Spinal delivery of sufentanil, alfentanil, and morphine in dogs. Physiologic and toxicologic investigations.

BACKGROUND: This study examines the behavioral effects and potential neurotoxicity of sufentanil, alfentanil, and morphine after chronic daily epidural (15-day) and intrathecal (28-day) administration in dogs. METHODS: Dogs were chronically implanted with a lumbar intrathecal or epidural catheter and received daily injections for 28 or 15 days, respectively, of saline or one of three mu agonists: sufentanil (intrathecal 5, 25, or 50 micrograms/0.5 ml; epidural 10, 50, or 100 micrograms/2.0 ml), alfentanil (intrathecal 40 or 400 micrograms/0.5 ml; epidural 80 or 800 micrograms/2.0 ml), or morphine (intrathecal 0.5 or 5 mg/0.5 ml; epidural 1 or 10 mg/2.0 ml). Dogs were examined for antinociception (skin twitch) and neurobehavioral changes. When the animals were killed, cisternal cerebrospinal fluid was taken for clinical chemistry, and after perfusion fixation, spinal cord tissue was taken for histologic analysis. RESULTS: Bolus intrathecal and epidural injections of sufentanil, alfentanil, and morphine produced dose dependent antinociception, bradycardia, an initial tachypnea followed by a decrease in respiratory rate, hypothermia and somnolence. The order of potency was sufentanil > alfentanil > morphine on all measures. Over the extended period of drug delivery, a loss of response (tolerance) was observed on all measures. No abnormal morphologic or histologic effects were found when comparing the drug and dose groups. An inflammatory reaction secondary to the catheter was found in all animals. Intrathecal, but not epidural, catheters resulted in significant increases in cerebrospinal fluid protein and cell counts in vehicle animals. Values in drug treated animals did not differ significantly from the respective vehicle controls. A rapid systemic redistribution of all three drugs was observed. No differences were found in the pharmacokinetic parameters measured at day 1 and at the day of killing for any route. CONCLUSIONS: This large-animal model demonstrates the expected pharmacologic potency of these three agents and tolerance development. Based on cerebrospinal fluid and systematic histopathologic analyses, these three spinally administered agents showed no evidence of neurotoxicity over the range of doses/concentrations employed when given by the intrathecal or epidural route as compared to vehicle controls. Consideration of the toxicokinetics in this canine model suggests that it provides an appropriate test of the safety of these agents in concentrations which exceed those employed for daily intermittent epidural and intrathecal drug delivery in humans.

Characteristics of dose-dependent antagonism by beta-funaltrexamine of the antinociceptive effects of intrathecal mu agonists.

Using rats with chronic i.t. catheters, dose-response curves were carried out using the hot plate (HP) test for a number of receptor-preferring opioids. The ordering of activity (i.t. ED50; nmol) on the HP was: (D-Ala2, N-Me-Phe4, Gly5-ol) enkephalin (DAMGO 0.5); sufentanil (0.4); and morphine (6.6). To assess the effects of pretreatment with the irreversible mu ligand beta-funaltrexamine (beta-FNA), rats received saline, 0.2, 2.0 or 20.0 nmol of beta-FNA. After 24 hr, base-line response latencies were not different from control animals. Dose-response curves for morphine, sufentanil and DAMGO were then obtained. Pretreatment with beta-FNA resulted in a concentration-dependent rightward shift in the agonist dose-response curves with the dose-ratio values of the respective doses of beta-FNA being for morphine: 3.5, 15.7, and 37.3; sufentanil: 1.2, 1.9, and 5.3; and DAMGO: 1.9, 4.0 and 7.3. The slopes of the agonist dose-response curves also displayed mild reductions in slope, the magnitude of which was dependent upon beta-FNA pretreatment concentrations. Testing at 6 days after beta-FNA treatment revealed a significant recovery of effect. beta-FNA (20 nmol, i.t.) had no effect on a just maximally effective dose of ST-91 (90 nmol, i.t.), an alpha-2 adrenergic agonist. beta-FNA (20 nmol, i.t.), but not 2.0 nmol resulted in a modest but significant reduction in the effect of the delta agonist DPLPE (120 nmol). These data are interpreted as supportive of the hypothesis that the mu-preferring ligands differ in the number of spinal receptors that must be occupied to produce a given antinociceptive effect (i.e., they differ in intrinsic efficacy).

Effects of [N-(L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine (SCH32615), a neutral endopeptidase (enkephalinase) inhibitor, on levels of enkephalin, encrypted enkephalins and substance P in cerebrospinal fluid and plasma of primates.

In halothane-anesthetized and -ventilated cynomologus macaque monkeys, the effects of administering vehicle (n = 3) or the neutral endopeptidase inhibitor N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine (16 mg/kg, n = 5; or 100 mg/kg, n = 3, intravenously) was examined. Cisternal CSF aliquots were examined by radioimmunoassay: 1) for Met enkephalin; 2) after trypsin and carboxypeptidase B treatment for encrypted enkephalin (X-ENK); 3) for substance P; and 4) for unmetabolized drug. Similar measures were carried out in femoral artery and femoral venous plasma, except that substance P was not assayed. In CSF, prior to drug, low, but measurable levels of enkephalin (61 pg/ml), X-ENK (285 pg/ml) and substance P (16 pg/ml) were observed. Vehicle-injected animals showed no change from baseline levels over a 4-hr sampling period in either plasma or CSF levels. In contrast, following 16 mg/kg, in CSF, there was a significant 9-fold increase in MET and 11-fold increase in X-ENK at 30 min. CSF-substance P levels rose also by a factor of 2, with the peak effect observed at 60 min. All levels displayed a significant reduction by 4 hr. There was no statistical difference between the maximum effects observed with either the 16- or 100-mg/kg dose. Plasma peptide levels of enkephalin and X-ENK were not altered by drug. CSF displayed significant drug levels by 30 min, which were between 0.1 and 1% of levels observed concurrently in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)