Fluradoline (HP 494), a centrally acting analgesic with antidepressant properties: Analgesic pharmacology

Fluradoline, (HP 494), 2-fluoro-11-[β-(methylamino)ethylthio]dibenz[b, f]oxepin maleate, was assessed in a variety of antinociceptive testing procedures which are used to predict analgesic efficacy in man. The compound, after oral or systemic administration, effectively attenuated chemical-induced writhing, heat-induced tail flick, pressure-induced clip biting and hypersensitivity, and tail shock-induced lever pressing. When used for comparative purposes, morphine and/or codeine were also active in all tests, while the tricyclic antidepressant, imipramine, was weakly or not active. The pharmacologic profile differs from that of opiates in that the antinociceptive effect is not reversed by naloxone, and there is no cross tolerance to morphine and no interaction in in vitro binding studies using ³H-naloxone as the ligand. These data show that fluradoline has the potential for clinical effectiveness as an analgesic agent with a unique mechanism of action that differs from those of opiates and imipramine.     

Fluradoline (HP 494), a centrally acting analgesic with antidepressant properties: Antidepressant pharmacology

Fluradoline (HP 494), a tricyclic dibenz (b, f) oxepine derivative with an analgesic profile, was tested for antidepressant activity. After oral administration, fluradoline was twice as potent as imipramine and similar in potency to desmethylimipramine in blocking tetrabenazine-induced ptosis. Like standard antidepressants, fluradoline selectively increased response rates for electrical stimulation of the median forebrain bundle using internal capsule-lesioned rats. Response rates in nonlesioned rats were unaffected. There was partial protection against yohimbine toxicity and no potentiation of 5-hydroxytryptophan-induced seizures in mice. When administered to squirrel monkeys, the EEG profile from cortically-placed electrodes resembled that found for imipramine. Using in vivo and in vitro techniques, it was shown that fluradoline was not a monoamine oxidase inhibitor; however, the compound did block the reuptake of norepinephrine, serotonin and dopamine in brain homogenates. These results suggest that in addition to the analgesic profile, there is a concomitant antidepressant profile which may enhance the spectrum of activity of fluradoline.     

Etodolac in the management of pain: A clinical review of a multipurpose analgesic

Etodolac is a non-steroidal anti-inflammatory drug with analgesic properties. Its primary anti-inflammatory mechanism of action is through a selective effect on cyclo-oxygenase-2 (COX-2). It is rapidly absorbed after oral administration, and maximum plasma concentration (C_max) is reached in 1-2 h, with an elimination half-life (t1/2 ) of 6-8 h. Etodolac has been widely applied in the treatment of inflammatory arthritides such as rheumatoid arthritis, ankylosing spondylitis and gout and in osteoarthritis and has been shown to be efficacious and well tolerated. However, etodolac has other applications which rely primarily on its efficacy as an analgesic. In particular, etodolac has been evaluated in the treatment of a variety of different pain states. Etodolac has been observed to be efficacious in the treatment of acute pain following dental extraction, orthopaedic and urological surgery, and episiotomy, as well as in the treatment of pain due to acute sports injuries, primary dysmenorrhoea, tendonitis, bursitis, periarthritis, radiculalgia and low back pain. These studies indicate that etodolac is a multipurpose analgesic with many clinical applications in addition to its use in the treatment of inflammatory and degenerative forms of arthritis.     

草乌甲素的镇痛机制及其治疗疼痛的研究进展

草乌甲素具有良好的镇痛作用,用于多种疼痛的治疗。草乌甲素可作用于疼痛感知通路中的多个位点,发挥外周、中枢及其他镇痛机制。草乌甲素的临床治疗涉及到骨关节疼痛、癌性疼痛、带状疱疹相关性疼痛、急性疼痛和其他疼痛。对草乌甲素的镇痛机制和治疗各类疼痛的临床应用进行综述,以期对草乌甲素的临床治疗提供参考。     

In-vitro and in-vivo transdermal iontophoretic delivery of tramadol, a centrally acting analgesic

Objectives The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo. Methods To examine the effect of species variation and current strength on skin permeability of tramadol, in‐vitro skin permeation studies were performed using porcine ear skin, guinea‐pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in‐vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 µA/cm²) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included. Key findings The in‐vitro steady‐state skin permeation flux of tramadol current‐dependently increased without significant differences among the three different skin types. In the in‐vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in‐vivo steady‐state transdermal absorption rate was 499 µg/cm² per h as calculated by a constrained numeric deconvolution method. Conclusions The present study reveals that anodal iontophoresis provides current‐controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.     

葛根素对神经病理性痛模型小鼠的镇痛作用

目的探讨葛根素对神经病理性痛模型小鼠的镇痛作用,为临床开发新的镇痛药物奠定基础。方法结扎雌性C57BL/6小鼠单侧胫神经和腓总神经,建立坐骨神经分支选择损伤(spared nerve injury,SNI)神经病理性痛模型,利用机械刺激法和冷盘法分别观察腹腔注射不同剂量葛根素(100,75和25mg·kg-1)对SNI模型小鼠患侧脚掌痛阈的影响。结果 SNI模型小鼠腹腔注射75mg·kg-1葛根素可显著提高患侧脚掌的50%缩足阈值(P<0.01)和降低5min抬足次数(P<0.01),产生明显的镇痛作用,镇痛时间可维持60～70min;100mg·kg-1葛根素腹腔注射后虽然也可产生明显的镇痛作用,但作用时间较短,仅维持10～20min;25mg·kg-1葛根素腹腔注射后没有明显的镇痛作用。结论适当剂量的葛根素对神经病理性痛具有明显的镇痛作用。     

Cannabinoid pharmacological properties common to other centrally acting drugs

Cannabinoids produce a characteristic profile of in vivo effects in mice, including suppression of spontaneous activity, antinociception, hypothermia, and catalepsy. Measurement of these four properties, commonly referred to as the tetrad test, has played a key role in establishing the structure-activity relationship of cannabinoids acting at cannabinoid CB(1) receptors. The purpose of this study was to determine whether drugs acting at noncannabinoid CB(1) receptors produced a similar pharmacological profile. Mice were tested in this paradigm after being injected with Delta(9)-tetrahydrocannabinol and selected drugs from other drug classes. Delta(9)-Tetrahydrocannabinol dose-dependently produced all four effects with reversal by the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). Amphetamine, scopolamine, morphine, desipramine, pimozide, pentobarbital, ethanol, and diazepam were not fully active in at least one of the tests. Antipsychotics showed the greatest similarity to those of cannabinoids in the tetrad tests, although there were also distinct differences. Clozapine, haloperidol, thioridazine, and chlorpromazine (but not pimozide) were fully active in all four tests; however, unlike with Delta(9)-tetrahydrocannabinol, their effects were not blocked by SR 141716A. Further, whereas antipsychotics produced nearly 100% catalepsy, maximal catalepsy produced by Delta(9)-tetrahydrocannabinol was 60%. The mechanism through which antipsychotics produce these effects in mice is uncertain, but it differs from cannabinoid CB(1) receptor activation that mediates the effects of cannabinoids. While results of previous research suggest that the tetrad tests are a useful tool in examination of structure-activity relationships of cannabinoid CB(1) receptor agonists, the present results suggest that they must be used cautiously in the search for novel cannabinoid receptors.     

The problem of pain: Additive analgesic effect of tramadol and buprenorphine in a patient with opioid use disorder

Background: There is a paucity of published literature on the optimal treatment of pain in patients on buprenorphine treatment (BT) for opioid use disorder. Using this case report, we hope to demonstrate that tramadol may represent an effective treatment option for pain in patients on BT while encouraging future clinical trials. Case: The patient is a 56-year-old Caucasian male with a history of opiate use disorder on treatment with buprenorphine/naloxone 8/2?mg 2 times a day (BID) who was followed in an outpatient general psychiatry clinic that specializes in patients with co-occurring substance use disorders. Although maintaining sobriety from opioids, the patient continued to struggle with acute on chronic pain secondary to osteoarthritis that had left him walking with a cane. The patient was started on tramadol 50?mg 3 times a day (TID) for acute pain by his primary care physician (PCP) while he awaited surgical intervention. He reported analgesic effect with buprenorphine/naloxone but noted that it did not last the full period between his doses. He reported further improvement in his pain along with greater daily functioning with the additional use of tramadol, without side effects or withdrawal symptoms. Discussion: Current recommendations for pain management in patients on BT include discontinuation of BT therapy and/or addition of an adjunctive opioid analgesic (including additional buprenorphine/naloxone) while continuing agonist medication for treatment of opioid use disorder. However, determining which medication to use can be difficult, as there has been no literature examining this issue. In this case, the combination of buprenorphine and tramadol demonstrated an additive analgesic effect. Randomized control studies need to be performed to further understand the changes in pain measurement in patients on BT with tramadol compared with other adjunctive analgesic medications.     

Silperisone: a centrally acting muscle relaxant

Silperisone is a tolperisone like organosilicon compound with centrally acting muscle relaxant properties. Studies in mice showed that silperisone may have less propensity to cause CNS depressant or motor side effects than tolperisone or other antispastic drugs. In cats and rats, silperisone was an effective suppressant of monosynaptic and polysynaptic spinal reflexes and decerebrate rigidity. Its suppressant effect on the spinal reflexes was also demonstrated in the isolated hemisected rat spinal cord in vitro. The in vivo potency and efficacy of silperisone by i.v administration were similar to those of tolperisone and eperisone. However, in cats by intraduodenal administration and in mice by oral administration its duration of action was much longer and its functional bioavailability much higher than of the other two drugs. With regard to its profile of actions silperisone was similar to tolperisone with minor differences. The most striking difference was in pontine facilitation and bulbar inhibition of the patellar reflex. Tolperisone depressed both, whereas silperisone inhibited only the former. The mechanism underlying the spinal reflex depressant effects of silperisone involves the blockade of voltage gated neuronal sodium and calcium channels leading to a decreased release of excitatory transmitter and reduced neuronal excitability. In addition, silperisone has potassium channel blocking effect, which is stronger than that of tolperisone. Silperisone is absorbed rapidly and is extensively metabolized in rats. However, its metabolism in dogs and particularly in humans is much less extensive. The elimination half-life of silperisone in humans is 12 to 16 h, so that it can be administered once or twice daily. Phase I clinical studies with silperisone at doses up to 150 mg/day failed to detect any adverse effects at plasma concentrations considered to be effective in the preclinical tests. These findings suggested that silperisone might be a useful antispastic drug. However, findings in chronic animal toxicity studies led to the discontinuation of silperisone's development.     

Cyclodextrins: improving the therapeutic response of analgesic drugs: a patent review

Introduction: Cyclodextrins (CDs) are cyclic oligosaccharides that have recently been recognized as useful tools for optimizing the delivery of such problematic drugs. CDs can be found in at least 35 pharmaceutical products, such as anticancer agents, analgesic and anti-inflammatory drugs. Besides, several studies have demonstrated that CD-complexed drugs could provide benefits in solubility, stability and also improve pharmacological response when compared with the drug alone.

Areas covered: The patent search was conducted in the databases WIPO, Espacenet, USPTO, Derwent and INPI, using the keywords cyclodextrin, pain and its related terms (analgesia, hyperalgesia, hypernociception, nociception, antinociception, antinociceptive). We found 442 patents. Criteria such as the complexation of analgesic agents and evidence of improvement of the therapeutic effect were indispensable for the inclusion of the patent. So, 18 patents were selected.

Expert opinion: We noticed that some patents are related to the complexation of opioids, NSAIDs, as well as natural products, in different types of CDs. The use of CDs creates the prospect of developing new therapeutic options for the most effective treatment of painful conditions, allowing a reduction of dosage of analgesic drugs and the occurrence of side effects. Thus, CDs can be an important tool to improve the efficacy and pharmacological profile of analgesic drugs.     

镇痛药不同给药时机对中等面积二度烧伤患者换药镇痛效果的影响

目的 观察镇痛药的不同给药时机对烧伤换药所产生的疼痛强度及持续时间的影响。方法 男性下肢 烧伤患者40例按照随机数字表法均分为前换药组（Pre组）与后换药组（Post组）。Pre组患者于换药前30 min给予氟 比洛芬酯50 mg,Post组患者待换药结束后立刻给予相同剂量的氟比洛芬酯,记录2组患者换药过程中心率（HR）、收 缩压（SBP）、舒张压（DBP）及主观疼痛评分（数字评分法,NRS）的最高值（max）。同时记录2组患者自换药后0.5、1、 2、4、8、14及24 h的HR、SBP、DBP、NRS值及患者恢复至轻度疼痛时所需时间。结果 与Post组比较,Pre组在换药 过程中及换药结束后1 h内的HR、SBP及DBP均较低,4 h、14 h时SBP低于Post组,8 h时DBP低于Post组（P＜0.05）; 与Post组比较,Pre组在换药过程中及换药结束后4 h内的NRS均较低（P＜0.05）;与Post组比较,Pre组在换药结束后 可更快地恢复至轻度疼痛状态（P＜0.05）。结论 在烧伤换药前30 min给予镇痛药可明显减轻患者换药疼痛强度及 换药后疼痛持续时间。     

Decreased analgesic effect of morphine,but not buprenorphine,in patients with advanced P-glycoprotein+ cancers

BackgroundP-glycoprotein (P-gp) is expressed on the blood-brain barrier (BBB) and acts as a transporter regulating the analgesic effect of morphine. The P-gp is also expressed by different types of tumors. The aim of this study was to determine the potential association of the P-gp expression in malignant tumors with analgesic effects in patients.MethodsThe P-gp expression in 120 malignant tumors was examined by immunohistochemistry. The analgesic responses of individual patients to morphine and buprenorphine (BNP) were evaluated by visual analog scale (VAS). The levels of plasma morphine and BNP were determined by HPLC.ResultsWe found that there was no significant difference in the values of VAS between patients with P-gp⁺ and P-gp^?malignant tumors in responses to 0.000025 g × kg^?2 of BNP administered by patient-controlled intravenous analgesia (PCIA), accompanied by similar levels of plasma BNP in those patients. In contrast, the values of VAS in response to 0.00075 g × kg^?2 of morphine in patients with P-gp⁺ tumors were significantly greater than those in the patients with P-gp^? tumors, although similar levels of plasma morphine were detected in both groups of patients. Furthermore, treatment with a higher dose (0.0011 g × kg^?2) of morphine effectively controlled pain in those with P-gp⁺ tumors.ConclusionOur data indicated that patients with P-gp⁺ tumors required a higher dose of morphine to achieve an analgesic effect and that the P-gp expression in tumors may be valuable for predicting the analgesic responses of patients with severe pain to morphine.     

新型中枢降压药物莫索尼定

莫索尼定是一个新型的中枢降压药物。它通过兴奋咪唑Ⅰ_1受体和兴奋中枢肾上腺素α_2受体而发挥降压作用。临床研究表明莫索尼定在高血压治疗中具有疗效显著、服药方便、不良反应轻等优点。莫索尼定尚有改善葡萄糖代谢、增加胰岛素敏感性、改善血脂代谢等作用。     

Guanfacine hydrochloride: a centrally acting antihypertensive agent

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of guanfacine hydrochloride are reviewed. Guanfacine lowers blood pressure by activating CNS alpha adrenoreceptors, which results in sympathetic outflow leading to reduced vascular tone. However, initial hypotensive response to guanfacine may be caused by stimulation of peripheral presynaptic receptors that inhibit sympathetic nerve function. Guanfacine is rapidly and completely absorbed from the gastrointestinal tract and apparently undergoes extensive distribution to all tissues. Steady-state plasma concentrations may be reached in four days. About 30% is excreted renally; the rest is metabolized hepatically. Its long duration of action is related to a slow elimination half-life. In the few controlled clinical trials of guanfacine versus placebo, systolic and diastolic blood pressures were reduced in patients treated with guanfacine; daily dosages of guanfacine 1, 2, and 3 mg (as the hydrochloride salt) were comparable in efficacy. Several large open trials of guanfacine showed blood pressure reductions of about 16% after one year; some patients received other antihypertensive therapy concomitantly. Guanfacine and clonidine appear to have comparable effects in reducing both systolic and diastolic blood pressure when given as monotherapy and as step-2 therapy; data on the comparative blood-pressure-lowering effects of guanfacine and methyldopa are less consistent. Guanfacine's adverse reactions include dry mouth, sedation, and constipation. Adverse effects and reaction to sudden withdrawal of the drug may be less severe with guanfacine than with clonidine. A daily dose of guanfacine 1 mg (as the hydrochloride salt) at bedtime is recommended; 2 or 3 mg, or divided doses, may be given if needed. Once-daily administration and fewer adverse effects may give guanfacine some advantage over other centrally acting antihypertensive agents. Further study is needed to determine whether it will be adequate as first-line therapy.     

Comparative study of analgesic efficacy and morphine-sparing effect of intramuscular dexketoprofen trometamol with ketoprofen or placebo after major orthopaedic surgery

AIMS: Multimodal analgesia is thought to produce balanced and effective postoperative pain control. A combined therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates could result in synergistic analgesia by acting through different mechanisms. Currently there are very few parenterally administered NSAIDs suitable for the immediate postoperative period. Therefore, this study was undertaken to assess the analgesic efficacy, relative potency, and safety of parenteral dexketoprofen trometamol following major orthopaedic surgery. METHODS: One hundred and seventy-two patients elected for prosthetic surgery, were randomized to receive two intramuscular injections (12 hourly) of either dexketoprofen 50 mg, ketoprofen 100 mg or placebo in a double-blind fashion. Postoperatively, the patient's pain was stabilized, then they were connected to a patient- controlled analgesia system (PCA) of morphine for 24 h (1 mg with 5 min lockout). RESULTS: The mean cumulative amount of morphine (CAM) used was of 39 mg in the dexketoprofen group and 45 mg in the ketoprofen group vs 64 mg in the placebo group. (Reduction in morphine use was approximately one-third between the active compounds compared with placebo (adjusted mean difference of -25 mg between dexketoprofen and placebo and -23 mg between ketoprofen and placebo. These differences were statistically significant: P 相似文献   

Kinetic fate of potassium embelate, a non-narcotic centrally acting analgesic after oral and intravenous administration

The pharmacokinetics of oral and intravenous potassium embelate (20 mg/kg) was studied in rats. The results revealed that this compound follows a biexponential kinetic pattern. Absorption was complete (bioavailability 97%) and fast. The disposition half-life is 9.5 h on intravenous and 11 h on oral administration. High concentrations of the drug were found in brain between 0.25 and 2 h, which is in agreement with its pharmacological action. The kidney plays a major role in the excretion of the drug.     

Effect of homeopathy on analgesic intake following knee ligament reconstruction: a phase III monocentre randomized placebo controlled study

Aims

The efficacy of homeopathy is still under debate. The objective of this study was to assess the efficacy of homeopathic treatment (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) on cumulated morphine intake delivered by PCA over 24 h after knee ligament reconstruction.

Methods

This was an add-on randomized controlled study with three parallel groups: a double-blind homeopathic or placebo arm and an open-label noninterventional control arm. Eligible patients were 18–60 years old candidates for surgery of the anterior cruciate ligament. Treatment was administered the evening before surgery and continued for 3 days. The primary end-point was cumulated morphine intake delivered by PCA during the first 24 h inferior or superior/equal to 10 mg day⁻¹.

Results

One hundred and fifty-eight patients were randomized (66 in the placebo arm, 67 in the homeopathic arm and 25 in the noninterventional group). There was no difference between the treated and the placebo group for primary end-point (mean (95% CI) 48% (35.8, 56.3), and 56% (43.7, 68.3), required less than 10 mg day⁻¹ of morphine in each group, respectively). The homeopathy treatment had no effect on morphine intake between 24 and 72 h or on the visual analogue pain scale, or on quality of life assessed by the SF-36 questionnaire. In addition, these parameters were not different in patients enrolled in the open-label noninterventional control arm.

Conclusions

The complex of homeopathy tested in this study was not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction.

What is already known about this subject

• The efficacy of homeopathy is still under debate and a recent meta-analysis recommended further randomized double-blind clinical trials to identify any clinical situation in which homeopathy might be effective.

What this study adds

• The complex of homeopathy tested in this study (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) is not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction.

     

A new model to assess analgesic activity: Pain-induced functional impairment in the rat (PIFIR)

A new experimental model to assess analgesic activity of both analgesic and non-steroidal antiinflammatory drugs in described. It uses the unilateral intra-articular knee injection of an uric acid suspension in mineral oil to produce acute inflammation, pain, and functional motor impairment. The model, named “pain-induced functional impairment in the rat” (PIFIR) assesses analgesic activity by measuring the capacity to walk with the injured extremity. The procedure determines both the potencies of analgesic drugs and the time course of the effect. Analgesia of selected reference agents was followed for 4 h and the effect versus time curves were constructed. The area under the curve (effect versus time), an expression of the overall activity during the observation period, increased in a dose-dependent manner. The area under the curve, E_max, T_Emax, and ED₅₀ of reference agents tested are reported. The PIFIR procedure was sensitive to opiate and nonopiate analgetics (nonsteroidal antiinflammatory drugs) and possibly steroidal antiinflammatory drugs. These characteristics make it suitable for screening purposes. © 1993 Wiley-Liss, Inc.     

Influence of naloxone on the postoperative analgesic and respiratory effects of buprenorphine

Summary Eighty patients recovering from major operations were investigated to evaluate the influence of naloxone on the analgesic and respiratory depressant properties of buprenorphine. They were randomly assigned to two groups to self-administer either buprenorphine (Group B) or a mixture of buprenorphine and naloxone (fraction 60%; Group BN) in the early postoperative period by means of the On-Demand Analgesia Computer (ODAC). The duration of patient-controlled analgesia (PCA) was 21.0 h (B) or 23.5 h (BN), during which 12.2 (B) and 18.2 (BN) demands per patient were recorded, representing significantly different consumption of buprenorphine 0.80 (B) and 1.07 (BN) µg·kg^–1·h^–1. Retrospective pain scores were significantly better in Group B, and respiratory rate was significantly higher in Group BN. The analgesia was judged superior by 81% (B) and 88% (BN) of the patients compared to conventional postoperative pain treatment. The minimum effective buprenorphine concentration (MEC) varied greatly in both groups with no significant differences between them (median 0.4 ng·ml^–1, range 0.1–8.6 ng·ml^–1); intra-individual variability was lower (67.9% B, and 58.2% BN) than inter-individual variability (107.3% B and 84.0% BN). Accumulation in plasma and acute tolerance did not occur. Thus, admixture of 60% naloxone decreased both the analgesic and respiratory depressant effects of buprenorphine which were generally independent of plasma concentrations. The analgesia achieved with the buprenorphine/naloxone mixture under patient-controlled conditions was comparable to that of other narcotic analgesics. Accordingly, this drug combination may be expected to give clinically adequate analgesia without notable impairement of spontaneous respiration, whilst withdrawal symptoms would probably arise in drug addicts abusing other opiates.