User:EarlySleeper/sandbox

Pharmacokinetic interaction
The main metabolism of opioid drugs is through the CYP450 enzyme. The phase 1 metabolism of opioid drugs is mainly through CYP3A4 and CYP2D6 enzymes.


 * 1) Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.
 * 2) US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website.
 * 3) https://www.ajmc.com/view/a370_11sep_overholser_s276tos287

The majority of fentanyl, oxycodone, codeine and methadone undergoes phase 1 metabolism through CYP3A4 enzyme. As for CYP2D6 enzyme, it is responsible for the metabolism of codeine, with minor effects on oxycodone and methadone metabolism. Therefore CYP3A4 CYP2D6 enzymes inhibitors will increase the serum concentration of certain opioid drugs which may lead to overdose.

To prevent the overdose of opioids, naloxone can be co-prescribed with opioid analgesics. Naloxone is an opioid receptor antagonist that can reverse the effect of opioids. 0.04-2mg IV injection of naloxone can treat patients experiencing cardiac arrest or respiratory depression due to opioid toxicity.


 * 1) Dezfulian C, Orkin AM, Maron BA, et al. Opioid-associated out-of-hospital cardiac arrest: distinctive clinical features and implications for health care and public responses: A scientific statement from the American Heart Association. Circulation. 2021;143(16):e836-e870. doi:10.1161/CIR.0000000000000958 [PubMed 33682423]
 * 2) Panchal AR, Bartos JA, Cabañas JG, et al; Adult Basic and Advanced Life Support Writing Group. Part 3: adult basic and advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020;142(16)(suppl 2):S366-S468. doi:10.1161/CIR.0000000000000916 [PubMed 33081529]
 * 3) https://nida.nih.gov/publications/drugfacts/naloxone

Pharmacodynamic interaction
CNS depressing effect is one of the main side effects of opioid analgesics, especially for the higher potency opioids like fentanyl and meperidine. It was reported that antihistamines was found in 14.7% of opioid overdosed deaths in 2019 in the United States. Moreover, diphenhydramine, a first-generation antihistamine which exerts sedative effect, were related to more than 50% of the antihistamine related death. It was suggested that the CNS depressing effect of opioids synergised with the sedative effect of antihistamine, leading to respiratory depression and resulting in death


 * 1) https://www.healio.com/news/allergy-asthma/20221020/antihistamines-present-in-some-opioid-overdoses-deaths
 * 2) https://www.cdc.gov/mmwr/volumes/71/wr/mm7141a4.htm

CNS depressants like benzodiazepines and alcohol may also enhance the CNS depression effect of opioid analgesics. Therefore a synergetic effect will be created and the user may experience breath suppression which may result in death. Moreover, a study in 2015 regarding the co-administration of benzodiazepines and opioid analgesics showed an increased use of emergency service of the patients. Therefore generally opioid analgesics should not be co-prescribed with benzodiazepine anxiolytics like diazepam. Patients should also avoid consuming any alcohol when administering opioid analgesics as co-administration of opioid and alcohol leads to more than 60% of unintended overdoses and deaths.


 * 1) https://nida.nih.gov/research-topics/opioids/benzodiazepines-opioids#:~:text=Taking%20opioids%20in%20combination%20with,risk%20of%20life%2Dthreatening%20overdose.&text=Learn%20more%20about%20the%20effects,Control%20and%20Prevention%20(CDC).
 * 2) https://pubmed.ncbi.nlm.nih.gov/20630671/
 * 3) Nielsen S, Lintzeris N, Bruno R, et al. Benzodiazepine use among chronic pain patients prescribed opioids: associations with pain, physical and mental health, and health service utilization. Pain Med. 2015;16(2):356-366. doi:10.1111/pme.12594

The analgesic effects of opioids could also be synergised with NSAIDs (non-steroidal anti-inflammatory drugs) and paracetamol. Co-administration of NSAIDs and opioid analgesics may increase the analgesics effect and lead to a better pain-reliving effect. The use of paracetamol could also decrease the total dose of morphine required as supplemental analgesic agent after surgery.


 * 1) Miranda HF, Silva E, Pinardi G. Synergy between the antinociceptive effects of morphine and NSAIDs. Can J Physiol Pharmacol. 2004;82(5):331-338. doi:10.1139/y04-027
 * 2) Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen JF, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e873. doi: 10.1097/CCM.0000000000003299. PMID: 30113379.