Duration of analgesia and pruritus following intrathecal fentanyl for labour analgesia: no significant effect of A118G µ-opioid receptor polymorphism, but a marked effect of ethnically distinct hospital populations.

BACKGROUND: Genetic polymorphism (A118G) in the µ-opioid receptor has been reported to affect systemic opioid analgesia. However, reported pharmacogenetic effects on spinal opioid analgesia, particularly in labour, have been equivocal. METHODS: We prospectively assessed effects of the µ-opioid receptor A118G single nucleotide polymorphism (SNP) on analgesia after 20 µg of spinal fentanyl. We studied two ethnically distinct hospital populations (Miami and Jerusalem). Independent variables were A118G, ethnicity, and hospital. Primary outcome was time from spinal analgesia until analgesic request. Secondary outcomes were pain and pruritus, assessed at repeated intervals until analgesia request. RESULTS: One hundred and twenty-five nulliparous parturients in early labour were analysed. The allelic frequency of A118G was 14.8% (14.4% in Miami; 15.5% in Jerusalem). Time to analgesia request (sd) in Miami was 122 (44) min and in Jerusalem was 87 (32) min, P<0.001; Hispanic 123 (46) min vs Jew/Arab 87 (32) min, P<0.001; Black 121 (41) min vs Jew/Arab 87 (32) min, P=0.015. There was no significant effect of A118G. Survival analysis showed Miami > Jerusalem, P<0.001; Hispanics and Black > Jew/Arab, P<0.001; no effect of A118G. Within hospital groups, A118G had no effect on time to analgesic request; within genomic groups there was a significant difference between hospitals. The time-course for pruritus exactly paralleled the time-course for analgesia and was affected by hospital (P=0.006) and by ethnic group (P=0.03), but not by A118G. CONCLUSIONS: We found no significant effect for the A118G single nucleotide polymorphism (SNP) on analgesic duration after spinal fentanyl for labour. In contrast, ethnically distinct hospital population groups exerted a marked effect on the time-course of both analgesia and pruritus.

Novel pulsatile cerebrospinal fluid model to assess pressure manometry and fluid sampling through spinal needles of different gauge: support for the use of a 22 G spinal needle with a tapered 27 G pencil-point tip.

BACKGROUND: Parallel-walled spinal needles ≤ 22 G are routinely used for lumbar puncture, despite a reported ≥ 32% incidence of post-dural puncture headache. A tapered spinal needle (22 G shaft, 27 G tip) is in use in our institution. We hypothesized that despite the smaller dural puncture hole, this needle has similar cerebrospinal fluid (CSF) pressure equilibration times and CSF sampling times to a standard 22 G needle and assessed a range of spinal needles using an experimental pulsatile CSF reservoir. METHODS: The pulsatile CSF reservoir had an oscillating pressure varying between 25 and 15 cm H(2)O at a cycle frequency of 80 s(-1). We tested seven parallel-walled spinal needles (18-27 G) and the tapered 22/27 G needle. CSF pressure was measured every 2 s by manometry. The time to collect 1 ml CSF samples was measured. Saline 0.9% and mannitol 20% were tested separately. One-way ANOVA with Bonferroni post-hoc test was used to compare 22G, 27G and 22/27G needles. RESULTS: The mean [standard deviation (sd)] CSF pressure equilibration time (saline) was 40.7 (6.4), 108.7 (6.1), and 51.3 (4.6) s for the 22, 27, and 22/27 G needles (P< 0.0001 for comparisons between 27 G and other needles). The mean (sd) CSF sampling time (saline) was 40.3 (3.1), 225.3 (10.0), and 63.0 (5.2) s for the 22, 27, and 22/27 G needles (P< 0.0001 for comparisons between 27 G and other needles, and P= 0.019 between 22 and 22/27 G needles). Saline was different from mannitol for both measurements and all needles (P< 0.0001). CONCLUSIONS: A 22/27 G tapered spinal needle has similar flow properties to the 22 G needle, despite a 27 G tip.

A randomized controlled trial using patient-controlled epidural analgesia with 0.25% versus 0.0625% bupivacaine in nulliparous labor: effect on analgesia requirement and maternal satisfaction.

BACKGROUND: The effect of epidural local anesthetic concentration on analgesic action is still the subject of debate. This study compared the effect of a four-fold change in concentration of bupivacaine for epidural analgesia in labor. METHODS: Nulliparous women in early active labor were recruited. All women received analgesic drugs via a lumbar epidural catheter, and all received fentanyl 1 microg/kg with the epidural induction dose and no further opioids throughout the study. Patients were randomized to receive either a 5-mL bolus followed by a 5-mL/h infusion of concentrated (0.25%) bupivacaine or a 20-mL bolus followed by a 20-mL/h infusion of dilute (0.0625%) bupivacaine. Patient-controlled epidural analgesia of the study solution was then used to assess additional analgesia requirements. Analgesic requirement, maternal satisfaction and obstetric outcome were compared. RESULTS: For subjects receiving 0.25% bupivacaine, the median total dose of drug administered was greater (117 vs. 90 mg, P=0.0008), and the mean maternal satisfaction score was less (82 vs. 93, P=0.04) than with the 0.0625% solution. CONCLUSIONS: Larger volumes of more dilute solutions may result in dose sparing and provide more effective labor analgesia. This study supports the continued trend towards dilute local anesthetic mixtures for labor epidural analgesia.

Mu-opioid receptor (A118G) single-nucleotide polymorphism affects alfentanil requirements for extracorporeal shock wave lithotripsy: a pharmacokinetic-pharmacodynamic study.

BACKGROUND: There are diverse reports concerning the single-nucleotide polymorphism (SNP) A118G in the gene coding for the mu-opioid receptor. This study assessed pharmacokinetic-pharmacodynamic relationships in patients with acute pain (water-immersed extracorporeal shock wave lithotripsy). METHODS: Ninety-nine patients (ASA I-II, age 18-70) were assessed in this prospective observational study. Blinding was achieved by determining genotype only after the procedure. I.V. alfentanil was administered by patient-controlled administration (loading dose, 10 microg kg(-1); continuous infusion, 20 microg kg(-1) h(-1); bolus, 3 microg kg(-1); lockout time, 1 min); no other analgesic or sedating medication was used. RESULTS: The allelic frequency was 15.2% in our population. The G118 SNP (AG/GG) was associated with a 27% increase in plasma alfentanil concentration (P=0.034), a 54% increase in alfentanil dose (P=0.009), a 47% increase in dose per kg body weight (P=0.004), a 55% increase in dose per kg corrected for stimulus intensity (P=0.002), a 112% increase in the numbers of attempted boluses (P=0.015), a 79% increase in the numbers of successful boluses (P=0.013), and a 153% increase in the numbers of failed boluses (P=0.042). Despite the increased alfentanil self-administration, the G118 SNP was associated with a 52% increase in verbal analogue pain scores over the same period of time (P=0.047). CONCLUSIONS: We demonstrated increased opioid requirement for alfentanil in patients with the G118 SNP, who self-administered a higher dose, achieved higher plasma concentration, and yet complained of more severe pain. This observation suggests that G118 SNP impairs the analgesic response to opioids.

Pulse oximeter perfusion index as an early indicator of sympathectomy after epidural anesthesia.

BACKGROUND: The pulse oximeter perfusion index (PI) has been used to indicate sympathectomy-induced vasodilatation. We hypothesized that pulse oximeter PI provides an earlier and clearer indication of sympathectomy following epidural anesthesia than skin temperature and arterial pressure. METHODS: Forty patients received lumbar epidural catheters. Patients were randomized to receive either 10 ml 0.5% bupivacaine or 10 ml 0.25% bupivacaine. PI in the toe, mean arterial pressure (MAP) and toe temperature were all assessed at baseline and at 5, 10 and 20 min following epidural anesthesia. The effect of epidural anesthesia over time was assessed by repeated measures analysis of variance. Additionally, we defined clinically evident sympathectomy criteria (a 100% increase in the PI, a 15% decrease in MAP and a 1 degrees C increase in toe temperature). The numbers of patients demonstrating these changes for each test were compared using the McNemar test for each time point. RESULTS: Twenty-nine subjects had photoplethysmography signals that met a priori signal quality criteria for analysis. By 20 min, PI increased by 326%, compared with a 10% decrease and a 3% increase in MAP and toe temperature, respectively. For PI 15/29, 26/29 and 29/29 of the subjects met the sympathectomy criteria at 5, 10 and 20 min, respectively, compared with 4/29, 6/29 and 18/29 for MAP changes and 3/29, 8/29 and 14/29 for toe temperature changes. CONCLUSIONS: PI was an earlier, clearer and more sensitive indicator of the development of epidural-induced sympathectomy than either skin temperature or MAP.

Antepartum continuous epidural ropivacaine therapy reduces uterine artery vascular resistance in pre-eclampsia: a randomized, dose-ranging, placebo-controlled study.

BACKGROUND: No therapy is currently available to improve the reduced uteroplacental blood flow (UPBF) that characterizes pre-eclampsia. We hypothesized that sympathectomy induced by epidural local anaesthesia reduces uterine vascular resistance (which is inversely correlated with UPBF) in pre-eclampsia. METHODS: Ten pregnant women between 24 and 32 weeks of gestation with pre-eclampsia and uterine artery flow abnormalities were randomized to antepartum continuous epidural therapy (ACET) or control. ACET was initiated by a 5 day dose-ranging trial (ACET-1) of 0.04, 0.06, 0.08, and 0.1% ropivacaine and saline placebo, each at 10 ml h(-1) for 24 h. Doses were randomized and double-blind. Doppler ultrasound indices of vascular resistance were assessed at baseline and after each 24 h dosing period in both uterine arteries. Subsequently, these ACET patients were administered 0.1% ropivacaine until delivery (ACET-2), with one additional randomized double-blind placebo day. RESULTS: Five patients were randomized to ACET. In each patient, one uterine artery exhibited a dose-dependent reduction in vascular resistance (P=0.035), a response that returned to baseline following placebo (P<0.001). The contralateral uterine artery exhibited either increased vascular resistance or no change. In all cases, the uterine artery that responded to ACET had higher baseline resistance than its pair (P=0.043). Baseline right-left difference in resistance between paired uterine arteries was greatly diminished following ACET. Although ACET patients had a mean (sd) duration to delivery of 19 (9) days compared with control 2 (1) days (P=0.008), this should be interpreted with caution because of demographic differences between groups. CONCLUSIONS: ACET reduces uterine artery resistance in pre-eclampsia <32 weeks. Uteroplacental re-distribution is a novel observation and warrants further investigation.

Methadone is safe for treating hospitalized patients with severe pain.

PURPOSE: Methadone is still regarded as a second line opioid for patients suffering from severe pain, and is rarely used in hospitalized patients. The infrequent use of methadone is probably due to its long plasma half-life that could lead to accumulation and toxicity. In the present study we report that clinically effective analgesic doses of methadone, given either epidurally or orally, can be used safely for prolonged treatment in hospitalized patients. CLINICAL FEATURES: Over a five-year period we administered methadone at Hadassah Hospital in Jerusalem to 3,954 in-patients with severe pain, 12% of whom were younger than 17 yr. Satisfactory pain relief was recorded in more than 85% of the patients. None of the patients treated with oral methadone developed serious side effects. Three patients, treated with epidural methadone (0.09%), developed a clinically significant respiratory depression. In all three cases, epidural pump failure or pump misprogramming resulted in methadone overdose. None of the children or adults treated with methadone developed addiction during hospitalization. CONCLUSION: Based on its analgesic properties and marked safety profile, we suggest that methadone could be added to the analgesic armamentarium of in-hospital health-care providers. Moreover, methadone could serve as the opioid of first choice in some in-patient populations.

Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats.

PURPOSE: To assess the role of esmolol, a beta1 receptor blocker, in the modulation of pain in the absence of anesthesia. METHODS: Rats were chronically instrumented to record mean arterial blood pressure (MAP) and heart rate (HR). Animals were divided into three groups. Group 1 [esmolol high (EH) 150 mg x kg(-1) x hr(-1); n = 9], Group 2 [esmolol low (EL) 40 mg x kg(-1) x hr(-1); n = 7] and Group 3 saline (n = 9). Formalin 5% was injected in the rat hind paw. Formalin-induced lifting, MAP and HR were recorded at five minute intervals for 35 min after formalin injection. RESULTS: Formalin was associated with an early (Phase 1; 0-5 min) and late nociceptive response (Phase 2; 10-35 min). Esmolol did not affect Phase 1. Although low dose esmolol had minimum effects on nociceptive Phase 2, it was diminished with high dose esmolol. Formalin induced biphasic increases in MAP and HR. Although esmolol did not affect the initial increase in MAP, high dose esmolol blunted the secondary increase in MAP Both low and high doses of esmolol inhibited formalin-induced tachycardia during the first 30 min. CONCLUSION: Our data suggest that esmolol leads to analgesia and reduction of cardiovascular responses to pain.

Intraplantar injection of dextrorphan, ketamine or memantine attenuates formalin-induced behaviors.

The possible prophylactic effects of local injection of NMDA receptor antagonists that are currently used in humans was investigated in the present study. Intraplantar pretreatment with either 5 mM dextrorphan (DEX), 10 mM memantine (MEM) or 10 mM ketamine (KET) significantly attenuated formalin-induced lifting and licking behaviors, however flinching behavior was not effected. Control experiments indicated that these drug actions could be attributed to local and not systemic effects of the antagonists. We hypothesize that these actions result from blocking NMDA receptors present on unmyelinated sensory axons in the skin. These data suggest that peripheral NMDA receptors contribute to nociceptor activation and can be manipulated to reduce pain of peripheral origin. Since DEX, MEM and KET are currently used in humans and considered clinically safe, they have potential therapeutic value in the treatment of physiologic or pathologic pain states which are induced or maintained by peripheral nociceptor activity. Topical or local application would avoid the side effects that can accompany systemic or intrathecal injection of NMDA antagonists.

Oral methadone for the treatment of severe pain in hospitalized children: a report of five cases.

OBJECTIVE: Pain relief is still inadequate in many hospitalized patients, especially children in whom suboptimal use of analgesic drugs is still common. In the past 2 years, oral methadone has been used extensively in our institution for treating children with persistent pain from cancer, burns, or trauma who were capable of oral intake and whose pain was not relieved by nonopioid medications. SETTING: Tertiary university hospital. PATIENTS: Of the 70 children treated thus far with oral methadone, five are described in the present report. MAIN OUTCOME MEASURE: Pain relief, acceptability, and side effects of oral methadone in children with pain. RESULTS: Treatment with oral methadone (0.1% in 10% glucose, dose range of 0.2-0.6 mg/kg/day) for time periods of up to 6 weeks resulted in a rapid onset and stable pain relief, with no major side effects. No adverse responses were encountered after discontinuation of treatment. In three of the children, a parent-controlled analgesia regimen was successfully employed. CONCLUSIONS: Oral methadone can be recommended for babies and children who have severe pain that is not alleviated by nonopioid medications and who are capable of oral intake.

Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test.

The present study demonstrates that local cutaneous administration of either the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 or the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) significantly attenuates formalin-induced nociceptive behaviors. Specifically, pretreatment with either drug reduced the magnitude and time course of lifting and licking behavior in the late phase of formalin pain; however, flinching behavior was not affected. In contrast, post-treatment of formalin pain with either antagonist did not affect lifting and licking behavior, although flinching behavior was mildly attenuated. We hypothesize that these actions result from blocking of peripheral glutamate receptors located on unmyelinated axons at the dermal-epidermal junction. These data suggest that peripheral glutamate receptors on cutaneous axons can be manipulated to reduce certain aspects of pain of peripheral origin. This route of administration offers the advantage of avoiding the side effects of systemic administration.

The racemic metoprolol H2-antagonist interaction.

The effects of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of multiple-dose metoprolol were investigated in 12 normal, healthy male volunteers. The pharmacokinetics of metoprolol were assessed in terms of racemic metoprolol and the individual (R)- and (S)-enantiomers with a stereoselective assay. Ranitidine had no effect on the pharmacodynamics or pharmacokinetics of metoprolol. Although not affecting the pharmacodynamics of metoprolol, cimetidine did produce an increase in the bioavailability of metoprolol through inhibition of enzymes responsible for the first-pass elimination of the beta-blocker. The effect was stereoselective, with the major effect being on the less pharmacologically active (R)-enantiomer.

Leukotriene B4, a mediator of inflammation present in synovial fluid in rheumatoid arthritis.

Leukotriene B4 (LTB4), generated from arachidonic acid following lipoxygenase activity by a variety of inflammatory leucocytes, has been shown to be present in synovial fluid from patients with active rheumatoid arthritis. It does not persist as such, being converted to less active metabolites. The role of LTB4 as one of the natural mediators of inflammation is discussed.

Leukotriene B4, an inflammatory mediator in gout.

Leukotriene B4 (LTB4), a metabolite of arachidonic acid and a potent cytotaxin, is generated by human peripheral polymorphonuclear leucocytes (PMNs) exposed to monosodium urate crystals (MSU). The leukotriene is present in gouty effusions in concentrations significantly greater than those found in synovial fluid from patients with active rheumatoid arthritis or osteoarthritis. Further metabolism and biological deactivation of LTB4 by PMNs are partly inhibited by MSU. It is concluded that LTB4 is an important chemical mediator in an acute gouty attack.

Isomers of leukotriene B4 possess different biological potencies.

Rat elicited polymorphonuclear leucocytes (PMNs), when exposed to the ionophore A23187, release three isomers of leukotriene B4. The three isomers have been purified and tested for their ability to induce the chemokinesis of human PMNs in vitro, the aggregation of rat PMNs in vitro and changes in vascular permeability in rabbit skin in vivo in the presence of PGE2. The results demonstrate that all three isomers are biologically active and that the enzymatically produced isomer, in which the conjugated triene contains one cis and two trans double bonds, is more potent than the two diastereoisomers of LTB4 which contain all trans double bonds in the conjugated triene and which are produced by non-enzymatic hydrolysis.