Henk Noorduin

Comparison of intravenous and intranasal sufentanil absorption and sedation

The absorption and sedation following an intranasal dose of sufentanil were evaluated and compared with those of the same dose given intravenously. Sixteen adult patients scheduled for elective surgery were randomly allocated to receive as premedication 15 μgsufentanil either intravenously or intranasally. Before administration and at fixed time intervals thereafter, the degree of sedation was assessed, vital signs were recorded and venous blood samples were taken for the determination of sufentanil plasma concentrations. Peroperative sedation of rapid onset and limited duration was seen in both groups. However, the onset of sedation was more rapid after intravenous injection. At 10 min, all patients in the TV group were sedated versus only two in the intranasal group (P < 0.01). No significant intergroup differences in sedation were seen at 20 to 60 min. This clinical effect is in agreement with the measured plasma levels, which were significantly lower after intranasal application at 5and 10 min, being 36 and 56 per cent of those after IV dosing, respectively. From 30 min, plasma concentrations were virtually identical for the two routes of administration. The AUCo-120 min after intranasal dosing was 78 per cent of that after intravenous injection. Intranasal dosing induced no clinically significant changes in vital signs, whereas after IV sufentanil, a clinically significant decrease in PaO2 was seen at 5 min. The results of this study show that sufentanil, when administered intranasally, is rapidly and effectively absorbed from the human nasal mucosa, so that this route may be an attractive alternative for a premedicant, avoiding the discomfort of an intravenous or intramuscular injection.RésuméNous avons comparé les voies intraveineuse et intranasale quant á l’absorption du sufentanil et á la sédation produite. Ainsi, en pré-opératoire d’ interventions électives, 16 adultes randomisés ont reccu 15 meg de sufentanil par voie veineuse ou nasale. Nous avons évalué l’effet sédatif, mesuré les signes vitaux et les niveaux sériques de sufentanil avant et á intervalle régulier aprés la prise du médicament. Un effet sédatif de courte durée est apparu rapidement avec le mode nasal alors que par mode vieneux, cemême effet survenait de façon encore plus pricoce. En fait, à dix minutes, il y avait sédation chez tous les patients du groupe veineux contre seulement deux patients du groupe nasal (P < 0,01) alors qu’á 20 et 60 minutes, les deux groupes étaient comparables. L’effet sédatifpeut être mis en paralléle avec les niveaux sériques de sufentanil qui á cinq et dix minutes post-instillation nasale n’atteignaient respectivement que 36 et 56 pour cent de ceux observé post-injection. A partir de 30 minutes, les niveaux sériques des deux groupes étaient pratiquement indentiques. Entre 0 et 120 minutes, l’aire sous la courbe des niveaux sériques (AUCo-120) atteints par voie nasale equivalait á 78 pour cent de celle produite par voie veineuse. Cinq minutes post-sufentanil IV, nous avons observé” une baisse significative de la PaO2 tandis que par voie nasale, les signes vitaux demeuraient inchangés. Ainsi, chez Vhumain, la muqueuse nasale absorbe rapidement le sufentanil et présente done une alternative á l’injection intraveineuse ou intramusculaire de la prém⩋ication.

Fentanyl Delivery from an Electrotransport System: Delivery is a Function of Total Current, Not Duration of Current

This open‐label, parallel study of 28 men was conducted to evaluate the pharmacokinetics and safety of fentanyl delivered by the E‐TRANS (fentanyl) electrotransport transdermal system (ALZA Corporation, Palo Alto, CA). The E‐TRANS (fentanyl) system provided electrically assisted, transdermal, continuous delivery of fentanyl. Treatments consisted of no current (group A); a constant current of 100 μA for 26 hours plus 4 additional doses at varying currents for varying times during hour 25 (groups B, C, D); a constant current of 100 μA for 26 hours plus 4 additional doses at 1,200 μA over 2.5 minutes during hour 1 (group E); or 500 μA for 0.5 hours and 100 μA for 3.5 hours (group F). No fentanyl was detected in serum when no current had been applied. Mean serum fentanyl concentrations were similar regardless of current duration during hour 25 (treatments B, C, D). Increases in mean serum fentanyl concentrations were significantly lower during additional dosing for treatment E compared with treatments B, C, and D. Serum fentanyl concentrations sufficient for analgesia (1–3 ng/mL) were attained in treatments using the E‐TRANS (fentanyl) system with basal current of 100 μA for 26 hours. There were no safety issues after treatment with E‐TRANS (fentanyl) system with concurrent opioid antagonist (naltrexone) administration. The only adverse event requiring treatment was a headache (n = 1). The majority of subjects had no or barely perceptible erythema at the application site 24 hours after system removal. Application of E‐TRANS (fentanyl) resulted in therapeutically significant serum fentanyl concentrations over a range of applied currents. Overall serum fentanyl concentrations were higher when the skin had been primed by constant‐current fentanyl delivery.

Alfentanil kinetics in the elderly.

Alfentanil disposition after an intravenous bolus of 50 µg/kg was followed in 15 elderly surgical patients and was compared to that in nine young adults. A two‐compartment open model described alfentanil disappearance from plasma. Apparent volumes of distribution of the central compartment (201 and 211 ml/kg; X̄), at steady state (460 and 543 ml/kg), and of the AUC (746 and 722 ml/kg) in young adults and in elderly subjects did not differ. Plasma clearance was lower in elderly subjects (4.4 ml/min/kg) than in young adults (6.5 ml/min/kg), whereas terminal plasma t½ was longer in the elderly patients (137 and 83 min). Alfentanil dosage should therefore be reduced in elderly patients when large single doses, multiple doses, or long‐term infusions are required.

Intranasal sufentanil for pre-operative sedation.

Sufentanil, a short‐acting and potent narcotic agent, was studied as a premedicant administered by the nasal route. A total dose of 5 μg appeared to be too low, while either 10 or 20 μg was very effective in producing sedation. Side effects were minor. There appeared to be no differences between nose drops and spray. In a further study, sufentanil nose drops were compared with saline (0.9% in a double‐blind fashion. Sedation of rapid onset but of limited duration was observed in the majority of patients who received sufentanil.

Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma.

SummaryMaternal and umbilical venous plasma was obtained at delivery from 8 mothers and their neonates after an i.v. bolus injection of alfentanil, and from 6 mothers and their neonates after epidural administration of sufentanil. Plasma levels of total (free + bound) alfentanil in neonates were about 3.4-times lower than in their mothers. At 33–55 min after 30 µg sufentanil, total drug levels in mothers were around the limit of detection of the radioimmunoassay (0.05 ng/ml); in one mother who had received 250 µg, the plasma level of total sufentanil was 2.6-times higher than in her neonate. Plasma protein binding of alfentanil was 88.2% in mothers and 67.2% in neonates. Plasma protein binding of sufentanil was 90.7% in mothers and 79.3% in neonates. For both drugs, plasma protein binding was significantly related to the α1-acid glycoprotein (α1-AGP) level, which was about 2.5-times lower in the infants. Free alfentanil levels in mothers and neonates were similar. Free levels of sufentanil in mothers and neonates differed less from each other than did the total drug levels.

The constipation-inducing potential of morphine and transdermal fentanyl

Constipation is an almost universal side‐effect associated with chronic opioid analgesia. The resulting discomfort can for some patients be more severe than the pain itself, leading to a reduction of analgesic use and consequently to increased pain. Clinical trials consistently show less constipation in patients treated with transdermal fentanyl than in patients receiving oral morphine. Several reasons can be identified for this finding: owing to its higher lipophilicity, fentanyl penetrates the blood‐brain barrier more easily and lower dosing is possible; owing to the transdermal route of administration of fentanyl, comparatively less opioid is available in the gastrointestinal tract to block local opioid receptors; finally, the transdermal route of administration leads to stable plasma levels of fentanyl over 72 h and hence minimises the probability of overdosing that can occur with multiple daily dosing. Further research is needed to establish whether these effects can also be extrapolated to other peripheral effects of opioids such as nausea and vomiting.

Alfentanil kinetics in renal insufficiency

SummaryAlfentanil 100 µg/kg was administered as an i.v. bolus to 9 patients with severe chronic renal dysfunction (creatinine clearance 1.0±1.2 ml/min) requiring regular haemodialysis. Plasma alfentanil concentrations were measured by a specific radioimmunoassay. Individual plasma concentration-time curves were fitted to a two-compartment open model. Mean distribution and elimination half-lives were 3.7 min and 58 min, respectively. The apparent volumes of distribution of the central compartment and the total volume of distribution at steady-state were 91 ml/kg and 304 ml/kg, respectively. Alfentanil plasma clearance was 5.3±2.5 ml/min/kg. All the patients tolerated alfentanil well and no side-effects nor delayed recovery were observed.

Alfentanil Used in the Aged: A Clinical Comparison with Its Use in Young Patients

The clinical effects of an i.v. bolus dose of 50 micrograms kg-1 alfentanil were studied during surgical anaesthesia in 10 elderly patients and compared with those of the same dosage in nine young adults. Plasma samples, to determine alfentanil concentrations, were taken at regular intervals during the first hour following injection. Cardiovascular changes were minor. A transient fall in systolic blood pressure shortly after the alfentanil administration was seen in both groups but was more pronounced in the elderly patients. The quality of initial intra-operative analgesia was good in all patients. The duration of action of 50 micrograms kg-1 alfentanil, as judged by the occurrence of signs of insufficient analgesia, was longer in the elderly patients (mean: 36 min) than in young patients (mean: 22 min). The alfentanil plasma levels extrapolated for these time points were similar. Hence, the difference in duration of action must be due to the slower elimination from the body in the elderly patient, rather than an increased sensitivity. On these grounds, age should be one of the criteria for selecting the appropriate dose of alfentanil.

Klinische Aspekte von Alfentanil. Eine Übersicht

In dieser Ubersicht werden die klinischen Erfahrungen behandelt, die an 1106 Patienten im Rahmen von 28 klinischen Prufungen in 5 Landern (Niederlande, Belgien, GroBbritanien, U.S.A., Irland) mit Alfentanil erzielt wurden [1–28].