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Objectives: To determine the pharmacokinetics of butorphanol tartrate incorporated into poloxamer 407 (P407) after subcutaneous administration to orange-winged Amazon parrots (Amazona amazonica)., Animals: Six orange-winged Amazon parrots, ages 28 to 45 years., Procedures: A sterile formulation of butorphanol in P407 (But-P407) as a 25% gel was created to produce a concentration of 8.3 mg/mL. The formulation was administered SC at a dose of 12.5 mg/kg to all birds. Blood samples were collected at baseline prior to injection (time 0) and then at 0.08, 0.5, 1, 1.5, 4, 8, and 12 hours after drug administration. Butorphanol concentrations were quantitated via liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was performed using noncompartmental analysis and a commercially available software program., Results: Plasma concentrations of butorphanol remained > 100 ng/mL for > 4 hours for some birds (3/5) but were < 100 ng/mL for all birds by the 8-hour mark. Cmax and tmax were 346.9 ± 233.7 ng/mL and 1.3 ± 0.274 hours, respectively. Half-life was 1.56 ± 0.445 hours. No adverse effects were detected., Clinical Relevance: Butorphanol was absorbed from the But-P407 25% by the majority of the orange-winged Amazon parrots in this study (3/5), although to a lesser extent compared to Hispaniolan Amazon parrots. Absorption followed a pharmacokinetic profile compatible with a sustained-release drug. A dose of 12.5 mg/kg, SC, would be expected to provide antinociception for 4 to 8 hours, although pharmacodynamic studies in this species using this formulation have not demonstrated this.

The tranquilizer combination of butorphanol, azaperone, and medetomidine (BAM) has shown good efficacy for immobilization of wildlife, including black bears (Ursus americanus). BAM is antagonized with a combination of naltrexone and atipamezole. We immobilized 19 adult captive wild caught black bears and, except for three bears that were euthanized immediately, bears were recovered with naltrexone and atipamezole. Tissue residues (≥0.01 ppm) for the tranquilizers butorphanol, azaperone, and medetomidine were detected in liver and muscle of all three bears euthanized on day 0 postinjection (PI). Azaperone was not detected after 1 d PI. Residue for medetomidine was detected in two bears: in the liver 3 d PI and in the kidney 6 d PI. Butorphanol was reported in three bears: in fat 5 d PI, in kidney 6 d PI, and, surprisingly, in kidney, muscle, and fat 7 d PI. No tissue residues were detected in the three bears euthanized at 8 d PI. Tissue residues for the antagonists, naltrexone and atipamezole, were detected in bears euthanized 2 and 6 d PI, but not in tissues from animals euthanized at 7 or 8 d PI., (© Wildlife Disease Association 2020.)

OBJECTIVE To determine pharmacokinetics of butorphanol tartrate incorporated into poloxamer 407 (P407) after SC administration to Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 11 adult Hispaniolan Amazon parrots (6 males and 5 females; 11 to 27 years old). PROCEDURES A sterile formulation of butorphanol in P407 (But-P407) 25% (percentage determined as [weight of P407/weight of diluent] × 100]) was created (8.3 mg/mL). Five preliminary experiments (2 birds/experiment) were performed to determine the ideal dose for this species. The formulation then was administered (12.5 mg/kg, SC) to 8 birds. Blood samples were collected before (time 0) and 0.08, 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration. Some birds were used more than once, with a washout period of ≥ 3 months between subsequent treatments. Butorphanol concentrations were quantitated by use of liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was performed by use of noncompartmental analysis. RESULTS Maximal plasma butorphanol concentration was reached at 1.31 hours. Plasma concentrations of butorphanol remained > 100 ng/mL for > 3 hours (all birds) or > 4 hours (5/8 birds) but < 8 hours (all birds). Half-life of the terminal slope was 3.41 hours. No adverse effects were detected. CONCLUSIONS AND CLINICAL RELEVANCE Butorphanol was absorbed well from the But-P407 25% by Hispaniolan Amazon parrots, and absorption followed a pharmacokinetic profile compatible with a sustained-release drug. A dose of 12.5 mg/kg, SC, would theoretically provide analgesia for 4 to 8 hours. No adverse effects were detected. Studies on the pharmacodynamics of this formulation are necessary to confirm the degree and duration of analgesia.

Buprenorphine and carprofen, 2 of the most commonly used analgesics in mice, must be administered every 8 to 12 h to provide sustained analgesia. Sustained-release (SR) formulations of analgesics maintain plasma levels that should be sufficient to provide sustained analgesia yet require less frequent dosing and thus less handling of and stress to the animals. The pharmacokinetics of SR formulations of buprenorphine (Bup-SR), butorphanol (Butp-SR), fentanyl (Fent-SR), carprofen (Carp-SR), and meloxicam (Melox-SR) were evaluated in mice over 72 h and compared with those of traditional, nonSR formulations. Bup-SR provided plasma drug levels greater than the therapeutic level for the first 24 to 48 h after administration, but plasma levels of Bup-HCl fell below the therapeutic level by 4 h. Fent-SR maintained plasma levels greater than reported therapeutic levels for 12 h. Therapeutic levels of the remaining drugs are unknown, but Carp-SR provided plasma drug levels similar to those of Carp for the first 24 h after administration, whereas Melox-SR had greater plasma levels than did Melox for the first 8 h. Butp-SR provided detectable plasma drug levels for the first 24 h, with a dramatic decrease over the first 4 h. These results indicate that Bup-SR provides a stable plasma drug level adequate for analgesia for 24 to 48 h after administration, whereas Carp-SR, Melox-SR, Fent-SR, and Butp-SR would require additional doses to provide analgesic plasma levels beyond 24 h in mice.

Objective: To evaluate antinociceptive effects and pharmacokinetics of butorphanol tartrate after IM administration to American kestrels (Falco sparverius)., Animals: Fifteen 2- to 3-year-old American kestrels (6 males and 9 females)., Procedures: Butorphanol (1, 3, and 6 mg/kg) and saline (0.9% NaCl) solution were administered IM to birds in a crossover experimental design. Agitation-sedation scores and foot withdrawal response to a thermal stimulus were determined 30 to 60 minutes before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment. For the pharmacokinetic analysis, butorphanol (6 mg/kg, IM) was administered in the pectoral muscles of each of 12 birds., Results: In male kestrels, butorphanol did not significantly increase thermal thresholds for foot withdrawal, compared with results for saline solution administration. However, at 1.5 hours after administration of 6 mg of butorphanol/kg, the thermal threshold was significantly decreased, compared with the baseline value. Foot withdrawal threshold for female kestrels after butorphanol administration did not differ significantly from that after saline solution administration. However, compared with the baseline value, withdrawal threshold was significantly increased for 1 mg/kg at 0.5 and 6 hours, 3 mg/kg at 6 hours, and 6 mg/kg at 3 hours. There were no significant differences in mean sedation-agitation scores, except for males at 1.5 hours after administration of 6 mg/kg., Conclusion and Clinical Relevance: Butorphanol did not cause thermal antinociception suggestive of analgesia in American kestrels. Sex-dependent responses were identified. Further studies are needed to evaluate the analgesic effects of butorphanol in raptors.

Previous studies have validated the clinical use of opioids with kaap-receptor affinities for pain management in birds. Butorphanol, a kappa opioid receptor agonist and a mu opioid receptor antagonist, is currently considered by many clinicians to be the opioid of choice for this use. However, despite studies reporting the analgesic properties of butorphanol in psittacine birds, dosing intervals have not been established for any psittacine species. The goals of this study in the Hispaniolan Amazon parrot (Amazona ventralis) were to evaluate the pharmacokinetics of butorphanol tartrate after intravenous (IV), intramuscular (IM), and oral (PO) administration and to determine the bioavailability of butorphanol tartrate after oral administration. Twelve Hispaniolan Amazon parrots were used in the study, with a complete-crossover experimental design and a 3-month period separating each part of the study. The birds were randomly assigned to 3 groups (n = 4) for each stage. Butorphanol tartrate was administered once at a dose of 5 mg/kg in the basilic vein or pectoral muscles or as an oral solution delivered via feeding tube into the crop for the IV, IM, and PO studies, respectively. After butorphanol administration, blood samples were collected at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes for the IV and IM studies and at 5, 15, 30, 60, 90, 120, 180, 240, and 300 minutes for the PO study. Because of the size limitation of the birds, naive pooling of datum points was used to generate a mean plasma butorphanol concentration at each time point. For each study, birds in each group (n = 4) were bled 3 times after dosing. Plasma butorphanol concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were calculated. Butorphanol tartrate was found to have high bioavailability and rapid elimination following IM administration. In contrast, oral administration resulted in low bioavailability (< 10%), thus precluding the use of this route of administration for clinical purposes. Based on these results, in Hispaniolan Amazon parrots, butorphanol tartrate dosed at 5 mg/kg IV or IM would have to be administered every 2 and 3 hours, respectively, to maintain plasma concentrations consistent with published therapeutic levels. To our knowledge, this is the first published study presenting the pharmacokinetic analysis of butorphanol tartrate in a psittacine species as well as the first study presenting pharmacokinetic analysis of butorphanol after oral administration in any avian species.

Captive Asian elephants (Elephas maximus) are susceptible to lameness resulting from foot and joint pain, including chronic arthritis. In the past, opioid analgesics, such as butorphanol, have been used clinically for pain management. However, dosages used in treating elephants were often extrapolated from data in horses, with no pharmacokinetic information on the specific agents used in elephant species. In this pharmacokinetic study, six adult captive Asian elephants (5 female, 1 male castrate) were administered a 0.015 mg/kg dose of butorphanol by both i.v. and i.m. routes. A complete crossover design was used with a 3-wk washout period between treatments. Serial blood samples were collected immediately prior to butorphanol administration and at 5, 10, 20, and 40 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 24 h after administration. The butorphanol analysis was performed using a validated liquid chromatography-mass spectrophotometric assay with a limit of quantitation of 0.025 ng/ml. The mean Cmax after i.m. administration was 7.9 ng/ml, with a corresponding Tmax, of 40 min and t(1/3), of 7.1 h. After i.v. administration, the mean Vd(ss) was 1.4 L/kg and the mean Cl(p) was 0.26 L/kg/h. Mean i.m. bioavailability was 37%. The results indicate that butorphanol used at 0.015 mg/kg i.m. or i.v. could be useful in elephants when given for pain control.

Objective: To determine the pharmacokinetics of butorphanol in cats following IM and buccal transmucosal (BTM) administration, to determine the relative bioavailability of butorphanol following BTM administration, and to extrapolate a plasma concentration associated with antinociception on the basis of existing data from pharmacologic studies of butorphanol in cats., Animals: 6 healthy adult cats., Procedures: Following IM or BTM butorphanol tartrate (0.4 mg/kg) administration to cats in a 2-way crossover trial, plasma samples were obtained from blood collected via a central venous catheter during a 9-hour period. Plasma butorphanol concentrations were determined by high-performance liquid chromatography., Results: Data from 1 cat contained outliers and were excluded from pharmacokinetic analysis. Mean+/-SD terminal half-life of butorphanol for the remaining 5 cats was 6.3+/-2.8 hours and 5.2+/-1.7 hours for IM and BTM administration, respectively. Peak plasma butorphanol concentrations were 132.0 and 34.4 ng/mL for IM and BTM administration, respectively. Time to maximal plasma concentration was 0.35 and 1.1 hours for IM and BTM administration, respectively. Extent of butorphanol absorption was 37.16% following BTM application. On the basis of data from extant pharmacologic studies of butorphanol in cats, mean+/-SD duration of antinociception was 155+/-130 minutes. The estimated plasma concentration corresponding to this time point was 45 ng/mL., Conclusions and Clinical Relevance: In cats, IM butorphanol administration at 0.4 mg/kg maintained a plasma concentration of >45 ng/mL for 2.7+/-2.2 hours, whereas BTM administration at the same dose was not effective at maintaining plasma concentrations at >45 ng/mL.

Background: Despite frequent clinical use, information about the pharmacokinetics (PK), clinical effects, and safety of butorphanol in foals is not available., Objectives: The purpose of this study was to determine the PK of butorphanol in neonatal foals after IV and IM administration; to determine whether administration of butorphanol results in physiologic or behavioral changes in neonatal foals; and to describe adverse effects associated with its use in neonatal foals., Animals: Six healthy mixed breed pony foals between 3 and 12 days of age were used., Methods: In a 3-way crossover design, foals received butorphanol (IV and IM, at 0.05 mg/kg) and IV saline (control group). Butorphanol concentrations were determined by high-performance liquid chromatography and analyzed using a noncompartmental PK model. Physiologic data were obtained at specified intervals after drug administration. Pedometers were used to evaluate locomotor activity. Behavioral data were obtained using a 2-hour real-time video recording., Results: The terminal half-life of butorphanol was 2.1 hours and C0 was 33.2 +/- 12.1 ng/mL after IV injection. For IM injection, Cmax and Tmax were 20.1 +/- 3.5 ng/mL and 5.9 +/- 2.1 minutes, respectively. Bioavailability was 66.1 +/- 11.9%. There were minimal effects on vital signs. Foals that received butorphanol spent significantly more time nursing than control foals and appeared sedated., Conclusions and Clinical Importance: The disposition of butorphanol in neonatal foals differs from that in adult horses. The main behavioral effects after butorphanol administration to neonatal foals were sedation and increased feeding behavior.

Objective: To determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in red-tailed hawks (RTHs) and great horned owls (GHOs)., Animals: 6 adult RTHs and 6 adult GHOs., Procedures: Each bird received an injection of butorphanol (0.5 mg/kg) into either the right jugular vein (IVj) or the pectoral muscles in a crossover study (1-week interval between treatments). The GHOs also later received butorphanol (0.5 mg/kg) via injection into a medial metatarsal vein (IVm). During each 24-hour postinjection period, blood samples were collected from each bird; plasma butorphanol concentrations were determined via liquid chromatography-mass spectrometry., Results: 2- and 1-compartment models best fit the IV and IM pharmacokinetic data, respectively, in both species. Terminal half-lives of butorphanol were 0.94 +/- 0.30 hours (IVj) and 0.94 +/- 0.26 hours (IM) for RTHs and 1.79 +/- 1.36 hours (IVj), 1.84 +/- 1.56 hours (IM), and 1.19 +/- 0.34 hours (IVm) for GHOs. In GHOs, area under the curve (0 to infinity) for butorphanol after IVj or IM administration exceeded values in RTHs; GHO values after IM and IVm administration were less than those after IVj administration. Plasma butorphanol clearance was significantly more rapid in the RTHs. Bioavailability of butorphanol administered IM was 97.6 +/- 33.2% (RTHs) and 88.8 +/- 4.8% (GHOs)., Conclusions and Clinical Relevance: In RTHs and GHOs, butorphanol was rapidly absorbed and distributed via all routes of administration; the drug's rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs.

As yet no transdermal topical formulations have been developed for the treatment of chronic itch. We developed a formulation containing 2 mg butorphanol tartrate in 100 microl purified water encapsulated into multilamellar phospholipid vesicles. Drug permeation experiments were studied with Franz diffusion chambers using human skin in vitro and on rat skin in vivo. Histological analysis of rat skins was performed to evaluate skin irritation of the formulation in vivo. Physical properties showed stable formulation with desirable viscosity. In vitro dermal penetration rate data suggest that there was significant permeation at time-points 2 h and 4 h, and a steady state was achieved afterwards to 24 h. Maximal plasma butorphanol concentration was noted at 2 h and steady state was achieved at 8 h. Visual skin assessment as well as histological analysis of excised rat skin did not demonstrate any evidence of inflammation and irritation. In vitro and in vivo analysis demonstrated release of a consistent amount of butorphanol in a sustained manner for 24 h. This liposomal transdermal delivery formulation could serve as a method to deliver butorphanol for patients with chronic pruritus.

Objective: To compare serum concentrations of liposome-encapsulated butorphanol tartrate (LEBT) and standard butorphanol tartrate (STDBT) following SC and IM administration, respectively, and to evaluate analgesic effects of LEBT and STDBT after parenteral administration to Hispaniolan parrots., Animals: 11 adult Hispaniolan parrots., Procedure: The ability of LEBT to prolong the duration of analgesia in an avian species was tested. Blood samples were collected at serial time points after SC administration of LEBT (10 mg/kg or 15 mg/kg) or IM administration of STDBT (5 mg/kg). Serum concentrations of butorphanol tartrate were determined by use of a commercial immunoassay that measured parent drug and metabolites. Analgesic efficacy was evaluated in parrots exposed to electrical and thermal stimuli. Foot withdrawal thresholds were recorded at baseline and at serial time points after LEBT (15 mg/kg), liposome vehicle, STDBT (2 mg/kg), or physiologic saline (0.9% NaCl) solution administration., Results: LEBT had a prolonged in vivo release for up to 5 days. Negligible serum butorphanol and butorphanol metabolite concentrations were obtained at 24 hours after IM administration of STDBT. Analgesic efficacy of LEBT as measured by foot withdrawal threshold to noxious thermal and electrical stimuli persisted for 3 to 5 days following SC administration of LEBT., Conclusions and Clinical Relevance: SC administration of LEBT provided analgesia and detectable serum butorphanol concentrations in Hispaniolan parrots for up to 5 days. The use of LEBT may allow for substantial improvement in long-term pain relief without subjecting birds to the stress of handling and multiple daily injections.

The goal of this study was to assess the antinociceptive activity of a single dose of hydromorphone or butorphanol and to examine the effect of their coadministration on thermal thresholds in cats. Thermal thresholds were measured after IM administration of hydromorphone (0.1 mg/kg), butorphanol (0.4 mg/kg), a combination of butorphanol and hydromorphone (0.4 and 0.1 mg/kg), or saline to each of 6 cats in a randomized, blinded, crossover study design. There were at least 12 days between treatments. Thermal thresholds were measured by a thorax-mounted thermal threshold-testing device specifically developed for cats. Thermal thresholds were measured before treatment, at varying intervals to 12 hours, and at 24 hours after treatments. Data were analyzed by an analysis of variance with a repeat factor of time. Dysphoria was associated with butorphanol administration but not with hydromorphone or hydromorphone-butorphanol combined administration. Vomiting was seen with hydromorphone but not with butorphanol or hydromorphone-butorphanol combined. The control treatment group was stable over time (P = .22; mean threshold, 40.1 degrees C). Thresholds were significantly (P < .05) higher than the control treatment between 15 and 165 minutes for butorphanol, between 15 and 345 minutes for hydromorphone, and between 15 and 540 minutes for hydromorphone-butorphanol combined. The addition of butorphanol to hydromorphone decreased the intensity of antinociception during the 1st 2 hours but extended the duration of observable antinociception from 5.75 to 9 hours. The present study suggests that the combination of butorphanol and a pure OP3 (mu) receptor agonist clinically does not produce increased analgesia and indeed may result in decreased analgesia.

Objective: To evaluate disposition of butorphanol after i.v. and i.m. administration, effects on physiologic variables, and analgesic efficacy after i.m. administration in llamas., Design: Nonrandomized crossover study., Animals: 6 healthy adult male llamas., Procedure: Butorphanol (0.1 mg/kg [0.045 mg/lb] of body weight) was administered i.m. first and i.v. 1 month later. Blood samples were collected intermittently for 24 hours after administration. Plasma butorphanol versus time curves were subjected to pharmacokinetic analysis. Two months later, butorphanol (0.1 mg/kg) was administered i.m., and physiologic variables and analgesia were assessed., Results: Extrapolated peak plasma concentrations after i.v. and i.m. administration were 94.8 +/- 53.1 and 34.3 +/- 11.6 ng/ml, respectively. Volume of distribution at steady state after i.v. administration was 0.822 +/- 0.329 L/kg per minute and systemic clearance was 0.050 +/- 0.014 L/kg per minute. Slope of the elimination phase was significantly different, and elimination half-life was significantly shorter after i.v. (15.9 +/- 9.1 minutes) versus i.m. (66.8 +/- 13.5 minutes) administration. Bioavailability was 110 +/- 49% after i.m. administration. Heart rate decreased and rectal temperature increased. Somatic analgesia was increased for various periods. Two llamas became transiently sedated, and 2 became transiently excited after butorphanol administration., Conclusions and Clinical Relevance: Although i.v. administration of butorphanol results in a short half-life that may limit its analgesic usefulness, the elimination half-life of butorphanol administered i.m. is likely to be clinically useful. The relationship among plasma butorphanol concentration, time, and analgesia differed with the somatic analgesia model; clinically useful analgesia may occur at lower plasma concentrations than those reported here.

Objective: To determine an infusion rate of butorphanol tartrate in horses that would maintain therapeutic plasma drug concentrations while minimizing development of adverse behavioral and gastrointestinal tract effects., Animals: 10 healthy adult horses., Procedure: Plasma butorphanol concentrations were determined by use of high-performance liquid chromatography following administration of butorphanol by single IV injection (0.1 to 0.13 mg/kg of body weight) or continuous IV infusion (loading dose, 17.8 microg/kg; infusion dosage, 23.7 microg/kg/h for 24 hours). Pharmacokinetic variables were calculated, and changes in physical examination data, gastrointestinal tract transit time, and behavior were determined over time., Results: A single IV injection of butorphanol was associated with adverse behavioral and gastrointestinal tract effects including ataxia, decreased borborygmi, and decreased defecation. Elimination half-life of butorphanol was brief (44.37 minutes). Adverse gastrointestinal tract effects were less apparent during continuous 24-hour infusion of butorphanol at a dosage that resulted in a mean plasma concentration of 29 ng/ml, compared with effects after a single IV injection. No adverse behavioral effects were observed during or after continuous infusion., Conclusions and Clinical Relevance: Continuous IV infusion of butorphanol for 24 hours maintained plasma butorphanol concentrations within a range associated with analgesia. Adverse behavioral and gastrointestinal tract effects were minimized during infusion, compared with a single injection of butorphanol. Continuous infusion of butorphanol may be a useful treatment to induce analgesia in horses.

The potential for a pharmacokinetic interaction between butorphanol nasal spray and cimetidine, under steady state conditions, was evaluated in 16 healthy male volunteers. Subjects received either a 1 mg butorphanol nasal spray every 6 h or a 300 mg cimetidine tablet every 6 h on days 1 4, the combination of two compounds every 6 h on days 5-8 and the original treatment as described in the first segment (days 1-4) on days 9-12. Serial blood and urine samples were collected on days 4, 8 and 12, and additional blood samples were taken immediately, prior to the morning dose on days 3, 7 and 11. Based on the analysis of the Cmin samples, the plasma concentrations of cimetidine and butorphanol achieved steady state by the third day of dosing. No statistically significant differences were found in the plasma concentrations of butorphanol or cimetidine (except for t1/2 and MRT) between any of the treatment phases. Butorphanol nasal spray and cimetidine can be co-administered without any adjustment of dosage for either drug.

1. The pharmacokinetics of butorphanol were evaluated in 18 female volunteers with varying degrees of renal function following a single, 1 mg transnasal dose of butorphanol tartrate. The creatinine clearance (CLCR) values for subjects in the normal (NOR), moderately impaired (MI), and severely impaired (SI) groups were > or = 70 ml min-1, 30-60 ml min-1, and < or = 30 ml min-1, respectively. 2. Serial blood and urine samples were collected immediately after dosing for 48 h. Plasma concentrations of butorphanol were determined using a specific radioimmunoassay. Urine concentrations of butorphanol and its metabolites (hydroxy-butorphanol, norbutorphanol and their glucuronide conjugates) were determined using h.p.l.c. with fluorescence detection. 3. There was no significant difference between the three treatments for peak plasma concentration of butorphanol and time to peak. Statistically significant differences were detected among the study groups for AUC, t1/2, MRT, and CLR with the mean values for severely impaired subjects significantly different from those of normal renal subjects; mean values for moderately impaired subjects were not significantly different from either the normal or severely impaired groups for all respective parameters. 4. The elimination half-life of butorphanol increased from 5.75 h in NOR to 10.48 h in SI. A similar trend was observed for MRT. Creatinine clearance (CLCR) significantly correlated with CLR (r = 0.563, P = 0.019), CLT/F (r = 0.505, P = 0.033), t1/2 (r = -0.554, P = 0.017) and lambda (r = 0.606, P = 0.008). 5. Although the exposure of butorphanol was greater in subjects with renal impairment, there was no trend for an increase in the number of adverse experiences reported by subjects with renal dysfunction. 6. Patients with less than 30 ml min-1 creatinine clearance may require less frequent administration of transnasal butorphanol as compared with subjects with normal or moderately impaired renal function.

The safety, pharmacokinetics, and pharmacodynamics of the investigational partial opioid agonist, mirfentanil, were determined in a dose-escalating, Phase 1 study in healthy male volunteers. Hemodynamic, central nervous system, and respiratory monitoring were used for safety assessment. The electroencephalogram (EEG) was evaluated as a surrogate measure of drug effect. Butorphanol was chosen as the control drug. In the mirfentanil group (n = 8) the dose was increased in sequential subjects from 25 micrograms.kg-1.min-1 for 30 min to 450 micrograms.kg-1.min-1 for 15 min, and in the butorphanol group (n = 10) from 2 micrograms.kg-1.min-1 for 30 min to 25 micrograms.kg-1.min-1 for 15 min. In the mirfentanil group, serious side effects were observed at plasma concentrations more than 2000 ng/mL: heart rates exceeded 130 bpm (n = 2), epileptiform EEG potentials (n = 2), and a convulsion (n = 1). The clearance of mirfentanil was high (5.8-7.2 L/min), and the volume of distribution large (247-348 L). The EEG of the subjects receiving mirfentanil showed no changes typical for opioids. Butorphanol however, caused intermittent slowing in the delta and theta ranges. The results of our study define the upper limit of safe plasma concentrations in future mirfentanil studies.