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At least 19 recordsLinked to original sources
PubMed2003

[Postoperative pain therapy with tilidin and tilidin retard as an oral patient-controlled analgesia after uncomplicated myocardial revascularization].

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.

Administration, Oral↗
PubMed2002

Sequential first-pass metabolism of nortilidine: the active metabolite of the synthetic opioid drug tilidine.

The disposition of nortildine, the active metabolite of the synthetic opioid drug tilidine, was investigated in healthy volunteers in a randomized, single-dose, three-way crossover design. Three different treatments were administered: tilidine 50 mg intravenously, tilidine 50 mg orally, and nortilidine 10 mg intravenously. The plasma concentrations of tilidine, nortilidine, and bisnortilidine were determined and subjected to pharmacokinetic analysis using noncompartmental methods. The systemic bioavailability of tilidine was low (7.6% +/- 5.3%) due to a pronounced first-pass metabolism. The areas under the plasma concentration versus time curves (A UC) of nortilidine were similar following either oral or intravenous administration of tilidine 50 mg (375 +/- 184 vs. 364 +/- 124 ng.h.ml(-1)). AUC of nortilidine was 229 +/- 42 ng.h.ml(-1) after IV infusion of nortilidine 10 mg and thus much greater than after IV tilidine corrected for differences in dose. Nortilidine had a much lower volume of distribution (275 +/- 79 vs. 1326 +/- 477 L) and a somewhat lower clearance (749 +/- 119 vs. 1198 +/- 228 ml/min) than tilidine. About two-thirds of the dose of tilidine was metabolized to nortilidine, although only half of the latter fraction was available in the peripheral circulation. Nortilidine was subsequently metabolized to bisnortilidine. The mean ratio of the AUC of bisnortilidine to nortilidine was 0.65 +/- 0.14 following IV administration of nortilidine but 1.69 +/- 0.38 and 1.40 +/- 0.27 following oral and intravenous administration of tilidine, respectively. The shapes of the plasma concentration-time curves of the metabolites and parent drug declined in parallel, indicating that the disposition of the metabolites is formation rate limited. Thus, although two-thirds of the dose of tilidine is metabolized to nortilidine, only one-third of the dose is available systemically as nortilidine for interaction with the opiate receptors after both intravenous and oral dosing of tilidine. The remaining part of nortilidine is retained in the liver and is subsequently metabolized to bisnortilidine and yet unknown compounds.

Administration, Oral↗
PubMed1986

Evaluation of tilidine for morphine-like subjective effects and euphoria.

Tilidine is an opioid analgesic that has been abused predominantly by the oral route. Studies of parenterally administered tilidine in animals did not clearly indicate a dependence potential of the morphine type. In this study we examined the abuse potential of orally and parenterally administered tilidine in humans. Both orally and intramuscularly given tilidine produced miosis and morphine-like subjective effects in non-dependent subjects. Oral tilidine was 1/8-1/10 as potent and intramuscular tilidine was 1/22 as potent as parenteral morphine in producing morphine-like subjective and miotic effects. Intramuscular tilidine suppressed and did not precipitate signs of abstinence in morphine-dependent subjects. However, intramuscularly given tilidine produced toxic effects not seen with morphine. Meperidine, codeine and d-propoxyphene produced morphine-like subjective and miotic effects, but also produced toxic effects at the highest doses tested. The results suggest that tilidine has a potential to be abused, that this potential is less than that of parenteral morphine and that tilidine is more likely to be abused orally than by the intramuscular route.

Administration, Oral↗
PubMed1997

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.

Adult↗
PubMed1983

Antagonism between tilidine and naloxone on cerebral potentials and pain ratings in man.

The effects of the opioid tilidine and the opiate antagonist naloxone on somatosensory evoked potentials (SSEP) and pain ratings (E), elicited by electrical skin stimuli with randomized intensities, were investigated for different, orally administered tilidine and naloxone combinations in a double-blind Latin square design in 15 healthy humans. A high correlation between SSEP amplitudes and E was found for all treatments investigated. Tilidine (100 mg) decreased both SSEP amplitudes and E by about 25% compared to the placebo. No significant differences were found between the analgesic effects of tilidine and TN8 (tilidine 100 mg; naloxone 8 mg). The effects of both treatments were significantly different from those of the naloxone, placebo and TN32 treatments (tilidine 100 mg; naloxone 32 mg), indicating a marked naloxone-induced reversal of tilidine analgesia. Naloxone (32 mg) increased the SSEP amplitudes. No naloxone-induced hyperalgesia was seen in the pain ratings.

Adult↗
PubMed2001

Pharmacokinetics of tilidine in terminal renal failure.

The aim of the present study was to investigate the pharmacokinetics of tilidine and its metabolites during the dialysis procedure and in the dialysis-free interval. Tilidine is a prodrug that is metabolized presystemically into the active metabolite nortilidine. Nortilidine is degraded thereafter to bisnortilidine and several polar metabolites. Nine patients with a creatinine clearance < 5 ml/min were treated in a crossover design with single oral doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis-free interval. Blood samples were taken frequently and analyzed for tilidine, nortilidine, and bisnortilidine. Drug and metabolite concentrations were also measured in aliquots of dialysate collected during dialysis. Only negligible amounts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The presystemic apparent clearance of the prodrug tilidine was decreased significantly during the dialysis-free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteers. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function seems not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis.

Adult↗
PubMed1978

[Critical comments on a case history "a death case involving tilidine" (author's transl)].

The author looks critically at the description of a suicide case involving a barbiturate dose that could not be determined exactly and doses of hydroxyzine and tilidine. Drugs with a short and a medium short duration of action obviously had the greatest effect. There was no description of an investigation of the gastric contents. The concentration of barbiturates in the blood alone was sufficient to cause death. The deceased also took hydroxyzine, and then finally 750 mg tilidine in capsule form. Tilidine's action is relatively slow in onset. The author discusses tilidine's possible contribution to the cause of death and comes to a different conclusion from the authors of the case report, especially as regards the key words "Tilidine--Intoxication". The authors of the case report ought to have called it "A Death Case Involving Barbiturates, Hydroxyzine and Tilidine" rather than giving is such a suggestive title as "A Death Case Involving Tildine". This would have been a more accurate representation of the facts and would have assisted the reader to grasp the complex toxicological situation more clearly.

Barbiturates↗
PubMed1975

The interaction of tilidine and pethidine in postoperative pain.

The mode of interaction between the new, non-narcotic analgesic tilidine and pethidine was studied in the treatment of postoperative pain. The potency ratio 3:1 (pethidine:tilidine) found previously was used in the comparison. Thus 0.25 mg/kg of pethidine with 0.75 mg/kg of tilidine and 0.5 mg/kg of pethidine with 1.5 mg/kg of tilidine were compared with 0.5 mg/kg and with 1.0 mg/kg of pethidine. These drug combinations proved to be equipotent with the pethidine dosages used. Consequently the mode of interaction seemed to be additive synergism. The onset of action was slightly faster with pethidine, but the duration of action was longer with pethidine-tilidine combinations. Respiratory depression and sedation were less evident after pethidine-tilidine combinations than after equianalgesic doses of pethidine. Circulatory effects were similar in all groups. No statistical difference in other side effects could be demonstrated between the groups.

Adolescent↗
PubMed1998

Poisoning with tilidine and naloxone: toxicokinetic and clinical observations.

The opioid analgesic tilidine and its metabolites were detected by high performance liquid chromatography (HPLC) with UV-detection in serum from a 28 year-old woman who ingested 100 ml Valoron (o)N containing 6.94 g of tilidine and about 0.56 g of naloxone with suicidal intention. Data on the toxicokinetics of tilidine in severe poisonings are missing. Therefore we followed serum concentrations of tilidine and metabolites for 48 or 96 h and for the first time calculated basic kinetic parameters in a massive life threatening poisoning. Serum concentration of tilidine 3 h after ingestion was 38.1 mg/l which is about 70 times of the upper therapeutic level in man and about ninefold above toxic concentrations known so far. The concentration of nortilidine, the primary active metabolite at this time was 18.8 mg/l. The terminal elimination half life's of tilidine and nortilidine were explicit, prolonged with 23.9 and 13.9 h respectively. The competitive opiate antagonist naloxone, which is added as a part of the industrially produced preparation Valoron N solution to minimise oral abuse is not able to prevent ventilatory depression in massive overdoses.

Adult↗
PubMed1977

[Double-blind study on the analgesic efficacy of tilidine (valoron) and pethidine (dolantin) in gastro-intestinal endoscopies and liver biopsies (author's transl)].

In a double-blind trial involving 99 patients, equi-analgesic doses of tilidine and pethidine (100 mg of each i.m.) were compared as to their effectiveness in laparoscopies, gastroscopies, esophagoscopies and liver needle biopsies. The two substances produced equally analgesic effects both during and after the various procedures, with the exception of the liver biopsies, in which tilidine was shown to be significantly more effective than pethidine. Whereas no sedation was noted in connection with tilidine medication, pethidine produced a marked, undesirable sleepiness in 12% of the cases observed. Due to the high analgesic efficacy and tolerance of tilidine found in both this and numerous other clinical trials and to its particular advantages over pethidine and other opiates (no respiratory depression, no effect on intestinal motility) tilidine can be recommended for premedication in gastrointestinal endoscopies and liver needle biopsies. Tilidine (Valoron) is not subject to the restrictions imposed by the West German narcotics laws.

Analgesia↗
PubMed1977

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.

Administration, Oral↗
PubMed1986

Negative reinforcing properties of naloxone in the non-dependent rhesus monkey: influence on reinforcing properties of codeine, tilidine, buprenorphine, and pentazocine.

Scheduled infusions of naloxone (1-100 micrograms/kg/inf.) and of buprenorphine (250 micrograms/kg/inf.) generated drug avoidance behavior in the non-dependent rhesus monkey under a continuous avoidance-escape paradigm. Pentazocine (1-100 micrograms/kg/inf.) codeine, (1-100 micrograms/kg/inf. and tilidine (1-250 micrograms/kg/inf.) were ineffective. Addition of varying doses of naloxone to scheduled infusions of codeine, tilidine, and pentazocine generated avoidance behavior not present with scheduled infusions of these opioids alone. The naloxone doses necessary for generation of avoidance behavior were low with the agonists codeine and tilidine, higher with the weak antagonist pentazocine, and highest with the strong antagonist buprenorphine. When monkeys were presented with the fixed tilidine-naloxone combination (100 + 8 parts) and pentazocine-naloxone combination (100 + 1 part) and the buprenorphine-naloxone combination (100 + 66 parts) presently in clinical use only the tilidine-naloxone combination generated drug avoidance behavior to an appreciable extent.

Animals↗
PubMed1978

The opiate-like action of tilidine is mediated by metabolites.

The analgesic effect of tilidine in rats is completely antagonized by the narcotic antagonist naloxone. Radioreceptor assays revealed, however, that the main metabolites of tilidine, nortilidine and bisnortilidine, rather than tilidine exhibit affinity to opiate receptors. These findings were confirmed in studies using the electrically stimulated guinea pig ileum and the mouse vas deferens. Chronic tilidine administration to rats caused a considerable degree of physical dependence, which was expected from the ability of the intact animal to metabolize tilidine. In the isolated ileum from chronically morphinized guinea pigs, both nortilidine and bisnortilidine fully substituted for morphine in preventing induction of withdrawal, indicating dependence liability of these metabolites.

Analgesia↗
PubMed1978

Tilidine abuse and dependence.

Tilidine (Valoron) is a new strong analgesic which was introduced into the market in West Germany in 1970. In February 1978 tilidine was placed under the regulations of the German Narcotics Act because it had rapidly become an easily acquired substitute for opiates on the drug scene. Cases have become known where tilidine dependence developed during the treatment of pain in patients without any preceding addiction to other drugs. The relevant literature on tilidine is reviewed in regard to pharmacological, epidemiological and clinical aspects of tilidine dependence and abuse.

Adult↗
PubMed2004

Actions of tilidine and nortilidine on cloned opioid receptors.

Tilidine, alone or combined with naloxone to prevent drug abuse, is used as an oral opioid analgesic. Although the analgesic action of tilidine and its active metabolite nortilidine is reversed by naloxone and therefore believed to involve the activation of the Mu opioid (MOP, OP3, mu) receptor, this has never been studied in recombinant systems. We have measured the selectivity of tilidine and nortilidine for human opioid and opioid-like receptors stably expressed in CHO-K1 cells, using the inhibition of the forskolin (FK)-induced accumulation of cAMP as endpoint. In cells expressing the MOP receptor, tilidine and nortilidine inhibited cAMP accumulation with IC50 of 11 microM and 110 nM, respectively. The agonist effects of nortilidine and [D-Ala2-MePhe4-Gly5-ol]enkephalin (DAMGO) on the MOP receptor were reversed by naloxone with very similar IC50 (1.2 versus 1.8 nM). At concentrations up to 100 microM, tilidine and nortilidine had no agonist effect on the DOP, KOP and NOP receptors. In conclusion, this study on cloned human receptors demonstrates that nortilidine is a selective agonist of the MOP receptor.

Animals↗
PubMed1976

[ On the metabolism of ethyl-DL-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride (Tilidine-HCl). 2nd Communication: Studies with 14C-labelled substance on rats and dogs].

Absorption, distribution, metabolism and excretion of the potent analgesic ethyl-DL-trans-2-timethylamino-1-phenyl-chclohex-3-ene-trans-1-carboxylate-hydrochloride (tilidine-HCl, Gö 1261 C, active ingredient of Vloron) were investigated in rats and dogs, using the radioactively labelled substance. Following oral administration, tilidine-HCl is rapidly and completely absorbed from the duodenum. During absorption, tilidine undergoes a marked first-pass effect. In plasma several metabolites are found, part of them occurring in higher concentrations than the unchanged substance. The metabolites are also formed rapidly after parenteral administration, unchanged tilidine being found in higher concentrations than any of the metabolites at all times measured. Following both routes of administration, the Met. I (nortilidine), also possessing a strong analgesic activity, reaches similar plasma levels. 14C distribution studies in rats showed a relatively high concentration of the radioactivity in the excretory organs, liver and kidneys. In brain, muscle tissue and blood much lower 14C concentrations are found. The concentrations measured in the foetal organs correspond to those in the muscle tissue of the mother animals and are, therefore, much lower than in most maternal organs. The radioactivity is eliminated from the foetal organs at the same rate as from the maternal organs. Tilidine is rapidly and completely eliminated with the excrements, nearly exclusively in the form of metabolic products. Rats eliminate 50% of the given radioactivity via the kidneys. The relatively high fecal elimination is based on the biliary metabolites. Following intraduodenal and intravenous administration to rats with an interrupted enterohepatic circulation, about 80% of the dose is eliminated with bile. The biliary metabolites are partly reabsorbed. In dogs, approx. 80% of the applied radioactivity is eliminated with urine.

Administration, Oral↗
PubMed1986

Evaluation of chronic toxicity and carcinogenesis in rodents with the synthetic analgesic, tilidine fumarate.

The carcinogenic potential of tilidine fumarate, a synthetic analgesic, was studied for 80 and 104 weeks in mice and rats, respectively. Groups of 50 albino CF1 mice and 65 albino Wistar rats of each sex received tilidine fumarate-lactose blend (1:1) at doses of 100, 40 and 16 mg/kg. The control groups consisted of 100 mice and 115 rats of each sex and received the lactose vehicle only. Treatment-related non-neoplastic changes consisted of reversible, increased cytoplasmic eosinophilia of hepatocytes in high and mid dose rats corresponding to areas of proliferating smooth endoplasmic reticulum; and an increased incidence in high dose rats of proliferative or cystic lesions of the biliary epithelium. Adequate survival rates allowed stringent statistical analysis of neoplasia. Tilidine did not evoke increased tumor incidences or changes in the average latency or onset of tumors in either species. The most frequent tumors represented spontaneous neoplasia characteristic of historical background incidence in these strains. In mice, the only statistically significant (P less than 0.01) variation in tumor incidence was an increased rate of lung alveologenic adenocarcinomas in females at 100 mg/kg (24%), compared with the concurrent untreated controls (10%), but without a statistically significant difference from historical control data (27%). Female rats given 100 mg/kg showed statistically significant (P less than 0.01) decreased incidences of mammary fibroadenoma and pituitary adenoma. From these data, it was concluded that the synthetic analgesic tilidine does not possess tumorigenic potential in rodents.

Administration, Oral↗
PubMed1991

[Analgesia using oral administration of tilidine naloxone for extracorporeal shockwave lithotripsy. A double blind study].

Reduction in pain perception during ESWL due to a technical modification of the lithotriptor was expected and prompted a reassessment of anaesthesia techniques for ESWL. In this study the need for analgesic treatment had to be investigated. After satisfactory preliminary results in a previous pilot study, the value of the oral combination of the anti-anxiety drug dipotassium clorazepate on the evening before ESWL together with the analgesic tilidine-naloxone before treatment was tested in a randomised double-blind study in 120 patients. In case of intolerable pain during the treatment all patients were free to ask for additional intravenous analgesic medication (fentanyl). During ESWL, 28.3% of the tilidine-N group patients and 6.7% of the placebo group were pain-free, whereas intolerable pain was reported by 30% of the tilidine-N group and 56.7% of the placebo group. Therefore, 70% of the tilidine-N group patients were treated without any additional analgesic or sedative medication. The good experience with this oral anaesthesia approach, the lack of significant side effects and a good acceptance by the patients warrant further recommendation of this technique.

Administration, Oral↗