Marlene Paulino dos Reis

Dose-response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty.

This study was designed to examine postoperative analgesia with intrathecal neostigmine in a randomized, blinded trial with morphine as the active control in patients undergoing anterior and posterior vaginoplasty.A secondary aim was to provide preliminary data on the interaction between these two drugs. The incidence of adverse effects was also assessed. Forty-eight patients were divided into eight groups (50 micro gram, 100 micro gram, and 200 micro gram morphine [M]; saline; 50 micro gram, 100 micro gram, and 200 micro gram neostigmine [N]; and 50 micro gram morphine + 50 micro gram neostigmine). Anesthesia was provided with a balanced technique. All patients stayed 24 h in the recovery room where adequacy of postoperative analgesia and side effects were assessed. Increasing doses of intrathecal morphine (50 micro gram, 100 micro gram, and 200 micro gram) and intrathecal neostigmine (50 micro gram, 100 micro gram, and 200 micro gram) showed a dose-dependent pattern of analgesia (P < 0.001). The M50 + N50 combination resulted in a better analgesic effect with fewer side effects than M50, N50, and control groups. These preliminary data suggest that spinal neostigmine produces analgesia for vaginoplasty surgery similar in duration to spinal morphine and that the combination of morphine and neostigmine may allow a reduction in the dose of each component for postoperative analgesia. (Anesth Analg 1996;82:1182-7)

The effects of early or late neurolytic sympathetic plexus block on the management of abdominal or pelvic cancer pain

&NA; Neurolytic sympathetic plexus block (NSPB) has been proposed to prevent the development of pain and improve the quality of life of patients with cancer, thus questioning the WHO protocol that proposes the use of invasive methods only as a final resort. This study evaluates the pain relief, opioid consumption and quality of life provided by the use of NSPB in two different phases of cancer pain and compares them with that provided by pharmacological therapy only. Sixty patients with abdominal or pelvic cancer pain were divided into three groups and observed for 8 weeks. In group I, neurolytic celiac (NCPB) or superior hypogastric plexus block (SHPB), or lumbar sympathetic ganglion chain block (LSGCB) was performed with alcohol in patients using NSAID and a weak oral opioid or morphine (dose≤90 mg/day) and reporting VAS≥4. In group II, NCPB, SHPB or LSGCB were performed on patients using NSAID and morphine (dose≥90 mg/day) and reporting VAS≥4. The patients of group III received pharmacological therapy only. The patients of groups I and II had a significant reduction of pain (P<0.004), opioid consumption (P<0.02) and a better quality of life (P<0.006) than those of group III, but no significant differences between groups I and II were seen in these aspects. Opioid‐related adverse effects were significantly greater in group III (P<0.05). The occasional neurolysis‐related complications were transitory. The results suggest NSPB for the management of cancer pain should be considered earlier in the disease.

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.

Intrathecal neostigmine for postoperative analgesia after orthopedic surgery

STUDY OBJECTIVE To establish a dose-response curve for the analgesic effect of intrathecal neostigmine in patients undergoing below knee surgery with spinal anesthesia. To assess adverse effects, principally nausea and vomiting. DESIGN Randomized, double-blind, prospective study. SETTING Teaching hospital. PATIENTS 60 ASA physical status I and II premedicated patients undergoing orthopedic surgery (tibial or ankle reconstruction). INTERVENTION Spinal anesthesia was performed at the sitting position, L3-L4 interspace, 4 ml final volume, injected at a rate of 1 ml/10 sec. The control group (CG) received 15 mg hyperbaric bupivacaine 0.5% plus saline. The 25 micrograms neostigmine group (25NG) received 15 mg hyperbaric bupivacaine plus 25 micrograms neostigmine; the 50 micrograms neostigmine group (50NG) received 15 mg hyperbaric bupivacaine plus 50 micrograms neostigmine; and the 100 micrograms neostigmine group (100NG) received 15 mg hyperbaric bupivacaine plus 100 micrograms neostigmine. Patients were placed supine after the spinal punction. MEASUREMENTS AND MAIN RESULTS Time to first rescue analgesics, analgesia, and adverse effects at constant intervals were assessed using the 10 cm visual analog scale (VAS). Intrathecal neostigmine produced a dose-independent reduction in the postoperative rescue analgesic consumption (p < 0.0001). The time to first rescue analgesics was similar among groups (p > 0.05), and the overall 24-hour VAS pain scores were lowest for patients who had spinal neostigmine (p < 0.02). The 100NG group had the highest incidence of postoperative nausea and vomiting of all the groups (p < 0.05). CONCLUSION Intrathecal neostigmine produced a dose-independent analgesia and a dose-dependent incidence of adverse effects with the doses studied.

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.

Analgesic effect of subarachnoid neostigmine in two patients with cancer pain

&NA; Two patients suffering with severe pain due to metastatic abdominal neoplasm were selected to examine whether subarachnoid neostigmine provided effective pain relief. Neostigmine was injected through a catheter introduced into the subarachnoid space at L4–L5. Patients were monitored for changes in arterial blood pressure, cardiac and respiratory rates, body temperature, level of consciousness and neurologic change. Pain was classified by the patients on a verbal four‐grade scale, and analgesia was classified on a verbal three‐grade scale. Complete pain relief was obtained 2 h after neostigmine (0.2 mg) in one patient and 4 h after neostigmine (0.1 mg) in the second patient. Pain of mild intensity returned 20 and 22 h after drug administration, respectively. Gastrointestinal discomfort was observed in both cases, but nausea and vomiting occurred only in the patient treated with the highest dose of neostigmine. No significant change in the monitored parameters was observed, except for a 6‐h period of decreased blood pressure in the patient treated with the lower dose of neostigmine which required no specific treatment. The results obtained in these anecdotal cases indicate that subarachnoid neostigmine may provide analgesia in patients with pain arising from neoplasia, but further studies using controlled trials are needed before the drug is brought into clinical use.

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.

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.