The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria: is this still the same disease?

OBJECTIVE: To examine the implications of using the new classification criteria for rheumatoid arthritis (RA) in clinical practice in a cohort of patients with very early arthritis. METHODS: The study group comprised 301 disease-modifying antirheumatic drug-naive patients with early arthritis. The baseline diagnosis was assessed by applying the 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria for RA as well as established diagnostic criteria for other rheumatic diseases. Diagnostic and prognostic data were collected after 2 years of followup. Fulfillment of the 2010 ACR/EULAR criteria was evaluated in the subset of patients in whom undifferentiated arthritis (UA) was diagnosed when the 1987 ACR criteria were applied, and fulfillment of RA criteria over time was tested by applying the 2 different criteria sets. RESULTS: The median arthritis duration at baseline was 4 months (range 0-12 months). At baseline, 28% of the patients fulfilled the 1987 ACR criteria, and 45% fulfilled the 2010 ACR/EULAR criteria for RA. Among the patients classified as having UA at baseline according to the 1987 ACR criteria, 36% had fulfilled the 2010 ACR/EULAR criteria already at baseline. Among the patients classified as having UA at baseline but who fulfilled the 1987 ACR criteria after 2 years of followup, 85% had fulfilled the 2010 ACR/EULAR criteria at baseline. Patients with early disease who fulfilled the 2010 ACR/EULAR criteria were less likely to be autoantibody positive and more likely to have monarthritis at presentation than those fulfilling the 1987 ACR criteria. CONCLUSION: Use of the 2010 ACR/EULAR criteria clearly allows earlier diagnosis of RA, although the clinical picture is slightly different on the group level, and RA may be falsely diagnosed in some patients with self-limiting disease.

Síntomas durante el tratamiento del dolor oncológico conforme a las directrices de la OMS: estudio longitudinal de la prevalencia, la severidad y la etiología de los síntomas / Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology

La mayoría de los pacientes con cáncer avanzado presentan diversos síntomas que pueden reducir la eficacia del tratamiento analgésico y deteriorar su calidad de vida. En el presente estudio se determina la prevalencia, la etiología y la severidad de los síntomas en 593 pacientes oncológicos tratados en una unidad de dolor. Los pacientes recibieron analgésicos no opiáceos, opiáceos y coadyuvantes siguiendo las directrices de la OMS para el alivio del dolor oncológico. Otros síntomas fueron tratados sistemáticamente con la medicación coadyuvante apropiada. La intensidad del dolor y de otros síntomas se determinó por medio de una autoevaluación realizada todos los días por los propios pacientes; además, en cada visita los médicos de la unidad de dolor evaluaron la etiología de los síntomas y la severidad de confusión, coma y obstrucción gastrointestinal. Los pacientes recibieron tratamiento durante un periodo medio de 51 días. La eficacia del tratamiento analgésico fue buena en el 70 por ciento, satisfactoria en el 16 por ciento e inadecuada en el 14 por ciento de los pacientes. El tratamiento inicial consiguió reducir significativamente el número medio de síntomas de cuatro a tres. La prevalencia y la severidad de anorexia, actividad limitada, confusión, cambios de humor, insomnio, estreñimiento, dispepsia, disnea, tos, disfagia y síntomas urinarios se redujeron significativamente; las de sedación, otros síntomas neuropsiquiátricos y sequedad de boca aumentaron significativamente, mientras que las de coma, vértigo, diarrea, náuseas, vómitos, obstrucción intestinal, eritema, prurito y sudoración no experimentaron ningún cambio. Los síntomas más frecuentes fueron actividad limitada (74 por ciento de los días), cambios de humor (22 por ciento), estre ñ imiento (23 por ciento), náuseas (23 por ciento) y sequedad de boca (20 por ciento).Las valoraciones más altas de la severidad de los síntomas correspondieron a actividad limitada, sedación, coma, obstrucción intestinal, disfagia y síntomas urinarios. De los 23 síntomas, sólo el estreñimiento, el eritema y la sequedad de boca se atribuyeron casi siempre a efectos secundarios del tratamiento analgésico. Como conclusión, la elevada p revalencia y la severidad de muchos síntomas en pacientes con cáncer avanzado pueden reducirse combinando el tratamiento analgésico con el control sistemático de los síntomas. No obstante, durante una parte importante del tratamiento persisten los síntomas generales, neuropsiquiátricos y gastrointestinales y el alivio del dolor fue inadecuado en el 14 por ciento de los pacientes. Así pues, el control del dolor oncológico tiene que enmarcarse dentro de los cuidados paliativos, considerando todas las posibilidades existentes para el control de los síntomas (AU)

[Postoperative pain therapy with hydromorphone and metamizole. A prospective randomized study in intravenous patient-controlled analgesia (PCA)]. / Postoperative Schmerztherapie mit Hydromorphon und Metamizol. Eine prospektiv randomisierte Untersuchung im Rahmen der intravenösen patientenkontrollierten Analgesie (PCA).

Most potent opioid analgesics available in Germany have been investigated for use in postoperative patient-controlled analgesia (PCA). To conclude an older comparative series, it was the aim of the present study to define analgesic potency, side effects and patient acceptance of hydromorphone and its interaction with the non-opioid analgesic metamizole. A total of 120 patients recovering from elective abdominal or orthopaedic surgery, performed under standardised general anaesthesia, were randomised into 3 double-blind treatment groups to receive intravenous PCA demand doses of hydromorphone 283 micrograms (low dose, LD), 566 micrograms (high dose, HD) or a combination of hydromorphone 283 micrograms and metamizole 50 mg (low dose hydromorphone + metamizole, LM). Demand-independent low-dose background infusions were added to deliver hydromorphone at 67.9 micrograms/h in all groups, with additional metamizole at 12 mg/h in group LM. Lockout times were set to 2 min. After an average observation time of 24.5 +/- 2.6 h (mean, SD) since start of PCA, cumulative PCA hydromorphone doses in groups LD, HD and LM were 7.8 +/- 3.3, 12.1 +/- 4.8 and 7.5 +/- 2.0 mg, respectively, with the well known large inter-individual variability in all groups. Although hydromorphone consumption was significantly higher in group HD, self-reported pain intensities (VAS, retrospective pain scores) were quite comparable between the groups. Low dose, PCA bolus-linked metamizole did not significantly reduce hydromorphone consumption nor improve patient acceptance. Side-effects were typical for potent postoperative opioids, but never required special treatment; haemodynamic or respiratory complications were not observed in any patient. It can be concluded by comparison with other PCA opioid investigations performed under the same study protocol that hydromorphone is about 3-4 times as potent an analgesic as morphine under the conditions of intravenous postoperative PCA. Due to a favourable patient acceptance, hydromorphone can be recommended as a suitable alternative to other opioids for the treatment of postoperative pain.

[Anesthesiology education and training in Germany. Results from a representative questionnaire]. / Zur Lage der anästhesiologischen Weiter- und Fortbildung in Deutschland. Ergebnisse einer Repräsentativumfrage.

The aim of the present investigation, initiated by the German Academy of Education in Anaesthesiology (DAAF), was to obtain valid information about education and training strategies of German anaesthetists, in order to highlight weaknesses and strengths for better planning and performance of future efforts in this area. For this reason, a questionnaire with 23 items was distributed to 2000 German anaesthetists during the years 1993-1995 and of these 1290 questionnaires could then be evaluated (response rate 64.5%). The most important means of education and training were classical media such as text books and journals. Modern techniques such as videos, tapes or computer-assisted anaesthesia simulators were poorly used. Refresher courses, repetitoria and hospitations in other departments were, despite infrequent use, considered to be effective means of education and training and should be made more available. Systematic theoretical education was provided particularly seldom in most hospitals. Respondents considered anaesthetic complications and mishaps, intensive care and pain medicine to be the main top topics for continuing medical education. German anaesthetists seem highly motivated for education and training and spend on average about 5.5 h per week for personal learning and refreshing, a figure that is quite comparable to international standards. Hospital and department heads are mostly believed to have positive attitudes to education and training. Most respondents were in favour of strict rules for education and training measures, which includes the obligation to prove their certified attendance (as yet not required in Germany). On the other hand, the majority voted against making the continued recognition as a specialist in anaesthesiology dependent on completion of a performance control.

Transdermal fentanyl for the management of cancer pain: a survey of 1005 patients.

Transdermal fentanyl was released in Germany in 1995. From October 1996 to February 1998 transdermal treatment was documented for 1005 patients (506 men and 499 women with a mean age of 60 years, range 20-92 years) with chronic pain in an open survey including 290 physicians from hospitals and general practitioners throughout Germany. Most patients suffered from cancer pain and only 11 patients had chronic pain from non-malignant disease. Physicians were asked to complete a questionnaire for patients treated with transdermal fentanyl on initiation of therapy (day 0), and days 3, 6, 18, 30 thereafter, followed by monthly follow-up intervals. Patients were asked to complete a pain diary. Transdermal therapy was documented from day 0 for 824 patients, while 181 patients had been treated with transdermal fentanyl before admission in the survey. Most of the other 824 patients had been treated with other step 3 opioids (55% of the patients) or step 2 opioids (23%) before conversion to transdermal fentanyl, whereas 8% had been treated only with non-opioids and 14% had received analgesics only as required or not at all before initiation of transdermal therapy. The most important reasons for switching to transdermal opioid therapy were insufficient pain relief with the previous medication followed by a variety of gastrointestinal symptoms impeding oral analgesic therapy. Initial fentanyl doses ranged from 0.6 to 9.6 mg/day (25 to 400 microg/h) with a median of 1.2 mg/day (50 microg/h). Median doses slowly increased throughout the observation period to 2.4 mg/day (100 microg/h) after 4 months of treatment. Most patients continued transdermal therapy until the time of death (47% of patients). Other reasons for discontinuation were inadequate pain relief (10%), pain relief with other analgesic regimens (10%), other symptoms than pain (5%), rejection of transdermal therapy by the patient (6%) or miscellaneous (16%). Adverse events were documented as the reason for discontinuation of transdermal therapy in 49 patients (5%). Dyspnoea was documented for seven patients as the reason for discontinuation. One of these patients, as well as another patient with an episode of apnoea, had to be treated with artificial respiration for several hours, but both patients recovered without sequelae. Transdermal therapy with fentanyl was safe and efficient in this national survey. Transdermal fentanyl can be recommended for treatment of moderate to severe cancer pain and probably may even be used as a first-line drug on step 3 of the World Health Organization recommendations in selected patient groups.

[Lack of pre-emptive analgesic effect of low-dose ketamine in postoperative patients. A prospective, randomised double-blind study]. / Klinische Untersuchung über die präemptive Analgesie durch niedrig dosiertes Ketamin Eine prospektive, randomisierte Doppelblindstudie im Vergleich zu Placebo.

NMDA receptors are assumed to play an important role for neuronal plasticity. In vitro and animal experiments confirmed that NMDA antagonistic drugs can prevent hyperexitability of dorsal root neurons after strong pain stimuli. Clinical data, however, are more or less controversial in this respect. It was the aim of the present prospective, randomised, double-blind study to verify if low-dose preoperative ketamine, an NMDA antagonist, provides relevant postoperative analgesia in surgical patients and to re-examine positive results published by other investigators. 80 ASA I-II patients undergoing elective laparoscopic or proctologic surgery received at induction of general anaesthesia a single i.v. bolus dose of either ketamine 0.15 mg/kg or placebo (0.9% NaCl). Postoperative analgesia was provided by i.v. patient-controlled analgesia (PCA) using the opioid piritramide. Cardiovascular parameters, respiration, sedation, cumulative piritramide consumption and pain scores (visual analogue scale 1-10, verbal rating scale 0-4) were monitored at 1, 2, 3, 4, 5, 6, 12 and 24 hours after surgery. Additionally, a retrospective pain score was documented after the 24 hours observation period. There was no statistically significant difference in any study parameter. Cumulative PCA piritramide consumption after 24 hours was 25.0+/-16.2 mg in the ketamine group and 29.5+/-20.4 mg in the placebo group. Ketamine-specific side effects such as hallucinations or bad dreams were not observed. It is concluded that under the study conditions used, low dose ketamine, contrary to previously reported results [30], does not provide a clinically relevant pre-emptive analgesic effect in postoperative patients.

[Development and state of the in-patient palliative care institutions in Germany]. / Entwicklung und Stand der stationären palliativmedizinischen Einrichtungen in Deutschland.

In April 1999 altogether 114 inpatient units providing palliative care (50 palliative care units, 64 inpatient-hospices) offered a total of 989 beds. Compared to 1993 this has been an increase of 256%, compared to 1997 of 60%. The number of available beds, compared to 1997, increased markedly (58%), with a availability of 12 beds per one million residents. However, there are still major deficits: the distribution of the units is very irregular and the number of available beds is still to low, compared to the estimated need of 50 inpatient beds per one million residents. The quality of palliative care shows significant deficits (e. g. the availability of nursing staff, cooperation with pain clinics, standardised documentation, education). Differences between palliative care wards and hospices were huge. According to the definition of the German Society for Palliative Care, a palliative care ward should provide a ratio of at least 1.4 nursing staff per bed, however, only 18% of the palliative care units fulfil this definition. Only few hospices and half of the palliative care units worked in close cooperation with pain clinics. Despite a significant increase in units and inpatient beds providing palliative care, there still is a major deficit in the overall number of beds and the quality of palliative care.

[Morphine dose and side effects: a comparison of older and younger patients with tumor pain]. / Morphindosis und Nebenwirkungen--Ein Vergleich älterer mit jüngeren Tumorschmerzpatienten.

UNLABELLED: BACKGROUND AND GOAL OF STUDY: Older patients are said to be more sensitive to analgesics and to have a higher risk of side effects due to pharmacokinetic changes developing with old age. On account of this many elderly patients with cancer pain are denied adequate analgesic treatment. We compared efficacy and side effects of cancer pain management in different age groups. METHODS: From 1994 to April 1996 577 cancer patients were treated in our pain clinic according to WHO-Guidelines. Efficacy and side effects were evaluated for 508 patients (< 65 years = G1: 323 patients, 65-74 years = G2: 127 patients, > 74 years = G3: 58 patients) with a computerised documentation system. RESULTS: 508 patients were treated on 42,123 days and revisited on 5572 controls. 30 patients were treated longer than 1 year (G1 21 patients, G2 6 patients, G3 3 patients). 143 patients were treated until death. 286 patients were treated on 19,448 days with oral morphine. (G1: 1712 days; G2: 3645 days; G3: 2364 days). Geriatric patients (G3) received significantly higher doses of morphine than younger patients. Adjuvant drugs were given on 81% of treatment days (G1 84%, G2 75%, G3 75%). Incidence and intensity of side effects were not increased in older patients with the exception of urinary disorders. CONCLUSIONS: Geriatric patients with cancer pain can be treated as effectively according to WHO-Guidelines as younger patients. In our study patients in the old age group received significantly higher doses of oral morphine. When analgesic drugs are titrated according to individual needs, side effects are not more frequent or severe than in younger patients.

Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities.

Adenosine deaminases that act on RNA (ADARs) deaminate adenosines to produce inosines within RNAs that are largely double-stranded (ds). Like most dsRNA binding proteins, the enzymes will bind to any dsRNA without apparent sequence specificity. However, once bound, ADARs deaminate certain adenosines more efficiently than others. Most of what is known about the intrinsic deamination specificity of ADARs derives from analyses of Xenopus ADAR1. In addition to ADAR1, mammalian cells have a second ADAR, named ADAR2; the deamination specificity of this enzyme has not been rigorously studied. Here we directly compare the specificity of human ADAR1 and ADAR2. We find that, like ADAR1, ADAR2 has a 5' neighbor preference (A approximately U > C = G), but, unlike ADAR1, also has a 3' neighbor preference (U = G > C = A). Simultaneous analysis of both neighbor preferences reveals that ADAR2 prefers certain trinucleotide sequences (UAU, AAG, UAG, AAU). In addition to characterizing ADAR2 preferences, we analyzed the fraction of adenosines deaminated in a given RNA at complete reaction, or the enzyme's selectivity. We find that ADAR1 and ADAR2 deaminate a given RNA with the same selectivity, and this appears to be dictated by features of the RNA substrate. Finally, we observed that Xenopus and human ADAR1 deaminate the same adenosines on all RNAs tested, emphasizing the similarity of ADAR1 in these two species. Our data add substantially to the understanding of ADAR2 specificity, and aid in efforts to predict which ADAR deaminates a given editing site adenosine in vivo.

Cognitive impairment and its influence on pain and symptom assessment in a palliative care unit: development of a Minimal Documentation System.

Symptom assessment in the palliative care unit must consider the reduced physical and mental status of the patients. Standardized instruments are often not completed by patients with cognitive impairment. We tried to combine minimal burden for patients and staff with sufficient information content in a Minimal Documentation System (MIDOS) for pain and symptom assessment in palliative care patients. From January to July 1998, 108 patients (123 consecutive admissions) with a mean age of 63 years (range 32-87 years) were admitted to the palliative care unit. Pain was reported as the reason for admission in 70% of the patients, and 71% were treated with opioids. Using a cut-off point of 20/21, 35% of the patients were impaired in the Mini Mental State Examination (MMSE). The number of missing values in the Brief Pain Inventory (BPI) and the quality-of-life questionnaire SF-12 correlated highly with each other and with the MMSE sum score, but not with the summary scores of BPI or SF-12. Only 31 patients completed the SF-12 quality-of-life questionnaire. Age was not correlated to MMSE scores, and neither were opioid doses for 26 patients with slow-release oral morphine or for 20 patients with transdermal fentanyl. Only a minority of patients was able to use the numerical scale for symptoms other than pain, though most patients were able to score symptom intensity on the verbal categorical scale. Pain and symptom assessments were performed by the physician for 17% of the patients at admission, and for 16% of the follow-up controls because self-assessment was not possible. In this study, cognitive impairment prevented symptom assessment with longer and more complicated instruments such as the SF-12 in a large number of the patients admitted to the palliative care unit. Assessment instruments for patients with advanced disease must provide simple categorical scales and the possibility of being administered by interview.

Constipation and the use of laxatives: a comparison between transdermal fentanyl and oral morphine.

Constipation and the use of laxatives were investigated in patients with chronic cancer pain treated with oral morphine and transdermal fentanyl in an open sequential trial. Forty-six patients were treated with slow-release morphine 30-1000 mg/day for 6 days and 39 of these patients were switched to transdermal fentanyl 0.6-9.6 mg/day with a conversion ratio of 100:1. Median fentanyl doses increased from 1.2 to 3.0 mg/day throughout the 30-day transdermal treatment period. Twenty-three patients completed the study. Two patients died from the basic disease while treated with transdermal fentanyl, 12 patients were excluded for various reasons, and not enough data for evaluation were available for two patients. Mean pain intensity decreased slightly after conversion although the number of patients with breakthrough pain or requiring immediate-release morphine as a rescue medication was higher with transdermal fentanyl. The number of patients with bowel movements did not change after the opioid switch but the number of patients taking laxatives was reduced significantly from 78-87% of the patients per treatment day (morphine) to 22-48% (fentanyl). Lactulose was used mainly and was reduced most drastically, but other laxatives were also used less frequently. In this study transdermal fentanyl was associated with a significantly lower use of laxatives compared to oral morphine. The difference in the degree of constipation between the two analgesic regimens should be confirmed in a randomized double-blind study that takes into account both constipation and use of laxatives.

Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl.

Transdermal delivery allows continuous systemic application of opioids through the intact skin. This review analyses the pharmacokinetic properties of transdermal opioid administration in the context of clinical experience, with a focus on fentanyl. A transdermal therapeutic system (TTS) for fentanyl has been developed. The amount of fentanyl released is proportional to the surface area of the TTS, which is available in different sizes. After the first application of a TTS, a fentanyl depot concentrates in the upper skin layers and it takes several hours until clinical effects are observed. The time from application to minimal effective and maximum serum concentrations is 1.2 to 40 hours and 12 to 48 hours, respectively. Steady state is reached on the third day, and can be maintained as long as patches are renewed. Within each 72-hour period, serum concentrations decrease gradually over the second and third days. When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. The terminal half-life for TTS fentanyl is approximately 13 to 25 hours. The interindividual variability of serum concentrations, partly caused by different clearance rates, is markedly larger than the intraindividual variability. The effectiveness of TTS fentanyl was first demonstrated in acute postoperative pain. However, the slow pharmacokinetics and large variability of TTS fentanyl, together with the relatively short duration of postoperative pain, precluded adequate dose finding and led to inadequate pain relief or, especially, a high incidence of respiratory depression; such use is now contraindicated. Conversely, in cancer pain, TTS fentanyl offers an interesting alternative to oral morphine, and its effectiveness and tolerability in this indication has been demonstrated by a number of trials. Its usefulness in chronic pain of nonmalignant origin remains to be confirmed in controlled trials. In general, TTS fentanyl produces the same adverse effects as other opioids, mainly sedation, nausea, vomiting and constipation. In comparison with oral morphine, TTS fentanyl causes fewer gastrointestinal adverse events. The risk of hypoventilation is comparatively low in cancer patients. Sufentanil and buprenorphine may also be suitable for transdermal delivery, but clinical results are not yet available. Transdermal morphine is only useful if applied to de-epithelialised skin. However, iontophoresis may allow transdermal administration of opioids, including morphine, with a rapid achievement of steady state concentrations and the ability to adjust delivery rates. This would be beneficial for acute and/or breakthrough pain, and initial clinical trials are in progress.

Validation of the German version of the Brief Pain Inventory.

The Brief Pain Inventory is a comprehensive instrument for pain assessment and has been validated in several languages. A validated German version was not available until now. From March to May 1995 all outpatients of the pain clinic of the Department of Anesthesiology completed a questionnaire with the German versions of the Brief Pain Inventory (BPI) and the SF-36 quality-of-life questionnaire. The BPI was repeated after the consultation. The physician assessed the performance status score of the Eastern Cooperative Oncology Group (ECOG). The questionnaire was completed by 151 patients. Forty-two patients were excluded from evaluation for methodological reasons, so 109 patients were evaluated. As in the original version of the BPI, factor analysis showed a common factor for pain intensity and a second factor for pain-related interference with function. The comparative fit index of 0.86 confirmed this model. Responses before and after consultation correlated closely for the sum scores of the pain intensity items (Perarson correlation r = 0.976) as well as for the interference with function items (r = 0.974). Pain intensity in the BPI correlated with bodily pain in the SF-36 (r = 0.585). Sum scores of the pain interference items were higher in patients with deteriorated ECOG performance status, whereas sum scores of the intensity items were not changed. Validity and reliability of the German BPI were comparable to the original version. The BPI may be advantageous for palliative care patients, as it places only a small burden on the patient and offers easy criteria for evaluation. However, further research is needed to differentiate the impact of pain-related and disease-related interference with function on the BPI, and to find an algorithm for the evaluation of the BPI when values are missing.

High-dose tramadol in comparison to low-dose morphine for cancer pain relief.

Cancer pain treatment following the World Health Organization guidelines is effective and feasible. However, the evidence supporting the use of opioids for mild to moderate pain on the second step of the analgesic ladder is widely discussed. The present evaluation compares the efficacy and safety of high doses of oral tramadol (> or = 300 mg/d) with low doses of oral morphine (< or = 60 mg/d). Patients were included in this nonblinded and nonrandomized study if the combination of a nonopioid analgesic and up to 250 mg/d of oral tramadol was inadequate. 810 patients received oral tramadol for a total of 23,497 days, and 848 patients received oral morphine for a total of 24,695 days. The average dose of tramadol was 428 +/- 101 mg/d (range 300-600 mg/d); the average dose of morphine was 42 +/- 13 mg/d (range 10-60 mg/d). Additional nonopioid analgesics were given on more than 95% of days. Antiemetics, laxatives, neuroleptics, and steroids were prescribed significantly more frequently in the morphine group; the use of other adjuvants was similar in both groups. The mean pain intensity on a 0-100 numerical rating scale (NRS) was 27 +/- 21 (95% CI 26-29) in the tramadol and 26 +/- 20 (95% CI 24-27) in the morphine group (NS). The analgesic efficacy was good in 74% and 78%, satisfactory in 10% and 7%, and inadequate in 16% and 15% of patients receiving tramadol and morphine, respectively (NS). Constipation, neuropsychological symptoms, and pruritus were observed significantly more frequently with low-dose morphine; other symptoms had similar frequencies in both groups. These data suggest that tramadol can be used for the treatment of cancer pain, when nonopioids alone are not effective. High doses of tramadol are effective and safe.

Intravenous titration with morphine for severe cancer pain: report of 28 cases.

BACKGROUND: In a multicenter study, 28 patients with cancer pain and insufficient pain relief with analgesic treatment according to step II of the guidelines of the World Health Organization (WHO) were switched to oral slow-release morphine. METHODS: Patients received intravenous morphine through a patient-controlled pump (PCA) for the first 24 hours (bolus = 1 mg, lockout interval = 5 minutes, maximum dose = 12 mg/hour). From day 2 patients were treated with oral slow-release morphine. Daily doses were calculated from the requirements of the day before. Breakthrough pain was treated with PCA until stable doses were reached (<2 boluses/day) and then with oral immediate-release morphine solution. Pain intensity was reported in a diary four times a day, in addition to mood, activity, and quality of sleep once daily. RESULTS: Mean duration until adequate pain relief reported (<30 on a 101-step numerical scale; NRS) was 5 hours (range = 80-620 minutes). Mean pain intensity was reduced from 67 NRS to 22 NRS. Mean doses of oral morphine were 133 mg/day initially and then 154 mg/day on day 14. Serious adverse events such as respiratory depression were not observed. Two patients terminated the study due to progressive symptoms of gastrointestinal obstruction. Seventy-five percent of the patients evaluated the effectiveness of the analgesic regime as good. CONCLUSIONS: Dose finding with intravenous PCA may be appropriate for a small minority of patients with severe pain. Higher treatment costs and the risk of complications are drawbacks of this method compared with conventional oral titration.

The importance of internal loops within RNA substrates of ADAR1.

Adenosine deaminases that act on RNA (ADARs) are a family of RNA editing enzymes that convert adenosines to inosines within double-stranded RNA (dsRNA). Although ADARs deaminate perfectly base-paired dsRNA promiscuously, deamination is limited to a few, selected adenosines within dsRNA containing mismatches, bulges and internal loops. As a first step in understanding how RNA structural features promote selectivity, we investigated the role of internal loops within ADAR substrates. We observed that a dsRNA helix is deaminated at the same sites whether it exists as a free molecule or is flanked by internal loops. Thus, internal loops delineate helix ends for ADAR1. Since ADAR1 deaminates short RNAs at fewer adenosines than long RNAs, loops decrease the number of deaminations within an RNA by dividing a long RNA into shorter substrates. For a series of symmetric internal loops related in sequence, larger loops (>/=six nucleotides) acted as helix ends, whereas smaller loops (

Serum concentrations of tramadol enantiomers during patient-controlled analgesia.

AIMS: Tramadol, a centrally acting analgesic, is used as a racemate containing 50% of a (+)- and 50% of a (-)-enantiomer. This paper presents the pharmacokinetic results of postoperative patient-controlled analgesia using (+)-tramadol, (-)-tramadol or the racemate. METHODS: Ninety-eight patients recovering from major gynaecological surgery were treated in a randomised, double-blind study with (+)-tramadol, (-)-tramadol or the racemate. Following an i.v. bolus up to a maximum of 200 mg, patient-controlled analgesia with demand doses of 20 mg was made available for 24 h. Prior to each demand, the serum concentrations of the enantiomers of tramadol and its metabolite M1 were measured in 92 patients. RESULTS: The mean concentrations of tramadol during the postsurgery phase were 470+/-323 ng ml-1, 590+/-410 ng ml-1 and 771+/-451 ng ml-1 in the (+)-, racemate- and (-)-group, respectively ((+) vs (-), P<0.05); the mean concentrations of the metabolite M1 were 57+/-18 ng ml-1, 84+/-34 ng ml-1 and 96+/-41 ng ml-1 in the (+)-, racemate- and (-)-group, respectively ((+) vs (-) and (+) vs racemate, P<0.05). The mean concentrations of (+)-tramadol and (+)-M1 were lower in the racemate- than in the (+)-group (P<0.05), those of (-)-tramadol and (-)-M1 were lower in the racemate than in the (-)-group (P<0.05). In the racemate group, the mean serum concentrations of (+)-tramadol were higher than those of (-)-tramadol (P<0.05), whereas the mean serum concentrations of (-)-M1 were higher than those of (+)-M1 (P<0. 05). CONCLUSIONS: The therapeutic serum concentration of tramadol and M1 showed a great variability. The lowest mean concentrations were measured in the (+)-group and the highest in (-)-group. This is in agreement with the clinical finding that (+)-tramadol is a more potent analgesic than (-)-tramadol.