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[[File:opioids2.png|300px|thumb|right|Common substances that affect the u-opioid receptor: [[morphine]], [[codeine]], [[diacetylmorphine]] (''Heroin''), [[naloxone]] (''Narcan''), [[methadone]], [[tramadol]].]]
[[File:Slaapbol R0017601.JPG|250px|thumb|Poppy pod scored to release opium latex]]
[[File:Mohn z06.jpg|250px|thumb|Dried pods for preparation of tea or solvent extraction of alkaloids]]
'''Opioids''' are a class of [[psychoactive substances]] that resemble [[morphine]] or other opiates in their pharmacological effects.{{citation needed}} Opioids work by binding to opioid [[receptors]], which are found in the central and peripheral nervous system and the gastrointestinal tract.{{citation needed}} The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.
An '''opioid''' is any psychoactive chemical that resembles [[morphine]] or other [[opiates]] in its pharmacological effects. Opioids work by binding to [[Opioid receptor|opioid receptors]], which are found principally in the central and peripheral nervous system and the gastrointestinal tract. The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.
Although the term opiate is often used as a synonym for opioid, the term opiate is limited to drugs derived from the natural alkaloids found in the resin of the opium poppy (''Papaver somniferum'').<ref>{{Cite book|url=https://books.google.com/books?id=s8CXrbimviMC&pg=PA268|title=Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult - Online and Print|last=Hemmings|first=Hugh C.|last2=Egan|first2=Talmage D.|publisher=Elsevier Health Scienc,es|year=2013|isbn=1437716792|page=253|quote=Opiate is the older term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists).}}</ref>
While opioid is a more general term for substances that act primarily on opioid receptors, including natural occurring alkaloids, synthetic substances and opioid peptides.<ref name=":17">{{Cite book|url=https://books.google.com/books?id=s8CXrbimviMC&pg=PA268|title=Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult - Online and Print|last=Hemmings|first=Hugh C.|last2=Egan|first2=Talmage D.|publisher=Elsevier Health Sciences|year=2013|isbn=1437716792|page=253|quote=Opiate is the older term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists).}}</ref>
Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to the natural alkaloids found in the resin of the opium poppy (Papaver somniferum), while opioid refers to both opiates and synthetic substances, as well as to opioid peptides.
Opioid dependence can develop with ongoing administration, leading to a withdrawal syndrome with abrupt discontinuation.<ref>{{cite journal | vauthors=((Cammarano, W. B.)), ((Pittet, J.-F.)), ((Weitz, S.)), ((Schlobohm, R. M.)), ((Marks, J. D.)) | journal=Critical Care Medicine | title=Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients: | volume=26 | issue=4 | pages=676–684 | date= April 1998 | url=http://journals.lww.com/00003246-199804000-00015 | issn=0090-3493 | doi=10.1097/00003246-199804000-00015}}</ref> Opioids are not only well known for their addictive properties, but also for their ability to produce a feeling of euphoria, motivating some to use opioids recreationally.
Opioids are among the world's oldest known drugs; the therapeutic use of the opium poppy predates recorded history. The analgesic (painkiller) effects of opioids are due to decreased perception of pain and a decreased reaction to pain as well as increased pain tolerance. The side effects of opioids include [[Physical effects: Sedation|sedation]], [[Physical effects: Respiratory depression|respiratory depression]], [[Physical effects: Constipation|constipation]], and a strong sense of [[Physical effects: Euphoria|euphoria]]. Opioids can cause [[Physical effects: Cough suppression|cough suppression]], which can be both an indication for opioid administration or an unintended side effect. Opioid dependence can develop with ongoing administration, leading to a withdrawal syndrome with abrupt discontinuation. Opioids are not only well known for their addictive properties, but also for their ability to produce a feeling of euphoria, motivating some to use opioids recreationally.
==Chemistry==
Opioids are based upon [[morphine]] and opium-like structures. They work via their similar chemical structures to the endogenous opioids in the body. Morphine derived opioids, known as morphinans, contain a benzene ring attached to two partially unsaturated cyclohexane rings (phenanthrene) and a 4th nitrogenous ring attached to the core at carbons 9 and 13. There are several classes of opioids which differ greatly in structure from each other. For example, [[fentanyl]] and its analogues are structurally unique from [[morphinans]] and [[tramadol]] derivatives.
=Chemistry=
==Pharmacology==
Opioids are based upon [[morphine]] and opium-like structures. They work via their similar chemical structures to the endogenous opioids in the body. The morphine-based opioids generally contain a benzene ring attached to two partially unsaturated cyclohexane rings, known as the phenanthrene group.
[[File:Opioid_metabolism.png|thumb|Metabolic pathway of [[codeine]] and [[morphine]] courtesy of [https://www.pharmgkb.org/pathway/PA146123006 Pharmgkb.org] ]]
=Mechanism of Action=
Opioids are known to mimic endogenous endorphins. Endorphins are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement. This mimicking of natural endorphins results in the drug's [[Physical euphoria|euphoric]], [[Pain relief|analgesic]] (pain relief) and [[Anxiety suppression|anxiolytic]] (anti-anxiety) effects.<ref>{{cite journal | vauthors = Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR | title = The runner's high: opioidergic mechanisms in the human brain | journal = Cerebral Cortex | volume = 18 | issue = 11 | pages = 2523–31 | date = November 2008 | pmid = 18296435 | doi = 10.1093/cercor/bhn013 }}</ref>
Opioids act on the three main classes of [[opioid receptor]] in the nervous system, μ, κ, δ (mu, kappa, and delta). Each opioid is measured by its [[agonistic]] or [[antagonistic]] effects towards the receptors, with the responses to the different receptor sub-types (e.g. μ1 and μ2) providing even more effects.
=Subjective effects=
===Receptor types===
Opioids act on the three main classes of opioid receptor in the nervous system, μ, κ, δ (mu, kappa, and delta).<ref name="receptors">Opioid - Chapter 2: The Endogeneous Opioid Systems
(http://www.stoppain.org / Beth Israel Medical Center's Department of Pain Medicine and Palliative Care) | https://web.archive.org/web/20110719072413/http://www.stoppain.org/pcd/_pdf/OpioidChapter2.pdf</ref> Each opioid is measured by its [[agonist]]ic or [[antagonist]]ic effects towards the receptors, with the responses to the different receptor sub-types (e.g., μ1 and μ2) providing even more effects. Opioid receptors are found mainly within the brain, but also within the spinal cord and digestive tract.<ref>{{cite journal | vauthors=((Holzer, P.)) | journal=Regulatory peptides | title=Opioid receptors in the gastrointestinal tract | volume=155 | issue=1–3 | pages=11–17 | date=5 June 2009 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163293/ | issn=0167-0115 | doi=10.1016/j.regpep.2009.03.012}}</ref>
====='''Delta (δ)'''=====
The delta receptor is responsible for the [[analgesia]], antidepressant and convulsant effects as well as physical dependence.<ref name="receptors" />
====='''Kappa (κ)'''=====
The kappa receptor is responsible for the [[analgesia]], [[anticonvulsant]], [[dissociative]] and [[deliriant]] effects as well as dysphoria, neuroprotection and [[sedation]].<ref name="receptors" />
====='''Mu (μ)'''=====
The mu receptor is responsible for [[analgesia]], physical dependence, [[respiratory depression]], [[euphoria]], and possible [[vasodilation]].<ref name="receptors" />
===Physical effects===
Agonists of mu opioid receptors produce sedative, euphoric, and anxiolytic effects largely through the interaction of the mu receptors with serotonin, dopamine, and norepinephrine. Activation of mu receptors allows for the disinhibition of serotonin and dopamine neurons by blocking the inhibitory effects of GABA on serotonin and dopamine neurons, thus increasing activity and release of serotonin and dopamine.<ref>https://www.sciencedirect.com/science/article/abs/pii/S1043661818306145</ref> Mu receptors additionally inhibit the activity of norepinephrine neurons, leading to sedation, anxiolysis, and respiratory depression.<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274960/</ref>
*'''[[Physical effects: Pain relief|Pain relief]]''' - This component is subjectively different from other anaesthetics as it does not necessarily remove the pain entirely whilst still remaining equal in terms of its effectiveness. Instead of directly suppressing pain these substances simply dull the perceived sensation and cover it up with feelings of physical and emotional pleasure.
*'''[[Physical effects: Respiratory depression|Respiratory depression]]''' - At low to moderate doses, this effect results in the sensation that the breath is slowed down mildly to moderately, but does not cause noticeable impairment. At high doses and overdoses, opioid-induced respiratory depression can result in a shortness of breath, abnormal breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses can result in a coma or death without immediate medical attention.
*'''[[Cognitive effects: Euphoria|Euphoria]]''' - By both u agonism and downstream dopamine reinforcement
The nociceptin receptor is responsible for [[anxiety]], [[depression]], appetite and development of tolerance to μ agonists.<ref name="pmid10742280">{{cite journal | vauthors = Calo' G, Guerrini R, Rizzi A, Salvadori S, Regoli D | title = Pharmacology of nociceptin and its receptor: a novel therapeutic target | journal = British Journal of Pharmacology | volume = 129 | issue = 7 | pages = 1261–83 | date = April 2000 | pmid = 10742280 | pmc = 1571975 | doi = 10.1038/sj.bjp.0703219 }}</ref><ref>{{cite journal | vauthors = Toll L, Bruchas MR, Calo' G, Cox BM, Zaveri NT | title = Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems | journal = Pharmacological Reviews | volume = 68 | issue = 2 | pages = 419–57 | date = April 2016 | pmid = 26956246 | doi = 10.1124/pr.114.009209 | url = http://pharmrev.aspetjournals.org/content/68/2/419 }}</ref>
*'''[[Cognitive effects: Increased motivation|Increased motivation]]''' - Some opioids (such as [[kratom]] are more stimulating than others and seem to enhance motivation
*'''[[Cognitive effects: Suppression of anxiety|Suppression of anxiety]]'''
===Visual effects===
====='''Zeta (ζ)'''=====
*'''[[Visual effects: Internal hallucinations (opioids)|Internal hallucinations]]''' - State of semi-consciousness during nodding stage
The zeta opioid receptor, also known as opioid growth factor receptor (OGFr) is responsible for tissue growth, neural development, and is further implicated in the development in some cancers.<ref name="pmid10519055">{{cite journal | vauthors = Zagon IS, Wu Y, McLaughlin PJ | title = Opioid growth factor and organ development in rat and human embryos | journal = Brain Res. | volume = 839 | issue = 2 | pages = 313–22 |date=August 1999 | pmid = 10519055 | doi = 10.1016/S0006-8993(99)01753-9 | url = | issn = }}</ref><ref name="pmid12854052">{{cite journal | vauthors = Sassani JW, Zagon IS, McLaughlin PJ | title = Opioid growth factor modulation of corneal epithelium: uppers and downers | journal = Curr. Eye Res. | volume = 26 | issue = 5 | pages = 249–62 |date=May 2003 | pmid = 12854052 | doi = 10.1076/ceyr.26.4.249.15427| url = | issn = }}</ref><ref name="pmid10024694">{{cite journal | vauthors = Zagon IS, Smith JP, McLaughlin PJ | title = Human pancreatic cancer cell proliferation in tissue culture is tonically inhibited by opioid growth factor | journal = Int. J. Oncol. | volume = 14 | issue = 3 | pages = 577–84 |date=March 1999 | pmid = 10024694 | doi = 10.3892/ijo.14.3.577| url = | issn = }}</ref><ref name="pmid10200353">{{cite journal | vauthors = McLaughlin PJ, Levin RJ, Zagon IS | title = Regulation of human head and neck squamous cell carcinoma growth in tissue culture by opioid growth factor | journal = Int. J. Oncol. | volume = 14 | issue = 5 | pages = 991–8 |date=May 1999 | pmid = 10200353 | doi = 10.3892/ijo.14.5.991| url = | issn = }}</ref><ref name="pmid17974995">{{cite journal |vauthors=Cheng F, Zagon IS, Verderame MF, McLaughlin PJ |title=The opioid growth factor (OGF)-OGF receptor axis uses the p16 pathway to inhibit head and neck cancer |journal=Cancer Research |volume=67 |issue=21 |pages=10511–8 |date=November 2007 |pmid=17974995 |doi=10.1158/0008-5472.CAN-07-1922 |url= |issn=}}</ref><ref name="pmid19297547">{{cite journal |vauthors=Donahue RN, McLaughlin PJ, Zagon IS |title=Cell Proliferation of Human Ovarian Cancer is Regulated by the Opioid Growth Factor - Opioid Growth Factor Receptor Axis |journal=American Journal of Physiology. Regulatory, Integrative and Comparative Physiology |volume= 296|issue= 6|pages= R1716–25|date=March 2009 |pmid=19297547 |doi=10.1152/ajpregu.00075.2009 |url= |issn=}}</ref> The endogenous ligand for OGFr is met-enkephalin, which is also a powerful endogenous delta opioid receptor agonist.<ref name="Stein1999">{{cite book | author = Christoph Stein | title = Opioids in pain control: basic and clinical aspects | url = https://books.google.com/books?id=4Rfr8cQayvgC&pg=PA22 | accessdate = 25 November 2011 | year = 1999 | publisher = Cambridge University Press | isbn = 978-0-521-62269-1 | pages = 22–23}}</ref>
=Pharmacological Classes=
==Subjective effects==
===Naturally occurring===
{{Preamble/SubjectiveEffects}}
[[File:Slaapbol R0017601.JPG|thumb|Poppy pod scored to release opium latex]]
{{effects/base
[[File:Mohn z06.jpg|thumb|Dried pods for preparation of tea or solvent extraction of alkaloids]]
|{{effects/physical|
'''[[Opiates]]''' are the class of naturally forming opioid agonist alkaloids, which are found within the latex of the Opium Poppy (''Papaver Somniferum''), and in smaller quantities within other species of poppy.
*[[Morphine]]
*'''[[Stimulation]] or [[Sedation]]''' - At light doses, mu opioid agonists often produce mild to moderate stimulation due to enhancing dopamine and serotonin signaling, which gradually changes to sedation with higher doses due to inhibition of norepinephrine. Opioids with stronger activity at kappa and nociceptin opioid receptors such as [[fentanyl]] and [[morphine]] tend to be more sedating than opioids which primarily act on mu opioid receptors like [[kratom]] and [[tianeptine]]
*[[Codeine]]
*'''[[Respiratory depression|Respiratory depression]]''' - At low to moderate doses, this effect results in the sensation that the breath is slowed down mildly to moderately, but does not cause noticeable impairment. At high doses and overdoses, opioid-induced respiratory depression can result in a shortness of breath, abnormal breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses can result in a coma or death without immediate medical attention.
*[[Thebaine]] (Not recreational, used as precursor for semi-synthetic opioids)
*'''[[Pain relief]]'''
*Other alkaloids contribute to the effects of poppy pod/seed tea and other preparations of the raw latex
*'''[[Itchiness]]'''
*'''[[Constipation]]'''
*'''[[Cough suppression]]'''
*'''[[Decreased libido]]'''
*'''[[Difficulty urinating]]'''
*'''[[Nausea]]'''
*'''[[Stomach cramps]]'''
*'''[[Pupil constriction]]'''
*'''[[Orgasm suppression]]'''
}}
|{{effects/cognitive|
*'''[[Cognitive euphoria]]''' - This can be described as a powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
*'''[[Motivation enhancement]]''' - Some opioids (such as [[kratom]]) are more stimulating than others and seem to enhance motivation.
*'''[[Anxiety suppression]]'''
*'''[[Compulsive redosing]]'''
*'''[[Dream potentiation]]'''
*'''[[Increased music appreciation]]'''
}}
{{effects/visual|
====Suppressions====
*'''[[Effect::Double vision]]''' - At high doses, opioids can cause the eyes un-focus and re-focus uncontrollably. This creates a blurred effect and double vision that is present no matter where one focuses their eyes.
====Hallucinatory states====
*'''[[Internal hallucinations]]''' - One may experience feelings of hypnagogia during a state of "nodding" which is often accompanied by vivid dream-like visions.
*'''[[Naloxone]]''' (Narcan) - This is a powerful antagonist which precipitates instant withdrawal and is used to recover from overdose.
</li>
</ul>
</div>
</div>
===Semi-synthetic===
<div class="flex-column">
'''[[Opioids]]''' refers to both semi-synthetic and fully-synthetic opioid agonists. Natural opioid agonists can be converted by chemical syntheses to a variety of substances, which have differing duration and potency.
*[[Kratom]] contains mitragynine alkaloids which are responsible for the μ-opioid receptor agonism of kratom leaf, its extracts and other preparations.
<li class="featured list-item">
*[[α-carboxamido-clonitazene]]
*[[α-methyl-metonitazene]]
*[[Acetoxynitazene]]
*[[Bronitazene]]
*[[Butonitazene]]
*[[Clonitazene]]
*[[Dimetonitazene]]
*[[Ethylnitazene]]
*[[Ethylthionitazene]]
*[[Etodesnitazene ]] (Etazene)
*[[Etoetonitazene]]
*[[Etonitazene]]
*[[Etonitazepipne]]
*[[Etonitazepyne]]
*[[Fluonitazene]]
*[[Isotonitazene]]
*[[Methylnitazene]]
*[[Methylthionitazene]]
*[[Metodesnitazene]] (Metazene)
*[[meta-Metonitazene]]
*[[Metonitazene]]
*[[N-desethyl-isotonitazene]]
*[[Nitazene]]
*[[O-Desmethyl-etonitazene]]
*[[Propylnitazene]]
*[[Protodesnitazene]]
*[[Protonitazene]]
*[[t-Butylnitazene]]
=Toxicity and Harm Potential=
</li>
When used in safe dosages, in terms of physical and neurological toxicity most opiods are remarkably safe with the long term effects generally only consisting of constipation. The negative aspects associated with opioids do not stem from toxicity but psychological addiction and dependence.
</ul>
</div>
</div>
==Tolerance and addiction potential==
==Toxicity and harm potential==
Due to the overwhelmingly euphoric nature of these substances, the recreational use and abuse of opioids has an extremely high rate of addiction and dependence. This is combined with a tolerance which builds up quickly, necessitating that the user take increasingly high dosages in order to get the same effects.
{{toxicity}}
The short-term non-chronic use of opioids is not associated with any physical or neurological toxicity.{{citation needed}}
===Discontinuation===
===Long term effects===
'''Post abuse withdrawal symptoms''' (''PAWS'') are commonly reported following abuse of opioids over a period of several days. PAWS are not expected to occur in opioid-naive individuals or those who use infrequently, as it is caused by the downregulation of opioid receptors in response to repeated administration.
The long-term use of opioids causes hormonal imbalance in both men and women.<ref>{{cite journal | vauthors=((Brennan, M. J.)) | journal=The American Journal of Medicine | title=The effect of opioid therapy on endocrine function | volume=126 | issue=3 Suppl 1 | pages=S12-18 | date= March 2013 | issn=1555-7162 | doi=10.1016/j.amjmed.2012.12.001}}</ref> In men, this opioid-induced androgen deficiency results in abnormally low levels of sex hormones, particularly testosterone.<ref>{{cite journal | vauthors=((Smith, H. S.)), ((Elliott, J. A.)) | journal=Pain Physician | title=Opioid-induced androgen deficiency (OPIAD) | volume=15 | issue=3 Suppl | pages=ES145-156 | date= July 2012 | issn=2150-1149}}</ref>
====Onset and duration====
This negative change in endocrine function in males can lead to: reduced libido, erectile dysfunction, fatigue, depression, reduced facial and body hair, decreased muscle mass, and weight gain.
The perceived effects of ''PAWS'' differs between individuals and for each opioid. The onset and duration are intrinsically linked to the substance's clearance half-life, μ-opioid receptor affinity, and the individual's current level of tolerance.
====Symptoms====
Another often observed long-term effect is hyperalgesia, an increase in the pain sensitivity of the person. This is specially seen in chronic pain patients on high dose opioid regimes. There is some evidence that NMDA antagonists like [[ketamine]] and opoids that are also weak NMDA antagonist such as [[methadone]], [[levorphanol]] and [[tramadol]] may help delay the onset of hyperalgesia or even revert it.<ref>{{cite journal | vauthors=((Lee, M.)), ((Silverman, S. M.)), ((Hansen, H.)), ((Patel, V. B.)), ((Manchikanti, L.)) | journal=Pain Physician | title=A comprehensive review of opioid-induced hyperalgesia | volume=14 | issue=2 | pages=145–161 | date= April 2011 | issn=2150-1149}}</ref>
''PAWS'' covers a broad range of symptoms. Most commonly the user will experience flu-like effects such as congestion and sneezing, rebound sensitivity to pain and tactile stimulation, restless leg syndrome, insomnia and diarrhea.
Opioids with a short half-life, such as [[diacetylmorphine]] (Heroin) are well known to induce withdrawal symptoms in tolerant individuals within several hours of having cleared the body. Longer eliminating opioids like [[methadone]] will exhibit symptoms of withdrawal much later, but the effects will linger far in excess of shorter acting opioids as the body will take longer to reach homeostasis.
It is strongly recommended that one use [[responsible drug use|harm reduction practices]] when using this class of substances.
====Mitigation====
===Tolerance and addiction potential===
''PAWS'' can be mitigated by slowly tapering the dosage over a period of days, which will let receptors recover somewhat before discontinuation. This will lessen severity of symptoms but likely prolong their duration. Switching to a weaker opioid such as [[codeine]] or even [[Kratom]] can lessen the perceived symptoms but is likely to also prolong the period of withdrawal. Switching to a shorter acting opioid like [[diacetylmorphine]] (Heroin) prior to discontinuation will shorten the duration of symptoms when coming from a longer eliminating opioid such as [[methadone]].
Due to the highly euphoric nature of these substances, the recreational use and abuse of opioids has an extremely high rate of addiction and dependence. This is combined with a tolerance which builds up quickly, necessitates that the user take increasingly high dosages in order to get the same effects.
Alternatively, the specific opioid in use can be substituted with less euphoric opioids such as buprenorphine; or high doses of the anti-diarrhea medication [[loperamide]] (Imodium), which does not cross the blood/brain barrier due to endogenous uptake inhibition caused by p-Glycoprotein, but provides relief of homeostatic symptoms by agonism of peripheral opioid receptors.
The risk of fatal opioid overdoses rise sharply after a period of cessation and [[relapse]], largely because of reduced tolerance.<ref>Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider) | http://www.businessinsider.com.au/philip-seymour-hoffman-overdose-2014-2</ref> To account for this lack of tolerance, it is safer to only dose a fraction of one's usual [[dosage]] if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment.<ref>{{cite journal | vauthors=((Siegel, S.)), ((Hinson, R. E.)), ((Krank, M. D.)), ((McCully, J.)) | journal=Science | title=Heroin “Overdose” Death: Contribution of Drug-Associated Environmental Cues | volume=216 | issue=4544 | pages=436–437 | date=23 April 1982 | url=https://www.science.org/doi/10.1126/science.7200260 | issn=0036-8075 | doi=10.1126/science.7200260}}</ref>
====Precipitated withdrawal====
===Dangerous interactions===
Some combinations of drugs are known to induce the state of withdrawal by blocking the receptors. [[Naloxone]] (Narcan), which can be administered to recover from an opioid overdose, has a higher affinity to μ-opioid receptors than most opioids so knocks off any agonists then blocks the binding site until eliminated from the body. Multiple doses of naloxone may be required as overdose can reoccur if the original opioid has a longer elimination half life (note, there are exceptions, like that one particular opioid which covalently bonds to the receptor site).
{{DangerousInteractions/Intro}}
{{DangerousInteractions/Opioids}}
[[Buprenorphine]] (Subutex), often used in addiction therapy or as prescribed, also has a higher affinity than many other opioids and will cause precipitated withdrawal symptoms if another type of opioid is coadministered before it has been eliminated.
It is strongly discouraged to combine these substances, particularly in common to heavy doses.
Common substances that affect the u-opioid receptor: morphine, codeine, diacetylmorphine (Heroin), naloxone (Narcan), methadone, tramadol.Poppy pod scored to release opium latexDried pods for preparation of tea or solvent extraction of alkaloids
Opioids are a class of psychoactive substances that resemble morphine or other opiates in their pharmacological effects.[citation needed] Opioids work by binding to opioid receptors, which are found in the central and peripheral nervous system and the gastrointestinal tract.[citation needed] The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.
Although the term opiate is often used as a synonym for opioid, the term opiate is limited to drugs derived from the natural alkaloids found in the resin of the opium poppy (Papaver somniferum).[2]
While opioid is a more general term for substances that act primarily on opioid receptors, including natural occurring alkaloids, synthetic substances and opioid peptides.[3]
Opioid dependence can develop with ongoing administration, leading to a withdrawal syndrome with abrupt discontinuation.[4] Opioids are not only well known for their addictive properties, but also for their ability to produce a feeling of euphoria, motivating some to use opioids recreationally.
Opioids are based upon morphine and opium-like structures. They work via their similar chemical structures to the endogenous opioids in the body. Morphine derived opioids, known as morphinans, contain a benzene ring attached to two partially unsaturated cyclohexane rings (phenanthrene) and a 4th nitrogenous ring attached to the core at carbons 9 and 13. There are several classes of opioids which differ greatly in structure from each other. For example, fentanyl and its analogues are structurally unique from morphinans and tramadol derivatives.
Opioids are known to mimic endogenous endorphins. Endorphins are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement. This mimicking of natural endorphins results in the drug's euphoric, analgesic (pain relief) and anxiolytic (anti-anxiety) effects.[5]
Receptor types
Opioids act on the three main classes of opioid receptor in the nervous system, μ, κ, δ (mu, kappa, and delta).[6] Each opioid is measured by its agonistic or antagonistic effects towards the receptors, with the responses to the different receptor sub-types (e.g., μ1 and μ2) providing even more effects. Opioid receptors are found mainly within the brain, but also within the spinal cord and digestive tract.[7]
Delta (δ)
The delta receptor is responsible for the analgesia, antidepressant and convulsant effects as well as physical dependence.[6]
Agonists of mu opioid receptors produce sedative, euphoric, and anxiolytic effects largely through the interaction of the mu receptors with serotonin, dopamine, and norepinephrine. Activation of mu receptors allows for the disinhibition of serotonin and dopamine neurons by blocking the inhibitory effects of GABA on serotonin and dopamine neurons, thus increasing activity and release of serotonin and dopamine.[8] Mu receptors additionally inhibit the activity of norepinephrine neurons, leading to sedation, anxiolysis, and respiratory depression.[9]
Nociceptin
The nociceptin receptor is responsible for anxiety, depression, appetite and development of tolerance to μ agonists.[10][11]
Zeta (ζ)
The zeta opioid receptor, also known as opioid growth factor receptor (OGFr) is responsible for tissue growth, neural development, and is further implicated in the development in some cancers.[12][13][14][15][16][17] The endogenous ligand for OGFr is met-enkephalin, which is also a powerful endogenous delta opioid receptor agonist.[18]
Subjective effects
Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWikicontributors. As a result, they should be viewed with a healthy degree of skepticism.
It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.
Physical effects
Stimulation or Sedation - At light doses, mu opioid agonists often produce mild to moderate stimulation due to enhancing dopamine and serotonin signaling, which gradually changes to sedation with higher doses due to inhibition of norepinephrine. Opioids with stronger activity at kappa and nociceptin opioid receptors such as fentanyl and morphine tend to be more sedating than opioids which primarily act on mu opioid receptors like kratom and tianeptine
Respiratory depression - At low to moderate doses, this effect results in the sensation that the breath is slowed down mildly to moderately, but does not cause noticeable impairment. At high doses and overdoses, opioid-induced respiratory depression can result in a shortness of breath, abnormal breathing patterns, semi-consciousness, or unconsciousness. Severe overdoses can result in a coma or death without immediate medical attention.
Double vision - At high doses, opioids can cause the eyes un-focus and re-focus uncontrollably. This creates a blurred effect and double vision that is present no matter where one focuses their eyes.
Hallucinatory states
Internal hallucinations - One may experience feelings of hypnagogia during a state of "nodding" which is often accompanied by vivid dream-like visions.
This toxicity and harm potential section is a stub.
As a result, it may contain incomplete or even dangerously wrong information! You can help by expanding upon or correcting it. Note: Always conduct independent research and use harm reduction practices if using this substance.
The short-term non-chronic use of opioids is not associated with any physical or neurological toxicity.[citation needed]
Long term effects
The long-term use of opioids causes hormonal imbalance in both men and women.[19] In men, this opioid-induced androgen deficiency results in abnormally low levels of sex hormones, particularly testosterone.[20]
This negative change in endocrine function in males can lead to: reduced libido, erectile dysfunction, fatigue, depression, reduced facial and body hair, decreased muscle mass, and weight gain.
Another often observed long-term effect is hyperalgesia, an increase in the pain sensitivity of the person. This is specially seen in chronic pain patients on high dose opioid regimes. There is some evidence that NMDA antagonists like ketamine and opoids that are also weak NMDA antagonist such as methadone, levorphanol and tramadol may help delay the onset of hyperalgesia or even revert it.[21]
It is strongly recommended that one use harm reduction practices when using this class of substances.
Tolerance and addiction potential
Due to the highly euphoric nature of these substances, the recreational use and abuse of opioids has an extremely high rate of addiction and dependence. This is combined with a tolerance which builds up quickly, necessitates that the user take increasingly high dosages in order to get the same effects.
The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance.[22] To account for this lack of tolerance, it is safer to only dose a fraction of one's usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment.[23]
Dangerous interactions
Warning:Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).
Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely
Stimulants - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the user and cause respiratory arrest.
Benzodiazepines - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position blackouts/memory loss likely.
DXM - Generally considered to be toxic. CNS depression, difficulty breathing, heart issues, and liver toxicity have been observed. Additionally if one takes DXM, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
GHB/GBL - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position
Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
MXE - MXE can potentiate the effects of opioids but also increases the risk of respiratory depression and organ toxicity.
Nitrous - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are common.
PCP - PCP may reduce opioid tolerance, increasing the risk of overdose.
Tramadol - Increased risk of seizures. Tramadol itself is known to induce seizures and it may have additive effects on seizure threshold with other opioids. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present.
Grapefruit - While grapefruit is not psychoactive, it may affect the metabolism of certain opioids. Tramadol, oxycodone, and fentanyl are all primarily metabolized by the enzyme CYP3A4, which is potently inhibited by grapefruit juice[24]. This may cause the drug to take longer to clear from the body. it may increase toxicity with repeated doses. Methadone may also be affected[24]. Codeine and hydrocodone are metabolized by CYP2D6. People who are on medicines that inhibit CYP2D6, or that lack the enzyme due to a genetic mutation will not respond to codeine as it can not be metabolized into its active product: morphine.
↑Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR (November 2008). "The runner's high: opioidergic mechanisms in the human brain". Cerebral Cortex. 18 (11): 2523–31. doi:10.1093/cercor/bhn013. PMID18296435.
↑Zagon IS, Wu Y, McLaughlin PJ (August 1999). "Opioid growth factor and organ development in rat and human embryos". Brain Res. 839 (2): 313–22. doi:10.1016/S0006-8993(99)01753-9. PMID10519055.
↑Sassani JW, Zagon IS, McLaughlin PJ (May 2003). "Opioid growth factor modulation of corneal epithelium: uppers and downers". Curr. Eye Res. 26 (5): 249–62. doi:10.1076/ceyr.26.4.249.15427. PMID12854052.
↑Zagon IS, Smith JP, McLaughlin PJ (March 1999). "Human pancreatic cancer cell proliferation in tissue culture is tonically inhibited by opioid growth factor". Int. J. Oncol. 14 (3): 577–84. doi:10.3892/ijo.14.3.577. PMID10024694.
↑McLaughlin PJ, Levin RJ, Zagon IS (May 1999). "Regulation of human head and neck squamous cell carcinoma growth in tissue culture by opioid growth factor". Int. J. Oncol. 14 (5): 991–8. doi:10.3892/ijo.14.5.991. PMID10200353.
↑Cheng F, Zagon IS, Verderame MF, McLaughlin PJ (November 2007). "The opioid growth factor (OGF)-OGF receptor axis uses the p16 pathway to inhibit head and neck cancer". Cancer Research. 67 (21): 10511–8. doi:10.1158/0008-5472.CAN-07-1922. PMID17974995.
↑Donahue RN, McLaughlin PJ, Zagon IS (March 2009). "Cell Proliferation of Human Ovarian Cancer is Regulated by the Opioid Growth Factor - Opioid Growth Factor Receptor Axis". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 296 (6): R1716–25. doi:10.1152/ajpregu.00075.2009. PMID19297547.
↑Brennan, M. J. (March 2013). "The effect of opioid therapy on endocrine function". The American Journal of Medicine. 126 (3 Suppl 1): S12–18. doi:10.1016/j.amjmed.2012.12.001. ISSN1555-7162.
↑Smith, H. S., Elliott, J. A. (July 2012). "Opioid-induced androgen deficiency (OPIAD)". Pain Physician. 15 (3 Suppl): ES145–156. ISSN2150-1149.
↑Lee, M., Silverman, S. M., Hansen, H., Patel, V. B., Manchikanti, L. (April 2011). "A comprehensive review of opioid-induced hyperalgesia". Pain Physician. 14 (2): 145–161. ISSN2150-1149.
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