Nightmares and hallucinations with aprepitant and opium powder: a suspected drug-drug interaction.

Polypharmacy of elderly oncology patients and fragmented medication management are well-known risk factors for drug-drug interactions (DDIs). These interactions can occur among antineoplastic, ongoing chronic treatment(s) and chemotherapy-associated treatments, like antiemetics. Clinically relevant interactions based on enzyme- or transporter-inhibition phenomena of active drugs can increase the frequency of their DDIs. We describe a strongly suspected elderly cancer patient's DDI between aprepitant and opium powder in the context of an irinotecan-based regimen manifested by nightmares and visual hallucinations. We discuss this DDI's hypothetical pharmacological mechanisms and management.

Evaluation of spinal anesthesia blockade time with 0. 5% hyperbaric bupivacaine, with or without sufentanil, in chronic opioid users: a randomized clinical trial / Avaliação do tempo de bloqueio da raquianestesia com bupivacaína a hiperbárica 0, 5%, com ou sem sufentanil, em usuários crônicos de opioides: um estudo clínico randômico

Abstract Objective: The primary outcome of this study was to evaluate the effect of adding sufentanil to hyperbaric bupivacaine on duration of sensory blockade of spinal anesthesia in chronic opioid users in comparison with non-addicts. Methods: Sixty patients scheduled for orthopedic surgery under spinal anesthesia were allocated into four groups: group 1 (no history of opium use who received intrathecal hyperbaric bupivacaine along with 1 mL saline as placebo); group 2 (no history of opium use who received intrathecal bupivacaine along with 1 mL sufentanil [5 µg]); group 3 (positive history of opium use who received intrathecal bupivacaine along with 1 mL saline as placebo) and group 4 (positive history of opium use who received intrathecal bupivacaine along with 1 mL sufentanil [5 µg]). The onset time and duration of sensory and motor blockade were measured. Results: The duration of sensory blockade in group 3 was 120 ± 23.1 min which was significantly less than other groups (G1 = 148 ± 28.7, G2 = 144 ± 26.4, G4 = 139 ± 24.7, p = 0.007). The duration of motor blockade in group 3 was 145 ± 30.0 min which was significantly less than other groups (G1 = 164 ± 36.0, G2 = 174 ± 26.8, G4 = 174 ± 24.9, p = 0.03). Conclusions: Addition of 5 µg intrathecal sufentanil to hyperbaric bupivacaine in chronic opioid users lengthened the sensory and motor duration of blockade to be equivalent to blockade measured in non-addicts.

Resumo Objetivo: Avaliar o efeito da adição de sufentanil à bupivacaína hiperbárica na duração do bloqueio sensorial da raquianestesia em usuários crônicos de opioides em comparação com não adictos. Métodos: Foram distribuídos em quatro grupos 60 pacientes agendados para cirurgia ortopédica sob raquianestesia: Grupo 1 (sem história de uso de ópio, recebeu bupivacaína hiperbárica intratecal juntamente com 1 mL de solução salina como placebo); Grupo 2 (sem história de uso de ópio, recebeu bupivacaína intratecal juntamente com 1 mL de sufentanil [5 µg]); Grupo 3 (com história de uso de ópio, recebeu bupivacaína intratecal juntamente com 1 mL de solução salina como placebo) e Grupo 4 (com história de uso de ópio, recebeu bupivacaína intratecal juntamente com 1 mL de sufentanil [5 µg]). O tempo de início e a duração dos bloqueios sensitivo e motor foram registrados. Resultados: A duração do bloqueio sensorial no Grupo 3 foi de 120 ± 23,1 min, um tempo significativamente menor do que nos outros grupos (G1 = 148 ± 28,7, G2 = 144 ± 26,4, G4 = 139 ± 24,7, p = 0,007). A duração do bloqueio motor no Grupo 3 foi de 145 ± 30,0 min, um tempo significativamente menor do que nos outros grupos (G1 = 164 ± 36.0, G2 = 174 ± 26.8, G4 = 174 ± 24,9; p = 0,03). Conclusões: A adição de 5 µg de sufentanil intratecal à bupivacaína hiperbárica em usuários crônicos de opioides aumenta a duração dos bloqueios sensorial e motor de forma equivalente ao bloqueio avaliado em não adictos.

Evaluation of spinal anesthesia blockade time with 0.5% hyperbaric bupivacaine, with or without sufentanil, in chronic opioid users: a randomized clinical trial.

OBJECTIVE: The primary outcome of this study was to evaluate the effect of adding sufentanil to hyperbaric bupivacaine on duration of sensory blockade of spinal anesthesia in chronic opioid users in comparison with non-addicts. METHODS: Sixty patients scheduled for orthopedic surgery under spinal anesthesia were allocated into four groups: group 1 (no history of opium use who received intrathecal hyperbaric bupivacaine along with 1mL saline as placebo); group 2 (no history of opium use who received intrathecal bupivacaine along with 1mL sufentanil [5µg]); group 3 (positive history of opium use who received intrathecal bupivacaine along with 1mL saline as placebo) and group 4 (positive history of opium use who received intrathecal bupivacaine along with 1mL sufentanil [5µg]). The onset time and duration of sensory and motor blockade were measured. RESULTS: The duration of sensory blockade in group 3 was 120±23.1min which was significantly less than other groups (G1=148±28.7, G2=144±26.4, G4=139±24.7, p=0.007). The duration of motor blockade in group 3 was 145±30.0min which was significantly less than other groups (G1=164±36.0, G2=174±26.8, G4=174±24.9, p=0.03). CONCLUSIONS: Addition of 5µg intrathecal sufentanil to hyperbaric bupivacaine in chronic opioid users lengthened the sensory and motor duration of blockade to be equivalent to blockade measured in non-addicts.

The effect of perioperative analgesic drugs omnopon and dexketoprofen on the functional activity of immune cells in murine model of tumor surgery.

We aimed to investigate the effect of perioperative analgesia with nonselective cyclooxygenase-2 inhibitor dexketoprofen and opioid drug omnopon on the functional activity of immune cells in tumor excision murine model. Lewis lung carcinoma cells were transplanted into hind paw of C57/black mice. On the 23th day tumor was removed. Analgesic drugs were injected 30 min before and once a day for 3 days after the surgery. Biological material was obtained a day before, 1 day and 3 days after the tumor removal. IFN-γ, IL-4, IL-10 and TGF-ß mRNA levels in splenic cells were assessed by quantitative real-time RT-PCR. Cytotoxic activity of splenocytes was estimated by flow cytometry. We found that in splenocytes of mice received opioid analgesia IL-10 mRNA level was increased 2.3 times on day one after the surgery compared to preoperative level (P < 0.05), while in dexketoprofen group this parameter did not change. IFN-γ gene expression level on day 3 after tumor removal was 40% higher in splenocytes of dexketoprofen treated mice as compared with omnopon treated animals (P < 0.05). Cytotoxic activity of splenocytes on day 3 postsurgery was (62.2 ± 2.4)% in dexketoprofen against (50.2 ± 3.3)% in omnopon group. In conclusion, perioperative analgesia with cyclooxygenase inhibitor dexketoprofen in contrast to opioid analgesia with omnopon preserves higher functional activity of murine immune cells in the experimental model of tumor surgery.

The pharmacology of medieval sedatives: the "Great Rest" of the Antidotarium Nicolai.

ETHNOPHARMACOLOGICAL RELEVANCE: Past practices of compound drugs from different plant ingredients enjoyed remarkable longevity over centuries yet are largely dismissed by modern science as subtherapeutic, lethal or fanciful. AIM OF THE STUDY: To examine the phytochemical content of a popular medieval opiate drug called the "Great Rest" and gauge the bioavailability and combined effects of its alkaloid compounds (morphine, codeine, hyoscyamine, scopolamine) on the human body according to modern pharmacokinetic and pharmacodynamic parameters established for these compounds. CALCULATIONS AND THEORY: We reviewed the most recent studies on the pharmacodynamics of morphine, codeine, hyoscyamine and scopolamine to ascertain plasma concentrations required for different physiological effects and applied these findings to dosage of the Great Rest. RESULTS: Given the proportional quantities of the alkaloid rich plants, we calculate the optimal dose of Great Rest to be 3.1±0.1-5.3±0.76 g and reveal that the lethal dose of Great Rest is double the therapeutic concentration where all three alkaloid compounds are biologically active. CONCLUSION: This study helps establish the effective dose (ED50), toxic dose (TD50) and lethal dose (LD50) rates for the ingestion of raw opium, henbane and mandrake, and describes their probable combined effects, which may be applied to similar types of pre-modern pharmaceuticals to reveal the empirical logic behind past practices.

Correlation between expression of CatSper family and sperm profiles in the adult mouse testis following Iranian Kerack abuse.

Illicit drug use can be an important cause of male infertility. The aim of this study was to investigate the effects of an Iranian illicit drug, Kerack, on sperm parameters, testicular structure and CatSper genes expression of mice. In this study, 25 male mice were divided into five groups consisting of control, sham and three experimental groups. All animal in experimental groups were addicted to Kerack for 7 days. These experimental groups include experimental I which was given Kerack at a dose of 5 mg/kg, experimental II, 35 mg/kg and experimental III, 70 mg/kg, intraperitoneally twice a day for a period of 35 days. Mice were then sacrificed and spermatozoas were removed from cauda epididymis and analyzed for count, motility, morphology (normal/abnormal) and viability. Right testes were removed, weighed and processed for light microscopic studies whereas left testes removed were subjected to total mRNA extraction for using in real-time PCR (RT-PCR). The results were analyzed by performing anova (Tukey's tests) and Pearson correlation coefficient. Sperm parameters and seminiferous epithelium thickness were decreased in experimental groups (dose-dependently) vs. sham and control groups (p < 0.05). RT-PCR results showed that CatSper 2, 3, 4 genes expressions were reduced with 35 and 70 mg/kg injected Kerack when compared with control testes (p ≤ 0.05). However, CatSper1 expression was only reduced with high dose injected Kerack (70 mg/kg) in comparison to control testes (p ≤ 0.05). This study shows the deleterious effects of Kerack used in Iran on testis structure and sperm parameters in general, and particularly sperm morphology in adult mouse. It could down-regulate the expression of CatSper genes, resulting in depression of sperm motility.

Opium consumption is negatively associated with serum prostate-specific antigen (PSA), free PSA, and percentage of free PSA levels.

Addiction to opium continues to be a major worldwide medical and social problem. The study addressing the association between opium consumption and serum prostate-specific antigen (PSA) level is lacking. We determined the effects of opium consumption on serum PSA levels in opium-addict men. Our study subjects comprised 438 opium-addict men with a mean age of 52.2 ± 6.4 years (group 1). We compared these men with 446 men who did not indicate current or past opium use (group 2). Serum total PSA (tPSA), free PSA (fPSA), % fPSA, and sex hormones were compared between the 2 groups. The mean serum tPSA level was significantly lower in group 1 (1.05 ng/mL) than in controls (1.45 ng/mL) (P = 0.001). Opium consumption was also associated with lower fPSA (P = 0.001) and % fPSA (P = 0.001). Serum free testosterone level in opium-addict patients (132.5 ± 42 pg/mL) was significantly lower than that in controls (156.2 ± 43 pg/mL) (P = 0.03). However, no significant correlation existed between tPSA and free testosterone levels (r = 0.28, 95% CI, -0.036 to 0.51, P = 0.34). Among the patients with cancer in group 1, 35% were found to have high-grade tumor (Gleason score ≥ 7) compared with 26.7% in group 2 (P = 0.02). Total PSA and fPSA were strongly correlated with duration of opium use (r = -0.06, 95% CI, -0.04 to -0.08, P = 0.0001; and r = -0.05, 95% CI, -0.03 to -0.07, P = 0.0001, respectively). Opium consumption is independently and negatively associated with serum tPSA, fPSA, and % fPSA levels.

Opium addiction increases interleukin 1 receptor antagonist (IL-1Ra) in the coronary artery disease patients.

BACKGROUND: There is evidence that opium addiction has immunosuppressant effects. Coronary artery disease (CAD) is a condition resulted from atherosclerosis which is dependent on the immune response. PURPOSE: To evaluate plasma levels of interleukin-6 and interleukin-1Ra in 30 patients with three-vessel coronary artery disease, ejection fraction of more than 35% and to evaluate their changes after prognostic treadmill test in 15 opium addicted and 15 non-addicted patients. METHODS: The participants underwent prognostic treadmill test and plasma levels of interleukin-6 (IL-6) and interleukin-1Ra (IL-1Ra) were evaluated with ELISA method before, just after and 4 hours after the test. RESULTS: IL-1Ra (2183 pg/ml) tended to decrease over time in the opium addicted group (1372 pg/ml after prognostic treadmill test and 1034 pg/ml 4 hours after that), although such decrease did not reach the statistical significance. IL-1Ra levels were significantly higher in opium addicted than in non addicted patients. Opium addiction had no significant effect on IL-6 changes. CONCLUSION: Consumption of opium in CAD patients is associated with higher IL-1Ra levels.

Effect of opium on glucose metabolism and lipid profiles in rats with streptozotocin-induced diabetes.

BACKGROUND: This experimental study was performed to determine the impact of opium use on serum lipid profile and glucose metabolism in rats with streptozotocin-induced diabetes. MATERIAL AND METHODS: To determine the effect of opium, 20 male rats were divided into control (n = 10) and opium-treated (n = 10) groups. After diabetes induction, the animals were investigated for daily glucose measurements for 35 days. Serum lipid profile and haemoglobin A1c (HbA(1c)) were assayed at the baseline (before induction of diabetes) and at 35-day follow-up. RESULTS: The glycaemia levels in the rats treated with opium were similar to the levels measured in the control rats (544.8 +/- 62.2 mg/dl v. 524.6 +/- 50.0 mg/dl, P = 0.434). In addition, there was no difference between the opium-treated rats and control rats in HbA(1c) (6.5 +/- 0.5% v. 6.6 +/- 0.2%, P = 0.714). Compared to the control rats, the serum total cholesterol, high density lipoprotein (HDL), triglyceride and lipoprotein (a) in the test animals were similar. CONCLUSION: Opium use has no significant effect on glucose metabolism and serum lipid profile in rats with induced diabetes.

Opium can differently alter blood glucose, sodium and potassium in male and female rats.

To determine the effects of opium on serum glucose, potassium and sodium in male and female Wistar rat, opium solution (60 mg/kg) injected intraperitoneally and the same volume of distilled water was used as control (7 rats in each group). Blood samples were collected at 0, 30, 60, 120, 240 and 360 minutes after injection from orbit cavity and the values of serum glucose, sodium (Na(+)) and potassium (K(+)) were measured. The data were then analyzed by the repeated measure ANOVA based on sex and case-control group. P < 0.05 considered as significant difference. Serum glucose increased significantly at 30, 60, 120 and 240 minutes after opium solution injection, in female rats compared to a control group. However, the male rats had this rise at 30, 60 and 120 minutes after opium solution injection compared to control group. While serum glucose in male rats was significantly higher than females at 30, 60 and 120 minutes, this value was higher in the female rats at 360 minutes. Therefore, serum glucose alterations following opium injection was significantly different in groups and in the sexes at different times. Sodium (Na(+)) rose at 60, 240 and 360 minutes significantly in all rats compared to control group. However, sodium alteration following opium injection was significantly different only between treated and control groups but sex-independent at all times. Potassium (K(+)) increased significantly at 60, 120, 240 and 360 minutes in male rats, compared to a control group. In female rats K(+) significantly raised at 30, 120, 240 and 360 minutes. Therefore, the alteration of K(+) in male and female rats was found time dependent and sex independent. According to our results, opium increased serum glucose in male and female rats differently, and it interferes with metabolic pathways differently on a gender dependent basis. Opium raised serum Na(+) and K(+), thus it interfere with water regulation and blood pressure via different mechanism.

Pharmacological analysis of paregoric elixir and its constituents: in vitro and in vivo studies.

Paregoric elixir is a phytomedicinal product which is used widely as an analgesic, antispasmodic and antidiarrheal agent. Here, we investigated the pharmacological actions and some of the mechanisms of action of paregoric elixir and compared its action with some of its components, the alkaloids morphine and papaverine. The paregoric elixir given orally to mice did not present relevant toxic effects, even when administered in doses up to 2000-fold higher than those used clinically. However, it showed an antinociceptive action that was more potent, but less efficacious, than morphine. In contrast to morphine, its effect was not dose-dependent and not reversed by the non-selective opioid antagonist naloxone. Moreover, paregoric elixir produced tolerance, but did not cause cross-tolerance, with the antinociceptive actions of morphine. When assessed in the gastrointestinal motility in vivo, paregoric elixir elicited graduated reduction of gastrointestinal transit. Finally, like morphine and papaverine, paregoric elixir concentration-dependently inhibited electrically-induced contraction of the guinea pig isolated ileum. In vivo and in vitro gastrointestinal actions of paregoric elixir were not reversed by naloxone. Collectively, the present findings lead us to suggest that the pharmacological actions produced by paregoric elixir are probably due to a synergic action of its constituents.

The effect of opioids on the development of postoperative intra-abdominal adhesions.

People addicted to opium rarely develop intra-abdominal adhesions after abdominal surgery. We aimed to evaluate the effect of opium or morphine on preventing postoperative adhesions in rats. Sixty-three rats were randomly divided into a control group, opium-addicted group, and morphine-addicted group in a double-blind study. Drug dependency was checked by using naloxone. Animals were then operated on and the cecum was abraded. At reoperation 3 weeks later the magnitude of adhesions was evaluated by a scoring system. There was a significant difference between the control, opium-addicted, and morphine-addicted groups with regard to the length (P < .001), thickness (P < .05), and severity of adhesions (P < .05). Opium or morphine reduces the severity of postoperative adhesions. Elucidation of the opioid receptor(s) involved in this process would enable the use of selective ligands and offer a pharmacologic strategy in preventing adhesion formation.

Toxins.

Exposures to toxins are prevalent, frequently complicate surgical emergencies, and impact critical care. A fundamental understanding of pathophysiologic principles and management strategies is essential for the anesthesiologist frequently responsible for the acute care of patients who have toxicologic exposures. Given their pervasiveness and ability to confound the clinical presentations in the perioperative or intensive care setting, substances of abuse and asphyxiants warrant particular attention and a high degree of vigilance.

Effect of rat immunization with antimorphine antibodies on morphine sensitivity and predisposition to dependence formation.

Active immunization of rats with mouse antibodies to morphine leads to the formation of antiidiotypic antibodies. This is paralleled by an increase in animal sensitivity to the analgesic and positive reinforcing effects of morphine, slower development of tolerance and formation of craving. These data indicate the possibility of active immunization against antibodies to morphine/heroin for the prevention of opium addiction relapses.

Stimulation of lipid peroxidation and impairment of glutathione-dependent defense system in Wistar rats treated with cryptopine, a rare non-narcotic opium alkaloid.

The present study was designed to evaluate the effect of repeated oral administration of cryptopine at differential dosing regimens (50, 100, 150, 200 mg/kg bwt) in vivo on lipid peroxide measures, glutathione levels (GSH) and activity of glutathione S-transferase (GST) and glutathione reductase (GR) in the liver, spleen, kidney and lung of Male Wistar rats after a 5 day treatment period. In all the tissues examined, we observed an increase in lipid peroxidation and a decline in glutathione content and activity of glutathione S-transferase and glutathione reductase in a dose-dependent manner. The decrease in GSH content did not definitively correlate with a concomitant increase of lipid peroxidation in all the tissues. Our results ensemble that the enhancement of lipid peroxidation in the tissues investigated is a consequence of depletion of glutathione to certain critical levels and impairment of the glutathione-dependent enzyme systems viz. GST and GR. Our study potentiates that decreased levels of GSH may lead to lipid peroxidation, one of the key events in cellular damage. The inhibition of GST also suggests that the detoxification of the alkaloid could be suppressed following acute exposures. Conclusively, it appears that cryptopine in vivo disturbs the cellular defense system, so that it tips in the direction of autoxidative lipid peroxidation, producing cytotoxicity.

Effect of opium smoking on concentrations of carcinoembryonic antigen and tissue polypeptide antigen.

Previous studies have related opium and its pyrolysates to the risk of developing certain cancers. The aim of this work was to evaluate the clinical usefulness of determining carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) levels in habitual opium smokers. Serum CEA concentrations were measured in 128 opium smokers and in 44 controls of cigarette only smokers and 47 normal non-smokers by an EIA-based assay. TPA levels were also determined in serum and urine of a subgroup in the study population. The results indicated that serum CEA concentrations are higher in opium smokers than in healthy tobacco smokers (p = 0.004) and non-smokers (p = 0.001). The amount of opium used correlated with the serum CEA level (r = 0.276, p < 0.0001). The mean urine and serum TPA levels of the opium-addicted population were also higher than that of the non-smoking control group, but the differences were not statistically significant. We conclude that opium smoking is associated with elevated serum CEA levels. Therefore, for management of opium users with neoplastic diseases, increased levels of serum CEA should be viewed with caution to avoid misdiagnosis.

Sphincter of Oddi dysfunction in patients addicted to opium: an unrecognized entity.

BACKGROUND: Opiate-induced sphincter of Oddi dysfunction (SOD) as a clinical entity has not been described. METHODS: Eight chronic opium addicts (all men, mean age 61.3 years, mean duration of addiction 24.75 years) presenting with pancreatobiliary pain and a dilated bile duct with or without dilated pancreatic duct on abdominal US were studied. All patients underwent ERCP and biliary sphincterotomy. In addition, pancreatic sphincterotomy was performed in 4 patients with a dilated pancreatic duct. OBSERVATIONS: At ERCP, the bile duct was dilated in 8 and pancreatic duct in 4 patients. There was delayed drainage of contrast (>45 minutes) from the bile duct in all 7 patients studied, whereas delayed drainage from the pancreatic duct (>9 minutes) was incidentally observed in 3 patients. In 6 patients followed after sphincterotomy for at least 2 years, there was marked relief of symptoms. Transabdominal US at 2 years follow-up revealed a normal bile duct in 5 and persistent albeit minimal dilatation in 1 patient. Acute pancreatitis developed in 4 patients after ERCP and sphincterotomy, which was fatal in one. No patient had any abnormality in the gallbladder on initial or follow-up transabdominal US. CONCLUSION: SOD in opium addicts is a distinct clinical entity, mainly seen in men in this population, that is characterized by a long history of opium addiction and the absence of prior cholecystectomy or associated gallstone disease. Most patients are seen with the classic clinical picture of SOD with marked long-term improvement in symptoms after endoscopic sphincterotomy.

[Immunomodulatory role of opioids in the central nervous system].

Endogenous and exogenous opioids can influence and modulate neuronal and glial cell function via an opioid receptor mediated mechanism, leading to either protection or damage of the brain. Opiates such as morphine have been postulated to promote the progression of HIV-1 and the development of secondary opportunistic infections. Kappa opioid receptor ligands, on the other hand, may play a neuroprotective role. More studies are needed to delineate how opioids exert their effects on glial cells as well as neurons with the goal of developing new therapeutic approaches for neurodegenerative disease.