Topical review on the abuse and misuse potential of tramadol and tilidine in Germany.

BACKGROUND: Tramadol and tilidine (in combination with naloxone) are used as weak opioid analgesics in Germany. Tramadol is not scheduled in the German Narcotic Drugs Act. Tilidine is scheduled, whereas Tilidine in fixed combinations with naloxone is exempt from some of the provisions of the Narcotic Drugs Act. Recent reports on misuse of both substances led to an evaluation of their potential for misuse, abuse, and dependency by the expert advisory committee established by the German Federal Government, resident at the Federal Institute for Drugs and Medical Devices. METHODS: A subcommittee formulated key questions and identified available data sources for each of these questions. Additional information was solicited where necessary, including a survey among a panel of pharmacists, a survey in an addiction clinic, analysis of prescription patterns, and information from the boards of pharmacists of the federal states and the Federal Bureau of Criminal Investigation. RESULTS: Analgesic efficiency in the treatment of acute and chronic pain has been proven for both tramadol and tilidine/naloxone. For tramadol, high evidence has been confirmed in systematic reviews, and tramadol is listed in national and international guidelines on acute and chronic pain management. Animal and human studies found a low potential for misuse, abuse, and dependency for both substances. Information from 2 tramadol safety databases allowed calculation of the incidence of abuse or dependency as 0.21 and 0.12 cases per million defined daily dosages (DDDs), with lower incidences in recent years. For tilidine/naloxone, the incidence was calculated as 0.43 cases per million DDDs for oral solution and 0.18 for slow-release tablets. In an online survey among German pharmacies as well as in the reports from state pharmacy boards, fraud attempts were repeated more frequently with tilidine/naloxone than with tramadol in the last 2 years. The Federal Bureau of Criminal Investigations reported prescription fraud only with tilidine/naloxone and predominantly in the region of Berlin. Dependency on tramadol or tilidine/naloxone is reported only rarely from addiction counseling centers. One third of the patients surveyed in an addiction clinic reported experiences with tramadol or tilidine/naloxone, but mostly with duration of less than 4 weeks and with a medical prescription based on a reasonable indication. Also, occasional illegal use of opioid analgesics as a substitute of heroin was reported. An evaluation of pooled data from statutory health insurance companies found 2.5% of persons receiving at least 1 prescription of tramadol or the combination of tilidine and naloxone in 2009 (1.6% with tramadol and 1.0% with tilidine/naloxone). High usage with more than 180 DDDs per year was found in 8.6% of patients treated with tramadol and 17.2% of patients with tilidine/naloxone. CONCLUSIONS: In conclusion, the subcommittee of the expert advisory committee found a low potential for misuse, abuse, and dependency for tramadol, and a low prevalence in clinical practice. Considerable less information is available for the combination of tilidine and naloxone. However, the cumulation of evidence indicated a higher risk of misuse, abuse, and dependency for tilidine/naloxone solution, but not for slow-release tablets.

Comparison of Relaxometry Between Ulnar Nerve and Posterior Tibial Nerve After Cisatracurium Administration Using Electromyography.

Background: Electromyography can be used for quantitative neuromuscular monitoring during general anesthesia, mostly using the stimulation train-of-four (TOF) pattern. Relaxometry measures the muscular response of the adductor pollicis muscle to electrical stimulation of the ulnar nerve, which is routinely used in clinical practices for monitoring the neuromuscular block. However, when it is not always possible to be used for all patients, the posterior tibial nerve is a suitable alternative. Objectives: Using electromyography, we compared the neuromuscular block between the ulnar and the posterior tibial nerves. Methods: In this study, the participants were 110 patients who met inclusion criteria and submitted their written consent. Following the administration of cisatracurium intravenously, the patients had relaxometry performed simultaneously on the ulnar and the posterior tibial nerves using electromyography. Results: Eighty-seven patients were included in the final analysis. The onset time was 296 ± 99 s at the ulnar nerve and 346 ± 146 s at the tibial nerve, with a mean difference of -50 s and a standard deviation of 164 s. The 95% limits of agreement ranged from -372 s to 272 s. The relaxation time was 105 ± 26 min at the ulnar nerve and 87 ± 25 min at the tibial nerve, with a mean difference of 18 min and a standard deviation of 20 min. Conclusions: Using electromyography, no statistically significant difference was noticed between the ulnar and the posterior tibial nerve during the neuromuscular block. The onset time and the relaxation time assessed with an electromyogram to compare the stimulation of the ulnar and posterior tibial nerves showed large limits of agreement.

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.

BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate. CONCLUSIONS: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain.

BACKGROUND: Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition. This randomized, open-label phase 3 study (ClinicalTrials.gov Identifier: NCT00361504) assessed the long-term safety and tolerability of tapentadol extended release (ER) in patients with chronic knee or hip osteoarthritis pain or low back pain. METHODS: Patients were randomized 4:1 to receive controlled, adjustable, oral, twice-daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCl controlled release (CR; 20 to 50 mg) for up to 1 year. Efficacy evaluations included assessments at each study visit of average pain intensity (11-point numerical rating scale) over the preceding 24 hours. Treatment-emergent adverse events (TEAEs) and discontinuations were monitored throughout the study. RESULTS: A total of 1,117 patients received at least 1 dose of study drug. Mean (standard error) pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 (0.05) and 7.6 (0.11) at baseline and decreased to 4.4 (0.09) and 4.5 (0.17) at endpoint. The overall incidence of TEAEs was 85.7% in the tapentadol ER group and 90.6% in the oxycodone CR group. In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1% and 36.8% of patients; gastrointestinal TEAEs led to discontinuation in 8.6% and 21.5% of patients. CONCLUSION: Tapentadol ER (100 to 250 mg bid) was associated with better gastrointestinal tolerability than oxycodone HCl CR (20 to 50 mg bid) and provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis or low back pain for up to 1 year.

Receptor mediation and nociceptin inhibition of bradykinin-induced plasma extravasation in the knee joint of the rat.

OBJECTIVE AND DESIGN: The aim was to investigate the signaling mechanisms and regulation of bradykinin (BK)-induced inflammation in rat knee joint. MATERIALS AND METHODS: Knee joints of anesthetized rats were perfused with BK (0.1-1.0 microM), and synovial plasma extravasation (PE) was evaluated by spectrophotometrical measurement of Evans Blue leakage. To examine the signaling pathway, B1 antagonist [des-Arg10]-HOE140 (0.1-1.0 microM) and B2 antagonist HOE140 (0.05-1.0 microM), calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 (0.5-1.0 microM), prostaglandin E2 antagonist AH-6809 (0.1-1.0 microM), and histamine H1 antagonist mepyramine (0.1-1.0 microM) were used. Nociceptin (0.0001-1.0 microM) and antagonist J-113397 were tested for modulation of BK-induced PE. The analyses were compared side-by-side with 5-hydroxytryptamine-induced PE. RESULTS: BK perfusion dose-dependently induced PE, which was blocked by HOE140, CGRP8-37, AH-6809, and mepyramine. It was also inhibited by nociceptin, which could be reversed by antagonist J-113397. In contrast, 5-hydroxytryptamine-induced PE was biphasically regulated by nociceptin and was not antagonized by CGRP8-37. CONCLUSIONS: BK-induced PE is mediated by B2 receptors and may involve CGRP, prostaglandin, and histamine pathways. BK-induced PE is inhibited by nociceptin through the activation of ORL1 receptors. There are differences between BK- and 5-hydroxytryptamine-induced inflammation in signaling and modulation.

Epidemiology of sepsis in Germany: results from a national prospective multicenter study.

OBJECTIVE: To determine the prevalence and mortality of ICU patients with severe sepsis in Germany, with consideration of hospital size. DESIGN: Prospective, observational, cross-sectional 1-day point-prevalence study. SETTING: 454 ICUs from a representative nationwide sample of 310 hospitals stratified by size. Data were collected via 1-day on-site audits by trained external study physicians. Visits were randomly distributed over 1 year (2003). PATIENTS: Inflammatory response of all ICU patients was assessed using the ACCP/SCCM consensus conference criteria. Patients with severe sepsis were followed up after 3 months for hospital mortality and length of ICU stay. MEASUREMENTS AND RESULTS: Main outcome measures were prevalence and mortality. A total of 3,877 patients were screened. Prevalence was 12.4% (95% CI, 10.9-13.8%) for sepsis and 11.0% (95% CI, 9.7-12.2%) for severe sepsis including septic shock. The ICU and hospital mortality of patients with severe sepsis was 48.4 and 55.2%, respectively, without significant differences between hospital size. Prevalence and mean length of ICU stay of patients with severe sepsis were significantly higher in larger hospitals and universities (

A comparison of opioid-related adverse events with fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia in acute postoperative pain.

OBJECTIVE: This analysis compared opioid-related adverse events (ORADEs) observed with fentanyl iontophoretic transdermal system (ITS) versus morphine intravenous (iv.) patient-controlled analgesia (PCA) in the management of postoperative pain. METHODS: Safety data from four Phase IIIB randomized, active-comparator trials were pooled for this analysis (n = 1288 fentanyl ITS and 1313 morphine iv. PCA patients). Treatment-emergent adverse events were collected via spontaneous report. In this post hoc analysis, ORADEs were defined as apnea, confusion, constipation, dyspnea, hypotension, hypoventilation, hypoxia, ileus, nausea, pruritus, somnolence, tachycardia, urinary retention and vomiting. Odds ratios (OR) and 95% CI were calculated for all ORADEs and p-values were based on logistic regression with treatment as effect. RESULTS: There were fewer patients in the fentanyl ITS group compared with the morphine iv. PCA group who experienced at least one ORADE (52.7 vs 59.1%, respectively; OR: 0.772: 95% CI: 0.661-0.901; p = 0.0011). The ORADEs that occurred less frequently in the fentanyl ITS group than in the morphine iv. PCA group included hypotension (3.7 vs 5.5%, respectively; OR: 0.667; 95% CI: 0.459-0.969; p = 0.0338), hypoventilation (0.9 vs 1.9%, respectively; OR: 0.444; 95% CI: 0.217-0.906; p = 0.0256), nausea (40.3 vs 44.5%, respectively; OR: 0.842; 95% CI: 0.721-0.984; p = 0.0310), pruritus (5.5 vs 9.4%, respectively; OR: 0.559; 95% CI: 0.413-0.757; p = 0.0002) and tachycardia (1.6 vs 2.8%, respectively; OR: 0.489; 95% CI: 0.277-0.863; p = 0.0136). No ORADEs occurred more frequently in the fentanyl ITS group compared with the morphine iv. PCA group. CONCLUSION: Fentanyl ITS, in the management of acute postoperative pain, offered safety advantages in terms of ORADEs compared with morphine iv. PCA.

Switching from reservoir to matrix systems for the transdermal delivery of fentanyl: a prospective, multicenter pilot study in outpatients with chronic pain.

Matrix systems for transdermal fentanyl will replace the reservoir systems in Europe. In an industry-independent, prospective, multicenter pilot study, 46 outpatients with chronic pain were asked to assess pain intensity, sleep interference, adverse events, and multiple secondary parameters during administration of the last reservoir and the first two matrix patches. There was no difference in pain intensity, sleep interference, and the rate of adverse events between both systems. Self assessment on a 6-step numeric rating scale (1 = very good, 6 = insufficient) comparing the two systems (reservoir vs. matrix) showed that skin compatibility (2.6 vs. 1.5), adhesive properties (3.2 vs. 1.8), wearability/comfort (2.8 vs. 1.5), and general satisfaction (2.5 vs. 1.8) improved significantly with the new matrix technology. At study endpoint, 91% of patients preferred the matrix system for future use. The new fentanyl matrix system is characterized by a high level of general satisfaction, ease of use, patient acceptance, and improved skin compatibility. Reservoir and matrix systems appear to have comparable efficacy and safety so that outpatients can be switched directly from the reservoir to the matrix system without difficulties and new dose titration.

Efficiency of 7.2% hypertonic saline hydroxyethyl starch 200/0.5 versus mannitol 15% in the treatment of increased intracranial pressure in neurosurgical patients - a randomized clinical trial [ISRCTN62699180].

INTRODUCTION: This prospective randomized clinical study investigated the efficacy and safety of 7.2% hypertonic saline hydroxyethyl starch 200/0.5 (7.2% NaCl/HES 200/0.5) in comparison with 15% mannitol in the treatment of increased intracranial pressure (ICP). METHODS: Forty neurosurgical patients at risk of increased ICP were randomized to receive either 7.2% NaCl/HES 200/0.5 or 15% mannitol at a defined infusion rate, which was stopped when ICP was < 15 mmHg. RESULTS: Of the 40 patients, 17 patients received 7.2% NaCl/HES 200/0.5 and 15 received mannitol 15%. In eight patients, ICP did not exceed 20 mmHg so treatment was not necessary. Both drugs decreased ICP below 15 mmHg (p < 0.0001); 7.2% NaCl/HES 200/0.5 within 6.0 (1.2-15.0) min (all results are presented as median (minimum-maximum range)) and mannitol within 8.7 (4.2-19.9) min (p < 0.0002). 7.2% NaCl/HES 200/0.5 caused a greater decrease in ICP than mannitol (57% vs 48%; p < 0.01). The cerebral perfusion pressure was increased from 60 (39-78) mmHg to 72 (54-85) mmHg by infusion with 7.2% NaCl/HES 200/0.5 (p < 0.0001) and from 61 (47-71) mmHg to 70 (50-79) mmHg with mannitol (p < 0.0001). The mean arterial pressure was increased by 3.7% during the infusion of 7.2% NaCl/HES 200/0.5 but was not altered by mannitol. There were no clinically relevant effects on electrolyte concentrations and osmolarity in the blood. The mean effective dose to achieve an ICP below 15 mmHg was 1.4 (0.3-3.1) ml/kg for 7.2% NaCl/HES 200/0.5 and 1.8 (0.45-6.5) ml/kg for mannitol (p < 0.05). CONCLUSION: 7.2% NaCl/HES 200/0.5 is more effective than mannitol 15% in the treatment of increased ICP. A dose of 1.4 ml/kg of 7.2% NaCl/HES 200/0.5 can be recommended as effective and safe. The advantage of 7.2% NaCl/HES 200/0.5 might be explained by local osmotic effects, because there were no clinically relevant differences in hemodynamic clinical chemistry parameters.

Meta-analysis of the efficacy of the fentanyl iontophoretic transdermal system versus intravenous patient-controlled analgesia in postoperative pain management.

OBJECTIVE: This meta-analysis was conducted to analyze and compare the efficacy outcomes associated with the fentanyl iontophoretic transdermal system (ITS) and morphine intravenous (IV) patient-controlled analgesia (PCA) in the management of postoperative pain. RESEARCH DESIGN AND METHODS: This meta-analysis assessed the efficacy of the fentanyl ITS versus morphine IV PCA using data from four randomized, active-controlled trials (n = 1271 fentanyl ITS and 1298 morphine IV PCA patients). Main outcome measures were patient global assessment (PGA) of the method of pain control at 24 h. RESULTS: Fentanyl ITS and morphine IV PCA did not significantly differ regarding 'good' and 'excellent' ratings on the PGA of the method of pain control at 24 h (odds ratio = 0.95, p = 0.66), however, fentanyl ITS was superior in terms of 'excellent' PGA ratings at that time point (odds ratio = 1.53, p < 0.0001). No significant differences were found in weighted mean pain intensity scores at 24, 48 and 72 h. CONCLUSIONS: In this meta-analysis, fentanyl ITS was as efficacious as morphine IV PCA and may offer additional benefits as demonstrated by its 'excellent' PGA ratings.

Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia.

The opioid analgesic tramadol is a racemate and consists of 50% (+)- and 50% (-)-enantiomer. This study investigated analgesic efficacy and safety of both enantiomers after intravenous (i.v.) injection in comparison with the racemate. Ninety-eight patients recovering from major gynaecological surgery under opioid-free halothane anaesthesia were treated in a randomised, double-blind study with (+)-tramadol, (-)-tramadol or the racemate. Following an individualised i.v. loading dose up to a maximum of 200 mg, patient-controlled analgesia with demand doses of 20 mg was made available for 24 h. The primary criterion was of efficacy was the decrease of pain intensity on a 5-point verbal rating scale from severe or maximum pain to mild or no pain intensity on a 5-point verbal rating scale from severe or maximum pain to mild or no pain within the first hour after the loading dose. The secondary criterion was patient satisfaction with pain relief during the 24-h observation period stated in the final interview. Patients who terminated the study prematurely were evaluated as non-responders. Of patients treated with (+)-tramadol, tramadol racemate, and (-)-tramadol, 12%, 15%, and 53% of treated patients, respectively, terminated the study prematurely because of inefficacy. Of patients treated with (+)-tramadol, racemate or (-)-tramadol 67%, 48% and 38%, respectively, were considered responders regarding the primary criterion of efficacy (P = 0.061), and 82%, 76%, or 41% with respect to the secondary criterion (P = 0.001). Assessment of laboratory screening, adverse events, vital signs and blood gas monitoring showed no serious drug-related events. Nausea and vomiting were the most frequently reported non-serious side effects and were most often seen with (+)-tramadol. Taking into account both efficacy and safety aspects, the racemate seems to be superior to either enantiomer alone.

Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred to a pain service.

Although pain assessment is a vital preliminary step towards the satisfactory control of cancer pain, data on the prevalence of different pain syndromes are rare. In a prospective study of 2266 cancer patients, we assessed localisations, aetiologies and pathophysiological mechanisms of the pain syndromes. Thirty percent of the patients presented with 1, 39% with 2 and 31% with 3 or more distinct pain syndromes. The majority of patients had pain caused by cancer (85%) or antineoplastic treatment (17%); 9% had pain related to cancer disease and 9% due to aetiologies unrelated to cancer. Pain could be classified as originating from nociceptors in bone (35%), soft tissue (45%) or visceral structures (33%) or otherwise as of an neuropathic origin (34%). In most patients, pain syndromes were located in the lower back (36%), abdominal region (27%), thoracic region (23%), lower limbs (21%), head (17%) and pelvic region (15%). The main pain syndrome was also coded according to the IASP Classification of Chronic Pain. Regions and systems affected by the main pain syndrome showed large variation depending on the site of cancer origin, whereas temporal characteristics, intensity and aetiology were not markedly influenced by the cancer site. The variety of pain syndromes evaluated in our patients confirms the importance of comprehensive pain assessment prior to treatment.

Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study.

This paper reports on the experience gained using World Health Organization Guidelines for cancer pain relief over a 10-year period in an anaesthesiology-based pain service associated with a palliative care programme. The course of treatment of 2118 patients was assessed prospectively over a period of 140,478 treatment days. Non-opioid analgesics (WHO step I) were used on 11%, weak opioids (WHO step II) on 31% and strong opioids (WHO step III) on 49% of treatment days. Administration was via the enteral route on 82% and parenterally on 9% of treatment days. On the remaining days, either spinally applied opioids (2%) or other treatments (6%) were utilised. Fifty-six percent of the patients were treated with morphine. Morphine dose escalation was observed in about one-half of the patients being cared for until death, whereas the other half had stable or decreasing doses over the course of treatment. Co-analgesics were administered on 37% of days, most often antidepressants (15%), anticonvulsants (13%) and corticosteroids (13%). Adjuvants to treat symptoms other than pain were prescribed on 79% of days, most commonly laxatives (42%), histamine-2-receptor antagonists (39%) and antiemetics (35%). In addition, palliative antineoplastic treatment was performed in 42%, nerve blocks in 8%, physiotherapy in 5%, psychotherapy in 3% and TENS in 3% of patients. A highly significant pain reduction was achieved within the 1st week of treatment (P < 0.001). Over the whole treatment period, good pain relief was reported in 76%, satisfactory efficacy in 12% and inadequate efficacy in 12% of patients. In the final days of life, 84% rated their pain as moderate or less, while 10% were unable to give a rating. Analgesics remained constantly effective in all 3 steps of the WHO ladder. Other clinical symptoms were likewise significantly reduced at 1 week after initial assessment, with the exception of neuropsychiatric symptoms. During the course of treatment, the latter were the major symptoms on 23% of days, followed by nausea (23%), constipation (23%) and anorexia (20%). Our results emphasise once again the marked efficacy and low rate of complications associated with oral and parenteral analgesic therapy as the mainstay of pain treatment in the palliative care of patients with advanced cancer. Wide dissemination of WHO guidelines among doctors and healthcare workers is thus necessary to effect a clear improvement in the treatment of the many patients suffering from cancer pain in the clinical and home setting.

Assessment and treatment of neuropathic cancer pain following WHO guidelines.

Neuropathic pain syndromes are one of the major problems of cancer pain treatment. The present study surveys 593 cancer patients treated by a pain service following the WHO guidelines for relief of cancer pain. Of these, 380 presented with nociceptive, 32 with neuropathic and 181 with mixed (nociceptive and neuropathic) pain. In patients with nociceptive, mixed and neuropathic pain, the average duration of evaluated pain treatment was 51, 53 and 38 days, respectively. Non-opioid or opioid analgesics were given to 99%, 96% and 79%, antidepressants to 8%, 25% and 19%, anticonvulsants to 2%, 22% and 38% and corticosteroids to 26%, 35% and 22% of patients, respectively. Systemic analgesia was supported by palliative antineoplastic treatment (48%, 56% and 38% of patients), nerve blocks (3%, 6% and 6%), psychotherapy (3%, 7% and 3%), physiotherapy (6%, 12% and 13%) and transcutaneous electric nerve stimulation (1%, 6% and 6%). Analgesic treatment resulted in a significant pain relief in all groups of patients, as the mean pain intensity (NRS) decreased from 66 (nociceptive), 65 (mixed) and 70 (neuropathic) on admission to 26, 30 and 28 after 3 days and 18, 17 and 21 at the end of survey. The total outcome of pain treatment was not predicted by the designation to nociceptive, mixed or neuropathic pain. In conclusion, neuropathic cancer pain is not intractable and can be relieved in the majority of patients by treatment following the WHO guidelines.

Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology.

Most patients with advanced cancer develop diverse symptoms that can limit the efficacy of pain treatment and undermine their quality of life. The present study surveys symptom prevalence, etiology and severity in 593 cancer patients treated by a pain service. Non-opioid analgesics, opioids and adjuvants were administered following the WHO-guidelines for cancer pain relief. Other symptoms were systematically treated by appropriate adjuvant drugs. Pain and symptom severity was measured daily by patient self-assessment; the physicians of the pain service assessed symptom etiology and the severity of confusion, coma and gastrointestinal obstruction at each visit. The patients were treated for an average period of 51 days. Efficacy of pain treatment was good in 70%, satisfactory in 16% and inadequate in 14% of patients. The initial treatment caused a significant reduction in the average number of symptoms from four to three. Prevalence and severity of anorexia, impaired activity, confusion, mood changes, insomnia, constipation, dyspepsia, dyspnoea, coughing, dysphagia and urinary symptoms were significantly reduced, those of sedation, other neuropsychiatric symptoms and dry mouth were significantly increased and those of coma, vertigo, diarrhea, nausea, vomiting, intestinal obstruction, erythema, pruritus and sweating remained unchanged. The most frequent symptoms were impaired activity (74% of days), mood changes (22%), constipation (23%), nausea (23%) and dry mouth (20%). The highest severity scores were associated with impaired activity, sedation, coma, intestinal obstruction, dysphagia and urinary symptoms. Of all 23 symptoms, only constipation, erythema and dry mouth were assessed as being most frequently caused by the analgesic regimen. In conclusion, the high prevalence and severity of many symptoms in far advanced cancer can be reduced, if pain treatment is combined with systematic symptom control. Nevertheless, general, neuropsychiatric and gastrointestinal symptoms are experienced during a major part of treatment time and pain relief was inadequate in 14% of patients. Cancer pain management has to be embedded in a frame of palliative care, taking all the possibilities of symptom management into consideration.

Transdermal fentanyl and initial dose-finding with patient-controlled analgesia in cancer pain. A pilot study with 20 terminally ill cancer patients.

This pilot study evaluated the efficacy and side effects of a combination of initial patient-controlled analgesia (PCA) for dose-finding with transdermal fentanyl administration. Twenty inpatients, requiring strong opioids for severe cancer pain, received intravenous fentanyl on an on-demand basis over a 24-h period. The amount of fentanyl administered was then used as a guideline for selecting a suitable transdermal therapeutic system (TTS) on the 2nd day, which remained in place for 3 days. The size of a 2nd TTS, being used from day 5 to 7, was adjusted according to the amount of supplementary intravenous fentanyl doses on day 3. From day 4 to 7 intravenous fentanyl was stopped, and subcutaneous morphine was made available as a rescue medication. A standardized adjuvant medication was allowed. Pain intensity, pain relief, quality of sleep, mood, general state of health, activity, mobility, rescue morphine consumption and side effects were assessed using a diary after baseline pain and symptoms were recorded. Vital functions were monitored and fentanyl plasma levels were measured daily in 15 patients. The use of TTS fentanyl in combination with initial dose titration using PCA gave rapid and statistically significant pain relief. Patient compliance and acceptance were excellent. In the absence of severe side effects the main complaints were dryness of the mouth and constipation. Increasing pain intensity and increasing supplementary morphine requirements as well as decreasing plasma fentanyl levels on day 7 may indicate that conversion ratios from intravenous to transdermal administration should be increased or that TTS should be changed earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of tramadol.

Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.

Experiences with continuous intra-arterial blood gas monitoring: precision and drift of a pure optode-system.

OBJECTIVE: The utility of continuous intra-arterial blood gas analysis (CBGA) with combined electrochemical and optode sensors has been demonstrated. More recently, a pure optode sensor with a changed sensing element architecture has become available. The aim was to determine the measurement accuracy and long-term stability of the new sensor. DESIGN: A prospective explorative study was performed. Simultaneous measurements of intermittent blood gas analyses (IBGA) (ABL 610, Radiometer, Copenhagen) and CBGA (Diametrics Medical, High Wycombe, Bucks., UK) were compared using Bland-Altman analysis. PATIENTS: Twenty-five patients admitted to the ICU and requiring mechanical ventilation for an expected minimum of about 96 h were included. RESULTS: Mean monitoring time was 106.1 (range 15-231) hours. Bias and precision for PO(2 )were -0.2 kPa (1%)+/-1.8 kPa (9.5%); PCO(2): 0.03 kPa (0.6%)+/-0.44 kPa (9.3%); pH: -0.001 (0.01%)+/-0.04 (0.45%). The sensor showed no change of measurement characteristics during 4 days of measurement. However, in 69 cases continuous monitoring was interrupted (reversible sudden drops of PO(2) measurement) possibly caused by thrombotic deposition and/or sensor bending and accidental sensor retraction. CONCLUSIONS: The precision and bias of the PCO(2)- and pH-sensing elements were in line with the findings of the older sensor technology. The possibility that the PO(2) optode could offer greater accuracy than the older technology is suggested by comparisons with results reported in previous studies. No sensor drift occurred during long-term measurement over more than 4 days.

Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery.

BACKGROUND: Recurrent laryngeal nerve monitoring (RLNM) has been suspected to reduce postoperative RLN paralysis (RLNP). However, functional outcome of RLNM in comparison with no nerve identification and visual nerve identification only has not been analyzed. METHODS: Analysis of 16,448 consecutive multi-institutional operations resulted in 29,998 nerves at risk. Three groups of different RLN treatment were compared: group 1, no RLN identification; group 2, visual RLN identification; and group 3, visual RLN identification and electromyographic monitoring. RLNM was performed with a bipolar needle electrode that was placed through the cricothyroid ligament into the vocal muscle. RESULTS: Risk factors for permanent RLNP were recurrent benign and malignant goiter (odds ratios, [ORs]), 4.7, and 6.7, respectively), primary surgery in thyroid malignancy (OR, 2.0), lobectomy (OR, 1.8), no nerve identification (OR, 1.4), low or medium volume hospital (OR, 1.3), and low volume surgeons (OR, 1.2). CONCLUSIONS: Based on these data, visual nerve identification was identified to be the gold standard of RLN treatment in thyroid surgery. RLNM is a promising tool for nerve identification and protection in extended thyroid resection procedures. However, because of the overall low frequency of RLNP, no statistical difference compared with visual nerve identification only was reached in the setting of this study.

Involvement of endogenous opioid systems in nociceptin-induced spinal antinociception in rats.

The present study investigates the involvement of opioid receptors in the antinociceptive effects of nociceptin in the spinal cord of the rat. Intrathecal administrations of 5 and 10 nmol of nociceptin significantly increase the withdraw response latencies to noxious thermal and mechanical stimulations. This nociceptin-induced antinociceptive effect is significantly attenuated by intrathecal injection of (Nphe(1))nociceptin(1-13)-NH(2), a selective antagonist of the nociceptin receptor (opioid receptor-like receptor ORL1), indicating an ORL1 receptor-mediated mechanism. This antinociceptive effect is also significantly attenuated by intrathecal injections of naloxone (a nonselective opioid receptor antagonist), naltrindole (a selective delta-opioid receptor antagonist), and beta-funaltrexamine (a selective mu-opioid receptor antagonist) in a dose-dependent manner, but not by the selective kappa-opioid receptor antagonist norbinaltorphimine. Since it is unlikely that nociceptin acts by direct binding to opioid receptors, these results suggest a possible interaction between the nociceptin/ORL1 and opioid systems in the dorsal horn of the rat spinal cord.