Pharmacokinetics and pharmacodynamics of rocuronium in young adult and elderly patients undergoing elective surgery.

OBJECTIVE: To evaluate the impact of advanced age on rocuronium kinetic disposition in ASA I-III patients undergoing elective surgeries. METHODS: Young adult (20-50 years, n = 15) and elderly patients (65-85 years, n = 14) submitted to surgery under general anaesthesia were investigated. All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol. Rocuronium-induced neuromuscular block was monitored by train of four stimulations of the adductor muscle of the thumb on the ulnar nerve. The pharmacokinetic parameters were calculated by non-compartmental analysis. The relationship between rocuronium plasma concentration and the neuromuscular blockade was described by a sigmoidal Emax model. KEY-FINDINGS: Elderly patients presented decreased Cl (2.1 ml/kg per min vs 2.8 ml/kg per min; P = 0.0123); increased AUC/dose (507.8 µg min/ml (mg/kg) vs 392.2 µg min/ml/(mg/kg); P = 0.0168) and reduced volume of distribution (285.4 ml/kg vs 435.6 ml/kg, P = 0.0434) compared to young adults. The concentrations required to achieve 50% of maximum neuromuscular block (EC50) were similar for young adult (338.8 ng/ml) and elderly (462.7 ng/ml) patients (P > 0.05). CONCLUSIONS: Elderly patients showed increased AUC/D and reduced total Cl compared to young adult patients due to the age-related reduced renal function. Differences in the PK-PD properties of rocuronium in elderly population are due to changes in drug disposition rather than to alterations in the sensitivity to the drug.

Impact of fraction unbound, CYP3A, and CYP2D6 in vivo activities, and other potential covariates to the clearance of tramadol enantiomers in patients with neuropathic pain.

The pharmacokinetics of tramadol is characterized by a large interindividual variability, which is partially attributed to polymorphic CYP2D6 metabolism. The contribution of CYP3A, CYP2B6, fraction unbound, and other potential covariates remains unknown. This study aimed to investigate the contribution of in vivo activities of cytochrome P450 (CYP) 2D6 and 3A as well as other potential covariates (CYP2B6 genotype to the SNP g.15631G>T, fraction unbound, age, body weight, creatinine clearance) to the enantioselective pharmacokinetics of tramadol. Thirty patients with neuropathic pain and phenotyped as CYP2D6 extensive metabolizers were treated with a single oral dose of 100 mg tramadol. Multiple linear regressions were performed to determine the contribution of CYP activities and other potential covariates to the clearance of tramadol enantiomers. The apparent total clearances were 44.9 (19.1-102-2) L/h and 55.2 (14.8-126.0) L/h for (+)- and (-)-tramadol, respectively [data presented as median (minimum-maximum)]. Between 79 and 83% of the overall variation in apparent clearance of tramadol enantiomers was explained by fraction unbound, CYP2D6, and CYP3A in vivo activities and body weight. Fraction unbound explained 47 and 41% of the variation in clearance of (+)-tramadol and (-)-tramadol, respectively. Individually, CYP2D6 and CYP3A activities were shown to have moderate contribution on clearance of tramadol enantiomers (11-16% and 11-18%, respectively). In conclusion, factors affecting fraction unbound of drugs (such as hyperglycemia or co-administration of drugs highly bound to plasma proteins) should be monitored, because this parameter dominates the elimination of tramadol enantiomers.

The New Portable Transcutaneous Electrical Nerve Stimulation Device Was Efficacious in the Control of Primary Dysmenorrhea Cramp Pain.

INTRODUCTION: Transcutaneous electrical nerve stimulation (TENS) is an established method for pain relief in dysmenorrhea. A feasible advantage would be the study of a portable device. The purpose of the study was to evaluate the effectiveness and safety of a new portable TENS device (TANYX®) for menstruation cramps. MATERIALS AND METHODS: Forty women were evaluated in a double-blind, prospective, randomized fashion, divided into sham and active groups. TENS was applied medially at the suprapubic region, for 30-min duration at eight-hour intervals, up to seven days. The placebo group (PG) received sham device. The TENS group (TG) applied an active 85 Hz frequency TENS. Efficacy measures were pain relief evaluated on a visual analog scale (VAS) and diclofenac intake, and quality of life represented by: 1) capacity to get out of the bed, 2) food or drink intake, 3) missing routine daily activities such as work or school, and 4) quality of sleep. RESULTS: The active TENS device induced a prompt onset of pain relief in a strictly segmental manner nearby the dermatomes where the TENS was applied at the skin, and there was a drop in mean pain score from 8 to 2 cm (p < 0.001). Diclofenac consumption was also significantly reduced (p < 0.01), compared with the PG. Quality of life improved significantly in TG when compared with PG (p < 0.05). Three months after the beginning of the study, 14/20 of the women were still using the active device regularly. No adverse effects were observed. CONCLUSIONS: The portable, disposable, active TENS device induced a prompt onset of pain relief and improved the quality of life, without adverse effects, in patients with painful cramps associated with dysmenorrhea.

Efficacy of the Greater Occipital Nerve Block for Cervicogenic Headache: Comparing Classical and Subcompartmental Techniques.

AIM: The aim of the study was to compare the efficacy of the greater occipital nerve (GON) block using the classical technique and different volumes of injectate with the subcompartmental technique for the treatment of cervicogenic headache (CH). METHODS: Thirty patients acted as his/her own control. All patients were submitted to the GON block by the classical technique with 10 mg dexamethasone, plus 40 mg lidocaine (5 mL volume). Patients were randomly allocated into 1 of 3 groups (n = 10) when pain VAS was > 3 cm. Each group was submitted to a GON subcompartmental technique (10 mg dexamethasone + 40 mg lidocaine + nonionic iodine contrast + saline) under fluoroscopy using either 5, 10, or 15 mL final volume. Analgesia and quality of life were evaluated. RESULTS: The classical GON technique resulted in 2 weeks of analgesia and less rescue analgesic consumption, compared to 24 weeks after the subcompartmental technique (P < 0.01). Quality of life improved at 2 and 24 weeks after the classical and the suboccipital techniques, respectively (P < 0.05). The data revealed that groups were similar regarding analgesia when compared to volume of injection (P > 0.05). CONCLUSIONS: While the classical technique for GON block resulted in only 2 weeks of analgesia, the subcompartmental technique resulted in at least 24 weeks of analgesia, being 5 mL volume sufficient for the performance of the block under fluoroscopy.

Analgesia after Epidural Dexamethasone is Further Enhanced by IV Dipyrone, but Not IV Parecoxibe Following Minor Orthopedic Surgery.

BACKGROUND: Epidural administration of dexamethasone has been suggested for pain control after minor orthopedic surgery. This study was conducted to assess its efficacy after such surgery, combined or not to IV dipyrone, IV parecoxibe or their combination. METHODS: 91 patients were randomly assigned to seven groups. Patients were submitted to spinal bupivacaine anesthesia combined to epidural administration of either 10 ml saline or 10 mg dexamethasone diluted to 10-ml volume. Patients also received 10 ml IV saline or 1 gr dipyrone and/or 40 mg parecoxibe diluted to 10 ml with saline. Control group (CG) received epidural and IV saline. Dexamethasone group (DexG) received epidural dexamethasone and IV saline. Dipyrone group (DipG) received epidural saline and IV dipyrone. Dex-Dip G received epidural dexamethasone and IV dipyrone. Parecoxibe group (ParG) received epidural saline and IV parecoxibe. Dex-ParG received epidural dexamethasone and IV parecoxibe. Finally, Dex-Dip-ParG received epidural dexamethasone and IV dipyrone plus IV parecoxibe. RESULTS: The CG expressed 4h of analgesia and sooner requested pain killer. DexG was similar to DipG or ParG or Dex-ParG (7-hours), and they requested less ketoprofen compared to the CG (P < 0.05). However, the Dex-DipG and the Dex-Dip-ParG resulted in longer time to demand pain killer (17-hours) and less ketoprofen consumption in 24-hours (P < 0.002). Adverse effects were similar among groups. CONCLUSIONS: The analgesia secondary to epidural dexamethasone was enhanced by IV dipyrone, while no effects were observed by the addition of IV parecoxibe.

Intrathecal ketorolac enhances intrathecal morphine analgesia following total knee arthroplasty.

BACKGROUND: Total knee arthroplasty represents one of the most painful surgeries. The aim of the study was to compare analgesia and adverse effects of intrathecal (IT) ketorolac versus IT morphine, versus the combination of IT ketorolac and morphine. MATERIALS AND METHODS: After ethical approval and patient consent, 80 patients undergoing knee arthroplasty were randomized to one of 4 groups. All groups received 15 mg IT bupivacaine plus IT test drug (2 ml). The control group (CG) received saline as IT test drug. The morphine group (MG) received IT 200 g morphine, the ketorolac group (KG) IT 2 mg ketorolac and the morphine-ketorolac group (MKG) 200 g morphine + 2 mg ketorolac as test drugs. Pain and adverse effects were evaluated. P > 0.05 was considered significant. RESULTS: The MG and KG were similar in their times to time to first rescue analgesic (440 ± 38 min and 381 ± 44 min, respectively). Both groups were longer when compared to the CG (170 ± 13 min) (P > 0.01). The MG and KG had lesser ketoprofen consumption compared to the CG (P > 0.05). The time to first rescue analgesic was longer to the MKG (926 ± 222 min) (15 h) compared to CG (P > 0.001) and to the MG and the KG (P > 0.01). MKG displayed lesser ketoprofen consumption compared to MG and KG (P > 0.05) and to the CG (P > 0.02). CONCLUSIONS: The data suggest a role for spinal ketorolac and morphine in orthopaedic surgery because this combination of agents provided 15 h of analgesia compared to 7 h after each drug alone, with no significant side-effects.

The antinociceptive effect of local or systemic parecoxib combined with lidocaine/clonidine intravenous regional analgesia for complex regional pain syndrome type I in the arm.

We evaluated the efficacy of local or systemic parecoxib combined with lidocaine/clonidine IV regional analgesia in complex regional pain syndrome (CRPS) type 1 in a dominant upper limb. Thirty patients with CRPS type 1 were divided into three groups. The control group (CG) received both IV saline in the healthy limb and IV loco-regional 1 mg/kg of lidocaine + 30 mug of clonidine, diluted to a 10-mL volume with saline. The systemic parecoxib group (SPG) received a regional block similar to that administered to the CG but with systemic 20 mg of parecoxib, whereas the IV regional anesthesia with parecoxib group (IVRAPG) received an extra IV 5 mg of loco-regional parecoxib compared with the CG. The block was performed once a week for 3 consecutive weeks. Analgesia was evaluated by the 10-cm visual analog scale (VAS) and rescue analgesic consumption. The IVRAPG showed less daily ketoprofen (milligrams) consumption in the second and third weeks compared with the other groups (P < 0.05). The IVRAPG also showed less ketoprofen consumption when comparing the first and second week with the third week (P < 0.05). The VAS score comparison among groups revealed that groups were similar during the first and second week observation, although the IVRAPG showed smaller VAS scores in the third week compared with both CG and SPG (P < 0.05). We conclude the IV 5 mg of parecoxib was an effective antiinflammatory drug combined with clonidine/lidocaine loco-regional block in CRPS type 1.

The combination of epidural clonidine and S(+)-ketamine did not enhance analgesic efficacy beyond that for each individual drug in adult orthopedic surgery.

STUDY OBJECTIVES: To evaluate the benefit of epidural clonidine and S(+)-ketamine combination through the epidural route in adult orthopedic surgery. DESIGN: Randomized double-blinded study. SETTING: Teaching hospital. PATIENTS: Scheduled to undergo knee surgery, 56 American Society of Anesthesiologists physical status 1 and 2 adult patients. INTERVENTIONS: Patients were randomized to 1 of 4 groups to receive the combined epidural-intrathecal technique. A 10-mL epidural injection of either study drug or normal saline was first administered to all patients. Intrathecal anesthesia was performed with 15 mg of bupivacaine. The control group (CG) received epidural saline. The 0.1-mg/kg S(+)-ketamine epidural group received 0.1 mg/kg epidural S(+)-ketamine. The 0.5-microg/kg clonidine epidural group received 0.5 microg/kg epidural clonidine. The S(+)-ketamine/clonidine group received 0.1 mg/kg epidural S(+)-ketamine plus 0.5 microg/kg epidural clonidine. MEASUREMENTS AND MAIN RESULTS: Pain and adverse effects were evaluated by visual analog scale. Rescue analgesics were available to patients. The groups were demographically similar. Sensory level to pinprick, surgical and anesthetic time, and visual analog scale scores for pain at first rescue medication were similar among the groups. The time to first rescue analgesic (minute) was lowest in CG (P < .005). The CG required more rescue analgesics in 24 hours than any of the other groups (P < .0005). Patients who received either epidural clonidine, S(+)-ketamine, or both displayed similar analgesia. The frequency of adverse effects was similar among groups (P > .05). CONCLUSIONS: The association of epidural clonidine or S(+)-ketamine did not result in a greater analgesic effect in the model of acute postoperative pain studied, although the interaction of epidural clonidine and S(+)-ketamine is not attributable to sharing of a common second messenger system.

Antinociceptive effect of low-dose intrathecal neostigmine combined with intrathecal morphine following gynecologic surgery.

BACKGROUND: The purpose of this study was to determine whether combination of 1-5 microg intrathecal neostigmine would enhance analgesia from a fixed intrathecal dose of morphine. METHODS: A total of 60 patients undergoing gynecologic surgery were randomized to one of five groups. Patients received 15 mg bupivacaine plus 2 ml of the test drug intrathecally (saline, 100 microg morphine, or 1-5 microg neostigmine). The control group received spinal saline as the test drug. The morphine group received spinal morphine as test drug. The morphine + 1 microg neostigmine group received spinal morphine and 1 microg neostigmine. The morphine + 2.5 microg neostigmine group received spinal morphine and 2.5 microg neostigmine. Finally, the morphine + 5 microg neostigmine group received spinal morphine and 5 microg neostigmine. RESULTS: The groups were demographically similar. The time to first rescue analgesic (minutes) was longer for all patients who received intrathecal morphine combined with 1-5 microg neostigmine (median, 6 h) compared with the control group (median, 3 h) (P < 0.02). The morphine group (P < 0.05) and the groups that received the combination of 100 microg intrathecal morphine combined with neostigmine (P < 0.005) required less rescue analgesics in 24 h compared with the control group. The incidence of perioperative adverse effects was similar among groups (P > 0.05). CONCLUSIONS: The addition of 1-5 microg spinal neostigmine to 100 microg morphine doubled the duration to first rescue analgesic in the population studied and decreased the analgesic consumption in 24 h, without increasing the incidence of adverse effects. The data suggest that low-dose spinal neostigmine may improve morphine analgesia.

Epidural morphine and neostigmine for postoperative analgesia after orthopedic surgery.

UNLABELLED: In this study, we examined the side effects and analgesia of the combination of epidural neostigmine and morphine in patients undergoing orthopedic surgery. Sixty patients undergoing knee surgery were divided into four groups. The intrathecal anesthetic was 15 mg of bupivacaine. The epidural test drug was diluted in saline to a final volume of 10 mL. The control group received saline as the epidural test drug. The morphine group received 0.6 mg of epidural morphine. The neostigmine group (NG) received 60 micro g of epidural neostigmine. The morphine/neostigmine group received 0.6 mg of epidural morphine combined with 60 micro g of epidural neostigmine. The groups were demographically the same and did not differ in intraoperative characteristics. The visual analog scale score at first rescue analgesic and the incidence of adverse effects were similar among groups (P > 0.05). One patient from the NG complained of intraoperative nausea, closely related to spinal hypotension. Postoperatively, two patients from the NG had vomited once. The time (min) to first rescue analgesic was longer in the morphine/neostigmine group ( approximately 11 h) compared with the other groups (P < 0.05). The analgesic consumption (number of analgesic administrations in 24 h) was larger in the control group compared with the other groups (P < 0.05). IMPLICATIONS: The combination of epidural morphine and epidural neostigmine resulted in postoperative analgesia (11 h) devoid of side effects, being an alternative analgesic technique in the population studied.

Double-blind evaluation of transdermal nitroglycerine as adjuvant to oral morphine for cancer pain management.

STUDY OBJECTIVES: To examine analgesia and adverse effects following transdermal application of nitroglycerine (a nitric oxide generator) combined with oral morphine, in cancer pain patients. DESIGN: Randomized, double-blind study. SETTING: Teaching hospital. PATIENTS: 36 patients suffering from cancer pain. INTERVENTIONS: Patients were divided into two groups (n = 18). All patients were regularly taking oral amitriptyline 50 mg at bedtime. Pain was evaluated using a 10-cm visual analog scale (VAS). The morphine regimen was individually adjusted to a maximal oral dose of 80 to 90 mg/day, to maintain the VAS score less than 4/10 cm. When patients complained of pain (VAS equal or greater than 4/10), despite taking 80 to 90 mg of oral morphine daily, the transdermal test drug was supplemented as follows: the control group received a placebo patch daily, and the nitroglycerine group received a 5-mg/24-hour nitroglycerine patch daily. Patients were free to manipulate their daily morphine consumption at the time the test drug was administered, to keep VAS less than 4/10 cm. After the introduction of the transdermal test drug, patients were evaluated by the staff on a weekly basis as outpatients, over four consecutive weeks. MEASUREMENTS AND MAIN RESULTS: The groups were similar in respect to demographic data and VAS pain scores before the treatment. The daily consumption of oral morphine was smaller in the nitroglycerine group compared with the control group after the 14th day of evaluation (p < 0.002). Patients from the control group in general complained of somnolence, compared with the nitroglycerine group. CONCLUSION: Transdermal nitroglycerine was an effective coadjuvant analgesic. In conjunction with its opioid tolerance sparing function, delivery of nitric oxide donors together with opioids may be of significant benefit in cancer pain management in delaying morphine tolerance and decreasing the incidence of adverse effects related to high doses of opioids.

Clonidine as coadjuvant in eye surgery: comparison of peribulbar versus oral administration.

STUDY OBJECTIVE: To determine whether the administration of peribulbar or oral clonidine would enhance analgesia and anesthesia in ophthalmologic surgery. DESIGN: Randomized double-blind study. SETTING: Teaching hospital. PATIENTS: 60 ASA physical status I and II adult patients scheduled for unilateral ophthalmologic surgery with peribulbar block. INTERVENTIONS: Patients were assigned to one of 4 groups, and premedicated with oral 2 mL volume (clonidine or placebo). The peribulbar eye block consisted of local anesthetics plus 1 mL of the test drug. The control group (CG) received oral saline as premedication and peribulbar saline as the test drugs. The clonidine eye group (Clo-eye G) received oral saline and peribulbar 30 microg clonidine. The clonidine oral group (Clo-oral G) received oral 150 microg clonidine and peribulbar saline. The clonidine eye+oral group (Clo eye+oral G) had oral 75 microg clonidine and peribulbar 15 microg clonidine. MEASUREMENTS AND MAIN RESULTS: Perioperative assessment included anesthesia, analgesia, blood cortisol; and adverse effects. The groups were demographically similar. The latency time to the onset of the peribulbar block was shorter in the Clo-eye G compared to the CG (p < 0.05). The CG presented higher blood pressure levels throughout surgery, compared to the others (p < 0.05). The time to first rescue analgesics was longer in all patients who received peribulbar clonidine compared to the CG (p < 0.05). Analgesic consumption was lesser in the Clo-eye G compared to the CG (p < 0.05). The blood cortisol level was higher during the intraoperative period in all groups (preoperative vs. intraoperative values) (p < 0.01). CONCLUSION: Despite the higher intraoperative blood cortisol levels, 30 microg peribulbar clonidine decreased the onset time to anesthesia, while 15 and 30 microg peribulbar clonidine prolonged the time to first rescue analgesics in patients under peribulbar block, without increasing the frequency of adverse effects. Conversely, oral administration of clonidine alone did not enhance anesthesia or analgesia following eye block, suggesting a local mechanism of action of clonidine.