Biodistribution of liposomes after extradural administration in rodents

We have mapped over 24 h the biodistribution of 99mTc-labelled multilamellar and small unilamellar liposomes in rabbits and rats by scintigraphic imaging after extradural injection. Multilamellar vesicles formed a depot at the site of injection; small unilamellar vesicles spread immediately along the extradural space and entered the systemic compartment 30 min after injection. Well-delineated liver and kidney labellings were seen after 24 h. The use of 3H-cholesterol- labelled small unilamellar vesicles suggested hepatic capture of intact liposomes with sizes averaging 0.05 microns drained unmodified into the systemic circulation through the extradural lymphatics. These results have led to the selection of multilamellar vesicles (0.1-15 microns size range) for clinical trials using liposome-associated local anaesthetics.      

Aseptic meningitis after intrathecal baclofen injection

StUDY DESIGN: Two case reports of aseptic meningitis after intrathecal baclofen injection. OBJECTIVES: To report an unusual complication of intrathecal baclofen injection during test injections. SETTING: Department of Neurological Rehabilitation, R Poincaré H?pital (Paris-Ile de France-Ouest University). CASE REPORTS: We present two cases of chemical meningitis after intrathecal baclofen injections by lumbar puncture. These cases presented with febrile meningeal syndromes during the 24 h following intrathecal baclofen injection. Direct cerebrospinal fluid (CSF) examination and CSF cultures were negative. An intense cellular reaction was observed with a marked predominance of neutrophils. Meningitis resolved spontaneously over 3-4 days. CONCLUSIONS: Chemical meningitis is a rare complication of intrathecal baclofen injections that must be recognized. It is a diagnosis of exclusion and its pathophysiological mechanism remains unclear.     

Cephalad movement of morphine and fentanyl in humans after intrathecal injection

BACKGROUND: Despite decades of use, controversy remains regarding the extent and time course of cephalad spread of opioids in cerebrospinal fluid (CSF) after intrathecal injection. The purpose of this study was to examine differences between two often used opioids, morphine and fentanyl, in distribution in the CSF after intrathecal injection. METHODS: Eight healthy volunteers received intrathecal injection of morphine (50 microg) plus fentanyl (50 microg) at a lower lumbar interspace. CSF was sampled through a needle in an upper lumbar interspace for 60-120 min. At the end of this time, a sample was taken from the lower lumbar needle, and both needles were withdrawn. CSF volume was determined by magnetic resonance imaging. Pharmacokinetic modeling was performed with NONMEM. RESULTS: Morphine and fentanyl peaked in CSF at the cephalad needle at similar times (41 +/- 13 min for fentanyl, 57 +/- 12 min for morphine). The ratio of morphine to fentanyl in CSF at the cephalad needle increased with time, surpassing 2:1 by 36 min and 4:1 by 103 min. CSF concentrations did not correlate with weight, height, or lumbosacral CSF volume. The concentrations of morphine and fentanyl at both sampling sites were well described by a simple pharmacokinetic model. The individual model parameters did not correlate with the distance between the needles, CSF volume, patient height, or patient weight. CONCLUSIONS: Fentanyl is cleared more rapidly from CSF than morphine, although their initial distribution in the first hour after injection does not differ greatly. The pharmacokinetic model demonstrates that mixing is the primary determinant of early concentrations and is highly variable among individuals.     

Intrathecal anaesthesia alters intracellular Ca2+/Mg2+ homeostasis in the spinal cord neurones of experimental rats

BACKGROUND: AND OBJECTIVE: The effect of anaesthesia induced by intrathecal injection of 6.3% MgSO4 or 4% lidocaine on intracellular electrolyte homeostasis in spinal cord neurones of a rat model was investigated. METHODS: Intracellular Ca2+, Mg2+, Na+ and K+ concentrations were determined at different times after intrathecal administration of NaCl (saline, a control group), MgSO4 or lidocaine. RESULTS: In both thoracic and lumbar spinal cord segments, Ca2+ concentrations rose significantly 30 min and 2 h after 6.3% MgSO4 injection, and after 24 h were still significantly increased compared with the values obtained from the control group which were subjected to sham 'anaesthesia' by saline injection (172, 121 and 108 ng mg-1 protein vs. control 23 ng mg-1 protein, respectively, in the thoracic segment and 222, 229 and 176 ng mg-1 protein vs. control 43 ng mg-1 protein, respectively, in the lumbar segment). Lidocaine injection also produced a significant increase in intracellular Ca2+ in the thoracic and lumbar spinal cord segments (69, 64 and 53 ng mg-1 protein vs. control 33.4 ng mg-1 protein and 26, 94 and 46 ng mg-1 protein vs. 23 ng mg-1 protein respectively). Only a modest rise in intracellular Mg2+ was observed after intrathecal MgSO4 or lidocaine injection (27 ng mg-1 protein vs. 23 ng mg-1 protein). Na+ and K+ concentrations decreased 24 h after MgSO4 and 1 h after lidocaine injection. CONCLUSION: Intrathecal anaesthesia by MgSO4 or lidocaine alters intracellular electrolyte homeostasis in spinal cord neurones of experimental rats. A possible common mechanism of action via Ca2+ ion channels is discussed.     

Distribution, tolerability and tissue compatibility of intrathecal tizanidine in the sheep

Background : Tizanidine (TZD) is an alpha-2-adrenergic drug with potential spinal analgesic action and could be a substitute or additive for intrathecal (i.t.) opiates in chronic pain treatment. However, long-term tolerability and tissue compatibility are not yet established.
Methods : Three sheep were infused intrathecally with TZD up to 4000 μg/d over a time period of up to 440 d using implantable drug administration devices; one control animal was infused with vehicle only; standard values were collected from untreated sheep. CSF samples and blood samples were analyzed to determine pharmacokinetics and systemic redistribution. Behavioral effects were studied. The spinal cord tissue was investigated using standard laboratory histology.
Results : Bolus kinetics after i.t. injection of TZD are best described by a two-phase model. Elimination half-lives of TZD in CSF were 15 min and 152 min, respectively. Clearance of TZD from lumbar CSF was 0.48 ml/min. Doses higher than 500 μg i.t. caused dose-dependent motor inactivity and sleepiness. Continuous i.t. TZD up to 4 mg/d was well tolerated regarding behavior, physical activity, heart rate, muscle strength, and coordination. Minor elevations of CSF cell counts and total protein were detected both in saline and TZD-treated animals, presumably due to local irritation by the catheter and repeated sampling procedures. Histological evaluation of the spinal cord and adjacent tissues showed no abnormalities.
Conclusion : The long-term intrathecal infusion of TZD is well tolerated and non-toxic in the sheep. The data favor clinical trials in patients with chronic pain.     

Dural and Arachnoid Membraneous Protection of the Abducens Nerve at the Petroclival Region

The goal of this study was to determine the membranous protection of the abducens nerve in the petroclival region. The petroclival portion of the abducens nerve was studied in ten dissections from five cadaveric head specimens. One of the heads was used for histological sections. Four heads were injected with colored latex for microsurgical dissections. The histological sections were prepared from petroclival dura mater, embedded in paraffin blocks, stained, sectioned in the axial, coronal, and sagittal planes, and evaluated by light microscopy. The abducens nerve was covered by a dural sleeve and arachnoidal membrane during its course within the petroclival area. Following the petrous apex, the abducens nerve was fixed by a sympathetic plexus and connective tissue extensions to the lateral wall of the cavernous segment of the internal carotid artery and to the medial wall of Meckel's cave. Fibrous trabeculations inside the venous space were attached to the dural sleeve. The lateral clival artery accompanied the dural sleeve of the abducens nerve and supplied the petroclival dura mater. The arterioles accompanying the abducens nerve through the subarachnoid space supplied the nerve within the dural sleeve. The arachnoid membrane covered the abducens nerve within the dural sleeve to the petrous apex, and arachnoid granulations found on the dural sleeve protruded into the venous space. The extension of the arachnoid membrane to the petrous apex and the presence of arachnoid granulations on the dural sleeve suggest that the subarachnoid space continues in the dural sleeve.     

Interaction between a NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 in antinociception in the spinal cord

Background: The intrathecal N -methyl- d -aspartate (NMDA) receptor antagonist, AP-5 and the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, YM 872 showed inhibition on both acute and facilitated nociception in our previous study. The present study was performed to investigate the interaction between intrathecal AP-5 and YM 872 in antinociception for acute and chronic nociception.
Methods: Sprague–Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of AP-5 or YM 872. The effects of the combination were tested by an isobolographic analysis using 50% effective dose (ED50). Total fractional dose was calculated as (ED50 dose of AP-5 in combination)/(ED50 dose of AP-5 alone)+(ED50 dose of YM 872 in combination)/(ED50 dose of YM 872 alone).
Results: Intrathecally administered AP-5, YM 872, and their combination produced dose-dependent increases of the tail-flick latency and decreases in the number of flinches in both phase 1 and 2 of the formalin test. The ED50 values of the combination were significantly lower than the calculated additive values ( P <0.01). Total fractional dose value was 0.22 in the tail flick test, 0.12 in the phase 1 and 0.14 in the phase 2 of the formalin test.
Conclusion: An NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 had synergistic antinociceptive effects on both acute thermal and inflammatory induced acute and facilitated nociception.     

Intrathecal morphine. Double-blind evaluation of optimal dosage for analgesia after major lumbar spinal surgery.

STUDY DESIGN: A prospective, randomized, double-blind study. OBJECTIVES: To evaluate the efficacy and safety of three different dosages of intrathecal morphine sulfate for postoperative analgesia after lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: Analgesia and respiratory depression after intrathecal morphine sulfate injection are dose related. The optimal dose to use for major spinal surgery is not known. METHODS: Sixty patients undergoing posterolateral lumbar fusion with or without decompression were divided randomly into 3 groups of 20 patients each. Anesthesia, monitoring, and surgery were similar for all patients. Just before closing of the wound, morphine sulfate was injected into the dural sack under direct visualization. Patients in groups 1-3 received 0.2 mg, 0.3 mg, and 0.4 mg morphine, respectively. Routine analgesia, consisting of diclofenac, was prescribed to use if necessary. Measurements were made and compared between the groups at zero hours (on admission to the Intensive Care Unit), 6 hours, 12 hours, 18 hours, and 24 hours after surgery. RESULTS: At zero hours and at 12 hours after surgery, pain levels were similar in groups 2 and 3, but were significantly higher in group 1 (P < 0.05). The respiratory rate was significantly lower in group 3 than in the other two groups (P < 0.05), and the arterial CO2 tension (PaCO2) was consistently higher in group 3. PaCO2 decreased in all three groups over the first 24 hours. Pruritus and nausea did not differ among the three groups. CONCLUSIONS: For adult patients undergoing posterolateral lumbar fusion, 0.3 mg (0.004 mg/kg) is probably the optimal dose of intrathecal morphine to manage pain.     

Evidence that liposome incorporation of cyclosporine reduces its toxicity and potentiates its ability to prolong survival of cardiac allografts in mice

Using liposomes, multilamellar lipid vesicles (MLV), we have found that liposome-incorporated cyclosporine is not only less toxic but also more effective in prolonging survival of cardiac allografts in mice. Following intravenous injection of liposome-incorporated drug, cyclosporine levels in blood were shown to decrease rapidly, while concentrations in spleen were higher (when compared with concentration following administration of commercial preparation). In this context, possible mechanisms of the beneficial effect of liposome-incorporated cyclosporine are discussed.     

Role of Spinal NO in Antiallodynic Effect of Intrathecal Clonidine in Neuropathic Rats

Background: The role of spinal nitric oxide (NO) in neuropathic pain remains uncertain. Although intrathecal clonidine causes NO release in the spinal cord, the functional role of spinal No in clonidine-produced analgesia has not been examined. The objectives of this study were to assess the role of spinal NO in maintenance of allodynia and to determine the role of spinal NO in the antiallodynic effect of intrathecal clonidine.

Methods: Allodynia was produced in rats by tight ligation of the left L5-L6 spinal nerves. Intrathecal catheters were inserted with tips in the lumbar intrathecal space. Mechanical allodynia was determined by application of von Frey filaments to the left hindpaw. In the first series of experiments, allodynia was assessed before and after intrathecal injection of saline, L-arginine, an NO donor (SNAP), two NO synthase inhibitors (TRIM and NMMA), or an NO scavenger (PTIO). In the second series of experiments, 20 [micro sign]g of clonidine was injected intrathecally 15 min after intrathecal injection of saline, TRIM, NMMA, or PTIO.

Results: Allodynia was not affected significantly by intrathecal injection of L-arginine, SNAP, TRIM, NMMA, or PTIO. The antiallodynic effect produced by intrathecal injection of clonidine was attenuated significantly by pretreatment with TRIM, NMMA, or PTIO.     

Lumbar epidural morphine in humans and supraspinal analgesia to experimental heat pain

BACKGROUND: Epidural administration of morphine is a common analgesic technique to manage pain. Morphine spreads from the epidural space to the cerebrospinal fluid and then rostrally, causing side effects mediated by the brain stem. However, data on the rostral spread of morphine-mediated analgesia are sparse. This study examined the rostral spread of analgesic effects on heat and electrical pain after epidural administration of morphine. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, 5 mg morphine or saline placebo were injected into the lumbar epidural space in nine healthy volunteers. Correct needle placement was confirmed with fluoroscopy. Analgesia to experimental nociceptive heat and electrical stimuli was measured at lumbar (L4), thoracic (T10), cervical (C2), and trigeminal (V2) levels before and 2, 5, 10, and 24 h after epidural injection. Plasma samples for assaying morphine concentrations were drawn before and after each analgesic evaluation. RESULTS: Epidural morphine significantly attenuated experimental heat pain at all dermatomes tested compared with saline placebo. Analgesic effects were significant at L4 after 2, 5, and 10 h, at T10 after 5, 10, and 24 h, and at V2 after 10 h. Electrical pain was attenuated at the lumbar and thoracic but not at the cervical dermatome. Analgesic effects were significant at L4 after 2, 5, and 10 h and at T10 after 5 and 10 h. Morphine plasma concentrations were below the detection limit (1 ng/ml) in eight of the nine subjects 10 h after epidural injection. CONCLUSIONS: Lumbar epidural injection of morphine attenuated cutaneous heat pain up to the trigeminal dermatome during a 24-h observation period. In a clinical context, this implies that some types of pain may be attenuated up to the supraspinal level after lumbar epidural administration of morphine.     

Intrathecal Adenosine following Spinal Nerve Ligation in Rat: Short Residence Time in Cerebrospinal Fluid and No Change in A1 Receptor Binding

Background: Intrathecal adenosine produces a remarkably prolonged effect to relieve mechanical hypersensitivity after peripheral nerve injury in animals. The purpose of the current study was to investigate whether this reflected an alteration in kinetics of adenosine in cerebrospinal fluid or in the number of spinal A1 adenosine receptors after nerve injury.

Methods: Male rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Two weeks later, a lumbar intrathecal catheter and intrathecal space microdialysis catheter were inserted. Adenosine, 20 [mu]g, was injected intrathecally in these and in normal rats, and microdialysates of the intrathecal space were obtained. Radioligand binding studies of adenosine A1 receptors were determined in spinal cord tissue from other normal and spinal nerve-ligated rats.

Results: Adenosine disappeared from rat cerebrospinal fluid within 30 min after intrathecal injection, with no difference between normal and spinal nerve-ligated animals. A1 adenosine receptor binding sites in the spinal cord were increased after spinal nerve ligation. This increase disappeared when adenosine deaminase was added to the membrane homogenates, suggestive of decreased endogenous adenosine in the membranes of nerve-ligated animals.     

CB2受体激动剂JWH015对大鼠神经病理性疼痛的治疗作用

目的 研究鞘内注射CB2受体激动剂JWH015对背根节慢性压迫(chronic compression of the dorsal root ganglia,CCD)大鼠痛阈和脊髓背角磷酸化NMDA受体NR2B亚基表达的影响,探讨CB2受体激动剂的镇痛作用及其可能机制.方法 鞘内置管成功后的雄性SD大鼠84只,随机分为3组:假手术+50%二甲基亚砜(dimethyl sulphoxide,DMSO)组(Sham组)、CCD+50%DMSO组(Vehicle组)、CCD+JWH015组(JWH015组).Sham组和Vehicle组各有6只大鼠在假手术或CCD后第7天(鞘内未给药)取脊髓标本,作为免疫组织化学法检测脊髓背角Tyr-1472磷酸化NR2B亚基表达的基础值.其余大鼠在假手术或CCD后第7天分别鞘内注射50%DMS010μl或JWH015 10μg.假手术或CCD之前、鞘内给药之前、之后1、2、4、8、24、72 h分别记录机械刺激缩足反射阈值(paw withdrawal mechanical threshold,PWMT)和热刺激缩足反射潜伏期(paw withdrawalthermal latency,PWTL)(n=6),鞘内给药之后4、8、24、72 h分别取脊髓标本(n=6),应用免疫组织化学法检测脊髓背角Tyr-1472磷酸化NR2B亚基的表达情况.结果 鞘内给药前Vehicle组和JWH015组大鼠的PWMT和PWTL均较基础值明显下降(P<0.01);与Vehicle组相比,JWH015组在给药后1、2、4 h PWMT和PWTL显著升高(P<0.01),但在给药后8、24、72 h差异无统计学意义(P>0.05);Sham组大鼠脊髓背角Tyr-1472磷酸化NR2B业基均呈低水平表达,但在CCD后第7天表达水平明显增强;鞘内注射50%DMSO后在各时间点均未能减弱CCD大鼠脊髓背角Tyr-1472磷酸化NR2B亚基的表达;鞘内注射JWH015在给药后4、8 h能明显减弱CCD大鼠脊髓背角Tyr-1472磷酸化NR2B亚基的表达,但在给药后24、72 h Tyr-1472磷酸化NR2B亚基的表达再次增强.结论 CB2受体激动剂JWH015对大鼠的神经病理性疼痛有治疗作用,该作用可能与抑制脊髓背角Tyr-1472磷酸化NR2B亚基的表达有关.     

Multiple cerebral hemorrhages following chymopapain chemonucleolysis. Case report

A case of multiple cerebral hemorrhages following chymopapain chemonucleolysis is reported. The authors believe the probable etiology was intrathecal extravasation of chymopapain after injection of the drug into a lumbar disc space.     

A huge intraspinal teratocarcinoma associated with an arachnoid cyst in a child

The authors report a 11-year-old girl with a huge intraspinal malignant teratoma associated with spinal arachnoid cyst. At seven year of age, suprasellar tumor was diagnosed and the patient received radiation therapy for tumor bed with total dose of 4,225 rads. As the result, marked decrease of the size of tumor was seen by follow-up CT scan. Serum alphafetoprotein (AFP) and human chorionic gonadotropin (HCG) level were at 51ng/ml and 31IU/l when total dose of 2,000 rads were over, and they decreased to 3ng/ml and 6.6IU/l at the dose of 4,225 rads respectively. The histology of the suprasellar tumor was unverified. She was discharged without any neurological deficits. For next 24 months, she received intrathecal administration of Methotrexate by repeated lumber puncture in 14 times. She remained intact neurologically. At eleven years of age, four years later, she started complaining of the right leg pain. On the examination, hypesthesia in the L distribution and stiff neck with positive straight leg raising test were observed. Urinary and bowel function were intact. CT scan of the head revealed residual of the suprasellar tumor but the size of the tumor was unchanged. Myelography showed complete block at the level of L. Laminectomy at L was performed and brownish cyst was found in the intradural space. Aspiration of cyst content and cyst wall resection were carried out. Histology of the cyst membrane was arachnoid and spinal arachnoid cyst was diagnosed. The postoperative course was uneventful until 13th postoperative day, when acute progressive paraparesis and numbness of bilateral toes were seen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lumbar Epidural Morphine in Humans and Supraspinal Analgesia to Experimental Heat Pain

Background: Epidural administration of morphine is a common analgesic technique to manage pain. Morphine spreads from the epidural space to the cerebrospinal fluid and then rostrally, causing side effects mediated by the brain stem. However, data on the rostral spread of morphine-mediated analgesia are sparse. This study examined the rostral spread of analgesic effects on heat and electrical pain after epidural administration of morphine.

Methods: In a randomized, double-blinded, placebo-controlled, crossover study, 5 mg morphine or saline placebo were injected into the lumbar epidural space in nine healthy volunteers. Correct needle placement was confirmed with fluoroscopy. Analgesia to experimental nociceptive heat and electrical stimuli was measured at lumbar (L4), thoracic (T10), cervical (C2), and trigeminal (V2) levels before and 2, 5, 10, and 24 h after epidural injection. Plasma samples for assaying morphine concentrations were drawn before and after each analgesic evaluation.

Results: Epidural morphine significantly attenuated experimental heat pain at all dermatomes tested compared with saline placebo. Analgesic effects were significant at L4 after 2, 5, and 10 h, at T10 after 5, 10, and 24 h, and at V2 after 10 h. Electrical pain was attenuated at the lumbar and thoracic but not at the cervical dermatome. Analgesic effects were significant at L4 after 2, 5, and 10 h and at T10 after 5 and 10 h. Morphine plasma concentrations were below the detection limit (1 ng/ml) in eight of the nine subjects 10 h after epidural injection.     

Respiratory depression after intrathecal injection of morphine: value of in situ naloxone

A case of delayed respiratory depression following an intrathecal injection of hyperbaric morphine hydrochloride is reported. This injection was made during a lumbar myelography in a 60 year old patient suffering from metastatic epiduritis unrelieved by oral or parenteral drugs. The differences in densities between the CSF, hyperbaric opiate solution and contrast medium explain the migration of the morphine hydrochloride from the lumbar thecal space to the basal cisternae, giving a fall in the responsiveness to CO2 of the brain stem respiratory centres. Parenteral naloxone did not reverse this ventilatory depression. Only the myosis and the analgesia disappeared. After 16 h of various attempts of reversal by parenteral injections, an intrathecal injection of naloxone was tried. This small dose (0.1 mg), given intrathecally, resulted in a prompt return to normal of respiratory function.     

Transitory block of the arachnoid granulations following subarachnoid haemorrhage

The arachnoid granulations of the superior sagittal sinus were examined for blockage by erythrocytes in 43 cases of subarachnoid haemorrhage. Ten cases had survived for more than two weeks after the haemorrhage. Among 33 cases with acute haemorrhage, 17 had evidence of blocking of the granulations. The severity of the block varied from complete clogging of nearly all granulations to slight filling of a few of them. Cases with some days' survival showed evidence of phagocytosis of the entrapped erythrocytes by macrophages. Several of the cases with old haemorrhage had groups of haemosiderin macrophages in the granulations but none showed fibrosis (except for one single villus). It is concluded that clogging of the arachnoid granulations may contribute to the raised intracranial pressure in some cases of acute subarachnoid haemorrhage. However, the observations do not support the hypothesis that the haemorrhage may lead to fibrosis or scarring of the granulations with chronic impairment of the cerebrospinal fluid resorption and subsequent hydrocephalus.     

Pharmacokinetics and clinical effects of intramuscular scopolamine plus morphine A comparison of two injection sites

Background: Intramuscular scopolamine plus morphine pre-medication is traditionally used when prominent sedative or antisialogogue effect is needed. Knowledge of the pharmacokinetics of scopolamine is limited due to low plasma concentrations found after therapeutic doses. This investigation compares the pharmacokinetics and the clinical responses of this drug combination injected into two commonly used injection sites.
Methods: Twelve ASA class 1 patients scheduled for minor surgery under spinal anaesthesia received scopolamine 6 μg/kg plus morphine 200 μg/kg injected in either deltoid (group D, n=6) or gluteal (group G, n=6) muscle.
Results: The peak plasma concentrations of scopolamine after deltoid or gluteal injection (2.2 vs 1.6 μg/1) and the time they were reached (17 vs 19 min) were comparable. The absorption of morphine was similar in both groups (T_max 16 min), but the peak plasma concentrations were higher after deltoid injection (71 vs 49 μg/1). The individual variation in the elimination half-lives of both scopolamine and morphine was smaller after deltoid injection (T½ scopolamine 1.9±0.7 vs 2.1±1.1 h, morphine 1.3±0.7 vs 2.3±1.5 h). Moderate slowing (25%) of heart rate was found in both groups. A heavy sedation and antisialogogue effect (VAS) was found in both groups with faster occurrence of maximal effect in group D (60 vs 120–180 min).
Conclusion: More predictable pharmacokinetics and clinical effects of intramuscular scopolamine plus morphine premedication can be achieved after an injection into deltoid muscle.     

Efficacy of a low-dose spinal morphine with bupivacaine for postoperative analgesia in children undergoing hypospadias repair

Background:  Children undergoing hypospadias repair need to be protected from highly unpleasant sensory and emotional experiences during and after surgery. We designed a double-blinded, randomized, and placebo-controlled study to compare the efficacy of a low-dose (2 μg·kg⁻¹) of intrathecal morphine with placebo for postoperative pain control of children undergoing repair of hypospadias surgery with spinal anesthesia.
Methods:  Fifty-four children were randomly assigned to one of two spinal anesthesia groups. Group M ( n  = 27) received hyperbaric bupivacaine plus 2 μg·kg⁻¹ of preservative-free morphine and group P ( n  = 27) received hyperbaric bupivacaine plus 0.9% NaCl (placebo) under inhalation anesthesia. General anesthetics were discontinued subsequent to the block. The primary outcome was the presence of pain-requiring analgesics during the first 12 h after the spinal block. Side effects were also recorded. The analgesic effects were evaluated by using the Children's Hospital of Eastern Ontario Pain Scale.
Results:  Forty-nine patients completed the trial. Fifteen patients (60%) in group P received supplementary analgesics within the first 12 h compared to only four patients (16.7%) in group M ( P  = 0.005). Mean duration of analgesia was 480 ± 209 and 720 ± 190 min in group P and group M respectively ( P  = 0.009). The groups were similar in postoperative side effects.
Conclusion:  Spinal anesthesia provided by hyperbaric bupivacaine is adequate for distal hypospadias repair in children, but adding 2 μg·kg⁻¹ intrathecal morphine provides better postoperative pain control when compared to placebo in these children.