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PubMed2005

Effect of postoperative analgesic protocol on limb function following onychectomy in cats.

OBJECTIVE: To evaluate the analgesic effects of topical administration of bupivacaine, i.m. administration of butorphanol, and transdermal administration of fentanyl in cats undergoing onychectomy. DESIGN: Prospective study. ANIMALS: 27 healthy adult cats. PROCEDURE: Cats were randomly assigned to 1 of 3 treatment groups, and unilateral (left forefoot) onychectomy was performed. Gait analysis was performed before and 1, 2, 3, and 12 days after surgery. All forces were expressed as a percentage of the cat's body weight. RESULTS: On day 2, peak vertical force (PVF) was significantly decreased in cats treated with bupivacaine, compared with cats treated with butorphanol or fentanyl. The ratio of left forelimb PVF to PVF of the other 3 limbs was significantly lower on day 2 in cats treated with bupivacaine than in cats treated with fentanyl. No significant differences in vertical impulse (VI) were found between groups on any day. Values for PVF, VI, and the PVF ratio increased progressively following surgery. However, for all 3 groups, values were still significantly decreased, compared with baseline values, 12 days after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that limb function following onychectomy is significantly better in cats treated with fentanyl transdermally or butorphanol i.m. than in cats treated with bupivacaine topically. Regardless of the analgesic regimen, limb function was still significantly reduced 12 days after surgery, suggesting that long-term analgesic treatment should be considered for cats undergoing onychectomy. Irrigation of the surgical incisions with bupivacaine prior to wound closure cannot be recommended as the sole method for providing postoperative analgesia in cats undergoing onychectomy.

Administration, Topical↗
PubMed1999

Field immobilization and euthanasia of American opossum.

Seventeen recently trapped opossum, Didelphis virginiana, (median weight 2.45 kg; range = 1.6-5.0 kg; quartiles = 1.8-3.3 kg) were immobilized with either telazol (15 or 30 mg/kg) or a mixture of medetomidine (100 micrograms/kg), butorphanol (0.2 mg/kg), and ketamine HCl (10 mg/kg) based on estimated weights. Anesthetized animals were subjected to cardiac puncture for blood withdrawal and toe pinch. Euthanasia was accomplished by intracardiac administration of 1 ml of concentrated pentobarbital sodium/phenytoin solution. Weights were underestimated for 14 of 17 animals, but were within 0.5 kg of the actual weight. Both drug combinations provided rapid and calm immobilization. Median time to recumbency for the medetomidine-butorphanol-ketamine group (n = 5) was 6 min (range = 4-10 min; quartiles = 6 and 8 min). The median time to recumbency was not statistically different for the low (n = 6) and high dose (n = 6) telazol groups, 3 and 3.5 min respectively (quartiles 3; 3.5 and 4; 5.5 min). The stronger heart beat with telazol immobilization facilitated cardiac puncture. All five animals administered the medetomidine-butorphanol-ketamine mixture and three of six animals given the low telazol dose reacted to cardiac puncture. Only one of six animals given the estimated 30 mg/kg dose of telazol reacted slightly to cardiac puncture. We conclude that 30 mg/kg telazol provides sufficient immobilization and analgesia to allow accurate cardiac puncture of the opossum if the procedure is performed within 5 to 10 min of recumbency. Intracardiac administration of concentrated pentobarbital sodium/phenytoin solution followed by bilateral thoracotomy provides appropriate euthanasia suitable for field situations.

Analgesics↗
PubMed1999

Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure.

The discriminative stimulus and subjective effects of opioid mixed agonist-antagonists were assessed in volunteer nondependent heroin users trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. administration of 2 ml of saline, 1 mg of hydromorphone, and 4 mg of hydromorphone (a morphine-like mu agonist). Other subjective, behavioral, and physiological measures were concurrently collected. The discrimination was readily learned by six of the eight subjects. After training, generalization curves were determined for the following i.m. drug conditions: hydromorphone (0.375-4.0 mg), pentazocine (7.5-60 mg), butorphanol (0.75-6 mg), nalbuphine (3-24 mg), and buprenorphine (0.075-0.6 mg). All five of the test drugs were discriminated significantly or showed trends toward being discriminated as hydromorphone 1 mg-like at one or more dose levels. Hydromorphone showed an inverted U-shaped dose-effect function on the hydromorphone 1 mg-like discrimination. Subjective effect measures produced clearer differentiation among the test drugs than did drug discrimination performance. The present results differ from those of a previous study that observed a close relationship between the results of the discrimination measure and subjective effect measures. The previous study used similar methods and test drugs but different training drugs (e.g., 3 mg of hydromorphone versus 6 mg of butorphanol versus saline). It appears that both the sensitivity of drug discrimination performance to between-drug differences and the relationship between discriminative and subjective effects depends upon the specific discrimination that is trained (e.g., two-choice or three-choice). The present high dose-low dose-saline discrimination procedure appears useful for assessing partial agonist activity. The present data are consistent with partial agonist activity for pentazocine, butorphanol, nalbuphine, and buprenorphine.

Adult↗
PubMed1992

Cardiopulmonary and behavioral effects of combinations of acepromazine/butorphanol and acepromazine/oxymorphone in dogs.

Cardiopulmonary and behavioral effects of the following tranquilizer-opioid drug combinations were compared in conscious dogs: acepromazine (0.22 mg/kg of body weight, IV) and butorphanol (0.22 mg/kg, IV); acepromazine (0.22 mg/kg, IM) and butorphanol (0.22 mg/kg, IM); and acepromazine (0.22 mg/kg, IV) and oxymorphone (0.22 mg/kg, IV). Marked sedation and lateral recumbency that required minimal or no restraint was achieved with every drug combination. Analgesia was significantly better in dogs receiving oxymorphone than in dogs receiving butorphanol, as evaluated by response to toe pinch. There were no significant differences between the effects of the 3 drug combinations on heart rate, respiratory rate, arterial blood pressure, body temperature, and arterial pH, PCO2, PO2, and bicarbonate concentration. Heart rate, respiratory rate, and systolic arterial pressure decreased significantly over time with all drug combinations. Total recovery time (minutes from the initial injection to standing) was significantly longer in the dogs given acepromazine and oxymorphone.

Acepromazine↗
PubMed1989

Drug discrimination in human postaddicts: agonist-antagonist opioids.

To assess the stimulus properties of opioid mixed agonist-antagonist drugs in humans, postaddict volunteers were trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. given saline (4 ml), hydromorphone (3 mg/70 kg) and pentazocine (45 mg/70 kg). Subjects earned monetary reinforcement by correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were also collected. After training, subjects were tested for their ability to discriminate between the three drugs; generalization curves for the training drugs and three mixed agonist-antagonist test drugs (butorphanol, nalbuphine and buprenorphine) were then determined. In generalization testing both hydromorphone and pentazocine produced dose-related increases in drug-appropriate responses and in characteristic subjective effects measures. Butorphanol produced dose-related increases in identifications as pentazocine and in those subjective effect measures increased by pentazocine. Nalbuphine was not consistently identified as either pentazocine or hydromorphone and produced relatively flat dose-response functions on most of the subjective effect measures. At the three highest doses tested buprenorphine was identified in 50% of trials as hydromorphone and in 50% of trials as pentazocine in the discrimination measures and increased subjective effect scales which were characteristic of both hydromorphone and pentazocine. The results are most consistent with butorphanol having the stimulus properties of a kappa agonist and both nalbuphine and buprenorphine having the stimulus properties of partial mu agonists although the profiles of observed drug effects were complicated and not entirely consistent with a simple mu/kappa opioid receptor model.

Adult↗
PubMed1987

Comparative analgesia of xylazine, xylazine/morphine, xylazine/butorphanol, and xylazine/nalbuphine in the horse, using dental dolorimetry.

Xylazine, morphine, butorphanol, and nalbuphine were evaluated in 5 adult male horses, using dental dolorimetry. Comparisons were made at 30, 60, and 100 minutes after IV drug administration. Peak analgesia and the time to develop peak analgesia also were compared. Xylazine induced a marked increase in the tooth pulp pain threshold measurements as did the xylazine/narcotic combinations. Statistical differences were not detectable between these treatments. Xylazine and xylazine/butorphanol were better analgesics than was butorphanol alone at 30 and 60 minutes. Xylazine resulted in peak analgesia faster than did butorphanol or the combination of xylazine/butorphanol. Additive analgesic effects were not detected with the combined treatments.

Analgesics↗
PubMed1979

Butorphanol/acetaminophen double-blind study in postoperative pain.

An oral butorphanol/acetaminophen (4 mg/650 mg) combination product was evaluated for analgesic activity in 120 postoperative patients employing a double-blind experimental design. The combination product was significantly (p less than 0.05) superior to either butorphanol (4 mg) or acetaminophen (650 mg) as well as placebo. Except for acetaminophen which was only significantly different (p less than 0.05) from placebo at 2 hours according to pain relief, all other treatments were superior to placebo over the entire 4 hour observation period. The data demonstrate that butorphanol and acetaminophen have at least additive analgesic activity with a suggestion of synergism. A single tablet dose of the combination product (butorphanol 2 mg/acetaminophen 325 mg) was evaluated in a second study involving 60 patients and was significantly (p less than 0.05) superior to placebo. Both studies demonstrate that the butorphanol/acetaminophen combination product has potent analgesic activity with a minimal side effect profile.

Acetaminophen↗
PubMedDate not supplied

Opiate mixed agonist-antagonist interactions with histamine antagonists vs. morphine.

Anecdotal reports of polydrug abuse in humans using tripelennamine and pentazocine prompted our investigation of drug interactions between tripelennamine, morphine and various synthetic mixed agonist-antagonists in mice. Pentazocine, nalbuphene and butorphanol, at doses of 4.0-8.0 mg/kg, all showed frank or borderline intrinsic antinociceptive activity and potentiated the tripelennamine response, whereas cyclazocine, an experimental compound with very strong mixed agonist-antagonist qualities at 5.0 mg/kg, showed intrinsic antinociceptive activity but was not potentiated by tripelennamine and actually blocked the tripelennamine response. In a comparative study, pentazocine, butorphanol and nalbuphene had no effect on morphine antinociception whereas cyclazocine completely abolished the antinociceptive effects of morphine. Cimetidine blocked the response of cyclazocine, but not nalbuphene, pentazocine or butorphanol. Our findings demonstrate that the mechanism of action of cyclazocine is significantly different from that of the other mixed agonist-antagonists studied. They also suggest possible histaminergic involvement in antinociception, as well as a locus for antinociception separate from the opiate receptor.

Analgesics↗
PubMed1996

Discriminative stimulus effects on enadoline in pigeons.

The discriminative stimulus effects of enadoline were characterized in pigeons responding under a fixed-ratio 20 schedule of food presentation and discriminating between intramuscular injections of the kappa opioid agonist enadoline and saline. Cumulative doses of enadoline dose-dependently increased drug-key responding with the training dose of enadoline (0.178 mg/kg) producing > or = 90% drug key responding (% DR). In time course studies, doses of enadoline larger than 0.32 mg/kg produced > or = 90% DR for more than 40 min. Naltrexone antagonized both the discriminative stimulus and the rate-decreasing effects of enadoline (pA2 = 6.79 and 6.73, respectively); in some pigeons, naltrexone produced an unsurmountable antagonism of the enadoline discriminative stimulus. Substitution tests using the kappa agonists U-50,488, spiradoline, U-69,593 and ethylketocyclazocine resulted in > or = 90% DR in most, but not all, pigeons; at larger doses, all compounds markedly decreased response rates. Up to rate-decreasing doses, nalorphine, dynorphin A(1-13) amide (DYN), nalbuphine, butorphanol, morphine and ketamine failed to occasion > or = 90% DR; nalbuphine, nalorphine, butorphanol, but not DYN, antagonized the discriminative stimulus and the rate-decreasing effects of enadoline. This study established stimulus control with enadoline in pigeons and results from substitution studies in these pigeons support the view that the enadoline discriminative stimulus is mediated by kappa opioid receptors; these results further demonstrate that nalbuphine and butorphanol have kappa antagonist actions in pigeons. The negative results obtained with DYN are in contrast to previous demonstrations of kappa agonist effects for DYN and might provide support for the hypothesized importance of nonopioid systems in the effects of this peptide.

Animals↗
PubMed1996

Indicators of postoperative pain in cats and correlation with clinical criteria.

OBJECTIVE: To identify clinical indicators that may help identity postoperative pain in cats after ovariohysterectomy. ANIMALS: Healthy, laboratory animal source cats. PROCEDURE: Clinical indicators of pain were identified, and relief from pain in response to butorphanol was studied in 5 groups of cats. 10 cats had 1 hour of general anesthesia only, followed by recovery without additional medication. 10 cats had general anesthesia and ovariohysterectomy, followed by recovery without additional medication. 10 cats had general anesthesia, ovariohysterectomy, and postoperative administration of 0.1 mg of butorphanol/kg of body weight. Another 10 cats had general anesthesia, ovariohysterectomy, and postoperative administration of 0.3 mg butorphanol/kg. 10 cats received 0.1 mg of butorphanol/kg, IM, only. Samples and recorded data were obtained before, during, and after the anesthesia period. Clinical variables measured included heart rate, blood pressure, respiratory rate, rectal temperature, PCV, and blood glucose concentration. Results were compared with changes in norepinephrine, epinephrine, and cortisol concentrations. RESULTS: Cats that did not receive analgesics had higher cortisol concentration than did cats without surgery and cats that received butorphanol after surgery. Systolic blood pressure measured by ultrasonic Doppler was found to be predictive of cortisol concentration, using a multiple linear regression model. CONCLUSIONS: Cortisol concentration increased in response to surgical stress and pain, and this increase was diminished by use of butorphanol. CLINICAL RELEVANCE: Systolic blood pressure was the best clinical predictor of postoperative pain.

Analgesics, Opioid↗
PubMed1997

Glutamate in opioid dependence.

The present review will concentrate on a discussion of recent investigations which implicate a critical linkage of three facets of the central nervous system mediation of opioid dependence, as evidenced by expression of acutely-precipitated withdrawal events. These are the kappa-opioid receptor subtype, the glutamatergic neuronal system and a specific brain locus, the locus coeruleus. The impetus for this line of investigation derives from a recognition that opioid analgesics, such as butorphanol (Stadol), exhibit a markedly different profile of activity at opioid receptors than does morphine yet have abuse liability and cause dependence readily. Emphasis will be placed on demonstration of a rodent model in which butorphanol administration induces dependence through a unique (in comparison with morphine) activation of the kappa-opioid receptor. The use of in vivo microdialysis techniques clearly identifies, in this model, that acutely-precipitated withdrawal from dependence on butorphanol results in focal increases in extracellular levels of glutamate within the locus coeruleus, and that the withdrawal syndrome can be mimicked by intracerebroventricular administration of exogenous glutamate, acting through the N-methyl-D-aspartate glutamate receptor subtype. The data confirm the participation of glutamate as a general phenomenon in opioid dependence, identify the locus coeruleus as a primary site for glutamatergic mediation of dependence, and suggest novel aspects to the neuropharmacology of opioid dependence with respect to the role of the kappa-opioid receptor.

Analgesics, Opioid↗
PubMed1998

[Anesthetic management by continuous total intravenous anesthesia].

Total intravenous anesthesia (TIVA) is one of the most recommended methods of anesthesia for the prevention of air pollution. But the intermittent administration of anesthetic agents has a disadvantage of elongating emergence time. When inexperienced residents undertake TIVA with larger doses of drugs to stabilize vital signs, it takes long emergence time. Therefore, we suggested a continuous TIVA with propofol, ketamine and vecuronium in combination with butorphanol (PKBt) or buprenorphine (PKBp). In this study, we compared emergence times in the subjects, who underwent general anesthesia with PKBt and PKBp. After induction with propofol (2 mg.kg-1), ketamine (0.5 mg.kg-1), vecuronium (0.1 mg.kg-1) and agonist-antagonist opioids, subjects in each group were maintained with continuous intravenous injection of propofol (2-10 mg.kg-1.h-1), ketamine (240 micrograms.kg-1.h-1) and vecuronium (80 micrograms.kg-1.h-1) in combination with butorphanol (8 micrograms.kg-1.h-1) or buprenorphine (0.4 microgram.kg-1.h-1). The emergence times were designated as Op time (the end of operation to awareness), Pr time (the end of propofol to awareness), and B time (the end of butorphanol or buprenorphine to awareness). The emergence times of Op, Pr and B were not different between the groups. The elderly patients showed longer B time than the younger. The patients with long anesthetic time showed longer B time than the patients with short anesthesia. The patients with general anesthesia combined with epidural anesthesia showed longer B time than the patients with only general anesthesia. But there were no differences in Op time and Pr time. We conclude that the continuous TIVA is useful to reduce emergence time and prevent air pollution.

Adolescent↗
PubMed2002

Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats.

RATIONALE: Sex differences in the antinociceptive effects of opioids have been reported in a variety of nociceptive assays, and it has been postulated that these differences are mediated by gonadal hormones. OBJECTIVES: The present study examined the influence of gonadectomy on opioid antinociception in male and female rats. METHODS: In a warm-water, tail-withdrawal procedure, the antinociceptive effects of the high-efficacy micro opioids etorphine and morphine; the low-efficacy micro opioids buprenorphine and dezocine; and the low-efficacy, mixed-action opioids butorphanol and nalbuphine were examined in intact and gonadectomized rats of the F344 and Sprague Dawley (SD) strains. RESULTS: The opioids examined were generally more potent in producing an antinociceptive effect in intact males than intact females, with larger sex differences observed with the less-effective opioids. In F344 males, gonadectomy produced small decreases in the potency of etorphine and morphine, and large decreases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. Similar effects were obtained in SD males, with gonadectomy decreasing the potency of each of the opioids tested. In F344 females, gonadectomy produced small increases in the potency of etorphine and large increases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. A similar effect was obtained in SD females, as gonadectomy increased the potency of etorphine, morphine, and buprenorphine. In both sexes, gonadectomy had a greater effect in F344 than SD rats. CONCLUSIONS: These findings suggest that gonadectomy decreases opioid antinociception in male rats and increases opioid antinociception in female rats. Additionally, the influence of gonadectomy on opioid antinociception appears to be determined by the relative effectiveness of the opioid tested and the rodent strain used.

Analgesics↗
PubMed2005

Assessment of psychological tension after premedication by measurement of salivary chromogranin A.

STUDY OBJECTIVE: Although some sedatives or analgesics are commonly used for premedication to reduce psychological tension before surgery or anesthesia, it remains unclear which drug is more suitable. Because salivary chromogranin A is a reliable index for estimating psychological tension, this variable was measured during the perioperative period after premedication. DESIGN: Prospective, randomized control study. SETTING: Operating room at a general hospital. PATIENTS: Thirty adult female patients undergoing abdominal total hysterectomy were randomly assigned to 3 groups of 10 patients each. INTERVENTIONS: On the day before surgery, saliva was collected, and 0.1 mg/kg of midazolam (midazolam group) or 0.02 mg/kg of butorphanol (butorphanol group) was injected intramuscularly 30 minutes before entering the operating rooms. For the control group, no premedication was performed. Saliva was collected as the patient entered the operating room and then the patient received an epidural catheter insertion followed 5 minutes later by collection of the saliva. MEASUREMENTS AND MAIN RESULTS: Salivary chromogranin A was assayed using a radioimmunoassay, and revised values calculated from the protein concentration of the saliva were regarded as data. Revised salivary chromogranin A levels increased in the control and butorphanol groups at the time of entrance to the operating room and after epidural treatment compared with the value of the day before surgery, whereas it did not change statistically in the midazolam group. CONCLUSIONS: From the standpoint of reducing psychological tension before surgery or anesthesia, midazolam as a sedative may be more suitable for premedication.

Adult↗
PubMed2004

Evaluation of intraperitoneal and incisional lidocaine or bupivacaine for analgesia following ovariohysterectomy in the dog.

OBJECTIVE: To determine if intraperitoneal (i.p.) and incisional (s.c.) lidocaine or bupivacaine provide analgesia following ovariohysterectomy (OHE). STUDY DESIGN: Prospective, randomized, controlled, blinded clinical trial. ANIMALS: Thirty dogs presenting to the Veterinary Teaching Hospital for elective OHE. METHODS: Dogs were pre-medicated with acepromazine and butorphanol, induced with thiopental and maintained with isoflurane. They were randomly assigned to three groups: 10 received 8.8 mg kg(-1) 2% lidocaine with epinephrine i.p. (LID); 10 received 4.4 mg kg(-1) 0.75% bupivacaine i.p. (BUP); and 10 received 0.9% saline i.p. (SAL) upon completion of OHE. All i.p. doses were standardized to 0.88 mL kg(-1) with saline. An additional 2 mL of undiluted solution was placed s.c. prior to incisional closure. Dogs were scored at 0.5, 1, 2, 3, 6, 8 and 18 hours post-extubation by one observer. Dogs were evaluated using a visual analogue scale (VAS) for pain and sedation, and a composite pain scale (CPS) that included physiologic and behavioral variables. Dogs were treated with 0.22 mg kg(-1) butorphanol + acepromazine if their VAS (pain) score was >50. Parametric variables were analyzed using Student's t-test or repeated measures ANOVA as appropriate. Non-parametric variables were analyzed by chi2-test. RESULTS: There were no significant differences in age, weight, incision length, surgery time, anesthesia time, or total thiopental dose among groups. Peak post-surgical pain scores for all groups occurred at 0.5 hours and returned to baseline by 18 hours. Dogs in the BUP group had significantly lower VAS-pain scores overall than dogs in the SAL group. Seven out of 10 dogs in the SAL group, 4/10 in the LID group and 2/10 in the BUP group were treated with supplemental acepromazine and butorphanol. No differences between groups were detected with the CPS. No adverse side-effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings support the use of i.p. and s.c. bupivacaine for post-operative analgesia following OHE in the dog.

Anesthetics, Local↗
PubMedDate not supplied

Selected aspects of the clinical pharmacology of visceral analgesics and gut motility modifying drugs in the horse.

Comparison of the visceral analgesic effects of xylazine, morphine, butorphanol, pentazocine, meperidine, dipyrone, and flunixin in a cecal distention model of colic pain indicated that xylazine produces the most relief from abdominal discomfort. Repeated administration of xylazine may reduce visceral pain so effectively that the seriousness of abdominal disease is obscured. Xylazine decreased propulsive motility in the jejunum and pelvic flexure of healthy ponies. Morphine and butorphanol also gave relief from visceral pain in the cecal distention model. Morphine may inhibit colonic, and butophanol jejunal, motility. Whether xylazine or opiate mediated decreases in gut motility cause clinically important slowing of ingesta transit is controversial and requires further investigation. The development of behavioral changes (i.e., apprehension and pawing) in horses given opiate therapy may limit the use of these drugs. Combinations of xylazine and morphine or butorphanol produce excellent, safe, visceral analgesia and sedation without untoward behavioral effects. Although flunixin fails to demonstrate good visceral analgesic effects in the cecal distention model, this drug produces analgesia in some cases of colic by blocking prostaglandin mediated induction of pain. Improvement of propulsive gut motility in patients with ileus may follow administration of neostigmine (which is particularly effective when the large bowel is hypomotile), naloxone (which experimentally stimulates propulsive colonic motility), and metoclopramide (which stimulates stomach and proximal small intestinal motility).

Analgesics↗
PubMed1996

Behavioral tolerance and cross-tolerance to the response rate-decreasing effects of mu opioids in rats.

The present study was designed to characterize the degree of cross-tolerance between the response rate-decreasing effects of morphine and three mu opioids with varying relative intrinsic efficacies at the mu receptor, buprenorphine, butorphanol and fentanyl, and a non-opioid (+) amphetamine, in a behavioral-tolerance paradigm. Lever pressing of rats was maintained by a fixed-ratio 20-schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine in separate groups of rats administered morphine either before (pre-session) or after (post-session) experimental sessions. Each of the mu opioids and the non-opioid (+)-amphetamine dose-dependently decreased response rates. In the pre-session group, daily administration of morphine shifted the morphine dose-effect curve 0.33 log unit rightward, indicating that tolerance had developed, and shifted the butorphanol dose-effect curve 0.96 log unit rightward. Daily pre-session administrations of morphine did not shift the dose-effect curves for buprenorphine, fentanyl, or (+)-amphetamine. In the post-session group, daily administration of morphine did not shift the morphine, butorphanol, buprenorphine, fentanyl, or (+)-amphetamine dose-effect curves. These data suggest that pharmacological variables, such as the drug's relative intrinsic efficacy at the mu receptor, can play a role in behavioral tolerance and cross-tolerance.

Journal Article↗
PubMed1996

Contribution of individual differences to discriminative stimulus, antinociceptive and rate-decreasing effects of opioids: importance of the drug's relative intrinsic efficacy at the mu receptor.

Rats were trained to discriminate 3.0mg/kg morphine from water in a standard two-lever drug discrimination procedure and tested in a hot water tail-withdrawal procedure. When tested with morphine, fentanyl, buprenorphine and butorphanol, individual animals showed a three- to ten-fold difference in the lowest dose that substituted completely for morphine, whereas 30- to 1000-fold differences were obtained with nalbuphine and levallorphan, respectively. Across repeated determinations, the dose-effect curves for morphine and nalbuphine remained relatively stable within an individual, suggesting that the profound individual differences with nalbuphine were not a consequence of variability in the dose-effect curve. In addition, despite the extremely shallow group dose-effect curves obtained with nalbuphine and levallorphan, intermediate levels of drug-appropriate responding were not evidenced in individual animals. In the tail withdrawal procedure, the doses of morphine and fentanyl required to produce the maximal levels of antinociception varied by approximately three-fold across individual rats. With butorphanol and nalbuphine, differences across animals were greater than 30-fold and 300-fold, respectively, whereas with levallorphan, substantial individual differences were observed in the maximal level of antinociception. Further analyses indicated that animals sensitive to the stimulus effects of nalbuphine and levallorphan were also sensitive to the antinociceptive effects of nalbuphine, levallorphan and butorphanol. In contrast to the individual differences obtained with the stimulus and antinociceptive effects of these opioids, the potency of these drugs for decreasing rate of responding was similar across animals. These findings indicate that the relative efficacy of an opioid at the mu receptor is an important determinant of individual differences in responsiveness to its stimulus and antinociceptive effects, but not to its rate-decreasing effects.

Journal Article↗