Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.     

Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain

Introduction: Neuropathic pain (NP) has several therapeutic options but efficacy is limited and adverse effects occur, such that additional treatment options are needed. A topical formulation containing amitriptyline 4% and ketamine 2% (AmiKet) may provide such an option.

Areas covered: This report summarizes both published and unpublished results of clinical trials with AmiKet. In post-herpetic neuralgia (PHN), AmiKet produces a significant analgesia which is comparable to that produced by oral gabapentin. In diabetic painful neuropathy, AmiKet showed a strong trend towards pain reduction. In mixed neuropathic pain, case series reports suggest a favourable response rate, but are limited by trial characteristics. AmiKet is absorbed minimally following topical administration. Over 700 patients have now received topical AmiKet in clinical regimens, and it is well-tolerated with the adverse effects mainly being application site reactions. Both agents are polymodal, and several mechanisms may contribute to the peripheral efficacy of AmiKet.

Expert opinion: Topical AmiKet has the potential to be a first-line treatment option for PHN, and to be useful in other NP conditions. Furthermore, AmiKet has the potential to be an adjunct to systemic therapies, with the targeting of a peripheral compartment in addition to central sites of action representing a rational drug combination.     

Intranasal Ketamine and Its Potential Role in Cancer‐Related Pain

Cancer‐related pain continues to be a significant therapeutic challenge, made more difficult by contemporary opioid use and diversion concerns. Conventional treatment using a tiered approach of nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and adjuvant agents is limited; and alternatives are needed for patients with rapidly progressing pain and those who develop hyperalgesia and tolerance to opioids. Ketamine, an N‐methyl‐d ‐aspartate (NMDA) selective antagonist, has historically been used for anesthesia in adult and pediatric populations but has also been investigated for depression, bipolar disorder, and general and postoperative pain management. As an analgesic, low‐dose ketamine decreases morphine requirements and rates of nausea and vomiting, suggesting a potentially beneficial role in cancer‐related pain. Ketamine is typically administered intravenously and has a rapid onset of action with a relatively short half‐life (2–3 hours) but is inconvenient for use in an ambulatory setting. Oral bioavailability is low and erratic, limiting application of this route for chronic use. Intranasal administration has a number of potential advantages, including avoidance of first‐pass hepatic metabolism, no need for venous access, ability to repeat doses quickly, and rapid absorption. Although early studies of intranasal ketamine are promising in a number of indications, information is more limited in its use as an adjunct in cancer‐related pain. We review the background, rationale, pharmacokinetics, and clinical and safety data using intranasal ketamine as an adjunctive agent and its potential in cancer‐related pain.     

Fentanyl nasal spray for the treatment of cancer pain

Introduction: Breakthrough pain, a transitory flare of pain in patients with otherwise controlled chronic pain, has been well characterized in cancer patients but despite medical awareness, sometimes remains underdiagnosed and therefore undertreated.

Areas covered: Oral transmucosal fentanyl citrate (OTFC) and fentanyl buccal tablets are the first medications developed specifically for the treatment of breakthrough pain in opioid-tolerant patients. Since oral administration of fentanyl is not an option for many cancer patients, the development of intranasal fentanyl spray (INFS) emerged as a more effective method of administration. Intranasal administration of fentanyl has several advantages over the oral/gastrointestinal route and clinical trials have shown that it is superior to OTFC while being well tolerated and more acceptable by the majority of patients.

Expert opinion: The aim of this review is to summarize the pharmacological characteristics and data obtained from clinical studies of INFS in the past few years, and present Fentanyl Pectin Nasal Spray (PecFent), which uses an innovative delivery system and is now approved in the EU. Finally, we discuss the impact that it may have in the future management of breakthrough pain in cancer patients, because an accurate diagnosis followed by the best treatment is crucial for effective pain alleviation.     

维拉帕米增强氯胺酮对神经病理性疼痛的拮抗作用

目的探讨钙通道拮抗剂维拉帕米对静脉全麻药氯胺酮拮抗神经病理性疼痛的影响。方法 48只健康♂大鼠随机分为正常对照组(N)、假手术组(S)、疼痛模型组(M)、氯胺酮给药组(K)、维拉帕米给药组(V)以及维拉帕米和氯胺酮联合给药组(V+K)共6组,通过大鼠坐骨神经松扎制备坐骨神经慢性缩窄性损伤(CCI)神经病理性疼痛模型。各组大鼠从手术后d1～14每天腹腔注射相应不同的药物,N、S和M组大鼠给予生理盐水,K组大鼠给予10μg.g-1的氯胺酮溶液,V组大鼠给予5μg.g-1的维拉帕米溶液,V+K组先给予维拉帕米(5μg.g-1)溶液,20 min后再给予氯胺酮溶液。在手术前1 d和手术后1、3、7、11 d和14 d给药后10 min分别用Hargreaves法测量热缩足潜伏期,VonFrey细丝测量机械刺激缩足反射阈值。结果在手术前各组之间的痛觉无差异,在手术和给药后各时间点模型组大鼠的热缩足潜伏期和机械刺激缩足反射阈值均降低,而氯胺酮改善了CCI大鼠的热痛觉过敏和机械痛觉超敏,维拉帕米单独给药对CCI大鼠的痛觉无影响,但联合用药时维拉帕米增强了氯胺酮的镇痛效应。结论维拉帕米能够增强氯胺酮拮抗CCI大鼠神经病理性疼痛的作用。     

右美托咪定滴鼻预防硬膜外分娩镇痛爆发痛的效果观察

目的探讨右美托咪定滴鼻预防硬膜外分娩镇痛爆发痛的效果。方法选择单胎足月初产妇100例,美国麻醉医师协会(ASA)Ⅰ或Ⅱ级,随机分为对照组和右美托咪定滴鼻组(观察组)。观察组在硬膜外镇痛后20 min给予0.8μg/kg右美托咪定滴鼻,对照组给予等量生理盐水滴鼻。记录各组爆发痛发生率、首次爆发痛发生时间、患者自控硬膜外镇痛(PCEA)按压次数、镇痛药总量、产妇满意度和产程时间,评价右美托咪定滴鼻对硬膜外分娩镇痛爆发痛的预防效果。记录硬膜外镇痛前(T0)、镇痛后1 h(T₁)、2 h(T₂)、3 h(T₃)、4 h(T₄)、宫口开全时(T₅)、胎儿娩出时(T₆)产妇的疼痛视觉模拟评分(VAS)、Ramsay镇静评分、胎心率(FHR)及新生儿Apgar评分、脐动脉血气分析值等,评估其对产妇及新生儿的安全性的影响。结果本研究最终纳入91例产妇,年龄20～36岁。与对照组(45例)相比,观察组(46例)爆发痛发生率显著降低,首次爆发痛发生时间显著推迟,PCEA次数与...     

Ketamine for chronic pain: risks and benefits

The anaesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (4–14 days) show long-term analgesic effects up to 3 months following infusion. The side effects of ketamine noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, haemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain.     

Comparison of pharmacokinetics of Alprazolam after intranasal and intragastric administration in rats

Objective To compare the pharmacokinetics of Alprazolam after intranasal and intragastic administration in rats and evaluate the practicability of Alprazolam as a nasal drug delivery system.Methods 12 rats were randomly divided into two groups.The fate of drug in the serum of rats was monitered after intranasal and intragastic administration of Alprazolam 2 mg·kg-1.Serum levels of Alprazolam were determined by reversed-phase HPLC with Diode array detectors(DAD).Chromatographic conditions were adopted with ODS column as solid phase,methanaol-0.02 M ammonium acetate(pH=5.0)(60∶40)as mobile phase at a flow rate of 1.0 mL·min-1.The detection wavelength was 223 nm.The concentration-time data were analyzed using 3P87 program,and the pharmacokinetic parameters were compared by t-test.Results The pharmacokinetic characteristics were fit to two and one compartment opened model after intranasal and intragastic administration of Alprazolam,respectively.The drug absorption was quicker and the serum concentrations of Alprazolam was significantly higher in rats after intranasal administration group than that intragastic administration group(P<0.05).The eliminate parameters between the two groups were no significant difference(P>0.05).Means of pharmacokinetic parameters in intranasal and intragastic groups were:Ka 37.35±22.98 vs 11.57±12.47 h-1(P<0.05),t1/2ka0.025±0.013 vs 0.156±0.122 h(P<0.05),β(Ke)0.3131±0.1194 vs 0.3091±0.1216 h-1(P>0.05),t1/2β(t1/2Ke)2.51±0.99 vs 2.54±0.97 h(P>0.05),tmax 0.156±0.069 vs 0.618±0.414 h(P<0.01),Cmax 353.11±96.30 vs 62.09±35.08 μg·L-1(P<0.01),AUC 1111.6±473.2 vs 274.1±185.3 μg·L-1·h(P<0.01).Conclusions Alprazolam was absorbed quickly in rats after intranasal administration.And the serum concentration and bioavailability can be significantly increased after intranasal administration,which may be an effective preparation as nasal drug delivery system.     

Innovative clinical trial design for pediatric therapeutics

Until approximately 15 years ago, sponsors rarely included children in the development of therapeutics. US and European legislation has resulted in an increase in the number of pediatric trials and specific label changes and dosing recommendations, although infants remain an understudied group. The lack of clinical trials in children is partly due to specific challenges in conducting trials in this patient population. Therapeutics in special populations, including premature infants, obese children and children receiving extracorporeal life support, are even less studied. National research networks in Europe and the USA are beginning to address some of the gaps in pediatric therapeutics using novel clinical trial designs. Recent innovations in pediatric clinical trial design, including sparse and scavenged sampling, population pharmacokinetic analyses and ‘opportunistic’ studies, have addressed some of the historical challenges associated with clinical trials in children.     

The absolute bioavailability of racemic ketamine from a novel sublingual formulation

Aim

The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability.

Methods

The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25 mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales.

Results

The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min–max) time of the peak plasma concentration was 0.75 h (0.25–1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability.

Conclusion

Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.     

卡巴拉汀脂质体的制备及其大鼠鼻腔给药的药代动力学

制备卡巴拉汀脂质体,研究其在大鼠鼻腔给药的药代动力学。采用硫酸铵梯度法制备包载卡巴拉汀的脂质体,考察粒径、zeta电位和包封率,测定脂质体在磷酸盐缓冲液中的释放;大鼠鼻腔给予卡巴拉汀脂质体,以安替比林为内标,采用高效液相色谱-串联质谱法(HPLC/MS)测定血浆中卡巴拉汀的浓度,运用DAS 2.0软件拟合药代动力学参数。经筛选制备的脂质体包封率为(33.41±6.58)%,平均粒径在154～236 nm,zeta电位(-10.47±2.41)mV。脂质体的体外释放符合一级动力学方程。大鼠鼻腔给药后,Cmax,Tmax和AUC0-∞分别为(1.50±0.15)mg.L-1,15 min和(89.06±8.30)mg.L-1.min。卡巴拉汀制备成脂质体经大鼠鼻腔给药后,吸收迅速,血药浓度可以达到一定水平。     

经鼻点滴枸橼酸芬太尼注射液用于控制爆发性癌痛的临床观察

目的探讨经鼻点滴枸橼酸芬太尼注射液用于控制爆发性癌痛(BTCP)的有效性。方法 18例晚期癌症且合并BTCP住院患者,均口服吗啡缓释片控制基础性癌痛,口服吗啡即释剂控制BTCP。随机分为两组(n=9):观察组在BTCP时改用枸橼酸芬太尼注射液1ml(50μg)滴鼻。对照组:继续用吗啡即释剂控制BTCP。结果观察组与对照组镇痛起效时间分别为(18.34±6.33)和(25.11±4.26)min,观察组显著短于对照(P<0.05)。观察组BTCP最大强度评分显著低于对照组(P<0.05),而患者满意度评分显著高于对照组(P<0.01)。结论枸橼酸芬太尼注射液滴鼻用于控制BTCP,给药方便,起效迅速,患者满意度高,有一定的临床应用价值。     

硫酸吗啡栓治疗癌痛的Ⅱ期临床试验

[摘要]目的：评价硫酸吗啡栓直肠给药治疗中重度慢性癌痛的有效性和安全性。方法：采用多中心、随机、双盲、双模拟、阳性药物平行对照临床试验,将132例中重度慢性癌痛患者随机分为试验组和对照组,试验组患者每次经肛门给予硫酸吗啡栓1枚,同时口服硫酸吗啡片模拟片1片,对照组患者每次口服硫酸吗啡片1片,同时经肛门给予硫酸吗啡栓模拟药1枚。每日硫酸吗啡栓用量不得超过100mg,共按需给药7d。结果：试验组、对照组患者d1第1次、第2次用药后疼痛强度（PI）较治疗前均明显下降(P<0.05),与用药前相比的疼痛强度差两组之间相比,差异无统计学意义(P>0.05);硫酸吗啡栓能明显缓解患者的疼痛症状,与对照组相比,差异无统计学意义(P>0.05);试验组有效率与对照组相比,差异无统计学意义(P>0.05)。两组患者在d2~d7疼痛强度进行组间比较,差异无统计学意义(P>0.05)。结论：硫酸吗啡栓直肠给药治疗中重度慢性癌痛安全有效。     

Emerging concepts on the use of ketamine for chronic pain

ABSTRACT

Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.

Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine’s action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.

Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine’s analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine’s ability to modulate the affective-motivational dimension of pain.     

A randomized trial of the safety,pharmacokinetics and pharmacodynamics of edoxaban,an oral factor Xa inhibitor,following a switch from warfarin

Aims

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of edoxaban, an oral direct factor Xa inhibitor, in healthy subjects switching from warfarin.

Methods

Seventy-two subjects were randomized to edoxaban 60 mg once daily (n = 48) or matching placebo (n = 24) for 5 days at 24 h after the last dose of warfarin treatment (INR 2.0 to 3.0). Safety/tolerability was the primary outcome measure. Pharmacokinetics, INR, aPTT, anti-FXa, thrombin generation and other coagulation assays were assessed.

Results

Seventy-two subjects were randomized and 64 subjects received at least one dose of edoxaban (n = 43) or placebo (n = 21) after achieving a target INR of 2.0 to 3.0 on warfarin treatment. Edoxaban 60 mg administered 24 h post-warfarin appeared to be safe and well tolerated. Adverse events were similar across treatments. For bleeding-related adverse events, eight subjects tested positive for faecal occult blood, five subjects during warfarin treatment and three subjects during edoxaban treatment. The mean (SD) baseline (post-dose of warfarin) INR was 2.31 (0.193) which increased to 3.84 (0.744) over 2 h during the edoxaban treatment (P < 0.0001 vs. placebo), returning to post-warfarin baseline within 12 h. A similar time course of effects for the other coagulation assays was observed in accordance with the drugs'' mechanisms of action.

Conclusion

In this study of healthy subjects, edoxaban administered 24 h after the last dose of warfarin was safe and well tolerated with transient increases across the various coagulation assays above post-warfarin baseline levels.     

A review of the second-generation antihistamine ebastine for the treatment of allergic disorders

Ebastine is a once-daily, non-sedating, selective, long-acting, second-generation antihistamine. The use of ebastine is indicated in patients suffering from intermittent and persistent allergic rhinitis and chronic idiopathic urticaria. Ebastine 10 mg/day, appears as effective as other second-generation antihistamines, such as cetirizine and loratadine. Ebastine 20 mg/day is indicated in patients with moderate and severe allergic symptoms. No cardiovascular effects of ebastine are described, although there is a pharmacokinetic interaction when ketoconazole or macrolides are co-administered. Ebastine has no relevant effects on the psychomotor performance. Even with ebastine 20 mg/day skilled performance does not appear to be impaired. Furthermore, ebastine 5 – 10 and 2.5 mg, appears to be efficient and can be used safely in children 6 – 11 and 2 – 5 years of age, respectively. Ebastine appears to be a safe, effective and well-tolerated second-generation antihistamine in the treatment of allergic rhinitis and chronic idiopathic urticaria.     

Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration

Summary Twelve children 1–5 y old were randomly assigned to receive midazolam 0.2 mg·kg^–1 either by the intravenous (IV) or intranasal (IN) routes.After IN administration the rapid onset of absorption was observed (t_max 12 min). After both routes of administration the half-life was similar (2.2 h IN and 2.4 h IV). After IN administration the apparent plasma clearance and volume of distribution were about twice as high as after IV administration.The results are consistent with an estimated mean bioavailability of 55%.     

Intranasal (2R, 6R)-hydroxynorketamine for acute pain: Behavioural and neurophysiological safety analysis in mice

Ketamine is known for its antinociceptive effect and is also used for treatment-resistant depression. However, the efficacy and safety of (2R, 6R)-hydroxynorketamine (HNK), a ketamine metabolite has been sparingly investigated for acute pain management. The current study aims at investigating the antinociceptive effect of intranasal (2R, 6R)-HNK using pre-clinical models of acute pain. Additionally, the behavioural and neurophysiological safety analyses were carried out for the effective time window. Antinociceptive efficacy of (2R, 6R)-HNK was evaluated using the hot plate test and Hargreaves' plantar test. The formalin test was carried out in both the acute and tonic phases. The neurophysiological and behavioural safety analyses were carried out separately for the haemodynamic function, cortical electroencephalography (EEG), and spontaneous behavioural functions. Analgesic effect of (2R, 6R)-HNK was evident by a significant increase in paw-withdrawal latency in both Hargreaves' and hot plate tests. Additionally, the (2R, 6R)-HNK showed a significant ameliorative effect on pain-related behaviour in the second phase of the formalin test. (2R, 6R)-HNK exhibited an anxiolytic effect without causing any significant changes in locomotor activity and haemodynamic parameters. Power spectral density (PSD) analysis of electroencephalogram revealed no significant changes except a comparative increase in the gamma band range. Both the locomotor functions in the open field test and the PSD value of delta wave indicated no sedative effect at the given dose of (2R, 6R)-HNK. The results demonstrated the pain-alleviating effect of (2R, 6R)-HNK without compromising the neurophysiological and behavioural function. Therefore, intranasal (2R, 6R)-HNK is suggested as a safe candidate for further clinical study in the management of acute pain.     

盐酸羟考酮控释片治疗晚期癌症疼痛的临床疗效及安全性分析

目的:观察盐酸羟考酮控释片治疗晚期癌症中重度癌性疼痛的疗效及不良反应。方法:回顾性分析我院肿瘤科2011年2月-2014年2月间,216例晚期中重度癌性疼痛患者予以盐酸羟考酮控释片镇痛治疗情况,初始剂量10~20 mg,q12h,根据疼痛情况调整剂量至无痛或基本无痛状态,评估镇痛效果和不良反应。结果:经最终剂量滴定后,盐酸羟考酮控释片用药剂量范围10~130 mg,q12h。疼痛完全缓解率52.8%(114例),部分缓解43.1%(93例),总的癌痛缓解率(CR+PR/总人数)95.8%。不良反应主要有便秘(84例)、头晕(33例)、恶心呕吐(45例)、厌食(27例)、嗜睡(9例)、尿储留(3例),但症状轻微且可控。结论:盐酸羟考酮控释片是晚期癌症中重度疼痛患者的有效治疗选择,其可以通过剂量滴定个体化给药的方式显著改善癌症患者的生活质量,且耐受性良好。     

Ketamine for the treatment of chronic non-cancer pain

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-d-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes.

Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions.

What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief.

Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.