Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl > alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio.
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PMID:Comparative clinical pharmacology of short-acting mu opioids in drug abusers. 866 83

Neuropathic pain has been suggested to be resistant to treatment with opiates. Such perceived lack of opioid responsiveness may be due to the dose-range over which specific opioid compounds have been studied as well as the efficacy of these compounds. Dihydroetorphine is a novel opiate that demonstrates significantly greater analgesic potency compared to morphine, and which also demonstrates diminished capacity for producing physical dependence in laboratory animals. The present study compared the intravenous (i.v.) efficacy, potency and duration of action of dihydroetorphine, fentanyl, heroin and morphine in producing anti-allodynic actions in a rat model of neuropathic pain (ligation of the L5/L6 nerve roots). All compounds produced significant anti-allodynic activity with dihydroetorphine being the most potent (A50 of 0.2 microg kg(-1), i.v.). Morphine was approximately 7440 times less potent than dihydroetorphine while heroin and fentanyl were approximately 163.5 and 6.9 times less potent in producing anti-allodynic actions. Dihydroetorphine also showed a maximal effect at 0.6 microg kg(-1) in all animals tested, while 100 microg kg(-1) was required for heroin to produce a maximal effect. Fentanyl and morphine did not elicit a maximum anti-allodynic response (74 and 76% maximum possible effect (%MPE), respectively). As expected, fentanyl showed a relatively brief duration of action (approximately 20 min at the highest tested dose), while dihydroetorphine and morphine demonstrated anti-allodynic actions for up to 45 min. Heroin had the longest duration of action, producing significant anti-allodynic effects for up to 90 min. These data show that dihydroetorphine and heroin produce potent and long-lasting anti-allodynic actions in this model. Additionally, in contrast to morphine and fentanyl, both dihydroetorphine and heroin were able to achieve a maximal response. The remarkable potency, maximal efficacy and duration of action of these compounds, particularly dihydroetorphine, suggests that these compounds may warrant further examination as potential therapeutic treatments for neuropathic pain states.
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PMID:Anti-allodynic actions of intravenous opioids in the nerve injured rat: potential utility of heroin and dihydroetorphine against neuropathic pain. 978 70

Iatrogenic tolerance and physical dependence have been documented in human neonates and infants infused with fentanyl or morphine i.v. to maintain continuous analgesia and sedation during extracorporeal membrane oxygenation (ECMO) and mechanical ventilation for the treatment of life-threatening pulmonary diseases. Using postnatal d 17 infant rats, the hypothesis was tested that sedative tolerance accompanies tolerance to fentanyl analgesia in the tail-flick test. Postnatal d 14 infant rats remained naive or received osmotic minipumps infusing saline (1 microL/h) or fentanyl citrate (60 microg x kg(-1) h(-1)). Seventy-two hours later, fentanyl's antinociceptive potency was reduced 3.1-fold in fentanyl-infused rats. Conscious sedation and deep sedation were examined with the cliff-avoidance and the righting-reflex procedures, respectively. Fentanyl-infused infants were tolerant to both the conscious and deep sedative effects of fentanyl. Another hypothesis tested was that very high receptor intrinsic activity opioids are less likely to produce tolerance, or to be cross-tolerant to other opioids. Dihydroetorphine is 5,000 to 10,000 times more potent than morphine. However, fentanyl-infused infant rats were cross-tolerant to the analgesic and sedative effects of dihydroetorphine. Interestingly, dihydroetorphine's analgesic efficacy was significantly reduced to a maximum analgesic efficacy (Emax) value of 40% maximum possible effect (MPE). Another concern was whether fentanyl tolerance would generalize to another class of sedatives, the benzodiazepines. This was especially relevant considering the widespread use of benzodiazepines like midazolam in ECMO and mechanical ventilation. Midazolam elicited no analgesia in the tail-flick test. Furthermore, fentanyl-tolerant rats were not cross-tolerant to the conscious or deep sedative effects of midazolam.
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PMID:Sedative tolerance accompanies tolerance to the analgesic effects of fentanyl in infant rats. 1083 24

Fentanyl has been shown to be a potent analgesic with a lower propensity to produce tolerance and physical dependence in the clinical setting. The present study was designed to investigate the mechanisms of fentanyl- or morphine-induced antinociception at both supraspinal and spinal sites. In the mouse tail-flick test, the antinociceptive effects induced by both fentanyl and morphine were blocked by either the mu1-opioid receptor antagonist naloxonazine or the mu1/mu2-opioid receptor antagonist beta-funaltrexamine (beta-FNA) after s.c., i.c.v. or i.t. injection. In contrast, both fentanyl and morphine given i.c.v. or i.t. failed to produce antinociception in mu1-deficient CXBK mice. These findings indicate that like morphine, the antinociception induced by fentanyl may be mediated predominantly through mu1-opioid receptors at both supraspinal and spinal sites in mice. We also determined the ED50 values for s.c.-, i.c.v.- and i.t.-administered fentanyl- or morphine-induced antinociception in mice. The ED50 values for s.c.-, i.c.v.- and i.t.-administered fentanyl-induced antinociception were 73.7, 18.5 and 1.2-fold lower than that of morphine, respectively. The present data clearly suggest the usefulness of peripheral treatment with fentanyl for the control of pain.
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PMID:Possible involvement of mu1-opioid receptors in the fentanyl- or morphine-induced antinociception at supraspinal and spinal sites. 1215 Jan 99

The utility of morphine for the treatment of chronic pain is hindered by the development of tolerance. Fentanyl has been shown to be a potent analgesic with a lower propensity to produce tolerance and physical dependence in the clinical setting. Previous finding has shown that fentanyl induces mu opioid receptor gene expression in PC-12 cells (Brain Res 859:217-223, 2000). In this report, we aim to identify the molecular mechanism of mu-opioid receptor (MOR) gene regulation by fentanyl. We demonstrated that the 4.7-kilobase MOR promoter could be induced by fentanyl in PC-12 cells, and we defined a partial cAMP response element (CRE) located at -106/-111 in 5'-untranslated region of the MOR gene. In electrophoretic mobility shift assay, cAMP response element-binding protein (CREB) was found in the protein-DNA complex formed on the CRE box. CREB was phosphorylated after forskolin induction, and both CREB and CREB-binding protein (CBP) binding to the endogenous MOR promoter was increased by forskolin in chromatin immunoprecipitation assay. The functional role of CREB in the induction of MOR gene was further elucidated by an experiment in which a dominant-negative mutant CREB, CREB-S133A, abolished the forskolin-mediated MOR induction. Moreover, we found that this CRE box is conserved in mouse, rat, and human MOR gene, implying physiological relevance in different species. Collectively, this study demonstrated that fentanyl-triggered MOR gene induction was mediated by the sequential activation of CREB and the binding of CREB and CBP to MOR promoter, thus provides direct evidence for lower propensity of fentanyl to produce tolerance.
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PMID:Transcriptional regulation of mu opioid receptor gene by cAMP pathway. 1464 71