Newton L. Pereira

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.

Transdermal nitroglycerine enhances spinal sufentanil postoperative analgesia following orthopedic surgery.

BACKGROUND Sufentanil is a potent but short-acting spinal analgesic used to manage perioperative pain. This study evaluated the influence of transdermal nitroglycerine on the analgesic action of spinal sufentanil in patients undergoing orthopedic surgery. METHODS Fifty-six patients were randomized to one of four groups. Patients were premedicated with 0.05-0.1 mg/kg intravenous midazolam and received 15 mg bupivacaine plus 2 ml of the test drug intrathecally (saline or 10 microg sufentanil). Twenty to 30 min after the spinal puncture, a transdermal patch of either 5 mg nitroglycerin or placebo was applied. The control group received spinal saline and transdermal placebo. The sufentanil group received spinal sufentanil and transdermal placebo. The nitroglycerin group received spinal saline and transdermal nitroglycerine patch. Finally, the sufentanil-nitroglycerin group received spinal sufentanil and transdermal nitroglycerine. Pain and adverse effects were evaluated using a 10-cm visual analog scale. RESULTS The time to first rescue analgesic medication was longer for the sufentanil-nitroglycerin group (785+/-483 min) compared with the other groups (P<0.005). The time to first rescue analgesics was also longer for the sufentanil group compared with the control group (P<0.05). The sufentanil-nitroglycerin group group required less rescue analgesics in 24 h compared with the other groups (P<0.02) and had lesser 24-h pain visual analog scale scores compared with the control group (P<0.005), although these scores were similar to the sufentanil and nitroglycerin groups (P>0.05). The incidence of perioperative adverse effects was similar among groups (P>0.05). CONCLUSIONS Transdermal nitroglycerine alone (5 mg/day), a nitric oxide generator, did not result in postoperative analgesia itself, but it prolonged the analgesic effect of spinal sufentanil (10 microg) and provided 13 h of effective postoperative analgesia after knee surgery.

Transdermal Ketamine as an adjuvant for postoperative analgesia after abdominal gynecological surgery using lidocaine epidural blockade

We examined the postoperative analgesia of a controlled delivery ketamine transdermal patch after minor abdominal gynecological surgery using lidocaine epidural blockade. Fifty-two patients were randomized to one of two groups. Epidural anesthesia was performed with 25 mL 2% plain lidocaine. At the end of the surgical procedure, a controlled delivery transdermal patch containing either ketamine (25 mg/24 h) (Ketamine group) or placebo (Placebo group) was applied. Pain and adverse effects were assessed hourly postoperatively for 24 h. IM dipyrone was available at patient request. The two groups were demographically similar. The time to first rescue analgesic was longer in the Ketamine group (230 ± 112 min) compared with the Placebo group (94 ± 54 min); (P < 0.00001). There were more dipyrone dose injections in 24 h in the Placebo group compared with the Ketamine group (P < 0.0001). The incidence of adverse effects was similar between groups. We conclude that the transdermal-controlled delivery of ketamine prolonged the duration of analgesia after minor gynecological procedures. Implications Transdermal delivery of ketamine was an useful adjuvant to postoperative analgesia after epidural lidocaine blockade in the population studied.

Transdermal nitroglycerine enhances spinal neostigmine postoperative analgesia following gynecological surgery.

BackgroundIntrathecal neostigmine causes analgesia by inhibiting the breakdown of acetylcholine. Experimental data suggest that the production of endogenous nitric oxide is necessary for tonic cholinergic inhibition of spinal pain transmission. The purpose of this study was to determine whether association of transdermal nitroglycerine would enhance analgesia from a low dose of intrathecal neostigmine in patients undergoing gynecologic surgery during spinal anesthesia. MethodsForty-eight patients were randomized to one of four groups. Patients were premedicated with use of 0.05–0.1 mg/kg intravenous midazolam and received 15 mg bupivacaine plus 1 ml test drug intrathecally (saline or neostigmine, 5 &mgr;g). Twenty to 30 min after the spinal puncture, a transdermal patch of either 5 mg nitroglycerin or placebo was applied. The control (Con) group received spinal saline and transdermal placebo. The neostigmine group received spinal neostigmine and transdermal placebo. The nitroglycerin group received spinal saline and a transdermal nitroglycerine patch. Finally, the neostigmine–nitroglycerin group received spinal neostigmine and transdermal nitroglycerine. Pain and adverse effects were evaluated using a 10-cm visual analog scale. ResultsPatients in the groups were similar regarding age, weight, height, and American Society of Anesthesiologists status. Sensory level to pin prick at 10 min, surgical duration, anesthetic duration, and visual analog scale score for pain at the time of administration of first rescue medication were statistically the same for all groups. The time to administration of first rescue analgesic (min) was longer in the neostigmine–nitroglycerin group (550 min; range, 458–1,440 min; median, 25–75th percentile) compared with the other groups (P < 0.001). The neostigmine–nitroglycerin group required fewer rescue analgesics in 24 h than did the control group (P < 0.0005), whereas the neostigmine group required less analgesics compared with the control group (P < 0.02). The incidence of perioperative adverse effects (nausea, vomiting, headache, back pain) was similar among groups (P > 0.05). ConclusionAlthough neither intrathecal 5 &mgr;g neostigmine alone nor transdermal nitroglycerine alone (5 mg/day) delayed the time to administration of first rescue analgesics, the combination of both provided an average of 14 h of effective postoperative analgesia after vaginoplasty, suggesting that transdermal nitroglycerin and the central cholinergic agent neostigmine may enhance each other’s antinociceptive effects at the dose studied.

Epidural nonsteroidal antiinflammatory drugs for cancer pain

A lthough pain relief with multimodal therapy is excellent in 45%-90% of cancer patients (l), dose escalation eventually occurs. The concurrent use of nonsteroidal antiinflammatory drugs (NSAIDS) to enhance opioid effects while decreasing the dose is recommended. Should NSAIDS and opioids fail, the spinal administration of opioids often results in improved analgesia with reduced opioid side effects w. Several reports have suggested a spinal site of action for NSAIDS (3-7) and synergy with spinal morphine (5). However, appropriate preclinical toxicity testing has not been performed for any commercially available NSAID, and intraspinal application is premature (8). We describe two cases in which epidural NSAIDS were administered by our ambulatory cancer patients without our initial knowledge or approval.

Influence of formulation on the physicochemical properties of casein microparticles

Casein microparticles (CAS/MP) have a potential clinical use for targeting drugs. However, the use of organic solvents in their preparation is undesirable. This study was designed to investigate the influence of preparation procedures in aqueous media on the formulation and physicochemical properties of CAS/MP. The first stage involved the influence of the coacervating agents (lactic acid, succinic anhydride, succinic acid and tartaric acid). The second stage studied was the influence of the ionic strength and the third, the influence of adding a thickener, hydroxypropyl cellulose or hydroxypropyl methycellulose (HPC or HPMC), and a plasticizing agent (gelatin). Some physicochemical properties of CAS/MP were evaluated. While the infrared and the thermal analysis showed that all coacervating agents were appropriate for coacervation, the scanning electron microscopy studies showed that the external morphology of the particles was more homogeneous when lactic acid was used. Utilizing lactic acid as the coacervating agent, there was a trend effect of adding NaCl implying that the increasing of the ionic strength resulted in better stability. Finally, the addition of 0.1% HPC plus either 0.25 or 0.5% gelatin resulted in homogeneous formulations. In conclusion, the use of lactic acid plus 0.1% HPC and 0.25% gelatin results in biodegradable and homogeneous CAS/MP, presenting a potentially useful drug delivery system.

Combined intrathecal fentanyl and neostigmine:: Therapy for postoperative abdominal hysterectomy pain relief

STUDY OBJECTIVE To evaluate the analgesic action of spinal neostigmine as part of a multimodal analgesic therapy approach including spinal neostigmine and spinal fentanyl for postoperative pain relief DESIGN Randomized, prospective study. SETTING Teaching hospital. PATIENTS 50 ASA physical status I and II patients undergoing abdominal hysterectomy. INTERVENTIONS Patients were assigned to one of five groups (n = 10) to receive 15 mg bupivacaine plus 1 ml of the test drug intrathecally. The control group (CG) received saline as the test drug, the fentanyl group (FG) received 25 microg fentanyl; the neostigmine group (NG) received 25 microg neostigmine; the fentanyl-neostigmine 10 microg group (FNG10) was given 10 microg fentanyl plus 10 microg neostigmine; and the fentanyl-neostigmine 25 microg group (FNG25) received 25 microg fentanyl plus 25 microg neostigmine. Pain and nausea were evaluated using a 10-cm visual analog scale (VAS). MAIN RESULTS The analgesic consumption, in 24 hours was greatest in CG, next highest in NG, FG, and FNG10 where consumption was the same in the three groups; and least in FNG25 (p < 0.05). The time to first rescue analgesic medication was greatest for FNG25 compared with the other groups (>5 hours compared with 2 to 3 hours; p < 0.05). VAS showed no statistically significant differences for pain impression, intraoperative and postoperative nausea, or occurrence of vomiting (p > 0.05). CONCLUSION The combination of 25 microg neostigmine with 25 microg fentanyl given intrathecally with 15 mg of hyperbaric bupivacaine delayed postoperative pain and lowered the number of rescue analgesics. Because the better quality of analgesia was obtained with an increased (although not statistically significant difference) incidence of untoward side effects, larger samples should be studied before its routine use is recommended.

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 &mgr;g 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.

Physicochemical characterization and enzymatic degradation of casein microcapsules prepared by aqueous coacervation

The use of biopolymers in sustained release systems has been studied by many research groups because of the bioavailability and biodegradability of these compounds. Casein is a natural biopolymer whose degradation results in biologically utilisable compounds. The objective of the present study was to assess the potential of casein microcapsules (CAS/MC) as sustained release systems using acetaminophen as a model drug. CAS/MC were prepared by aqueous coacervation in lactate buffer containing gelatin, hydroxypropyl cellulose (HPC) and lecithin. After preparation, the microcapsules were treated, or not, with glutaraldehyde as a cross-linking agent. CAS/MC were loaded using two distinct procedures, either by dissolving 50% of the drug (w/w), relative to casein, in the polymer dispersion or by dissolving the drug in the coacervating solution. The drug present in CAS/MC was quantified by HPLC after an enzymatic degradation assay, and the CAS/MC were analysed by scanning electron microscopy and thermal analysis (differential scanning calorimetry and thermogravimetrical analysis). Loading of the drug was ~ 8% (w/w), with high resistance to enzymatic attack. The absence of an acetaminophen melting peak indicated that there was no drug present on the surface of the cross-linked systems. In addition, loading was accompanied by a reduction of the specific heat capacity of the systems, which suggests a decrease in stability. The outer morphology of the encapsulating polymer was affected by the process of microencapsulation. The data suggest that the microencapsulation process of aqueous coacervation and cross-linking is appropriate for the preparation of microencapsulated systems for sustained drug delivery.

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.