P-Glycoprotein/ABCB1 Might Contribute to Morphine/Cisplatin-Induced Hepatotoxicity in Rats

To investigate combined effect of the anticancer drug cisplatin (CP) and the opiate analgesic morphine (MOR) on liver, rats were administered MOR (10 mg/kg/day i.p. for 10 days), with or without CP (7.5 mg/kg i.p. once at day 5 of the study). MOR or CP alone caused deterioration of liver function tests and induced damage to histological architecture of liver. In addition, each drug alone caused hepatic oxidative stress, as evident by significant increase of malondialdehyde and nitric oxide, as well as the significant decrease in GSH, catalase and SOD compared to control. Administration of either MOR or CP also caused liver inflammation, evident by the increase in the pro-inflammatory cytokines; TNF-α and IL-6. In addition, either MOR or CP induced liver apoptosis, as shown by significant increase in expression of the pro-apoptotic marker; caspase 3 compared to control. Either MOR or CP also caused up-regulation of the efflux transporter P-glycoprotein (P-gp). Combining MOR with CP caused deterioration in all parameters tested compared to CP alone. Thus, treatment with MOR worsened CP-induced hepatotoxicity through oxidative stress, inflammation and apoptosis mechanisms. In addition, both drugs contributed to the up-regulation of P-gp, which might be a new mechanism for their hepatotoxic effects.

Mortality Risk in Chronic Kidney Disease Patients Transitioning to Dialysis: Impact of Opiate and Non-Opiate Use

Background: Population-based studies show there is a high prevalence of chronic kidney disease (CKD) patients suffering from chronic pain. While opiates are frequently prescribed in non-dialysis-dependent CKD (NDD-CKD) patients, there may be toxic accumulation of metabolites, particularly among those progressing to end-stage renal disease (ESRD). We examined the association of opiate versus other analgesic use during the pre-ESRD period with post-ESRD mortality among NDD-CKD patients transitioning to dialysis. Methods: We examined a national cohort of US Veterans with NDD-CKD who transitioned to dialysis over 2007–14. Among patients who received ≥1 prescription(s) in the Veterans Affairs (VA) Healthcare System within 1 year of transitioning to dialysis, we examined associations of pre-ESRD analgesic status, defined as opiate, gabapentin/pregabalin, other non-opiate analgesic, versus no analgesic use, with post-ESRD mortality using multivariable Cox models. Results: Among 57,764 patients who met eligibility criteria, pre-ESRD opiate and gabapentin/pregabalin use were each associated with higher post-ESRD mortality (ref: no analgesic use), whereas non-opiate analgesic use was not associated with higher mortality in expanded case-mix analyses: HRs (95% CIs) 1.07 (1.05–1.10), 1.07 (1.01–1.13), and 1.00 (0.94–1.06), respectively. In secondary analyses, increasing frequency of opiate prescriptions exceeding 1 opiate prescription in the 1-year pre-ESRD period was associated with incrementally higher post-ESRD mortality (ref: no analgesic use). Conclusions: In NDD-CKD patients transitioning to dialysis, pre-ESRD opiate and gabapentin/pregabalin use were associated with higher post-ESRD mortality, whereas non-opiate analgesic use was not associated with death. There was a graded association between increasing frequency of pre-ESRD opiate use and incrementally higher mortality.

Endomorphin analogs as potential analgesic drug

The search for novel, safe and efficient analgesics is an important but still elusive goal for medicinal chemists. Morphine and other plant-derived alkaloids have been used for centuries to alleviate strong, acute or chronic pain. However, administration of morphine is accompanied by serious side-effects, such as physical dependence, respiratory depression, constipation, decrease of blood pressure. Although in recent times a number of effective opiate derived analogs has been developed for clinical use, the ideal opiate analgesic lacking side-effects attributed to the use of morphine still remains out of reach.Opiates exert their antinociceptive activity by activation of the μ-opioid receptors. Therefore, the search for natural and synthetic ligands of this receptor has become an attractive goal. The discovery in 1997 of two endogenous ligands of the µ-opioid receptor, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), gave hope that they could be used as analgesics devoid of at least some of undesired side-effects of morphine. However, the exogenous administration of EMs as analgesics is of little therapeutic value because these peptides are quickly degraded by proteolytic enzymes and have a very limited ability to effectively penetrate the blood-brain barrier (BBB) due to their small size and hydrophilic nature. The aim of the project was the search for novel peptide analogs based on EM structure which would be stable against proteolytic enzymes and could produce strong antinociception after intravenous or oral administration.

Treatment of Severe Cancer Pain by Transdermal Fentanyl

The goal of research was to determine the frequency, intensity, time of occurrence, duration and causes of breakthrough pain (BTP) in patients whose carcinoma pain was treated by transdermal fentanyl. (TDF). A prospective study was conducted in a hospice for recumbent patients of the Centre for Palliative Care (hospice) University Clinical Centre Tuzla from October 2009 to December 2010. 33 patients in terminal stage of carcinoma, who had been treated by transdermal fentanyl due to their excruciating pain (7-10 mark on numerica! scale) with initial dosage of 25 μg as a strong opiate analgesic, were monitored within the time period of 10 days. In the statistics we used the even T - test, the Wilcox test and Mann -Whitney test. The difference was seen to be significant at p < 0,05. Treatment by transdermal fentanyl significantly reduces the intensity of strong carcinoma pain (p < 0.0001), with a frequent requirement for dose increase with bone metastasis. The intensity of BTP is higher compared to the pain experienced upon reception. The frequency and intensity of BTP are significantly reduced already in the second day of treatment by transdermal fentanyl (p = 0,0024). The BTP is most intense in patients with neck and head tumours (9,26 ± 0,66), and most frequent with abdomen and pelvic tumour. The biggest number of BTP (68.3 %) occurs within first three days of treatment. BTP most frequently occurs in the evening or at night (between 18:00 and 06:00 h in 62,2 % of the cases), with the duration of usually less than 15 minutes (65,2% of the cases). In 61,6 % cases the occurrence of BTP is related to physical activities or psychosocial incidents, while the cause is undetermined in 38,4 % of examinees.BTP is most frequent within first three days of treatment by TDF. Using the optimal dosage a good control of carcinoma pain is enabled, regardless of the occurrence of bone metastasis, while it also helps reduce the frequency and intensity of BTP.