Systemic review of trials on the use of tramadol in the treatment of acute and chronic pain

BACKGROUND: The purpose of the study was to verify the effectiveness of tramadol in the treatment of non-oncologic chronic pain, oncologic chronic pain and postoperative acute pain, applying the principles of meta-analytic analysis to randomized clinical trials (TCR). METHODS: I: Medline research of the TCR on the question in the period between 1989-1999, II: exclusion of single TCR through the question of Moore and Mcquay; calculation of the relative risk reduction (RRR), of the number needed to treat (NNT), of the odds ratio (OR) and of the typical odds ratio (TOR) of the trials which responded to characteristics of correct randomization and blindness, which expressed citation of the patients excluded from trial, and patients with measurable analgesic effectiveness (number of patients with reduction of the pain intensity 50%). RESULTS: 52 trials extracted from Medline: 10 on the treatment of non-oncologic chronic pain, 36 on the treatment of postoperative acute pain and 6 on the treatment of oncologic chronic pain. Responded fully to requirements: 8 studies (3 for non-oncologic chronic pain, 3 for postoperative acute pain and 2 for oncologic pain). The OR was 0.55 (-0.31/1.41); 0.44 (1.04/1.92) and 0.98 (0.5/1.46); the RRR was 0.26 (-0.19/0.71), 0.38 (0.15/0.61), 0.005 (0.19/0.20) and the NNT 6.6 (6.39/6.81), 5.26 (5.12/5.4), infinity in the 3 trials selected between those that concern the treatment of the nononcologic chronic pain (with TOR: 0.57 and confidence index: 0.23-0.9); the OR was 0.36 (1.06/1.78), 0.78 (-0.08/-1.64) and 1.12 (0.54/1.69); the RRR was 0.26 (-0.18/0.7), 0.07 (-0.2/0.35), -0.01 (-0.09/0.07) and the NNT 4.7 (4.42/4.58), 20 (19.8/20.20), infinity in the trials on the treatment of postoperative acute pain (with TOR: 0.4 and confidence index: -0.6-0.86); the OR was 0.53 (-0.67/1.73), 0.27 (-0.71/1.12); the RRR was 0.19 (-0.33/0.72), 0.35 (0.02/0.68) and the NNT 7.1 (6.78/7.42), 3.57 (3.37/3.76) in those that involved the treatment of oncologic chronic pain (with TOR: 0.49 and confidence index: 0.36-0.8). CONCLUSIONS: Although the short number of trials which can treated by the metanalytic technique the treatment with tramadol, compared comparison's to drugs (morphine, pentazocine, bupremorphine, etc.) determined a slight improvement in analgesic parameters or at least in analgesic effectiveness.     

Molecular basis of inherited thrombocytopenias

Inherited thrombocytopenias (IT) are a heterogeneous group of diseases caused by at least 20 different genes. At present, these genes account for approximately 50% of cases, suggesting that novel genes have yet to be identified for a comprehensive understanding of platelet biogenesis defects. This review provides an update of ITs focusing on the molecular basis and potential pathogenic mechanisms affecting megakaryopoiesis and platelet production.     

Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency

The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.     

MYH9 related disease: four novel mutations of the tail domain of myosin‐9 correlating with a mild clinical phenotype

MYH9‐related disease (MYH9‐RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non‐muscle myosin IIA. All patients present congenital macrothrombocytopenia and inclusion bodies in neutrophils. Some of them can also develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end‐stage renal failure. We report four families, each with a novel mutation: two missense mutations, in exons 31 and 32, and two out of frame deletions in exon 40. They were associated with no bleeding diathesis, normal, or only slightly reduced platelet count and no extra‐hematological manifestations, confirming that alterations of the tail domain cause a mild form of MYH9‐RD with no clinically relevant defects.