Anesthesiology 2002 Jan;96(1):103-8
Department of Anesthesiology, Wake Forst University Schhol of Medicine, Winston-Salem, North Carolina 27157, USA.
BACKGROUND: Intrathecal adenosine produces a remarkably prolonged effect to relieve mechanical hypersensitivity after peripheral nerve injury in animals. The purpose of the current study was to investigate whether this reflected an alteration in kinetics of adenosine in cerebrospinal fluid or in the number of spinal A1 adenosine receptors after nerve injury. METHODS: Male rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Two weeks later, a lumbar intrathecal catheter and intrathecal space microdialysis catheter were inserted. Adenosine, 20 microg, was injected intrathecally in these and in normal rats, and microdialysates of the intrathecal space were obtained. Radioligand binding studies of adenosine A1 receptors were determined in spinal cord tissue from other normal and spinal nerve-ligated rats. RESULTS: Adenosine disappeared from rat cerebrospinal fluid within 30 min after intrathecal injection, with no difference between normal and spinal nerve-ligated animals. A1 adenosine receptor binding sites in the spinal cord were increased after spinal nerve ligation. This increase disappeared when adenosine deaminase was added to the membrane homogenates, suggestive of decreased endogenous adenosine in the membranes of nerve-ligated animals. CONCLUSION: These data show that prolonged alleviation of hypersensitivity observed with intrathecal adenosine in this animal model of neuropathic pain is not due to prolonged residence in cerebrospinal fluid, although pharmacokinetics in tissues are unknown. Similarly, there is no evidence for up-regulation in spinal A1 adenosine receptors after spinal nerve ligation, and the adenosine deaminase experiment is consistent with a depletion of adenosine in spinal cord tissue after spinal nerve ligation.
PMID: 11753009, UI: 21621174
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Anesthesiology 2002 Jan;96(1):29-34
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. eisenach@wfubmc.edu
BACKGROUND: Preclinical studies of intrathecal adenosine suggest it may be effective in the treatment of acute and chronic pain in humans, and preliminary studies in volunteers and patients with a Swedish formulation of adenosine suggests it may be effective in hypersensitivity states but not with acute noxious stimulation. The purpose of this study was to screen for efficacy of a different formulation of adenosine marketed in the US, using both acute noxious stimulation and capsaicin-evoked mechanical hypersensitivity. METHODS: Following Food and Drug Administration and institutional review board approval and written informed consent, 65 volunteers were studied in two trials: an open-label, dose-escalating trial with intrathecal adenosine doses of 0.25-2.0 mg and a double-blind, placebo-controlled trial of adenosine, 2 mg. Cerebrospinal fluid was obtained for pharmacokinetic analysis, and pain ratings in response to acute heat stimuli and areas of mechanical hyperalgesia and allodynia after intradermal capsaicin injection were determined. RESULTS: Adenosine produced no effect on pain report to acute noxious thermal or chemical stimulation but reduced mechanical hyperalgesia and allodynia from intradermal capsaicin injection for at least 24 h. In contrast, residence time of adenosine in cerebrospinal fluid was short (< 4 h). CONCLUSIONS: These results show selective inhibition by intrathecal adenosine of hypersensitivity, presumed to reflect central sensitization in humans after peripheral capsaicin injection. The long-lasting effect is consistent with that observed in preliminary reports of patients with chronic neuropathic pain and is not due to prolonged residence of adenosine in cerebrospinal fluid.
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PMID: 11752998, UI: 21621163
Anesthesiology 2002 Jan;96(1):24-8
BACKGROUND: Preclinical studies of intrathecal adenosine suggest it may be effective in the treatment of acute and chronic pain in humans. A phase I safety trial of the intrathecal injection of a mannitol-containing formulation of adenosine in Sweden showed a considerable incidence of backache. We performed a phase I safety trial of intrathecal injection of the American formulation of adenosine, which lacks mannitol. METHODS: Following US Food and Drug Administration and institutional review board approval and written informed consent, 65 volunteers were studied in two trials: an open-label, dose-escalating trial with intrathecal adenosine doses of 0.25-2.0 mg (25 subjects) and a double-blind, placebo-controlled trial of adenosine, 2 mg (40 subjects). Blood pressure, heart rate, end-tidal carbon dioxide, and sensory, motor, and reflex neurologic functions were systematically examined for 24 h after injection, and volunteers were contacted by telephone at times up to 6 months after injection. RESULTS: Intrathecal adenosine did not affect blood pressure, heart rate, end-tidal carbon dioxide, or neurologic function. Headache was reported by 10 and back pain was reported by 8 of 30 subjects exposed to adenosine in the second double-blind trial, whereas none of these symptoms was reported by the 10 saline-treated subjects. CONCLUSION: These data support further investigation of intrathecal adenosine for analgesia in humans and suggest that this agent does not produce a high incidence of severe side effects.
PMID: 11752997, UI: 21621162
Anesthesiology 2002 Jan;96(1):17-23
Department of Anesthesiology, Groupe Hospitalier Pitie-Salpetriere, Assistance Publique-Hopitaux de Paris, Universite Pierre et Marie Curie, France. frederic.aubrun@psl.ap-hop.paris.fr
BACKGROUND: Intravenous morphine titration is used to obtain rapid and complete postoperative pain relief. Whether this titration can be safely administered in the elderly patients remains a matter for debate. METHODS: Intravenous morphine titration was administered as a bolus of 2 (body weight < or = 60 kg) or 3 (body weight > 60 kg) mg. The interval between each bolus was 5 min. There was no limitation in the number of boluses given until pain relief or severe adverse effect occurred. The visual analog scale threshold required to administer morphine was 30 mm, and pain relief was defined as a visual analog scale score of 30 mm or less. Patients were divided into two groups: young and elderly (age > or = 70 yr) patients. Data were expressed as mean +/- SD. RESULTS: Eight hundred seventy-five patients (83%) were young and 175 patients (17%) were elderly. At the end of morphine titration, the visual analog scale score and the number of patients with pain relief were not significantly different between groups. The total dose of morphine per kilograms of body weight administered was not significantly different between groups (0.15 +/- 0.10 vs. 0.14 +/- 0.09 mg/kg, not significant). No significant differences were observed in the incidence of morphine-related adverse effects (13 vs. 14%, not significant), the number of sedated patients (60 vs. 60%, not significant), and the number of patients whose titration had to be stopped (2 vs. 2%, not significant). CONCLUSION: Intravenous morphine titration can be safely administered to elderly patients. Because titration is adapted to individual pain, the same protocol can be applied to young and elderly patients.
PMID: 11752996, UI: 21621161
Anesthesiology 2002 Jan;96(1):2-4
PMID: 11752993, UI: 21621158
JAMA 2002 Feb 6;287(5):647-8
St Luke's Medical Center, Milwaukee.
[Medline record in process]
PMID: 11829708, UI: 21819164
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