Pain
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The aim of the present study was to examine the role of the spinal serotonergic system in the pain relieving effect of spinal cord stimulation (SCS) using a rat model of mononeuropathy. Tactile withdrawal thresholds, cold responses and heat withdrawal latencies were assessed before and after SCS. In some rats, SCS produced an attenuation of the hypersensitivity following nerve injury (SCS responding rats). ⋯ It was also found that i.t. administration of a sub-effective dose of serotonin in SCS non-responding rats markedly enhanced the pain relieving effect of SCS on tactile and cold hypersensitivity, while there was no effect on heat hyperalgesia. This enhanced effect on tactile hypersensitivity could be partially blocked by a GABA(B) receptor antagonist (CGP 35348) but not by a muscarinic M(4) receptor antagonist (Muscarinic toxin 3) administered i.t. shortly before the 5-HT injection. In conclusion, there is evidence that the spinal 5-HT system plays an important role in the mode of action of SCS involving the activation of descending serotonergic pathways that may inhibit spinal nociceptive processing partially via a GABAergic link.
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Pain in early life can enhance the response to subsequent injury, but effects are influenced by both the nature and timing of neonatal injury. Using plantar hindpaw incision, we investigated how postnatal age influences the response to repeat surgical injury two weeks later. The degree and time course of behavioural changes in mechanical withdrawal threshold were measured, and injury-related hyperalgesia was further quantified by flexion reflex electromyographic responses to suprathreshold mechanical stimuli 24 h following incision. ⋯ Repeat peri-operative, but not a single pre-operative sciatic block, prevented the enhanced response to repeat incision two weeks later. Our results show that the first postnatal week represents a critical period when incision increases hyperalgesia following repeat surgery two weeks later, and effects are initiated by peripheral afferent activity. This has potential therapeutic implications for the type and duration of peri-operative analgesia used for neonatal surgery.
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Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer, but it causes acute peripheral neuropathy (acral paresthesias triggered by exposure to cold) and chronic neuropathy (abnormal of sensory and motor dysfunction). Oxaliplatin is metabolized to oxalate and dichloro(1,2-diaminocyclohexane)platinum (Pt(dach)Cl(2)). Although the chelating of Ca(2+) with oxalate eliminated from oxaliplatin is thought as one of the reasons for the neuropathy, there is little behavioral evidence. ⋯ The pre-administration of calcium or magnesium (0.5mmol/kg, i.v.) before oxaliplatin or oxalate prevented the cold hyperalgesia but not mechanical allodynia. However, the treatment with calcium or magnesium after the development of neuropathy could not attenuate the cold hyperalgesia or mechanical allodynia. These findings suggest the involvement of oxalate in oxaliplatin-induced cold hyperalgesia but not mechanical allodynia, and usefulness of prophylactic treatments with calcium and magnesium on the acute peripheral neuropathy.
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Review Meta Analysis
Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment.
Regard of functional pharmacogenetic polymorphisms may further the success of pain therapy by adopting individualized approaches. The mu-opioid receptor gene (OPRM1) 118A>G polymorphism is a promising candidate for both opioid effects and pain because of both biological reasonability and apparent experimental and clinical evidence. We analyzed its importance for pain therapy using a meta-analytic approach to studies relating it to opioid pain therapy. ⋯ Only weak evidence of an association with less nausea (effect size, Cohen's d=-0.21, p=0.037) and of increased opioid dosage requirements (d=0.56, p=0.018) in homozygous carriers of the G allele was obtained. This indicates that despite initially promising results, available evidence of the clinical relevance of the OPRM1 118A>G polymorphism does not withhold a meta-analysis. This discourages basing personalized therapeutic concepts of pain therapy on OPRM1 118A>G genotyping at the present state of evidence.
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Review Meta Analysis
A systematic review of adverse events in placebo groups of anti-migraine clinical trials.
In analgesic clinical trials, adverse events are reported for the painkiller under evaluation and compared with adverse events in the placebo group. Interestingly, patients who receive the placebo often report a high frequency of adverse events, but little is understood about the nature of these negative effects. In the present study, we compared the rates of adverse events reported in the placebo arms of clinical trials for three classes of anti-migraine drugs: NSAIDs, triptans and anticonvulsants. ⋯ For example, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of these trials. These results suggest that the adverse events in placebo arms of clinical trials of anti-migraine medications depend on the adverse events of the active medication against which the placebo is compared. These findings are in accordance with the expectation theory of placebo and nocebo effects.