Physical compatibility and in vivo evaluation
Abstract The objectives of this study were first to investigate the compatibility and physical stability of drug admixtures destined for s.c. administration through elastomeric infusion pumps to terminally ill cancer patients followed up at home by staff of the Palliative Care Unit (AECC), “La Paz” Hospital, Madrid and secondly, to evaluate the local side-effects related to the infusion of some of the drug mixtures to a population of 50 patients. The drug mixtures prepared included combinations of two, three, four and five of the following drugs: morphine hydrochloride, 60 mg/day; midazolam hydrochloride, 15 mg/day; haloperidol lactate, 7.5 mg/day; hyoscine-Nbutyl- bromide, 60 mg/day; dexamethasone sodium phosphate, 16 mg/day; metoclopramide hydrochloride, 40 mg/day, and tramadol, 400 mg/day. Out of 86 mixtures evaluated in vitro, 52 were found to be physically compatible. Precipitation was always obtained when dexamethasone sodium phosphate at the concentrations assayed was combined with haloperidol lactate and/or midazolam hydrochloride. However, no precipitation occurred when morphine hydrochloride, the opioid most frequently used in patients of this type, and dexamethasone sodium phosphate were combined. Of the drug mixtures that were physically compatible, 18 were administered to the patient population evaluated. Very good symptom control was obtained with all of them, and especially with the mixture of morphine + midazolam + haloperidol + hyoscine, which is the one most frequently administered to cancer patients for palliative care in the final stages of life in our Unit.
Postoperative Pain Therapy After Lumbar Disc Surgery
Introduction
The introduction of microsurgical techniques has dramatically reduced the degree of postoperative painand the duration of hospital stay associated with lumbar disc surgery. However, many of these patients stillexperience postoperative back pain, delaying hospital discharge and return to normal activity . Multiple modalities, including corticosteroids, morphine, bupivacaine or propacetamol, have been advocated by anaesthesists or neurosurgeons to reduce postoperative pain after lumbar discectomy .Although no studies have been performed to evaluate the effcacy of a combination of morphine and diclofenac in pain therapy after lumbar disc surgery, several neurosurgeons use these drugs in the management of patients after lumbar discectomy. Therefore this study of a special postoperative administration of the weak opioid tramadol and the NSAID diclofenac was undertaken to determine whether this special pain management with well-tried and reliable analgesics provides any benefit in patients who underwent microsurgical lumbar discectomy.
Filed under Cognitive Articles, Scientific Articles, Tramadol | Comment (0)Impact of the CYP2D6 metaboliser status on the pupillary response
This is to reply to the comments provided by Slanar et al to our article “The effects of tramadol on static and dynamic pupillometry in healthy subjects—the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status” published in Eur J Clin Pharmacol (2005) 61: 257–266. Slanar et al compared their own data [1, 2] with our work. However, there are some limitations to directly compare both studies: – We used a placebo-controlled crossover study design. This allowed us to perform intra-subject comparisons between effects induced by either placebo and verum. This can be regarded as the highest possible level of standardisation within a clinical trial. The data obtained after administration of placebo can be used to evaluate possible background noise, diurnal rhythms or other influencing factors. – We administered an immediate release formulation of tramadol, whereas Slanar et al used slow release capsules. As a consequence the studies can be expected to differ in the velocity of the PK/PD response. – Furthermore, we performed a stereoselective bioanalytic method to differentiate between the enantiomers of tramadol and its +M1. This is crucial for pupillometry studies because the various enantiomers are known to contribute to a certain degree to either a μ or non-μ action component which are known to induce either decreases or increases of the pupil size. – In addition to static pupillometry, we provided data from dynamic pupillometry. This added essential information, as tramadol administered to PMs was found to effect only dynamic pupillometry. In general, it appears to be difficult to directly compare drug-induced effects on pupil size between different studies. Important factors such as study design, accuracy of the measuring devices, sampling frequency, light conditions etc. may have a significant impact on the effects reported.We would therefore like to address those points in more detail. In our study, we administered tramadol as an immediate release formulation, resulting in a faster absorption of tramadol, whereas Slanar et al used slow-release capsules. Accordingly, we observed maximum serum concentrations at 2 h for both tramadol enantiomers and between 2.5 and 3 h for both enantiomers of M1. Irrespective of the assumed subtype, the miosis in
Determination of Tramadol
A sensitive, enantioseJective high-performance liquid chromatographic method has been developed for the separation and individual quantitative determination of (+)- and (-)-tramadol and (+)- and (-)-O-desmethyltramadol (M1) in plasma and urine. Extraction from plasma and urine was performed by solid-phase extraction (SPE) on disposable butyl silica (100 mg) extraction cartridges. Separation of the enantiomers of tramadol and M1 was achieved on a ChiralpakAD column containing amylase tris-(3,5-dimethylphenylcarbamate) as chiral selector. The mobile phase was isohexane-ethanol-diethylamine, 97:2.8:0.1 (v/v). Quinidine was used as internal standard. The analytes were detected by use of fluorescence detection. The limit of quantification for tramadol and M1 was 5 nM in plasma and 25 nM in urine. Recoveries were approximately 90% for tramadol and M1 in both plasma and urine. Linearitywas observed for both enantiomers of tramadol and M1 in both plasma (r 2 > 0.999) and urine (r 2 > 0.997). The intra and inter-day precision (CV) did not exceed 6.0%. The applicability of the method was demonstrated by means of two clinical studies - a pharmacokinetic study in which a healthyvolunteer received 150 mg tramadol hydrochloride as a single oral dose and a study in which poor and extensive CYP2D6 metabolizers received 50 mg tramadol hydrochloride as a single oral dose.
Trends in consumption of opioid analgesics in Slovak Republic
Introduction
The management of patients with chronic pain is a common clinical challenge. Indeed, chronic pain is often inadequately controlled in patients with cancer and noncancer chronic pain. Because of the complex nature of chronic pain, successful long-term treatment is more difficult than with acute pain [1]. The World Health Organization (WHO) considers a country’s morphine consumption to be an important indicator of progress in pain relief [2]. The management of pain demands frequent reevaluation of the patient and a readiness to reevaluate the therapeutic plan in the case of either insufficient pain relief or adverse effects related to opioid analgesics [3]. The annual consumption of morphine, including the use for non-cancer pain, has increased substantially in developed countries [4]. Recent guidelines and evidencebased recommendations for the use of opioids in other conditions than acute and cancer pain have advised the use of sustained-release or long-acting opioids, thus avoiding repeated injection for chronic pain. The WHO analgesic ladder has placed opioids on step 2 and step 3 when other strategies have failed to provide sufficient pain control and the quality of life is poor [5, 6]. Pediatric and geriatric subpopulations are at especially high risk of undertreatment [6]. Inadequate treatment occurs partly due to reluctance to initiate opioid analgesics and fear of abuse, although international and national expert groups have determined that opioid analgesics are essential for the relief of pain [7].
Filed under Cognitive Articles, Scientific Articles, Tramadol | Comment (0)Intravenous Ketoprofen in Postoperative Pain Treatment after Major Abdominal Surgery
Abstract. In recent years considerable attention has been paid to the treatment of postoperative pain, with regard to the favorable effect of adequate analgesia on patient outcome. Multimodal analgesia (e.g., opioids and nonsteroidal anti-inflammatory drugs [NSAIDs] or local anesthetics) is recommended for effective postoperative pain relief. There are few data on the use of NSAIDs in postoperative pain treatment after abdominal surgery. We conducted a randomized, double-blind, placebocontrolled study to assess the analgesic efficacy and safety of ketoprofen after major abdominal surgery. One and nine hours postoperatively patients received 100 mg of ketoprofen i.v. (n = 21) or placebo (n = 22) in addition to a pain-treatment protocol consisting of continuous infusion of tramadol 200 mg and metamizol 5 g over 24 hours with additional 25 mg i.v. tramadol in case of inadequate analgesia. Pain was assessed by numeric rating scale at rest and at deep breath 3, 6, 12, and 24 hours postoperatively and the total dose of tramadol used in the first 24 hours was recorded. Patients in the ketoprofen group had significantly lower pain scores both at rest and at deep breath, at 3 (p < 0.01), 6, and 12 hours (p < 0.05) postoperatively. The 24-hour use of tramadol was significantly lower in the ketoprofen group (p < 0.01), with less nausea and vomiting. There were no bleeding complications or other adverse events related to ketoprofen therapy. The study showed the value of short-term use of ketoprofen to improve the quality of analgesia after major abdominal surgery without significant adverse effects.
Filed under Cognitive Articles, Scientific Articles, Tramadol, Новости | Comment (0)Postoperative Schmerztherapie bei Kindern und Jugendlichen
Noch immer wird kindlicher postoperativer Schmerz in den meisten Kliniken unzureichend behandelt [21].Kinder erhalten weniger, seltener und daruber hinaus noch schwachere Analgetika als Erwachsene [4]. Nach neuesten neuroanatomischen und neurophysiologischen Erkenntnissen zeigen Kinder allerdings gleiches Schmerzempfinden wie Erwachsene.Demnach muss bei ihnen von einer erheblichen schmerztherapeutischen Unterversorgung ausgegangen werden.Dafur wesentliche Ursachen sind in mangelnden physiologischen und pharmakologischen Grundkenntnissen der verantwortlichen Arzte zu suchen. Unzureichende Uberwachungsmoglichkeiten und damit verbunden die – berechtigte – Angst vor ernsten Nebenwirkungen fuhren auch bei engagierten Kollegen immer wieder dazu, Kindern eine effektive Schmerztherapie vorzuenthalten. Kurzlich wurden in verschiedenen Landern Empfehlungen zur postoperativen Schmerztherapie bei Kindern veroffentlicht [8, 11, 24].Auch in Deutschland findet die Kinderschmerztherapie in den Empfehlungen einer interdisziplinaren Expertenkommission zur Behandlung akuter perioperativer und posttraumatischer Schmerzen Berucksichtigung [24]. Eine konsequente Umsetzung der dort dargestellten Therapiemoglichkeiten bei Kindern erscheint umso dringlicher, weil durch den Einsatz kurz wirksamer Substanzen in der Narkosefuhrung (Remifentanil,Sevofluran) neue Anforderungen an die fruhe postoperative Schmerztherapie gestellt werden. Continue reading »
Filed under Cognitive Articles, Scientific Articles, Tramadol, Новости | Comment (0)The Effectiveness of Analgesics in Traumatic Injuries of the Extremities
INTRODUCTION
Trauma and its related morbidity and mortality are serious health problems, especially for patients 5 to 35 years of age.1 It is important to evaluate the extent of trauma, provide initial interventions, and plan a treatment schedule using the trauma management techniques of emergency departments (ED). The first aim of the emergency physician is to save lives and protect vital functions of the patients with traumatic injuries. Priority should be given to vital areas such as the head, thorax, abdomen, and damaged blood vessels. After evaluation and treatment of these areas, fractures and wounds in the extremities should be treated.2 Wounds that occur after trauma to the extremities should be considered in their entire spectrum, ranging from soft-tissue contusion to traumatic amputation. Cutaneous and subcutaneous wounds include tendon rupture, muscle rupture, ligament injuries, rupture of the menisci and of the joint capsule, subluxation of joints, luxations, and multiple fractures; these may occur singly or in any combination. Some of these injuries require emergency intervention, whereas others may be treated electively. Emergency care of injuries to the extremities should begin by controlling pain and swelling. Open fractures should be closed and then dislocations should be treated.3,4 It is recommended that pain should be controlled by means of a drug administered intravenously, which affects the central nervous system (CNS).5 This study examines the relative efficacy of analgesics such as tramadol hydrochloride, metamizole sodium, and diclofenac sodium in patients who presented to the Konya State Hospital emergency service with traumatic injuries and fractures of the extremities.
Filed under Cognitive Articles, Scientific Articles, Tramadol, Новости | Comment (0)Slow-release tramadol for treatment of chronic malignant pain – an open multicenter trial
Introduction
The WHO guidelines have set the standard for the treatment of chronic cancer pain [34] and have been shown to be effective and safe in a number of studies . The introduction of slow-release preparations of a variety of opioid and nonopioid compounds has considerably increased patient comfort and simplified treatment regimens. However, until recently few clinically useful opioids for the treatment of mild to moderate pain as detailed in step 2 of the WHO analgesic ladder have been available as slow-release preparations . Tramadol is an aminocyclohexanol derivative with m-agonist activity, which also inhibits noradrenaline and serotonin reuptake [24]. Both mechanisms are believed to contribute synergistically to its analgesic effects, its potency being about a fourth to a tenth of that of morphine. General pharmacology, safety and efficacy of tramadol have been extensively reviewed recently . The safety and effectiveness of oral, IR tramadol in treatment of mild to moderate chronic cancer pain has been established in several uncontrolled trials Three controlled crossover studies demonstrated similar pain relief in patients treated with tramadol and patients treated with low-dose morphine or buprenorphine. Various oral, rectal and parenteral formulations of Tramadol are available for the treatment of cancer patients. A pH-independent slow-release preparation, which now is available in several countries, has been shown to result in prolonged analgesia (data on file, Grunenthal report FO-PK 383, 1996). Two controlled, double blind trials demonstrated equi-analgesia of immediate- and slow-release tramadol in patients with chronic low back pain . An open trial in cancer patients showed similar or better efficacy of slow-release tramadol compared with buprenorphine . The aim of this open study was to show whether the twice-daily administration of the slow-release preparation of tramadol effectively controlled chronic malignant pain during initial dose finding and long-term treatment and what doses were necessary to achieve this effect, and to assess the safety and the tolerability of this regimen during administration over a period of 6 weeks.
Filed under Scientific Articles | Comment (0)Comparison of efficacy of intraarticular application of tenoxicam, bupivacaine and tenoxicam: bupivacaine combination
Introduction
Improvements in the anaesthetic, analgesic and surgical techniques, evolution of short-acting drugs and common use of regional anaesthetic/analgesic techniques, allow more cases to become outpatient surgery. Arthroscopic knee surgery is one of the most common surgical procedures done in outpatient settings; however, postoperative pain is believed to be the major barrier for discharge and early rehabilitation. A variety of analgesic techniques, such as systemic drug medication, central blockades, peripheral blockades, pre-emptive analgesia and intraarticular drug administration, have been tried to prevent or treat pain due to arthroscopic knee surgery . Some of the techniques require expensive equipment and monitoring, some produce inadequate analgesia and some involve the risk of discharge delay or recurrent admission. Satisfactory analgesia has been provided by intraarticular bupivacaine; however, the analgesic effect does not last long. Much research has been done to prolong analgesia such as supplementing with ketamine, clonidine, morphine or nonsteroidal analgesics . Nonsteroidal analgesics are found to be effective in improving analgesia after arthroscopic knee surgery, but the optimal route is still speculative . In this study we evaluated and compared the efficacy of intraarticular application of a long-lasting nonsteroidal analgesic drug, tenoxicam, a long-lasting local anaesthetic bupivacaine and combination of the two on postoperative analgesia after arthroscopic knee surgery.
Filed under Cognitive Articles, Scientific Articles, Tramadol, Новости | Comment (0)Randomized double-blind, double-dummy crossover clinical trial of oral tramadol
Abstract Tramadol is commonly used as second step drug of the analgesic ladder. In circumstances where the oral route is unavailable, rectal administration of opioids might be a simple alternative. The aim of this study was to compare the analgesic activity and tolerability of Tramadol by oral and rectal administration in a double-blind, double-dummy crossover trial. The study included 60 cancer patients with cancer pain no longer responsive to non-opioid drugs. Each patient initially received oral tramadol 50 mg (drops), followed by tramadol sustained release 100 mg orally, and placebo rectally, or tramadol 100 mg rectally and placebo orally, twice a day, in a randomized sequence, on each of 3 days. Patients were allowed to take 50 mg of oral tramadol by drops as needed (four doses per day, to a maximum of 400 mg/day, including the basal dose given by the oral or rectal route). Pain intensity and relief and symptom scores were recorded every day and at the end of each phase of the crossover. The mean age of the patients was 66.1 years (SD 13.5 years); 36 were female, and 44 completed both periods. Patients dropped out due to adverse effects (15 patients) and refusal (1 patient). No differences in the use of rescue dose of oral tramadol were observed between the groups. No differences in pain intensity and relief scores, or in other symptoms between the two treatments were observed. No differences in treatment efficacy as judged by the clinician (P=0.73), in patient compliance (P=0.35), or in patient satisfaction regarding treatment (P<0.35) were found. No differences in adverse effects were found between the two treatments (25.5%, 13 patients, and 20.4%, 11 patients, with oral and rectal treatment, respectively). The proportion of preferences favored oral administration for both physicians (P=0.0002) and patients (P=0.002). Rectal administration of tramadol appears a reliable, noninvasive alternative method of pain control for patients no longer responsive to non-opioid analgesics, unable to take oral tramadol.
Filed under Scientific Articles | Comment (0)Liquid Chromatographic Assay for Simultaneous Determination of Tramadol and Its Active Metabolite in Human Plasma.
Introduction
Tramadol hydrochloride, (1RS, 2RS)-2-[(dimethylamino)- methyl]-l-(3-methoxyphenyl)-cyclohexanol hydrochloride (Figure 1), is a centrally acting analgesic that has an analgesic efficacy and potency that ranges between weak opioids and morphine [1, 2]. The drug acts as an opiate agonist, by selective activity at the la-opioid receptor. In addition to opiate agonist activity, Tramadol inhibits reuptake of norepinephrine and serotonin, which appears to contribute to the drug’s analgesic effect [3]. Tramadol is metabolized in the liver mainly to O-demethyltramadol, mono-N-demethyltramadol, and di-N,O-demethyltramadol [4]. Of these compounds, only O-demethyltramadol is pharmacologically active. The affinity of this metabolite for the p-opioid receptor is about 200 times greater than that of the parent compound, tramadol [1]. The currently used preparation of tramadol is a racemic mixture of (+)-tramadol ((1R, 2R)-2-[(dimethylamino)- methyl]-l-(3-methoxyphenyl)-cyclohexanol hydrochloride) and (-)-tramadol ((IS, 2S)-2-[(dimethylamino)- methyl]-l-(3-methoxyphenyl)-cyclohexanol hydrochloride) [4]. Although the (+)-enantiomer exhibited ten-fold higher analgesic activity than the (-)-enantiomer [5], the racemic mixture of (+)- and (-)-tramadol has shown more pharmacologhic potency than the individual enantiomers in different clinical and preclinical studies [4]. Racemic tramadol can be estimated in biological fluids by gas chromatography with a nitrogen-selective detector [6], by GC-MS [7, 8] or LC methods coupled to UV [9-11] or fluorimetric detection [12]. The sample clean-up procedures of biological samples were based on liquid-liquid extraction after alkalization, and solid-phase extraction. Tramadol extraction recoveries range between 50-86 % when liquid-liquid extraction procedures were used, and is 100 % when solid-phase extraction is used [9-12]. O-demethyltramadol extraction recoveries range: 65.5-91% using liquid-liquid extraction procedures [9-11]. GC methods are specific and allow tramadol quantitation < 10 ng mL -1, using 1 mL samples. However, these methods include a tedious and time-consuming, threestep liquid-liquids extraction procedure [6-8]. Only five analytical procedures are described in the literature. Such methods are, however, insufficiently sensitive when sub-therapeutic drug levels are to be measured, as frequently occurs in pharmacokinetic studies. Moreover, only two of these methods allow O-demethyltramadol quantitation [10-11]. Nevertheless, the limit of quantitation of O-demethyltramadol in these methods lay between 80-200 ng mL -1. This paper reports a sensitive and selective method for the quantitation of Tramadol and O-demethyltramadol plasma levels over 1-1000 ng mL -1 range, which may be used when working with small samples.
Filed under Cognitive Articles, Scientific Articles, Tramadol, Новости | Comment (0)Myoclonus of probable spinal origin as a potential side effect of tramadol
Tramadol is a synthetic compound analogous to codeine and has an effect on mild to moderate pain .Myoclonus can develop during treatment with opioids by different routes of administration (oral, intramuscular, intravenous, intrathecal) .We reported here a case of myoclonus of probable spinal origin induced by intravenous administration of Tramadol. A 33 year-old healthy female acutely developed continuous irregular symmetric jerks of proximal limb and abdominal muscles.A continuous hiccup was present too.Her past history was negative except for recent administration of tramadol 100 mg/day i. v. for abdominal pain. Neurological examination disclosed the presence of diffuse jerks involving muscles of shoulder girdle, abdominal wall, neck flexors, and quadriceps.Myoclonic jerks were present both when lying flat and when standing. The other findings were unremarkable, in particular there was no abnormal movement of the bulbar muscles, eyes and distal muscles of limbs. The myoclonic jerks were not associated with somatosensory or audiogenic stimuli.Vigilance and higherorder functions were normal. There was no evidence of weakness, impairment of vibration, pinprick and touch sense, cerebellar function or cranial nerves. Tendon reflexes were symmetric and moderately brisk. Plantar response was flexor and abdominal reflexes were present on both sides. EEG-EMG polygraphs with recording from quadriceps and middle aspect of rectus abdominii was performed within 1 hour after admission. Continuous EMG bursts lasting 150–200ms were present in both muscles. Their firing frequency in quadriceps was lower than that in rectus abdominii and the jerks in one muscle did not seem to be time-related to those in the other muscle.No correlates with these bursts were found on EEG,which was normal. There was a marked increase in serum creatine kinase (6457 U/L) and the patient complained of an aching muscle pain.
Tramadol in Musculoskeletal Pain – A Survey
Introduction
In the 1980s the WHO proposed guidelines for the treatment of cancer pain , the central feature of which was the three-step analgesic ladder. Step 1 is a nonopioid analgesic (e.g. aspirin, NSAID, paracetamol); if pain persists, a weak opioid (e.g. codeine) may be added in Step 2; if this proves inadequate, a strong opioid (e.g. morphine) can be substituted in Step 3 for the weak opioid. Treatment at each step may be supplemented by adjuvant therapy (e.g. antidepressants, glucocorticoids). This ladder approach is applied successfully and widely for the treatment of cancer pain. However, it has also proved useful as a treatment approach for chronic non-cancer pain. Our personal analgesic ladder for treating rheumatological pain is illustrated in Fig. 1; ibuprofen is used as an NSAID in Step 1. If pain is insufficiently controlled, tramadol is used as a weak opioid in Step 2 (in preference to codeine, a drug that commonly causes constipation to a degree that may jeopardise the continuation of treatment). If pain still persists after tramadol, morphine or transdermal fentanyl is used in Step 3. Although originally proposed for (and still used in) the management of cancer pain, the same analgesic ladder is now used for all types of pain. For the ischaemic pain of peripheral vascular disease the principles of the analgesic ladder are applied in conjunction with prostaglandins and aetiological treatment. For postoperative pain, Step 1 (NSAIDs) is used after minor surgery, through to Step 3 (i.v. opioids) after major surgery. The analgesic ladder has also proved its value in osteoarthritis (OA) and low back pain, reflecting the greater numbers of patients with chronic musculoskeletal pain now being seen in pain clinics.
EFFECT OF MICROINJECTION OF MORPHINE AND TRAMADOL
It has been shown in recent years that analgesia arising after stimulation of the nuclei raphe, the periaqueductal gray
matter, nucleus of the traetus solitarius, and certain other brain zones is accompanied by hypertension, tachycardia, and changes in the regional blood flow. It is considered that antinociceptive structures are involved in the regulation not only of pain, but also of the responses of the cardiovascular system, and that they may be the substrate for realization of both the painrelieving and the hemodynamic action of narcotic analgesics. A special place in the integration of functional processes of different modalities during pain is played by the locus coeruleus in the medulla, which contains opiate peptides as well as noradrenalin, and which has multiple anatomical connections with antinociceptive and vasomotor structures of the brain, and also with the spinal cord . However, changes in pain after injection of opiate analgesics into the locus coeruleus, their neurophysiological and neurochemical mechanisms, and their association with changes in nociceptive responses of the arterial blood pressure (BP) still remain completely unstudied.