Selective down-regulation of α4ß2 neuronal nicotinic acetylcholine receptors in the brain of uremic rats with cognitive impairment.

Cognitive impairment is common in patients with chronic kidney disease. Brain nicotinic acetylcholine receptors modulate cognitive functions, such as learning and memory. Pharmacological cholinergic enhancement is useful in patients with cognitive dysfunction. The major nicotinic acetylcholine receptor subtypes in the brain are heteromeric α4ß2 and homomeric α7 receptors. To study the involvement of neuronal acetylcholine receptors in cognitive impairment in uremic rats, bilateral nephrectomy was performed. 24 weeks after nephrectomy, memory was assessed using the one trial step-down inhibitory avoidance test. Neuronal nicotinic acetylcholine receptors in the brain were studied by radioligand binding, immunoprecipitation, Western blot and sucrose gradient experiments. We demonstrated that rats with severe renal failure show disorders of short term memory. Long term memory was not altered in these rats. The number of functional α4ß2 heteromeric neuronal nicotinic receptors was decreased in the brains of rats with severe renal failure. There was a significant correlation between the degree of renal impairment and the number of heteromeric nicotinic acetylcholine receptors in the brain. The down-regulation of functional α4ß2 receptors in the brains of rats with severe renal failure was not due to a reduction of α4 or ß2 subunit proteins. The number of α7 homomeric neuronal nicotinic acetylcholine receptors was not altered. These findings may have important clinical significance for the management of cognitive impairment in patients with chronic kidney disease.

An extracellular RRR motif flanking the M1 transmembrane domain governs the biogenesis of homomeric neuronal nicotinic acetylcholine receptors.

We have previously demonstrated that the highly conserved R209, that flanks the M1 transmembrane segment of nicotinic acetylcholine (ACh) receptors, is required for the transport of assembled homomeric neuronal α7 nicotinic ACh receptors to the cell surface. In the present paper we show that basic residues at positions 208 and 210 are necessary for the assembly of α7 receptors. On the contrary, a basic residue at position 210 of α3 subunit decreases the assembly of heteromeric neuronal α3ß4 nicotinic ACh receptors. A basic residue at position 210 of the ß4 subunit slightly decreases α3ß4 receptor expression. We conclude that a pre-M1 RRR motif is necessary for the biogenesis of homomeric α-bungarotoxin-sensitive neuronal α7 nicotinic ACh receptors.

Single dose dipyrone for acute postoperative pain.

BACKGROUND: Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought. OBJECTIVES: To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain. SEARCH STRATEGY: The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010. SELECTION CRITERIA: Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs. DATA COLLECTION AND ANALYSIS: Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected. MAIN RESULTS: Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls.Over 70% of participants experienced at least 50% pain relief over 4 to 6 hours with oral dipyrone 500 mg compared to 30% with placebo in five studies (288 participants; NNT 2.4 (1.9 to 3.2)). Fewer participants needed rescue medication with dipyrone (7%) than with placebo (34%; four studies, 248 participants). There was no difference in participants experiencing at least 50% pain relief with 2.5 g intravenous dipyrone and 100 mg intravenous tramadol (70% vs 65%; two studies, 200 participants). No serious adverse events were reported. AUTHORS' CONCLUSIONS: Based on very limited information, single dose dipyrone 500 mg provides good pain relief to 70% of patients. For every five individuals given dipyrone 500 mg, two would experience this level of pain relief who would not have done with placebo, and fewer would need rescue medication, over 4 to 6 hours.

Recommendations for using opioids in chronic non-cancer pain.

1. The management of chronic pain should be directed by the underlying cause of the pain. Whatever the cause, the primary goal of patient care should be symptom control. 2. Opioid treatment should be considered for both continuous neuropathic and nociceptive pain if other reasonable therapies fail to provide adequate analgesia within a reasonable timeframe. 3. The aim of opioid treatment is to relieve pain and improve the patient's quality of life. Both of these should be assessed during a trial period. 4. The prescribing physician should be familiar with the patient's psychosocial status. 5. The use of sustained-release opioids administered at regular intervals is recommended. 6. Treatment should be monitored. 7. A contract setting out the patient's rights and responsibilities may help to emphasize the importance of patient involvement. 8. Opioid treatment should not be considered a lifelong treatment.

Systematic review of factors affecting the ratios of morphine and its major metabolites.

In a systematic review of 57 studies with information on 1232 patients we examined the effect of age, renal impairment, route of administration, and method of analysis on the ratios of morphine-3-glucuronide:morphine (M3G:M) and morphine-6-glucuronide:morphine (M6G:M) and the relative concentrations of M3G and M6G. Across all studies the range of the ratios of metabolites to morphine was wide (0.001-504 for M3G:M, and 0-97 for M6G:M). Neonates produced morphine glucuronides at a lower rate than older children or adults. Metabolite ratios were higher in renal impairment. Routes of administration which avoided first pass metabolism (intravenous, transdermal, rectal, intramuscular, epidural and intrathecal) resulted in lower metabolite production than oral, buccal or sublingual. Metabolite production was similar for single and multiple dosing. There was no evidence of differences between methods of assay. There was a high correlation between the two glucuronide metabolites in spite of the different situations studied, supporting a single glucuronidating enzyme. Morphine was present in CSF at a fourfold higher concentration than the glucuronide metabolites.

Lack of morphine-6-glucuronide antinociception after morphine treatment. Is morphine-3-glucuronide involved?

Morphine, morphine-6-glucuronide (M6G) tolerance and cross-tolerance between morphine and M6G have been evaluated in mice. Daily administration of equipotent doses of M6G and morphine induced similar declines in antinociception over 9 days of treatment. However, a higher dose of M6G than morphine is required in tolerant animals to recover the initial response. In studies where daily morphine doses were substituted by M6G administration, on specific days, there was a significant fall in M6G antinociception on those days immediately following morphine administration, relative to the response to continued morphine (a decrease of 53.7% on day 2, P < 0.001 and a decrease of 62.5% on day 11, P < 0.05) and M6G (a decrease of 45.4% on day 2, P < 0.05) exposure. The decrease was independent of treatment duration and dosage. This decrease in the antinociceptive effect of M6G after morphine was avoided after clofibrate treatment, an inhibitor of (-)morphine metabolism. Determination of morphine and its metabolites in plasma revealed that morphine-3-glucuronide (M3G) concentration was significantly lower (P < 0.001) in animals treated with clofibrate (8.3 +/- 8.3 ng/ml) than in controls (422 +/- 80 ng/ml). The dose-response curve for M6G was shifted to the right by prior administration of M3G. These results suggest that during morphine treatment the antinociceptive effect of M6G may be antagonized by the other metabolite, M3G.