Inter- and intra-patient variability in breakthrough pain episodes of opioid-treated patients with underlying chronic pain. An observational, prospective and multicenter study / Variabilidad inter- e intra-individual en pacientes con dolor irruptor tratados con opioides. Estudio observacional, prospectivo y multicéntrico

Objective: Since, to date, there are few epidemiological data assessing the diversity in the characteristics of breakthrough pain episodes, the present study was performed to assess the intra-individual variability in the episodes of breakthrough pain in patients with underlying chronic pain controlled with opioids. Methods: An observational, prospective and multicenter study (CADI study) was conducted in the context of the routine clinical practice of Spanish pain specialists recruiting opioidtreated patients with underlying chronic pain. Data were recorded in three visits (baseline, at 7 and 28 days post-inclusion) and by the patient on a patient´s diary card, specifically designed to characterise the first 8 breakthrough pain episodes (type, intensity –using 100 mm Visual Analog Scale– and duration of pain), to assess the intra-individual and inter-individual variability in the intensity, duration and typology of episodes of breakthrough pain. Results: 50 opioid-treated patients were recruited (23 with oncologic pain and 27 with non oncologic pain, mean age of 61.1 years, 62 % females). For all three parameters, inter-patient variability was higher than intra-patient variability throughout the episodes. Nevertheless, we found intra-patient variability in maximum pain intensity, pain intensity at the end of the episode, pain relief and duration of the episode. Conclusions: This is the first study to quantify the intrapatient variability of breakthrough pain. The results show a great variability in terms of intensity and duration of the episode and its typology. Although inter-patient variability is higher, the intra-patient variability is important enough to be taken into account in optimizing the approach and treatment selection (AU)

Objetivos: Debido a los pocos datos epidemiológicos existentes que evalúen la diversidad de las características de los episodios de dolor irruptivo, se realizó el presente estudio, cuyo principal objetivo fue evaluar la variabilidad intraindividual de las crisis de dolor irruptivo en pacientes con dolor crónico controlado con opioides. Métodos: Este estudio observacional, prospectivo y multicéntrico (estudio CADI) se llevó a cabo en el contexto de la práctica clínica habitual, en Unidades del Dolor de España, con la participación de pacientes tratados con opioides para el dolor crónico. Los datos fueron registrados en tres visitas (basal, a los 7 y 28 días después de la inclusión) y por el propio paciente, en un Diario del Paciente, específicamente diseñado para caracterizar los primeros 8 episodios de dolor irruptivo (tipo, intensidad −utilizando la Escala Analógica Visual (EVA)− y duración del dolor) con el objetivo de evaluar la variabilidad intraindividual e interindividual en la intensidad, duración y tipología de los episodios de dolor irruptivo. Resultados: Se reclutaron 50 pacientes, 23 con dolor oncológico y 27 con el dolor no oncológico (edad media de 61,1 años; 62 % de mujeres). Aunque para los tres parámetros medidos, la variabilidad entre pacientes fue mayor que la variabilidad intrapaciente, la variabilidad intraindividual fue significativa en la evaluación de la máxima intensidad del dolor, la intensidad del dolor al final del episodio, el alivio del dolor y la duración del episodio de dolor irruptivo. Conclusiones: Este es el primer estudio que cuantifica la variabilidad intraindividual del dolor irruptivo. Los resultados muestran una gran variabilidad en cuanto a la intensidad y la duración del episodio y su tipología. Aunque la variabilidad entre pacientes es mayor, la variabilidad intrapaciente es lo suficientemente importante como para ser tenida en cuenta para la mejor aproximación y selección del tratamiento (AU)

Methyl-beta-carbolinium analogs of MPP+ cause nigrostriatal toxicity after substantia nigra injections in rats.

Eleven beta-carbolinium compounds (beta C+s) and MPP+ were stereotaxically injected (40-200 nmol in 5 microliter of vehicle) unilaterally into the substantia nigra of anesthetized adult male Sprague-Dawley rats. The rats were sacrificed after three weeks. The ipsilateral striatum was analyzed for dopamine and DOPAC levels with HPLC. The brainstem injection site was fixed and cut coronally. The largest lesion area in each animal was measured using NIH IMAGE. Three beta C+s produced lesions whose mean areas were nearly as large as that produced by MPP+ (defined as 100%): 2,9-Me2-harman (94%), 2-Me-harmol (74%), and 2,9-Me2-norharman (57%). Three other compounds produced somewhat smaller lesions: 2-Me-harmaline (34%), 6-MeO-2-Me-harman (29%), and 2-Me-harmine (25%). The remaining compounds were ineffective (< or = 12%): norharman, 2-Me-norharman, 2-Me-harman, harmine, and 2-Me-6-MeO-harmalan. A 40 nmol dose of MPP+ reduced ipsilateral striatal dopamine to 0.6% of control. None of the beta C+s approached this, although several did significantly reduce striatal dopamine at doses of either 40 nmol (2,9-Me2-harman (37%), 2,9-Me2-norharman (42%), and 2-Me-harman (63%)) or 200 nmol (2-Me-harmaline (23%), norharman (63%), and 2-Me-norharman (64%)). There was a moderate negative correlation between lesion size and dopamine level (r = -0.65). There were also moderately strong correlation between lesion size and dopamine level (r = -0.65). There were also moderately strong correlations (r = 0.39-0.78) between the beta C+ nigral lesion area or striatal dopamine level potencies and their previously described IC50 values for inhibiting mitochondrial respiration or their toxicity to PC12 cells in culture. Interestingly, our correlation analysis revealed a remarkably strong correlation between beta C+ Ki MAO-A values and their toxicity to PC12 LDH release (r = -0.84) or PC12 protein loss (r = 0.79). Although beta C+s appear to be less specific toxins than MPP+, their levels in human substantia nigra are 8-20-fold higher than in cortex, making their role as relatively selective nigral toxins in Parkinson's disease plausible.

Inhibition of mitochondrial succinate oxidation--similarities and differences between N-methylated beta-carbolines and MPP+.

N-Methylated beta-carbolinium compounds (N-Me-BCs), including 2-N-methyl and 2,9-N,N-dimethyl analogs, structural analogs of 1-methyl-4-phenylpyridinium (MPP+), may be endogenously bioactivated, MPP(+)-like toxins, capable of inducing parkinsonism. Both MPP+ and selected N-Me-BCs inhibit NADH-linked mitochondrial respiration (Complex I). We now show that both also inhibit succinate-supported (Complex II) respiration, the greatest inhibition (80%) being seen for 2,9-dimethylharmanium. Complex I inhibition occurs at MPP+ concentrations (IC50 = 0.17 mM) about one order of magnitude lower than Complex II inhibition (greater than 1.2 mM). In contrast, Complex I and Complex II inhibition by the N-Me-BCs tested occurred at similar concentrations (I, 0.1 mM; II, 0.25 mM) and concentrations similar to Complex I inhibition by MPP+. 2,9-N,N-Dimethyl-BCs, which are the permanently charged BC analogs of MPP+, show inhibitory characteristics similar to MPP+: slow onset of inhibition, potentiation by TPB, and reversal by DNP. The fact that succinate oxidation cannot bypass the Complex II inhibition by N-Me-BCs could enhance any chronic neurotoxicity of N-Me-BCs.

Mitochondrial respiratory inhibition by N-methylated beta-carboline derivatives structurally resembling N-methyl-4-phenylpyridine.

Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated beta-carbolines (2-Me beta Cs) and 2-methylated 3,4-dihydro-beta-carbolines (2-MeDH beta Cs), which encompass the MPP+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD(+)-linked O2 consumption (6-min preincubations) was as follows: MPP+ = 2-methylharmine greater than 2-methylharmol = 2-methylharmaline much greater than 2-methylharmalol greater than 2-methylnorharman greater than 6-OH-2-methylharmalan much greater than 2-methylharman. Similar to MPP+, 2-MeDH beta C/2-Me beta C inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDH beta C/2-Me beta C inhibitory time courses, which were unlike MPP+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic beta-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP+ rather than 2-Me beta Cs. Succinate-supported respiration was also significantly blocked by 2-MeDH beta Cs/2-Me beta Cs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD(+)-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDH beta Cs/2-Me beta Cs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-Me beta Cs.