Short summary

The experience of pain and the efficacy of morphine are influenced by many factors such as age, sex, disease states - like morbid obesity or obstructive sleep apnea (OSA), psycho-social factors, environmental exposures, co-medication, and genetic variation. The present study will investigate the effects of obesity, OSA and genetic variation on the effects of morphine which is still the standard of care for perisurgical pain management, including bariatric surgery.

Rationale

OSA affects a large and increasing part of the population, the prevalence in North America reaching as much as 15% of the adult population. OSA is defined as repeated collapse of the upper airway causing intermittent hypoxia, during sleep. Obesity is associated with OSA, and both are related to excess mortality, hypertension, left and right ventricular dysfunction and inflammation.

The relationship between obesity and OSA is complex. While obesity is the major cause of OSA and treatment of obesity mitigates OSA severity, unmanaged OSA may further exacerbate weight gain and metabolic abnormalities.

Perioperative care of individuals with both obesity and OSA is a major concern due to the potential risk of harm. While morphine is highly effective in treating moderate to severe pain, its suppressive effects on the respiratory drive demands caution particularly in obese patients with OSA. Despite consensus among physicians specialized in perioperative care to restrict or avoid opioids in patients with OSA, the evidence of concern and guide safe opioid practice in this population is limited. The American Society of Anaesthesiologists and the Society of Anaesthesia and Sleep Medicine have issued practice guidelines for the perioperative management of patients with OSA to reduce the risk of adverse outcomes. However, the relevant recommendations are primarily based on retrospective case reports and consensus opinions. Likewise, Evidence-based Enhanced Recovery after Surgery Guidelines for Bariatric Surgery clearly recognize the benefits of minimizing perioperative opioids and strongly advocate the use of opioid sparing regimens in these patients. On the other hand, it is well established that inadequate analgesia in the perioperative period significantly increases complication rates; and more so in obese patients, in whom pain-related shallow breathing predisposes to perioperative respiratory complications such as pneumonia.

A better understanding of the pharmacokinetics and pharmacodynamics of morphine, the genes involved, and the interplay between obesity and OSA-altered morphine metabolism will provide new insight into more effective and safer treatment and allow for a more personalized morphine dosage regimen in the perioperative setting.

Description of the cohort

We will conduct an open label pharmacokinetic-pharmacodynamic comparison of 0.1mg morphine/kg lean bodyweight as an intravenous bolus in 4 different groups.

The trial is powered to detect a difference in relative morphine exposure. However, we will also investigate the efficacy of morphine on the response to experimental pain stimuli and investigate whether individual genotypes and mental states are associated with changes in morphine PK or PD in these specific patient groups.

The subjects will be recruited to the relevant group according to BMI and presence of OSA:

Group 1

Data and biological material

1) Pharmacokinetic data: Based upon collected timestamped bloodsamples concentrations of prolactine, morphine and relevant metabolites are quantified. The laboratory work will be carried out at the Department of Public Health, Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark.

2) Pharmacodynamic data: Data is generated based upon direct measurement of the nociceptive response to a tonic stimulus of: cold, heat, and pressure. Pain intensities - where applicable will be measured with a NRS from 0 (no pain) to 10(unbearable pain). Pain detection thresholds will be measured in either time (sec), temperature ( °C) or pressure (kPa).

3) Pharmacogenetic data: Based on bloodsamples obtained, subjects are categorized as W/W, v/W, or v/v for the two target genes: COMT and OPRM1. The laboratory work will be carried out at the central laboratory at the university Hospital of Southern Denmark.

4) Questionnaire data: At the pretrial visit the subjects will be asked to fill-out 5 different questionnaires via the OPEN/REDCap online entry option. This will be done on-site and one time only. All questionnaires are translated and validated in Danish.

Collaborating researchers and departments

Department of Anaesthesia and Intensive Care, University Hospital of Southern Denmark

• Morten Overgaard, Senior physician and PhD-student

Hospital Pharmacy University Hospital of Southern Denmark Department of clinical pharmacology Odense University Hospital

• Troels K Bergmann, Associate professor and Chief physician, PhD.

Department of Endocrinology University Hospital of Southern Denmark

• Claus Bogh Juhl, Professor and Chief Physician MD, PhD.

Mech-Sense and Dept. Gastroenterology & Hepatology Aalborg University Hospital

• Asbjørn Mohr Drewes, Professor, MD, PhD, DMSc