[Piritramide : A critical review]. / Piritramid : Eine kritische Übersicht.

BACKGROUND: In many European countries and particularly in Germany, piritramide is the first choice opioid analgesic for the management of postoperative and posttraumatic pain. OBJECTIVE: The aim of this study was to review the pharmacological properties of piritramide and to evaluate whether these result in any clinical advantages with respect to effectiveness, safety and side effect profile compared to other strong opioids. MATERIAL AND METHODS: A systematic literature search was conducted in PubMed and Google Scholar and 27 articles published between 1961 and 2015 were retrieved and included in this review. RESULTS: Piritramide is a strong opioid that can only be administered parenterally. After intravenous injection it is effective after 17 min with pain relief lasting for up to 6 h. It is metabolized in the liver to inactive compounds, which is advantageous compared to morphine where active metabolites can accumulate in patients with renal failure. Piritramide is highly lipophilic resulting in a long context-sensitive half-life, making it unsuitable for continuous infusions. Studies further suggest that the side effect profile of piritramide is comparable to morphine. CONCLUSION: So far there is little evidence to support the widespread use of piritramide as first-line opioid analgesic for postoperative pain management in Germany. Especially lacking are in-depth studies about its mechanisms of action, receptor pharmacology, dose-response relationships and clinical dosing regimens. It is therefore questionable why piritramide is given priority.

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.

Pharmacokinetics of piritramide in newborns, infants and young children in intensive care units.

Piritramide is indicated for treatment of postoperative pain and analgosedation in the intensive care unit (ICU) setting. In an open prospective study the pharmacokinetics of piritramide were investigated in four groups: newborns (NB, age: 1-28 days) (n=8), infants 1 (IF1, age: 2-4 months) (n=7), infants 2 (IF2, age: 5-12 months) (n=14) and young children (YC, age: 2-4 years) (n=10). The recommended paediatric dose range for therapy of postoperative pain is 50-200 microg/kg. Piritramide was administered intravenously as a single dose by bolus injection of 50 microg/kg. Blood samples were collected at 0, 15, 45, 90 min and 3, 6, 9, 12 h after application, and urine samples were collected before application and during the following intervals: 1-2, 2-6, 6-12 h. Piritramide was measured in blood and urine by HPLC-ESI-MS. The following pharmacokinetic parameters: maximum plasma concentration (C(max)), distribution half-life (t 1/2 alpha), elimination half-life (t 1/2 beta), total clearance (Cl(t)) and median volume of distribution at equilibrium (Vd(ss)) were calculated using a non-compartment and a two-compartment model for the disposition of piritramide (TOPFIT and NONMEM-pharmacokinetic analysis). Newborns (NB) showed the highest maximum plasma concentrations (median+/-SD) C(max) (79+/-240 microg/l) compared to the other three groups (IF1 36+/-367, IF2 12+/-81 and YC 16+/-9 microg/l) without statistical significance. The median elimination half-lives (t 1/2 beta) were 702+/-720 min in NB, 157+/-102 min in IF1, 160+/-68 min in IF2 and 166+/-143 min in YC. For t 1/2 beta the difference between NB and the other three groups (IF1, IF2 and YC) was statistically significant (Mann-Whitney-U, P<0.05). Cl(t) was 15.9+/-16.7, 46.6+/-76.9, 235.5+/-454.1 and 338+/-168.1 ml/min in NB, IF1, IF2 and YC respectively. The total clearance increased exponentially with an elimination half-life of 702 min from 15.9 ml/min in NB to 46.6 ml/min in IF2. Differences between the NB/IF1 groups and IF2/YC groups were significantly significant (NB vs. IF2, NB vs. YC, IF1 vs. IF2 and IF1 vs. YC). Vd(ss) was 2.0+/-4.93, 1.7+/-2.5, 7.0+/-5.2 and 6.7+/-2.2 l/kg in NB, IF1, IF2 and YC respectively. In comparison to group IF1 the Vd(ss) was significantly larger in groups IF2 and YC (Mann-Whitney U, P<0.05). Newborns showed a high initial concentration and a distinct prolongation of the elimination half-life of piritramide compared to infants, young children and adults. Therefore, dosage needed to treat postoperative pain should be reduced, and the repetitive doses should be geared to the analgesic effects. In infants and young children the elimination of piritramide is increased compared to adults; therefore the duration of the effects of piritramide will be shortened, and dose intervals ought to be reduced. Subsequent clinical trials for detailed dose adjustment of piritramide in paediatric patients comparing pharmacokinetics and effectiveness are needed.

Death during patient-controlled analgesia: piritramide overdose and tissue distribution of the drug.

We report about a fatality during patient-controlled analgesia (PCA). Piritramide peripheral blood concentration was measured with 0.1 mg/l and exceeded the normal therapeutic range. Therefore, a fatal overdose was considered as the cause of death with respiratory depression as the underlying pathophysiological mechanism. The tissue distribution was studied; highest concentrations of piritramide were measured in kidney, bile and urine. Due to a large volume of distribution a difference in the drug concentration found in heart and peripheral bloods the phenomenon of drug redistribution was observed. Confronted with toxicological results, investigations revealed, that the PCA pump had been changed during a previous servicing from displaying mg/h to ml/h, therefore, the anesthetist had entered "1.5" assuming mg/h, but actually applying 1.5 ml/h (which was therefore equivalent to 2.25 mg/h, given a concentration in the cartridge of 1.5 mg piritramide/ml). In total, 61.5 ml (instead of 61.5 mg) had been infused, equivalent to 92.25 mg piritramide. This case report is a further example that human errors can play a crucial role in the safety of medical equipment. Experts in anesthesia recommended human factors engineering design principles to improve the safety of medical devices.

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.

Piritramide and alfentanil display similar respiratory depressant potency.

BACKGROUND: The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C50 for the depression of CO2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action. METHODS: Twenty-three patients received either alfentanil (2.3 microg x kg(-1) x min-1, 14 patients, as published previously) or piritramide (17.9 microg x kg(-1) x min(-1), nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO2 (PaCO2) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO2 was used to describe the PaCO2 data. RESULTS: The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k(elCO2) (elimination rate constant of CO2) 0.144 (-) min(-1), F (gain of the CO2 response) 4.0 (fixed according to literature values) (28%), C50 (both drugs) 61.3 microg l-1 (41%), k(eo alfentanil) 0.654 (-) min(-1) and k(eo piritramide) 0.023 (-) min(-1). Assigning separate C50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C50. CONCLUSION: Since the C50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.

Population pharmacokinetics of piritramide in surgical patients.

BACKGROUND: Piritramide is a synthetic opioid used for postoperative analgesia in several European countries. The authors present a mixed-effects model of its population pharmacokinetics in patients undergoing surgery. METHODS: After institutional approval and informed patient consent was obtained, 29 patients who were classified as American Society of Anesthesiologists physical status I or II and aged 21-82 yr were enrolled in the study. They received 0.2 mg/kg piritramide as an intravenous bolus before anesthesia was induced. Central venous blood samples were drawn for as long as 48 h after administration of the drug. The plasma concentration of piritramide was determined by gas chromatography. The concentration-time data were analyzed by mixed-effects modeling. Target-controlled infusions and intermittent bolus regimens were simulated to identify a regimen suitable for patient-controlled analgesia based on population pharmacokinetics and published pharmacodynamic data. RESULTS: The pharmacokinetics of piritramide were described adequately by a linear three-compartment model. Patient age and weight were significant covariates. The values of the pharmacokinetic parameters are: V1 = 50.5 [1], V2 = 150 x (1 + 9.32 x 10(-3) x (age - 47 yr)) [l], V3 = 212 x (1 + 6.37 x 10(-3) x (age - 47 yr)) [l], Cl1 = 0.56 x (1 - 6.14 x 10(-3) x (age - 47 yr)) [l/min], Cl2 = 8.25 x (1 + 2.02 x 10(-2) x (Wt - 74 kg)) [l/min], Cl3 = 0.80 [l/min]. The age of 47 yr and the weight of 74 kg refer to the median values for these factors in the patients studied. Rapid distribution, slow distribution, and elimination half-lives for the median patient are 0.05, 1.34, and 10.43 h, respectively. The context-sensitive half-time after a 24-h infusion is predicted at 10.5 h in a 75-yr-old patient compared with 7 h for the median patient. CONCLUSIONS: Piritramide is distributed extensively and eliminated slowly. The pharmacokinetic profile of the drug allows for intermittent bolus administration even when constant effect compartment concentrations are desirable, e.g., for PLA.

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.

Pharmacokinetics of piritramide after an intravenous bolus in surgical patients.

BACKGROUND: Piritramide is a synthetic opioid analgesic which is commonly used for postoperative analgesia. It is structurally related to meperidine, exhibiting full mu-receptor agonism. Pharmacokinetic data of the drug have not been reported so far. METHODS: Plasma protein binding of piritramide was studied in vitro. The kinetics were examined after a single intravenous bolus (0.2 mg/kg) in 10 male patients aged 22-53 years undergoing elective minor surgery. Plasma and urine concentrations were determined by gas chromatography in samples drawn before and after the bolus. The concentration vs. time data were evaluated by nonlinear regression analysis, and the mean values and SD of the individual pharmacokinetic parameters were calculated. A three-compartment body model was fitted to the data. RESULTS: The volume of distribution at steady state was 4.7 (0.7)l/kg, systemic plasma clearance was 7.8 (1.5) (mean (SD)) ml/kg/min. Renal clearance of unchanged piritramide was negligible (0.13 (0.09) ml/kg/min). The terminal elimination half-life was 8.0 (1.4) h. In vitro, the free fraction in plasma of piritramide did not change over the therapeutic concentration range (5.5 (1.3)% at a pH of 7.35) but decreased considerably with pH within the physiological range. CONCLUSION: Since the elimination half-life of piritramide appears to exceed the duration of clinically effective analgesia observed during the treatment of acute pain, the dose of piritramide should be titrated carefully during long-term treatment to avoid accumulation that may lead to adverse effects.