Heeseung Lee

Effects of Butorphanol on Morphine-induced Itch and Analgesia in Primates

Background:Butorphanol is an opioid analgesic with partial agonist actions at &mgr;- and &kgr;-opioid receptors (MOR and KOR). Previous studies have demonstrated that both MOR antagonists and KOR agonists are effective in alleviating intrathecal morphine–induced itch in primates. The aim of the study was to investigate the effectiveness of butorphanol as an antipruritic and to elucidate the receptor mechanisms underlying butorphanol’s antipruritic effect in primates. Methods:Adult rhesus monkeys were used in the behavioral assays for measuring itch/scratching and analgesia. The dose–response curves of butorphanol were studied using selective MOR and KOR antagonists. In addition, the effect of butorphanol as an antipruritic was studied on subcutaneous and intrathecal morphine–induced itch and analgesia. KOR-selective antagonists were further used to compare the degrees of MOR and KOR activation underlying the antipruritic effect of butorphanol. Results:Butorphanol alone produced analgesia with slight itch responses, and both effects were blocked by a MOR antagonist, clocinnamox (0.1 mg/kg). In contrast, a KOR antagonist, 5′-guanidinylnaltrindole (1 mg/kg), increased butorphanol-elicited itch. Systemic butorphanol (0.0032–0.032 mg/kg) dose-dependently attenuated systemic or intrathecal morphine–induced itch. In addition, butorphanol either potentiated or maintained morphine-induced analgesia without producing sedation. KOR-selective antagonists, 5′-guanidinylnaltrindole (1 mg/kg) and nor-binaltorphimine (3.2 mg/kg), only partially reversed the antipruritic effect of butorphanol with different durations of KOR antagonism. Conclusions:Butorphanol is effective in attenuating systemic or spinal morphine–induced itch without reducing morphine analgesia. This study provides functional evidence that both partial MOR and KOR agonist actions contribute to the effectiveness of butorphanol as an antipruritic in primates.

Characterization of scratching responses in rats following centrally administered morphine or bombesin

The aim of this study was to characterize scratching behavior elicited by central administration of morphine or bombesin in rats, and to determine the role of opioid receptors in scratching induced by both pruritogenic agents. Central administration included intracisternal (i.c.), intrathecal (i.t.), and intracerebroventricular (i.c.v.) routes. Scratching events made with hind paws were counted by observers blinded to treatment conditions. Intracisternal morphine (0.01–0.1 μg) produced dose-dependent increases in scratching; the maximum response to i.c. morphine 0.1 μg was approximately 500 scratches within a 1-hour period. Neither i.t. nor i.c.v. morphine significantly increased scratching. Bombesin (0.01−0.32 μg) elicited robust scratching following i.c. administration. The maximum response to i.c. bombesin 0.32 μg was approximately 4000 scratches within a 1-hour period. Both i.t. and i.c.v. bombesin produced profound scratching at similar doses. Antagonist studies confirmed that mu-opioid receptors selectively mediate i.c. morphine-induced scratching. However, selective mu-, kappa-, and delta-opioid antagonists did not attenuate i.c. bombesin-induced scratching. These results demonstrate that morphine and bombesin elicit scratching through different receptor mechanisms, at different central sites, and to different degrees.

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

RationaleCarrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates.ObjectiveThe aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs).ResultsTail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception.ConclusionUsing two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.

Antinociceptive synergy between the cannabinoid receptor agonist WIN 55,212-2 and bupivacaine in the rat formalin test.

BACKGROUND:The analgesic interaction between cannabinoids and local anesthetics has not been investigated. We sought to determine the nature of the interaction between the intrathecal cannabinoid receptor agonist (WIN 55,212-2) and bupivacaine using the formalin test. METHODS:Lumbar intrathecal catheters were implanted in male Sprague-Dawley rats. After intrathecal administration of WIN 55,212-2, bupivacaine, or their combination, 50 &mgr;L of 5% formalin was injected subcutaneously into the hindpaw. Dose–response curves were established and the respective ED50 (50% effective dose) values were determined for each agent alone. Fixed-ratio combinations of WIN 55,212-2 and bupivacaine were tested for combined antinociceptive effects in the formalin test and an isobolographic analysis was performed to characterize the pharmacologic interaction of both drugs. RESULTS:Intrathecally administered WIN 55,212-2, bupivacaine, or their combination produced a dose-dependent decrease in the number of flinches during Phase 1 and 2 of the formalin test. Isobolographic analysis revealed a synergistic interaction between intrathecal WIN 55,212-2 and bupivacaine in both phases of the formalin test. In combination, the ED50 value was significantly smaller than the theoretical additive value (P < 0.05). CONCLUSIONS:These results demonstrate that intrathecally coadministered WIN 55,212-2 and bupivacaine provide synergistic antinociceptive interaction in both phases of the formalin test.

Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates

How neuropeptides in the primate spinal cord regulate itch and pain is largely unknown. Here we elucidate the sensory functions of spinal opioid-related peptides and gastrin-releasing peptide (GRP) in awake, behaving monkeys. Following intrathecal administration, β-endorphin (10–100 nmol) and GRP (1–10 nmol) dose-dependently elicit the same degree of robust itch scratching, which can be inhibited by mu-opioid peptide (MOP) receptor and GRP receptor (BB2) antagonists, respectively. Unlike β-endorphin, which produces itch and attenuates inflammatory pain, GRP only elicits itch without affecting pain. In contrast, enkephalins (100–1000 nmol) and nociceptin-orphanin FQ (3–30 nmol) only inhibit pain without eliciting itch. More intriguingly, dynorphin A(1–17) (10–100 nmol) dose-dependently attenuates both β-endorphin- and GRP-elicited robust scratching without affecting pain processing. The anti-itch effects of dynorphin A can be reversed by a kappa-opioid peptide (KOP) receptor antagonist nor-binaltorphimine. These nonhuman primate behavioral models with spinal delivery of ligands advance our understanding of distinct functions of neuropeptides for modulating itch and pain. In particular, we demonstrate causal links for itch-eliciting effects by β-endorphin-MOP receptor and GRP-BB2 receptor systems and itch-inhibiting effects by the dynorphin A-KOP receptor system. These studies will facilitate transforming discoveries of novel ligand-receptor systems into future therapies as antipruritics and/or analgesics in humans.

Effect of intraoperative infusion of ketamine on remifentanil-induced hyperalgesia.

Background Opioid induced hyperalgesia (OIH) is related with high opioid dosage, a long duration of opioid administration, and abrupt discontinuation of infused opioids in anesthetic settings. Ketamine is known to attenuate OIH efficiently, but methods of administration and methods to quantify and assess a decrease in OIH vary. We demonstrated the existence of remifentanil-induced hyperalgesia and investigated the ability of ketamine to attenuate OIH. Methods Seventy-five patients undergoing laparoscopic gynecologic surgery under remifentanil-based anesthesia were assigned to one of the following groups: (1) group RL (remifentanil 0.05 µg/kg/min), (2) group RH (remifentanil 0.3 µg/kg/min), or (3) group KRH (remifentanil 0.3 µg/kg/min + ketamine 0.5 mg/kg bolus with 5 µg/kg/min infusion intraoperatively). Desflurane was administered for maintenance of anesthesia to target bispectral index scores (40-60) and hemodynamic parameters (heart rate and blood pressure < ± 20% of baseline values). All parameters related to OIH and its attenuation induced by ketamine were investigated. Results There was no significant difference among the three groups related to demographic and anesthetic parameters except the end-tidal concentration of desflurane. Additional analgesic consumption, numerical rating scale scores at 6 and 24 h, and cumulative fentanyl dose were significantly higher in group RH than in the other two groups. The value difference of the Touch-Test sensory evaluation was significantly higher negative in group RH than in the other two groups. Conclusions Remifentanil-induced hyperalgesia is significantly attenuated by intraoperative bolus and infusion of ketamine. Ketamine also decreased tactile sensitization, as measured by Touch-Test sensory evaluation.

Effect of flumazenil on recovery from anesthesia and the bispectral index after sevoflurane/fentanyl general anesthesia in unpremedicated patients

Background Benzodiazepines have a hypnotic/sedative effect through the inhibitory action of γ-aminobutyric acid type A receptor. Flumazenil antagonizes these effects via competitive inhibition, so it has been used to reverse the effect of benzodiazepines. Recently, flumazenil has been reported to expedite recovery from propofol/remifentanil and sevoflurane/remifentanil anesthesia without benzodiazepines. Endogenous benzodiazepine ligands (endozepines) were isolated in several tissues of individuals who had not received benzodiazepines. Methods Forty-five healthy unpremedicated patients were randomly allocated to either flumazenil or a control groups. Each patient received either a single dose of 0.3 mg of flumazenil (n = 24) or placebo (n = 21). After drug administration, various recovery parameters and bispectral index (BIS) values in the flumazenil and control groups were compared. Results Mean time to spontaneous respiration, eye opening on verbal command, hand squeezing on verbal command, extubation and time to date of birth recollection were significantly shorter in the flumazenil group than in the control group (P = 0.004, 0.007, 0.005, 0.042, and 0.016, respectively). The BIS value was significantly higher in flumazenil group than in the control group beginning 6 min after flumazenil administration. Conclusions Administration of a single dose of 0.3 mg of flumazenil to healthy, unpremedicated patients at the end of sevoflurane/fentanyl anesthesia without benzodiazepines resulted in earlier emergence from anesthesia and an increase in the BIS value. This may indicate that flumazenil could have an antagonistic effect on sevoflurane or an analeptic effect through endozepine-dependent mechanisms.

The changes of heart rate variability after unilateral stellate ganglion block.

Background The effect of the unilateral stellate ganglion block (SGB) on cardiovascular regulation remains controversial. We wished to evaluate the changes in heart rate variability (HRV) after a unilateral stellate ganglion block in patients with head and neck pain in the present study. Methods Patients with head and neck pain (n = 89) were studied. HRV was determined before and after a C6 unilateral stellate ganglion block (right-sided SGB, 40; left-sided SGB, 49) using a paratracheal technique with 1% mepivacaine (6 ml). Results There were no significant differences in HRV indices before and after right-sided SGB. The log scale of power in the high frequency range (lnHF) was increased and ratio of power in the low frequency range (LF) to power in the high frequency range (HF) ratio was decreased after left-sided SGB. Conclusions These results demonstrated that left-sided SGB increased parasympathetic activities in patients with head and neck pain.

The Pentax airway scope versus the Macintosh laryngoscope: Comparison of hemodynamic responses and concentrations of plasma norepinephrine to tracheal intubation.

Background The Pentax Airway Scope (AWS) is a video laryngoscope designed to facilitate tracheal intubation with a high-resolution image. The Pentax AWS has been reported to cause less hemodynamic stress than the Macintosh laryngoscope. The aims of this study are to investigate the differences in hemodynamic responses and norepinephrine concentrations to tracheal intubation between procedures using he Pentax AWS and the Macintosh laryngoscope. Methods Forty patients (American Society of Anesthesiologists class I-II, age range: 18-60 years) were randomly assigned to be intubated with either the Pentax AWS or the Macintosh laryngoscope while under general anesthesia. Routine monitoring, including invasive arterial blood pressure and bispectral index, were applied. Thiopental (4 mg/kg), fentanyl (1 µg/kg), midazolam (0.05 mg/kg), and rocuronium (0.6 mg/kg) were administered for anesthetic induction. Systolic, diastolic, and mean blood pressures and heart rates were recorded pre-intubation, immediately post-intubation (T0), and over the following 10 minutes at one minute intervals (T1, T2, T3, T4, T5…T10). Patient blood was sampled for norepinephrine concentrations pre-intubation (baseline) and post-intubation (T1). Evidence of sore throat was evaluated 30 min and 24 hr after extubation. Data were transformed to % basal and expressed as mean ± SD. Results The systolic, diastolic, and mean blood pressure, and heart rate at T0 and T4 were significantly different between the two groups. There was no significant difference in plasma norepinephrine between the two groups. The difference in incidence of sore throat was not significant between the two groups. Conclusions Pentax-AWS for tracheal intubation has greater hemodynamic stability than the Macintosh blade laryngoscope.

The frequency of fentanyl-induced cough in children and its effects on tracheal intubation

STUDY OBJECTIVE To determine if fentanyl-induced cough was dose-dependent in children and whether it could affect tracheal intubation. DESIGN Prospective, randomized, double-blinded study. SETTING Operating room of a university-affiliated hospital. PATIENTS 160 ASA physical status I pediatric patients, aged two to 14 years, scheduled for elective surgery during general anesthesia and requiring orotracheal intubation. INTERVENTIONS Patients were divided into two groups. Group 1 patients were given fentanyl at a dosage of one microg/kg; Group 2 patients received two microg/kg of fentanyl. Induction of anesthesia was conducted immediately following cough cessation or one minute after the end of injection with propofol 2.5 mg/kg. At loss of eyelash reflex, rocuronium 0.6 mg/kg was given intravenously (IV). Two minutes later, tracheal intubation was started. MEASUREMENTS Onset and degree of cough and intubating conditions were observed and recorded. MAIN RESULTS No statistically significant differences in frequency of coughing or in intubating conditions between the two groups were noted. Cough severity in Group 1 was statistically lower than that of Group 2 (P < 0.05). Onset of cough in Group 2 (12.2 +/- 3.4 sec) was statistically shorter than in Group 1 (16.9 +/- 7.6 sec, P < 0.05). CONCLUSION Fentanyl at doses of one and two microg/kg may induce coughing in pediatric patients.