Prediction of postoperative opioid analgesia using clinical-experimental parameters and electroencephalography.

BACKGROUND: Opioids are often used for pain treatment, but the response is often insufficient and dependent on e.g. the pain condition, genetic factors and drug class. Thus, there is an urgent need to identify biomarkers to enable selection of the appropriate drug for the individual patient, a concept known as personalized medicine. Quantitative sensory testing (QST) and clinical parameters can provide some guidance for response, but better and more objective biomarkers are urgently warranted. Electroencephalography (EEG) may be suitable since it assesses the central nervous system where opioids mediate their effects. METHODS: Clinical parameters, QST and EEG (during rest and tonic pain) was recorded from patients the day prior to total hip replacement surgery. Postoperative pain treatment was performed using oxycodone and piritramide as patient-controlled analgesia. Patients were stratified into responders and non-responders based on pain ratings 24 h post-surgery. Parameters were analysed using conventional group-wise statistical methods. Furthermore, EEG was analysed by machine learning to predict individual response. RESULTS: Eighty-one patients were included, of which 51 responded to postoperative opioid treatment (30 non-responders). Conventional statistics showed that more severe pre-existing chronic pain was prevalent among non-responders to opioid treatment (p = 0.04). Preoperative EEG analysis was able to predict responders with an accuracy of 65% (p = 0.009), but only during tonic pain. CONCLUSIONS: Chronic pain grade before surgery is associated with the outcome of postoperative pain treatment. Furthermore, EEG shows potential as an objective biomarker and might be used to predict postoperative opioid analgesia. SIGNIFICANCE: The current clinical study demonstrates the viability of EEG as a biomarker and with results consistent with previous experimental results. The combined method of machine learning and electroencephalography offers promising results for future developments of personalized pain treatment.

OPRM1 and ABCB1 polymorphisms and their effect on postoperative pain relief with piritramide.

Genetic factors may contribute to the differential response to opioids. The aim of this study was to evaluate the association between polymorphisms of µ1-opioid receptor gene OPRM1 (rs1799971), and P-glycoprotein transporter gene ABCB1 (rs1045642, rs2032582), and piritramide efficacy under postoperative patient-controlled analgesia (PCA). In 51 patients, OPRM1 variant was associated with decreased efficacy in early postoperative period evidenced by sum of pain intensity difference in the 0-6 h postoperative period (SPID(0-6)), (F=3.27, p=0.029). Mean (SD) SPID(0-6) was observed in the 118AA genotype 22.9 (6.1) mm, which was significantly higher from the 118GG genotype 10.0 (4.4) mm, p=0.006. The lowest cumulative dose was recorded in 118AA genotype 19.1 (9.8) mg, which was significantly less than in the 118GG genotype group 36.6 (6.1) mg, p=0.017. Opioid-induced adverse effects were observed in 11, 30, and 100 % of patients in 118AA, 118AG, and 118GG genotype groups, respectively (p<0.05). Piritramide efficacy and safety was not significantly affected by ABCB1 (rs1045642, rs2032582) polymorphisms. Variant OPRM1 118G allele is associated with decreased acute postoperative pain relief after piritramide. Decreased efficacy leads to higher drug consumption under PCA settings, which however, does not fully compensate insufficient pain relief, but increases incidence of adverse effects.

Prospective evaluation of the pharmacodynamics of piritramide in neonates and infants.

Piritramide is a synthetic opioid commonly used in Germany and Austria for the analgesia of pediatric patients. Little pharmacokinetic and pharmacodynamic data for the pediatric population is available. The aim of this investigation was to gain pharmacodynamic data on postsurgical analgesia and the side effects of piritramide. The study was approved by the Ethics Committee of the Medical Faculty. Data were collected in an open, prospective clinical trial. After obtaining the parents' informed written consent, patients received a bolus of piritramide 50 mug/kg for postsurgical analgesia or to prevent pain resulting from invasive procedures. Titration doses of 15 microg/kg were allowed. Vital signs and pain intensity were closely monitored. Data from 39 patients could be included in the analysis. Of the patients, 95% were in the immediate postsurgical course, 5% had piritramide for invasive procedures, and 46% of the patients were ventilated. The mean piritramide dosage was 64 +/- 24 microg/kg. Pharmacodynamic analysis showed adequate analgesia for at least 50% of the spontaneously breathing patients for 120 min after piritramide bolus. More than 50% of the ventilated patients showed inadequate analgesia at any point in time after piritramide bolus. Fifty-nine percent (59%) of the ventilated patients received additive analgesia versus 31% of spontaneously breathing patients. No relevant changes of vital signs could be observed. One patient received naloxone for apnea. We conclude that dosages of more than 50-70 microg/kg are needed for sufficient analgesia in ventilated postsurgical infants. In spontaneously breathing patients, 50-70 microg/kg provides a 120-min period of analgesia for more than 50% of patients. Cardiovascular stability of the patients was good and, with one exception, there was no respiratory depression.

[Experimental study of the use of piritramide as intrathecal analgesic]. / Cercetari experimentale privind utilizarea piritramidei ca analgezic intratecal.

Opioids proved their advantages as general and intrathecal (i.t.) analgesics. Piritramide (P), a largely used analgesic opioid today, has not been studied in i.t. administration. Our experimental research aimed in determining the efficiency, security and optimal dose of i.t. P. In 9 adult mongrel dogs equally randomized in 3 groups we injected i.t. P 1.3 mg x kg-l (group 1), P 0.8 mg x kg-l (group 2) and sodium chloride 0,9% (group 3) and we registered the motility, the pain reaction to electrical and mechanical nociceptive stimuli, the respiratory rate and amplitude, electrocardiogram, heart rate, mean arterial blood pressure electroencephalogram and, for 2 subjects from group 1, electromyogram. The P-induced analgesia was strong, dose-dependent, and segmental, with a time of onset of 5-8 min, duration of 1h 45 min-2h 30 min, and prolonged residual analgesic level for 5-6 h. The dogs from the 1st group presented moderate side effects: bradypnea, tachycardia and arterial hypotension at 5 min, reduction in the posterior limbs motility, sleep. We could conclude that i.t. piritramide 0.8 mg x kg-l provides a solid, segmental, long-lasting analgesia, without marked adverse effects.

Pharmacodynamic modelling of the analgesic effects of piritramide in postoperative patients.

BACKGROUND: The concentration-effect relationship of piritramide, a synthetic opioid analgesic predominantly used for postoperative analgesia and analgosedation, has not been reported so far. METHODS: Twenty-four patients of both genders aged 58.1 (11.7) yr (mean (SD)) received inhalational anaesthesia for abdominal surgery. Postoperative pain was assessed with a visual analogue scale (VAS). Analgesia was provided with piritramide, infused at a rate of 7 micrograms.kg-1.min-1 until analgesia was considered sufficient (VAS < 25) or up to a maximum dose of 0.2 mg/kg. The plasma concentrations of piritramide were determined by gas chromatography. An inhibitory fractional sigmoid Emax-model was used to describe the relation between effect site concentration and perceived pain. RESULTS: The equilibration half-life between plasma and effect site concentrations (T1/2 (keo)) was 16.8 min (median; range: 4.4-41.6 min). The steady-state plasma concentration required to produce 50% of maximum analgesia (EC50) was 12.1 ng/ml (range: 2.9-29.8 ng/ml) and correlated with initial pain intensity. The slope factor gamma was 1.9 (range: 0.5-6.1) and increased with age. Clinically relevant respiratory depression did not occur. Due to the relatively large equilibration half-life of the effect compartment, the context-sensitive half-time of the effect site concentrations after short-time administration (< 2 h) clearly exceeded those of alfentanil, sufentanil, and fentanyl. CONCLUSIONS: The analgesic effect of piritramide was adequately described by an inhibitory fractional Emax-model. In order to overcome the pronounced hysteresis, piritramide should initially be administered as an intravenous bolus of at least 5 mg.

[Use of propofol (diprivan) for induction of anesthesia in neurosurgical patients. I. Pressor reaction to laryngoscopy and intubation of the trachea]. / Primenenie propofola (diprivana) dlia induktsii anestezii u neirokhirurgicheskikh bol'nykh. I. Pressornaia reaktsiia na laringoskopiiu i intubatsiiu trakhei.

Pressor reaction to laryngoscopy and intubation of the trachea was studied in 32 patients with neurosurgical diseases of the brain (supratentorial tumors and arterial aneurysms) under conditions of induction anesthesia with propofol (diprivan) in the mean dose of 2.85 mg/kg. Diprivan alone did not block the development of pronounced pressor reaction to intubation. Combination of diprivan in the same dose with dipidolor (0.4 mg/kg) ensured complete blocking of the pressor reaction in neurosurgical patients. Combination of diprivan and fentanyl (2.85 mg/kg) blocked the development of a pressor reaction not so effectively and not in all the examinees.

Pulmonary venodilation by isoflurane improves gas exchange during Escherichia coli bacteremia.

OBJECTIVE: To determine how isoflurance affects the longitudinal distribution of pulmonary vascular resistance and pulmonary gas exchange during Escherichia coli bacteremia. DESIGN: Prospective, controlled study with open-label assignment of animals to two groups. SETTING: Laboratory. SUBJECTS: Goehingen minipigs. INTERVENTIONS: Induction of acute respiratory failure by a 4-hr infusion of live E. coli bacteria in 12 animals; six animals anesthetized with methohexital/piritramide; six animals anesthetized with isoflurane. The control group consisted of four animals that received the same surgical procedure, but no E. coli infusion. Two animals were anesthetized with methohexital/piritramide and two with isoflurane, respectively. MEASUREMENTS AND MAIN RESULTS: Cardiac output and pressures were measured by means of an arterial catheter, Swan-Ganz catheter, and a left atrial catheter. Effective pulmonary capillary pressure was evaluated graphically from a pulmonary artery occlusion pressure decay. Arterial-alveolar PO2 ratio was calculated to evaluate pulmonary function. Measurements were performed before and after 1, 2, and 3.5 hrs of E. coli infusion. Statistical significance was tested with analysis of variance (ANOVA). E. coli infusion caused hypodynamic shock, an increase in pre- and postcapillary pulmonary vascular resistance and respiratory failure. Postcapillary pressure gradient and effective pulmonary capillary pressure were lower in the isoflurane-group. Methohexital-anesthetized animals developed pulmonary dysfunction after 1 hr of bacteremia, whereas isoflurane-anesthetized animals developed pulmonary dysfunction after 3.5 hrs of E. coli infusion (significantly different, ANOVA, p < .05). There were no significant changes in the sham group. CONCLUSIONS: Isoflurane is a pulmonary venodilator. During lethal E. coli infusion, it ameliorates the increase in pulmonary capillary pressure and preserves pulmonary function until vascular permeability increases.

[Effect of dipidolor on hemodynamics and respiration in rats after exposure to gamma-radiation and cytostatics]. / Vliianie dipidolora na gemodinamiku i dykhanie u krys posle vozdeistviia gamma-oblucheniia i tsitostatikov.

It was shown in experiments on anesthetized rats that intramuscular administration of dipidolor (5 mg/kg) failed to exert any effect on the functioning of the cardiovascular and respiratory systems of the animals which previously had been irradiated with the dose of 50 Gy or given intravenous injections of platidyam (5 mg/kg) or cyclophosphane (50 mg/kg).

Arrhythmogenic, antiarrhythmic and inotropic properties of opioids. Effects of piritramide, pethidine and morphine compared on heart muscle isolated from rats.

Since the effects in the intact organism are complicated by central as well as peripheral effects, we compared the direct cardiac effects of three commonly used opioids on isolated heart muscle. Concentration-response curves for electrophysiological and inotropic effects of piritramide, pethidine and morphine (10(-6)-10(-4) mol/l) on spontaneously beating and electrically stimulated rat atria were obtained. Piritramide decreased spontaneous frequency, induced arrhythmia and cardiac arrest. It had no significant effect on effective refractory period and electrical threshold for excitation, but decreased contractile force. Pethidine increased effective refractory period, had no effect on electrical threshold and increased contractile force. Morphine induced no significant electrophysiological effects, but decreased contractile force slightly. These results indicate direct negative chronotropic and arrhythmogenic actions of piritramide, possible class III antiarrhythmic action of pethidine and lack of major direct cardiac effects of morphine.

[Comparative clinical investigations on the cardiovascular effects of piritramide (dipidolor) and fentanyl (author's transl)]. / Vergleichende klinische Untersuchungen von Herz-Kreislauf-Effekten zwischen Piritramid (Dipidolor) und Fentanyl.

In 36 patients with acquired heart disease effects of 0.15 mg/kg piritramide on hemodynamics, inotropic state and myocardial oxygen consumption were investigated during and after cardiac surgery (basic neuroleptanalgesia). It could be demonstrated, that piritramide is not inducing any negative inotropic effects compared to a control group (n = 36) and a fentanyl group (0.003 mg/kg, n = 31). There were only small changes in HR, SV, PRA and PLA. A slight decrease in Part, PLV, and arterial perfusion pressure during extracorporeal circulation is interpreted as a peripheral vasodilatation. The resulting decrease in heart work caused a significant decrease in myocardial oxygen consumption (-18%), which is of special advantage in patients with coronary heart disease.

[Effects of dipidolor, seduxen, pipolfen and their combinations on the vasomotor reflex and respiration]. / Vliianie dipidolora, seduksena i pipol'fena i ikh kombinatsii na vazomotornyi refleks i dykhanie.

Diazepam has been shown to facilitate while dipidolor and pipolphen to inhibit the vasomotor reflexes. Administration of dipidolor after diazepam and pipolphen is conducive to preservation of the inhibitory action of the analgesic on the vasomotor reflexes, the depressant effect of the drug on respiration being eliminated.

Dissociative effects of piretanide on proximal tubular PO4 and HCO3 transport.

The effect of piretanide on renal electrolyte transport was evaluated by simultaneous micropuncture and clearance studies. In chronically thyroparathyroidectomized (TPTX) dogs, the drug caused an increased percentage excretion (%E) of sodium (from 0.6 +/- 0.1 to 15.2 +/= 1.8%, P less than 0.01) as well as of calcium (from 1.0 +/- 0.2 to 17.8 +/- 1.7%, P less than 0.001) and bicarbonate (from 1.2 +/- 0.4 to 5.9 +/- 0.9, P less than 0.001), but there was no change in %E of phosphate (4.0 +/- 0.9 to 6.6 +/- 1.6, P less than 0.10). In the presence of a constant infusion of parathyroid hormone (PTH) the drug caused a greater degree of natriuresis, calciuria, and bicarbonaturia and a significant increase in %E of PO4 (from 7.4 +/- 1.6 to 20.0 +/- 2.1, P less than 0.05). Proximal fractional reabsorption (PFR) of PO4 was unaffected, but there was a significant decrease in PFR of sodium, calcium, and bicarbonate in the TPTX dogs. The presence of PTH did not alter the effects of piretanide on PFR of phosphate and bicarbonate. There was no change in urinary or tubular fluid pH in either group of dogs. These data indicate that piretanide dissociates proximal PO4 transport from that of sodium and bicarbonate. In the presence of PTH, the drug inhibits PO4 transport beyond the late proximal convoluted tubule. In addition, tubular (and urinary) pH appears to be an important regulator of PO4 transport, especially in the absence of PTH.