Discriminative stimulus effects of tramadol in humans

Tramadol is an unscheduled atypical analgesic that acts as an agonist at μ-opioid receptors and inhibits monoamine reuptake. Tramadol can suppress opioid withdrawal, and chronic administration can produce opioid physical dependence; however, diversion and abuse of tramadol is low. The present study further characterized tramadol in a three-choice discrimination procedure. Nondependent volunteers with active stimulant and opioid use (n = 8) participated in this residential laboratory study. Subjects were trained to discriminate between placebo, hydromorphone (8 mg), and methylphenidate (60 mg), and tests of acquisition confirmed that all volunteers could discriminate between the training drugs. The following drug conditions were then tested during discrimination test sessions: placebo, hydromorphone (4 and 8 mg), methylphenidate (30 and 60 mg), and tramadol (50, 100, 200, and 400 mg). In addition to discrimination measures, which included discrete choice, point distribution, and operant responding, subjective and physiological effects were measured for each test condition. Both doses of hydromorphone and methylphenidate were identified as hydromorphone- and methylphenidate-like, respectively. Lower doses of tramadol were generally identified as placebo, with higher doses (200 and 400 mg) identified as hydromorphone, or opioid-like. The highest dose of tramadol increased ratings on the stimulant scale, but was not significantly identified as methylphenidate-like. Tramadol did not significantly increase subjective ratings associated with reinforcement. Taken together, these results extend previous work with tramadol as a potential medication for the treatment of opioid dependence and withdrawal, showing acute doses of tramadol exhibit a profile of effects similar to opioid agonists and may have abuse liability in certain populations.     

Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic.

Tramadol hydrochloride produced dose-related antinociception in mouse abdominal constriction [ED50 = 1.9 (1.2-2.6) mg/kg i.p.], hot-plate [48 degrees C, ED50 = 21.4 (18.4-25.3) mg/kg s.c.; 55 degrees C, ED50 = 33.1 (28.2-39.1) mg/kg s.c.] and tail-flick [ED50 = 22.8 (19.2-30.1) mg/kg s.c.] tests. Tramadol also displayed antinociceptive activity in the rat air-induced abdominal constriction [ED50 = 1.7 (0.7-3.2) mg/kg p.o.] and hot-plate [51 degrees C, ED50 = 19.5 (10.3-27.5) mg/kg i.p.] tests. The antinociceptive activity of tramadol in the mouse tail-flick test was completely antagonized by naloxone, suggesting an opioid mechanism of action. Consistent with this, tramadol bound with modest affinity to opioid mu receptors and with weak affinity to delta and kappa receptors, with Ki values of 2.1, 57.6 and 42.7 microM, respectively. The pA2 value for naloxone obtained with tramadol in the mouse tail-flick test was 7.76 and was not statistically different from that obtained with morphine (7.94). In CXBK mice, tramadol, like morphine, was devoid of antinociceptive activity after intracerebroventricular administration, suggesting that the opioid component of tramadol-induced antinociception is mediated by the mu-opioid receptor. In contrast to the mouse tail-flick test and unlike morphine or codeine, tramadol-induced antinociception in the mouse abdominal constriction, mouse hot-plate (48 degrees or 55 degrees C) or rat hot-plate tests was only partially antagonized by naloxone, implicating a nonopioid component. Further examination of the neurochemical profile of tramadol revealed that, unlike morphine, it also inhibited the uptake of norepinephrine (Ki = 0.79 microM) and serotonin (0.99 microM). The possibility that this additional activity contributes to the antinociceptive activity of tramadol was supported by the finding that systemically administered yohimbine or ritanserin blocked the antinociception produced by intrathecal administration of tramadol, but not morphine, in the rat tail-flick test. These results suggest that tramadol-induced antinociception is mediated by opioid (mu) and nonopioid (inhibition of monoamine uptake) mechanisms. This hypothesis is consistent with the clinical experience of a wide separation between analgesia and typical opioid side effects.     

The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels

BACKGROUND AND OBJECTIVE: Tramadol is a racemic drug that may act through a monoaminergic effect of (+)- and (-)-tramadol and through an opioid effect of its metabolite (+)-Ml. The objective of this study was to investigate the relationship between relief of pain and serum concentrations of tramadol and Ml in tramadol treatment of painful polyneuropathy. METHODS: In a randomized, double-blind, placebo-controlled trial of 200 to 400 mg/day tramadol, serum concentrations of (+)- and (-)-tramadol and (+)- and (-)-Ml were determined in 28 of 34 patients. Ongoing and touch-evoked pain was rated daily by the patients by use of 0- to 10-point numeric rating scales during two 4-week treatment periods. RESULTS: Tramadol significantly reduced both on-going (P = .002) and touch-evoked pain (P < .001). There was no relation between relief of on-going and touch-evoked pain and serum concentrations of (+)-tramadol, (-)-tramadol, (+)-M1, or (-)-M1 (P = .11 to P = .89). Seventeen of the patients were categorized as responders for on-going pain and 16 for touch-evoked pain. Responders for on-going pain tended to have higher serum concentrations of (+)-Ml than nonresponders (median, 27 nmol/L versus 16 nmol/L; P = .08). Isobolograms showed that the fraction of nonresponders was higher among patients with low concentrations of both tramadol and (+)-Ml both for on-going (P = .009) and touch-evoked (P = .02) pain. CONCLUSION: The opioid effect of (+)-Ml may be of importance for tramadol relief of on-going neuropathic pain but, in general, relief of neuropathic pain seems to depend on both the monoaminergic effect of (+)- and (-)-tramadol and the opioid effect of (+)-Ml.     

Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol

We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. In contrast, O-desmethyltramadol showed low membrane permeability, and OCT1 overexpression increased O-desmethyltramadol uptake 2.4-fold. This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.     

Desmetramadol Has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized,Double-Blind,Placebo- and Active Comparator-Controlled Trials

Desmetramadol is an investigational analgesic consisting of (+) and (-) enantiomers of the tramadol metabolite O-desmethyltramadol (M1). Tramadol is racemic and exerts analgesia by monoaminergic effects of (-)-tramadol and (-)-M1, and by the opioid (+)-M1. Tramadol labeling indicates cytochrome P450 (CYP) isozyme 2D6 ultrarapid metabolizer can produce dangerous (+)-M1 levels, and CYP2D6 poor metabolizers insufficient (+)-M1 for analgesia. We hypothesized that desmetramadol could provide the safety and analgesia of tramadol without its metabolic liabilities. We conducted consecutive double-blind, randomized, placebo-controlled, 3 segment cross-over trials A and B to investigate the steady-state pharmacokinetics and analgesia of 20 mg desmetramadol and 50 mg tramadol in 103 healthy participants without (n = 43) and with (n = 60) cotreatment with the CYP inhibitor paroxetine. In the absence of CYP inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed every 6 hours gave equivalent steady-state (+)-M1, similar adverse events, and analgesia significantly greater than placebo, but equal to each other. In trial B, CYP inhibition significantly depressed tramadol steady-state (+)-M1, reduced its adverse events, and led to insignificant analgesia comparable with placebo. In contrast, CYP inhibition in trial B had no deleterious effect on desmetramadol (+)-M1 or (-)-M1, which gave significant analgesia as in trial A and superior to tramadol (P = .003). Desmetramadol has the safety and efficacy of tramadol without its metabolic liabilities.ClinicalTrials.gov registrationsNCT02205554, NCT03312777PerspectiveTo our knowledge, this is the first study of desmetramadol in humans and the first to show it provides the same safety and analgesia as tramadol, but without tramadol's metabolic liabilities and related drug–drug interactions. Desmetramadol could potentially offer expanded safety and usefulness to clinicians seeking an alternative to schedule II opioids.     

Comparison of the antiemetic efficacy of tropisetron and droperidol with patient-given tramadol

We compared the antiemetic efficacy of tropisetron versus droperidol in women given tramadol after total hysterectomy. Forty patients were randomly allocated to group 1 (n = 20, tropisetron 0.05 mg/kg intravenously) or group 2 (n = 20, droperidol 15 micrograms/kg intravenously). Tramadol infusion (intravenously), for post-operative analgesia, was started at fascia closure. Incidences of post-operative nausea and vomiting, pain intensity, tramadol use, and the need for a rescue antiemetic (metoclopramide 10 mg) were recorded 0 h, 2 h, 6 h, 12 h, 24 h and 48 h post-operatively. Vomiting and nausea incidences were reported fewer in group 1 than in group 2, but statistical significance was only reached for vomiting incidence 6 h post-operation. Tropisetron seems to have better antiemetic properties than droperidol in patients receiving tramadol because of the length of its duration of action. Further studies, investigating alternative ways of managing post-operative nausea and vomiting, and the use of tramadol for post-operative analgesia, are needed.     

Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter,randomized, double-blind,placebo-controlled outpatient study

BACKGROUND: Tramadol and acetaminophen (APAP) have both shown efficacy in the treatment of lower back pain. The combination of these 2 agents has demonstrated synergistic analgesic action in animal models at specific ratios. OBJECTIVE: This study assessed the long-term (3-month) efficacy and safety of tramadol 37.5 mg/APAP 325 mg combination tablets in the treatment of chronic lower back pain. METHODS: Patients with at least moderate lower back pain (pain visual analog [PVA] score >/=40 mm on a 100-mm scale) were randomized to receive up to 8 tablets of tramadol/APAP per day or placebo for 91 days. Medication was titrated from 1 to 4 tablets/d by day 10. The primary efficacy measure was PVA score at the final visit. Secondary measures included scores on the Pain Relief Rating Scale (PRRS), Short-Form McGill Pain Questionnaire (SF-MPQ), Roland Disability Questionnaire (RDQ), and 36-Item Short-Form Health Survey (SF-36); the incidence of discontinuation due to insufficient pain relief (Kaplan-Meier analysis); and overall assessments of medication by the patients and investigators. RESULTS: Three hundred eighteen patients (161 tramadol/APAP, 157 placebo) were included in the intent-to-treat population, defined as all patients who took >/=1 dose of study medication and had >/=1 postrandomization efficacy measurement. The mean age of the study population was 53.9 years, 63.2% were female, 90.3% were white, and the mean baseline PVA score was 70.0 mm. There were no significant differences between groups at baseline. Tramadol/APAP significantly improved final PVA scores (P = 0.015) and final PRRS scores (P < 0.001) compared with placebo. Tramadol/APAP also significantly improved RDQ scores (P 相似文献   

Isolated tramadol overdose associated with Brugada ECG pattern

Tramadol is a commonly prescribed synthetic opioid analgesic. In humans, electrocardiogram (ECG) changes consistent with sodium-channel blockade have not been described in overdoses with tramadol. We report a case of isolated tramadol overdose associated with a Brugada ECG pattern. A review of the literature reveals no previous human cases of tramadol overdose causing ECG changes consistent with sodium-channel blockade. However, in vitro blockade of sodium-channels has been demonstrated with high concentrations of tramadol. Tramadol overdose should be recognized as a cause for the manifestation of a Brugada ECG pattern in the setting of suicidal intoxication.     

Synergistic interaction between dexamethasone and tramadol in a murine model of acute visceral pain

Tramadol is effective in the management of mild to moderate postoperative pain, but its administration is associated with nausea and vomiting. Patients treated with tramadol, often receive dexamethasone as antiemetic. The aim of our investigation was to assess if the two drugs interact in a murine model of acute visceral pain. Using the acetic acid writhing test in mice, we assessed the antinociceptive effects of tramadol and dexamethasone (a glucocorticoid with antiemetic effect) administrated individually and in a 1 : 1 fixed ratio combination. Tramadol and dexamethasone induced a dose-dependent inhibition of the writhing response when administered individually, with ED(50) values of 2.9 [2.09-4.31, 95% confidence limit (CL)] mg/kg, and 0.13 (0.05-0.29, 95% CL) mg/kg, respectively. The ED(50) of the combination was 0.13 (0.01-0.29, 95% CL) mg/kg; the isobolographic and interaction index analysis revealed a synergistic interaction. The results suggest that the combination of tramadol and dexamethasone could be beneficial in the management of postoperative pain in humans.     

Impact of CYP2D6 genotype on postoperative tramadol analgesia

Genetic polymorphisms result in absent enzyme activity of CYP2D6 (poor metabolizers, PM) in about 10% of the Caucasian population. This study investigates whether the PM genotype has an impact on the response to tramadol analgesia in postoperative patients. A prospective study design was used and 300 patients recovering from abdominal surgery were enrolled. After titration of an individual loading dose, patients could self-administer 1 ml bolus doses of the drug combination tramadol 20 mg/ml, dipyrone 200 mg/ml and metoclopramide 0.4 mg/ml via patient-controlled analgesia (PCA). Patients' genotype was analyzed considering the most prevalent PM associated CYP2D6 mutations using a real-time PCR and hybridization based genotyping method. Demographic data, surgery related variables, pain scores, analgesic consumption and need for rescue medication were compared between extensive metabolizers (EM) and PM. The primary outcome criterion 'response' was defined as responder or non-responder status by the need for rescue medication and patients' satisfaction at the final interview. Demographic and surgery related data were comparable between EM (n=241) and PM (n=30). The percentage of non-responders was significantly higher in the PM group (46.7%) compared with the EM group (21.6%; p=0.005). Tramadol loading dose amounted to 108.2+/-56.9 and 144.7+/-22.6 mg (p<0.001) in EM and PM, respectively. More patients displaying the PM genotype needed rescue medication in the recovery room and during PCA period than patients with at least one wild type allele (21.6 versus 43.3%, p=0.02). PM for CYP2D6 showed a lower response rate to postoperative tramadol analgesia than EM. Therefore, CYP2D6 genotype has an impact on analgesia with tramadol. Pharmacogenetics may explain some of the varying response to pain medication in postoperative patients.     

Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study

BACKGROUND: Tramadol is widely prescribed, even to the eldest patients. Although age-related differences in pharmacologic responsiveness are to be expected, the pharmacodynamic and pharmacokinetic (PK) properties of tramadol have not been systematically compared between patients of various ages. OBJECTIVE: The aim of this study was to explore the effectiveness, PK properties, and safety profile of 2 galenic tramadol formulations in 3 similarly sized age groups with malignant and nonmalignant pain of moderate to severe intensity. METHODS: This prospective, age-group-controlled study was conducted at the ambulatory pain clinic of the Landeskrankenhaus K?rnten, Klagenfurt, Austria. Male and female adults with malignant and nonmalignant pain of moderate to severe intensity were eligible. Patients were stratified into similarly sized age groups, as follows: >or=75, 65-<75, and <65 years. Patients first received the immediate-release galenic formulation of tramadol (tramadol IR) until steady state was achieved, followed by the sustained-release formulation (tramadol SR) until steady state. Serum concentrations of tramadol and its active metabolite (O-desmethyl-tramadol [M1]) were measured using gas chromatography to estimate the age-related PK handling of the analgesic drug. Three validated scales were used to measure pain intensity during the study: a 100-mm visual analog scale (VAS), an 11-point numeric analog scale (NAS), and a 4-point verbal rating scale (VRS). Tolerability was assessed by evaluating daily answers about the potential occurrence of adverse events (and respective details such as type and severity) from baseline until the end of the observation period. RESULTS: A total of 100 patients were enrolled (58 women, 42 men; mean [SD] age, 65.2 [15.0] years; >or=75, 30 patients; 65-<75, 31 patients; and <65 years, 39 patients). Predominant causes of pain were neoplasms (27.4% of causes) and injury and other external causes (20.8%), and diseases of the musculoskeletal and connective-tissues systems (19.8%). Fifty-five patients completed the study and provided all data as planned. Mean (SEM) steady-state tramadol IR doses were 250 (20.2), 277 (39.8), and 325 (33.1) mg/d in patients aged >or=75, 65-<75, and 65 years, respectively (P = NS); tramadol SR, 278 (27.5), 306 (39.7), and 340 (35.1) mg/d (P = NS). Serum concentrations of tramadol and M1 were statistically similar across all 3 age groups. Overall, mean pain intensity scores, as measured using the VAS and NAS, were decreased from baseline (62.4 [2.0] mm and 6.22 [0.22] points, respectively) to steady state with tramadol IR (23.6 [2.9] mm and 2.65 [0.30] points) and tramadol SR (16.9 [2.5] mm and 1.91 [0.26] points) (all, P < 0.001). Pain intensity before and improvements during both treatment phases were similar across all 3 age groups. RESULTS: for pain intensity on the VRS also did not find age-related differences. The predominant adverse effects were nausea (27.0% of patients), dizziness and giddiness (18.0%), and malaise and fatigue (15.0%); no significant differences in adverse events were found between age groups. CONCLUSIONS: The fate of tramadol and its active metabolite, and their clinical effects, have been examined here for the first time in a prospective cohort study, which compared patients aged <65 years, 65-<75 years, and >or=75 years. In contrast to expectations, it was concluded that tramadol IR and tramadol SR were both generally well tolerated and effective in the treatment of moderate to severe pain in any of the 3 age groups in these patients. Although the eldest group of patients consumed, on average, 20% less tramadol (P = NS) than the youngest group, the PK properties of both drugs were not changed when given to elderly patients.     

曲马多与氯胺酮对瑞芬太尼麻醉后早期疼痛的预防效果观察

目的比较曲马多与氯胺酮对瑞芬太尼麻醉后早期疼痛的预防效果和不良反应。方法60例全凭静脉麻醉联合喉罩下行腹腔镜胆囊切除手术的患者分为3组（每组20例）,分别在手术近结束缝合皮肤时静脉注射曲马多2mg/kg（T组）、氯胺酮0.5mg/kg（K组）、生理盐水2ml（C组）。所有患者以丙泊酚、瑞芬太尼、罗库溴铵麻醉诱导,术中以丙泊酚、瑞芬太尼维持麻醉,术毕送麻醉后恢复室。当患者出现中等程度疼痛[疼痛视觉模拟评分（VAS）≥6分）]时给予曲马多2mg/kg,记录术后苏醒时间、喉罩拔除时间、VAS评分、术后镇痛药物使用率以及各项生命体征和不良反应,苏醒后30min内评分,VAS≥6分者视为镇痛失败。结果3组患者手术结束后苏醒时间、喉罩拔除时间以及各时点心率、血压比较差异均无显著性意义（P〉0.05）;苏醒后1min、10min、20min、0.5h、4h的VAS评分T组、K组均低于C组（P〈0.05）;镇痛药物使用率T组、K组均低于C组（P〈0.01）,T组亦低于K组（P=0.01）;术后躁动率T组、K组均显著低于C组（P〈0.01）。结论曲马多对瑞芬太尼麻醉后早期疼痛有明显预防作用,与氯胺酮比较效应更强。     

Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial

OBJECTIVE: To compare tramadol/acetaminophen (APAP) and placebo for the management of acute migraine pain. BACKGROUND: Tramadol/APAP tablets reduced moderate-to-moderately severe acute pain in controlled studies of other painful conditions. METHODS: This randomized, double-blind, placebo-controlled, parallel group study enrolled adults with migraine pain as per International Headache Society criteria. Subjects took tramadol/APAP (total dose, 75 mg/650 mg) or placebo for a typical migraine with moderate-to-severe pain. Severity of pain and migraine-related symptoms were recorded before study medication and at 0.5, 1, 2, 3, 4, 6, and 24 hours after study medication. RESULTS: Efficacy analyses included 305 subjects (154 tramadol/APAP and 151 placebo). Treatment response was higher for tramadol/APAP than a placebo at 2 hours after dosing (55.8% vs. 33.8%, P < .001) and at every other assessment from 30 minutes (12.3% vs. 6.6%) through 6 hours (64.9% vs. 37.7%) (all P< or = .022). Subjects in the tramadol/APAP group were more likely than those in the placebo group to be pain-free at 2 hours (22.1% vs. 9.3%), 6 hours (42.9% vs. 25.2%), and 24 hours (52.7% vs. 37.9%) (all P< or = .007). Two hours after dosing, moderate-to-severe symptoms that were less common for tramadol/APAP than placebo included photophobia (34.6% vs. 52.2%, P= .003) and phonophobia (34.3% vs. 44.9%, P = .008), but not migraine-related nausea (38.5% vs. 29.4%, P= .681). Treatment-related adverse events included nausea, dizziness, vomiting, and somnolence. CONCLUSIONS: Tramadol/APAP reduces the severity of pain, photophobia, and phonophobia associated with migraine headache, but does not reduce migraine-associated nausea. Tramadol/APAP might be an appropriate option for the management of moderate-to-severe migraine headache.     

Tramadol in post-herpetic neuralgia: a randomized,double-blind,placebo-controlled trial

The efficacy and safety of sustained-release tramadol compared to placebo in the treatment of post-herpetic neuralgia were evaluated in a multicenter, randomized, double-blind, parallel-group study in 127 outpatients. Treatment was administrated for 6 weeks. The dose of tramadol could be increased from 100 mg/day to 400 mg/day (300 mg/day in patients more than 75 years old). Groups were compared on changes in pain intensity on a Visual Analogue Scale (VAS) between inclusion and the 6th week of treatment (covariance analysis as main analysis and repeated measures analysis as complementary analysis) in the per protocol (PP) population. The randomized population comprised 127 patients aged 35-85 years, mostly females (72.4%). Groups were comparable at inclusion both in the intent to treat (ITT) population (63 patients in the tramadol group and 62 patients in the placebo group) and in the PP population (53 patients in the tramadol group and 55 patients in the placebo group). Mean pain intensity on day 43 adjusted on day 1 (covariance analysis) was significantly lower in the tramadol group than in the placebo group in both the PP (P=0.0499), and the ITT (P=0.031) populations. The two groups significantly differed on change in pain intensity over time (repeated measures analysis) in the ITT population (P=0.012). The percentage of pain relief over the 6th week was significantly higher in the tramadol group than in the placebo group (P=0.017). During the 6th week, patients in the tramadol group required less rescue medication than patients in the placebo group (P=0.022). No significant difference was found between groups either in pain intensity on a 5-point Verbal Scale (VRS) or in quality of life measurements. Tramadol was administered at an average dosage of 275.5 (89.7) mg/day after a 1-week dose-adaptation period. Tramadol was well tolerated. No notable difference appeared between groups either in the percentage of patients with treatment-associated adverse events (TAAE) (29.7% in the tramadol group and 31.8% in the placebo group) or in the total number of TAAE (31 in the tramadol group and 28 in the placebo group).     

Single-dose intravenous tramadol for acute migraine pain in adults: a single-blind, prospective, randomized, placebo-controlled clinical trial

BACKGROUND: Tramadol, an atypical opioid, is a narcotic analgesic used for pain management. A search of the current literature found no studies examining the efficacy of intravenous tramadol on migraine pain. OBJECTIVE: The aim of this study was to investigate the efficacy and tolerability of a single dose of intravenous tramadol hydrogen chloride 100 mg in comparison with placebo in patients presenting with migraine. METHODS: Adult migraineurs admitted consecutively to the emergency department of the Kocaeli University Hospital were enrolled in this single-blind (patients), prospective, randomized, placebo-controlled clinical trial. Patients were randomized to receive a 30-minute infusion of either intravenous tramadol (n = 17; 100 mg in 100-mL saline) or placebo (n = 17; 100-mL saline). Pain response was defined as a decrease of visual analogue scale (VAS) (0-100 mm) score to <50% of the pretreatment (baseline) value and a decrease of 4-point verbal scale (FPVS) score (0 = none, 1 = mild, 2 = moderate, 3 = severe) to mild or none. Pain-free response was defined as a decrease of both VAS and FPVS scores to 0. Pain was assessed at baseline and at 30 minutes and 1 hour after treatment completion. Migraine symptoms (eg, photophobia, phonophobia, nausea, vomiting) and adverse events (AEs) were assessed at the same time. A follow-up was also conducted by phone 24 hours after treatment. RESULTS: Forty-four migraineurs were screened and 34 (28 women and 6 men; mean [SD] age, 39.5 [10.4] years; all were white) were enrolled in the study. Each group contained 11 patients with severe pain and 6 patients with moderate pain at baseline FPVS. At the end of 1 hour, pain response was reported by significantly more patients in the tramadol group than in the placebo group (12 [70.6%] vs 6 [35.3%]; P = 0.040). Pain-free response was reported by 5 (29.4%) patients in the tramadol group and 2 (11.8%) patients in the placebo group, although the difference was not statistically significant. Symptoms associated with migraine were also relieved in all patients reporting pain response. No AEs were observed. However, at the 24-hour follow-up, 1 patient in the tramadol group reported transient blurred vision and dizziness within the day of infusion. Headache recurrence was reported by 2 (16.7%) of the 12 patients with pain response in the tramadol group and 1 (16.7%) of 6 patients with pain response in the placebo group. CONCLUSIONS: Intravenous tramadol appeared to be more effective than placebo in pain response rate at the end of the first hour. The slow infusion of tramadol 100 mg in 100-mL saline solution was well tolerated in this group of adult migraineurs.     

Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice

Tramadol is one of the most widely used centrally acting analgesics worldwide. Because of its multimodal analgesic mechanism (opioid plus nonopioid), the adverse effects profile of tramadol, similar to its analgesic profile, can be atypical compared with single-mechanism opioid analgesics. The comparison is often favorable (e.g., less respiratory depression or abuse), but it is sometimes cited as unfavorable in regard to seizure potential. As part of a broader study of this analgesic, we compared seizure induction in mice produced by administration of tramadol, the enantiomers and metabolites [M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N,N-didesmethyl tramadol), M4 (O,N,N-tridesmethyl tramadol), and M5 (O,N-didesmethyl tramadol)] of tramadol, and opioid and nonopioid reference compounds. We found that tramadol, its enantiomers, and M1 to M5 metabolites were of intermediate potency in this endpoint (on either a milligram per kilogram or millimole per kilogram basis). The SD50 (estimated dose required to induce seizures in 50% of test group) of tramadol to antinociceptive ED50 ratio was almost identical to that of codeine. The enantiomers of tramadol were about equipotent to tramadol on this endpoint. The M1 to M5 metabolites (and M1 enantiomers) of tramadol were less potent than tramadol. The relative potency of tramadol to opioids was not altered by quinidine (an inhibitor of CYP4502D6), noxious stimulus (48 degrees C hot-plate), multiple dosing, or in reserpinized mice. Tramadol seizures were increased by naloxone, principally at high tramadol doses and due to an effect on the (-)enantiomer that overcame the opposite effect on the (+)enantiomer. No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine.     

Antagonistic Effects of Ondansetron and Tramadol? A Randomized Placebo and Active Drug Controlled Study

Opposing effects of ondansetron and tramadol on the serotonin pathway have been suggested which possibly increase tramadol consumption and emesis when co-administered. In a randomized, double-blinded study, 179 patients received intravenous ondansetron, metoclopramide, or placebo for emesis prophylaxis. Analgesic regimen consisted of tramadol intraoperative loading and subsequent patient-controlled analgesia. Tramadol consumption and response to antiemetic treatment were compared. Additionally, plasma concentrations of ondansetron and (+)O-demethyltramadol and CYP2D6 genetic variants were analyzed as possible confounders influencing analgesic and antiemetic efficacy. Tramadol consumption did not differ between the groups. Response rate to antiemetic prophylaxis was superior in patients receiving ondansetron (85.0%) compared with placebo (66.7%, P = .046), with no difference to metoclopramide (69.5%). Less vomiting was reported in the immediate postoperative hours in the verum groups (ondansetron 5.0%, metoclopramide 5.1%) compared with placebo (18.6%; P = .01). Whereas plasma concentrations of (+)O-demethyltramadol were significantly correlated to CYP2D6 genotype, no influence was detected for ondansetron. Co-administration of ondansetron neither increased tramadol consumption nor frequency of PONV in this postoperative setting.     

Emergency department management of acute migraine in children in Canada: a practice variation study

OBJECTIVES: Evidence-based guidelines for the treatment of children with migraine are limited given the paucity of randomized controlled trials, especially in the emergency department (ED). Our objectives were to: (1) characterize the treatment of children with migraine in the ED; (2) determine whether treatment varies in pediatric versus mixed (pediatric and adult) EDs. METHODS: Children aged 5 to 17 years presenting to 4 regional emergency departments in Edmonton, Alberta, Canada during the 2003/2004 fiscal year with a diagnostic code of headache or migraine were selected. A standardized retrospective chart abstraction was performed and migraine or probable migraine cases were classified based on the International Classification of Headache Disorders II. RESULTS: Three hundred and eighty-two cases were identified of which 48.7% (n = 186/382) met sufficient criteria for migraine. No treatment was given in 44.2% (n = 169/382). Simple oral analgesics (23.3%; n = 89/182) and dopamine antagonists (metoclopramide and prochlorperazine; 20.7%; n = 79/182) were prescribed first-line most commonly. Opiate medications (5.5%), ketorolac (4.7%), dihydroergotamine (1%) were prescribed first-line infrequently. There was a significant difference in the management choices between pediatric and mixed adult/pediatric EDs (chi(2)= 19.695; df = 5; P= .001). The pediatric ED was more likely to prescribe a dopamine antagonist (12.9 vs 6.8%; P= .044) while the mixed adult/pediatric EDs were more likely to prescribe an opiate (28.1% vs 18.4%; P= .031). Children with migraine in all EDs were significantly more likely to receive drug therapy (68.3% vs 42.9%; P < .001) or a dopamine antagonist (32.3% vs 9.7%; P < .001). Polypharmacy (31.2%; n = 119/382) and neuroimaging (29.1%; n = 111/382) were common. Outcome was poorly documented overall. No adverse events were recorded. CONCLUSIONS: Significant variation in practice in the management of acute headaches in children was observed between mixed population and pediatric-only emergency physicians in the same city. Most children do not receive any drug therapy. Children presenting to the pediatric ED were significantly more likely to receive a dopamine antagonist while opiates were prescribed more commonly in the mixed ED. More clinical trials are required in children to clarify areas of clinical uncertainty on which evidence-based practice guidelines can be formed.     

曲马朵缓释片用于肺癌术后镇痛效果观察

[目的]观察曲马朵缓释片和曲马朵普通片治疗肺癌术后疼痛的疗效.[方法]将30例病人随机分成实验组和对照组,实验组给予曲马朵缓释片100 mg,12 h 口服1次;对照组给予曲马朵普通片50 mg,6 h口服1次.[结果]曲马朵缓释片与曲马朵普通片镇痛效果相同,组间差异无统计学意义.[结论]曲马朵缓释片对肺癌术后中度急性疼痛的镇痛效果确切.