Tilidine - an overview | ScienceDirect Topics (2022)

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J.K. Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM, in Meyler's Side Effects of Drugs, 2016


The effect of voriconazole 400mg on the pharmacokinetics and analgesic effects of tilidine 100mg have been investigated in 16 healthy volunteers in a placebo-controlled study [111]. Voriconazole caused a 20-fold increase in the serum AUC of tilidine and the AUC of nortilidine increased 2.5-fold; the serum concentrations of bisnortilidine were much reduced. The onset of analgesic activity occurred later with voriconazole, concordant with the prolonged tmax of nortilidine from 0.78 to 2.5 hours, due to additional inhibition of nortilidine metabolism to bisnortilidine. After voriconazole the AUC under the pain withdrawal versus time curve was reduced compared, mainly because of a shorter withdrawal time. Thus, voriconazole significantly inhibited the sequential metabolism of tilidine, with increased exposure to the active metabolite, nortilidine. Furthermore, the incidence of adverse events was almost doubled after voriconazole and tilidine.

A worldwide yearly survey of new data in adverse drug reactions and interactions

A.H. Ghodse, S. Galea, in Side Effects of Drugs Annual, 2012

Tilidine [SEDA-33, 223]

Drug–drug interactions Voriconazole The interaction of tilidine with voriconazole, a potent inhibitor of CYP2C19 and CYP3A4, has been investigated in 16 healthy volunteers [182c]. Voriconazole inhibited the metabolism of tilidine, increased the concentration of its active metabolite nortilidine, and increased the incidence of adverse reactions. The most frequent adverse reactions included mild dizziness (94%), nausea (75%), headache (56%), visual disturbances and photophobia (50%), vomiting (38%), and itching (31%). Tilidine alone was not associated with visual disturbances. The interaction almost doubled the incidence of adverse reactions (from 40 to 79 events). There were no serious adverse reactions.

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Opioids : Clinical Use

Stephen B. McMahon FMedSci, FSB, in Wall & Melzack's Textbook of Pain, 2013

Barriers to Clinical use of Opioids

Major barriers to opioid use continue to exist in many situations and many countries, although major progress has been made, primarily because of the relentless efforts of theWorld Health Organization (WHO) (1986, 1996). The major barriers are insufficient knowledge, inappropriate attitudes, regulatory and organizational issues, and economics (Anderson 2010). “Opiophobia” (Morgan 1985, Zenz and Willweber-Strumpf 1993), defined as “customary underutilisation of opioid analgesics based on irrational and undocumented fear,” is a behavior that is modeled, reinforced, and perpetuated at all levels of the health and legal system, beginning with the attitudes of government bodies, continuing with physicians, nurses, pharmacists, and allied health professionals, and finishing with the patients, their relatives, and the general population (Zenz and Willweber-Strumpf 1993).

The insufficient and inappropriate knowledge about the pharmacology of opioids is largely a result of the “dual pharmacology” of opioids, that is, the significant differences between opioid laboratory pharmacology (in experimental animals, healthy volunteers, addicts) and opioid clinical pharmacology (in pain patients) (McQuay 1999). These differences are primarily explained by the absence or presence of pain and lead to inappropriate fear of opioid-related adverse effects such as respiratory depression, tolerance, physical dependence, and psychological addiction. As an example, deficits in knowledge about the difference between physical dependence and psychological addiction influence drug dispensing by pharmacists (Joranson and Gilson 2001).

Even with good factual knowledge, a positive intention can lead to a negative outcome driven by attitude. A study revealed an overall positive attitude of nurses toward the use of opioids, with 94% approving the use of opioids for patient comfort (Edwards etal 2001). The same study also stated that one-third of the nurses would administer the least possible opioid prescribed and nearly half of them would encourage the patient to have a non-opioid instead of an opioid.

Patients’ fear is a factor that is less often addressed. In a study of 80 patients with chronic pain, 32% expressed concerns about addiction, 16% about withdrawal, and 12% of the stigma of opioid use (Casarett etal 2002). Fear of tolerance, more than of addiction, was considered a factor in increased pain intensity reporting (Paice etal 1998). In addition, patients’ attitudes toward pain and suffering, knowledge about resources available for pain relief, and intention to use them can be quite variable (Fins 1997).

Fear of regulatory scrutiny, added to the lack of detailed knowledge about often complex laws governing the use of opioids, continues to perpetuate underprescription (Rothstein etal 1998). Laws and regulations governing the production and distribution of opioids have been established by international treaties and national and state laws and regulations. The Single Convention on Narcotic Drugs, adopted in 1961 and amended in 1972, is the international treaty that regulates the production, manufacture, import, export, and distribution of “narcotics” for medical use (International Narcotics Control Board [INCB] 1972). Although its emphasis is on combating illicit drug trafficking and it is not intended to reduce medical use of opioids, perception and practical implications have created an invisible barrier.

A worldwide yearly survey of new data in adverse drug reactions

A.H. Ghodse, S. Galea, in Side Effects of Drugs Annual, 2011


Tilidine is a low to medium potency analgesic. It undergoes rapid first-pass metabolism to its active metabolites, nortilidine and bisnortilidine. Its analgesic activity is largely exerted through nortilidine which is a potent agonist at μ opioid receptors.

Drug–drug interactions


In 16 volunteers, there was an interaction of tilidine with voriconazole, resulting in a 20-fold increase in tilidine exposure [172c]. Voriconazole inhibits the metabolism of tilidine, resulting in increased exposure to the active metabolite nortilidine. This interaction was associated with an increased incidence of adverse drug reactions (from 40 to 79). The adverse reactions included dizziness (94%), nausea (75%), headache (56%), visual disturbances/photophobia (50%), vomiting (38%), and pruritus (31%).

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In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016


The effect of voriconazole 400mg on the pharmacokinetics and analgesic effects of tilidine 100mg have been investigated in 16 healthy volunteers in a placebo-controlled study [111]. Voriconazole caused a 20-fold increase in the serum AUC of tilidine and the AUC of nortilidine increased 2.5-fold; the serum concentrations of bisnortilidine were much reduced. The onset of analgesic activity occurred later with voriconazole, concordant with the prolonged tmax of nortilidine from 0.78 to 2.5 hours, due to additional inhibition of nortilidine metabolism to bisnortilidine. After voriconazole the AUC under the pain withdrawal versus time curve was reduced compared, mainly because of a shorter withdrawal time. Thus, voriconazole significantly inhibited the sequential metabolism of tilidine, with increased exposure to the active metabolite, nortilidine. Furthermore, the incidence of adverse events was almost doubled after voriconazole and tilidine.

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Respiratory Tract

Peter Greaves MBCHB FRCPATH, in Histopathology of Preclinical Toxicity Studies (Third edition), 2007

Safety assessment

The high incidence and the inherent variability of pulmonary adenomas and adenocarcinomas in conventional mouse carcinogenicity bioassays sometimes gives rise to statistically significant differences between control and treatment groups. There is considerable risk in over-interpretation of such group differences in conventional mouse bioassays. In the analysis of group differences, consideration needs to be given to tissue sampling procedure, age-standardization, historical control incidence, effects on food intake as well as the results of mutagenicity studies and carcinogenicity bioassays in other rodent species. Indeed, a considerable number of widely employed therapeutic agents of different classes have produced an increase in benign or malignant pulmonary tumours in carcinogenicity studies performed in mice without this proving of any significance to humans. Davies and Monro counted at least 17 drugs of this type in the 1994 Physicians' Desk Reference of the United States.234

For instance, in a carcinogenicity bioassay in which CF1 mice were treated for 80 weeks with the synthetic analgesic tilidine fumarate, a statistically significant difference (p > 0.01) was reported in the incidence of lung adenocarcinomas between the top dose female group (24%) and concurrent controls (10%).235 It was argued that group differences did not indicate tumorigenic potential of tilidine fumarate on the basis that the incidence in the high dose group was within the historical control range (27%) and that there was no tumorigenic effect in a parallel 104 week rat carcinogenicity study.

A more difficult evaluation concerned metronidazole, a nitroimidazole which is an important therapeutic agent active against anaerobic organisms and trichomonas species. Administration of this compound led to an increased incidence of pulmonary adenomas and carcinomas in three separate mouse carcinogenicity bioassays.236,237 The analysis of these findings was somewhat complicated by evidence that metronidazole shows mutagenic activity in bacterial assays using some strains of Salmonella typhimurium. It was argued that the risk to human patients was slight because the increase in prevalence in pulmonary tumours was likely to be a result of changes in nutritional status of the mice through the effect of metronidazole on gut flora, as similar differences could occur between ad libitum fed mice and those fed the same but restricted diet.237 It was also postulated that the positive findings in bacterial mutagenesis assays were an inherent part of the antibacterial activity of metronidazole as a result of nitroreduction that does not occur in normal mammalian tissues. This conclusion was supported by negative effects in hamster carcinogenicity bioassays as well as lack of excess cancer risk in women followed up for 10 years or more.237

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The Genetics of Drugs of Abuse Metabolism

Markus R. Meyer, in Biological Research on Addiction, 2013


As described above, orally administered drugs enter the central blood circulation after enteral absorption and passing the liver. Compounds can be metabolized in various extend by enzymes located in the enterocytes and/or hepatocytes. This part of metabolism is named “first-pass metabolism.” In turn, the extent of first-pass metabolism has an important impact on the bioavailability of a compound. Besides the liver and gut, metabolism can take place in other organs containing metabolizing enzymes, particularly those with direct contact with the environment like lungs. The metabolizing enzymes include mainly cytochrome P450 (CYP) oxygenases, UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione S-transferases (GSHs). The metabolism mediated by these enzymes can be divided into phase I (functionalization) and phase II (conjugation) reactions. The modified and thus more water-soluble xenobiotics can then be excreted. Usually, end products of metabolism are pharmacologically inactive, whereas some drugs (so-called prodrugs) need to be bioactivated to acting metabolites (e.g. tilidine to nortilidine). However, such bioactivation can also lead to toxic products.

For enzymes involved in these steps, genetic polymorphisms are known. For example, CYP genes are polymorphic and may be responsible for interindividual differences in drug responses. The reasons for these differences can first be found in the genotype of the individual. Genes for certain enzyme systems may be absent or overexpressed. The most important phase I enzyme family that is polymorphically expressed is the family of CYP isoenzymes. About 10% of the Caucasian and <1% of the Japanese population are slow metabolizers regarding CYP2D6 and are therefore called poor metabolizers (PMs). The activity of the enzyme is markedly reduced due to various mutations or complete loss of the corresponding gene. The rest of the population belongs to the type of rapid metabolizers (also called extensive metabolizers (EMs)) or to the type of the so-called ultrarapid metabolizers (UMs). Overexpression (gene duplication) can be observed among parts of the African and oriental population. Many drugs such as tricyclic antidepressants, neuroleptics, and opioids are metabolized by CYP2D6. Variations in CYP1A2 can affect the metabolism of caffeine, leading to fast, medium, and slow turnover. CYP2B6 is missing in 3–4% of the Caucasian population being, for instance, important in the metabolism of methadone. CYP2B6 is one of the most polymorphic CYP genes in humans, with over 100 described single-nucleotide polymorphisms, numerous complex haplotypes, and distinct ethnic frequencies. A CYP2C9 deficit is present in 1–3% of the Caucasian population, affecting in general the turnover of nonsteroidal anti-inflammatory drugs such as diclofenac and ibuprofen. About 3–6% of the Caucasian and 15–20% of the Asian population are individuals with inactive enzyme CYP2C19, which metabolizes many drugs such as the antidepressant clomipramine and the thienopyridine class antiplatelet agent clopidogrel. Concerning CYP3A4, only a few mutations are known. Besides CYPs, most of the other phase I metabolizing enzymes are expressed polymorphically, for example the monamine oxidase A (MAO) and tryptophane hydroxylase. Their activity can have an important impact on pharmacotherapy with antidepressants. Also, the induction of enzymes, particularly CYP enzymes, can have an important impact on the pharmacotherapy or on the interaction with drugs of abuse. A series of xenobiotics such as carbamazepine, cyclosporine, and tamoxifen have been identified that lead to increased expression of enzymes of the CYP3A family. They can bind to the pregnane X receptor (PXR), which is the transcription factor for the regulation of the CYP3A gene expression. Such an enzyme induction leads to an increased metabolism of the administered substance due to upregulated enzyme expression. Not only synthetics can influence the gene expression, but natural products such as hyperforin, a natural ingredient of St. John’s wort, too can have an extremely high affinity to PXR. Further important CYP inducers are, for instance, omeprazole for CYP1A2, ethanol and isoniazid for CYP2E1, and rifampicin and several barbiturates for CYP2C9.

In addition, changes in enzyme activity must be taken into consideration resulting from interactions with other drugs of abuse or therapeutically administered drugs. Such interactions can also occur with nonpharmacologically active compounds such as food ingredients. Cigarette smoke and charbroiled meat, for instance, are able to induce the activity of CYP1A2.

Besides the phase I enzyme family, the phase II enzymes such as the uridine diphosphate glucuronosyltransferase UGT1A1, the thiopurin methyltransferases, the GSHs, GSTM1, and GSTT1, and the arylamine N-acetyl transferases (NAT) also can show polymorphisms. In humans, the two NAT genes are known to encode NAT1 or NAT2. For both enzymes, a polymorphism is known that leads to the phenotypes of slow and fast acetylation. The frequency of individual phenotypes has strong ethnic differences. Among the Caucasians, 40–70% are slow metabolizers, whereas among Japanese or Chinese, only 10–20% are poor metabolizers.

For assessment or prediction of all these variations, it is important to know whether an individual has a reduced or an increased turnover in these steps due to genetic variations or due to drug/food interactions by enzyme inhibition or induction. It is of great importance to know which enzymes are involved in the particular metabolic steps of all used drugs and/or drugs of abuse to predict such variations. Furthermore, pharmacogenomic variations may influence kinetic calculations.

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The role of human drug self-administration procedures in the development of medications

S.D. Comer, ... S.L. Walsh, in Drug and Alcohol Dependence, 2008

The approach of adding an antagonist to an agonist as an abuse-deterrent has been used for several medications (e.g., pentazocine, tilidine, methadone and buprenorphine) and has been studied using the standard approach of measuring subjective responses, as well as self-administration procedures. For example, Suboxone® (sublingual tablets containing buprenorphine combined with naloxone) was primarily developed because of concerns about parenteral abuse of Subutex® (sublingual tablets containing buprenorphine). Given the low sublingual bioavailability, but high parenteral bioavailability of naloxone, this approach is primarily intended to deter intravenous and potentially intranasal abuse of buprenorphine. Weinhold et al. (1992) compared the effects of intramuscular administration of buprenorphine alone and buprenorphine in combination with naloxone in non-opioid-dependent individuals who abuse heroin. The buprenorphine and naloxone combination reduced subjective and physiological effects, relative to buprenorphine alone, suggesting that the combination would have lower abuse liability. A subsequent study conducted in recently detoxified, non-opioid-dependent heroin abusers also showed that the subjective effects of parenteral (in this case, intravenous) buprenorphine and buprenorphine in combination with naloxone differed significantly (Comer and Collins, 2002). However, the reinforcing effects, as assessed by self-administration, of buprenorphine alone compared to the combination did not differ in this study because both were able to alleviate some lingering, mild opioid withdrawal symptoms. Overall, these studies suggest that buprenorphine in combination with naloxone may have reduced abuse potential compared to buprenorphine alone in non-dependent heroin abusers in the absence of withdrawal symptomatology.

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Endogenous opiates and behavior: 2005

Richard J. Bodnar, Gad E. Klein, in Peptides, 2006

Heterodimerization of NOR and MOR impairs the ability of DAMGO to inhibit adenylate cyclase and stimulate MAPK phosphorylation [1254]. Whereas DAMGO stimulates ERK through calmodulin and PKC-epsilon, the kappa agonist, U69593, acts through phosphoinosositide 3-kinase, PKC-zeta and Ca2+ mobilization [79]. Both single and repeated nalmefene treatments increased occupancy of MOR that could persist for over 1 day [534]. Human neuroblastoma cells synthesize morphine through mechanisms involving (S)-[1,3,4-2H3]norlaudanosoline and [7-2H]salutaridinol [113]. Morphine and diamorphine were preserved in an intrasite gel mixture with no clear degradation over 28 days [1355]. Arachidonic acid inhibits ligand binding to MOR and muscarinic, but not nicotinic Ach receptors [117]. Tilidine and nortilidine inhibit cAMP accumulation in CHO-K1 cells expressing MOR, and the agonist effects of DAMGO and nortilidine were reversed by naloxone with very similar IC-50 values. Tilidine and nortilidine had no agonist effects on DOR, KOR or NOR [1183]. A SAR and biological evaluation were conducted on novel trans-3,4-dimethyl-4-arylpiperidine derivatives as opioid antagonists [287]. Protein regulators of G-protein signaling accelerate the hydrolysis of GalphaGTP to terminate signaling at effectors and thereby restrict the amplitude of opioid effects. The efficient deactivation of GalphazGTP subunits by RGS-Rz proteins prevents mu receptor desensitization [397]. Whereas acute buprenorphine down-regulated MOR, the addition of clorazepate reduced the level of MOR down-regulation in the hippocampus, hypothalamus and thalamus [271]. The 26-base pair-polypyrimidine stretch of the MOR proximal promoter interacts with four members of the poly(C)binding protein family [596], and regulates MOR gene expression [609]. A major species of mouse MOR mRNA was identified for its promoter-dependent functional polyadenylation signal [1301]. MOR binding is observed in the central part of the rat sinoatrial node [1138]. MOR activation phosphorylates the STAT5 signal transducers and activators of transcription factors that are also activated by G-protein-coupled receptors [784]. Morphine increased central serine racemase and d-amino acid oxidase mRNA [1327]. NPFF and MOR couple to the carboxy termini of the alpha-ii, alpha-i2, alpha-i3 and alpha-o subunits of the G-protein receptors, whereas preincubation with a NPFF analogue reduces the Delt-1-induced increases of carbachol-induced release of Ca2+ from SH-SY5Y neuroblastoma cells [815]. Coupling a benzoyl group to 6-alpha-naloxamine greatly enhanced its MOR affinity [1317]. Compounds with 4,5-oxygen bridge-opened 6-cyano-substituted N-methylmorphinans were synthesized and were potent mu agonists [1120]. Chronic morphine treatment produced up-regulation of Galpha-i2 and cytoskeletal proteins in MOR-expressing Chinese hamster ovary cells [1312]. MOR KO mice had lower NPY mRNA levels in C/P and NAC and lower SP mRNA levels in the ventromedial hypothalamus [1325]. Repeated administration of a tropane analogue, WF-23, failed to alter mu opioid-stimulated [35S]GTPgammaS binding, but reduced this response elicited by agonists at D2, 5-HT-1A and alpha-2-adrenergic receptors in the stiratum, hippocampus and amygdala respectively [869]. Ramelteon binds to melatonin MT1 and MT2 receptors, but has no affinity for opioid, DA or benzodiazepine receptors [576].

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