User:Dayakgill/Opioid overdose

Talk Page Exercise:
Hello! Our group's name is Blue's Clues and we are aiming to improve parts of this article over the coming months. We would like to start with editing the Lead writing style and structure to better facilitate a logical flow of thought while ensuring that the citations are appropriate. The largest contribution we hope to make is to the 'Mechanisms' subheading which currently lacks details about the biochemical pathways involved in opioid overdose. We aim to conduct thorough research on this subject and add to the information already found on the page. Finally, we hope to explore the concept of mental health as a risk factor in order to support the claims made in the Lead. This is our first editing endeavour so any help or comments are appreciated! Dayakgill (talk) 15:36, 23 October 2020 (UTC) Sahrishmasood (talk) 15:36, 23 October 2020 (UTC) NoThisIsPatrick3000 (talk) 15:44, 23 October 2020 (UTC)

Update: While conducting research for our contributions, we found a paper that suggests the GABA neurotransmitter study may not be associated with opioid-related respiratory depression. We have outlined our adjustments to this section in our sandbox (under Mechanisms edits > Proposed edits) and would appreciate any feedback before we publish our changes!

Sahrishmasood (talk) 17:15, 30 October 2020 (UTC)

Lead Edits
An opioid overdose is toxicity due to excessive consumption of opioids (i.e morphine, heroin, fentanyl, tramadol, and methadone). This preventable pathology can be lethal due to respiratory depression which can cause hypoxia. Symptoms include insufficient breathing, small pupils, and unconsciousness, however onset can depend on the method of ingestions, the dosage and individual risk factors. Among those who survive an overdose, complications can include permanent brain damage.

Risk factors for opioid overdose include opioid dependence, use of opioids by injection, use of high doses of opioids, mental disorders, and use of opioids together with alcohol, benzodiazepines, or cocaine. Risk of overdose is particularly high following detoxification. Dependence on prescription opioids can occur from their use to treat chronic pain. Diagnosis of an opioid overdose is based on symptoms and examination.

Initial treatment involves supporting the person's breathing and providing oxygen. Naloxone is then recommended among those who are not breathing to reverse the opioid's effects. Giving naloxone into the nose or as an injection into a muscle appear to be equally effective. Among those who refuse to go to hospital following reversal, the risks of a poor outcome in the short term appear to be low. Efforts to prevent deaths from overdose include improving access to naloxone and treatment for opioid dependence.

Opioid use disorders resulted in 122,000 deaths globally in 2015, up from 18,000 deaths in 1990. In the United States, over 49,000 deaths involved opioids in 2017. Of those, about 20,000 involved prescription opioids and 16,000 involved heroin. In 2017, opioid deaths represented more than 65% of all drug overdose related deaths in the United States. The opioid epidemic is believed to be in part due to assurances in the 1990s by the pharmaceutical industry that prescription opioids were safe.

Mechanisms Edits
ORIGINAL TEXT:

Permanent brain damage may occur due to cerebral hypoxia or opioid-induced neurotoxicity. Opioids inhibit the medulla's chemoreceptors through the mu and delta receptors. Opioids bind to receptors that are part of the endogenous opioid system as well as other central nervous neurotransmitter systems, binding to excitatory neurotransmitters like dopamine or glutamate, or inhibitory neurotransmitters like GABA. The main excitatory chemoreceptor, glutamate, and main inhibitory chemoreceptor, GABA, are the main neurotransmitters that control respiration. Because of its fatal consequences, opioid induced respiratory depression is one of the major limiting factors of its analgesic effects. Opioids vary in the rate of metabolism amongst individuals. The rate of metabolism of opiates vary due to genetic factors while tolerance of the opiates can determine risk.

^ GABA information may not be true according to a 2011 study

PROPOSED EDITS:

Opioids are able to bind with neurological opioid receptors to provoke analgesic, sedative, and euphoric effects. However they can cause abnormally slow breathing, which leads to hypoxia. Opioid’s function by stimulating specific G-protein coupled receptors distributed throughout the body—including the brain, skin and spinal cord. Three of the major opioid receptors include mu (MOR), kappa (KOR), delta (DOR), and nociception (NOR), each playing a role in eliciting the effects associated with opioids. An opioid overdose results from over-activation of these receptors, and thus the opiate pathway, which can cause permanent brain damage from cerebral hypoxia or neurotoxicity.

MORs have an analgesic effect on the brain, and are found in various parts of the nervous system including the cerebral cortex and thalamus. These receptors can be found in the nucleus accumbens, the pleasure centre of the brain, as well as the amygdala. KORs, in the hypothalamus, produce a similar analgesic effect. However, instead of binding with endorphins, they bind with dynorphins to stimulate anti-reward effects —dysphoria— and other negative effects of withdrawal. While MORs are the source of addiction, KORs contribute to continued abuse, as they generate dysphoria in response to increasing stress levels, via corticotropin-releasing factor (CRF). This further exacerbates erratic shifts in mood during withdrawal periods, thus prompting relapse. DORS, found in the basal ganglia of the limbic system, are able to stimulate anxiolytic effects (i.e. anxiety reduction) by binding with enkephalins, although this requires further research. The most recent addition to these receptors are the NORs. Although they have been determined to be receptors to certain ligands from opioids, their role has similarly not been researched enough within the scientific community to conclude their mechanism.

When opioids are ingested, the ligand binds to these constitutively active receptors and work to reduce neural activity. This is accomplished by inhibiting adenylyl cyclase and cyclic AMP, which are necessary for communication within the central nervous system. There is research indicating that opioids reduce neurotransmitters—and thus pain perception—by disrupting ion channels and vesicle fusion. When individuals have prolonged exposure to opioids, these receptors can become internalized, leading to insurmountable tolerance which causes individuals to further indulge in the narcotic.

There are many side effects associated with this abuse, among which hypoxia is the most dangerous. This is typically caused by respiratory depression, which has been linked to KORs and DORs. The brain uses oxygen for various metabolic processes that regulate the homeostasis of the body. In animal studies, it was found that opioids act on specific regions of the central nervous system associated with respiratory regulation, including the medulla and pons. The proposed mechanism for reduced oxygen involves the disruption of synchronous respiration involving potassium ion channels and pre-Bötzinger complex. During cerebral hypoxia, there is a lack of sufficient oxygen supply to the brain which can cause brain damage and fatal consequences.

Dayakgill (talk ) 02:00, 29 October 2020 (UTC) NoThisIsPatrick3000 (talk) 17:46, 29 October 2020 (UTC) Sahrishmasood (talk) 14:38, 30 October 2020 (UTC)

Metabolism
Opioids are primarily metabolized in the liver, before being excreted through urine. Opioids are metabolized either by phase 1 metabolism, phase 2 metabolism, or both, which can lead to the activation or inhibition of these drugs. Phase 1 metabolism consists of different cytochromes P450, a set of enzymes, catalyzing hydrolysis, reduction and oxidation reactions to create an activate metabolite. In contrast, Phase 2 metabolism causes the opioids to undergo conjugation, with little to no interaction with the CYP pathway. The opioids undergo phase 1 and phase 2 metabolism until they are sufficiently hydrophilic to be renally excreted.

There are various factors that play a significant role in the level at which the opioid is metabolized. For phase 1 metabolism, the CYP family has several polymorphisms which can account for the difference in therapeutic responses within each individual. This diversification leads to opioids being modified slower or faster, and thus remain in the bloodstream for a longer or shorter time, respectively. Therefore, they are able to dictate the resulting level of symptoms exhibited.

Sahrishmasood (talk) 00:08, 10 November 2020 (UTC)