Patient-controlled analgesia with fentanil and midazolam in children with postoperative neurosurgical pain

Background Pain is the most common discomfort experienced by children undergoing major operations. It is most often not adequately treated because of inexperience and unfounded fears related to the use of opioid drugs. In adults, patient-controlled analgesia (PCA) is widely administered, while in children, its use with opioid drugs is still under evaluation for safety and efficacy. Objectives The objective of the study is to evaluate the safety and efficacy of an opioid drug (fentanil) administered by PCA associated with a sedative-adjuvant drug (midazolam) administered by continuous infusion in children having undergone major neurosurgical procedures. Materials and methods Sixteen children with moderate to severe postoperative pain were treated with fentanil by PCA (booster doses of 1 μg/kg) plus continuous infusion of midazolam (2 μg/kg per min) by an intravenous route. To evaluate safety and efficacy of this analgesic protocol, different subjective and objective parameters were monitored at 4-h intervals. In addition, patients’ satisfaction was assessed by a questionnaire at the end of the treatment. Main results All children experienced a good degree of analgesia and did not require any other analgesic drug during the treatment. Both subjective and objective parameters improved after starting pain-relieving treatment, and no major side effects occurred. The analysis of the answers of the questionnaire administered to the children showed a high grade of satisfaction. Conclusions PCA with fentanil plus continuous infusion of midazolam is a safe and efficacious method for analgesia in children with moderate to severe postoperative neurosurgical pain. The association of midazolam to fentanil also contributes to control anxiety and stress in this subset of patients and does not show any important side effects.     

Enhanced analgesic effects of tramadol and common trace element coadministration in mice

Chronic pain is managed mostly by the daily administration of analgesics. Tramadol is one of the most commonly used drugs, marketed in combination with coanalgesics for enhanced effect. Trace elements are frequent ingredients in dietary supplements and may enhance tramadol's analgesic effect either through synergic mechanisms or through analgesic effects of their own. Swiss Weber male mice were divided into nine groups and were treated with a combination of the trace elements Mg, Mn, and Zn in three different doses and a fixed dose of tramadol. Two groups served as positive (tramadol alone) and negative (saline) controls. Nociceptive assessment by tail‐flick (TF) and hot‐plate (HP) tests was performed at baseline and at 15, 30, 45, and 60 min after intraperitoneal administration. Response latencies were recorded and compared with the aid of ANOVA testing. All three trace elements enhanced tramadol's analgesic effect, as assessed by TF and HP test latencies. Coadministration of these trace elements led to an increase of approximately 30% in the average pain inhibition compared with the tramadol‐alone group. The most effective doses were 0.6 mg/kg b.w. for Zn, 75 mg/kg b.w. for Mg, and 7.2 mg/kg b.w. for Mn. Associating trace elements such as Zn, Mg, and Mn with the standard administration of tramadol increases the drug's analgesic effect, most likely a consequence of their synergic action. These findings impact current analgesic treatment because the addition of these trace elements may reduce the tramadol dose required to obtain analgesia. © 2015 Wiley Periodicals, Inc.     

Fentanyl for breakthrough pain: a systematic review

The purpose of this article is to systematically review the use of fentanyl as an analgesic for breakthrough pain. This article found that the oral transmucosal fentanyl (OTFC) had a quicker onset to analgesia than oral immediate-release opioids. Intranasal fentanyl (INFS) had a quicker onset to analgesia than buccal tablets, which in turn had a quicker onset to analgesia than OTFC. Patient acceptance and global rating of efficacy were greater for INFS than for buccal fentanyl. OTFC and INFS have been used effectively to reduce acute pain in children who are opioid-naive. Abuse and addiction to OTFC, fentanyl buccal tablets and INFS was low, owing to patient selection.     

Is epidural preemptive analgesia effective in lower abdominal surgery?

In this study, we aimed to investigate the preemptive analgesic efficacy of epidural application of fentanly-bupivacaine combination. A total of 60 patients admitted for total abdominal hysterectomy were included in this study after the approval of the ethic committee, and the patients were randomly classified into three groups. An epidural catheter was inserted to all patients through L2-3 or L3-4 space before general anesthesia induction. 2 micrograms/kg fentanyl in 0.25% bupivacaine in 10 ml serum saline was applied to the preemptive analgesia group (Group P) 20 minutes before the incision, and to the post-incisional analgesia group (Group E) 20 minutes after the incision, whereas control group received 10 ml serum saline 20 minutes before the incision through the epidural catheter. Pain scores were assessed with 100 mm Visual Analogue Scale (VAS) and four point Verbal Rating Scale (VRS) at 1., 2., 4., 6., 12., 24., 48. hours postoperatively. First analgesic requirement time and total analgesic consumption for 48 hours were also recorded. The VAS and VRS values in the postoperative 48 hours were significantly lower in Group P compared with the other groups (p < 0.05). First analgesic requirement time was also significantly prolonged in Group P (p < 0.001). Total analgesic consumption in Group P was significantly lower than the other two groups (p < 0.05). As a result we observed that preemptive administration of epidural fentanyl-bupivacaine combination reduces the postoperative pain and analgesic consumption in lower abdominal surgery.     

Isobolographic analysis of interaction between cyclooxygenase inhibitors and tramadol in acetic acid-induced writhing in mice

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. Combined use of NSAIDs and opioids has been indicated for achieving better analgesia with reduced side effects. The present study was aimed at evaluating the combination of different NSAIDs, which inhibit cyclooxygenase (COX) enzymes and tramadol against acetic acid-induced writhing in mice. The expected beneficial effect of combination regimen was analyzed by isobolographic analysis. The oral and intrathecally administered tramadol, a mu-opioid and naproxen, a nonselective COX inhibitor produced dose-dependent antinociception, however, rofecoxib, a selective COX-2 inhibitor lacked analgesic efficacy in writhing test. Isobolographic analysis showed synergistic or supra-additive interactions for the combinations of naproxen and tramadol after oral and intrathecal administration. However, similar interaction was not observed when tramadol was combined with rofecoxib. Pretreatment with naloxone partially reversed the antinociceptive effect of tramadol per se and its combination with naproxen without modifying the per se effect of NSAID. The results demonstrated marked synergistic interaction between naproxen and tramadol and such interaction involved opioid as well as non-opioid mechanisms of tramadol and inhibition of COX-1 but not COX-2 by naproxen.     

Treatment of restless legs syndrome with tramadol: an open study

BACKGROUND: Tramadol is a central analgesic that seems to have fewer side effects and a lower abuse potential than classical opioids. Since the treatment of restless legs syndrome (RLS) with levodopa or classical opioids is problematic, new treatment possibilities would be valuable. METHOD: We treated 12 patients who fulfilled at least the minimal diagnostic criteria proposed by the International Restless Legs Syndrome Study Group as well as the criteria proposed by Gibb and Lees, some of them treatment resistant or prone to side effects of previous medications, with 50 to 150 mg of tramadol per day in an open study. The follow-up lasted from 15 to 24 months. RESULTS: Ten patients reported clear amelioration and 1 reported slight amelioration of their symptoms, while 1 reported no effect. Tramadol was described to be the most effective treatment and free of side effects when compared with several other treatments. No major tolerance against treatment effect emerged among those who needed only a single evening dose. CONCLUSION: Compared with other treatments for RLS, tramadol seems to be superior in some cases, possibly because of its unique pharmacodynamic profile. Controlled studies are needed. Meanwhile, we believe that tramadol should be considered before other opioids are prescribed. We recommend intermittent treatment and careful monitoring.     

Effects of tramadol on alpha2-adrenergic receptors in the rat brain

In recent years, it has been postulated that tramadol, used mainly for the treatment of moderate to severe pain, might display a potential as an antidepressant drug. The present study investigated the effects of acute and repeated tramadol administration on the binding of [³H]RX 821002, a selective α₂-adrenergic receptor ligand, in the rat brain. Male Wistar rats were used. Tramadol (20 mg/kg, i.p.) administered acutely (single dose), at 24 h after dosing, induced a significant decrease in the α₂-adrenergic receptors in all brain regions studied. The most pronounced effects were observed in all subregions of the olfactory system, nucleus accumbens and septum, thalamus, hypothalamus, amygdala, and cerebral cortex. Repeated treatment with tramadol (20 mg/kg, i.p., once daily for 21 days) also induced statistically significant downregulation of [³H]RX 821002 binding sites in the rat brain. However, the effect—although statistically significant—was less pronounced than in the group treated acutely with the drug. Since drugs such as mianserin and mirtazapine are potent antagonists of central α₂-adrenergic receptors and are effective antidepressants, it is tempting to suggest that, in addition to other alterations induced by tramadol, downregulation of these receptors may represent a potential antidepressant efficacy. On the other hand, one should be careful to avoid the treatment of chronic pain with tramadol in patients already receiving antidepressant drugs. Tramadol-induced downregulation of α₂-adrenergic receptors—when combined with ongoing antidepressant therapy with drugs, which themselves inhibit serotonin reuptake or are antagonists of α₂-adrenergic receptors—might cause threatening complications.     

Effect of acute and chronic tramadol on [3H]-norepinephrine-uptake in rat cortical synaptosomes.

1 Tramadol hydrochloride is a centrally acting opioid analgesic whose efficacy and potency is only five to ten times lower than that of morphine. Opioid, as well as non-opioid mechanisms, may participate in the analgesic activity of tramadol. 2 [3H]-NE uptake in isolated rat cortical synaptosomes was studied in the presence of tramadol, desipramine, methadone, and morphine. Desipramine and tramadol inhibited synaptosomal [3H]-NE uptake with apparent Kis of 7.3 +/- 0.66 and 1.4 +/- 0.0045 microM, respectively. Methadone was active at a 10-fold higher concentration (Ki: 87 +/- 5.6 microM). In contrast, morphine essentially failed to inhibit [3H]-5-HT uptake (Ki: 0.75 +/- 0.40 M). 3 Methadone, morphine, and tramadol were active in the hot plate test with ED50s of 6.2, 9.3, and 40 mg kg-1, respectively. 4 [3H]-NE uptake was examined in synaptosomes prepared from rats 30 min after receiving a single dose of morphine, methadone or tramadol. Only tramadol (31 mg kg-1, i.p.) decreased uptake of the transmitter, with an ED50 equal to that in the hot plate test. 5 Animals were chronically treated for 15 days with increasing doses of tramadol (20 to 125 mg kg-1, i.p.). Twenty-four hours after the last drug injection, a challenge dose of tramadol (40 mg kg-1, i.p.) was administered. Chronic tramadol was still able to reduce [3H]-NE uptake by 35%. 6 These results further support the hypothesis that [3H]-NE uptake inhibition may contribute to the antinociceptive effects of tramadol. The lack of tolerance in [3H]-NE uptake, together with the absence of behavioural alteration after chronic tramadol treatment proposes that tramadol holds potential over classical opioids in the treatment of pain disorders.     

Patient-controlled epidural analgesia in labour: the addition of fentanyl or clonidine to bupivacaine

In this study, we studied 45 healthy parturients with singleton vertex presentation. Patients were allocated randomly to receive either 0,125 % bupivacaine with 2 micro g/ml fentanyl or 0,125 % bupivacaine with 1,5 micro g/ml clonidine for epidural labour analgesia. A patient controlled epidural analgesia (PCEA) pump was programmed as follows: basale infusion rate: 6 ml/h, demand bolus: 5 ml, lockout interval: 10 min. Efficacy of analgesia was evaluated using visual analogue scale. Maternal and fetal cardiovascular variables, Apgar scores of the newborn at 1-5 min and umbilical arterial blood gas measurements were recorded. The duration of stages of labour and total analgesic consumption were also noted. Systolic blood pressure decreased significantly at 3rd h in bupivacaine plus fentanyl group. Although all patients experienced a good analgesia, pain scores in bupivacaine plus clonidine group were lower than bupivacaine plus fentanyl group. The analgesic requirement in bupivacaine plus clonidine group was less than the other group. There were no significant differences in fetal heart rate, Apgar scores or umbilical blood gases. In conclusion, the addition of clonidine to epidural bupivacaine for PCEA was superior to bupivacaine plus fentanyl for analgesia and analgesic requirement during labour.     

Comparison of efficacy and side effects of epidural tramadol and morphine in patients undergoing laminectomy: a repeated dose study

Tramadol acts through multiple mechanisms and has a low risk of post operative respiratory depression. We compared the efficacy of epidural tramadol with that of morphine for postoperative analgesia in these patients. The demographic data and the summed pain intensity difference scores (SPID) were similar in both the groups. The time to first supplementary dose was significantly shorter in the tramadol group compared to the morphine group (p<0.05). No patient in either group suffered respiratory depression.     

Selective potentiation of opioid analgesia by nonsteroidal anti-inflammatory drugs

Opioids are often used in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of moderate to severe pain. In this study we have examined interactions between these two classes of drugs. NSAIDs are inactive in the radiant heat tail-flick test, an assay of moderate to severe pain in which opioids are effective. In this assay, ibuprofen potentiated the analgesic actions of hydrocodone and oxycodone, shifting their ED(50) values by 2.5-fold and 4.6-fold despite its inactivity when given alone. These opioid/NSAID interactions were dependent upon both the opioid and the NSAID. Neither aspirin nor ketorolac influenced hydrocodone actions in this model and ibuprofen did not potentiate fentanyl or morphine analgesia. Together, these studies demonstrate potent interactions between selected combinations of opioids and NSAIDS and may help explain the clinical utility of combinations. However, the findings also illustrate differences between the drugs within each class.     

Distinct mechanisms underlying pronociceptive effects of opioids

In addition to analgesia, opioids may also produce paradoxical pain amplification [opioid-induced hyperalgesia (OIH)] either on abrupt withdrawal or during continuous long-term application. Here, we assessed antinociceptive and pronociceptive effects of three clinically used opioids at C-fiber synapses in the rat spinal dorsal horn in vivo. During 60 min of intravenous infusions of remifentanil (450 μg·kg?1·h?1), fentanyl (48 μg·kg?1·h?1), or morphine (14 mg·kg?1·h?1), C-fiber-evoked field potentials were depressed and paired-pulse ratios (PPR) were increased, indicating a presynaptic inhibition by all three opioids. After withdrawal, postsynaptic responses were enhanced substantially for the remaining of the recording periods of at least 3 h. Withdrawal from remifentanil led to long-term potentiation (LTP) of synaptic strength in C-fibers via activation of spinal μ-opioid receptors (MORs) and spinal NMDA receptors (NMDARs). Fentanyl and morphine caused an enhancement of synaptic transmission at C-fibers, which involved two distinct mechanisms: (1) an opioid withdrawal LTP that also required activation of spinal MORs and NMDARs and that was associated with a decrease in PPR suggestive of a presynaptic mechanism of its expression, and (2) an immediate-onset, descending facilitation of C-fiber-evoked field potentials during and after intravenous infusion of fentanyl and morphine. Immediate-onset, descending facilitation was mediated by the activation of extraspinal MORs, descending serotonergic pathways, and spinal 5-hydroxytryptamine-3 receptors (5-HT?Rs). Our study identified fundamentally different pronociceptive effects of clinically used opioids and suggests that OIH can be prevented by the combined use of NMDAR and 5-HT?R antagonists.     

咪唑安定、芬太尼联合布比卡因用于妇产科术后硬膜外自控镇痛的临床观察

目的 探讨咪唑安定、芬太尼联合布比卡因用于妇产科术后硬膜外自控镇痛(PCEA)的临床效果观察.方法 对我院2008-11 2012-03收治的ASAI～Ⅱ级采用连续硬膜外麻醉且术后采用PCEA镇痛的病人78例,随机分为观察组和对照组各39例,观察组应用咪唑安定、芬太尼联合布比卡因进行镇痛;对照组应用芬太尼和布比卡因进行镇痛.分别观察2组患者的镇痛效果、疼痛评分、生命体征及不良反应.结果 观察组优良率为97.43％,明显高于对照组的69.23％,2组镇痛,比较差异有统计学意义(P＜0.05).观察组中恶心呕吐3例,皮肤瘙痒2例;对照组中恶心呕吐4例,皮肤瘙痒1例,2组间比较差异无统计学意义(P＞0.05),2组中均无尿潴留及呼吸抑制的发生.结论 眯唑安定、芬太尼复合布比卡因用于妇产科术后是安全有效的,且不良反应轻微,值得临床推广应用.     

Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice

We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.     

Comparison of ropivacaine, ropivacaine plus tramadol and ropivacaine plus morphine in patients undergoing minor hand surgery

In our study we aimed to compare the effects of ropivacaine alone, ropivacaine plus tramadol HCl, and ropivacaine plus morphine HCl used as intravenous regional anesthesia (IVRA), on duration to the initiation of analgesia, total analgesia time, analgesic requirement, sedation levels and hemodynamic parameters. 53 patients undergoing minor hand surgery were included into the study. Patients were randomly divided into three groups to receive 40 ml of ropivacaine 0.2 % (Group R, n=18), ropivacaine 0.2 % plus 1 mg/kg tramadol HCl (Group RT, n=18), and ropivacaine 0.2 % plus 0.1 mg/kg morphine HCl (Group RM, n=17) as IVRA. Following the injection, the durations for the initiation of analgesia were recorded. Levels of sedation, analgesia (VAS) and hemodynamic parameters were recorded in 5 minute intervals throughout first 35 minutes intraoperatively and at 1, 5, 10, 15, 20, 30, 45 and 60th minutes postoperatively. Patients were asked about the initiation of pain and requirements of analgesic at the first postoperative day. The duration to the initiation of analgesia was similar between the groups. Total analgesia time was found to be 304.0 +/- 317.6 min in Group R, 327.0 +/- 316.5 min in Group RT, and 635.9 +/- 492.3 min in Group RM. The difference between Group R and RM was statistically significant (p<0.05). Analgesic requirements were similar between the groups (p>0.05). Mild local anesthetic toxicity was observed in Group RM in two patients. We conclude that, when used as IVRA, ropivacaine alone or with tramadol or morphine produced similar analgesia and surgery conditions, and ropivacaine plus morphine had more adverse effects besides its longer duration of analgesia.     

Blocking mu opioid receptors in the spinal cord prevents the analgesic action by subsequent systemic opioids

Systemically administered mu opioids may produce analgesia through inhibition of the ascending nociceptive transmission and activation of descending pathways. However, the relative importance of the spinal and supraspinal sites in the analgesic action of systemic opioids remains uncertain. It has been shown that systemic morphine can inhibit dorsal horn neurons independent of the descending system. In this study, we determined the extent to which spinal mu opioid receptors mediate the analgesic effect of systemic mu opioids. Rats were instrumented with an intrathecal catheter with the tip placed in the lumbar spinal cord. Nociception was measured by testing the paw withdrawal threshold in response to a noxious radiant heat or pressure stimulus. Surprisingly, intrathecal pretreatment with naloxone or H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP, a specific mu opioid receptor antagonist) completely blocked the inhibitory effect of intravenous morphine on mechanical nociception. Intrathecal naloxone or CTAP also abolished the effect of intravenous morphine on the withdrawal latency of the hindpaw, but not the forepaw, measured with a radiant heat stimulus. Furthermore, the inhibitory effect of subcutaneous fentanyl on mechanical nociception was eliminated by CTAP injected intrathecally. Intrathecal CTAP similarly abolished the effect of subcutaneous fentanyl on thermal nociception of the hindpaw but not the forepaw. Therefore, this study provides new information that when spinal mu opioid receptors are blocked, subsequent systemic administration of mu opioids fails to produce an analgesic effect. This finding highlights the important role of mu opioid receptors in the spinal cord in the antinociceptive action of opioids.     

Contribution of G-Protein α-Subunits to Analgesia,Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine

While opioids produce both analgesia and side effects by action at μ-opioid receptors (MORs), at spinal and supraspinal sites, the potency of different opioids to produce these effects varies. While it has been suggested that these differences might be because of bias for signaling via β-arrestin versus G-protein α-subunits (Gα), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of Gα subunits, we evaluated the role of Gα_i/o subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gα_i2, Gα_i3, and Gα_o markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for Gα_i1, as well as Gα_i2 and Gα_i3, but not Gα_o, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gα_i1 and Gα_i2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while Gα_i1 AS-ODN markedly reduced AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E₂-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gα_i3 and Gα_o AS-ODN-treated rats, respectively. In contrast, none of the Gα_i/o AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gα_i/o subunits is necessary for the analgesia and side effects of two of the most clinically used opioid analgesics. The design of opioid analgesics that demonstrate selectivity for individual Gα_i/o may produce a more limited range of side effects and enhanced analgesia.SIGNIFICANCE STATEMENT Biased μ-opioid receptor (MOR) agonists that preferentially signal through G-protein α-subunits over β-arrestins have been developed as an approach to mitigate opioid side effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense to different Gα_i/o subunits play a role in hyperalgesia and analgesia induced by subanalgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G-protein α-subunits.     

Behavioral effects of lipopolysaccharide in rats: involvement of endogenous opioids

Activation of the immune system in response to either infection or lipopolysaccharide (LPS) produces neurophysiological, neuroendocrine and behavioral changes. Some of the physiological consequences of LPS are mediated by endogenous opioid peptides. The following studies were designed to characterize the effects of LPS in several behavioral paradigms, and to determine the role of opioids in mediating these effects. The effects of LPS on locomotor and self-care activity were assessed in the open field test. Rats were injected with either saline or a dose of LPS (25, 50, 100, or 1000 μg/kg). 4 h later, the animals were placed in an open field and the numbers of line crossings, rearings and grooming episodes were counted. LPS significantly suppressed the three open field behaviors in a dose-related manner. The effect of LPS on sensitivity to pain was determined using the hot-plate and tail-flick tests. Administration of LPS (200 μg/kg) increased pain sensitivity in the hot plate test 30 min after drug administration, but produced a significant analgesic response 4 h after drug administration in both tests. Further characterization of LPS-induced analgesia demonstrated that it began about 2 h after and disappeared 30 h after the administration of LPS. Administration of naltrexone completely blocked the analgesic effects of LPS 4 h after its administration, but had no effect on LPS-induced suppression of activity in the open field. The effect of LPS on body temperature was biphasic, producing hypothermia at 2 h and hyperthermia at 8–30 h after its administration. Naltrexone had no effect on the body temperature changes induced by LPS. These results suggest that endogenous opioids mediate the analgesic effects of LPS, but they are involved neither in mediating LPS-induced suppression of locomotor and self care behaviors nor in alterations of body temperature.     

Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells

Surgery stress has been shown to be associated in rat with decreased natural killer (NK) cell activity and enhancement of tumor metastasis. We have previously shown that the analgesic drug tramadol stimulates NK activity both in the rodent and in the human. In the present study, we analyze, in the rat, tramadol ability to prevent the effect of experimental surgery on NK activity and on the enhancement of metastatic diffusion to the lung of the NK sensitive tumor model MADB106. The administration of tramadol (20 and 40 mg/kg) before and after laparatomy significantly blocked the enhancement of lung metastasis induced by surgery. In contrast, the administration of 10 mg/kg of morphine was not able to modify this enhancement. The modulation of NK activity seemed to play a central role in the effect of tramadol on MADB106 cells. In fact, both doses of tramadol were able to prevent surgery-induced NK activity suppression, while the drug significantly increased NK activity in normal non-operated animals. Morphine, that in normal rats significantly decreased NK cytotoxicity, did not prevent surgery-induced immunosuppression. The good analgesic efficacy of tramadol combined with its intrinsic immunostimulatory properties suggests that this analgesic drug can be particularly indicated in the control of peri-operative pain in cancer patients.     

氟比洛芬酯与曲马多开颅术后镇痛的临床效果比较

目的比较氟比洛芬酯与曲马多用于颅脑手术术后镇痛的临床效果及不良反应。方法选择择期颅脑手术术后患者60例,随机分为两组,每组30例。A组：于手术结束前30min静脉给予氟比洛芬酯1．5mg／kg,B组于手术结束前30min静脉给予曲马多2mg／kg,观察术后1h、3h、6h内的疼痛视觉模拟评分（visual analogue scale,VAS）、镇静、恶心、呕吐现象,记录血氧、心率、呼吸频率。结果A组各时段镇痛满意程度明显高于B组（P〈0．05）;不良反应中恶心、呕吐普遍低于B组（P〈0．05）;结论氟比洛芬酯静脉推注用于颅脑手术术后镇痛效果确切,不良反应发生率较曲马多显著降低。