Tilidine

Tilidine is a synthetic analgesic drug belonging to the group of opioid analgesics. The pharmaceutical is used for the treatment of severe and very severe pain. Tilidine itself is a prodrug with a weak opioid effect. Tilidine is first metabolized in the liver to the active metabolites nortilidine and bisnortilidine. Nortilidine is responsible for the main effect. In the WHO pain management schedule, tilidine is classified as a weak opioid analgesic (level II) for moderate-severe pain. Thus, compared to morphine, tilidine is about 5 times weaker.

Tilidine is metabolised in the liver to the actual active substance nortilidine. Nortilidine attaches to opiate receptors in the central and peripheral nervous system and suppresses pain perception and transmission.

After oral administration, tilidine is rapidly absorbed. It is subject to a pronounced first-pass effect. The conversion of tilidine to the more potent active metabolite nortilidine occurs with the involvement of CYP3A4 and CYP2C19. Inhibition of these enzymes may thus alter the efficacy and tolerability profile of tilidine. The analgesic effect occurs after 10-15 minutes. After oral administration of 100 mg of tilidine (plus 8 mg of naloxone), the peak effect is reached in approximately 25-50 minutes. The mean half-life is about 3.5 hours. The duration of action is reported to be 4-6 hours. Tilidine is 90% metabolized and renally eliminated. The remainder appears in the feces.

Depending on the degree of restriction, in hepatic impairment the maximum plasma concentration of nortilidine is lower than in hepatic healthy subjects and the half-life is prolonged. In cases of severe hepatic impairment, therapy is questionable.

Tilidine should not be given during pregnancy or should only be given after a strict risk-benefit assessment, as no or only limited experience is available. Tilidine passes into breast milk. Therefore, breastfeeding should be discontinued if treatment is absolutely necessary during lactation.

Data on the effects of tilidine on human fertility are not available.

The required dose is determined individually: up to 6 x daily 50-100 mg of tilidine hydrochloride in drop form or 2-3 x daily one sustained-release tablet containing 50-200 mg of tilidine hydrochloride. In paediatrics, the guideline value of 0.5 mg/kgKG applies as a single dose.

Very common: nausea and vomiting at the beginning of treatment (with further treatment these occur only frequently to occasionally or rarely).

Frequent: dizziness, drowsiness, fatigue, headache, nervousness, diarrhoea, abdominal pain, increased sweating.

Occasional: Somnolence.

Side effects of unknown frequency: hallucinations, confusional state, euphoric mood, tremor, hyperreflexia, clonus, indigestion, respiratory depression.

Concurrent administration of serotonergic medicines may increase the risk of serotonin syndrome, a potentially life-threatening condition. These include, for example

selective serotonin reuptake inhibitors (SSRIs)

serotonin-norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants

Triptans

5-HT3 receptor antagonists

drugs that affect the serotonin neurotransmitter system (e.g. mirtazapine, trazodone, tramadol)

Monoamine oxidase (MAO) inhibitors.

Under the influence of alcohol or in combination with tranquilizers, there is a mutual potentiation and prolongation of central nervous system effects.

CYP3A4 and/or CYP2C19 inhibitors (e.g., voriconazole) may result in a significant increase in tilidine exposure and increase in nortilidine concentrations. Enhancement of the analgesic effect is possible with concomitant risk of respiratory depression. In the case of continuous anticoagulation with phenprocoumon, a decrease in the Quick value is possible (controls of the prothrombin time).

Monopreparations: Valoron® (CH)Combination preparations: Valoron N ^® (D), Valtran® (B), numerous generics (D)

Tilidine was patented by Gödecke in 1967 and introduced to the market as Valoron® in 1970. To reduce the risk of abuse, tilidine is mostly available as a fixed combination with naloxone.

Tilidine is listed in the BtMG under Schedule III (narcotics that can be marketed and prescribed). To counteract potential abuse, tilidine is used in combination with the opioid receptor antagonist naloxone. Naloxone cancels the central depressant and peripheral effects of tilidine. The mixing ratio with naloxone is such that the analgesic effect of tilidine is not impaired. Combination preparations with naloxone are not subject to the BtMG only if they are in solid preparations with delayed release of the active substance.

1. Graefe KH et al. Nociceptive System. In: Graefe KH et al (Eds) Pharmacology and Toxicology. Georg Thieme Publisher Stuttgart p. 228-239