User:Dayakgill/Opioid overdose

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Talk Page Exercise:[edit]

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)

Bibliography[edit]

Introduction:

  • No external sources needed

Mechanisms:

  1. Historical Review: Opiate Addiction and Opioid Receptors
  2. Endogenous and Exogenous Opioids in Pain
  3. The Cholinergic System as a Treatment Target for Opioid Use Disorder

Risk Factors - Mental Health:

  1. Risk Factors for Opioid-Use Disorder and Overdose
  2. The Cholinergic System as a Treatment Target for Opioid Use Disorder
  3. Conditional probabilities of substance use disorders and associated risk factors: Progression from first use to use disorder on alcohol, cannabis, stimulants, sedatives and opioids

Lead Edits[edit]

An opioid overdose is toxicity due to excessive consumption of opioids (i.e morphine, heroin, fentanyl, tramadol, and methadone).[1][2] 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.[3] [4] 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.[4][5][6] Risk of overdose is particularly high following detoxification.[4] Dependence on prescription opioids can occur from their use to treat chronic pain.[4] Diagnosis of an opioid overdose is based on symptoms and examination.[1]

Initial treatment involves supporting the person's breathing and providing oxygen.[7] Naloxone is then recommended among those who are not breathing to reverse the opioid's effects.[7][1] Giving naloxone into the nose or as an injection into a muscle appear to be equally effective.[8] Among those who refuse to go to hospital following reversal, the risks of a poor outcome in the short term appear to be low.[8] Efforts to prevent deaths from overdose include improving access to naloxone and treatment for opioid dependence.[4][9]

Opioid use disorders resulted in 122,000 deaths globally in 2015, up from 18,000 deaths in 1990.[10][11] In the United States, over 49,000 deaths involved opioids in 2017.[6] Of those, about 20,000 involved prescription opioids and 16,000 involved heroin.[6] In 2017, opioid deaths represented more than 65% of all drug overdose related deaths in the United States.[6] The opioid epidemic is believed to be in part due to assurances in the 1990s by the pharmaceutical industry that prescription opioids were safe.[2]

Mechanisms Edits[edit]

ORIGINAL TEXT:

Permanent brain damage may occur due to cerebral hypoxia or opioid-induced neurotoxicity.[12][13] Opioids inhibit the medulla's chemoreceptors through the mu and delta receptors.[14] 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.[15] Because of its fatal consequences, opioid induced respiratory depression is one of the major limiting factors of its analgesic effects.[16] 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.[17]

^ 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.[18] However they can cause abnormally slow breathing, which leads to hypoxia. [18] Opioid’s function by stimulating specific G-protein coupled receptors distributed throughout the body—including the brain, skin and spinal cord.[19] 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.[20] 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.[13]

MORs have an analgesic effect on the brain, and are found in various parts of the nervous system including the cerebral cortex and thalamus.[18] These receptors can be found in the nucleus accumbens, the pleasure centre of the brain, as well as the amygdala. [18] 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 .[18] 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).[18] This further exacerbates erratic shifts in mood during withdrawal periods, thus prompting relapse.[18] 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.[18] 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.[21]

When opioids are ingested, the ligand binds to these constitutively active receptors and work to reduce neural activity.[20] This is accomplished by inhibiting adenylyl cyclase and cyclic AMP, which are necessary for communication within the central nervous system.[20] There is research indicating that opioids reduce neurotransmitters—and thus pain perception—by disrupting ion channels and vesicle fusion.[20] 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.[22]

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.[23] [24] 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.[24] The proposed mechanism for reduced oxygen involves the disruption of synchronous respiration involving potassium ion channels and pre-Bötzinger complex.[24] During cerebral hypoxia, there is a lack of sufficient oxygen supply to the brain which can cause brain damage and fatal consequences.[23]

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

  1. ^ a b c Boyer EW (July 2012). "Management of opioid analgesic overdose". The New England Journal of Medicine. 367 (2): 146–55. doi:10.1056/NEJMra1202561. PMC 3739053. PMID 22784117.
  2. ^ a b "Opioid Overdose Crisis". National Institute on Drug Abuse. 1 June 2017. Retrieved 29 November 2017.
  3. ^ Malamed, Stanley F. (2007). Medical Emergencies in the Dental Office - E-Book. Elsevier Health Sciences. p. 387. ISBN 978-0323075947.
  4. ^ a b c d e "Information sheet on opioid overdose". WHO. November 2014.
  5. ^ Park TW, Lin LA, Hosanagar A, Kogowski A, Paige K, Bohnert AS (2016). "Understanding Risk Factors for Opioid Overdose in Clinical Populations to Inform Treatment and Policy". Journal of Addiction Medicine. 10 (6): 369–381. doi:10.1097/ADM.0000000000000245. PMID 27525471. S2CID 8871126.
  6. ^ a b c d Cite error: The named reference NIDA-deaths was invoked but never defined (see the help page).
  7. ^ a b de Caen AR, Berg MD, Chameides L, Gooden CK, Hickey RW, Scott HF, et al. (November 2015). "Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation. 132 (18 Suppl 2): S526–42. doi:10.1161/cir.0000000000000266. PMC 6191296. PMID 26473000.
  8. ^ a b Chou R, Korthuis PT, McCarty D, Coffin PO, Griffin JC, Davis-O'Reilly C, et al. (December 2017). "Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review". Annals of Internal Medicine. 167 (12): 867–875. doi:10.7326/M17-2224. PMID 29181532.
  9. ^ "Opioid epidemic: 6 key steps that states should take now". American Medical Association. 9 September 2019. Retrieved 14 October 2020.
  10. ^ GBD 2015 Mortality and Causes of Death Collaborators (October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281. {{cite journal}}: |author= has generic name (help)CS1 maint: numeric names: authors list (link)
  11. ^ GBD 2013 Mortality and Causes of Death Collaborators (January 2015). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. {{cite journal}}: |author= has generic name (help)CS1 maint: numeric names: authors list (link)
  12. ^ "Heroin". National Institute on Drug Abuse. July 2017. Retrieved 29 November 2017.
  13. ^ a b Cunha-Oliveira T, Rego AC, Oliveira CR (June 2008). "Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs". Brain Research Reviews. 58 (1): 192–208. doi:10.1016/j.brainresrev.2008.03.002. hdl:10316/4676. PMID 18440072. S2CID 17447665. Since morphine can induce neurotoxicity (Hu et al., 2002; Mao et al., 2002; Lim et al., 2005), it may contribute to the neurotoxic effects of heroin. However, we showed that 6-MAM and morphine do not contribute to street heroin neurotoxicity in cultured cortical neurons (Cunha-Oliveira et al., 2007). In accordance, a recent study suggests that heroin has a higher neurotoxic potential in comparison with morphine (Tramullas et al., 2008).
  14. ^ White JM, Irvine RJ (July 1999). "Mechanisms of fatal opioid overdose". Addiction. 94 (7): 961–72. doi:10.1046/j.1360-0443.1999.9479612.x. PMID 10707430.
  15. ^ Watson SJ, Akil H, Khachaturian H, et al. Opioid systems: Anatomical, physiological and clinical perspectives. In: Opioids Past, Present and Future, Hughes J, Collier HO, Rance MJ, Tyers MB (Eds), Taylor & Francis, London 1984. p.145.
  16. ^ Pattinson KT (June 2008). "Opioids and the control of respiration". British Journal of Anaesthesia. 100 (6): 747–58. doi:10.1093/bja/aen094. PMID 18456641.
  17. ^ Smith HS (July 2009). "Opioid metabolism". Mayo Clinic Proceedings. 84 (7): 613–24. doi:10.4065/84.7.613. PMC 2704133. PMID 19567715.
  18. ^ a b c d e f g h Wang, Shaocheng (2019). "Historical Review: Opiate Addiction and Opioid Receptors". Cell Transplantation. 28 (3): 233–238. doi:10.1177/0963689718811060. ISSN 0963-6897. PMC 6425114. PMID 30419763.
  19. ^ Wang, Shaocheng (2019). "Historical Review: Opiate Addiction and Opioid Receptors". Cell Transplantation. 28 (3): 233–238. doi:10.1177/0963689718811060. ISSN 0963-6897. PMC 6425114. PMID 30419763.
  20. ^ a b c d Corder, Gregory; Castro, Daniel C.; Bruchas, Michael R.; Scherrer, Grégory (2018-07-08). "Endogenous and Exogenous Opioids in Pain". Annual review of neuroscience. 41: 453–473. doi:10.1146/annurev-neuro-080317-061522. ISSN 0147-006X. PMC 6428583. PMID 29852083.
  21. ^ Al-Hasani, Ream; Bruchas, Michael R. (2011). "Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior". Anesthesiology. 115 (6): 1363–1381. doi:10.1097/ALN.0b013e318238bba6. ISSN 0003-3022. PMC 3698859. PMID 22020140.
  22. ^ Kiyatkin, Eugene A. (2019). "Respiratory depression and brain hypoxia induced by opioid drugs: morphine, oxycodone, heroin, and fentanyl". Neuropharmacology. 151: 219–226. doi:10.1016/j.neuropharm.2019.02.008. ISSN 0028-3908. PMC 6500744. PMID 30735692.
  23. ^ a b Kiyatkin, Eugene A. (2019). "Respiratory depression and brain hypoxia induced by opioid drugs: morphine, oxycodone, heroin, and fentanyl". Neuropharmacology. 151: 219–226. doi:10.1016/j.neuropharm.2019.02.008. ISSN 0028-3908. PMC 6500744. PMID 30735692.
  24. ^ a b c Imam, Mohammad Zafar; Kuo, Andy; Ghassabian, Sussan; Smith, Maree T. (2018). "Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression". Neuropharmacology. 131: 238–255. doi:10.1016/j.neuropharm.2017.12.032. ISSN 1873-7064. PMID 29273520.

Risk Factors[edit]

Metabolism[edit]

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)

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