Tilidine and dipyrone (metamizole) in cold pressor pain: A pooled analysis of efficacy, tolerability, and safety in healthy volunteers.

The cold pressor test (CPT) is widely implemented and offers a simple, experimental acute pain model utilizing cold pain. Previous trials have frequently paired the CPT with opioids in order to investigate the mechanisms underlying pharmacological analgesia, due to their known analgesic efficacy. However, opioid side effects may lead to unblinding and raise concerns about the safety of the experimental setting. Despite the established clinical efficacy of dipyrone (metamizole), its efficacy, tolerability, and safety in cold pressor pain has not been systematically addressed to date. This pooled analysis included data of 260 healthy volunteers from three randomized, placebo-controlled, double-blind substudies using the CPT following a pre-test-post-test-design. These substudies allow for comparing a single dose of 800 mg dipyrone with two different doses of the opioid tilidine/naloxone (50/4 mg and 100/8 mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication-attributed side effects, as well as changes of blood pressure and heart rate. We demonstrate that both opioid doses and dipyrone had a comparable, significant analgesic effect on cold pressor pain. However, dipyrone was associated with significantly less self-reported adverse effects and these were not significantly different from those under placebo. These results indicate that the combination of dipyrone and the CPT provides a safe, tolerable, and effective experimental model for the study of pharmacological analgesia. In combination with a CPT, dipyrone may be useful as a positive control, or baseline medication for the study of analgesic modulation.

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.

Segmental hair analysis for differentiation of tilidine intake from external contamination using LC-ESI-MS/MS and MALDI-MS/MS imaging.

Segmental hair analysis has been used for monitoring changes of consumption habit of drugs. Contamination from the environment or sweat might cause interpretative problems. For this reason, hair analysis results were compared in hair samples taken 24 h and 30 days after a single tilidine dose. The 24-h hair samples already showed high concentrations of tilidine and nortilidine. Analysis of wash water from sample preparation confirmed external contamination by sweat as reason. The 30-day hair samples were still positive for tilidine in all segments. Negative wash-water analysis proved incorporation from sweat into the hair matrix. Interpretation of a forensic case was requested where two children had been administered tilidine by their nanny and tilidine/nortilidine had been detected in all hair segments, possibly indicating multiple applications. Taking into consideration the results of the present study and of MALDI-MS imaging, a single application as cause for analytical results could no longer be excluded. Interpretation of consumption behaviour of tilidine based on segmental hair analysis has to be done with caution, even after typical wash procedures during sample preparation. External sweat contamination followed by incorporation into the hair matrix can mimic chronic intake. For assessment of external contamination, hair samples should not only be collected several weeks but also one to a few days after intake. MALDI-MS imaging of single hair can be a complementary tool for interpretation. Limitations for interpretation of segmental hair analysis shown here might also be applicable to drugs with comparable physicochemical and pharmacokinetic properties.

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.

[Chronic non-cancer-related pain. Long-term treatment with rapid-release and short-acting opioids in the context of misuse and dependency]. / Chronische nichttumorbedingte Schmerzen. Langzeitbehandlung mit schnell freisetzenden und kurz wirksamen Opioiden im Kontext von Missbrauch und Abhängigkeit.

Annually published data show a continual increase in the volume of opioid prescriptions in Germany, thus indicating an intensification of opioid therapy. The majority of opioids are prescribed to treat chronic non-cancer-related pain. On the basis of current guidelines, as well as in terms of the lack of data regarding long-term use of opioids and their effectiveness beyond a period of 3 months, this development must be viewed critically. With reference to four case reports, we discuss and evaluate opioid therapy in relation to medication misuse and the development of drug dependency. Particular emphasis is placed on the administration of rapid-release and short-acting opioid preparations, which we consider to be particularly problematic.

Contribution of CYP2C19 and CYP3A4 to the formation of the active nortilidine from the prodrug tilidine.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The analgesic activity of tilidine is mediated by its active metabolite, nortilidine, which easily penetrates the blood-brain barrier and binds to the µ-opioid receptor as a potent agonist. Tilidine undergoes an extensive first-pass metabolism, which has been suggested to be mediated by CYP3A4 and CYP2C19; furthermore, strong inhibition of CYP3A4 and CYP2C19 by voriconazole increased exposure of nortilidine, probably by inhibition of further metabolism. The novel CYP2C19 gene variant CYP2C19*17 causes ultrarapid drug metabolism, in contrast to the *2 and *3 variants, which result in impaired drug metabolism. WHAT THIS STUDY ADDS: Using a panel study with CYP2C19 ultrarapid and poor metabolizers, a major contribution of polymorphic CYP2C19 on tilidine metabolic elimination can be excluded. The potent CYP3A4 inhibitor ritonavir alters the sequential metabolism of tilidine, substantially reducing the partial metabolic clearances of tilidine to nortilidine and nortilidine to bisnortilidine, which increases the nortilidine exposure twofold. The lowest clearance in overall tilidine elimination is the N-demethylation of nortilidine to bisnortilidine. Inhibition of this step leads to accumulation of the active nortilidine. AIMS: To investigate in vivo the effect of the CYP2C19 genotype on the pharmacokinetics of tilidine and the contribution of CYP3A4 and CYP2C19 to the formation of nortilidine using potent CYP3A4 inhibition by ritonavir. METHODS: Fourteen healthy volunteers (seven CYP2C19 poor and seven ultrarapid metabolizers) received ritonavir orally (300 mg twice daily) for 3 days or placebo, together with a single oral dose of tilidine and naloxone (100 mg and 4 mg, respectively). Blood samples and urine were collected for 72 h. Noncompartmental analysis was performed to determine pharmacokinetic parameters of tilidine, nortilidine, bisnortilidine and ritonavir. RESULTS: Tilidine exposure increased sevenfold and terminal elimination half-life fivefold during ritonavir treatment, but no significant differences were observed between the CYP2C19 genotypes. During ritonavir treatment, nortilidine area under the concentration-time curve was on average doubled, with no differences between CYP2C19 poor metabolizers [2242 h ng ml(-1) (95% confidence interval 1811-2674) vs. 996 h ng ml(-1) (95% confidence interval 872-1119)] and ultrarapid metabolizers [2074 h ng ml(-1) (95% confidence interval 1353-2795) vs. 1059 h ng ml(-1) (95% confidence interval 789-1330)]. The plasma concentration-time curve of the secondary metabolite, bisnortilidine, showed a threefold increase of time to reach maximal observed plasma concentration; however, area under the concentration-time curve was not altered by ritonavir. CONCLUSIONS: The sequential metabolism of tilidine is inhibited by the potent CYP3A4 inhibitor, ritonavir, independent of the CYP2C19 genotype, with a twofold increase in the exposure of the active nortilidine.

Direct monitoring changes of salbutamol concentration in serum by chemiluminescent imaging.

We report in this manuscript, the use of direct ammonium persulfate-enhanced chemiluminescence (CL) imaging, to monitor changes to measure serum salbutamol concentration in subjects of different haptoglobin (Hp) phenotypes at different dosing time. It was noted that CL generated from Hp was decreased due to salbutamol's reducibility, which was used for monitoring salbutamol concentration in serum. The serum from the subjects treated by oral administration of salbutamol, was collected at different dosing time and was separated by polyacrylamide gel electrophoresis (PAGE) prior to the CL detection. According to CL images, samples were separated into three groups based on the Hp phenotypes. The curves of CL signal intensity versus time were obtained for each group, and we demonstrated that there were more significant variables on binding ability between groups. The maximum salbutamol concentration in the serum appeared after 4h, which was in agreement with the literature. In addition, the binding constants of salbutamol to Hp were determined by a fluorescence-based method, whose results were in agreement with the phenomenon of the greater salbutamol metabolism rate for Group Hp 1-1 than Group Hp 2-2. The presented method can monitor changes of salbutamol concentration in serum directly, making the procedures much simple, convenient, rapid and has the property of lower cost. It provided us with excellent reference information for the individual dosage regimen of different Hp groups, which hopefully could become a potential method for further pharmaceutical research.

[The transdermal 7-day buprenorphine patch--an effective and safe treatment option, if tramadol or tilidate/naloxone is insufficient. Results of a non-interventional study]. / 7-Tage-Pflaster mit Buprenorphin--eine Option, wenn die Therapie mit Tramadol bzw. Tilidin/Naloxon unzureichend ist. Ergebnisse einer nicht interventionellen Studie.

The transdermal 7-day buprenorphine matrix patch provides a constant and user-friendly pain management when chronic musculoskeletal pain requires opioids. This analysis of clinical routine data evaluated the benefit of this treatment for patients previously receiving oral long-term treatment with weak opioids alone. Data of 310 patients previously treated with tramadol or tildate/naloxone and part of a multicentre observational study with 3295 patients were analyzed. In 89.7% of the 310 patients oral treatment with weak opioids was replaced by the 7-day buprenorphine patch due to insufficient analgesia. During treatment with the 7-day buprenorphine patch there was a clinically significant decrease of the mean pain intensity at rest during the day from 5.7 to 2.9, on physical effort during the day from 7.3 to 3.8 and at night from 5.2 to 2.3 (11-point NRS scale, p < or = 0.001). In addition, quality of life aspects such as mobility, self-reliance and quality of sleep improved, which are relevant for individual patient satisfaction with pain management. For patients with previous long-term tramadol or tilidate/naloxone treatment the switch to the 7-day buprenorphine matrix patch proved to be effective and safe for the management of chronic pain. The user-friendly 7-day application interval contributes to improving compliance and a reducing exposure to tablets.

[Postoperative pain therapy with tilidin and tilidin retard as an oral patient-controlled analgesia after uncomplicated myocardial revascularization]. / Die postoperative Schmerztherapie mit Valoron-N-Lösung und Valoron-N-retard. Tabletten als orales Patienten-kontrolliertes Analgesieverfahren nach herzchirurgischen Routine-Bypassoperationen.

OBJECTIVE: The purpose of this study was to evaluate whether or not the combination of tilidin and tilidin retard as oral patient-controlled analgesia provide a suitable pain management in patients after uncomplicated myocardial revascularization. METHODS: We conducted a randomised phase IV study to evaluate the effectiveness of postoperative analgesia with tilidin and tilidin retard. Patients with a baseline tilidin retard and tilidin liquid demand medication (group B, 42 patients) were compared with a base line paracetamol and tramadol-HCl liquid demand medication (group A, 44 patients). All patients received the first dose of study medication at the second postoperative day after evaluation of the individual pain score using NRS (numeric rating scale). RESULTS: Pain relief in group B was significantly better only at the second postoperative day (NRS 1,8 compared to 3,3 in group A), associated with tolerable side effects and comfortable handling. CONCLUSION: The combination of sustained release with immediate release drugs as a patient controlled analgesia provides suitable and comfortable analgesia after myocardial bypass surgery.