thresholds in humans. In the present study, the hypothesis that a patient's underlying pain status affects his pain tolerance to an incident HBD stimulus was tested. Twenty-seven chronic pain patients with a variety of clinical problems unresponsive to conventional algological therapy were scheduled for neurosurgical procedures. These patients were evaluated pre- and postoperatively by the HBD procedure. On initial testing, drug-free pain patients showed significantly higher pain tolerance thresholds than normal volunteers (P less than 0.02, Mann-Whitney U test). Postoperatively, incident pain tolerance thresholds in the HBD test were reduced from pre-surgical levels in these patients and were indistinguishable from the second evaluation latencies of volunteers (P greater than 0.05). Twenty-four of the 27 patients reported significant pain relief following surgery. Our results show that, in chronic pain patients, endogenous pain significantly affected incident pain perception in the HBD test when compared with the responses of normal pain-free volunteers. Consequently, HBD may be useful in objectively assessing chronic pain and its relief by neurosurgical procedures.
This study addresses mechanisms of the clinical, encephalopathic uremic illness and its suppression by dialysis. Renoprival rats were treated with peritoneal dialysis (8 exchanges per day, 30 min dwell), or untreated (attrition group), and their EEG's were automatically sampled overnight and subjected to power spectrum analysis as an index of encephalopathy. As in man the background rhythm of the quantified EEG (Q.EEG) in the attrition group slowed with time as extracellular fluid composition became increasingly abnormal; these changes were normalized by therapeutic dialysis (TD) using standard, commercial dialysate. However, Q.EEG slowing was only partially normalized by solute-specific dialysis using "mock uremic dialysate" (M-UD), prepared from laboratory chemicals to equal plasma concentrations in preterminal uremic rats of urea, creatinine, potassium, phosphorus, calcium, magnesium, bicarbonate, sodium, and chloride. When only phosphate was added to TD, the Q.EEG slowed to the same level achieved after M-UD. We conclude that uremic encephalopathy in this model is produced by an unknown neurotoxin and augmented by one or more of the M-UD solutes, phosphate being a likely candidate. To localize the encephalopathic effect, regional brain glucose uptake was estimated in 20 discrete brain areas. Significance of reduced uptake in three areas is discussed.
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