Anne Brokjær

Traditional measures of normal anal sphincter function using high-resolution anorectal manometry (HRAM) in 115 healthy volunteers

High‐resolution anorectal manometry (HRAM) is a relatively new method for collection and interpretation of data relevant to sphincteric function, and for the first time allows a global appreciation of the anorectum as a functional unit. Historically, traditional anal manometry has been plagued by lack of standardization and healthy volunteer data of variable quality. The aims of this study were: (i) to obtain normative data sets for traditional measures of anorectal function using HRAM in healthy subjects and; (ii) to qualitatively describe novel physiological phenomena, which may be of future relevance when this method is applied to patients.

Electroencephalography and analgesics

To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy. We searched PubMed with MeSH terms ‘analgesics’, ‘electroencephalography’ and ‘evoked potentials’ for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified. Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N‐methyl‐D‐aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed. This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients.

Pharmacological challenges in chronic pancreatitis.

Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion. Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases food intake is more or less substituted with alcohol, tobacco and coffee. Alcohol and drug interaction are known to influence the pharmacokinetics by altering either drug absorption or by affecting liver metabolism. Since patients suffering from chronic pancreatitis experience severe pain, opioids are often prescribed as pain treatment. Opioids have intrinsic effects on gastrointestinal motility and hence can modify the absorption of other drugs taken at the same time. Furthermore, the increased fluid absorption caused by opioids will decrease water available for drug dissolution and may hereby affect absorption of the drug. As stated above many factors can influence drug absorption and metabolism in patients with chronic pancreatitis. The factors may not have clinical relevance, but may explain inter-individual variations in responses to a given drug, in patients with chronic pancreatitis.

Neurophysiology of the esophagus

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the methods and characteristics of esophageal afferents in humans; the pitfalls in characterization of mechanosensitive afferents; the sensitization of esophageal afferents in human studies; the brain source modeling in the understanding of the esophagus–brain axis; the use of evoked brain potentials in the esophagus; and measuring descending inhibition in animal and human studies.

Population pharmacokinetics of morphine and morphine-6-glucuronide following rectal administration – A dose escalation study

INTRODUCTION To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. MATERIAL AND METHODS This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. RESULTS A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. CONCLUSION A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.

Objective Markers of the analgesic response to morphine in experimental pain research

INTRODUCTION In experimental pain research the effect of opioids is normally assessed by verbal subjective response to analgesia. However, as many confounders in pain assessment exist, objective bed-side assessment of the effect is highly warranted. Therefore, we aimed to assess the effect of morphine on three objective pharmacodynamic markers (pupil diameter, prolactin concentration and resting electroencephalography (EEG)) and compare the changes from placebo with subjective analgesia on experimental muscle pain for convergent validation. METHODS Fifteen healthy male participants received placebo or 30 mg rectal morphine at two separate sessions. At baseline and several time points after drug administration, the central effects of morphine were assessed by experimental muscle pain, pupil diameter, prolactin concentration and resting EEG. RESULTS Morphine increased tolerance to muscle pain, together with significant reductions in pupil diameter and increase in prolactin concentration (all P < 0.001). Miosis was induced simultaneously with the onset of analgesic effect 30 min after dosing, while a significant increase in prolactin concentration was seen after 45 min. The change in pupil diameter was negatively correlated to change in tolerated muscle pressure (r = -0.40, P < 0.001), whereas the increase in prolactin concentration was positively correlated (r = 0.32, P = 0.001). The effect of morphine on EEG was seen as a decrease in the relative theta (4-7.5 Hz) activity (P = 0.03), but was not significant until 120 min after dosing and did not correlate to the increase in tolerated muscle pressure (r = -0.1, P=0.43). DISCUSSION Prolactin concentration and pupil diameter showed similar temporal development, had good dynamic ranges and were sensitive to morphine. Thus, both measures proved to be sensitive measures of morphine effects. EEG may give additive information on the brains response to pain, however more advanced analysis may be necessary. We therefore recommend using pupil diameter in studies where a simple and reliable objective measure of the morphine-induced central activation is needed.

The effects of morphine and methylnaltrexone on gastrointestinal pain in healthy male participants

Opioid antagonists are increasingly used to abolish the gastrointestinal side effects of opioids. However, they can potentially interfere with local analgesia exerted via opioid receptors in the gut. Thus, in the current study we aimed to explore the effect of rectal morphine before and after blocking opioid receptors outside the central nervous system with methylnaltrexone (MNTX).

Pharmacologic treatments for esophageal disorders.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role for ketamine and other alternative treatments in esophageal disorders; the use of linaclotide in the treatment of esophageal pain; the alginate test as a diagnostic criterion in gastroesophageal reflux disease (GERD); the use of baclofen in treatment of GERD; the effects of opioids on the esophagus; the use of antagonists on the receptor level in GERD; the effect of local formulation of drugs on the esophageal mucosa; and the use of electroencephalographic fingerprints to predict the effect of pharmacological treatment.

Phonocardiographic Recordings of First and Second Heart Sound in Determining the Systole/Diastole-Ratio during Exercise Test

The objective was to examine whether a microphone can be used to detect first and second heart sound during an exercise test and if these recordings can be used to calculate S/D-ratios in healthy subjects. Furthermore the objective was to describe the changes in systolic and diastolic duration under cardiac stress.

Objective methods for the assessment of the spinal and supraspinal effects of opioids

Abstract Background and purpose Opioids are potent analgesics. Opioids exert effects after interaction with opioid receptors. Opioid receptors are present in the peripheral- and central nervous system (CNS), but the analgesic effects are primarily mediated via receptors in the CNS. Objective methods for assessment of opioid effects may increase knowledge on the CNS processes responsible for analgesia. The aim of this review was to provide an overview of the most common objective methods for assessment of the spinal and supraspinal effects of opioids and discuss their advantages and limitations. Method The literature search was conducted in Pub Med (http://www.ncbi.nlm.nih.gov/pubmed) from November 2014 to June 2016, using free-text terms: “opioid”, “morphine” and “oxycodone” combined with the terms “pupillometry,” “magnetic resonance spectroscopy,” “fMRI,” “BOLD,” “PET,” “pharmaco-EEG”, “electroencephalogram”, “EEG,” “evoked potentials,” and “nociceptive reflex”. Only original articles published in English were included. Results For assessment of opioid effects at the supraspinal level, the following methods are evaluated: pupillometry, proton magnetic resonance spectroscopy, functional resonance magnetic imaging (fMRI), positron emission tomography (PET), spontaneous electroencephalogram (EEG) and evoked potentials (EPs). Pupillometry is a non-invasive tool used in research as well as in the clinical setting. Proton magnetic resonance spectroscopy has been used for the last decades and it is a non-invasive technique for measurement of in vivo brain metabolite concentrations. fMRI has been a widely used non-invasive method to estimate brain activity, where typically from the blood oxygen level-dependent (BOLD) signal. PET is a nuclear imaging technique based on tracing radio labeled molecules injected into the blood, where receptor distribution, density and activity in the brain can be visualized. Spontaneous EEG is typically quantified in frequency bands, power spectrum and spectral edge frequency. EPs are brain responses (assessed by EEG) to a predefined number of short phasic stimuli. EPs are quantified by their peak latencies and amplitudes, power spectrum, scalp topographies and brain source localization. For assessment of opioid effects at the spinal level, the following methods are evaluated: the nociceptive withdrawal reflex (NWR) and spinal EPs. The nociceptive withdrawal reflex can be recorded from all limbs, but it is standard to record the electromyography signal at the biceps femoris muscle after stimulation of the ipsilateral sural nerve; EPs can be recorded from the spinal cord and are typically recorded after stimulation of the median nerve at the wrist. Conclusion and Implications The presented methods can all be used as objective methods for assessing the centrally mediated effects of opioids. Advantages and limitations should be considered before implementation in drug development, future experimental studies as well as in clinical settings. In conclusion, pupillometry is a sensitive measurement of opioid receptor activation in the CNS and from a practical and economical perspective it may be used as a biomarker for opioid effects in the CNS. However, if more detailed information is needed on opioid effects at different levels of the CNS, then EEG, fMRI, PET and NWR have the potential to be used. Finally, it is conceivable that information from different methods should be considered together for complementary information.