Ola Dale

• Norwegian University of Science and Technology

Aims To measure all‐cause mortality risk after an ambulance‐attended non‐fatal opioid overdose and associations with number of days following attendance, and individual and clinical characteristics. Design A prospective observational study. Setting Oslo, Norway. Participants Patients treated with naloxone for opioid overdose by Oslo Emergency Se...

The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in pa...

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of th...

Introduction: The administration of the opioid antagonist naloxone in the community is a measure to prevent death from opioid overdose. Approved nasal naloxone sprays deliver initial doses of 0.9 to 8 mg. The level of the initial community dose is controversial, as the scientific base is weak. Areas covered: In this review knowledge of the pharm...

Aims: To measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre-hospital environment. Design: Randomised, controlled, double-dummy, blinded, non-inferiority trial, and conducted at two centres. Setting: Participants were included by ambulance staff in Oslo and Trondheim, Norway, and treated at the place where t...

Purpose Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. Methods We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or wit...

The purpose was to present a total description, distribution, and ranking of chronic pain conditions in the general population. This was based on structured clinical examinations of a random sample from a population-based survey (HUNT3) with a calculated oversampling of participants with chronic pain. Supplemented with access to hospital reports, t...

Introduction Intranasal (IN) naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared with injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers,...

Background: Amidst the ongoing opioid crisis there are debates regarding the optimal route of administration and dosages of naloxone. This applies both for lay people administration and emergency medical services, and in the development of new naloxone products. We examined the characteristics of naloxone administration, including predictors of dos...

Introduction: Amidst the ongoing opioid crisis there are debates regarding the optimal route of administration and dosages of naloxone. This applies both for lay people administration and emergency medical services, and in the development of new naloxone products. We examined the characteristics of naloxone administration, including predictors of d...

Background: Bystander administration with naloxone nasal spray can prevent deaths from opioid overdose. To achieve optimal nasal absorption of naloxone, the spray must be administered at low volume with high concentration of the drug. The study aimed to investigate the bioavailability and absorption pattern for a new naloxone nasal spray. Materia...

Naloxone is a well-established essential medicine for the treatment of life-threatening heroin/opioid overdose in emergency medicine. Over two decades, the concept of ‘take-home naloxone’ has evolved, comprising pre-provision of an emergency supply to laypersons likely to witness an opioid overdose (e.g. peers and family members of people who use o...

Background and aims: Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular (i.m.) naloxo...

Purpose Pharmacodynamic studies of naloxone require opioid agonism. Steady state condition may be achieved by remifentanil TCI (target controlled infusion). Opioid agonism can be measured by pupillometry. It is not known whether there are arteriovenous concentration differences for naloxone. The aim was thus to further develop a model for studying...

Purpose: This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg. Methods: Two-way crossover in 12 healthy volunteers receiving naloxone while receivin...

Background: Although the United States and numerous other countries are amidst an opioid overdose crisis, access to safe injection facilities remains limited. Methods: We used prospective data from ambulance journals in Oslo, Norway to describe the patterns, severity, and outcomes of opioid overdoses, and compared these characteristics among variou...

Background Epidemiological studies of chronic pain frequently report high prevalence estimates. However, there is little information about the development and natural course of chronic pain. Methods We followed a random sample of participants from a population‐based study (HUNT 3) with annual measures over four years. Results Among those without...

Issues: Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and c...

Purpose: Nasal naloxone is wanted for bystander administration in opioid overdose and as a needle-free alternative for emergency medical personnel. Epidemiologic studies have indicated a therapeutic effect of bystander administration of low-concentration/high-volume formulations. The objective for this study was to describe the nasal pharmacokinet...

The practice of extensive and systematic use of off-label administration of nasal naloxone has been going on for years. Stake-holders should have facilitated development of sustainable non-injectables having consideration for the four basic principles of medical ethics: beneficence, maleficence, justice and autonomy, as well as medication and medic...

Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to d...

Although persons with chronic pain are frequent users of the health care system, they report poor satisfaction with health care services. Participants with persistent opioid use in Nord-Trøndelag Health Study (HUNT)3 report severe pain in spite of treatment. The aim of the study was to test the hypothesis that subjects with persistent opioid use ha...

There are concerns about potential increasing use of over-the-counter (OTC) analgesics. The aims of this study were to examine 1) the prevalence of self-reported use of OTC analgesics; 2) the prevalence of combining prescription analgesics drugs with OTC analgesics and 3) whether lifestyle factors such as physical activity were associated with prev...

To the Editor: In their video, Ortega et al. (March 25 issue)¹ highlight important aspects of the intranasal administration of naloxone. We feel that the use of unapproved, dilute formulations of naloxone should be discouraged in both laypeople and professional practitioners. Ortega et al. favor the intravenous route of access if easily obtained, c...

Background The clearance of sedatives and analgesics may be reduced by therapeutic hypothermia. However, little is known about the concentrations of such drugs during rewarming. The aim of this study was to describe the serum concentrations of sedatives and analgesics during rewarming from therapeutic hypothermia. Methods Blood samples were collect...

In previous studies on prescription patterns of opioids accurate data on pain are missing, and previous epidemiological studies of pain lack accurate data on opioid use. The present linkage study which investigates the relationship between pain and opioid use is based on accurate individual data from the complete national Norwegian prescription dat...

This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl. CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (...

Background The reported prevalence of chronic pain ranges from 11% to 64%, and although consistently high, the calculated economic burden estimates also vary widely between studies. There is no standard way of classifying chronic pain. We have repeated measurements of pain in a longitudinal population study to improve validity ofthe case ascertainm...

The use of nitrous oxide in modern anaesthesia has been questioned. We surveyed changes in use of nitrous oxide in Scandinavia and its justifications during the last two decades. All 191 departments of anaesthesia in the Scandinavian countries were requested by email to answer an electronic survey in SurveyMonkey. One hundred and twenty-five (64%)...

Population-based studies have reported conflicting findings on the relationship between physical activity and pain, and most studies reporting a relationship are cross sectional. Temporal relationships are therefore difficult to infer and associations may be subject to confounding from a variety of other factors. The aim of the current study was to...

Objective: The objective of the present study was to determine whether genetic variability in UDP-glucuronosyltransferase (UGT) genes, together with clinical factors, contribute to variability in morphine glucuronide (M6G and M3G) to morphine serum concentration ratios in patients with advanced cancer receiving chronic morphine therapy. Materials...

CONTEXT: Corticosteroids are frequently used in cancer patients for their analgesic properties. The evidence for analgesic effects of corticosteroids in palliative care has not been established. OBJECTIVES: To assess the evidence for the use of corticosteroids in cancer pain management. METHODS: A systematic literature search was performed. The art...

Therapeutic hypothermia may induce pharmacokinetic changes that may affect the level of sedation. We have compared the disposition of morphine, midazolam, fentanyl, and propofol in therapeutic hypothermia with normothermia in man. METHODS: Fourteen patients treated with therapeutic hypothermia (TH) following cardiac arrest (33-34 °C) were compared...

Pharmacokinetic (PK) and pharmacodynamic (PD) data were available from a study of a nasal delivery system for the opioid analgesic fentanyl, together with data on the kinetics of fentanyl in arterial blood in man, and in the lung and brain of sheep. Our aim was to reconcile these data using a physiologically-based population recirculatory PK-PD mod...

Reports regarding the ability of the anesthetic drug ketamine to attenuate the inflammatory response to surgery are conflicting. In this systematic review we examined the effect of perioperative ketamine administration on postoperative inflammation as assessed by concentrations of the biomarker interleukin-6 (IL-6). This study was based on a system...

Methods for classifying chronic pain in population studies are highly variable, and prevalence estimates ranges from 11% to 64%. Limited knowledge about the persistence of pain and the validity of recall questions defining chronic pain make findings difficult to interpret and compare. The primary aim of the current study was to characterize the per...

To compare two protocols for sedation and analgesia during therapeutic hypothermia: midazolam and fentanyl versus propofol and remifentanil. The primary outcome was the time from discontinuation of infusions to extubation or decision not to extubate (offset time). Secondary outcomes were blood pressure, heart rate, use of vasopressors and inotropic...

Our aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days. Fo...

Here we provide the updated version of the guidelines of the European Association for Palliative Care (EAPC) on the use of opioids for the treatment of cancer pain. The update was undertaken by the European Palliative Care Research Collaborative. Previous EAPC guidelines were reviewed and compared with other currently available guidelines, and cons...

The relationship between oxycodone and metabolite serum concentrations and clinical effects has not previously been investigated in cancer pain patients. The aim of this study was to assess whether there is a relationship between oxycodone concentrations and pain intensity, cognitive functioning, nausea, or tiredness in cancer patients. Also, oxymo...

Aim: Defined daily dose (DDD) is the most common measurement unit used in drug consumption studies. The DDD for opioids may not reflect their relative clinical potencies. The aim of this study was to explore whether opioid consumption data may be interpreted differently when adding oral morphine equivalent (OMEQ) dose as a measurement unit compared...

Opioid switching is a treatment strategy in cancer patients with unacceptable pain and/or adverse effects (AEs). We investigated whether patients switched to methadone by the stop and go (SAG) strategy have lower pain intensity (PI) than the patients switched over three days (3DS), and whether the SAG strategy is as safe as the 3DS strategy. In thi...

Opioids are recommended by the World Health Organization for moderate to severe cancer pain. Oxycodone is one of the most commonly used opioids and is metabolized in the liver by CYP3A4 and CYP2D6 enzymes. The aim of this cross-sectional study was to assess the relationship between oxycodone pharmacokinetics, pharmacodynamics and the CYP2D6 genotyp...

According to a Cochrane review on opioid switching, sound evidence on the practice of substituting one strong opioid with another to improve pain control and reduce adverse effects was lacking in 2004. A systematic search strategy was developed to include studies after 2004, with adult cancer patients switching between strong opioids and reporting...

The evidence for an association between leisure-time physical activity and prevalence of pain is insufficient. This study investigated associations between frequency, duration, and intensity of recreational exercise and chronic pain in a cross-sectional survey of the adult population of a Norwegian county (the Nord-Trøndelag Health Study; HUNT 3)....

Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population u...

The platelet inhibitor clopidogrel is administered to patients treated with therapeutic hypothermia following cardiac arrest due to acute coronary syndromes. Interactions with proton pump inhibitors and genetics are factors with a known potential to attenuate the platelet inhibition of clopidogrel. In patients treated with therapeutic hypothermia,...

Health-related quality of life (HRQoL) has been characterized as the ultimate goal for health interventions such as physical activity (PA). We assessed how frequency, duration, and intensity of PA were related to HRQoL in younger (<65 yr) and older (≥65 yr) females and males. This population-based cross-sectional study explored associations between...

Oxycodone is widely used for the treatment of cancer pain, but little is known of its pharmacokinetics in cancer pain patients. The aim of this study was to explore the relationships between ordinary patient characteristics and serum concentrations of oxycodone and the ratios noroxycodone or oxymorphone/oxycodone in cancer patients. Four hundred an...

Intranasal opioid formulations have been investigated as a new route of administration that may offer a rapid onset and short duration of analgesic effect. These characteristics are required for the optimal treatment of certain types of pain, e.g., breakthrough cancer pain, such that the temporal characteristics of the analgesic effect mirror those...

The opioids morphine and oxycodone are potent analgesics that are available as extended-release and immediate-release tablets. Indications are the same for both; i.e. severe acute pain and chronic pain (non-malignant or malignant). Few clinical studies have compared morphine and oxycodone directly. There is no evidence to support that one is superi...

Opioids are recommended for control of moderate-to-severe, chronic, malignant, and nonmalignant pain. A controlled-release formulation of the opioid oxymorphone has recently been launched. The aim of this review was to assess the effectiveness of oxymorphone as an analgesic in chronic pain. A systematic search for published studies of oral oxymorph...

Pain is a major symptom in 70% of patients with advanced cancer. We analyzed data of 251 cancer patients (142 men and 109 women aged 29-89 years, Karnofsky status 10-90, 65.7+/-13.9) for association of a reduced-function haplotype in the GTP cyclohydrolase 1 (GCH1) gene with cancer pain therapy. The interval between cancer diagnosis and opioid ther...

BACKGROUND AND AIM OF INVESTIGATION: Intramuscular (IM) administration has been considered to be safer than intravenous (IV) for opioids on wards, but a comparative knowledge of patient safety and analgesic potency following a single dose of IV and IM administration is lacking. This study was carried out to compare patient safety and analgesic effi...

The European Association for Palliative Care guidelines for treatment of cancer pain recommend a double dose (DD) of immediate-release morphine at bedtime instead of single doses (SD) repeated every four hours throughout the night. A previous open controlled study reported more side effects after DD than after SD. The present study was a randomized...

We have investigated the arterio-venous difference in the pharmacokinetics of 50 microg fentanyl during the first hour following nasal administration and documented its tolerability in opioid-naïve middle-aged to elderly patients. Twelve male patients (range in age 47-84 years) scheduled for transurethral resection of the prostate gland received a...

This topical review addresses methadone's pharmacology, its application in malignant and non-malignant pain conditions, practical issues related to methadone for the treatment of pain and its influence on QTc time. Relevant papers were identified in PubMed and EMBASE. Methadone is advocated by experts as a second line opioid when first line opioids...

During cardiopulmonary bypass (CPB), hypoperfusion and reperfusion may cause oxidative stress and lipid peroxidation that generates ethane. The aim of this pilot study was to assess the feasibility of frequent sampling of exhaled ethane during cardiac surgery. After approval of the Research Ethics Committee, 10 patients undergoing combined aortic v...

To compare the time course of morphine and metabolite concentrations in serum and cerebrospinal fluid (CSF) after intravenous and intramuscular administration after surgery. This was a randomized double-blind, double-dummy study in patients who had undergone hip replacement surgery. Morphine (M, 10 mg) was administered intravenously (IV) or intramu...

Methadone is used as an alternative opioid when first line opioids fail to provide adequate pain control. Highly variable morphine:methadone dose ratios make switching challenging and little is known about the pharmacokinetics of long lasting methadone treatment for pain. Twelve patients treated with morphine for chronic non-malignant pain were swi...

Therapeutic hypothermia is used primarily to limit the ischemic damage following cardiac arrest. The main goal for the treatment is the brain. Therapeutic hypothermia is resource demanding and is therefore done in intensive care units with strong competence in treatment and monitoring of critically ill patients. This review focuses mainly on physio...

Bidirectional nasal drug delivery is a new administration principle with improved deposition pattern that may increase nasal drug uptake. Twelve healthy subjects were included in this open, non-randomized 3-way crossover study: midazolam (3.4 mg) intravenously (1 mg mL (-1)), or nasally by bidirectional or traditional spray (2 x100 microL of a 17 m...

Case reports and retrospective studies suggest that methadone causes an increase in QTc (QT time corrected for heart rate) time and risk of torsades de pointes arrhythmia. No prospective studies in pain patients have been conducted, and data on whether a methadone-induced increase in QTc time persists during long-term treatment have not been report...

The object of this study was to compare the effect of chitosans of different number-average molecular weights (MWs) and degrees of acetylation (F(A)) on transepithelial transport of morphine in Caco-2 cells. Caco-2 monolayers on polycarbonate (PC) membranes (0.5 cm(2)) were incubated with morphine (10 microM) or mannitol (55 microM) for 180 min. Sa...

Patients with unstable coronary disease have changes in the hemostatic system. These patients are often treated with low molecular weight heparin. In patients who are accepted for coronary artery bypass grafting, treatment with low molecular weight heparin is frequently continued until surgery. We hypothesized that in coronary artery bypass graftin...

Reexploration for hemorrhage after cardiac surgery is associated with increased morbidity and mortality. Elderly cardiac surgical patients have an increased risk of excessive bleeding and reexploration. In the present study we investigated the perioperative hemostatic function in elderly patients compared with younger patients undergoing coronary a...

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Twelve patients with poor pain control or unacceptable side effects during treatment with morphine were switched to methadone and followed for nine months in this open prospective study. Primary outcomes were patient preference for opioid and pain control while physical, cognitive and role functioning were secondary outcomes. The morphine dose was...

The individual variability of opioid pharmacology suggests that the patients' genetic disposition influences the response to opioids. Given the complexity of morphine pharmacology, variability may be caused by several genes. Data suggest that variability in genes encoding the enzyme metabolising morphine (UGT2B7 gene), mu-opioid receptors (OPRM1 ge...

Previous studies have shown conflicting results regarding the effect of autotransfusion of mediastinal shed blood after coronary artery bypass grafting (CABG) on the serum levels of myocardial band (MB) isoenzymes of creatine kinase (CK-MB) and cardiac troponins. The effect of autotransfusion on serum levels of human heart fatty acid binding protei...

The individual variability of opioid pharmacology suggests that the patients' genetic disposition influences the response to opioids. Given the complexity of morphine pharmacology, variability may be caused by several genes. We review data which shows that variability in genes coding the enzyme metabolizing morphine (UGT2B7 gene), mu-opioid recepto...

Catechol-O-methyltransferase (COMT) inactivates dopamine, epinephrine and norepinephrine in the nervous system. A common functional polymorphism (Val158Met) leads to a three- to-four-fold variation in the COMT enzyme activity, the Met form displaying lower enzymatic activity. The Val158Met polymorphism affects pain perception, and subjects with the...