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PubMed1998

Tolerance and cross-tolerance to the rate-suppressing effects of opioids in butorphanol-treated rats: influence of maintenance dose and relative efficacy at the mu receptor.

The purpose of the present investigation was to examine the development of tolerance to the rate-suppressing effects of mu and kappa opioids in rats administered either 3.0 (low) or 30 (high) mg/kg per day of butorphanol, an opioid with low relative efficacy at the mu receptor. The mu opioids butorphanol, buprenorphine, morphine, fentanyl and sufentanil, and the kappa opioid U50,488 dose-dependently suppressed responding under all conditions examined. In rats administered the low maintenance dose of butorphanol, tolerance developed to the effects of butorphanol, buprenorphine and morphine, but not to fentanyl and sufentanil. In rats administered the high maintenance dose, tolerance developed to all of the mu opioids examined. In both treatment groups, the degree to which tolerance developed was greater for butorphanol and buprenorphine than for morphine, fentanyl and sufentanil; and the degree to which tolerance developed to these mu opioids was greater in rats administered the high maintenance dose of butorphanol. The tolerance that developed to morphine, fentanyl and sufentanil was not altered when tested at both 23 and 47 h following the previous maintenance dose of butorphanol, suggesting that these changes were not due to any acute pharmacological interactions between butorphanol and the test compound (i.e., antagonism). Tolerance was also conferred to the kappa opioid U50,488 in both groups of rats, and in rats administered the high maintenance dose, this effect was obtained when tested 23 and 47 h following the previous maintenance dose of butorphanol. Physical dependence developed in rats administered the high maintenance dose of butorphanol, as evidenced by the development of enhanced sensitivity to the rate-suppressing effects of naloxone, and the finding that 30 mg/kg naloxone decreased body weight in a time-dependent manner. No physical dependence was apparent in rats administered the low maintenance dose of butorphanol. These data suggest that during chronic treatment with butorphanol, (1) greater degrees of tolerance are conferred to drugs possessing low efficacy at the mu opioid receptor, (2) tolerance is enhanced as the maintenance dose of the toleragen is increased, and (3) mu-opioid tolerance may be observed under conditions that do not produce mu-opioid dependence.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2003

Changes of the level of G protein alpha-subunit mRNA by tolerance to and withdrawal from butorphanol.

Butorphanol was infused continuously into cerebral ventricle at a constant rate of 26 nmol/microl/h for 3 days, and the withdrawal from opioid was rendered 7 h after the cessation of infusion. The G-protein alpha-subunit has been implicated in opioid tolerance and withdrawal. The effects of continuous infusion of butorphanol on the modulation of G protein alpha-subunit mRNA were investigated by using in situ hybridization techniques. In situ hybridization showed marked changes in the levels of Galpha s during butorphanol tolerance and withdrawal. Specifically, the level of Galpha s mRNA was significantly decreased in almost all areas of brain except hippocampus during the butorphanol withdrawal. It was also decreased in the septum and cerebellar granule layer in butorphanol tolerant rats. The level of Galpha i mRNA was significantly decreased only in the cerebral cortex of butorphanol tolerant rat. However, no such change was noted during the withdrawal from butorphanol. The level of Galpha o mRNA was not changed either in butorphanol tolerant or in the butorphanol withdrawal rats. No alterations were noted in the level of [3H]forskolin binding to adenylyl cyclase in butorphanol tolerant as well as withdrawing rats. The levels of pCREB were significantly elevated in the hippocampus in the butorphanol withdrawal rats. These results suggest that region-specific changes of G protein alpha-subunit mRNA and pCREB without marked changes in the level of adenylyl cyclase may underlie the tolerance to and withdrawal from butorphanol.

Animals↗

PubMed1996

Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists.

The discriminative stimulus effects of butorphanol were examined in separate groups of pigeons trained to discriminate either a low (0.1 mg/kg), medium (1.0 mg/kg) or high (5.6 mg/kg) dose of butorphanol from saline. The mu-selective opioid antagonist naloxone was considerably more potent than the delta-selective opioid antagonist naltrindole in antagonizing the effects of butorphanol. In each of the training dose groups, the mu opioid agonists morphine, l-methadone and fentanyl, as well as buprenorphine, (-)-pentazocine, nalbuphine, (-)-metazocine and nalorphine, substituted completely for the butorphanol stimulus. The rank order of potency for these compounds in substituting for the butorphanol stimulus was similar across training dose groups and similar to those reported in studies in which fentanyl or morphine were used as training stimuli. (-)-N-allylnormetazocine (NANM) and levallorphan substituted completely for the butorphanol stimulus in the low-dose group, and substituted partially for and antagonized partially the butorphanol stimulus in the medium- and high-dose groups. The kappa opioid agonists spiradoline, bremazocine, U50,488 and U69,593 substituted partially for butorphanol in the low-dose group, an effect that was not reversed by naloxone. In the medium- and high-dose groups, these kappa opioid agonists produced predominantly saline-appropriate responding. The delta opioid agonist BW373U86 substituted completely for butorphanol in the low-dose group, and naltrindole was more potent than naloxone in antagonizing these effects. In the medium- and high-dose groups, BW373U86 substituted partially for the butorphanol stimulus. Unlike the substitution patterns produced by the mu, kappa and delta opioid agonists, the sigma/phencyclidine compounds (+)-cyclazocine and (+)-NANM and the barbiturate pentobarbital produced predominantly saline-appropriate responding in all training dose groups. The present findings suggest that opioids with agonist activity at mu, kappa and delta opioid receptors share similar stimulus effects with a low training dose of butorphanol, whereas only opioids with agonist activity at the mu opioid receptor share stimulus effects with a medium and high training dose of butorphanol.

Analgesics, Opioid↗

PubMed2004

Proteomic analysis of phosphotyrosyl proteins in the rat brain: effect of butorphanol dependence.

Butorphanol (17-cyclobutylmethyl-3,14-dihydroxymorphinan) tartrate (Stadol) is a mixed agonist-antagonist opioid analgesic agent that is about five to seven times as potent as morphine in analgesic effects. The chronic use of butorphanol produces physical dependence in humans and animals. Phosphorylation plays a very important role in developing butorphanol dependence; however, global phosphorylation events induced by chronic butorphanol administration have not been reported. The aim of this study is to determine the alteration of tyrosine phosphorylation of brain frontal cortical proteins in butorphanol-dependent rats using a proteomic approach. Dependence was produced by continuous intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/microl/hr) for 72 hr via osmotic minipump in rats. Similar patterns of protein expression were detected by two-dimensional electrophoresis (2-DE) in brain frontal cortex of butorphanol-dependent and saline-treated control rats. All 65 phosphotyrosyl (p-Tyr) protein spots detected in pH 3-10 phosphotyrosine 2-DE of control rat brains were detected in butorphanol-dependent rat brains. The densities of most p-Tyr protein spots were increased in butorphanol-dependent rat brains compared to saline-treated control samples. Eighteen additional p-Tyr protein spots were detected in pH 3-10 2-DE images of butorphanol-dependent rat brains. Immobilized pH strips with three different narrow pH ranges were examined to improve the resolution of p-Tyr proteins in 2-DE gels. Fifty-three p-Tyr protein spots were identified as known proteins involved in cell cytoskeleton, cell metabolism, and cell signaling. This proteomic approach can provide useful information for understanding the complex mechanism of butorphanol dependence in vivo.

Animals↗

PubMed1989

A comparison of recovery in outpatients receiving fentanyl versus those receiving butorphanol.

The frequency of postanesthesia side effects and times to reach "benchmarks" in the recovery process for IV preinduction doses of 20 micrograms/kg butorphanol, 40 micrograms/kg butorphanol, or a 2 micrograms/kg dose of fentanyl were compared in a double-blinded study involving ambulatory surgical patients. The authors hypothesized that all drugs would perform equally well in all study areas. Sixty ASA physical status I and II women undergoing laparoscopic tubal sterilization were randomly assigned to one of three groups: Group I (n = 20) received 20 micrograms/kg butorphanol as a preinduction agent; Group II (n = 20) received 40 micrograms/kg butorphanol; Group III (n = 20) received 2 micrograms/kg fentanyl. Anesthesia management for all groups was the same. Statistically significant variance was found in time to discharge-ready status and duration of nausea (p less than 0.05) between 40 micrograms/kg butorphanol and 2 micrograms/kg fentanyl, but no significant difference was found between 20 micrograms/kg butorphanol and 2 micrograms/kg fentanyl in these areas. Statistically significant variance was found in duration of dizziness and time to obtain a 10 on the Aldrete Post Anesthesia Recovery Score (APARS) between 40 micrograms/kg butorphanol and 20 micrograms/kg butorphanol and 40 micrograms/kg butorphanol and 2 micrograms/kg fentanyl. From the study, 20 micrograms/kg butorphanol appears to be as suitable as 2 micrograms/kg fentanyl for use as a preinduction narcotic analgesic, whereas 40 micrograms/kg butorphanol appears to be unsuitable due to increased duration of nausea, dizziness, and time to score 10 on APARS and reach discharge-ready status.

Adult↗

PubMedDate not supplied

Antinociceptive effects of oxymorphone-butorphanol-acepromazine combination in cats.

OBJECTIVE: To determine the antinociceptive effects of oxymorphone, butorphanol, and acepromazine individually and in combination to a noxious visceral stimulus in cats. STUDY DESIGN: Randomized, blinded controlled study. ANIMALS: Eight healthy mixed-breed cats (four male, four female) weighing 4.4 +/- 1.2 kg and aged 1 to 2 years old. METHODS: A silastic balloon catheter was inserted per rectum and inflated at various pressures. Physiological parameters (respiratory rate, pulse rate, and blood pressure) were also recorded. Subjects were administered individual and combined intravenous (i.v.) doses of 0.025, 0.05, 0.10, and 0.20 mg/kg oxymorphone and 0.025, 0.05, 0.10, and 0.20 mg/kg butorphanol. A further study of various ratios of butorphanol and oxymorphone (3:1, 2:1, 1:1, 1:2, and 1:3), at a combined equivalent dose of 0.1 mg/kg, was performed in four cats per dose combination. In a separate study, four cats were administered combined i.v. doses of 0.05 mg/kg each of oxymorphone and butorphanol or 0.05 mg/kg each of oxymorphone, butorphanol, and acepromazine. RESULTS: Combined doses of 0.05 and 0.10 mg/kg of oxymorphone and butorphanol showed mainly additive with some synergistic antinociceptive interactions and the combined dose of 0.2 mg/kg of each agent demonstrated additional antinociceptive effects, P < .05. Additional studies showed that various ratios of the two agents at a total combined dose of 0.10 mg/kg i.v. did not produce levels of antinociception that were significantly different from each other, P > .05. Acepromazine (ACE) significantly increased the magnitude of antinociception at 15 minutes when administered in combination with oxymorphone and butorphanol, P < .05. Also, physiological variables were unaffected by these drug combinations. CONCLUSIONS: Low doses of oxymorphone and butorphanol in combination can produce greater levels of antinociception than when used individually. ACE, in conjunction with oxymorphone and butorphanol, produced even greater levels of antinociception than the two-opioid drug combination. CLINICAL RELEVANCE: Oxymorphone, butorphanol, and ACE can be used in combination to produce additive or synergistic effects without adverse effects in cats. These data suggest that ACE and butorphanol at low doses given as preanesthetic medication followed by a mu opioid (eg, oxymorphone) after surgery at low doses may provide an effective method of pain management in the cat.

Acepromazine↗

PubMedDate not supplied

Antinociceptive effects of hydromorphone, butorphanol, or the combination in cats.

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.

Analgesics↗

PubMed1995

Butorphanol: characterization of agonist and antagonist effects in rhesus monkeys.

The effects of butorphanol were studied in assays of antinociception, respiratory depression, sedation, diuresis and reinforcing effects in rhesus monkeys, and opioid binding in monkey brain. Butorphanol (0.003-0.1 mg/kg s.c.) was effective in the warm-water tail withdrawal assay in 50 degrees C water but not in 55 degrees C. Over a similar dose range, butorphanol caused substantial respiratory depression, without an obvious plateau. Constrained quadazocine apparent pA2 analysis on the respiratory depressant and antinociceptive effects of butorphanol yielded different values between the two assays (respiratory depression pA2 = 6.61; antinociception pA2 = 8.26). Butorphanol (0.1 mg/kg) antagonized the antinociceptive effects of etonitazene in 55 degrees C water, but caused a nonparallel leftward shift in the U50,488 dose-effect curve; both effects were probably due to butorphanol's intermediate efficacy at mu receptors. Butorphanol (0.0001-0.003 mg/kg per injection i.v.) was self-administered; unlike other mu opioid agonists, its maximum effect was depressed after pretreatment with quadazocine (0.01-1.0 mg/kg). Butorphanol (0.003-0.32 mg/kg) was devoid of substantial sedative or muscle relaxant effects, as measured by observational rating scales. Butorphanol (0.01-0.1 mg/kg s.c.), unlike U50,488 (0.01-0.32 mg/kg) did not cause diuresis. Kappa agonist or antagonist effects of butorphanol were not detected in the present studies. This profile is consistent with butorphanol's binding characteristics in rhesus monkey brain which indicated 12-fold mu:kappa selectively and 34-fold mu:delta selectivity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1995

Lack of pharmacokinetic interaction between butorphanol tartrate nasal spray and sumatriptan succinate.

The pharmacokinetics of butorphanol tartrate given in a nasal spray with and without the co-administration of sumatriptan succinate were studied in 24 healthy men and women. In this crossover design study, all subjects received 2 treatments: a single 1-mg dose of butorphanol nasal spray and a 1-mg dose of butorphanol nasal spray plus a single 6-mg subcutaneous (SC) dose of sumatriptan. There was a two-week washout period between sessions. Serial blood samples were collected and plasma samples analyzed using validated radioimmunoassay and high-performance liquid chromatography/electrochemical procedures to determine the concentrations of unchanged butorphanol and sumatriptan, respectively. There were no statistically significant differences for butorphanol between the 2 treatments on any of the following pharmacokinetic parameters: Cmax, tmax, AUC, t1/2, CL/f, and Vz/f. Similarly, the pharmacokinetic parameters obtained for sumatriptan (given with butorphanol nasal spray) were comparable with the literature values obtained for a single 6-mg SC dose of sumatriptan. These data show a lack of pharmacokinetic interaction between butorphanol nasal spray and sumatriptan. Butorphanol nasal spray and sumatriptan were well tolerated. The adverse experience profiles of butorphanol nasal spray were comparable between the treatments, with and without sumatriptan. It can be concluded that regimens of butorphanol nasal spray and sumatriptan need not be changed for either pharmacokinetic or safety considerations when the two compounds are co-administered in treating acute migraine attacks.

Administration, Intranasal↗

PubMed1998

Visceral analgesic tolerance to intrathecal butorphanol in rats.

PURPOSE: Recent experimental data suggest that intrathecal (it) kappa-opioid agonists produce profound visceral analgesia. This study investigated the development of visceral analgesic tolerance to it butorphanol, a potent kappa-agonist that has fewer side effects than commonly used it opioids. Understanding of this tolerance could make it butorphanol more effective in treating chronic visceral pain. METHODS: This was a randomized, controlled animal study involving 80 Sprague-Dawley rats. Rats implanted with lumbar it catheters were infused either with it saline or butorphanol (52 nmol.hr-1) for 96 hr. Six hours afterwards, each rat was challenged once with one of the differing it butorphanol doses to construct dose-response curves. Visceral analgesia was evaluated by the abdominal writhing responses to the acetic acid injected intraperitoneally. The time of the first writhe and the total number of writhes were recorded. RESULTS: For both the saline- and butorphanol-infused groups, a higher challenge dose of it butorphanol produced longer time for the first writhe to occur (P < 0.01, one-way ANOVA), and fewer writhes occurring within 30 min (P < 0.01, one-way ANOVA). However, the dose response curves of the butorphanol-infused groups were shifted rightward (P < 0.001, partial F test). CONCLUSION: The challenge doses of it butorphanol produced dose-dependent visceral analgesia in both the saline- and butorphanol-infused groups, confirming its efficacy. The butorphanol-infused groups showed dose-response shifts, demonstrating the development of tolerance to this visceral analgesia.

Acetic Acid↗

PubMed1994

Tolerance development to butorphanol: comparison with morphine.

In order to evaluate and to compare the time course, dose response, and the degree of tolerance development to butorphanol and morphine, rats were continuously intracerebroventricularly (ICV) infused with saline vehicle (1 microliter/h), butorphanol (6.5, 13, 26, and 52 nmol/microliters/h), or morphine (1.6, 6.5, and 26 nmol/microliters/h) through osmotic minipumps for 1 to 3 days. The tail-flick responses were determined pre-, during, and postinfusion. Tolerance to morphine developed faster than that to butorphanol. The antinociceptive response to the ICV challenge dose (6 h after the termination of drug infusion) of butorphanol or morphine was decreased significantly and there was a negative correlation between the dose of the drug infused and the observed antinociceptive response. In terms of butorphanol and morphine tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. In tail-flick tests, the shifts of the dose-response curves for butorphanol and morphine in tolerant animals were 11.8- and 46.3-fold, respectively. However, in the acetic acid writhing test, the shifts of the dose-response curves for butorphanol and morphine in tolerant animals were 11.3- and 11.7-fold, respectively. These results suggest that there is a greater degree of tolerance to morphine than there is to butorphanol, but the degree of butorphanol tolerance is still substantial. In addition, two pain assays (tail flick vs. writhing) yielded different estimations of tolerance in a comparison of morphine and butorphanol.

Animals↗

PubMed1994

Psychopharmacology and abuse potential of transnasal butorphanol.

The effects of butorphanol administered by a nasal spray (transnasal, TN) and by intramuscular (IM) injection were compared to determine the onset of action, relative potency, profile of effects, and relative abuse liability of TN butorphanol. TN/IM placebo and TN and IM butorphanol (1, 2, and 4 mg) were tested in seven male opioid abusers not currently physically dependent on opioids using a double-blind, double-dummy, Latin square design. Measures of subjective, behavioral and physiological response were assessed. The onset and duration of action of butorphanol administered by the IM and TN routes were similar at low doses, but onset of TN butorphanol 4 mg was slower than that of 4 mg IM. IM butorphanol produced miosis, some opiate-like behavioral and subjective effects, and increasing dysphoric sedation and perceptual effects with increasing dose. TN and IM butorphanol 1 and 2 mg produced effects that were qualitatively and quantitatively similar; however, TN butorphanol 4 mg was less potent than 4 mg IM. Pharmacodynamic evidence suggests that the abuse potential of TN butorphanol is not different from that of IM butorphanol.

Administration, Intranasal↗

PubMed1996

The absolute bioavailability and pharmacokinetics of butorphanol nasal spray in patients with hepatic impairment.

OBJECTIVE: The objective of the study was to investigate the effects of hepatic impairment on the absolute transnasal bioavailability and pharmacokinetics of butorphanol. STUDY DESIGN: Twelve (eight men and four women) healthy subjects and 12 (eight men and four women) patients with hepatic impairment received a 1 mg dose of butorphanol by intravenous or transnasal administration on two separate occasions. Hepatic function was assessed by antipyrine and indocyanine green clearance tests. Serial blood and urine samples were collected after each dose. Plasma samples were analyzed for butorphanol, and urine samples were analyzed for butorphanol and its metabolites. RESULTS: No statistical difference in maximum plasma concentration (Cmax) for butorphanol was observed between the two groups of volunteers after transnasal administration. However, total plasma clearance (CL), steady-state volume of distribution, area under the concentration-time curve [AUC(0-infinity)], and elimination half-life of butorphanol in patients with hepatic impairment were significantly altered (approximately twofold to threefold). The absolute transnasal bioavailability of butorphanol was significantly higher (approximately 20%) in patients with hepatic impairment. A greater fraction of the administered dose was recovered from the urine in hepatically impaired patients compared to that in healthy subjects (23% to 31% versus 10% to 11%). There was a significant reduction in CL of indocyanine green and antipyrine in hepatically impaired patients. The percentage of reduction in butorphanol CL was highly correlated to the estimated degree of portosystemic shunts in the patients with hepatic impairment. CONCLUSION: Based on the comparable Cmax but the increased AUC in patients with liver dysfunction, the initial dose of butorphanol nasal spray may not need to be adjusted. However, the subsequent dosing intervals for butorphanol should be prolonged.

Administration, Intranasal↗

PubMed1985

Effects of butorphanol and its metabolites on the levels of monoamines and their metabolites in the rat brain.

The effects of butorphanol and its main metabolites, norbutorphanol and hydroxybutorphanol, on the contents of monoamines and their metabolites in various regions of the rat brain were compared with those of morphine and pentazocine using the HPLC-ECD method. The administrations of morphine and pentazocine increased dopamine turnover in the striatum and hypothalamus in a drug dose-dependent manner. The stimulative effects of butorphanol on the dopamine system were weaker than those of morphine and pentazocine, and there were no dose-dependencies in these effects of butorphanol. Butorphanol, morphine and pentazocine increased 5-HT turnover, but there was no drug dose-dependent effect in the case of butorphanol. These differences for the effects of butorphanol from those of morphine and pentazocine seemed to result from the antagonist-agonist property of butorphanol and from a different manner of interaction with the opioid receptor. The effects of butorphanol on the levels of the norepinephrine system were weak. It was considered that the effects of butorphanol on monoamine turnover were produced by the action of butorphanol itself, because norbutorphanol and hydroxybutorphanol showed little change on the level of monoamines and their metabolites.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Transnasal butorphanol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute pain management.

Butorphanol is a synthetic opioid agonist-antagonist analgesic with a pharmacological and therapeutic profile that has been well established since its launch as a parenteral formulation in 1978. The introduction of a transnasal formulation of butorphanol represents a new and noninvasive presentation of an analgesic for moderate to severe pain. This route of administration bypasses the gastrointestinal tract, and this is an advantage for a drug such as butorphanol that undergoes significant first-pass metabolism after oral administration. The onset of action and systemic bioavailability of butorphanol following transnasal delivery are similar to those after parenteral administration. The analgesic efficacy of transnasal butorphanol was generally superior to that of placebo in clinical trials in patients with moderate to severe postoperative pain or migraine headache. Results from single trials indicate that transnasal butorphanol provides pain relief comparable to that of intramuscular pethidine (meperidine) in postsurgical pain and comparable to or greater than intramuscular methadone in migraine headache. Moderate to severe musculoskeletal pain also appears to be responsive to transnasal butorphanol on the basis of results from 1 small noncomparative study. Tolerability of transnasal butorphanol parallels that of the injectable form, with somnolence, dizziness, nausea and/or vomiting reported most frequently. Thus, transnasal butorphanol is a novel formulation of an established analgesic which appears suitable for the short term treatment of moderate to severe pain, especially in an ambulatory setting. Transnasal butorphanol is likely to provide an alternative to oral opioid analgesics, particularly in the presence of nausea or vomiting, or to parenteral opioids when the oral route of administration is not appropriate.

Administration, Intranasal↗

PubMed2001

Pharmacokinetics and adverse effects of butorphanol administered by single intravenous injection or continuous intravenous infusion in horses.

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.

Analgesics, Opioid↗

PubMed1977

Comparison of analgesia by intravenous butorphanol and meperidine in patients with post-operative pain.

Intravenous doses of butorphanol tartrate (0.5 mg, 1.0 mg and 2.0 mg) and meperidine hydrochloride (20 mg and 40 mg) were compared under controlled conditions employing a double blind study design. Informed consent was obtained from all post-operative patients suffering from moderate to severe pain who participated in this study. Approximately 25 patients were included in each group. The data from 125 patients were subjected to statistical analysis. The results indicated that butorphanol is approximately 40 to 50 times more potent than meperidine. In addition, at most of the time intervals, there were no statistically significant differences between the responses to butorphanol 0.5 mg and 1 mg and meperidine 20 mg and 40 mg; but the response to butorphanol 2 mg was significantly (p less than 0.05) better than the low dose of each agent. The low doses of butorphanol (0.5 mg) and meperidine (20 mg) appear to have an effective duration of action of less than two hours. The larger doses (butorphanol 1.0 mg and 2.0 mg and meperidine 40 mg) appeared to produce a two- to four-hour duration of action. The largest butorphanol dose (2.0 mg) appeared to produce the longest duration of action. A comparison of the test groups with respect to the incidence and type of side effects showed that butorphanol 2.0 mg produced a greater incidence of drowsiness (39 per cent). The overall incidence of drowsiness for patients receiving either the 0.5 mg or 1.0 mg dose of butorphanol was 12 per cent, as compared with an 8 per cent overall incidence in the meperidine group. The incidence of other side effects was relatively low in all test groups. No significant differences were noted among the groups with regard to the onset (usually less than or equal to 30 minutes post-therapy) or the duration (usually less than or equal to 2 hours) of side effects. Butorphanol appears to be a safe and effective analgesic for the relief of moderate to severe post-operative pain.

Adult↗

PubMed1997

The pharmacokinetics of butorphanol and its metabolites at steady state following nasal administration in humans.

The single-dose and steady state pharmacokinetics of butorphanol and its metabolites, hydroxybutorphanol (HO-B) and norbutorphanol (NOR-B), were studied in nine healthy male volunteers. Each subject received a single 1 mg dose of butorphanol on days 1 and 6, and a 1 mg dose every 6 h (q6h) on days 2-5, via nasal administration. Serial blood and urine samples were collected for 24 h after the first dose on day 1 and for 72 h at steady state on day 6. Plasma and urine samples were analyzed for free and conjugated butorphanol, HO-B, and NOR-B. The plasma samples were analyzed using validated gas chromatography-electron capture negative chemical ionization-mass spectrometric methods and the urine samples were analyzed using a validated HPLC procedure. In the plasma, conjugated metabolites were not detected and only trace amounts of NOR-B were present. Therefore, pharmacokinetic parameters could not be estimated for NOR-B and conjugated metabolites. AUC0-->infinity of butorphanol after the first dose and AUC0-->tau at steady state were not statistically different, indicating that the kinetics of butorphanol were not significantly altered after repeated dosing. Steady state levels of butorphanol were attained within 3 days (d) of q6h dosing and the accumulation index was 1.2 for butorphanol. Due to a relatively long t1/2 of 15 h of HO-B compared to the dosing interval (q6h), the accumulation index was 6.0 for this metabolite. The evaluation of the molar plasma concentration ratio of HO-B to butorphanol as a function of time revealed that HO-B exhibits elimination-rate-limited kinetics. Similarly to butorphanol, steady state levels of HO-B were attained within 3 d of q6h dosing.

Administration, Intranasal↗