Mechanisms that underlie µ-opioid receptor agonist-induced constipation: differential involvement of µ-opioid receptor sites and responsible regions.

Reducing the side effects of pain treatment is one of the most important strategies for improving the quality of life of cancer patients. However, little is known about the mechanisms that underlie these side effects, especially constipation induced by opioid receptor agonists; i.e., do they involve naloxonazine-sensitive versus -insensitive sites or central-versus-peripheral µ-opioid receptors? The present study was designed to investigate the mechanisms of µ-opioid receptor agonist-induced constipation (i.e., the inhibition of gastrointestinal transit and colonic expulsion) that are antagonized by the peripherally restricted opioid receptor antagonist naloxone methiodide and naloxonazine in mice. Naloxonazine attenuated the fentanyl-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine or oxycodone. Naloxone methiodide suppressed the oxycodone-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine, indicating that µ-opioid receptor agonists induce the inhibition of gastrointestinal transit through different mechanisms. Furthermore, we found that the route of administration (intracerebroventricular, intrathecally, and/or intraperitoneally) of naloxone methiodide differentially influenced the suppressive effect on the inhibition of colorectal transit induced by morphine, oxycodone, and fentanyl. These results suggest that morphine, oxycodone, and fentanyl induce constipation through different mechanisms (naloxonazine-sensitive versus naloxonazine-insensitive sites and central versus peripheral opioid receptors), and these findings may help us to understand the characteristics of the constipation induced by each µ-opioid receptor agonist and improve the quality of life by reducing constipation in patients being treated for pain.

Clinical Use of Oral Opioid Therapy for Dyspnea in Patients With Advanced Heart Failure　- A Single-Center Retrospective Study.

Background: For patients with advanced heart failure, palliative care, including opioids, is needed as a treatment for refractory dyspnea. However, little evidence has been reported on the efficacy and safety of opioids, and their use is not well established. Methods and Results: We have introduced a protocol for the use of opioids for dyspnea in patients with advanced heart failure admitted to Saitama Citizens Medical Center. Following this protocol, differences in clinical variables and outcome were investigated between patients in whom opioids were initiated intravenously or subcutaneously (i.v./s.c. group; n=13) and patients in whom they were initiated orally (oral group; n=18). In a comparison of baseline characteristics, significantly more patients in the oral group had a history of hospitalization for heart failure within the past year, and significantly more patients were treated with dobutamine and tolvaptan. After initiation of opioid treatment, both groups showed improvement in dyspnea; however, serial changes in vital signs were significantly greater in the i.v./s.c. group. The survival rate was significantly higher in the oral group (P<0.0001), with 33% of patients discharged alive. Conclusions: The clinical use of oral opioids using a single-center protocol is reported, suggesting that oral opioids may be practical and effective for dyspnea in patients with advanced heart failure.

Use of oral hydromorphone in a patient with stage D heart failure.

Patients with advanced heart failure often experience dyspnea, fatigue, edema, and appetite loss. If these symptoms are refractory to treatment, palliative care via a team approach is necessary. We describe a patient with stage D heart failure whose dyspnea and overall condition improved with comprehensive medical treatments including conventional medications for heart failure, continuous infusions of catecholamine and diuretic, and oral hydromorphone. A 67-year-old man with a 12-year history of dilated cardiomyopathy was admitted to our hospital due to exacerbation of heart failure. Despite continuous infusion of catecholamine and diuretic, his dyspnea and liver and renal function continued to worsen. Oral hydromorphone was administered to relieve his refractory dyspnea, which also improved his conditions, continuous infusion of the catecholamine and diuretic could withdraw. Oral low-dose hydromorphone used in the present case might be a helpful agent for treating dyspnea in stage D heart failure patients with renal dysfunction.

[Survey on patients' satisfaction with opioid rescue guidance by pharmacists].

To examine the influence of drug therapy guidance by pharmacists on the use of a rescue dose (RD) for opioid analgesics (opioids) and pain as well as drug therapy guidance in cancer pain treatment, we conducted a patient satisfaction survey. The subjects were 56 cancer patients undergoing opioid therapy in hospitals belonging to the Symptom Control Research Group (SCORE-G). The survey period was 2 months (from November 1 until December 31, 2006). Drug therapy guidance regarding the use of RD was performed twice in each patient to evaluate the patients' satisfaction. RD was prescribed in 87.8% of the patients in the first guidance and in 80.5% in the second guidance periods. The proportion of patients who used RD significantly increased from 63.8% to 87.5%. Five items significantly improved in the second guidance period: "marked analgesic effects," "satisfaction with current treatment," "correct understanding of RD usage," "relief through RD," and "appropriate use of RD." On comprehensive evaluation following the second round of guidance, 81% of the patients reported overall satisfaction, and 78% reported the usefulness of guidance in pain treatment. These results suggest that positive guidance by pharmacists increases patients' satisfaction. In providing guidance, it was important to confirm the characteristics and side effects of opioids as well as the necessity of RD to patients accurately and repeatedly.

Implication of mGlu5 receptor in the enhancement of morphine-induced hyperlocomotion under chronic treatment with zolpidem.

Long-term exposure to zolpidem induces drug dependence, and it is well known that the balance between the GABAergic and glutamatergic systems plays a critical role in maintaining the neuronal network. In the present study, we investigated the interaction between GABAA receptor α1 subunit and mGlu5 receptor in the limbic forebrain including the N.Acc. after treatment with zolpidem for 7 days. mGlu5 receptor protein levels were significantly increased after treatment with zolpidem for 7 days, and this change was accompanied by the up-regulation of phospholipase Cß1 and calcium/calmodulin-dependent protein kinase IIα, which are downstream of mGlu5 receptor in the limbic forebrain. To confirm that mGlu5 receptor is directly involved in dopamine-related behavior in mice following chronic treatment with zolpidem, we measured morphine-induced hyperlocomotion after chronic treatment with zolpidem in the presence or absence of an mGlu5 receptor antagonist. Although chronic treatment with zolpidem significantly enhanced morphine-induced hyperlocomotion, this enhancement of morphine-induced hyperlocomotion was suppressed by treating it with the mGlu5 receptor antagonist MPEP. These results suggest that chronic treatment with zolpidem caused neural plasticity in response to activation of the mesolimbic dopaminergic system accompanied by an increase in mGlu5 receptor.