THE EFFECT OF PIRINITRAMIDE (R 3365) ON THE RESPIRATORY RESPONSE TO CO2 INHALATION.
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Analgesics↗
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Pirinitramide (R 3365), a potent analgesic with unusual chemical structure.
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Analgesics↗
[Phenoperidine and pirinitramide. Comparative study of 2 new analgesics].
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Analgesics↗
[PIRINITRAMIDE, R-3365 AND MORPHINE. A COMPARISON OF ANALGESIC POTENCY AND RESPIRATORY DEPRESSANT EFFECT].
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Analgesics↗
Opioid-induced respiratory depression is associated with increased tidal volume variability.
BACKGROUND AND OBJECTIVE: mu-agonistic opioids cause concentration-dependent hypoventilation and increased irregularity of breathing. The aim was to quantify opioid-induced irregularity of breathing and to investigate its time-course during and after an opioid infusion, and its ability to predict the severity of respiratory depression. METHODS: Twenty-three patients breathing spontaneously via a continuous positive airway pressure (CPAP) mask received an intravenous (i.v.) infusion of alfentanil (2.3 microg kg(-1) min(-1), 14 patients) or pirinitramide (piritramide) (17.9 microg kg(-1) min(-1), nine patients) until either a cumulative dose of 70 microg kg(-1) for alfentanil or 500 microg kg(-1) for pirinitramide had been achieved or the infusion had to be stopped for safety reasons. Tidal volumes (VT) and minute ventilation were measured with an anaesthesia workstation. For every 20 breaths, the quartile coefficient was calculated (Qeff20V(T)). RESULTS: Both the decrease of minute volume and the increase of Qeff20V(T) during and after opioid infusion were highly significant (P < 0.001, ANOVA). Patients in which the alfentanil infusion had to be terminated prematurely had lower minute volumes (P = 0.002, t-test) and higher Qeff20V(T) (P = 0.034, t-test) than those who received the complete dose. Changes in the regularity of breathing measured as Qeff20V(T) parallel those of minute ventilation during and after opioid infusion. CONCLUSIONS: Opioids cause a more complicated disturbance of the control of respiration than a mere resetting to higher PCO2. Furthermore, Qeff20V(T) appears to predict the severity of opioid-induced respiratory depression.
Adult↗
Remifentanil provides better protection against noxious stimuli during cardiac surgery than alfentanil.
BACKGROUND AND OBJECTIVE: We hypothesized that remifentanil-propofol cardiac anaesthesia, plus administration of pirinitramide (piritramide) upon cessation of the remifentanil infusion, would be associated with a shorter time to tracheal extubation than alfentanil-propofol anaesthesia, without the occurrence of major haemodynamic instability. METHODS: Haemodynamic stability and recovery characteristics of two remifentanil infusion regimens (0.5 microg kg(-1)min(-1); 0.25 microg kg(-1)min(-1)) were therefore compared with an alfentanil infusion regimen (1 microg kg(-1)min(-1)), in combination with target-controlled infusion of propofol, in a randomized blinded trial in 75 coronary artery surgery patients. RESULTS: Pirinitramide provided good postoperative analgesia without prolonging extubation times: median extubation time in minutes after stopping the opioid-sedative drugs was 300 in the higher-dose remifentanil group and 270 in the lower-dose remifentanil group and alfentanil group (P = 0.606). Significant time-by-treatment interactions were seen for systolic arterial pressure (P = 0.015), mean arterial pressure (P = 0.009) and diastolic arterial pressure (P = 0.006). No significant interaction (P = 0.489) and no constant treatment effect were seen for heart rate (P = 0.288). Time effects were highly significant (P < 0.0001) for all haemodynamic variables. Heart rate remained stable in all groups. In the higher-dose remifentanil group, blood pressure was significantly different and lower during surgery and in this group less bolus doses of the opioid-sedative drugs (P = 0.015) had to be given. CONCLUSION: The higher-dose remifentanil infusion provided superior suppression of haemodynamic responses to noxious stimuli with better haemodynamic stability.
Aged↗
The pharmacokinetics of piritramide after prolonged administration to intensive care patients.
BACKGROUND AND OBJECTIVE: The purpose of the present study was to determine the pharmacokinetics of the micro-agonist opioid pirinitramide (piritramide) after prolonged administration. METHODS: Nine patients requiring intensive care therapy and artificial ventilation for several days received piritramide with a median infusion rate of 5 mg h(-1) (range 4.8-10 mg h(-1)) for a median period of 69.9 h (range 49-89 h) for analgesia and sedation. After the end of the infusion, frequent arterial blood samples were withdrawn for 96 h and assayed for piritramide using a gas chromatographic method. Standard compartmental models were fitted to the individual concentration-time courses to characterize the elimination of piritramide after prolonged administration. RESULTS: The concentration-time course after the end of the infusion was adequately described with a three-compartment model in eight patients and a two-compartment model in one patient (standard two-stage geometric mean and 16-84% quantile: volumes of distribution V1 = 47.9 (26.8-85.8)L, V2 = 402 (241-672)L, V3 = 332 (124-885)L; clearances Cl1 = 66.5 (53.2-83.0)Lh(-1), Cl2 = 215 (125-369)Lh(-1), Cl3 = 18.4 (9.2-36.8) Lh(-1)). Both the steady-state volume of distribution (782 L) and the terminal elimination half-life (17.4 h) were larger than predicted from single bolus pharmacokinetic studies (412.5 L and 10.4 h, respectively), the context-sensitive half-time after more than 72 h of administration was 32% shorter than predicted (285 vs. 420 min). CONCLUSIONS: Despite increasing terminal elimination half-life and volume of distribution at steady state (increasing drug load for a given plasma concentration), the context-sensitive half-time of piritramide after 3 days of administration is lower than predicted from bolus kinetics, making the drug a suitable candidate for intensive care unit analgesia.
Adult↗
A randomized controlled double-blind trial comparing piritramide and morphine for analgesia after hysterectomy.
BACKGROUND AND OBJECTIVE: Efficacy and side-effects of piritramide (pirinitramide) and morphine, given intravenously for postoperative analgesia after hysterectomy, were compared in a randomized controlled double-blind trial in 92 ASA class I-III patients. METHODS: Administration was investigator-controlled during the first 90 min and subsequently via a patient-controlled device. Visual analogue scales for pain intensity and verbal rating scales for side-effects were taken repeatedly. RESULTS: Median visual analogue scores for pain intensity on a 100-mm scale 4, 8 and 24 h after surgery were 10, 8.5 and 5 mm in the piritramide group and 18, 10 and 8.5 mm in the morphine group. These differences are neither statistically nor clinically significant. Median values for nausea on a verbal rating scale from 0 to 3 were zero for both groups at all times with similar ranges. There was no difference in number of episodes of vomiting and retching and usage of antiemetics. The mean amount of piritramide used for initial titration was 15.2 mg; the respective amount of morphine was 15.4 mg. CONCLUSIONS: In this setting the two agents are equally effective and show a similar profile of side-effects.
Analgesia, Patient-Controlled↗
Implications of the use of neuromuscular transmission monitoring on immediate postoperative extubation in off-pump coronary artery bypass surgery.
BACKGROUND AND OBJECTIVE: When continuous infusions of neuromuscular blocking drugs are administered during lengthy interventions and no routine antagonism of their effects is applied, there is a dramatic incidence of residual curarization. We have examined whether the use of neuromuscular transmission monitoring results in differences in the incidence of postoperative residual curarization, the use of antagonist agents, and the endotracheal extubation rate and outcome after continuous infusion of rocuronium in patients undergoing off-pump coronary artery bypass surgery. METHODS: Twenty patients were assigned to group 1 (n = 10, non-blinded neuromuscular transmission monitoring) or group 2 (n = 10, blinded neuromuscular transmission monitoring). In group 1, patients were given rocuronium at an infusion rate of 6 microg kg(-1) min(-1). The rate was manually adjusted in order to maintain T1/T0 at 10%. In group 2, a rocuronium infusion was started 30 min after induction of anaesthesia, at a rate of 6 microg kg(-1) min(-1); this rate was left unchanged during surgery. The rocuronium infusion was discontinued on completion of all vascular anastomoses; propofol was stopped at the beginning of closure of the subcutis and pirinitramide (piritramide) 15 mg was administered intravenously. Remifentanil was discontinued at the beginning of skin closure and neostigmine (50 microg kg(-1)) administered at the end of surgery when the train-of-four ratio was < 0.9 in group 1, and routinely in group 2. A 20 min test period for spontaneous ventilation was allowed once surgery had been accomplished. When the train-of-four ratio was > or = 0.9 (group 1), patients were extubated if also breathing spontaneously, fully awake and able to follow commands. When they met the clinical criteria for normal neuromuscular function after induced blockade, patients in group 2 were extubated when fully awake and able to follow commands. RESULTS: In group 1, the rate of rocuronium infusion required to keep T1/T0 at 10% was 5 +/- 1.9 microg kg(-1) min(-1); this was not significantly different from the fixed rate in group 2 (P = 0.15). One patient in group 2 was excluded. Eight out of 10 and eight out of nine patients in groups 1 and 2, respectively, reached the extubation criteria. Three out of eight, and five out of eight, patients from groups 1 and 2, respectively, were extubated in the operating room. At that time of endotracheal extubation, all three patients from group 1, but only four of the five patients from group 2 had a train-of-four ratio > or = 0.9. In group 2, one patient was reintubated in the intensive care unit. The incidence of pharmacological reversal was high in group 1. CONCLUSIONS: Although we found no additional benefit of using neuromuscular transmission monitoring, it seems an absolute necessity for safety reasons. Pharmacological antagonism was mandatory. However, in our opinion, it is not wise routinely to perform immediate postoperative extubation in off-pump coronary artery bypass surgery.
Aged↗
Focal myopathy associated with chronic intramuscular injection of piritramide.
We report a patient in whom chronic intramuscular piritramide led to a focal fibrotic myopathy. Since piritramide myotoxicity has never been reported, we have studied its effect on rat skeletal muscle. Chronic intramuscular piritramide led to fibrous connective tissue replacement of rat skeletal muscle, similar to that found in the patient's muscle. Although the pathogenetic mechanism of piritramide myopathy is unclear, we caution against prolonged intramuscular use of piritramide to prevent this potentially debilitating adverse effect.
Adult↗
Quantitative determination of piritramide in human plasma and urine by off- and on-line solid-phase extraction liquid chromatography coupled to tandem mass spectrometry.
A method for the liquid chromatography/tandem mass spectrometric (LC/MS/MS) quantification of piritramide, a synthetic opioid, in plasma after conventional off-line solid-phase extraction (SPE) and in urine by on-line SPE-LC/MS/MS in positive electrospray mode was developed and validated. Applicability of the on-line approach for plasma samples was also tested. Deuterated piritramide served as internal standard. For the off-line SPE plasma method mixed cation-exchange SPE cartridges and a 150 x 2 mm C18 column with isocratic elution were used. For the on-line SPE method, a Waters Oasis HLB extraction column and the same C18 analytical column in a column-switching set-up with gradient elution were utilized. All assays were linear within a range of 0.5-100 ng/mL with a limit of detection of 0.05 ng/mL. The intra- and interday coefficients of variance ranged from 1.3 to 6.1% for plasma and 0.5 to 6.4% for urine, respectively. The extraction recovery for the off-line plasma assay was between 90.7 and 100.0%. Influence of matrix effects, and freeze/thaw and long-term stability were validated for both approaches; influence of urine pH additionally for quantification in urine.
Blood Chemical Analysis↗
Preoperative oral administration of fast-release morphine sulfate reduces postoperative piritramide consumption.
The aim of this prospective randomized placebo-controlled double-blind study was to investigate the effect of premedication with morphine sulfate on postoperative pain. Ninety-eight ASA I-III patients undergoing total replacement of the knee or hip joint were randomly assigned to one of two groups. Group 1 received 20 mg morphine sulfate p.o. approximately one hour before the start of surgery; group 2 received placebo. After surgery, piritramide was administered via patient-controlled analgesia over 24 hours. Piritramide consumption and pain scores (visual analog scale) were recorded. The duration of surgery (mean +/- SD) was comparable in the two groups (group 1: 145 +/- 42 min, group 2: 131 +/- 35 min). In group 1 the cumulative piritramide consumption during 24 hours postoperation was significantly less than in the placebo group (37.5 +/- 12.5 mg versus 46.8 +/- 22.1, t-test, p < 0.05), although similar pain scores were recorded (group 1: 4.8 +/- 1.8 and 3.6 +/- 1.7, group 2: 4.8 +/- 1.6 and 3.4 +/- 2.0, at 1 and 24 hours, respectively). These data show that the preoperative oral administration of morphine sulfate, regardless of its short half-life, can reduce postoperative consumption of opioids at similar pain levels.
Administration, Oral↗
[Postoperative pain therapy in minimally invasive direct coronary arterial bypass surgery. I.v. opioid patient-controlled analgesia versus intercostal block].
OBJECTIVE: Lately introduced cardiosurgical procedures such as MIDCAB enable an early extubation immediately after surgery. This also requires an adequate anesthesia regime and especially a sufficient postoperative analgesia. Patient controlled analgesia (PCA) and intercostal nerve blockade (ICB) were evaluated for their suitability for postoperative pain relief in patients undergoing a MIDCAB procedure. MATERIAL AND METHODS: After approval by the local ethic committee and obtaining written informed consent 43 patients were included in this study. Anesthesia was induced and maintained in a total intravenous standardised manner with propofol, remifentanil, cisatracurium and additionally glyceroltrinitrate, clonidine and esmolol were given as needed. After revascularisation patients were randomly assigned to one of two groups receiving either 7.5 mg piritramid i.v. before extubation and continuing a PCA with 2 mg boli and a 10 min lockout, or an ICB with ropivacaine 1% (4 times 5 ml). Additionally all patients received 1 g paracetamol rectally before induction of anesthesia and 1 g metamizol i.v. at the end of surgery. A rescue medication of 3.75 mg piritramid i.v. was allowed. A pain score (NRS 0-10), the Aldrete score (AS 0-12) and oxygen saturation were obtained 1, 4, and 8 h after extubation. RESULTS: The ICB group showed a significantly greater pain reduction in the first (5.8 +/- 1.8 vs. 7.3 +/- 1.9; P < 0.02) and fourth h (3.6 +/- 1.3 vs. 4.6 +/- 1.4; P < 0.02), respectively. Transfer to an intermediate care ward one hr after extubation was achieved more often in the ICB group according to the AS (ICB 9.6 +/- 1.5 vs. PCA 8.9 +/- 1.2; P < 0.05), too. There was no difference with respect to the oxygen saturation. The additional piritramid demand was 9.3 mg in the ICP group and 5 mg in the PCA group in the first 8 hours postoperative. CONCLUSION: ICB gives a better pain relief in the early postoperative phase after MIDCAB procedures compared to a PCA. Both regimes are adequate in order to provide a sufficient pain relief and help to avoid prolonged postoperative mechanical ventilation. These will enable an early transfer of patients to an intermediate care station and save ICU capacity.
Adult↗
[Delta(9)-tetrahydrocannabinol and the opioid receptor agonist piritramide do not act synergistically in postoperative pain].
BACKGROUND: It is concluded from animal experiments that cannabinoid receptor and mu-opioid receptor agonists act synergistically with respect to antinociception. In order to demonstrate this effect under clinical conditions, we conducted a randomized double blind trial with patients after radical prostatectomy. PATIENTS AND METHODS: From the evening before the operation until the morning of the second postoperative day, all patients received eight oral doses of either placebo or 5 mg Delta(9)-tetrahydrocannabinol (dronabinol). Postoperatively patients had access to patient-controlled analgesia with the micro-opioid agonist piritramide for 48 h. We expected patients receiving dronabinol to require significantly less piritramide compared to patients on placebo. RESULTS: The consumption of piritramide was recorded in 100 patients after radical retropubic prostatectomy with regional lymphadenectomy. Patients in the placebo group consumed 74 mg (median), interquartile range (IQR) 44-90 mg, patients in the verum group consumed 54 mg (median) IQR 46-88 mg. The difference between groups was not statistically significant. Plasma concentrations of Delta(9)-THC were measurable in all patients in the verum group. The levels (median) were 1.5 ng/ml (IQR 0.6-2.3), 1.3 ng/ml (IQR 0.5-2.2) and 1.9 ng/ml (IQR 0.8-2.7) on the day of operation, the first and second postoperative day, respectively. CONCLUSION: We found neither a synergistic nor even an additive antinociceptive interaction between Delta(9)-tetrahydrocannabinol and the micro-opioid agonist piritramide in a setting of acute postoperative pain.
Aged↗
[Patient-controlled analgesia with clonidine and piritramide].
UNLABELLED: Following parenteral administration, clonidine has analgesic effects at both cerebral and spinal levels. Patient-controlled analgesia (PCA) makes it possible to determine equipotent dosages of analgesics by relating analgesic consumption per time to the levels of analgesia obtained in comparable patient populations. Therefore, we studied the equipotency ratios of clonidine and piritramide and the incidence of undesired side effects in the treatment of postoperative pain in patients undergoing maxillo-facial surgery. METHODS: After approval of the local ethics committee and informed consent 40 patients (age > 18 year, ASA I-III) were studied. Following randomization, the patients each received a PCA device containing either clonidine (bolus 30 micrograms), or piritramide (bolus 1.5 mg) for treatment of postoperative pain (lockout interval 5 min in both groups). During the postoperative period, pain was determined using a visual analogue scale, while analgesic consumption, sedation, haemodynamic parameters, respiration rate, and the occurrence of undesired side effects were documented additionally. RESULTS: The groups had comparable distributions of biometric data, duration of anaesthesia, and ASA classification. Pain level decreased significantly (P < 0.0001) in both groups during the first 2 h of PCA. Mean arterial pressure and heart rate were lower (P < 0.05) in the clonidine group 4 and 6 h after PCA onset, while the degree of sedation after 2 (P < 0.01) and 6 (P < 0.05) h was higher than in the piritramide group. Nausea and vomiting were more frequent (P < 0.05) in the piritramide group. Both groups showed a wide interpatient variation in analgesic requirement. The equipotency ratio clonidine/piritramid was 1:63.7. CONCLUSION: Intravenous clonidine is a potent analgesic and is suitable or the treatment of postoperative pain following maxillo-facial surgery. The analgesic potency of 150 micrograms clonidine i.v. was equivalent to that of 9.56 mg piritramide i.v. Nausea and vomiting occurred more rarely in the clonidine group, while deeper sedation was observed more frequently than in the piritramide group. Owing to the wide interindividual variation of analgesic consumption, clonidine dosages have to be adjusted to the actual requirements.
Adolescent↗
[Patient-controlled analgesia. PCA in a three year old child after traumatic amputation].
We report the case of a 3-year-old boy, who received long-term parent-controlled analgesia after traumatic amputation of one leg. He underwent surgery 17 times for a period of 25 days. Parent-controlled analgesia was started four days after admission because analgesia with non-opioid analgetics (acetaminophen) proved to be insufficient. The pump was set to a bolus-dose of 23 micrograms kg-1 piritramide (dipidolor) and a lockout interval of 10 minutes. Permitted maximum cumulative dose in four hours was 5 mg piritramide. There was no continuous infusion of opioid. PCA and possible adverse effects were explained to the mother. A monitoring regimen was used to assess efficacy (pain intensity estimated by the mother), adverse effects (sedation score, occurrence of nausea and vomiting) and piritramide consumption. For fear of side effects opioid administration was insufficient in the beginning. After three days the mother used the PCA effectively and no additional analgesic medication was required. Nausea or other side effects were not observed. After seven days opioid consumption nearly doubled. Apart from tolerance, this might have resulted from the mother's caution in the first days. After 17 days the PCA was discontinued. Oral analgetics (tramadol) controlled the pain adequately. Management of postoperative pain in children is difficult and too often insufficient. PCA is a safe and effective method of providing postoperative pain relief. Feasibility was shown in adolescents and, more recently, in children aged five years and over. Only few reports are available describing long term use of PCA in children younger than five years. Our case suggests that PCA may also be used effectively and safely in children younger than five years, if experienced staff, a monitoring regimen and cooperative and well instructed parents are available.
Amputation, Traumatic↗
[Analgesia in colon surgery. Can the use of NSAIDs reduce the opioid consumption following conventional and laparoscopic interventions?].
BACKGROUND: The goal of our study was to evaluate the morphine-sparing effect of nonsteroidal anti-inflammatory drugs (NSAIDs) following both conventional and laparoscopic colon surgery. MATERIALS AND METHODS: In this prospective, randomized clinical trial, 180 patients were assigned to three groups. Two groups received either paracetamol or parecoxib/valdecoxib in addition to piritramid via patient-controlled or nurse-controlled analgesia pump. Patients in the control group received piritramid only. The total piritramid consumption during hospital stay was recorded. RESULTS: Total opioid consumption was significantly lower in the two groups who received NSAIDs. Comparing conventional and laparoscopic surgery, the latter group had much lower opioid consumption. CONCLUSION: The use of NSAIDs following colon surgery significantly reduces postoperative opioid consumption.
Acetaminophen↗
[Long-term experiences with mechanical patient-controlled analgesia pumps for therapy of postoperative pain in general surgery].
The efficiency and safety of patient-controlled analgesia (PCA) in the treatment of postoperative pain is well documented. An alternative to electrical systems is the disposable pump, which is cost effective. The aim of this study was to prove the efficiency and safety of PCA disposable pumps. Eighty patients (45 men, 35 women, mean age 50 +/- 16 years) were included and received single-use PCA pumps (Vygon Medical Products, Aachen, Germany) for postoperative pain control. A sufficient reduction in pain levels, measured by the Verbal Rating scale (VRS), was achieved in nearly all patients. For the first application, a single bolus of 7.0 +/- 2 mg piritramide (Dipidolor) was needed, the mean of treatment time was 56 +/- 31 h. We had two dropouts because of non-compliance, two patients felt dizzy, and one patient felt nauseous. Further side-effects were observed during treatment. Our study led us concluded that PCA therapy with mechanical, disposable pumps is a safe and efficient treatment for postoperative pain. Such a concept can be introduced without an "Acute Pain Service" if the staff are well trained.
Adolescent↗