Dopaminergic and serotonergic mechanisms in the modulation of pain : In vivo studies in human brain

Here we review the literature assessing the roles of the brain dopaminergic and serotonergic systems in the modulation of pain as revealed by in vivo human studies using positron emission tomography. In healthy subjects, dopamine D-2/D-3 receptor availability particularly in the striatum and serotonin 5-HT1A and 5-HT2A receptor availabilities in the cortex predict the subject's response to tonic experimental pain. High availability of dopamine D-2/D-3 or serotonin 5-HT2A receptors is associated with high pain intensity, whereas high availability of 5-HT1A receptors associates with low pain intensity. Chronic neuropathic pain is associated with high striatal dopamine D-2/D-3 receptor availability, for which low endogenous dopamine tone is a plausible explanation, although a compensatory increase in striatal dopamine D-2/D-3 receptor density may also contribute. In contrast, chronic musculoskeletal pain is associated with low baseline availability of striatal dopamine D-2/D-3 receptors. In healthy subjects, brain serotonin 5-HT1A as well as dopamine D-2/D-3 receptor availabilities associate with the subject's response criterion rather than the capacity to discriminate painful thermal stimuli suggesting that these neurotransmitter systems act mainly on non-sensory rather than sensory factors of thermally induced pain experience. Additionally, 5-HT1A receptor availability predicts the subject's discriminative ability but not response criterion for non-painful tactile test stimuli, while no such correlation is observed with dopamine D-2/D-3 receptors. These findings suggest that dopamine acting on striatal dopamine D-2/D-3 receptors and serotonin acting on cortical 5-HT1A and 5-HT2A receptors contribute to top-down pain regulation in humans.Peer reviewe

Transkraniaalinen magneettistimulaatio neuropaattisen kivun hoidossa

HALO-katsausHermoperäisen eli neuropaattisen kivun tai monimuotoisen paikallisen kipuoireyhtymän (CRPS) nykyiset hoito- ja kuntoutusmenetelmät auttavat vain osaa potilaista, joten uusien hoitomuotojen tarve on ilmeinen. Järjestelmälliseen kirjallisuuskatsaukseen haettiin tutkimukset aivojen sarjamagneettistimulaation (rTMS) vaikuttavuudesta ja turvallisuudesta hermovauriokipu- ja CRPS-potilailla, joille muut hoitomenetelmät eivät ole tuoneet riittävää kivun lievitystä. Vaikuttavuusarvio perustuu seitsemään satunnaistettuun, lumekontrolloituun tutkimukseen, joissa oli ¬samanaikainen vertailuryhmä, sekä kolmeen tutkimukseen, joissa potilas sai satunnaistetussa järjestyksessä aktiivista ja lumehoitoa. Useimmissa tutkimuksissa rTMS-hoito lievitti lyhytkestoisesti neuropaattista kipua lumestimulaatioon ¬verrattuna. Kipua lievittävä vaikutus oli suurin heti hoitojakson päättyessä ja pieneni seurannassa. Vaikutus CRPS-kipuun oli merkittävä mutta lyhytkestoinen. Raportoidut haitat olivat lieviä ja vaarattomia. Yleisin haittavaikutus oli päänsärky. Lyhytkestoisten seurantatutkimusten perusteella hermovauriokipupotilaat hyötyvät rTMS-hoidosta, jos muu hoito ei lievitä kipua riittävästi. Menetelmän pitkäaikaisesta vaikuttavuudesta ja ylläpitohoidon malleista tarvitaan lisää tutkimusta

Transkraniaalinen magneettistimulaatio neuropaattisen kivun hoidossa

HALO-katsausHermoperäisen eli neuropaattisen kivun tai monimuotoisen paikallisen kipuoireyhtymän (CRPS) nykyiset hoito- ja kuntoutusmenetelmät auttavat vain osaa potilaista, joten uusien hoitomuotojen tarve on ilmeinen. Järjestelmälliseen kirjallisuuskatsaukseen haettiin tutkimukset aivojen sarjamagneettistimulaation (rTMS) vaikuttavuudesta ja turvallisuudesta hermovauriokipu- ja CRPS-potilailla, joille muut hoitomenetelmät eivät ole tuoneet riittävää kivun lievitystä. Vaikuttavuusarvio perustuu seitsemään satunnaistettuun, lumekontrolloituun tutkimukseen, joissa oli ¬samanaikainen vertailuryhmä, sekä kolmeen tutkimukseen, joissa potilas sai satunnaistetussa järjestyksessä aktiivista ja lumehoitoa. Useimmissa tutkimuksissa rTMS-hoito lievitti lyhytkestoisesti neuropaattista kipua lumestimulaatioon ¬verrattuna. Kipua lievittävä vaikutus oli suurin heti hoitojakson päättyessä ja pieneni seurannassa. Vaikutus CRPS-kipuun oli merkittävä mutta lyhytkestoinen. Raportoidut haitat olivat lieviä ja vaarattomia. Yleisin haittavaikutus oli päänsärky. Lyhytkestoisten seurantatutkimusten perusteella hermovauriokipupotilaat hyötyvät rTMS-hoidosta, jos muu hoito ei lievitä kipua riittävästi. Menetelmän pitkäaikaisesta vaikuttavuudesta ja ylläpitohoidon malleista tarvitaan lisää tutkimusta

Voriconazole greatly increases the exposure to oral buprenorphine

PurposeBuprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.MethodsTwelve healthy volunteers were given either placebo or voriconazole (orally, 400mg twice on day 1 and 200mg twice on days 2-5) for 5days in a randomized, cross-over study. On day 5, they ingested 0.2mg (3.6mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0mg.ResultsVoriconazole greatly increased the mean area under the plasma concentration-time curve (AUC(0-18)) of buprenorphine (4.3-fold, PPeer reviewe

The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders

Background: Mechanisms underlying alleviation of neuropathic pain by repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) and right secondary somatosensory cortex (S2) are only partly known. Patients with chronic neuropathic pain often have comorbidities like depression and sleep problems. Through functional connectivity, rTMS of M1 and S2 may activate dorsolateral prefrontal cortex, the target for treating depression with rTMS. Thus, the analgesic effect of rTMS could be mediated indirectly via improvement of psychiatric comorbidities or sleep. We examined whether rTMS has an independent analgesic effect or whether its clinical benefits depend on effects on mood or sleep. We also evaluated if comorbid psychiatric or sleep disorders predict the treatment outcome. Methods: Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized controlled crossover rTMS study. Patients' psychiatric history was evaluated by a specialist in psychiatry. Intensity and interference of pain, mood, and the quality of sleep and life were evaluated at baseline and after 2 active (primary somatosensory cortex [S1]/M1 and S2) and placebo rTMS treatments. A logistic regression analysis was done to investigate predictors of treatment outcome. Results: The analgesic effect of the right S2 stimulation was not associated with improvement of psychiatric conditions or sleep, whereas S1 /M1 stimulation improved sleep without significant analgesic effect (P=0.013-0.0/16 in sleep scores). Psychiatric and sleep disorders were more common in patients than in the general population (P=0.000-0.001 in sleep scores), but these comorbidities did not predict the rTMS treatment outcome. Conclusion: We conclude that rTMS to the right S2 does not exert its beneficial analgesic effects in chronic neuropathic orofacial pain via indirect improvement of comorbid psychiatric or sleep disorders.Peer reviewe

Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects

Fam3c, a cytokine-like protein, is a member of the Fam3 family (family with sequence similarity 3) and has been implicated to play a crucial role in Epithelial-to- mesenchymal transition (EMT) and subsequent metastasis during cancer progression. A few independent genome-wide association studies on different population cohorts predicted the gene locus of Fam3c to be associated with bone mineral density and fractures. In this study, we examined the role of Fam3c during osteoblast differentiation. Fam3c was found to be expressed during osteogenic differentiation of both primary bone marrow stromal cells and MC3T3-E1 pre-osteoblasts. In differentiating osteoblasts, knockdown of Fam3c increased alkaline phosphatase expression and activity whereas overexpression of Fam3c reduced it. Furthermore, overexpression of Fam3c caused reduction of Runx2 expression at both mRNA and protein levels. Fam3c was localized in the cytoplasm and it was not secreted outside the cell during osteoblast differentiation and therefore, may function intracellularly. Furthermore, Fam3c and TGF-β1 were found to regulate each other reciprocally. Our findings therefore suggest a functional role of Fam3c in the regulation of osteoblast differentiation.</p

Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects

Peer reviewe

Acute pain intensity monitoring with the classification of multiple physiological parameters

Current acute pain intensity assessment tools are mainly based on self-reporting by patients, which is impractical for non-communicative, sedated or critically ill patients. In previous studies, various physiological signals have been observed qualitatively as a potential pain intensity index. On the basis of that, this study aims at developing a continuous pain monitoring method with the classification of multiple physiological parameters. Heart rate (HR), breath rate (BR), galvanic skin response (GSR) and facial surface electromyogram were collected from 30 healthy volunteers under thermal and electrical pain stimuli. The collected samples were labelled as no pain, mild pain or moderate/severe pain based on a self-reported visual analogue scale. The patterns of these three classes were first observed from the distribution of the 13 processed physiological parameters. Then, artificial neural network classifiers were trained, validated and tested with the physiological parameters. The average classification accuracy was 70.6%. The same method was applied to the medians of each class in each test and accuracy was improved to 83.3%. With facial electromyogram, the adaptivity of this method to a new subject was improved as the recognition accuracy of moderate/severe pain in leave-one-subject-out cross-validation was promoted from 74.9 ± 21.0 to 76.3 ± 18.1%. Among healthy volunteers, GSR, HR and BR were better correlated to pain intensity variations than facial muscle activities. The classification of multiple accessible physiological parameters can potentially provide a way to differentiate among no, mild and moderate/severe acute experimental pain.</p

Voriconazole greatly increases the exposure to oral buprenorphine

Purpose: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.Methods: Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2–5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg.Results: Voriconazole greatly increased the mean area under the plasma concentration–time curve (AUC0–18) of buprenorphine (4.3-fold, P Conclusions: Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.</p