Systematic evaluation of the nefopam–paracetamol combination in rodent models of antinociception

1. The aim of the present study was to explore the concept of multimodal anaesthesia using a combination of two non‐opioid analgesics, namely nefopam, a centrally acting non‐opioid that inhibits monoamine reuptake, and paracetamol, an inhibitor of central cyclo‐oxygenases. The antinociceptive characteristics of the combination were evaluated using four different animal models of pain. 2. In the mouse writhing test, antinociceptive properties were observed with ED₅₀ values of 1.5 ± 0.2 and 120.9 ± 14.8 mg/kg for nefopam and paracetamol, respectively. In the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind paw, with ED₅₀ values in the early phase of 4.5 ± 1.1 and 330.7 ± 80.3 mg/kg for nefopam and paracetamol, respectively, compared with 4.3 ± 0.2 and 206.1 ± 45.1 mg/kg for nefopam and paracetamol, respectively, in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. 3. In a rat incision model of postoperative thermal hyperalgesia, coadministration of nefopam at a non‐analgesic dose (3 mg/kg) with paracetamol at a low analgesic dose (300 mg/kg) showed the appearance of a strong antihyperalgesic effect, maintained for at least 3 h. In rat carrageenan‐induced tactile allodynia, the combination of low analgesic doses of nefopam (10 or 30 mg/kg) with a non‐analgesic dose of paracetamol (30 mg/kg), significantly blocked allodynia with a longer duration of efficacy. 4. In conclusion, coadministration of nefopam with paracetamol is worthy of clinical evaluation.     

Lack of effect of naltrexone on the spinal synergism between morphine and non steroidal anti-inflammatory drugs

To enhance analgesia, the combinatorial use of analgesic drugs with proven efficacies is a widely-used strategy to reduce adverse side effects. The present study charcaterizes the antinociceptive interaction of intrathecal morphine co-administered with different NSAIDs using isobolographic analysis.Antinoceptive activity was evaluated using a model for acute visceral pain, the writhing test of mice. The possible involvement of opioid receptors in the mechanism of action of the intrathecal co-administration of morphine and NSAIDs was investigated using the non-selective receptor antagonist naltrexone. The study demonstrated a synergistic antinociception of intrathecal administered combinations of morphine with the following NSAIDs: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supra additive effect was obtained with very low doses of each drug and it appeared to be independent of the COX-1 or COX-2 inhibition selectivity of each NSAID and was not significantly modified by intrathecal naltrexone. The findings of the present work suggest that the combination of opioids and NSAIDs has a direct action on spinal nociceptive processing, which may be achieved via mechanisms that are independent of the activation of opioid receptors. The ineffectiveness of naltrexone to reverse the analgesic activity of opioids + NSAIDs combinations indicates that other complex pain regulatory systems are involved in this effect.     

Isobolographic analysis of multimodal analgesia in an animal model of visceral acute pain

Multiple analgesic-drug combinations are commonly used in the management of acute and chronic pain in humans during multimodal or balanced analgesia. At present, these combinations are used empirically in clinical practice and are considered to be beneficial for the patient. Interactions between two antinociceptive drugs have been thoroughly examined, but the nature of interactions between three analgesics has not been studied. The antinociceptive interaction of ketoprofen (K) with a mixture of morphine (M) and paracetamol (P) was evaluated using a model of visceral acute tonic pain, the acetic-acid writhing test in mice. The i.p. administration of the combination M/P+K resulted in a significant potentiation of the antinociception induced either by K or by the synergic two-drug mixtures M/K, P/K and M/P. The effect of opioid, cholinergic, adrenergic and serotonergic antagonists on the analgesic interaction was assessed. The pretreatment of mice with atropine (1 mg/kg) did not produce any change in the synergistic interaction of the triple combination. The pretreatment with naltrexone (1 mg/kg) or tropisetron (1 mg/kg) reduced the intensity of M/P+K synergic interaction, while prazosin (0.1 mg/kg) significantly potentiated the synergy. The findings of this work suggest that the two major pathways of descending inhibitory systems, noradrenergic and serotonergic are significantly involved in the mechanism of the antinociceptive synergy induced by the triple combination. On the other hand, opioid pathways also seem to participate, since pretreatment with naltrexone reduced the synergy. In conclusion, the triple combination M/P+K induced a strong synergistic antinociceptive effect, which could be of interest for optimal multimodal clinical analgesia.     

Perioperative pain management

The under-treatment of postoperative pain has been recognised to delay patient recovery and discharge from hospital. Despite recognition of the importance of effective pain control, up to 70% of patients still complain of moderate to severe pain postoperatively.The mechanistic approach to pain management, based on current understanding of the peripheral and central mechanisms involved in nociceptive transmission, provides newer options for clinicians to manage pain effectively. In this article we review the rationale for a multimodal approach with combinations of analgesics from different classes and different sites of analgesic administration. The pharmacological options of commonly used analgesics, such as opioids, NSAIDs, paracetamol, tramadol and other non-opioid analgesics, and their combinations is discussed. These analgesics have been shown to provide effective pain relief and their combinations demonstrate a reduction in opioid consumption.The basis for using non-opioid analgesic adjuvants is to reduce opioid consumption and consequently alleviate opioid-related adverse effects. We review the evidence on the opioid-sparing effect of ketamine, clonidine, gabapentin and other novel analgesics in perioperative pain management. Most available data support the addition of these adjuvants to routine analgesic techniques to reduce the need for opioids and improve quality of analgesia by their synergistic effect. Local anaesthetic infiltration, epidural and other regional techniques are also used successfully to enhance perioperative analgesia after a variety of surgical procedures. The use of continuous perineural techniques that offer prolonged analgesia with local anaesthetic infusion has been extended to the care of patients beyond hospital discharge.The use of nonpharmacological options such as acupuncture, relaxation, music therapy, hypnosis and transcutaneous nerve stimulation as adjuvants to conventional analgesia should be considered and incorporated to achieve an effective and successful perioperative pain management regimen.     

Recent advances in the pharmacological management of pain

Pain is an unpleasant sensation that originates from ongoing or impending tissue damage. Management of different types of pain (acute, postoperative, inflammatory, neuropathic or cancer) is the most frequent issue encountered by clinicians and pharmacological therapy is the first line of approach for the treatment of pain. This review presents and discusses recent clinical advances regarding both the improvements in delivery of analgesic drugs and improvements in the design of analgesic molecules. The new modalities of administration of analgesics used in the clinic are reviewed, including skin patches, oral and mucosal sprays, transdermal delivery systems and intranasal administration. New insights are then presented on standard drugs used to relieve pain, such as opioids (including tramadol), NSAIDs including selective cyclo-oxygenase-2 inhibitors, paracetamol (acetaminophen), local anaesthetics and adjuvant analgesics such as antidepressants, anticonvulsants (gabapentin and pregabalin), cannabinoids, ketamine and others (e.g. nefopam). Although the understanding of pain mechanisms has improved significantly recently, much more is yet to be discovered and awaited. Broadening of our knowledge is needed to improve basic and clinical research in this field in order to better alleviate pain in millions of people.     

Controlled clinical trial of oral and parenteral nefopam hydrochloride. A novel and potent analgesic drug.

The results of a controlled, double-blind clinical trial are reported demonstrating the potency of analgesia produced by orally and parenterally administered nefopam HCl in hospitalized patients with pain principally of skeletal and neuromuscular origin. The drug is an analogue of orphenadrine, consisting of a cyclization of the diphenhydramine molecule. A double-blind, crossover study was made of the analgesic effects of intramuscular doses of 20 mg nefopam HCl, 50 mg pethidine, and saline placebo in 20 patients. Nefopam and pethidine were found to be equally effective and statistically superior to placebo. A double-blind, randomized study was made of orally administered nefopam HCl, 60 mg t.i.d., for three days and of placebo t.i.d. for three days in 80 patients. Nefopam was distinctly superior to placebo in analgesic effectiveness, both in the initial single dose and in maintaining therapeutic benefit for the duration of the three-day trial. It was concluded that nefopam is a potent analgesic of novel structure and unique physiologic properties.     

Spinal opioid analgesia. A critical update

Small spinal (intrathecal or extrathecal) doses of opioids induce a long-lasting and regional analgesic effect in various experimental animal models. Nowadays extrathecal morphine administration is considered an established method of controlling postoperative and cancer-induced pain conditions. The potency of morphine applied by the spinal route is higher than when the drug is applied by the intravenous (IV) route. Opioids which are more lipophilic than morphine will provide a marginally better analgesic effect when administered by the spinal route as compared with the IV route. Several controlled clinical trials in postoperative patients have demonstrated that a single dose of morphine administered by the spinal route gives a more long-lasting action than a similar IV dose. It is not known whether frequent patient-controlled administration of morphine may provide equally good analgesia without additional side effects. The use of spinal morphine in the treatment of cancer-related pain is based on clinical experience only. There are risks in replacing opioid administration by the oral or IV route with spinal opioids. Morphine should only be used in selected cases until the advantage of spinal opioid analgesia to control postoperative and cancer pain has been clearly defined in well-designed clinical studies. Spinal morphine dosages must be individualised according to the intensity of the nociceptive stimuli and should take into account intra-individual variability in drug responses due to pharmacokinetic and pharmacodynamic factors.     

Dexketoprofen-induced antinociception in animal models of acute pain: synergy with morphine and paracetamol

The antinociceptive activity of dexketoprofen was studied in mice using the acetic acid writhing test (acute tonic pain), the tail flick test (acute phasic pain) and the formalin assay (inflammatory pain). Isobolographic analysis was used to study the antinociceptive interactions between morphine and paracetamol co-administered with dexketoprofen. In the writhing test, the intraperitoneal administration of dexketoprofen or ketoprofen resulted in parallel dose-response curves with equal efficacy, but higher relative potency for dexketoprofen. In the tail flick test, the curves were parallel with similar efficacy and potency. The administration of morphine or paracetamol in both tests resulted in dose-response curves not parallel with that of dexketoprofen, which showed a potency between morphine and paracetamol. In the formalin assay, the antinociceptive activity of morphine during phase I was 122, 295 and 1695 times higher than dexketoprofen, ketoprofen and paracetamol, respectively. Isobolographic analysis demonstrated that the combination of sub-analgesic doses of dexketoprofen with morphine or with paracetamol was strongly synergic in all three tests. Synergistic drug combinations should improve effective pharmacological treatment of pain, minimizing drug specific adverse effects. These findings are undoubtedly worthy of additional controlled clinical trials in severe pain syndromes.     

Weak opiate analgesics: modest practical merits

(1) The first-line drugs for mild to moderate pain are non opiate analgesics, namely paracetamol and nonsteroidal antiinflammatory drugs (NSAIDs). (2) Codeine, dextropropoxyphene and tramadol are weak opiates; they are often used with paracetamol in fixed-dose combinations, in order to reinforce the analgesic effect of paracetamol. (3) These analgesic combinations have only been evaluated in a few situations associated with chronic and acute pain. And the endpoints used in clinical trials are designed more to show statistically significant differences than clear clinical differences. (4) In acute pain, available meta-analyses confirm that the first-line drug is paracetamol, or, if necessary, ibuprofen, a NSAID. (5) The paracetamol + codeine combination slightly increases the analgesic effect of paracetamol, but causes more adverse effects. Combinations of paracetamol + dextropropoxyphene and paracetamol + tramadol are even less useful. (6) The few available clinical trials fail to demonstrate that combining paracetamol with a NSAID is any more effective than either drug given alone, while adverse effects are increased. (7) Paracetamol is also the first-line treatment for chronic non cancer pain, such as low back pain or pain due to osteoarthritis of the hip. NSAIDs have no advantages over paracetamol in these settings. We found no trials of paracetamol + NSAID combinations. Combinations of paracetamol and weak opiates have been inadequately studied in this situation, and are only second-line options.     

Postoperative pain control in children: a guide to drug choice

Postoperative pain in children can usually be well controlled with a combination of analgesics, including acetaminophen (paracetamol), NSAIDs, opioids, and local/regional anesthesia. Recent research has shown that the dosage of acetaminophen required to provide analgesia is higher than the traditional dosages used for the regulation of elevated body temperature. Rectal administration of acetaminophen gives a lower and more variable bioavailability compared with oral administration. There is growing experience with the use of NSAIDs in children and several studies have demonstrated the relatively strong analgesic potential of these drugs. Titration of opioids to analgesic effect, and the use of nurse- and patient-controlled continuous opioid infusions in children have gained widespread use and, with proper education and supervision, are considered excellent methods of pain control. Local peripheral and central blocks decrease the need for anesthetics during surgery and provide effective postoperative pain relief.     

右美托咪定在多模式镇痛中应用的研究进展

围手术期镇痛的目的是缓解手术造成的疼痛及其带来的不良反应,防止外周及中枢敏化的发生。近年来,随着医疗行业的飞速发展和众多新型药物的不断出现,常联合不同作用机制的镇痛药物,或不同的镇痛措施,通过多种机制产生镇痛作用,即多模式镇痛以获得更好的镇痛效果,而使药物副作用减到最低。右美托咪定是一种选择性α2肾上腺素受体激动剂,其镇痛作用已被证实可以作为麻醉剂佐剂应用于临床。可与局部麻醉药或阿片类药物配伍、可应用于静脉注射或应用于各种神经阻滞等方式达到多模式镇痛。对右美托咪定在多模式镇痛中的应用进行综述。     

奈福泮用于食管癌根治术后自控镇痛的效果

目的评估奈福泮(Nefopam)用于食管癌术后患者静脉自控镇痛(Patient-controlled intravenous analgesia,PCIA)的效果及其安全性。方法40例食管癌根治术后患者,随机分为2组,每组20例。分别为奈福泮组(N组)和吗啡组(M组),接受PCIA。N组:奈福泮120mg;M组:吗啡40mg。每组都加入地塞米松10mg、胃复安20mg,生理盐水稀释至100ml。应用英国Graseby-9300便携式PCA输液泵,其内设置和控制的参数:全部采用负荷剂量+持续输注+人自控(LCP)模式,设置负荷量4ml;持续剂量为2ml/h;锁定时间为10min;PCA剂量为0.5ml。结果N组与M组的镇痛效果VAS评分分别为2.1±0.6和2.0±0.7,组间比较无显著性差异。PCA总按压次数/实进数(D/D),N组与M组比较无显著性差异(P≥0.05)。镇静评分(SS),不良反应的发生率N组明显低于M组,其中以恶心的发生率降低最为明显(P≤0.01)。结论奈福泮用于食管癌术后PCIA,其镇痛效果与吗啡相似,不良反应明显低于吗啡,利于患者术后恢复。     

The Effect of Paracetamol and Tropisetron on Pain: Experimental Studies and a Review of Published Data

Experimental studies suggest that paracetamol‐induced analgesia is mediated via central serotonergic pathways and attenuated by 5‐HT3‐antagonists. However, clinical studies do not support this, and 5‐HT3‐antagonists are expected to reduce pain by blocking the descending pronociceptive pathway. The current project tested whether tropisetron attenuates analgesia by paracetamol. Two randomized, double‐blind, crossover studies with 18 healthy male volunteers in each were performed. Pain stimuli were cold water immersion (cold pressor test), contact heat pain (study 1) and electrical stimulation (study 2). In both studies, tropisetron 5 mg i.v. or saline was administered, followed by paracetamol 2 g i.v. 30 min. later. Individual changes in heat and cold pain intensity, cold pain tolerance and unpleasantness were recorded. The same thresholds were also expressed as scores (% of the individual score at baseline). Additionally, previously published findings on the effects of paracetamol and its interaction with 5HT3‐antagonists in human experimental pain models were reviewed. After calculation of the sensory and pain scores (%), tropisetron seemed to amplify the analgesic action of paracetamol. Paracetamol 2 g i.v. did not show any statistically significant analgesia in thermal tests (study 1), or differences in sensory, pain detection or moderate pain thresholds of the electrical stimulus (study 2). As paracetamol did not have a measurable analgesic effect in these tests, no conclusions can be drawn about the interaction between paracetamol and tropisetron. However, tropisetron may have an analgesic effect of its own. Clinicians should not avoid using these drugs together, unless larger clinical studies indicate otherwise.     

The effects of nefopam on blood acid-base status in the rabbit: interactions with morphine in the mouse and rabbit

Nefopam, a non-narcotic analgesic, had only minor effects upon the blood pH, PCO2 and standard bicarbonate of the conscious rabbit. In contrast morphine caused a dose-dependent increase in PCO2 and standard bicarbonate. When nefopam was administered in conjunction with morphine (2.5 mg kg-1 and 1 mg kg-1 i.v. respectively) the increase in PCO2 was greater than with morphine alone. Nefopam also increased the antinociceptive and respiratory frequency depressant effects of morphine in the mouse.     

The role of descending fibers from the rostral ventromedial medulla in opioid analgesia in rats

There has been controversy as to whether the contribution of descending fibers from the rostral ventromedial medulla to opioid analgesia depends on the nature of the noxious stimulus eliciting pain. In the present study, inactivation of descending fibers by microinjection of muscimol (50 ng) in the rostral ventromedial medulla abolished morphine analgesia in the tail immersion and hot plate tests but decreased morphine analgesia by 60% in the formalin test. Analysis of the dose-response relation for morphine after inactivation of descending fibers revealed that, except for the tail immersion test, high doses of morphine could not overcome the block induced by muscimol. Also, morphine analgesia elicited supraspinally was not detectable when descending fibers were inactivated, suggesting that the analgesic effect of morphine in the brain requires a relay via the rostral ventromedial medulla. The analgesic effect of buprenorphine also depends on the integrity of descending fibers from the rostral ventromedial medulla. The results indicate that descending fibers from the rostral ventromedial medulla are critically important to the analgesic effect of opioids, regardless of the type of noxious stimulation eliciting pain. Residual analgesic effects of opioids after inactivation of descending fibers may be due to peripheral effects in the presence of inflammation.     

A B‐Vitamin mixture reduces the requirements of diclofenac after tonsillectomy: a double‐blind study

Pain observed after tonsillectomy is often severe and frequently requires the use of opioid analgesics. Non‐steroidal anti‐inflammatory drugs (NSAIDs) may reduce the need or avoid the use of opioids, but gastrointestinal side effects may limit their use. Sparing analgesic agents may reduce the requirement for NSAIDs and consequently their toxicity. It has been proposed that a B‐vitamin mixture produces analgesia in experimental pain models. The present study was carried out to establish if a B‐vitamin mixture was additive with the NSAID, diclofenac, in the treatment of postquirurgic pain. Two groups of 20 subjects, participated in the study. Group 1 received a B‐vitamin mixture infusion for 12 h before the tonsillectomy, whereas Group 2 received vehicle. Both groups received a 50‐mg diclofenac i.v. 8 h before surgery. Two hours after tonsillectomy, Group 1 received another B‐vitamin mixture infusion for 12 h and Group 2 again received vehicle. Pain intensity was evaluated by a visual analog scale (VAS). Then diclofenac (50 mg i.v.) was administered as required by the patient without exceeding 150 mg daily. Diclofenac consumption was recorded and VAS was evaluated for 54 h. Group 1 exhibited a lower pain intensity 2 h after tonsillectomy. Both groups showed similar analgesia. However, diclofenac consumption was approximately 30% lower in the group treated with the B‐vitamin mixture. These results indicate that B vitamins can spare the use of analgesic agents. Drug Dev. Res. 66:36–39, 2006. © 2006 Wiley‐Liss, Inc.     

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   

Multimodal analgesia: its role in preventing postoperative pain

Postoperative pain is a complex and multifactorial symptom that requires a thoughtful approach using a variety of treatment modalities to obtain an optimal outcome after surgery. Multimodal (or 'balanced') analgesia represents an approach to preventing postoperative pain where the patient is administered a combination of opioid and non-opioid analgesic drugs that act at different sites within the central and peripheral nervous systems in an effort to minimize opioid use and, therefore, to decrease opioid-related side effects. Despite widespread interest in this concept from both the anesthesia and surgery communities, very few prospective, randomized, controlled clinical investigations have been conducted that utilize this approach to improving patient comfort and facilitating recovery after surgery. Most of the published studies focus on the effects of a single therapeutic modality when it is added to an existing analgesic regimen. More recently, clinical investigators have begun to examine the beneficial effects of combined multimodal approaches in preventing postoperative pain by utilizing combinations of non-opioid analgesics to minimize the opioid analgesic requirements and opioid-related side effects. This review explores the theoretical basis for multimodal analgesia and the existing scientific evidence supporting its benefit in improving pain control after surgery. Recent investigations that have examined the impact of this therapeutic approach for improving clinically meaningful patient outcomes after surgery will be discussed.     

非甾体消炎药在术后急性疼痛治疗中的合理应用

非甾体消炎药是临床常用的解热镇痛药。它在术后多模式镇痛治疗中发挥着重要作用,但其在缓解疼痛、降低炎症反应的同时,可引起胃肠道、心血管等的不良反应。因此,只有合理应用NSAIDs,才能提高疗效,保证安全。