[Management of chronic pain using extended release tilidine : Quality of life and implication of comedication on tilidine metabolism]. / Management von chronischem Schmerz mit retardiertem Tilidin : Lebensqualität und Bedeutung der Komedikation für den Tilidinmetabolismus.

BACKGROUND AND OBJECTIVES: The synthetic opioid tilidine is often used in chronic pain treatment. However, the activation via metabolism in patients with concomitant medication and reduced liver or kidney function is not thoroughly investigated. We therefore studied pain treatment efficacy, health-related quality of live and the metabolism of tilidine in patients with chronic pain. METHODS AND MATERIALS: In all, 48 patients, who were on a stable dose of oral prolonged release tilidine for at least 7 days, were included in this observational multicenter study. Liver and kidney function were assessed in routine blood samples, concentrations of tilidine, nortilidine and bisnortilidine were determined using a validated LC/MS/MS method. Comedication was registered and patients experience with regard to quality of life, pain, gastrointestinal symptoms and adverse events was assessed in standardised questionnaires. RESULTS: On average a daily dose of 180 mg tilidine was taken. Dose normalized plasma concentrations of the active metabolite nortilidine ranged between 1.6 ng/ml and 76.5 ng/ml (mean 29.2 ± 25.1 ng/ml). Ratios between tilidine and nortilidine were on average 0.28 (median = 0.13, standard deviation = 0.67). Patients were on 1 to 14 different concomitant medications. About 66% of the patients had sufficient pain treatment. Almost no opioid-induced constipation was observed. Only few patients had decreased kidney or liver function which did not result in elevated nortilidine concentrations. CONCLUSION: Pain treatment using tilidine resulted in variable nortilidine concentrations which are obviously not strongly influenced by comedication or reduced liver or kidney function. Only a few side effects were observed with almost no opioid-induced constipation.

Treatment Options for Central Sleep Apnea: Comparison of Ventilator, Oxygen, and Drug Therapies.

Central sleep apnea (CSA) is a sleep-related disorder characterized by pauses in breathing during sleep when the brain respiratory network momentarily interrupts transmission of impulses to the respiratory musculature. CSA presents significant problems being an independent risk factor for cardiovascular events and death. There are several available treatment options according to CSA severity. Currently, adaptive servo-ventilation is considered best for CSA patients. The goal of the present study was to retrospectively investigate different treatment methods employed for CSA, such as different modes of ventilation, oxygen therapy, and drugs to determine the most effective one. Data were obtained from hospital records during 2010-2015. The diagnosis of CSA and the optimal treatment method were supported by polysomnography examinations. Devices used during sleep to support breathing included continuous positive airway pressure, bi-level positive airway pressure, or adaptive servo-ventilation. We classified 71 (2.9 %) patients as having CSA from 2,463 patients with sleep-disordered breathing. Of those 71 patients, 54 (76.1 %, 95 % CI 66.2-86.0 %) were male and 17 (23.9 %, 95 % CI 14.0-33.8 %) were female, and they had a mean age of 67.1 ± 14.1. Four (5.6 %) patients underwent a combination therapy, 39 (54.9 %) received a ventilator in proper ventilation mode, 25 (35.2 %) received oxygen therapy, 7 (9.9 %) received medication, and 4 (5.6 %) received no treatment. We conclude that although the majority of patients needed treatment for central sleep apnea, a clear advantage in using ventilators when compared to oxygen therapy or drug therapy could not be found.

[Efficacy of epidural steroid injections for chronic lumbar pain syndromes without neurological deficits. A randomized, double blind study as part of a multimodal treatment concept]. / Wirksamkeit periduraler Steroidinjektionen in der Therapie von nichtradikulären chronischen Rückenschmerzen. Eine randomisierte, doppelverblindete Vergleichsstudie im Rahmen eines multimodalen Behandlungskonzeptes.

BACKGROUND: Chronic lumbar pain syndromes without neurological deficits are generated by a multitude of causes. Functional, morphological and psychosocial factors are discussed. In many cases a diseased intervertebral disc is found on radiological examination but the clinical relevance of these findings is not clear. For this study it was postulated that a diseased disc results in a local inflammatory reaction therefore causing pain and impairing treatability of patients. An epidural injection of steroids can reduce inflammation and therefore improve treatability and ultimately treatment outcome. METHODS: A double blind randomized prospective trial was carried out. Patients treated in hospital for a chronic lumbar pain syndrome without neurological deficits within a multimodal treatment program were screened for indications for an epidural steroid injection (e.g. diseased lumbar disc and intention to treat). Patients eligible for the study were randomized into two groups. The treatment group received an epidural injection of 80 mg triamcinolone and 8 ml bupivacaine 0.25 %. The control group received only an epidural injection of 8 ml bupivacaine 0.25 %. RESULTS: In both groups pain intensity and treatability showed a statistically significant improvement after the epidural injection. The differences between the control and treatment groups were small and not clinically relevant. A small subgroup might profit from the steroid injection. In addition the treatability was dependent on psychometric values and the long-term outcome from a reduction of muscular skeletal dysfunctions. DISCUSSION: After the epidural injection the decrease in pain and increase in treatability was statistically significant. The mechanism of the improvement is not clear and should be examined further. The epidural injection of a steroid in this subgroup of patients did not lead to a clinical improvement in the outcome.

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.

Barriers to adequate analgesia in paediatric burns patients.

BACKGROUND: All children with burn injuries experience pain at some time during their management and recovery. Burn pain is challenging to manage, owing to a combination of factors. The process of achieving adequate analgesia involves the correct scripting of medication based on the doctor's knowledge, the correct fulfilling of that script, and patient compliance. OBJECTIVES: To assess two components of this process, correct scripting of medication based on the doctor's knowledge and the correct filling of that script, to highlight potential barriers to adequate analgesia for burn-injured patients being followed up at an outpatient department. Patient compliance was out of the scope of this study. METHODS: The study was conducted in the Pietermaritzburg Burn Service (PBS) in Pietermaritzburg, South Africa, and was undertaken in two parts. The first part was conducted through an anonymous, voluntary questionnaire completed by doctors working in hospitals referring to the PBS. The aim of the questionnaire was to identify deficits in knowledge of doctors regarding background analgesia for burn-injured children. The second part was conducted through an audit of the outpatient folders of children attending the PBS outpatient clinic to identify discrepancies between analgesia prescribed and analgesia supplied to the patient. RESULTS: Thirty-six doctors completed the questionnaire. While nearly all the doctors prescribed background analgesia, just over half (58%) prescribed paracetamol, and of those, only half prescribed the correct dose. Half of the doctors prescribed tilidine, and only half of them knew the correct dose. Forty-seven percent of the doctors prescribed both paracetamol and tilidine for background analgesia. The outpatient folders of 59 children attending the outpatient clinic were audited. Fifty-three patients were prescribed paracetamol. There was a statistically significant difference between the paracetamol volume prescribed and the volume supplied (p<0.0001). Twenty-four patients were prescribed ibuprofen. There was a statistically significant difference between the ibuprofen volume prescribed and the volume supplied (p<0.0001). CONCLUSIONS: Burn-injured children commonly receive inadequate analgesia in our setting. The reasons for this are multifactorial. The correct dose and the correct drugs for burn-related background pain are deficits in the knowledge of doctors who deal with this common problem. Furthermore, even if the correct drug and dose are prescribed, the correct volume of medication is often not issued by the pharmacy. This study highlights barriers to achieving adequate analgesia in children with burns being managed as outpatients. Potential strategies to overcome barriers include improving education with regard to pain management and burns at an undergraduate and postgraduate level, and improved supply chain management.

[Basic Knowledge of Drug Pain Therapy in the Palliative Situation]. / Basiswissen zur medikamentösen Schmerztherapie in der Palliativsituation.

This review provides an overview of the basic knowledge of drug pain therapy in the palliative situation. Pain is one of the main symptoms in 60 to 90 % of cancer patients. Pain also develops with neurological and other diseases that occur in end-of-life situations. To address this symptom, a holistic strategy is required that encompasses all physical, psychological, social, and spiritual aspects of the multi-dimensional pain experience ("total pain" concept).Drug treatment for cancer pain has been based on a stepwise approach for many years, starting with non-opioid analgesics, followed by moderate and strong opioids. In contrast, today's pain management is determined more by the actual intensity of this aversive event.The pain assessment should be tailored to identify a nociceptive vs. neuropathic pain component that needs to be challenged by the most appropriate drug therapies. Non-opioid analgesics are ideal substances for relieving nociceptive pain. Antidepressants and anticonvulsants reduce the intensity of new neuropathic pain. Opioids are suitable for all types of pain, but are restricted to a second line choice. Among all opioids are tilidine and tramadol prodrugs, which only relieve pain after activation in the liver. Drug-drug interactions may also block this activation. Rapid release opioids should be used for cancer breakthrough pain. Transdermal opioid applications are recommended for swallowing disorders, but usually not to initiate pain control. An opioid switch can be performed if side effects such as hallucinations for the selected opioid are more pronounced than the pain reduction.

[Acute pain management in proximal femoral fractures: femoral nerve block (catheter technique) vs. systemic pain therapy using a clinic internal organisation model]. / Akutschmerztherapie bei Patienten mit hüftgelenknahen Frakturen : N.-femoralis-Katheter-Analgesie vs. systemische Schmerztherapie unter Anwendung eines klinikinternen Organisationsmodells.

BACKGROUND: The aim of this study was to compare safety and efficacy of catheter-mediated femoral nerve block analgesia with systemic pain therapy in patients with proximal femoral fractures in the pre-operative and post-operative setting using a protocol for coordinating pain management. METHODS: In a prospective randomised trial of patients attending the emergency department, 100 individuals were selected with a clinically diagnosed proximal femoral fracture. Patients were divided into two equal groups A and B. Group A (n=50) received a catheter-mediated femoral nerve block with 1% prilocaine (40 ml) and post-operatively 0.2% ropivacaine (30 ml) 6 hourly. Group B (n=50) initially received intravenous metamizol (1 g) and a fixed combination of oral tilidine (100 mg) + naloxone (8 mg). Patients aged 90 years or more received a reduced dose (tilidine 75 mg + naloxone 6 mg). In the post-operative period regular oral ibuprofen (400 mg, 8 hourly) in addition to oral tilidine (50 mg) + naloxone (4 mg) was given as required for break through pain. Pain intensity was measured using a verbal rating scale (VRS) from 1 to 5: pain free (=1), mild pain (=2), moderate pain (=3), severe pain (=4), excruciating pain (=5). Pain scores were recorded at rest (R), during passive anteflection (30 degrees) of the hip (PA) on arrival and at 15 and 30 min after initial administration of analgesia. Thereafter, recordings were made 4 times a day up to the third post-operative day. RESULTS: Pain scores were comparable for both groups on admission (VRS in R 2.50 vs. 2.46; VRS during PA 4.30 vs. 4.34). Significant pain relief was achieved in both groups following initial administration of analgesia, but the total pain scores in group A were significantly lower than in group B (VRS in R 1.22 vs. 1.58, p<0.01 and VRS during PA 2.66 vs. 3.26; p<0.001). No difference was noted between the two groups during the first 3 post-operative days. No severe complications occurred as a result of analgesia, however, the catheter was dislodged in 20% of patients in group A resulting in the need for systemically administered analgesia. CONCLUSION: All patients presenting with proximal femoral fractures should receive adequate analgesia within the emergency department even prior to radiographic imaging. Femoral nerve block should be considered as the method of choice. The insertion of a femoral nerve block catheter has the dual advantage of early analgesia permitting repeated clinical examination in addition to continued post-operative pain management. The cumbersome logistics inherent in this technique within the clinical setting limits its practical application. An initial single-shot regional nerve block followed by a systemic post-operative analgesia protocol was considered an appropriate alternative. The execution of safe, consistent and appropriate regional nerve block anaesthesia is reliant on formal guidelines and protocols as agreed by the multidisciplinary teams involved with patient-directed pain management and good clinical practice.

Tilidine does not affect human sphincter of Oddi motility--a randomized, controlled study.

AIM: To investigate the effects of intravenous pentazocine and tilidine on sphincter of Oddi motility. METHODS: Twenty patients with suspected sphincter of Oddi dysfunction were enrolled in a prospective, double-blind study. Sphincter of Oddi motility was assessed by means of endoscopic manometry after injection of 0.9% saline, as well as after randomized dosing with either 30 mg pentazocine i.v. (n = 10) or 50 mg tilidine i.v. (n = 10). RESULTS: Pentazocine significantly increased the sphincter of Oddi baseline pressure from 32 +/- 21 mmHg (saline) to 41 +/- 19 mmHg (P = 0.002), whereas tilidine did not alter the sphincter baseline pressure (34 +/- 15 mmHg saline vs. 36 +/- 16 mmHg tilidine, P = 0.16). Furthermore, pentazocine increased the phasic sphincter contraction amplitude (108 +/- 16 mmHg saline vs. 121 +/- 18 mmHg pentazocine, P = 0.004), but tilidine was without any effect (125 +/- 24 mmHg saline vs. 125 +/- 21 mmHg tilidine, P = 0.93). The phasic sphincter of Oddi contraction frequency and duration were not influenced either by pentazocine or by tilidine. CONCLUSION: In contrast to 30 mg of pentazocine, 50 mg of tilidine does not affect sphincter of Oddi motility. Therefore, tilidine can be used during endoscopic manometry and for analgesia in pancreatobiliary disease.

Control of cancer pain with analgesics acting in the central nervous system.

Systemic administration of opioids is one of the traditional, but by no means optimized therapeutic procedures in cancer pain. Besides the underlying pathophysiology, appropriate treatment has to take into account the psychodynamics and behavior of the patient as well as his life expectancy. In view of this, therapy with centrally acting analgesics can be considered after administration of analgesics with peripheral action first and then of psychoactive agents. Nefopam is a centrally (but not spinally) acting analgesic with a novel activity profile. Its advantages and disadvantages in the treatment of carcinoma pain are outlined. The opiate agonist-antagonist principle has the advantage of a lower dependence and tolerance potential. In addition, the preparations pentazocine, tilidine plus naloxone, and buprenorphine deviate from the morphine derivatives in various constituent effects. Their actions and side effects are outlined. The optimization of control of cancer pain is not possible without taking into account the time dimension. In 50 pain patients with advanced cancer, the following main errors were observed in previous treatment of pain syndromes: (1) too early parenteral administration in the course of the disease; (2) underdosage; (3) application intervals that were too long; and (4) use of analgesics as needed by the patient or on request and not according to a time schedule.

Comparison of tilidine/naloxone, tramadol and bromfenac in experimental pain: a double-blind randomized crossover study in healthy human volunteers.

AIM: The analgesic efficacy and safety of single oral doses of two centrally acting compounds, the combination of 50 mg tilidine and 4 mg naloxone (Valoron N) and 50 mg tramadol (Tramal), were compared to 25, 50 and 75 mg of the non-steroidal antiinflammatory bromfenac in experimental pain. SUBJECTS AND METHODS: It was a placebo-controlled double-blind 6-way crossover study design with 12 human volunteers. Acute pain was generated by electrical tooth pulp stimulation. Treatment effects were determined by recording somatosensory-evoked potentials and by subjective pain rating. RESULTS: The tilidine/naloxone combination clearly was the most potent medication in this study, followed by bromfenac 75 mg, which produced an early pain relief. Tramadol produced poor analgesia, as did bromfenac 25 and 50 mg. There was no dose-response relationship for bromfenac. Control of plasma levels revealed pronounced interindividual differences in peak plasma concentrations for bromfenac, but not for tramadol. Tilidine/naloxone exerted adverse effects in 9, tramadol in 3 volunteers. Under medication with 25 and 50 mg bromfenac, respectively, only one subject reported adverse effects. No adverse effects were experienced with 75 mg bromfenac or placebo. CONCLUSION: The results support previous conclusions about the analgesic efficacy of tilidine/naloxone and tramadol in experimental pain. Moreover, the findings suggest that 75 mg bromfenac might be suitable for fast but short relief of pain of non-inflammatory genesis.

Comparative study of tilidine-naloxone and pentazocine in knee and hip osteoarthritis.

Fifty patients, twenty-five suffering from severe knee osteoarthritis and twenty-five from acute hip osteoarthritis, received pentazocine or a new preparation of tilidine-naloxone for a period of 2 weeks, in a double-blind study. The two drugs were found to have the same efficacy and tolerance in both diseases with a minor but not statistically significant superiority for tilidine-naloxone. Similar quantities of drugs were taken over the study period, while patients were allowed to take as many as 8 capsules per day to relieve pain. There were quite equivalent side-effects and no marked changes in laboratory tests.

Modern techniques to measure pain in healthy man.

This paper describes a series of experimental prerequisites in assessments to measure the efficacy of analgesic drugs in healthy man. Of course, there is no doubt that an analgesic has to prove its validity exactly where it ought to help; i.e. in the patient suffering from pain. But to objectify the mode of action, or to measure dose-response functions, to evaluate the optimal therapeutic dosage, or to compare the relative efficacy of the drug tested with known substances--all these investigations can best be performed in a sample of healthy, informed, intelligent and cooperative volunteers, as homogenous as possible. Various kinds of stimuli used in the experimental pain laboratory will be compared with respect to their usefulness in algesimetry; for example the CO2 laser stimulus and the intracutaneous electrical shock. New examples in the analysis of cerebral potentials evoked by painful stimuli will be presented, such as the principal component analysis, the maximum entropy method, and procedures of cerebral potential mappings. It will be shown that frequency transformation of stimulus-induced changes in the electroencephalogram can result in a powerful tool to verify effects even of the so-called weak analgesics, such as acetyl salicylic acid (Aspirin).

[Changes in the pattern of opioid analgesic consumption in Spain]. / Cambios en el patrón de consumo de analgésicos opioides en España.

BACKGROUND: Data from different sources have proved an infrautilization of opioid analgesics in Spain. A descriptive study has been conducted in order to know the utilization of these drugs and changes in the pattern of use in the last few years. MATERIAL AND METHOD: To know the consume of narcotic analgesic drugs, N02A group of the Anatomic Therapeutic Classification, a search was developed in the ECOM database from the Spanish Ministry of Health. This database contains information of drug preparations prescribed throughout the National Health Care System. RESULTS: The consumption of opioid analgesics in Spain has been multiplied by 5.2 during this period. It has increased from 94.7 defined daily dose per 1,000,000 inhabitants in 1985 to 489.4 in 1994. The most consumed drug in 1994 was dihydrocodeine, followed by tramadol. The number of defined daily dose per inhabitant and day of parenteral administration have decreased during the last years. CONCLUSIONS: Availability of new analgesic opioid drugs with better pharmacokinetic profiles has contributed to an increase of their consume in Spain.

A clinical comparison of tilidine hydrochloride and pentazocine, given orally for the treatment of postoperative pain.

A controlled, double-blind study involving 250 women was carried out ot assess the efficacy of oral tilidine 25, 50 and 100 mg in treating postepisiotomy pain, and to offer a comparison with oral pentazocine 50 mg. All the analgesics produced significant pain relief. At peak effect tilidine 50 mg produced very similar results to pentazocine 50 mg with tilidine 25 mg producing less, and tilidine 100 mg more pain relief. These results were not, however, statistically significant. In these postdelivery ambulant patients pentazocine 50 mg and tilidine 100 mg produced at 25% incidence of side-effects, mainly dizziness and drowsiness, but tilidine 25 mg produced significant analgesia with virtually no side-effects.

Double blind study with nefopam, tilidine and placebo, for postoperative pain suppression.

A double-blind study involving 101 patients was done to assess the efficacy of parenteral nefopam (0.66 mg/kg) for postoperative pain suppression, in comparison to tilidine (1.67 mg/kg) or placebo. The difference in painfree duration for both active drugs compared to placebo is significant, but no significant difference was present between them; although tilidine was a little longer acting. At no moment a significant difference was present in the pain score of the patients receiving one of both active drugs. Only minor changes of blood pressure, heart rate and respiratory frequency were seen and marked side effects were not present in any of the patients.