Joseph F. Foss

Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier and the potential to antagonize the peripherally mediated effects of opioids. The effectiveness of methylnaltrexone in preventing morphine‐induced changes in gastrointestinal motility and transit without affecting analgesia was evaluated in humans. Twelve healthy volunteers were given intravenous placebo, placebo plus 0.05 mg/kg morphine, or 0.45 mg/kg methylnaltrexone plus 0.05 mg/kg morphine. Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique, and analgesia was measured with use of the cold‐pressor test. Morphine significantly increased oral‐cecal transit time from 104.6 ± 31.1 minutes (mean ± SD) to 163.3 ± 39.8 minutes (p < 0.01). Methylnaltrexone prevented 97% of morphine‐induced increase in oral‐cecal transit time (106.3 ± 39.8 minutes; not significant compared with baseline; p < 0.01 compared with morphine alone). Methylnaltrexone did not affect the analgesic effect of morphine on both pain intensity and pain bothersomeness ratings. At a higher dose of morphine (0.1 mg/kg), our preliminary results indicated that 0.45 mg/kg methylnaltrexone also prevented the morphine‐induced delay in oral‐cecal transit time, with no effect on analgesia. Methylnaltrexone may be a useful adjunct to opioids for the relief of opioid‐induced constipation.

Comparing methods of clinical measurement: reporting standards for bland and altman analysis.

In this era of medical technology assessment and evidence-based medicine, evaluating new methods to measure physiologic variables is facilitated by standardization of reporting results. It has been proposed that assessing repeatability be followed by assessing agreement with an established technique. If the “limits of agreement” (mean bias ± 2SD) are not clinically important, then one could use two measurements interchangeably. Generalizability to larger populations is facilitated by reporting confidence intervals. We identified 44 studies that compared methods of clinical measurement published during 1996 to 1998 in seven anesthesia journals. Although 42 of 44 (95.4%) used the limits of agreement methodology for analysis, several inadequacies and inconsistencies in reporting the results were noted. Limits of agreement were defined a priori in 7.1%, repeatability was evaluated in 21.4%, and relationship (pattern) between difference and average was evaluated in 7.1%. Only one of the articles reported confidence intervals. A computer macro for the Minitab statistical package (State College, PA ) is described to facilitate reporting of Bland and Altman analysis with confidence intervals. We propose standardization of nomenclature in clinical measurement comparison studies. Implications: A literature review of anesthesia journals revealed several inadequacies and inconsistencies in statistical reports of results of comparison studies with regard to interchangeability of measurement methods. We encourage journal editors to evaluate submissions on this subject carefully to ensure that their readers can draw valid conclusions about the value of new technologies.

The safety and efficacy of oral methylnaltrexone in preventing morphine‐induced delay in oral‐cecal transit time

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine‐induced changes in gastroin‐testinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single‐blind oral placebo and intravenous placebo, followed by randomized, double‐blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral‐cecal transit time from 114.6 ± 37.0 minutes (mean ± SD) to 158.6 ± 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine‐induced increase in oral‐cecal transit time (110.4 ± 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single‐blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine‐induced delay in oral‐cecal transit time (p < 0.005 compared with morphine alone), and a dose‐dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long‐term opioid use.

Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis.

We studied 61 patients undergoing elective major non-cardiac surgery in a randomized, double-blind, placebo-control clinical trial to test the hypothesis that the addition of clonidine to a standardized general anesthetic could safely provide postoperative sympatholysis for patients with known or suspected coronary artery disease. Patients were allocated randomly to receive either placebo (n = 31) or clonidine (n = 30). The treatment group received premedication with a trans-dermal clonidine system (0.2 mg/d) the night prior to surgery, which was left in place for 72 h, and 0.3 mg oral clonidine 60–90 min before surgery. Clonidine reduced enflurane requirements, intraoperative tachycardia, and myocardial ischemia (1/28 clonidine patients vs 5/24 placebo, P = 0.05). However, clonidine decreased heart rates only during the first five postoperative hours; the incidence of postoperative myocardial ischemia (6/28 clonidine vs 5/26 placebo) did not differ between the two groups. Patients who experienced postoperative myocardial ischemia tended to have higher heart rates after surgery. Clonidine significantly reduced the plasma levels of epinephrine (P = 0.009) and norepinephrine (P = 0.026) measured on the first postoperative morning. There were no differences in the need for intravenous fluid therapy or antihypertensive therapy after surgery. The number of hours spent in an intensive care setting and the number of days spent in hospital were not different between the two groups. These results suggest that larger doses of clonidine should be investigated for their ability to decrease postoperative tachycardia and myocardial ischemia. (Anesth Analg 1994;79:1133–40)

A review of the potential role of methylnaltrexone in opioid bowel dysfunction.

Opioids are widely used analgesics in patients with advanced cancer. However, their effectiveness for pain relief is often limited by the most frequently occurring side effect, opioid bowel dysfunction (OBD). Because conventional laxation measures are often ineffective in treating OBD, alternative approaches need to be investigated. Opioid action on the gut appears to be mediated mainly by receptors in the gastrointestinal (GI) tract rather than by those in the central nervous system (CNS). Opioid antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the peripheral effects of opioids, but these agents can enter the CNS and reverse analgesia or cause opioid withdrawal symptoms. Methylnaltrexone (MNTX) is a novel quaternary derivative of naltrexone that does not cross the blood-brain barrier and acts as a selective peripheral opioid receptor antagonist. In normal volunteers, intravenous or oral MNTX reverses opioid-induced reduction in bowel motility without affecting analgesia. Bioavailability of MNTX is low after oral administration, and plasma levels do not correlate with its actions in the gut, suggesting a predominantly local luminal action of MNTX on the gut. In patients receiving long-term opioid therapy, MNTX administered intravenously or orally was effective in reducing the delay in oral-cecal transit and eliciting laxation responses in all subjects without causing withdrawal symptoms. MNTX is a peripherally selective opioid antagonist that may have clinical utility in managing OBD with minimal adverse effects.

Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study.

In this preliminary study, we evaluated the effects of methylnaltrexone, a peripheral opioid-receptor antagonist, on chronic opioid-induced gut motility and transit changes in four subjects with chronic methadone-induced constipation. Subjects participated in this single blind, placebo controlled study for up to 8 days. We gave placebo the first day; for the remainder of the study, we gave intravenous methylnaltrexone (0.05-0.45 mg/kg) twice daily. During the study period, we recorded oral-cecal transit time and opioid withdrawal symptoms, as well as laxation response based on the frequency and consistency of the stools. Subjects 1 and 2 who were administered methylnaltrexone 0.45 mg/kg, a dose previously administered in normal volunteers, showed immediate positive laxation. Subject 2, after positive laxation response, had severe abdominal cramping, but showed no opioid systemic signs of withdrawal. The subject was discontinued due to the cramping. In Subjects 3 and 4, we reduced the methylnaltrexone dose to 0.05-0.15 mg/kg. The latter two subjects also had an immediate laxation response during and after intravenous medication without significant side effects. The stool frequency of these four subjects increased from 1-2 times per week before the study to approximately 1.5 stool per day during the treatment period. Oral-cecal transit times of Subjects 1, 3, and 4 were reduced from 150, 150 and 150 min (after placebo) to 90, 60 and 60 min (with methylnaltrexone), respectively. Our preliminary results demonstrate that low dose intravenous methylnaltrexone effectively reversed chronic methadone-induced constipation and delay in gut transit time. Thus, we anticipate that cancer patients receiving chronic opioids may also have increased sensitivity to methylnaltrexone, and that low dose methylnaltrexone may have clinical utility in managing opioid-induced constipation in chronic-pain patients.

Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine

We investigated the effects of methylnaltrexone on morphine-induced inhibition of smooth muscle-strip contraction in isolated guinea-pig ileum and human small intestine. The longitudinal muscle-strip was immersed in a temperature-controlled (37 degrees C) bath containing a physiological solution of 95% O2 and 5% CO2 with pH 7.4. Muscle contraction was elicited by transmural electrical stimulation with a pulse duration of 0.5 ms at frequencies of 1-50 Hz for 5-10 s at 1-3-min intervals. Muscle contraction was blocked by tetrodotoxin or atropine in both preparations. When methylnaltrexone was applied to the bath, the force produced by muscle contraction was enhanced up to approximately 30%. Stimulation-elicited muscle contraction was inhibited by morphine, which decreased the force of contraction 42 +/- 9.5% (S.D.) in the human intestine preparation and 35 +/- 8.6% in guinea-pig ileum at the inhibitory concentration 70% (IC70). Methylnaltrexone effectively antagonized the effects of morphine-induced inhibition of muscle-strip contraction. In the guinea-pig ileum preparation, methylnaltrexone at 30, 100 and 300 nM blocked 25 +/- 10.5%, 74 +/- 7.2% and 89 +/- 9.9% of morphine-induced (300 nM) inhibition, respectively. In the human intestine preparation, methylnaltrexone at the same concentrations blocked 57 +/- 10.9%, 74 +/- 12.9% and 92 +/- 7.2% of morphine-induced (100 nM) inhibition, respectively. The relative ratio of methylnaltrexone to morphine was higher in human intestine (1:1) than in the guinea-pig ileum preparation (1:3). These data provide preliminary information for clinical studies to evaluate the efficacy of methylnaltrexone in preventing or reducing morphine-induced antimotility and antitransit actions.

Relative effectiveness of four preoperative tests for predicting adverse cardiac outcomes after vascular surgery : a meta-analysis

Various noninvasive tests have been proposed to stratify perioperative cardiovascular risk, including dipyridamole thallium scintigraphy (DTS), ejection fraction estimation by radionuclide ventriculography (RNV), ischemia monitoring by ambulatory electrocardiography (AECG), and dobutamine stress echocardiography (DSE). Which of these tests is most effective for predicting adverse perioperative cardiac outcome? To answer this question, and also to stimulate future studies, we evaluated 56 studies examining one or more of the four tests. We conducted meta-analysis on 20 studies that met the inclusion criteria. Outcome measures evaluated were cardiac death or myocardial infarction occurring during hospital stay or within 1 mo after surgery. Relative risk (RR), which is the probability of adverse cardiac outcome when the test is positive divided by the probability of adverse outcome when the test is negative, was used to combine evidence from different studies. An empirical Bayes procedure with a normal-normal hierarchic model was then used to obtain a meta-analytic confidence interval for the overall median of the relative risks. The between-study variance was estimated using the method of moments approach described by DerSimonian and Laird (Controlled Clin Trials 1986;7:177-88). Combined (median) RR [95% confidence interval (CI)] and the number of studies included in our meta-analysis for different evaluative tests were as follows: DTS 4.6 (2.1-10.4) (n = 6); RNV 3.7 (1.6-8.3) (n = 5); AECG 2.7 (1.4-5.1) (n = 6), and DSE 6.2 (1.7-22.8) (n = 3). We conclude that while DTS, RNV, AECG, and DSE are effective (the 95% CIs are greater than 1.0) in predicting the cardiac outcome after vascular surgery, the data are not definitive in determining the optimal test (95% CIs for RR overlap). Future studies should include DSE, as this test shows great promise for predicting adverse cardiac events after vascular surgery.

Effects of enteric‐coated methylnaltrexone in preventing opioid‐induced delay in oral‐cecal transit time

Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine‐induced delay in gastrointestinal transit time.

Effects of Low‐Dose Morphine on Gastric Emptying in Healthy Volunteers

Appropriate preoperative pain therapy for patients undergoing surgery may be withheld due to the fear that opioids will inhibit gastric emptying and increase the risk of aspiration. Previously, doses of 5 to 10 mg of morphine have been shown to delay gastric emptying time. However, the effect of lower doses of morphine on gastric emptying in humans has not been reported. In this study, the effects of intravenous morphine 0.05 mg/kg—3.5 mg for 70‐kg body weight, a dose that can cause analgesia—on gastric emptying were evaluated in a double‐blind, randomized, placebo‐controlled study in 15 healthy human volunteers using the acetaminophen test. Our data indicated that this low dose of morphine significantly prolonged the gastric emptying time. Thus, even small doses of morphine inhibit gastric emptying. This effect may be important in patients undergoing surgery, in patients receiving other oral medications after surgery in ambulatory settings, and in instances of patient‐controlled analgesia.