Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

BACKGROUND: Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. AIM: To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. METHODS: Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. RESULTS: Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. CONCLUSIONS: This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting.

Incompatible kidney donor candidates' willingness to participate in donor-exchange and non-directed donation.

Although paired donation, list donation and non-directed donation allow more recipients to receive living donor transplants, policy makers do not know how willing incompatible potential donors are to participate. We surveyed 174 potential donors ruled out for ABO-incompatibility or positive cross-match about their participation willingness. They were more willing to participate in paired donation as compared to list donation where the recipient receives the next deceased donor kidney (63.8% vs. 37.9%, p < 0.001) or non-directed donation (63.8% vs. 12.1%, p < 0.001). Their list donation willingness was greater when their intended recipients moved to the top versus the top 20% of the waiting list (37.9% vs. 19.0%, p < 0.001). Multivariate logistic regression modeling revealed that potential donors' empathy, education level, relationship with their intended recipient and the length of time their intended recipient was on dialysis also affected willingness. For paired donation, close family members of their intended recipient (odds ratio (OR) = 3.01, confidence intervals (CI) = 1.29, 7.02), with high levels of empathy (OR = 2.68, CI = 1.16, 6.21) and less than a college education (OR = 2.67, CI = 1.08, 6.61) were more willing to participate compared to other donors. Extrapolating these levels of willingness nationally, a 1-11% increase in living donation rates yearly (84-711 more transplants) may be possible if donor-exchange programs were available nationwide.

Sex differences in (-)-pentazocine antinociception: comparison to morphine and spiradoline in four rat strains using a thermal nociceptive assay.

The present study examined the influence of sex on the antinociceptive effects of (-)-pentazocine, morphine and spiradoline in four rat strains, using a warm-water (50, 52 and 55 degrees C) tail-withdrawal procedure. In F344, Lewis, Sprague-Dawley (SD) and Wistar rats, baseline latencies decreased with increases in water temperature, and at each water temperature latencies were longer in males than in their female counterparts. Morphine and spiradoline produced maximal or near maximal antinociceptive effects in males and females of each strain. Whereas morphine was generally more potent in males, sex differences were not consistently observed with spiradoline. In contrast, there were marked sex differences with (-)-pentazocine, and in each strain (-)-pentazocine was more potent and produced a greater maximal effect in males. The magnitude of the sex differences varied markedly across strains, with (-)-pentazocine being 2.5-fold more potent in males of the F344 strain, but 11-fold more potent in males of the Wistar strain. When collapsed across nociceptive stimulus intensities, sex differences were largest in the Wistar and Lewis strains and smallest in the SD and F344 strains. The present findings indicate that there are marked sex differences in (-)-pentazocine antinociception, and that the magnitude of this effect is genotype dependent.

Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids.

RATIONALE: Recent studies indicate that mu opioids are generally more potent and effective as antinociceptive agents in male than female rodents. OBJECTIVES: To evaluate the influence of sex on the development of tolerance to the antinociceptive effects of morphine and cross-tolerance to the lower efficacy mu opioids buprenorphine and dezocine in F344 and Lewis rats. METHODS: Using a warm-water tail-withdrawal procedure, the antinociceptive effects of morphine, buprenorphine and dezocine were determined before and during chronic morphine (5, 10 and 20 mg/kg, b.i.d., for 7 and 14 days) administration. RESULTS: Under acute conditions, morphine was more potent in males and during chronic morphine administration tolerance development was generally greater in males. As males were more sensitive to the acute effects of morphine, the functional chronic morphine dose (i.e., chronic morphine dose/acute morphine ED50) administered to males was larger than in females. Analyses of the relationship between the functional chronic morphine dose and tolerance indicated that morphine tolerance development was comparable in males and females. Under acute conditions, buprenorphine and dezocine were more potent and effective in males. During chronic morphine administration, cross-tolerance was conferred to these opioids as evidenced by rightward, and in some cases downward, shifts in their dose-effect curves. Decreases in the maximal effects produced by buprenorphine and dezocine were more frequently observed in females. CONCLUSIONS: That comparable levels of morphine tolerance were obtained in males and females when the functional chronic morphine dose was taken into consideration suggests that the mechanism underlying tolerance is not sex-dependent. Sex differences in the effectiveness of buprenorphine and dezocine when administered acutely and during chronic morphine administration further suggest that these opioids have lower efficacy at the mu opioid receptor in females.

Cocaine-like discriminative stimulus effects and [3H]dopamine uptake inhibition produced by selected partial opioid agonists.

Partial opioid agonists can produce their actions at opioid as well as some non-opioid sites. Although the receptor systems underlying these non-opioid effects are not completely clear, recent studies indicate the possible involvement of activity at the dopamine uptake site. One purpose of the present investigation was to examine the ability of selected partial opioid agonists (dezocine, meperidine and [+]-propoxyphene) with non-opioid actions to produce cocaine-like stimulus effects. Because non-opioid effects can be apparent under conditions in which opioid-mediated effects are blocked or at doses that markedly decrease responding, these opioids were also examined in combination with the opioid antagonist naltrexone. A second purpose was to determine the ability of these opioids to inhibit [3H]dopamine uptake in rat caudate putamen. Cocaine and the direct-acting dopamine agonist (-)-quinpirole, but not (+)-propoxyphene, butorphanol, morphine, U50,488 and pentobarbital, substituted completely for the cocaine stimulus. Dezocine substituted for the cocaine stimulus in the majority of the rats tested only when administered in combination with naltrexone. Meperidine also substituted for the cocaine stimulus in the majority of the rats tested, although this pattern of substitution was not consistently altered by naltrexone. Dezocine and meperidine inhibited [3H]dopamine uptake in a manner consistent with that produced by cocaine. The results suggest that dezocine and meperidine can produce cocaine-like stimulus effects and that these effects are likely mediated by activity at the dopamine uptake site.

Modulatory effects of dopamine D3/2 agonists on kappa opioid-induced antinociception and diuresis in the rat.

RATIONALE: The dopamine (DA) D3/2 agonist 7-OH-DPAT has been shown to attenuate the behavioral effects of the mu agonist morphine as well as the development of morphine tolerance. OBJECTIVES: To evaluate the effects of DA D3/2 agonists [7-OH-DPAT, (+)-PD128,907, quinelorane, (-)-quinpirole], a D1 agonist (SKF38393), a D1 antagonist [(+)-SCH23390], a DA antagonist (spiperone), and an indirect DA agonist (cocaine) on the antinociceptive effects of kappa agonists (spiradoline, U69,593, bremazocine) as well as the effects of D3/2 agonists on the diuretic effects of spiradoline. METHODS: Antinociception was determined using a warm water (50-55 degrees C) tail-withdrawal procedure and urine output was collected over a 2-h interval. RESULTS: The antinociceptive effects produced by the kappa agonists varied with the intensity of the nociceptive stimulus (water), as maximal or near maximal effects were obtained with spiradoline at 55 degrees C, U69,593 at 52 degrees C, and bremazocine at 50 degrees C water. 7-OH-DPAT produced a dose-dependent attenuation of the antinociceptive effects of spiradoline, U69,593, and bremazocine. Spiperone completely reversed the effects of 7-OH-DPAT on spiradoline antinociception. (+)-PD128,907 and quinelorane, but not (-)-quinpirole or the other DAergic agents examined, attenuated the antinociceptive effects of spiradoline in a dose- and time-dependent manner. The diuretic effects of spiradoline were attenuated by 7-OH-DPAT, (+)-PD128,907, quinelorane, and (-)-quinpirole, and this attenuation was reversed by spiperone. CONCLUSIONS: The present study demonstrated that some D3/2 agonists can modulate both the antinociceptive and diuretic effects of kappa agonists. These modulatory actions are similar to those obtained against the effects of mu agonists.

The dopamine D3/2 agonist 7-OH-DPAT attenuates the development of morphine tolerance but not physical dependence in rats.

RATIONALE: The dopamine (DA) D3/2 agonist 7-OH-DPAT attenuates the acute antinociceptive, discriminative stimulus, locomotor activating, and reinforcing effects of mu agonists (for example, morphine). OBJECTIVES: To examine the ability of 7-OH-DPAT to modulate the development of morphine tolerance and physical dependence in the rat. METHODS: Morphine antinociception was assessed using a warm water tail-withdrawal procedure before and following chronic treatment with morphine (15 mg/kg)/7-OH-DPAT (0.3-3.0 mg/kg). Physical dependence was assessed following naloxone-precipitated (1.0 mg/kg) withdrawal in rats treated chronically with morphine (15 and 7.5 mg/kg)/7-OH-DPAT (1.0-10 mg/kg). RESULTS: 7-OH-DPAT attenuated the antinociceptive effects of morphine in both morphine naive and tolerant rats. Additionally, morphine tolerance was attenuated by the coadministration of 7-OH-DPAT in a dose- and time-dependent manner. The magnitude of the attenuation obtained when morphine and 7-OH-DPAT were administered at the same time was similar to that obtained when administration of these drugs was separated by 6 h, indicating that 7-OH-DPAT did not alter morphine pharmacokinetics. In rats rendered tolerant to morphine, the subsequent coadministration of morphine/7-OH-DPAT failed to reverse morphine tolerance, but did attenuate its further development. The level of physical dependence (number and frequency of withdrawal signs) was greater in rats treated with 15 than 7.5 mg/kg morphine. Under both treatment conditions, physical dependence was not altered by 7-OH-DPAT. In morphine-dependent (15 mg/kg) rats, 7-OH-DPAT (3.0 and 10 mg/kg) failed to precipitate withdrawal. CONCLUSION: The D3/2 agonist 7-OH-DPAT can attenuate the antinociceptive effects of morphine in both acute and chronic preparations as well as the development of morphine tolerance. 7-OH-DPAT does not, however, alter morphine physical dependence.

Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the mu opioid receptor.

RATIONALE: Recent studies indicate that morphine is more potent as an antinociceptive agent in male than female rodents and monkeys. OBJECTIVES: To evaluate the influence of sex, nociceptive stimulus intensity and an opioid's relative efficacy on opioid-induced antinociception in rat strains (F344 and Lewis) that display differential sensitivity to morphine antinociception. METHODS: Antinociceptive testing was conducted using a rat warm-water (50-56 degrees C) tail-withdrawal procedure. Dose-response and time-course determinations were performed with various opioids. RESULTS: Across the nociceptive stimulus intensities tested, the high-efficacy mu opioids morphine, etorphine, and levorphanol were equally effective in males and females, but on average 2.5-fold more potent in males. At moderate stimulus intensities, the low-efficacy mu opioid buprenorphine was approximately 0.4-fold more potent in males, and at higher stimulus intensities more potent and effective (greater maximal effect) in males. At low stimulus intensities, the low-efficacy mu opioid dezocine and the mu/kappa opioid butorphanol were greater than 8.9-fold more potent in males, and at moderate stimulus intensities were more potent and effective in males. At a low stimulus intensity, the mu/kappa opioid nalbuphine was more potent and effective in males. At stimulus intensities in which buprenorphine, dezocine, butorphanol, and nalbuphine produced maximal effects in males but not females, these opioids antagonized the effects of morphine in females. Genotype-related differences were noted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between F344 and Lewis females. CONCLUSIONS: That sex differences in the potency and effectiveness of opioids increased with decreases in the opioid's relative efficacy and with increases in the nociceptive stimulus intensity suggests that the relative efficacy of mu opioids as antinociceptive agents is greater in male than female rats.

Antinociceptive effects of opioids following acute and chronic administration of butorphanol: influence of stimulus intensity and relative efficacy at the mu receptor.

RATIONALE: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. OBJECTIVE: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. METHODS: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50 degrees C (low temperature) and 55 degrees C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (-)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. RESULTS: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (-)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (-)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. CONCLUSIONS: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone.