Naloxone Reversal of Morphine- and Morphine-6-Glucuronide-induced Respiratory Depression in Healthy Volunteers

Olofsen, Erik; Dorp, Eveline van; Teppema, Luc J.; Aarts, Leon; Smith, T.; Dahan, Albert; Sarton, Elise

doi:10.1097/aln.0b013e3181d5e29d

Cited by 66 publications

(51 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…M6G's dissociation kinetics are much slower than those of morphine. Hence, when naloxone was administered to surmount respiratory depression by each of these agonists, its effect on morphine was rapid and maximally effective, whereas the effect on M6G was slow and partial and could not be improved by increasing the dose of naloxone (Olofsen et al, 2010). Hence, in the same way kinetic differences underlie differential blockade of in vivo morphine and M6G responses, they could also support differential sensitivity of DPDPE and deltorphin II-preferring sites for the different antagonists.…”

Section: B Putative Mechanisms Of D-opioid Receptor Pharmacological mentioning

confidence: 85%

See 1 more Smart Citation

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

View full text Add to dashboard Cite

Section: B Putative Mechanisms Of D-opioid Receptor Pharmacological mentioning

confidence: 85%

“…One of such examples was recently reported in human subjects for naloxone blockade of the respiratory depression induced by morphine and morphine-6-glucoronide (M6G) (Olofsen et al, 2010). M6G's dissociation kinetics are much slower than those of morphine.…”

Section: B Putative Mechanisms Of D-opioid Receptor Pharmacological mentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

View full text Add to dashboard Cite

“…These non-opioid adjuvants are different from naloxone, which is an opioid receptor antagonist and restores breathing by its antagonist effect at the MOR [1,17]. Naloxone is used to treat OIRD; however, owing to its mechanistic pathways, it will reduce or abolish opioid analgesia as well.…”

Section: The Ventilatory Control System and Opioid-induced Respiratormentioning

confidence: 99%

“…Naloxone is used to treat OIRD; however, owing to its mechanistic pathways, it will reduce or abolish opioid analgesia as well. An additional drawback of naloxone is its short half-life (its elimination half-life is 15 to 20 minutes [17]). Therefore, a single naloxone bolus injection may be followed by “re-narcotization” (that is, the return of OIRD following a [short] period of adequate ventilation, potentially putting the patient's life further at risk, especially when long-acting or high-dose opioids are the cause of OIRD).…”

Section: The Ventilatory Control System and Opioid-induced Respiratormentioning

confidence: 99%

Opioid-induced respiratory depression: reversal by non-opioid drugs

Schier¹,

Roozekrans²,

Velzen³

et al. 2014

F1000Prime Rep

Self Cite

View full text Add to dashboard Cite

The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K+-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to continuously monitor these patients, irrespective whether they are treated in-house or in an ambulatory setting.

show abstract

“…Naloxone is an antagonist of morphine-like receptors that is commonly used to reduce the side effects of drug abuse such as respiratory depression (20,21). Several studies have shown that naloxone, as an opioid receptors antagonist, has adjuvant effect.…”

Section: Introductionmentioning

confidence: 99%

Immune Responses of Mice Immunized with HBsAg Formulated in Naloxone/Alum Mixture: Comparison to Fendrix Vaccine

et al. 2017

View full text Add to dashboard Cite

Background: Hepatitis B virus (HBV) can cause cirrhosis of the liver and hepatocellular carcinoma. Due to the lack of sufficient immune response in whole population, several studies have been conducted to improve the efficacy of alum-based HBV vaccine. Here, naloxone/alum mixture as adjuvant was used for the hepatitis B surface antigen HBsAg vaccine and immune parameters evaluated in immunized mice. Objectives: The present study aimed at investigating the effect of naloxone/alum mixture for the HBsAg vaccine and comparing to Fendrix vaccine. Methods: Female Balb/c mice were vaccinated at day 0, 14, and 28 with alum-based vaccine or naloxone/alum mixture vaccine in different doses. Naloxone/alum vaccine groups received a dose of 3, 6, or 10 mg/kg of naloxone (NLX) in the vaccine formulation. One group received routine HBsAg alum vaccine and another group received Fendrix vaccine. Some groups received naloxone plus HBsAg without alum and a group received HBsAg without adjuvant. Phosphate buffered saline (PBS), naloxone, and alum were also injected into the control groups separately. Finally, the naloxone/alum formulated vaccine was compared with the Fendrix and routine alum-based vaccine with respect to the levels of total anti-HBS antibody, IFN-γ, IL-4, IgG1, IgG2a, and the level of lymphocyte proliferation. Results:The level of total anti-HBS antibody in naloxone formulated vaccine was comparable with Fendrix. Meanwhile, IFN-γ/IL-4 ratio level was significantly higher in naloxone formulated vaccine groups versus mere vaccine group. IgG2a was also higher in the naloxone formulated vaccine groups. Conclusions: Based on the data presented in the present study, it was found that naloxone/alum mixture has the ability to shift the immune response towards Th1 pattern and potentially increase immunity against infections.

show abstract

Naloxone Reversal of Morphine- and Morphine-6-Glucuronide-induced Respiratory Depression in Healthy Volunteers

Abstract: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.

Cited by 66 publications

References 26 publications

Molecular Pharmacology ofδ-Opioid Receptors

Molecular Pharmacology ofδ-Opioid Receptors

Opioid-induced respiratory depression: reversal by non-opioid drugs

Immune Responses of Mice Immunized with HBsAg Formulated in Naloxone/Alum Mixture: Comparison to Fendrix Vaccine

Contact Info

Product

Resources

About