Clara C. Faura

The Abstract and Plain language summary are available in Spanish in Appendix 7. The authors declare that there is unlikely to be any further studies to be included in this review and so it should be published as a 'stable review'. At November 2013, the decision was made to withdraw this review and start a new protocol which will comply with current Cochrane standards.

BACKGROUND AND PURPOSEThe perception of pain and its inhibition varies considerably between individuals, and this variability is still unexplained. The aim of the present study is to determine whether functional interactions between opioid receptors are involved in the inter‐individual variability in the sensitivity to μ‐opioid receptor agonists.EXPERIMENTAL APPROACHAnti‐nociceptive tests, radioligand binding, stimulation of [³⁵S]GTP–γ–S binding, inhibition of cAMP production and co‐immunoprecipitation experiments were performed in two strains of rat (Sprague–Dawley bred at our university – SDU – and Wistar) that differ in their sensitivity to opioids.KEY RESULTSThe increased anti‐nociceptive potency of µ‐opioid receptor agonists in SDU rats was reversed by the δ‐opioid receptor antagonist, naltrindole. Inhibition of the binding of [³H] naltrindole by µ‐opioid receptor agonists was different in brain membranes from SDU and Wistar rats. Differences were also evident in the effect of δ‐opioid receptor ligands on the binding of [³⁵S]GTP‐γ–S stimulated by µ‐opioid receptors agonists. No strain‐related differences were detected in spinal cord membranes. The potency of morphine to inhibit cAMP production in brain membranes varied between the strains, in the presence of deltorphin II and naltrindole. Co‐immunoprecipitation experiments demonstrated that δ‐opioid receptors were associated with μ‐opioid receptors to a higher extent in brain synaptosomal fractions from SDU than in those from Wistar rats.CONCLUSIONS AND IMPLICATIONSThere was increased supraspinal cross‐talk between μ and δ‐opioid receptors in SDU, as compared with Wistar rats. This was related to an enhanced sensitivity to anti‐nociception induced by µ‐opioid receptor agonists.

INTRODUCTION AND AIMS: Gastrointestinal (GI) symptoms are common in patients with chronic renal failure (CRF), but the pathogenesis of these symptoms is unclear. Abnormal gastric motility disorders and esophageal motor dysfunctions are commonly described in uremic patients. The gastrointestinal disorders possibly affect function and structure of the gastrointestinal tract and negatively impact on the nutritional status of the patients causing malnutrition which is a major problem with ESRD.

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 α3β4 nicotinic ACh receptors. A basic residue at position 210 of the β4 subunit slightly decreases α3β4 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.

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 methods 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.

Hypothyroxinemia affects 35–50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers’ organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

. 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. . 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. . 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. . The prescribing physician should be familiar with the patient's psychosocial status. . The use of sustained‐release opioids administered at regular intervals is recommended. . Treatment should be monitored. . A contract setting out the patient's rights and responsibilities may help to emphasize the importance of patient involvement. . Opioid treatment should not be considered a lifelong treatment.

Background Renal colic pain is extremely painful and requires immediate treatment with strong analgesics. Dipyrone is the most popular non‐opioid first line analgesic in many countries but in others it has been banned (e.g. USA, UK) because of its association with blood dyscrasias such as agranulocytosis. Since dipyrone is used in many countries (e.g. Brazil, Spain) there is a need to determine the benefits and harms of its use to treat renal colic pain. Objectives Assess quantitatively the analgesic efficacy and adverse effects of single‐dose dipyrone in adults with moderate to severe renal colic pain. Search methods Published reports were identified from electronic databases (MEDLINE, EMBASE, The Cochrane Library, LILACS) and additional studies were identified from the reference lists of retrieved reports. Date of the most recent search: January 2000. Selection criteria Inclusion criteria were: full journal publication; RCT with a double‐blind design; adult patients with baseline renal colic pain of moderate or severe intensity; treatment arms which included dipyrone (oral, intramuscular or intravenous administration) and a control; single dose data. Data collection and analysis Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief over 15‐30 minutes, 1‐2 hours and six hours. The proportion of patients with at least 50% pain relief was calculated. Single dose adverse effect data were collected. Main results Eleven studies with 1053 patients (550 on dipyrone) met the inclusion criteria. Unfortunately, few data were available for analysis; most analyses were based on the results of single, small trials and statistical pooling of the results was inappropriate. Efficacy estimates were calculated as the weighted mean percent of patients achieving at least 50% pain relief with the range of values from trials contributing to the analysis. However, these estimates were not robust. Commonly reported adverse effects with intravenous dipyrone were dry mouth and somnolence, and one study reported pain at the injection site. Insufficient information was available for safety analyses. Authors' conclusions Limited available data indicated that single dose dipyrone was of similar efficacy to other analgesics used in renal colic pain, although intramuscular dipyrone was less effective than diclofenac 75 mg. Combining dipyrone with antispasmolytic agents did not appear to improve its efficacy. Intravenous dipyrone was more effective than intramuscular dipyrone. Dry mouth and somnolence were commonly reported with intravenous dipyrone. None of the studies reported agranulocytosis.