Opioid use disorder#Management

File:Buprenorphine.svg.]]

Opiate misuse has been recorded at least since 300 BC. Greek mythology describes Nepenthe ("free from sorrow") and its use by the hero of the Odyssey. Opioids have been used in the Near East for centuries. The purification and isolation of opiates occurred in the early 19th century.Kosten TR, Haile CN. Opioid-Related Disorders. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014. http://accessmedicine.mhmedical.com/content.aspx?bookid=1130§ionid=79757372 Accessed 9 March 2017. In the early 2000s, buprenorphine was one of the first opioid dependence drugs approved in the U.S. to combat opioid abuse, after decades of research led to the development of drugs to fight opioid use disorder.{{Cite journal |last1=Heidbreder |first1=Christian |last2=Fudala |first2=Paul J. |last3=Greenwald |first3=Mark K. |date=2023 |title=History of the discovery, development, and FDA-approval of buprenorphine medications for the treatment of opioid use disorder |journal=Drug and Alcohol Dependence Reports |volume=6 |doi=10.1016/j.dadr.2023.100133 |pmc=10040330 |pmid=36994370}}

Levacetylmethadol (LAAM) was formerly used to treat opioid dependence. In 2003, its manufacturer discontinued production. There are no available generic versions. LAAM produced long-lasting effects, which allowed the person receiving treatment to visit a clinic only three times per week, as opposed to daily as with methadone.James W. Kalat, Biological Psychology. Cengage Learning. Page 81. In 2001, LAAM was removed from the European market due to reports of life-threatening ventricular rhythm disorders.EMEA 19 April 2001 [http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/12/WC500018335.pdf EMEA Public Statement on the Recommendation to Suspend the Marketing Authorisation for Orlaam (Levacetylmethadol) in the European Union] {{Webarchive|url=https://web.archive.org/web/20170204203042/http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/12/WC500018335.pdf|date=4 February 2017}} In 2003, Roxane Laboratories, Inc. discontinued it in the U.S.{{cite web |date=20 August 2013 |title=Orlaam (levomethadyl acetate hydrochloride) |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm153332.htm |archive-url=https://web.archive.org/web/20170118091650/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm153332.htm |archive-date=18 January 2017 |work=FDA Safety Alerts |publisher=U.S. Food and Drug Administration}}

The DSM-5 guidelines for the diagnosis of opioid use disorder require that the individual has a significant impairment or distress related to opioid uses.{{citation |author=American Psychiatric Association |title=Diagnostic and Statistical Manual of Mental Disorders (5th ed.) |pages=[https://archive.org/details/diagnosticstatis0005unse/page/540 540–546] |year=2013 |url=https://archive.org/details/diagnosticstatis0005unse/page/540 |location=Arlington |publisher=American Psychiatric Publishing |isbn=978-0-89042-555-8}} To make the diagnosis two or more of 11 criteria must be present in a given year:

1. More opioids are taken than intended
2. The individual is unable to decrease the number of opioids used
3. Large amounts of time are spent trying to obtain opioids, use opioids, or recover from taking them
4. The individual has cravings for opioids
5. Difficulty fulfilling professional duties at work or school
6. Continued use of opioids leading to social and interpersonal consequences
7. Decreased social or recreational activities
8. Using opioids despite being in physically dangerous settings
9. Continued use despite opioids worsening physical or psychological health (i.e. depression, constipation)
10. Tolerance
11. Withdrawal

The severity can be classified as mild, moderate, or severe based on the number of criteria present. The tolerance and withdrawal criteria are not considered to be met for individuals taking opioids solely under appropriate medical supervision. Addiction and dependence are components of a substance use disorder; addiction is the more severe form.

Signs and symptoms of opioid intoxication include:{{Cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK64116/table/A85633/ |title=[Table], Figure 4-4: Signs and Symptoms of Opioid Intoxication and Withdrawal | author = Center for Substance Abuse Treatment |date=2006 |website=www.ncbi.nlm.nih.gov |access-date=6 April 2019}}{{Div col|colwidth=20em}}

• Decreased perception of pain
• Euphoria
• Confusion
• Desire to sleep
• Nausea
• Constipation
• Miosis (pupil constriction)
• Bradycardia (slow heart rate)
• Hypotension (low blood pressure)
• Hypokinesis (slowed movement)
• Head nodding
• Slurred speech
• Hypothermia (low body temperature)

{{div col end}}

{{Main|Opioid overdose}}

File:Fentanyl. 2 mg. A lethal dose in most people.jpg. 2 mg (white powder to the right) is a lethal dose in most people.[https://www.dea.gov/galleries/drug-images/fentanyl Fentanyl]. Image 4 of 17. US DEA (Drug Enforcement Administration). See [https://web.archive.org/web/20181008000027/https://www.dea.gov/galleries/drug-images/fentanyl archive] with caption: "photo illustration of 2 milligrams of fentanyl, a lethal dose in most people". US penny is 19 mm (0.75 in) wide.]]

Signs and symptoms of opioid overdose include, but are not limited to:Kosten TR, Haile CN. Opioid-Related Disorders. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e ''New York, NY: McGraw-Hill; 2014. http://accessmedicine.mhmedical.com/content.aspx?bookid=1130§ionid=79757372 Accessed 9 March 2017.

• Pin-point pupils may occur. Patient presenting with dilated pupils may still be experiencing an opioid overdose.
• Decreased heart rate
• Decreased body temperature
• Decreased breathing
• Altered level of consciousness. People may be unresponsive or unconscious.
• Pulmonary edema (fluid accumulation in the lungs)
• Shock
• Death

File:OxyContin branded oxycodone 10mg (number side).jpg 10 mg, number facing up; the squares in the image represent one half centimeter, so the pill is around 0.75 cm in diameter.]]

{{main article|Opioid withdrawal}}

Opioid withdrawal can occur with a sudden decrease in, or cessation of, opioids after prolonged use.{{cite book |title=Diagnostic and statistical manual of mental disorders : DSM-5. |date=2013 |publisher=American Psychiatric Association |isbn=978-0-89042-554-1 |edition=5th |pages=547–549}}{{cite book|id={{NCBIBook|NBK526012}} | vauthors = Shah M, Huecker MR |title=Opioid Withdrawal |date=2019 |url=http://www.ncbi.nlm.nih.gov/books/NBK526012/ |publisher=StatPearls Publishing |pmid=30252268 |access-date=21 October 2019 }}{{cite journal | vauthors = Pergolizzi JV, Raffa RB, Rosenblatt MH | title = Opioid withdrawal symptoms, a consequence of chronic opioid use and opioid use disorder: Current understanding and approaches to management | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 45 | issue = 5 | pages = 892–903 | date = October 2020 | pmid = 31986228 | doi = 10.1111/jcpt.13114 | doi-access = free }} Onset of withdrawal depends on the half-life of the opioid that was used last.{{cite book | vauthors = Ries RK, Miller SC, Fiellin DA |url=https://books.google.com/books?id=j6GGBud8DXcC&pg=PA593 |title=Principles of Addiction Medicine |date=2009 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7477-2 |pages=593–594 }} With heroin this typically occurs five hours after use. With methadone, it may take two days.

The length of time that major symptoms occur also depends on the opioid used. For heroin withdrawal, symptoms are typically greatest at two to four days and can last up to two weeks.{{cite journal | vauthors = Rahimi-Movaghar A, Gholami J, Amato L, Hoseinie L, Yousefi-Nooraie R, Amin-Esmaeili M | title = Pharmacological therapies for management of opium withdrawal | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 6 | pages = CD007522 | date = June 2018 | pmid = 29929212 | pmc = 6513031 | doi = 10.1002/14651858.CD007522.pub2 }} Less significant symptoms may remain longer, in which case the withdrawal is known as post-acute-withdrawal syndrome.

{{Div col|colwidth=20em}}

• Agitation
• Anxiety
• Muscle pains
• Increased tearing
• Trouble sleeping
• Runny nose
• Sweating
• Yawning
• Goose bumps
• Dilated pupils
• Diarrhea
• Fast heart rate
• High blood pressure
• Abdominal cramps
• Shakiness
• Cravings
• Sneezing
• Bone pain
• Increased body temperature
• Hyperalgesia
• Ptosis (drooping eyelids)
• Teeth chattering
• Emotional pain
• Stress
• Weakness
• Malaise
• Alexithymia
• Dysphoria

{{div col end}}

Treatment of withdrawal may include methadone and buprenorphine. Medications for nausea or diarrhea may also be used.

Opioid use disorder can develop for many reasons, including systemic failures such as pervasive marketing strategies,{{Cite journal |last1=Connery |first1=Lucy |last2=Tomilin |first2=Kailyn |last3=Lynch |first3=Joshua |date=May 2025 |title=The Changing Demographics of the Opioid Epidemic |url=https://journals.lww.com/10.1097/01.EEM.0000000000000031 |journal=Emergency Medicine News |language=en |volume=47 |issue=4 |pages=14–15 |doi=10.1097/01.EEM.0000000000000031 |issn=1054-0725 }} over-prescribing, and self-medication.{{cite journal | vauthors = Chen KW, Banducci AN, Guller L, Macatee RJ, Lavelle A, Daughters SB, Lejuez CW | title = An examination of psychiatric comorbidities as a function of gender and substance type within an inpatient substance use treatment program | journal = Drug and Alcohol Dependence | volume = 118 | issue = 2–3 | pages = 92–99 | date = November 2011 | pmid = 21514751 | pmc = 3188332 | doi = 10.1016/j.drugalcdep.2011.03.003 }}Rizk JG, Saini J, Kim K, Pathan U, Qato DM. County-level factors associated with a mismatch between opioid overdose mortality and availability of opioid treatment facilities. *PLoS One*. 2024 Apr 5;19(4):e0301863. doi: [10.1371/journal.pone.0301863](https://doi.org/10.1371/journal.pone.0301863). PMID: 38578818; PMCID: PMC10997118. Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.{{cite journal | vauthors = Webster LR, Webster RM | title = Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool | journal = Pain Medicine | volume = 6 | issue = 6 | pages = 432–442 | year = 2005 | pmid = 16336480 | doi = 10.1111/j.1526-4637.2005.00072.x | doi-access = free }} Healthcare practitioners have long been aware that despite the effective use of opioids for managing pain, empirical evidence supporting long-term opioid use is minimal.{{cite journal | vauthors = Papaleontiou M, Henderson CR, Turner BJ, Moore AA, Olkhovskaya Y, Amanfo L, Reid MC | title = Outcomes associated with opioid use in the treatment of chronic noncancer pain in older adults: a systematic review and meta-analysis | journal = Journal of the American Geriatrics Society | volume = 58 | issue = 7 | pages = 1353–1369 | date = July 2010 | pmid = 20533971 | pmc = 3114446 | doi = 10.1111/j.1532-5415.2010.02920.x }}{{cite journal | vauthors = Noble M, Tregear SJ, Treadwell JR, Schoelles K | title = Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety | journal = Journal of Pain and Symptom Management | volume = 35 | issue = 2 | pages = 214–228 | date = February 2008 | pmid = 18178367 | doi = 10.1016/j.jpainsymman.2007.03.015 | doi-access = free }}{{cite journal | vauthors = Martell BA, O'Connor PG, Kerns RD, Becker WC, Morales KH, Kosten TR, Fiellin DA | title = Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction | journal = Annals of Internal Medicine | volume = 146 | issue = 2 | pages = 116–127 | date = January 2007 | pmid = 17227935 | doi = 10.7326/0003-4819-146-2-200701160-00006 | s2cid = 28969290 }}{{cite journal | vauthors = Kalso E, Edwards JE, Moore AR, McQuay HJ | title = Opioids in chronic non-cancer pain: systematic review of efficacy and safety | journal = Pain | volume = 112 | issue = 3 | pages = 372–380 | date = December 2004 | pmid = 15561393 | doi = 10.1016/j.pain.2004.09.019 | s2cid = 25807828 }}{{cite journal | vauthors = Goesling J, DeJonckheere M, Pierce J, Williams DA, Brummett CM, Hassett AL, Clauw DJ | title = Opioid cessation and chronic pain: perspectives of former opioid users | journal = Pain | volume = 160 | issue = 5 | pages = 1131–1145 | date = May 2019 | pmid = 30889052 | pmc = 8442035 | doi = 10.1097/j.pain.0000000000001493 }} Many studies of patients with chronic pain have failed to show any sustained improvement in their pain or ability to function with long-term opioid use.{{cite journal | vauthors = Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S | title = Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial | journal = JAMA | volume = 319 | issue = 9 | pages = 872–882 | date = March 2018 | pmid = 29509867 | pmc = 5885909 | doi = 10.1001/jama.2018.0899 | doi-access = free }}{{cite journal | vauthors = Eriksen J, Sjøgren P, Bruera E, Ekholm O, Rasmussen NK | title = Critical issues on opioids in chronic non-cancer pain: an epidemiological study | journal = Pain | volume = 125 | issue = 1–2 | pages = 172–179 | date = November 2006 | pmid = 16842922 | doi = 10.1016/j.pain.2006.06.009 | s2cid = 24858908 }}{{cite journal | vauthors = Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC | title = Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review | journal = Spine | volume = 39 | issue = 7 | pages = 556–563 | date = April 2014 | pmid = 24480962 | doi = 10.1097/BRS.0000000000000249 | s2cid = 25356400 }}

A 2024 literature review suggests that adverse childhood experiences (ACEs) are significantly associated with opioid use disorder later in life. ACEs include witnessing violence, experiencing abuse and neglect, and growing up with a family member with a mental health or substance abuse problem.{{Cite journal |last1=Regmi |first1=Sanjaya |last2=Kedia |first2=Satish K. |last3=Ahuja |first3=Nikhil A. |last4=Lee |first4=Guijin |last5=Entwistle |first5=Coree |last6=Dillon |first6=Patrick J. |date=July 2024 |title=Association Between Adverse Childhood Experiences and Opioid Use-Related Behaviors: A Systematic Review |url=https://journals.sagepub.com/doi/10.1177/15248380231205821 |journal=Trauma, Violence, & Abuse |language=en |volume=25 |issue=3 |pages=2046–2064 |doi=10.1177/15248380231205821 |pmid=37920999 |issn=1524-8380}}

Addiction is a chronic brain disorder characterized by compulsive drug use despite adverse consequences.{{cite journal | vauthors = Volkow ND, Koob GF, McLellan AT | title = Neurobiologic Advances from the Brain Disease Model of Addiction | journal = The New England Journal of Medicine | volume = 374 | issue = 4 | pages = 363–371 | date = January 2016 | pmid = 26816013 | pmc = 6135257 | doi = 10.1056/NEJMra1511480 | quote = Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder. }}{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |pages=364–375 |edition=2nd |chapter=Chapter 15: Reinforcement and Addictive Disorders}}{{cite web |title=Glossary of Terms |url=http://neuroscience.mssm.edu/nestler/glossary.html |website=Mount Sinai School of Medicine |publisher=Department of Neuroscience |access-date=9 February 2015 |archive-date=10 May 2019 |archive-url=https://web.archive.org/web/20190510151655/https://neuroscience.mssm.edu/nestler/glossary.html |url-status=dead}} Addiction involves the overstimulation of the brain's mesocorticolimbic reward circuit (reward system), essential for motivating behaviors linked to survival and reproductive fitness, like seeking food and sex.{{cite journal | vauthors = Schultz W | title = Neuronal Reward and Decision Signals: From Theories to Data | journal = Physiological Reviews | volume = 95 | issue = 3 | pages = 853–951 | date = July 2015 | pmid = 26109341 | pmc = 4491543 | doi = 10.1152/physrev.00023.2014 }} This reward system encourages associative learning and goal-directed behavior. In addiction, substances overactivate this circuit, causing compulsive behavior due to changes in brain synapses.Brain & Behavior Research Foundation (13 March 2019). "The Biology of Addiction". YouTube.

In the brain's mesolimbic region, Nucleus Accumbens (NAc) accepts releases of dopamine triggered by the neurotransmitters. The brain reward circuitry is rooted in these networks, interacting between the mesolimbic and prefrontal cortex; these systems link motivation, anti-stress, incentive salience, and wellbeing.{{Cite journal |last1=Gold |first1=Mark S |last2=Baron |first2=David |last3=Bowirrat |first3=Abdalla |last4=Blum |first4=Kenneth |date=September 15, 2020 |title=Neurological correlates of brain reward circuitry linked to opioid use disorder (OUD): Do homo sapiens acquire or have a reward deficiency syndrome? |journal=Journal of the Neurological Sciences |volume=418 |issue=117137 |doi=10.1016/j.jns.2020.117137 |pmid=32957037 |pmc=7490287 }}

The incentive-sensitization theory differentiates between "wanting" (driven by dopamine in the reward circuit) and "liking" (related to brain pleasure centers).{{cite journal | vauthors = Robinson TE, Berridge KC | title = Review. The incentive sensitization theory of addiction: some current issues | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 363 | issue = 1507 | pages = 3137–3146 | date = October 2008 | pmid = 18640920 | pmc = 2607325 | doi = 10.1098/rstb.2008.0093 }} This explains the addictive potential of non-pleasurable substances and the persistence of opioid addiction despite tolerance to their euphoric effects. Addiction surpasses mere avoidance of withdrawal, involving cues and stress that reactivate reward-driven behaviors. This is thought to be an important reason detoxification alone is unsuccessful 90% of the time.{{cite web | url=https://www.bccsu.ca/opioid-use-disorder/ | title=Opioid Use Disorder }}{{Cite web |date=11 June 2021 |title=Medically Supervised Withdrawal (Detoxification) from Opioids |url=https://pcssnow.org/courses/detoxification-from-opioids/ |website=pcssnow.org}}{{cite journal | vauthors = Weiss RD, Potter JS, Fiellin DA, Byrne M, Connery HS, Dickinson W, Gardin J, Griffin ML, Gourevitch MN, Haller DL, Hasson AL, Huang Z, Jacobs P, Kosinski AS, Lindblad R, McCance-Katz EF, Provost SE, Selzer J, Somoza EC, Sonne SC, Ling W | title = Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial | journal = Archives of General Psychiatry | volume = 68 | issue = 12 | pages = 1238–1246 | date = December 2011 | pmid = 22065255 | pmc = 3470422 | doi = 10.1001/archgenpsychiatry.2011.121 }}

File:Mesocorticolimbic Circuit.png plays a major role in opioid addiction.]]

Overexpression of the gene transcription factor ΔFosB in the nucleus accumbens plays a crucial role in the development of an addiction to opioids and other addictive drugs by sensitizing drug reward and amplifying compulsive drug-seeking behavior.{{cite journal | vauthors = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues in Clinical Neuroscience | volume = 15 | issue = 4 | pages = 431–443 | date = December 2013 | pmid = 24459410 | pmc = 3898681 | doi = 10.31887/DCNS.2013.15.4/enestler | quote = Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process. }}{{cite journal | vauthors = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = The American Journal of Drug and Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–437 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | s2cid = 19157711 }} Like other addictive drugs, overuse of opioids leads to increased ΔFosB expression in the nucleus accumbens.{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–637 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}{{cite journal | vauthors = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–1122 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 }}{{cite journal | vauthors = Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | journal = Journal of Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | year = 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112 }}

Opioids affect dopamine neurotransmission in the nucleus accumbens via the disinhibition of dopaminergic pathways as a result of inhibiting the GABA-based projections to the ventral tegmental area (VTA) from the rostromedial tegmental nucleus (RMTg), which negatively modulates dopamine neurotransmission.{{cite journal | vauthors = Bourdy R, Barrot M | title = A new control center for dopaminergic systems: pulling the VTA by the tail | journal = Trends in Neurosciences | volume = 35 | issue = 11 | pages = 681–690 | date = November 2012 | pmid = 22824232 | doi = 10.1016/j.tins.2012.06.007 | s2cid = 43434322 }}{{cite web |title=Morphine addiction – Homo sapiens (human) |url=http://www.genome.jp/kegg-bin/show_pathway?hsa05032 |website=KEGG |publisher=Kanehisa Laboratories |access-date=11 September 2014 |date=18 June 2013}} In other words, opioids inhibit the projections from the RMTg to the VTA, which in turn disinhibits the dopaminergic pathways that project from the VTA to the nucleus accumbens and elsewhere in the brain.

The differences in the genetic regions encoding the dopamine receptors for each individual may help to elucidate part of the risk for opioid addiction and general substance abuse. Studies of the D2 Dopamine Receptor, in particular, have shown some promising results. One specific SNP is at the TaqI RFLP (rs1800497). In a 2014 study of 530 Han Chinese heroin-addicted individuals from a Methadone Maintenance Treatment Program, those with the specific genetic variation showed higher mean heroin consumption by around double those without the SNP.{{cite journal | vauthors = Mistry CJ, Bawor M, Desai D, Marsh DC, Samaan Z | title = Genetics of Opioid Dependence: A Review of the Genetic Contribution to Opioid Dependence | journal = Current Psychiatry Reviews | volume = 10 | issue = 2 | pages = 156–167 | date = May 2014 | pmid = 25242908 | pmc = 4155832 | doi = 10.2174/1573400510666140320000928 }} This study helps to show the contribution of dopamine receptors to substance addiction and more specifically to opioid abuse.

Neuroimaging has shown functional and structural alterations in the brain.{{cite journal | vauthors = Goldstein RZ, Volkow ND | title = Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 652–669 | date = October 2011 | pmid = 22011681 | pmc = 3462342 | doi = 10.1038/nrn3119 }} Chronic intake of opioids such as heroin may cause long-term effects in the orbitofrontal area (OFC), which is essential for regulating reward-related behaviors, emotional responses, and anxiety.{{cite journal | vauthors = Schoenbaum G, Shaham Y | title = The role of orbitofrontal cortex in drug addiction: a review of preclinical studies | journal = Biological Psychiatry | volume = 63 | issue = 3 | pages = 256–262 | date = February 2008 | pmid = 17719014 | pmc = 2246020 | doi = 10.1016/j.biopsych.2007.06.003 }} Moreover, neuroimaging and neuropsychological studies demonstrate dysregulation of circuits associated with emotion, stress and high impulsivity.{{cite journal | vauthors = Ieong HF, Yuan Z | title = Resting-State Neuroimaging and Neuropsychological Findings in Opioid Use Disorder during Abstinence: A Review | journal = Frontiers in Human Neuroscience | volume = 11 | pages = 169 | date = 1 January 2017 | pmid = 28428748 | pmc = 5382168 | doi = 10.3389/fnhum.2017.00169 | doi-access = free }}

Opioid dependence can occur as physical dependence, psychological dependence, or both. Drug dependence is an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake). Dependence is a component of a substance use disorder.{{cite encyclopedia |section=Opioid Use Disorder: Diagnostic Criteria |title=Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition |url=http://pcssmat.org/wp-content/uploads/2014/02/5B-DSM-5-Opioid-Use-Disorder-Diagnostic-Criteria.pdf |publisher=American Psychiatric Association |pages=1–9 |access-date=27 March 2017 |archive-url=https://web.archive.org/web/20171126121952/http://pcssmat.org/wp-content/uploads/2014/02/5B-DSM-5-Opioid-Use-Disorder-Diagnostic-Criteria.pdf |archive-date=26 November 2017 |url-status=dead}} Opioid dependence can manifest as physical dependence, psychological dependence, or both.

Increased brain-derived neurotrophic factor (BDNF) signaling in the ventral tegmental area (VTA) has been shown to mediate opioid-induced withdrawal symptoms via downregulation of insulin receptor substrate 2 (IRS2), protein kinase B (AKT), and mechanistic target of rapamycin complex 2 (mTORC2).{{cite journal | vauthors = Vargas-Perez H, Ting-A Kee R, Walton CH, Hansen DM, Razavi R, Clarke L, Bufalino MR, Allison DW, Steffensen SC, van der Kooy D | title = Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive rats | journal = Science | volume = 324 | issue = 5935 | pages = 1732–1734 | date = June 2009 | pmid = 19478142 | pmc = 2913611 | doi = 10.1126/science.1168501 | bibcode = 2009Sci...324.1732V }} As a result of downregulated signaling through these proteins, opiates cause VTA neuronal hyperexcitability and shrinkage (specifically, the size of the neuronal soma is reduced). It has been shown that when an opiate-naive person begins using opiates in concentrations that induce euphoria, BDNF signaling increases in the VTA.{{cite journal | vauthors = Laviolette SR, van der Kooy D | title = GABA(A) receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non-dopaminergic neural motivational systems | journal = The European Journal of Neuroscience | volume = 13 | issue = 5 | pages = 1009–1015 | date = March 2001 | pmid = 11264674 | doi = 10.1046/j.1460-9568.2001.01458.x | s2cid = 46694281 }}

Upregulation of the cyclic adenosine monophosphate (cAMP) signal transduction pathway by cAMP response element binding protein (CREB), a gene transcription factor, in the nucleus accumbens is a common mechanism of psychological dependence among several classes of drugs of abuse.{{cite journal | vauthors = Nestler EJ | title = Reflections on: "A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function" | journal = Brain Research | volume = 1645 | pages = 71–74 | date = August 2016 | pmid = 26740398 | pmc = 4927417 | doi = 10.1016/j.brainres.2015.12.039 | quote = Specifically, opiates in several CNS regions including NAc, and cocaine more selectively in NAc induce expression of certain adenylyl cyclase isoforms and PKA subunits via the transcription factor, CREB, and these transcriptional adaptations serve a homeostatic function to oppose drug action. In certain brain regions, such as locus coeruleus, these adaptations mediate aspects of physical opiate dependence and withdrawal, whereas in NAc they mediate reward tolerance and dependence that drives increased drug self-administration. }} Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid-induced physical dependence.

A scale was developed to compare the harm and dependence liability of 20 drugs. The scale uses a rating of zero to three to rate physical dependence, psychological dependence, and pleasure to create a mean score for dependence.{{cite journal | vauthors = Nutt D, King LA, Saulsbury W, Blakemore C | title = Development of a rational scale to assess the harm of drugs of potential misuse | journal = Lancet | volume = 369 | issue = 9566 | pages = 1047–1053 | date = March 2007 | pmid = 17382831 | doi = 10.1016/S0140-6736(07)60464-4 | s2cid = 5903121 }} Selected results can be seen in the chart below. Heroin and morphine both scored highest, at 3.0.

A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for several specific variations, but the evidence for clinical differences in opioid effects is not clear. There is an estimated 50% genetic contribution to opioid use disorder.{{cite journal | vauthors = Dick DM, Agrawal A | title = The genetics of alcohol and other drug dependence | journal = Alcohol Research & Health | volume = 31 | issue = 2 | pages = 111–118 | date = 2008 | pmid = 23584813 | pmc = 3860452 }} The pharmacogenomics of the opioid receptors and their endogenous ligands have been the subject of intensive activity in association studies. These studies test broadly for a number of phenotypes, including opioid dependence, cocaine dependence, alcohol dependence, methamphetamine dependence/psychosis, response to naltrexone treatment, personality traits, and others.

Major and minor variants have been reported for every receptor and ligand coding gene in both coding sequences, as well as regulatory regions. Research on endogenous opioid receptors has focused around the OPRM1 gene, which encodes the μ-opioid receptor, and the OPRK1 and OPRD1 genes, which encode the κ and δ receptors, respectively.

Newer approaches shift away from analysis of specific genes and regions to screen the entire genome. These GWAS studies have yielded a number of implicated genes, although many of them code for seemingly unrelated proteins in processes such as cell adhesion, transcriptional regulation, cell structure determination, and RNA, DNA, and protein handling/modifying.{{cite journal | vauthors = Hall FS, Drgonova J, Jain S, Uhl GR | title = Implications of genome wide association studies for addiction: are our a priori assumptions all wrong? | journal = Pharmacology & Therapeutics | volume = 140 | issue = 3 | pages = 267–279 | date = December 2013 | pmid = 23872493 | pmc = 3797854 | doi = 10.1016/j.pharmthera.2013.07.006 }}

While over 100 variants have been identified for the opioid mu-receptor, the most studied mu-receptor variant is the non-synonymous 118A>G variant, which results in functional changes to the receptor, including lower binding site availability, reduced mRNA levels, altered signal transduction, and increased affinity for beta-endorphin. In theory, all these functional changes would reduce the impact of exogenous opioids, requiring a higher dose to achieve the same therapeutic effect. This points to a potential for greater addictive capacity in individuals who require higher dosages to achieve pain control.

Evidence linking the 118A>G variant to opioid dependence is mixed, with associations shown in some study groups but negative results in other groups. One explanation for the mixed results is the possibility of other variants that are in linkage disequilibrium with the 118A>G variant and thus contribute to different haplotype patterns more specifically associated with opioid dependence.{{cite journal | vauthors = Bruehl S, Apkarian AV, Ballantyne JC, Berger A, Borsook D, Chen WG, Farrar JT, Haythornthwaite JA, Horn SD, Iadarola MJ, Inturrisi CE, Lao L, Mackey S, Mao J, Sawczuk A, Uhl GR, Witter J, Woolf CJ, Zubieta JK, Lin Y | title = Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges | journal = The Journal of Pain | volume = 14 | issue = 2 | pages = 103–113 | date = February 2013 | pmid = 23374939 | pmc = 3564046 | doi = 10.1016/j.jpain.2012.10.016 }}

While opioid receptors have been the most widely studied, a number of other genes have been implicated in OUD. Higher numbers of (CA) repeats flanking the preproenkephalin gene, PENK, have been associated with opiate dependence.{{cite journal | vauthors = Khokhar JY, Ferguson CS, Zhu AZ, Tyndale RF | title = Pharmacogenetics of drug dependence: role of gene variations in susceptibility and treatment | journal = Annual Review of Pharmacology and Toxicology | volume = 50 | pages = 39–61 | date = 2010 | pmid = 20055697 | doi = 10.1146/annurev.pharmtox.010909.105826 | s2cid = 2158248 }} There have been mixed results for the MCR2 gene, encoding melanocortin receptor type 2, implicating both protection and risk to heroin addiction.

A number of enzymes in the cytochrome P450 family may also play a role in dependence and overdose due to variance in breakdown of opioids and their receptors. There are also multiple potential complications with combining opioids with antidepressants and antiepileptic drugs (both common drugs for chronic pain patients) because of their effects on inducing CYP enzymes.{{cite journal | vauthors = Solhaug V, Molden E | title = Individual variability in clinical effect and tolerability of opioid analgesics - Importance of drug interactions and pharmacogenetics | journal = Scandinavian Journal of Pain | volume = 17 | pages = 193–200 | date = October 2017 | pmid = 29054049 | doi = 10.1016/j.sjpain.2017.09.009 }} Genotyping of CYP2D6 in particular may play a role in helping patients with individualized treatment for OUD and other drug addictions.

Prevention approaches for opioid use disorder must consider clinical recommendations for prescribing/starting to take opioids, when they are clinically appropriate to use, and risks associated with opioid therapy.{{Cite web |url=https://www.cdc.gov/drugoverdose/prescribing/guideline.html |title=CDC Guideline for Prescribing Opioids for Chronic Pain {{!}} Drug Overdose {{!}} CDC Injury Center |date=31 August 2018 |website=www.cdc.gov |access-date=3 November 2018}} Improving opioid prescribing guidelines and practices can help reduce unnecessary exposure to opioids, which lowers the risk of developing OUD (opioid use disorder). Healthcare providers should strictly follow evidence-based guidelines to ensure safe and appropriate use.{{Cite journal |last1=Wakeman |first1=Sarah |last2=Larochelle |first2=Marc |last3=Ameli |first3=Omid |title=Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder |journal=JAMA Network Open|date=2020 |volume=3 |issue=2 |pages=e1920622 |doi=10.1001/jamanetworkopen.2019.20622 |pmid=32022884 |pmc=11143463 }}

Another way to prevent OUD is by educating the public about the risks of prescription opioids and illegal substances like fentanyl. Awareness campaigns, community outreach programs, and school-based education initiatives can help people make informed decisions about opioid use and recognize the signs of addiction early.{{Cite journal |last1=McCarty |first1=Dennis |last2=Priest |first2=Kelsey C. |last3=Korthuis |first3=P. Todd |date=2018-04-01 |title=Treatment and Prevention of Opioid Use Disorder: Challenges and Opportunities |journal=Annual Review of Public Health |language=en |volume=39 |issue=1 |pages=525–541 |doi=10.1146/annurev-publhealth-040617-013526 |pmid=29272165 |pmc=5880741 |issn=0163-7525}}

A strong association between adverse childhood experiences and opioid abuse later in life has been identified, suggesting that a high adverse childhood experiences score should be considered a risk factor for opioid abuse. Screening for adverse childhood experiences before prescribing or implementing interventions involving opioids can mitigate the potential for misuse.

Naloxone is used for the emergency treatment of an overdose.{{cite encyclopedia |title=Naloxone |url=http://www.hmdb.ca/metabolites/HMDB0015314 |encyclopedia=Human Metabolome Database – Version 4.0 |access-date=2 November 2017 |date=23 October 2017}} It can be given by many routes (e.g., intramuscular (IM), intravenous (IV), subcutaneous, intranasal, and inhalation) and acts quickly by displacing opioids from opioid receptors and preventing the activation of these receptors.{{cite web |title=Naloxone for Treatment of Opioid Overdose |url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM522690.pdf |website=U.S. Food and Drug Administration (FDA) |access-date=7 November 2017}} Naloxone kits are recommended for laypersons who may witness an opioid overdose, for people with large prescriptions for opioids, those in substance use treatment programs, and those recently released from incarceration.{{Cite web |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6423a2.htm |title=Opioid Overdose Prevention Programs Providing Naloxone to Laypersons — United States, 2014 |website=www.cdc.gov |access-date=9 March 2017}}

Since naloxone is a life-saving medication, many areas of the U.S. have implemented standing orders for law enforcement to carry and give it as needed.{{cite web |vauthors=Childs R |date=July 2015 |title=Law enforcement and naloxone utilization in the United States |url=https://www.fda.gov/downloads/Drugs/NewsEvents/UCM454810.pdf |website=U.S. Food and Drug Administration (FDA) |publisher=North Carolina Harm Reduction Coalition |access-date=2 November 2017 |pages=1–24}}{{cite web |title=Case studies: Standing orders |url=http://naloxoneinfo.org/case-studies/standing-orders |website=NaloxoneInfo.org |publisher=Open Society Foundations |access-date=2 November 2017 |archive-date=7 November 2017 |archive-url=https://web.archive.org/web/20171107015820/http://naloxoneinfo.org/case-studies/standing-orders |url-status=dead}} In addition, naloxone can be used to challenge a person's opioid abstinence status before starting a medication such as naltrexone, which is used in the management of opioid addiction.{{cite journal | vauthors = Schuckit MA | title = Treatment of Opioid-Use Disorders | journal = The New England Journal of Medicine | volume = 375 | issue = 4 | pages = 357–368 | date = July 2016 | pmid = 27464203 | doi = 10.1056/NEJMra1604339 | doi-access = free }}

Good Samaritan laws typically protect bystanders who administer naloxone. In the U.S., at least 40 states have Good Samaritan laws to encourage bystanders to take action without fear of prosecution.Christie C, Baker C, Cooper R, Kennedy CP, Madras B, Bondi FA. The president's commission on combating drug addiction and the opioid crisis. Washington, DC, US Government Printing Office, November 2017;1. As of 2019, 48 states give pharmacists the authority to distribute naloxone without an individual prescription.{{cite web |title=Naloxone Opioid Overdose Reversal Medication |url=https://cvshealth.com/thought-leadership/naloxone-opioid-overdose-reversal-medication |website=CVS Health |access-date=4 February 2019 |archive-date=19 September 2018 |archive-url=https://web.archive.org/web/20180919062029/https://cvshealth.com/thought-leadership/naloxone-opioid-overdose-reversal-medication |url-status=dead }}

Homicide, suicide, accidents and liver disease are also opioid-related causes of death for those with OUD.{{cite journal | vauthors = Morin KA, Vojtesek F, Acharya S, Dabous JR, Marsh DC | title = Evidence of Increased Age and Sex Standardized Death Rates Among Individuals Who Accessed Opioid Agonist Treatment Before the Era of Synthetic Opioids in Ontario, Canada | journal = Cureus | volume = 13 | issue = 10 | pages = e19051 | date = October 2021 | pmid = 34853762 | pmc = 8608679 | doi = 10.7759/cureus.19051 | doi-access = free }}{{cite journal | vauthors = Hser YI, Hoffman V, Grella CE, Anglin MD | title = A 33-year follow-up of narcotics addicts | journal = Archives of General Psychiatry | volume = 58 | issue = 5 | pages = 503–508 | date = May 2001 | pmid = 11343531 | doi = 10.1001/archpsyc.58.5.503 }} Many of these causes of death are unnoticed due to the often limited information on death certificates.{{cite journal | vauthors = Horon IL, Singal P, Fowler DR, Sharfstein JM | title = Standard Death Certificates Versus Enhanced Surveillance to Identify Heroin Overdose-Related Deaths | journal = American Journal of Public Health | volume = 108 | issue = 6 | pages = 777–781 | date = June 2018 | pmid = 29672148 | pmc = 5944879 | doi = 10.2105/ajph.2018.304385 }} Other risk factors for overdose mortality related to opioids at the individual level include clinical factors such as cardiovascular disease, comorbid mental disorders and psychological stress (e.g., depression), a history of substance use disorders, economic and community distress (e.g., low education, high unemployment), and characteristics such as male sex and middle age.Rizk JG, Saini J, Kim K, Pathan U, Qato DM. County-level factors associated with a mismatch between opioid overdose mortality and availability of opioid treatment facilities. *PLoS One*. 2024 Apr 5;19(4):e0301863. doi: [10.1371/journal.pone.0301863](https://doi.org/10.1371/journal.pone.0301863). PMID: 38578818; PMCID: PMC10997118.

The CDC Clinical Practice Guideline for Prescribing Opioids for Pain was developed to help guide healthcare professinals toward safe and evidence-based use of opioid therapy.{{Cite journal |last=Dowell |first=Deborah |date=2022 |title=CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022 |url=https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm |journal=MMWR. Recommendations and Reports |language=en-us |volume=71 |issue=3 |pages=1–95 |doi=10.15585/mmwr.rr7103a1 |pmid=36327391 |issn=1057-5987|pmc=9639433 }} Large U.S. retail pharmacy chains are implementing protocols, guidelines, and initiatives to take back unused opioids, providing naloxone kits, and being vigilant about suspicious prescriptions.{{Cite news |title=Our Commitment to Fight Opioid Abuse {{!}} CVS Health |url=https://cvshealth.com/thought-leadership/cvs-health-enterprise-response-opioid-epidemic |url-status=dead |archive-url=https://web.archive.org/web/20181103092110/https://cvshealth.com/thought-leadership/cvs-health-enterprise-response-opioid-epidemic |archive-date=3 November 2018 |access-date=3 November 2018 |work=CVS Health}}{{Cite web |title=Combat opioid abuse {{!}} Walgreens |url=https://www.walgreens.com/topic/pharmacy/combat_opioid_abuse.jsp |access-date=3 November 2018 |website=Walgreens}} Insurance programs can help limit opioid use by setting quantity limits on prescriptions or requiring prior authorizations for certain medications.{{Cite web |date=31 August 2018 |title=Prevent Opioid Use Disorder {{!}} Drug Overdose {{!}} CDC Injury Center |url=https://www.cdc.gov/drugoverdose/prevention/opioid-use-disorder.html |access-date=20 November 2018 |website=www.cdc.gov}}

Many U.S. officials and government leaders have become involved in implementing preventative measures to decrease opioid usage in the U.S.{{cite journal |vauthors=McCarty D, Priest KC, Korthuis PT |date=April 2018 |title=Treatment and Prevention of Opioid Use Disorder: Challenges and Opportunities |journal=Annual Review of Public Health |volume=39 |issue=1 |pages=525–541 |doi=10.1146/annurev-publhealth-040617-013526 |pmc=5880741 |pmid=29272165}} Targeted education of medical providers and government officials can lead to provisions affecting opioid distribution by healthcare providers.

The "CDC Clinical Practice Guideline for Prescribing Opioids for Pain-United States, 2022" provides recommendations related to opioid misuse, OUD, and opioid overdoses.{{cite journal | vauthors = Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R | title = CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022 | journal = MMWR. Recommendations and Reports | volume = 71 | issue = 3 | pages = 1–95 | date = November 2022 | pmid = 36327391 | pmc = 9639433 | doi = 10.15585/mmwr.rr7103a1 }} It reports a lack of clinical evidence that "abuse-deterrent" opioids (e.g., OxyContin), as labeled by the U.S. Food and Drug Administration, are effective for OUD risk mitigation.{{Cite web | work = Center for Drug Evaluation and Research | publisher = U.S. Food and Drug Administration |date=2 March 2021 |title=Abuse-Deterrent Opioid Analgesics |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/abuse-deterrent-opioid-analgesics }} CDC guidance suggests the prescription of immediate-release opioids instead of opioids that have a long duration (long-acting) or opioids that are released over time (extended release). Other recommendations include prescribing the lowest opioid dose that successfully addresses the pain in opioid-naïve patients and collaborating with patients who already take opioid therapy to maximize the effect of non-opioid analgesics.

While receiving opioid therapy, patients should be periodically evaluated for opioid-related complications and clinicians should review state prescription drug monitoring program systems. The latter should be assessed to reduce the risk of overdoses in patients due to their opioid dose or medication combinations. For patients receiving opioid therapy in whom the risks outweigh the benefits, clinicians and patients should develop a treatment plan to decrease their opioid dose incrementally.

Compartmental models are mathematical frameworks used to assess and describe complex topics such as the opioid crisis. Applied compartmental models are used in public health to assess the effectiveness of interventions in opioid use disorder. Most overdoses in 2020 were due to synthetic opioids, highlighting a need to incorporate synthetic opioid data in the models.{{Cite journal |last1=Spence |first1=Chelsea |last2=Kurz |first2=Mary E. |last3=Sharkey |first3=Thomas C. |last4=Miller |first4=Bryan Lee |date=2024-06-23 |title=Scoping Literature Review of Disease Modeling of the Opioid Crisis |url=https://www.tandfonline.com/doi/full/10.1080/02791072.2024.2367617 |journal=Journal of Psychoactive Drugs |language=en |pages=1–14 |doi=10.1080/02791072.2024.2367617 |pmid=38909286 |issn=0279-1072}}

For more specific mitigation strategies regarding opioid overdoses, see {{slink|opioid overdose|Prevention}}.

Opioid use disorders typically require long-term treatment and care with the goal of reducing the person's risks and improving their long-term physical and psychological condition.{{cite web |date=2004 |title=Treatment of opioid dependence |url=https://www.who.int/hiv/pub/idu/position_paper_substitution_opioid/en/index.html |url-status=dead |archive-url=https://web.archive.org/web/20100614053502/http://www.who.int/hiv/pub/idu/position_paper_substitution_opioid/en/index.html |archive-date=14 June 2010 |access-date=28 August 2016 |publisher=WHO}}{{update after|2018|3|7}}

First-line management involves the use of opioid replacement therapies, particularly methadone, naltrexone, and buprenorphine/naloxone. Withdrawal management alone is strongly discouraged, because of its association with elevated risks of HIV and hepatitis C transmission, high rates of overdose deaths, and nearly universal relapse.{{cite journal | vauthors = Amato L, Davoli M, Minozzi S, Ferroni E, Ali R, Ferri M | title = Methadone at tapered doses for the management of opioid withdrawal | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 2 | pages = CD003409 | date = February 2013 | pmid = 23450540 | pmc = 7017622 | doi = 10.1002/14651858.CD003409.pub4 }}{{cite journal | vauthors = MacArthur GJ, van Velzen E, Palmateer N, Kimber J, Pharris A, Hope V, Taylor A, Roy K, Aspinall E, Goldberg D, Rhodes T, Hedrich D, Salminen M, Hickman M, Hutchinson SJ | title = Interventions to prevent HIV and Hepatitis C in people who inject drugs: a review of reviews to assess evidence of effectiveness | journal = The International Journal on Drug Policy | volume = 25 | issue = 1 | pages = 34–52 | date = January 2014 | pmid = 23973009 | doi = 10.1016/j.drugpo.2013.07.001 }} This approach is seen as ineffective without plans for transition to long-term evidence-based addiction treatment, such as opioid agonist treatment.

Though treatment reduces mortality rates, the first four weeks after treatment begins and the four weeks after treatment ceases are the riskiest times for drug-related deaths.{{cite journal | vauthors = Sordo L, Barrio G, Bravo MJ, Indave BI, Degenhardt L, Wiessing L, Ferri M, Pastor-Barriuso R | title = Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies | journal = BMJ | volume = 357 | pages = j1550 | date = April 2017 | pmid = 28446428 | pmc = 5421454 | doi = 10.1136/bmj.j1550 }} These periods of increased vulnerability are significant because many of those in treatment leave programs during these periods. There is evidence that people with opioid use disorder who are dependent on pharmaceutical opioids may require a different management approach from those who take heroin.{{cite journal | vauthors = Nielsen S, Tse WC, Larance B | title = Opioid agonist treatment for people who are dependent on pharmaceutical opioids | journal = The Cochrane Database of Systematic Reviews | volume = 2022 | issue = 9 | pages = CD011117 | date = September 2022 | pmid = 36063082 | pmc = 9443668 | doi = 10.1002/14651858.CD011117.pub3 | collaboration = Cochrane Drugs and Alcohol Group }}

{{See also|Opioid agonist therapy|Heroin-assisted treatment}}Opioid replacement therapy (ORT), also known as opioid substitution therapy (OST), Medication for Addiction Treatment (MAT), or Medications for Opioid Use Disorder (MOUD), involves replacing an opioid, such as heroin.{{Cite web |date=14 March 2017 |title=Opioid substitution therapy or treatment (OST) |url=https://ec.europa.eu/home-affairs/content/opioid-substitution-therapy-or-treatment-ost_en |website=Migration and Home Affairs |publisher=European Commission}}Richard P. Mattick et al.: [https://webarchive.nla.gov.au/awa/20140211195842/http://www.nationaldrugstrategy.gov.au/internet/drugstrategy/Publishing.nsf/content/8BA50209EE22B9C6CA2575B40013539D/$File/mono52.pdf National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendation] Commonly used drugs for ORT are methadone and buprenorphine/naloxone (Suboxone), which are taken under medical supervision. Buprenorphine/naloxone is usually preferred over methadone because of its safety profile, which is considered significantly better, primarily with regard to its risk of overdose{{cite journal | vauthors = Whelan PJ, Remski K | title = Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds | journal = Journal of Neurosciences in Rural Practice | volume = 3 | issue = 1 | pages = 45–50 | date = January 2012 | pmid = 22346191 | pmc = 3271614 | doi = 10.4103/0976-3147.91934 | doi-access = free }} and effects on the heart (QTc prolongation).{{cite journal | vauthors = Martin JA, Campbell A, Killip T, Kotz M, Krantz MJ, Kreek MJ, McCarroll BA, Mehta D, Payte JT, Stimmel B, Taylor T, Haigney MC, Wilford BB | title = QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel | journal = Journal of Addictive Diseases | volume = 30 | issue = 4 | pages = 283–306 | date = October 2011 | pmid = 22026519 | pmc = 4078896 | doi = 10.1080/10550887.2011.610710 }}{{cite web | url=https://www.bccsu.ca/wp-content/uploads/2023/12/BC-OUD-Treatment-Guideline_2023-Update.pdf | title=A Guideline for the Clinical Management of Opioid Use Disorder }}

Buprenorphine/naloxone, methadone, and naltrexone are approved by the U.S. Food and Drug Administration (FDA) for medication-assisted treatment (MAT).{{Cite web |title=MAT Medications, Counseling, and Related Conditions |url=https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions |access-date=10 November 2022 |website=www.samhsa.gov }} In the U.S., the Substance Abuse and Mental Health Services Administration (SAMHSA) certifies opioid treatment programs (OTPs), where methadone can be dispensed at methadone clinics.{{Cite web |title=Methadone |url=https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions/methadone |access-date=10 November 2022 |website=www.samhsa.gov }} As of 2023, the Waiver Elimination (MAT Act), also known as the "Omnibus Bill", removed the federal requirement for medical providers to obtain a waiver to prescribe buprenorphine, in an attempt to increase access to OUD treatment.{{Cite web |title=Waiver Elimination (MAT Act) |date=10 January 2023 |url=https://www.samhsa.gov/medications-substance-use-disorders/waiver-elimination-mat-act}}

The driving principle behind ORT is the patient's reclamation of a self-directed life.{{Cite web |title=Medication-Assisted Treatment (MAT) |url=https://www.samhsa.gov/medication-assisted-treatment |access-date=9 November 2022 |website=www.samhsa.gov }} ORT facilitates this process by reducing symptoms of drug withdrawal and drug cravings. In some countries (not the U.S. or Australia), regulations enforce a limited time for people on ORT programs that conclude when a stable economic and psychosocial situation is achieved. (People with HIV/AIDS or hepatitis C are usually excluded from this requirement.) In practice, 40–65% of patients maintain abstinence from additional opioids while receiving opioid replacement therapy and 70–95% can reduce their use significantly. Medical (improper diluents, non-sterile injecting equipment), psychosocial (mental health, relationships), and legal (arrest and imprisonment) issues that can arise from the use of illegal opioids are concurrently eliminated or reduced. Clonidine or lofexidine can help treat the symptoms of withdrawal.{{cite journal | vauthors = Gowing L, Farrell M, Ali R, White JM | title = Alpha₂-adrenergic agonists for the management of opioid withdrawal | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 5 | pages = CD002024 | date = May 2016 | pmid = 27140827 | pmc = 7081129 | doi = 10.1002/14651858.CD002024.pub5 }}

The period when initiating methadone and the time immediately after discontinuing treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies. ORT has proved to be the most effective treatment for improving the health and living condition of people experiencing illegal opiate use or dependence, including mortality reduction{{cite journal | vauthors = Michels II, Stöver H, Gerlach R | title = Substitution treatment for opioid addicts in Germany | journal = Harm Reduction Journal | volume = 4 | issue = 1 | pages = 5 | date = February 2007 | pmid = 17270059 | pmc = 1797169 | doi = 10.1186/1477-7517-4-5 | doi-access = free }} and overall societal costs, such as the economic loss from drug-related crime and healthcare expenditure.

A review of UK hospital policies found that local guidelines delayed access to substitute opioids, for instance by requiring lab tests to demonstrate recent use or input from specialist drug teams before prescribing. Delays to access can increase people's risk of discharging themselves early against medical advice.{{Cite journal |date=16 November 2022 |title=Many hospital policies create barriers to good management of opioid withdrawal |url=https://evidence.nihr.ac.uk/alert/many-hospital-policies-create-barriers-to-good-management-of-opioid-withdrawal/ |journal=NIHR Evidence |doi=10.3310/nihrevidence_54639|s2cid=253608569 }}{{cite journal | vauthors = Harris M, Holland A, Lewer D, Brown M, Eastwood N, Sutton G, Sansom B, Cruickshank G, Bradbury M, Guest I, Scott J | title = Barriers to management of opioid withdrawal in hospitals in England: a document analysis of hospital policies on the management of substance dependence | journal = BMC Medicine | volume = 20 | issue = 1 | pages = 151 | date = April 2022 | pmid = 35418095 | pmc = 9007696 | doi = 10.1186/s12916-022-02351-y | doi-access = free }} ORT is endorsed by the World Health Organization, United Nations Office on Drugs and Crime, and UNAIDS as effective at reducing injection, lowering risk for HIV/AIDS, and promoting adherence to antiretroviral therapy.

Buprenorphine and methadone work by reducing opioid cravings, easing withdrawal symptoms, and blocking the euphoric effects of opioids via cross-tolerance,{{cite journal | vauthors = Bonhomme J, Shim RS, Gooden R, Tyus D, Rust G | title = Opioid addiction and abuse in primary care practice: a comparison of methadone and buprenorphine as treatment options | journal = Journal of the National Medical Association | volume = 104 | issue = 7–8 | pages = 342–350 | date = July 2012 | pmid = 23092049 | pmc = 4039205 | doi = 10.1016/S0027-9684(15)30175-9 }} and in the case of buprenorphine, a high-affinity partial opioid agonist, also due to opioid receptor saturation.{{cite journal | vauthors = Orman JS, Keating GM | title = Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence | journal = Drugs | volume = 69 | issue = 5 | pages = 577–607 | date = 2009 | pmid = 19368419 | doi = 10.2165/00003495-200969050-00006 | s2cid = 209147406 }}

Buprenorphine can be administered either as a standalone product or in combination with the opioid antagonist naloxone. This inclusion is strategic: it deters misuse by preventing the crushing and injecting of the medication, encouraging instead the prescribed sublingual (under the tongue) route. Buprenorphine/naloxone formulations are available as tablets and films;{{Cite web |title=Buprenorphine |url=https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions/buprenorphine |access-date=10 November 2022 |website=www.samhsa.gov }} these formulations operate efficiently when taken sublingually. In this form, buprenorphine's bioavailability remains robust (35–55%), while naloxone's is significantly reduced (~10%).{{cite journal | vauthors = Yokell MA, Zaller ND, Green TC, Rich JD | title = Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review | journal = Current Drug Abuse Reviews | volume = 4 | issue = 1 | pages = 28–41 | date = March 2011 | pmid = 21466501 | pmc = 3154701 | doi = 10.2174/1874473711104010028 }}

Buprenorphine's role as a partial opioid receptor agonist sets it apart from full agonists like methadone. Its unique pharmacological profile makes it less likely to cause respiratory depression, thanks to its "ceiling effect".{{cite web |title=Medications for Opioid Use Disorder – Treatment Improvement Protocol 63 |url=https://store.samhsa.gov/file/24396/download?token=DIYILzbP |access-date=20 November 2018 |website=Substance Abuse and Mental Health Services Administration}}{{Dead link|date=October 2022|bot=InternetArchiveBot|fix-attempted=yes}}{{Cite web |title=What is Buprenorphine? {{!}} UAMS Psychiatric Research Institute |url=https://psychiatry.uams.edu/clinical-care/cast/buprenorphine/ |access-date=17 November 2022 |website=psychiatry.uams.edu/ }} While the risk of misuse or overdose is higher with buprenorphine alone compared to the buprenorphine/naloxone combination or methadone, its usage is linked to a decrease in mortality. Approved in the U.S. for opioid dependence treatment in 2002,{{cite web |date=8 October 2002 |title=Subutex and Suboxone Approved to Treat Opiate Dependence |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm191521.htm |access-date=1 November 2014 |publisher=U.S. Food and Drug Administration (FDA)}} buprenorphine has since expanded in form, with the FDA approving a month-long injectable version in 2017.{{Cite web |title=Sublocade (buprenorphine) FDA Approval History |url=https://www.drugs.com/history/sublocade.html |access-date=10 November 2022 |website=Drugs.com }}

When initiating buprenorphine/naloxone therapy, several critical factors must be considered. These include the severity of withdrawal symptoms, the time elapsed since the last opioid use, and the type of opioid involved (long-acting vs. short-acting).{{Cite web |title=SAMHSA Buprenorphine Quick Start Guide |url=https://www.samhsa.gov/sites/default/files/quick-start-guide.pdf}} A standard induction method involves waiting until the patient exhibits moderate withdrawal symptoms, as measured by a Clinical Opiate Withdrawal Scale, achieving a score of around 12. Alternatively, "microdosing" commences with a small dose immediately, regardless of withdrawal symptoms, offering a more flexible approach to treatment initiation.{{cite journal | vauthors = Wong JS, Nikoo M, Westenberg JN, Suen JG, Wong JY, Krausz RM, Schütz CG, Vogel M, Sidhu JA, Moe J, Arishenkoff S, Griesdale D, Mathew N, Azar P | title = Comparing rapid micro-induction and standard induction of buprenorphine/naloxone for treatment of opioid use disorder: protocol for an open-label, parallel-group, superiority, randomized controlled trial | journal = Addiction Science & Clinical Practice | volume = 16 | issue = 1 | pages = 11 | date = February 2021 | pmid = 33579359 | pmc = 7881636 | doi = 10.1186/s13722-021-00220-2 | doi-access = free }} "Macrodosing" starts with a larger dose of Suboxone, a different induction strategy with its own set of considerations.{{cite web | url=https://www.uptodate.com/contents/opioid-use-disorder-pharmacologic-management | title=UpToDate }}

Methadone is a commonly used full-opioid agonist in the treatment of opioid use disorder. It is effective in relieving withdrawal symptoms and cravings in people with opioid addiction, and can also be used in pain control in certain situations.{{cite journal | vauthors = Koehl JL, Zimmerman DE, Bridgeman PJ | title = Medications for management of opioid use disorder | journal = American Journal of Health-System Pharmacy | volume = 76 | issue = 15 | pages = 1097–1103 | date = July 2019 | pmid = 31361869 | doi = 10.1093/ajhp/zxz105 }} While methadone is a widely prescribed form of OAT, it often requires more frequent clinical visits compared to buprenorphine/naloxone, which also has a better safety profile and lower risk of respiratory depression and overdose.{{cite web | url=https://www.bccsu.ca/about-opioid-addiction-treatment/ | title=About Opioid Addiction Treatment }}

Important considerations when initiating methadone include the patient's opioid tolerance, the time since last opioid use, the type of opioid used (long-acting vs. short-acting), and the risk of methadone toxicity.{{Cite web |title=West Virginia Department of Human Health & Resources_Burea for Medical Services_Methadone |url=https://dhhr.wv.gov/bms/Public%20Notices/Documents/Chapter_518.1__Methadone.pdf}} Methadone comes in different forms: tablet, oral solution, or an injection.

One of methadone's benefits is that it can last up to 56 hours in the body, so if a patient misses a daily dose, they will not typically struggle with withdrawal symptoms. Other advantages of methadone include reduction in infectious disease related to injection drug use, and reduced mortality. Methadone has a number of potential side effects, including slowed breathing, nausea, vomiting, restlessness, and headache.{{Cite web |title=Methadone Side Effects: Common, Severe, Long Term |url=https://www.drugs.com/sfx/methadone-side-effects.html |access-date=10 November 2022 |website=Drugs.com }}

Naltrexone is an opioid receptor antagonist used for the treatment of opioid addiction.{{Cite web |date=July 2013 |title=Vivitrol Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf |access-date=2 November 2017 |publisher=Alkermes Inc. |archive-date=10 February 2017 |archive-url=https://web.archive.org/web/20170210215309/http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf |url-status=dead }}{{cite journal | vauthors = Skolnick P | title = The Opioid Epidemic: Crisis and Solutions | journal = Annual Review of Pharmacology and Toxicology | volume = 58 | issue = 1 | pages = 143–159 | date = January 2018 | pmid = 28968188 | doi = 10.1146/annurev-pharmtox-010617-052534 | doi-access = free }} It is not as widely used as buprenorphine or methadone for OUD due to low rates of patient acceptance, non-adherence due to daily dosing, and difficulty achieving abstinence from opioids before beginning treatment. Dosing naltrexone after recent opioid use can lead to precipitated withdrawal. Conversely, naltrexone antagonism at the opioid receptor can be overcome with higher doses of opioids.{{cite journal | vauthors = Sullivan MA, Garawi F, Bisaga A, Comer SD, Carpenter K, Raby WN, Anen SJ, Brooks AC, Jiang H, Akerele E, Nunes EV | title = Management of relapse in naltrexone maintenance for heroin dependence | journal = Drug and Alcohol Dependence | volume = 91 | issue = 2–3 | pages = 289–292 | date = December 2007 | pmid = 17681716 | pmc = 4153601 | doi = 10.1016/j.drugalcdep.2007.06.013 }} Naltrexone monthly IM injections received FDA approval in 2010 for the treatment of opioid dependence in abstinent opioid users.{{Cite book |author=Center for Substance Abuse Treatment |url=https://www.ncbi.nlm.nih.gov/books/NBK64042/ |title=Chapter 4—Oral Naltrexone |date=2009 |publisher=Substance Abuse and Mental Health Services Administration (US)}}

{{See also|Heroin maintenance}}

Evidence of effects of heroin maintenance compared to methadone are unclear as of 2010.{{cite report |url=http://www.ncbi.nlm.nih.gov/books/NBK464853/ |title=Heroin Maintenance for Persons with Chronic Heroin Dependence | vauthors = Dalsbø TK, Steiro AK, Hammerstrøm KT, Smedslund G |publisher=Knowledge Centre for the Health Services at The Norwegian Institute of Public Health |pmid=29320074 |publication-place=Oslo, Norway |year=2010}} A Cochrane review found some evidence in opioid users who had not improved with other treatments.{{cite journal | vauthors = Ferri M, Davoli M, Perucci CA | title = Heroin maintenance for chronic heroin-dependent individuals | journal = The Cochrane Database of Systematic Reviews | volume = 2011 | issue = 12 | pages = CD003410 | date = December 2011 | pmid = 22161378 | pmc = 7017638 | doi = 10.1002/14651858.CD003410.pub4 | s2cid = 6772720 }} In Switzerland, Germany, the Netherlands, and the United Kingdom, long-term injecting drug users who do not benefit from methadone and other medication options may be treated with injectable heroin that is administered under the supervision of medical staff.{{cite journal | vauthors = Rehm J, Gschwend P, Steffen T, Gutzwiller F, Dobler-Mikola A, Uchtenhagen A | title = Feasibility, safety, and efficacy of injectable heroin prescription for refractory opioid addicts: a follow-up study | journal = Lancet | volume = 358 | issue = 9291 | pages = 1417–1423 | date = October 2001 | pmid = 11705488 | doi = 10.1016/S0140-6736(01)06529-1 | s2cid = 24542893 }} Other countries where it is available include Spain, Denmark, Belgium, Canada, and Luxembourg.{{cite web |title=Heroin Assisted Treatment | Drug Policy Alliance |url=http://www.drugpolicy.org/resource/heroin-assisted-treatment-hat |access-date=4 March 2016 |archive-date=16 March 2016 |archive-url=https://web.archive.org/web/20160316041752/http://www.drugpolicy.org/resource/heroin-assisted-treatment-hat |url-status=dead }} Dihydrocodeine in both extended-release and immediate-release form is also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.{{cite journal | vauthors = Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A | title = Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial | journal = Addiction | volume = 101 | issue = 12 | pages = 1752–1759 | date = December 2006 | pmid = 17156174 | doi = 10.1111/j.1360-0443.2006.01603.x }}

Dihydrocodeine is an opioid agonist.{{Cite web |title=Dihydrocodeine |url=https://pubchem.ncbi.nlm.nih.gov/compound/dihydrocodeine#section=Top |work=Pubchem}} It may be used as a second-line treatment.{{Cite web |title=Login |url=https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6747#f_uses |access-date=2 November 2018 |website=online.lexi.com}} A 2020 systematic review found low-quality evidence that dihydrocodeine may be no more effective than other routinely used medication interventions in reducing illicit opiate use.{{cite journal | vauthors = Carney T, Van Hout MC, Norman I, Dada S, Siegfried N, Parry CD | title = Dihydrocodeine for detoxification and maintenance treatment in individuals with opiate use disorders | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 2 | pages = CD012254 | date = February 2020 | pmid = 32068247 | pmc = 7027221 | doi = 10.1002/14651858.CD012254.pub2 }}An extended-release morphine confers a possible reduction of opioid use and with fewer depressive symptoms but overall more adverse effects compared to other forms of long-acting opioids. Retention in treatment was not found to be significantly different.{{cite journal | vauthors = Ferri M, Minozzi S, Bo A, Amato L | title = Slow-release oral morphine as maintenance therapy for opioid dependence | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD009879 | date = June 2013 | pmid = 23740540 | doi = 10.1002/14651858.CD009879.pub2 | pmc = 11976517 }} It is used in Switzerland and Canada.{{cite web |title=Bundesamt für Gesundheit – Substitutionsgestützte Behandlung mit Diacetylmorphin (Heroin) |url=http://www.bag.admin.ch/themen/drogen/00042/00629/00799/index.html?lang=de |url-status=dead |archive-url=https://web.archive.org/web/20160313061735/http://www.bag.admin.ch/themen/drogen/00042/00629/00799/index.html?lang=de |archive-date=13 March 2016}}

Pregnant women with opioid use disorder can also receive treatment with methadone, naltrexone, or buprenorphine.{{cite journal | vauthors = Tran TH, Griffin BL, Stone RH, Vest KM, Todd TJ | title = Methadone, Buprenorphine, and Naltrexone for the Treatment of Opioid Use Disorder in Pregnant Women | journal = Pharmacotherapy | volume = 37 | issue = 7 | pages = 824–839 | date = July 2017 | pmid = 28543191 | doi = 10.1002/phar.1958 | publisher = Wiley | s2cid = 13772333 }} Buprenorphine appears to be associated with more favorable outcomes compared to methadone for treating opioid use disorder (OUD) in pregnancy. Studies show that buprenorphine is linked to lower risks of preterm birth, greater birth weight, and larger head circumference without increased harm.{{cite journal | vauthors = Zedler BK, Mann AL, Kim MM, Amick HR, Joyce AR, Murrelle EL, Jones HE | title = Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta-analysis of safety in the mother, fetus and child | journal = Addiction | volume = 111 | issue = 12 | pages = 2115–2128 | date = December 2016 | pmid = 27223595 | pmc = 5129590 | doi = 10.1111/add.13462 }} Compared to methadone, it consistently results in improved birth weight and gestational age, though these findings should be interpreted with caution due to potential biases.{{cite journal | vauthors = Kinsella M, Halliday LO, Shaw M, Capel Y, Nelson SM, Kearns RJ | title = Buprenorphine Compared with Methadone in Pregnancy: A Systematic Review and Meta-Analysis | journal = Substance Use & Misuse | volume = 57 | issue = 9 | pages = 1400–1416 | date = 29 July 2022 | pmid = 35758300 | doi = 10.1080/10826084.2022.2083174 | doi-access = free }}

Buprenorphine use correlates with a lower risk of adverse neonatal outcomes, with similar risks of adverse maternal outcomes as methadone.{{cite journal | vauthors = Suarez EA, Huybrechts KF, Straub L, Hernández-Díaz S, Jones HE, Connery HS, Davis JM, Gray KJ, Lester B, Terplan M, Mogun H, Bateman BT | title = Buprenorphine versus Methadone for Opioid Use Disorder in Pregnancy | journal = The New England Journal of Medicine | volume = 387 | issue = 22 | pages = 2033–2044 | date = December 2022 | pmid = 36449419 | pmc = 9873239 | doi = 10.1056/NEJMoa2203318 | author-link4 = Sonia Hernández-Díaz }} Infants born to buprenorphine-treated mothers generally have higher birth weights, fewer withdrawal symptoms, and a lower likelihood of premature birth. They often require less treatment for neonatal abstinence syndrome and have mothers who are more likely to start treatment earlier in pregnancy, leading to longer gestations and larger infants.{{cite journal | vauthors = Meyer MC, Johnston AM, Crocker AM, Heil SH | title = Methadone and buprenorphine for opioid dependence during pregnancy: a retrospective cohort study | journal = Journal of Addiction Medicine | volume = 9 | issue = 2 | pages = 81–86 | date = 2015 | pmid = 25622120 | pmc = 4375023 | doi = 10.1097/ADM.0000000000000092 }}

{{Further|Addiction#Behavioral therapy}}Paralleling the variety of medical treatments, there are many forms of psychotherapy and community support for treating OUD. The primary evidence-based psychotherapies include cognitive behavioral therapy (CBT), motivational enhancement therapy (MET), contingency management (CM), and twelve-step programs. Community-based support such as support groups (e.g., Narcotics Anonymous) and therapeutic housing for those with OUD is also an important aspect of healing.{{cite journal | vauthors = Carley JA, Oesterle T | title = Therapeutic Approaches to Opioid Use Disorder: What is the Current Standard of Care? | journal = International Journal of General Medicine | volume = 14 | pages = 2305–2311 | date = 3 June 2021 | pmid = 34113160 | pmc = 8184146 | doi = 10.2147/IJGM.S295461 | doi-access = free }}{{cite journal | vauthors = Dugosh K, Abraham A, Seymour B, McLoyd K, Chalk M, Festinger D | title = A Systematic Review on the Use of Psychosocial Interventions in Conjunction With Medications for the Treatment of Opioid Addiction | journal = Journal of Addiction Medicine | volume = 10 | issue = 2 | pages = 93–103 | date = Mar–Apr 2016 | pmid = 26808307 | pmc = 4795974 | doi = 10.1097/ADM.0000000000000193 }}

Cognitive behavioral therapy (CBT) is a form of psychosocial intervention that systematically evaluates thoughts, feelings, and behaviors about a problem and works to develop coping strategies to work through those problems.{{Cite book |title=Cognitive behavior therapy : basics and beyond |vauthors=Beck JS |isbn=978-1-60918-504-6 |edition=Second |location=New York |publisher=The Guilford Press |pages=19–20 |oclc=698332858 |date=18 August 2011}} This intervention has demonstrated success in many psychiatric conditions (e.g., depression) and substance use disorders (e.g., tobacco).{{cite journal | vauthors = Huibers MJ, Beurskens AJ, Bleijenberg G, van Schayck CP | title = Psychosocial interventions by general practitioners | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 3 | pages = CD003494 | date = July 2007 | pmid = 17636726 | pmc = 7003673 | doi = 10.1002/14651858.CD003494.pub2 | hdl-access = free | hdl = 2066/52984 }} The use of CBT alone for OUD has declined due to lack of efficacy, and many rely on medication therapy or medication therapy with CBT, since both were found to be more efficacious than CBT alone. CBT has been shown to be more successful in relapse prevention than treatment of ongoing drug use. It is particularly known for its durability.{{cite journal | vauthors = Carroll KM, Onken LS | title = Behavioral therapies for drug abuse | journal = The American Journal of Psychiatry | volume = 162 | issue = 8 | pages = 1452–1460 | date = August 2005 | pmid = 16055766 | pmc = 3633201 | doi = 10.1176/appi.ajp.162.8.1452 }}

Motivational enhancement therapy (MET) is the manualized form of motivational interviewing (MI). MI leverages one's intrinsic motivation to recover through education, formulation of relapse prevention strategies, reward for adherence to treatment guidelines, and positive thinking to keep motivation high—which are based on a person's socioeconomic status, gender, race, ethnicity, sexual orientation, and readiness to recover.{{cite journal | vauthors = Vasilaki EI, Hosier SG, Cox WM | title = The efficacy of motivational interviewing as a brief intervention for excessive drinking: a meta-analytic review | journal = Alcohol and Alcoholism | volume = 41 | issue = 3 | pages = 328–335 | date = May 2006 | pmid = 16547122 | doi = 10.1093/alcalc/agl016 | doi-access = free }}{{Cite encyclopedia |title=Psychosocial interventions for opioid use disorder |encyclopedia=UpToDate |url=https://www.uptodate.com/contents/psychosocial-interventions-for-opioid-use-disorder |access-date=2 November 2017}} Like CBT, MET alone has not shown convincing efficacy for OUD. There is stronger support for combining it with other therapies.

Contingency Management Therapy (CMT) employs similar principles as operant behavioral conditioning, such as using incentives to reach certain goals (e.g., verified abstinence, usually in the form of urine drug testing). This form of psychotherapy has the strongest, most robust empirical support for treating drug addiction.{{cite journal | vauthors = Dutra L, Stathopoulou G, Basden SL, Leyro TM, Powers MB, Otto MW | title = A meta-analytic review of psychosocial interventions for substance use disorders | journal = The American Journal of Psychiatry | volume = 165 | issue = 2 | pages = 179–187 | date = February 2008 | pmid = 18198270 | doi = 10.1176/appi.ajp.2007.06111851 | s2cid = 29327821 }}

Outpatient clients are shown to have improved medication compliance, retention, and abstinence when using voucher-based incentives. One way this is implemented is to offer take-home privileges for methadone programs. Despite its effectiveness during treatment, effects tend to wane once terminated. Additionally, the cost barrier limits its application in the clinical community.

{{Main|Twelve-step program}}

While medical treatment may help with the initial symptoms of opioid withdrawal, once the first stages of withdrawal are through, a method for long-term preventative care is attendance at 12-step groups such as Narcotics Anonymous (NA).{{cite journal | vauthors = Melemis SM | title = Relapse Prevention and the Five Rules of Recovery | journal = The Yale Journal of Biology and Medicine | volume = 88 | issue = 3 | pages = 325–332 | date = September 2015 | pmid = 26339217 | pmc = 4553654 }} NA's 12-step process is based on the 12-step facilitation of Alcoholic Anonymous (AA) and centers on peer support, self-help, and spiritual connectedness. Some evidence also supports the use of these programs for adolescents.{{cite journal | vauthors = Sussman S | title = A review of Alcoholics Anonymous/ Narcotics Anonymous programs for teens | journal = Evaluation & the Health Professions | volume = 33 | issue = 1 | pages = 26–55 | date = March 2010 | pmid = 20164105 | pmc = 4181564 | doi = 10.1177/0163278709356186 }} Multiple studies have shown increased abstinence for those in NA compared to those who are not.{{cite journal | vauthors = Galanter M | title = Combining medically assisted treatment and Twelve-Step programming: a perspective and review | journal = The American Journal of Drug and Alcohol Abuse | volume = 44 | issue = 2 | pages = 151–159 | date = 28 October 2016 | pmid = 28387530 | doi = 10.1080/00952990.2017.1306747 | doi-access = free }}{{cite journal | vauthors = Gamble J, O'Lawrence H | title = An Overview of the Efficacy of the 12-Step Group Therapy for Substance Abuse Treatment | journal = Journal of Health and Human Services Administration | volume = 39 | issue = 1 | pages = 142–160 | date = Summer 2016 | pmid = 27483978 | doi = 10.1177/107937391603900108 }}{{cite journal | vauthors = Donovan DM, Ingalsbe MH, Benbow J, Daley DC | title = 12-step interventions and mutual support programs for substance use disorders: an overview | journal = Social Work in Public Health | volume = 28 | issue = 3–4 | pages = 313–332 | date = 26 August 2013 | pmid = 23731422 | pmc = 3753023 | doi = 10.1080/19371918.2013.774663 }} Members report a median abstinence length of 5 years.

Though medications and behavioral treatments are effective forms for treating OUD, relapse remains a common problem. The medical community has looked to novel technologies and traditional alternative medicines for new ways to approach the issues of continued cravings and impaired executive functioning. While consensus on their efficacy has not been reached, a number of reviews have shown promising results for the use of non-invasive brain stimulation (NIBS) for reducing cravings in OUD.{{cite journal | vauthors = Ward HB, Mosquera MJ, Suzuki J, Mariano TY | title = A Systematic Review of Noninvasive Brain Stimulation for Opioid Use Disorder | journal = Neuromodulation | volume = 23 | issue = 3 | pages = 301–311 | date = April 2020 | pmid = 32059080 | doi = 10.1111/ner.13108 | s2cid = 211122521 | pmc = 11528323 }}{{cite journal | vauthors = Young JR, Smani SA, Mischel NA, Kritzer MD, Appelbaum LG, Patkar AA | title = Non-invasive brain stimulation modalities for the treatment and prevention of opioid use disorder: a systematic review of the literature | journal = Journal of Addictive Diseases | volume = 38 | issue = 2 | pages = 186–199 | date = April–June 2020 | pmid = 32469286 | doi = 10.1080/10550887.2020.1736756 | s2cid = 216247971 }}

These results are consistent with the use of NIBS for reducing cravings of other substances. Investigations into the anecdotal evidence of psychedelics like ibogaine have also shown the possibility of decreased cravings and withdrawal symptoms.{{cite journal | vauthors = Köck P, Froelich K, Walter M, Lang U, Dürsteler KM | title = A systematic literature review of clinical trials and therapeutic applications of ibogaine | journal = Journal of Substance Abuse Treatment | volume = 138 | pages = 108717 | date = July 2022 | pmid = 35012793 | doi = 10.1016/j.jsat.2021.108717 }} Ibogaine is illegal in the U.S. but is unregulated in Mexico, Costa Rica, and New Zealand, where many clinics use it for addiction treatment.{{Cite web | vauthors = Sullivan K |date=24 January 2023 |title=The psychedelic ibogaine can treat addiction. The race is on to cash in. |url=https://theguardian.com/society/2023/jan/23/ibogaine-iboga-drug-addiction-psychedelic-gabon |website=The Guardian}} Research has shown a minor mortality risk due to its cardiotoxic and neurotoxic effects.

In 2024 the FDA approved the NET (NeuroElectric Therapy) device, which reduces withdrawal symptoms by neurostimulation. Used for three to five days of continuous treatment, NET delivers alternating current via surface electrodes placed trans-cranially at the base of the skull on each side of the head.{{cite web |last1=Passmore |first1=Grason |title=Revolutionary Kentucky-based opioid use disorder treatment device receives FDA approval |url=https://www.wkyt.com/2024/06/26/revolutionary-kentucky-based-opioid-use-disorder-treatment-device-receives-fda-approval/ |website=www.wkyt.com |access-date=29 June 2024 |language=en |date=26 June 2024}}{{Cite web |date=2019-03-08 |title=Clinical trial for medical device may prove worthy alternative to medication for opioid abstinence |url=https://today.wayne.edu/medicine/news/2021/10/13/clinical-trial-for-medical-device-may-prove-worthy-alternative-to-medication-for-opioid-abstinence-46323 |access-date=2024-06-29 |website=School of Medicine News |language=en}}

The stigma surrounding addiction can heavily influence opioid addicts not to seek help. Many people view addiction as a moral failing rather than a medical condition, which can lead to feelings of shame and isolation. This stigma can affect family members, making it difficult for them to support their loved ones effectively.{{Cite journal |last1=Hoffman |first1=Kim A. |last2=Terashima |first2=Javier Ponce |last3=McCarty |first3=Dennis |date=25 November 2019 |title=Opioid use disorder and treatment: challenges and opportunities |journal=BMC Health Services Research |volume=19 |issue=1 |page=884 |doi=10.1186/s12913-019-4751-4 |doi-access=free |pmid=31767011 |pmc=6876068 |url=https://link.springer.com/content/pdf/10.1186/s12913-019-4751-4.pdf }}

According to position papers on the treatment of opioid dependence published by the United Nations Office on Drugs and Crime and the World Health Organization, care providers should not treat opioid use disorder as the result of a weak moral character or will but as a medical condition.{{cite journal |vauthors=Santoro TN, Santoro JD |date=December 2018 |title=Racial Bias in the US Opioid Epidemic: A Review of the History of Systemic Bias and Implications for Care |journal=Cureus |volume=10 |issue=12 |pages=e3733 |doi=10.7759/cureus.3733 |pmc=6384031 |pmid=30800543 |doi-access=free}}{{cite book |url=http://whqlibdoc.who.int/unaids/2004/9241591153_eng.pdf |title=Substitution maintenance therapy in the management of opioid dependence and HIV/AIDS prevention |publisher=World Health Organization |year=2004 |isbn=978-92-4-159115-7}}{{cite web |date=2004 |title=Treatment of opioid dependence |url=https://www.who.int/hiv/pub/idu/position_paper_substitution_opioid/en/index.html |url-status=dead |archive-url=https://web.archive.org/web/20100614053502/http://www.who.int/hiv/pub/idu/position_paper_substitution_opioid/en/index.html |archive-date=14 June 2010 |access-date=28 August 2016 |publisher=WHO}}{{update after|2018|3|7}} Some evidence suggests the possibility that opioid use disorders occur due to genetic or other chemical mechanisms that may be difficult to identify or change, such as dysregulation of brain circuitry involving reward and volitional experience. It has also been hypothesized that endocrine and autonomic nervous system abnormalities can be opioid-induced. Critically, the endogenous opioid system is involved in reward; changes to this system affect experience and subsequent behavior.{{Cite journal |last1=Rosoff |first1=Daniel B. |last2=Smith |first2=George Davey |last3=Lohoff |first3=Falk W. |date=2021-02-01 |title=Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders: A Multivariable Mendelian Randomization Analysis |url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2772881 |journal=JAMA Psychiatry |volume=78 |issue=2 |pages=151–160 |doi=10.1001/jamapsychiatry.2020.3554 |pmid=33175090 |issn=2168-622X|hdl=1983/e11ccf17-a7a2-459c-b4f0-d7de5b092822 |hdl-access=free }} The exact mechanisms are unclear, leading to debate over the influence of biology and free will.{{cite journal |vauthors=Volkow ND, Koob GF, McLellan AT |date=January 2016 |title=Neurobiologic Advances from the Brain Disease Model of Addiction |journal=The New England Journal of Medicine |volume=374 |issue=4 |pages=363–371 |doi=10.1056/NEJMra1511480 |pmc=6135257 |pmid=26816013}}{{cite journal |vauthors=Hyman SE |date=January 2007 |title=The neurobiology of addiction: implications for voluntary control of behavior |url=https://philarchive.org/rec/STETNO-15 |journal=The American Journal of Bioethics |volume=7 |issue=1 |pages=8–11 |doi=10.1080/15265160601063969 |pmid=17366151 |s2cid=347138}}

Accessing appropriate treatment is often a significant barrier. Factors include:Rizk JG, Saini J, Kim K, Pathan U, Qato DM. County-level factors associated with a mismatch between opioid overdose mortality and availability of opioid treatment facilities. *PLoS One*. 2024 Apr 5;19(4):e0301863. doi: [10.1371/journal.pone.0301863](https://doi.org/10.1371/journal.pone.0301863). PMID: 38578818; PMCID: PMC10997118.{{Cite journal |last=Sigmon |first=Stacey C. |date=2014-04-01 |title=Access to Treatment for Opioid Dependence in Rural America: Challenges and Future Directions |url=https://doi.org/10.1001/jamapsychiatry.2013.4450 |journal=JAMA Psychiatry |volume=71 |issue=4 |pages=359–360 |doi=10.1001/jamapsychiatry.2013.4450 |pmid=24500040 |issn=2168-622X}}

• Availability of services: Many areas, especially rural regions, lack treatment facilities or qualified healthcare providers who specialize in opioid use disorder.
• Insurance coverage: People without insurance or those whose plans do not cover substance use disorder treatment may struggle to find affordable care.
• Transportation: For many, getting to treatment facilities can be challenging due to a lack of transportation options.
• Public stigma: Many communities may advocate against establishing treatment programs in their area due to stigma and perceptions of people with substance use disorders.

The United States passed the Comprehensive Addiction and Recovery Act (CARA) in 2016, with the aim to remove treatment barriers by allocating federal funds to increase accessibility to Medication Opioid Use Disorder (MOUD) treatment in rural areas. Telehealth could be a beneficial treatment alternative, especially for people in rural areas with limited access to MOUD treatment.{{Cite journal |last1=Showers |first1=Bernard |last2=Dicken |first2=Danielle |last3=Smith |first3=Jennifer S. |last4=Hemlepp |first4=Aaron |date=July 2021 |title=Medication for opioid use disorder in rural America: A review of the literature. |url=https://doi.apa.org/doi/10.1037/rmh0000187 |journal=Journal of Rural Mental Health |language=en |volume=45 |issue=3 |pages=184–197 |doi=10.1037/rmh0000187 |issn=2163-8969}}

The variety of treatment modalities available for OUD—such as medication-assisted treatment (MAT), counseling, and residential programs—can be overwhelming. Patients may have difficulty understanding which option best suits them, leading to confusion and potential disengagement from the treatment process. Withdrawal symptoms can be severe and uncomfortable, leading many people to relapse before they complete detoxification or engage fully in recovery programs. The fear of withdrawal often prevents people from seeking help altogether.{{Cite journal |last1=Kiluk |first1=Brian D. |last2=Kleykamp |first2=Bethea A. |last3=Comer |first3=Sandra D. |last4=Griffiths |first4=Roland R. |last5=Huhn |first5=Andrew S. |last6=Johnson |first6=Matthew W. |last7=Kampman |first7=Kyle M. |last8=Pravetoni |first8=Marco |last9=Preston |first9=Kenzie L. |last10=Vandrey |first10=Ryan |last11=Bergeria |first11=Cecilia L. |last12=Bogenschutz |first12=Michael P. |last13=Brown |first13=Randall T. |last14=Dunn |first14=Kelly E. |last15=Dworkin |first15=Robert H. |date=2023-01-01 |title=Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder A Review |journal=JAMA Psychiatry |volume=80 |issue=1 |pages=84–92 |doi=10.1001/jamapsychiatry.2022.4020 |issn=2168-622X |pmid=36449315|pmc=10297827 }}

File:2 milligrams of fentanyl on pencil tip. A lethal dose for most people. US Drug Enforcement Administration.jpg dose of fentanyl powder, on a pencil tip, is a lethal amount for most people.{{Cite web |title=One Pill Can Kill |url=https://www.dea.gov/onepill |access-date=15 November 2023 |website=US Drug Enforcement Administration |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115200822/https://www.dea.gov/onepill |url-status=live}}]]

{{see also|Opioid epidemic}}

Globally, the number of people with opioid dependence increased from 10.4 million in 1990 to 15.5 million in 2010. In 2016, the numbers rose to 27 million people who experienced this disorder.{{Cite web |title=WHO {{!}} Information sheet on opioid overdose |url=https://www.who.int/substance_abuse/information-sheet/en/ |access-date=6 April 2019 |website=WHO}} Opioid use disorders resulted in 122,000 deaths worldwide in 2015,{{cite journal | title = 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 | journal = Lancet | volume = 388 | issue = 10053 | pages = 1459–1544 | date = October 2016 | pmid = 27733281 | pmc = 5388903 | doi = 10.1016/S0140-6736(16)31012-1 | display-authors = 1 | vauthors = Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, Casey DC, Charlson FJ, Chen AZ, Coates MM, Coggeshall M, Dandona L, Dicker DJ, Erskine HE, Ferrari AJ, Fitzmaurice C, Foreman K, Forouzanfar MH, Fraser MS, Fullman N, Gething PW, Goldberg EM, Graetz N, Haagsma JA, Hay SI, Huynh C, Johnson CO, Kassebaum NJ, Kinfu Y, Kulikoff XR }} up from 18,000 deaths in 1990.{{cite journal | title = 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 | journal = Lancet | volume = 385 | issue = 9963 | pages = 117–171 | date = January 2015 | pmid = 25530442 | pmc = 4340604 | doi = 10.1016/S0140-6736(14)61682-2 | author1 = GBD 2013 Mortality and Causes of Death Collaborators }} Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013.

{{main|Opioid epidemic in the United States}}

File:3 waves of opioid overdose deaths. US timeline.png

The current epidemic of opioid abuse is the most lethal drug epidemic in U.S. history.Rizk JG, Saini J, Kim K, Pathan U, Qato DM. County-level factors associated with a mismatch between opioid overdose mortality and availability of opioid treatment facilities. *PLoS One*. 2024 Apr 5;19(4):e0301863. doi: [10.1371/journal.pone.0301863](https://doi.org/10.1371/journal.pone.0301863). PMID: 38578818; PMCID: PMC10997118. The crisis can be distinguished by waves of opioid overdose deaths as described by the Centers of Disease Control and Prevention.{{Cite web |title=Understanding the Opioid Overdose Epidemic |url=https://www.cdc.gov/opioids/basics/epidemic.html |website=cdc.gov|date=8 August 2023 }} The first wave began in the 1990s, related to the rise in prescriptions of natural opioids (such as codeine and morphine), semisynthetic opioids (oxycodone, hydrocodone, hydromorphone, and oxymorphone), and synthetic opioids like methadone.[https://www.cdc.gov/drugoverdose/data/analysis.html Opioid Data Analysis and Resources. Drug Overdose. CDC Injury Center]. Centers for Disease Control and Prevention. Click on "Rising Rates" tab for a graph. See data table below the graph.

In the U.S., "the age-adjusted drug poisoning death rate involving opioid analgesics increased from 1.4 to 5.4 deaths per 100,000 population between 1999 and 2010". The second wave dates to around 2010 with the rapid increase in opioid overdoses due to heroin. By this time, there were already four times as many deaths by overdose than in 1999.{{Cite web |url=http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf |title=Opioid Addiction 2016 Facts and Figures |author=American Society of Addiction Medicine}} The age-adjusted drug poisoning death rate involving heroin doubled from 0.7 to 1.4 deaths per 100,000 people between 1999 and 2011 and continued to increase to 4.1 in 2015.{{cite book |url=https://www.cdc.gov/nchs/data/hus/hus16.pdf |title=Health, United States, 2016: With Chartbook on Long-term Trends in Health |date=2017 |publisher=CDC, National Center for Health Statistics. |location=Hyattsville, MD. |page=4}}

The third wave of overdose deaths began in 2013, related to synthetic opioids, particularly illicitly produced fentanyl. While the illicit fentanyl market has continuously changed, the drug is generally sold as an adulterant in heroin. Research suggests that the rapid increase of fentanyl into the illicit opioid market has been largely supply-side-driven and dates to 2006. Decreasing heroin purity, competition from increased access to prescription medications, and dissemination of "The Siegfried Method" (a relatively simple and cost-effective method of fentanyl production) were major factors in street suppliers' inclusion of fentanyl in their products.{{cite journal | vauthors = Hempstead K, Yildirim EO | title = Supply-side response to declining heroin purity: fentanyl overdose episode in New Jersey | journal = Health Economics | volume = 23 | issue = 6 | pages = 688–705 | date = June 2014 | pmid = 23740651 | doi = 10.1002/hec.2937 }}{{cite journal | vauthors = Ciccarone D | title = The rise of illicit fentanyls, stimulants and the fourth wave of the opioid overdose crisis | journal = Current Opinion in Psychiatry | volume = 34 | issue = 4 | pages = 344–350 | date = July 2021 | pmid = 33965972 | pmc = 8154745 | doi = 10.1097/YCO.0000000000000717 }}

The current, fourth wave, which began in 2016, has been characterized by polysubstance overdose due to synthetic opioids like fentanyl mixed with stimulants such as methamphetamine or cocaine.{{cite journal |vauthors=Manchikanti L, Singh VM, Staats PS, Trescot AM, Prunskis J, Knezevic NN, Soin A, Kaye AD, Atluri S, Boswell MV, Abd-Elsayed A, Hirsch JA |author-link=John Prunskis |date=March 2022 |title=Fourth Wave of Opioid (Illicit Drug) Overdose Deaths and Diminishing Access to Prescription Opioids and Interventional Techniques: Cause and Effect |journal=Pain Physician |volume=25 |issue=2 |pages=97–124 |pmid=35322965}}{{cite journal | vauthors = Friedman J, Shover CL | title = Charting the fourth wave: Geographic, temporal, race/ethnicity and demographic trends in polysubstance fentanyl overdose deaths in the United States, 2010-2021 | journal = Addiction | volume = 118 | issue = 12 | pages = 2477–2485 | date = December 2023 | pmid = 37705148 | doi = 10.1111/add.16318 | doi-access = free }} In 2010, around 0.5% of opioid-related deaths were attributed to mixture with stimulants. This figure increased more than 50-fold by 2021, when about a third of opioid-related deaths, or 34,000, involved stimulant use.

In 2017, the U.S. Department of Health and Human Services (HHS) announced a public health emergency due to an increase in the misuse of opioids.{{Cite news |url=https://www.hhs.gov/opioids/about-the-epidemic/hhs-response/index.html |title=5-Point Strategy To Combat the Opioid Crisis |author=Digital Communications Division |date=8 May 2018 |work=U.S. Department of Health and Human Services |access-date=2 November 2018}} The administration introduced a strategic framework called the Five-Point Opioid Strategy, which includes providing access recovery services, increasing the availability of reversing agents for overdose, funding opioid misuse and pain research, changing treatments of people managing pain, and updating public health reports related to combating opioid drug misuse.{{Cite web |url=https://www.hhs.gov/opioids/sites/default/files/2018-09/opioid-fivepoint-strategy-20180917-508compliant.pdf |title=Strategy to Combat Opioid, Abuse, Misuse, and Overdose|website=U.S. Department of Health and Human Services |access-date=18 November 2018}}

Studies done in the U.S. from 2010 to 2019 revealed that about 86.6% of people in the U.S. who could have benefited from opioid use disorder treatment were not receiving it. Over the past decade, the uptake of medications for opioid use disorder has increased, but there are still many regions with a prevalence of opioid use disorder and lack of medical support.{{Cite journal |last1=Krawczyk |first1=Noa |last2=Rivera |first2=Bianca D. |last3=Jent |first3=Victoria |last4=Keyes |first4=Katherine M. |last5=Jones |first5=Christopher M. |last6=Cerdá |first6=Magdalena |date=December 2022 |title=Has the treatment gap for opioid use disorder narrowed in the U.S.?: A yearly assessment from 2010 to 2019" |journal=The International Journal on Drug Policy |volume=110 |pages=103786 |doi=10.1016/j.drugpo.2022.103786 |issn=1873-4758 |pmid=35934583|pmc=10976290 }}

The U.S. epidemic in the 2000s is related to a number of factors.{{cite journal |vauthors=Santoro TN, Santoro JD |date=December 2018 |title=Racial Bias in the US Opioid Epidemic: A Review of the History of Systemic Bias and Implications for Care |journal=Cureus |volume=10 |issue=12 |pages=e3733 |doi=10.7759/cureus.3733 |pmc=6384031 |pmid=30800543 |doi-access=free}} Rates of opioid use and dependency vary by age, sex, race, and socioeconomic status. With respect to race, the discrepancy in deaths is thought to be due to an interplay between physician prescribing and lack of access to healthcare and certain prescription drugs. Men are at higher risk for opioid use and dependency than women,{{Cite web |url=https://www.cdc.gov/drugoverdose/data/overdose.html |title=Prescription Opioid Overdose Data |website=Center for Disease Control and Prevention |access-date=12 September 2016}}{{Cite web |url=https://www.fda.gov/downloads/Drugs/NewsEvents/UCM300859.pdf |title=Populations at risk for opioid overdose | vauthors = Paulozzi L |date=12 April 2012 |website=U.S. Food and Drug Administration (FDA) |publisher=Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control Centers for Disease Control and Prevention |access-date=12 September 2016}} and men also account for more opioid overdoses than women, although this gap is closing. Women are more likely to be prescribed pain relievers, be given higher doses, use them for longer durations, and become dependent upon them faster.{{Cite web |url=http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf |title=Opioid Addiction: 2016 Facts and Figures |website=American Society of Addiction Medicine |access-date=12 September 2016}}

Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs.{{Cite web |url=https://www.pbs.org/wgbh/frontline/article/how-bad-is-the-opioid-epidemic/ |title=How Bad is the Opioid Epidemic? |website=PBS |access-date=12 September 2016}}{{cite journal | vauthors = Han B, Polydorou S, Ferris R, Blaum CS, Ross S, McNeely J | title = Demographic Trends of Adults in New York City Opioid Treatment Programs--An Aging Population | journal = Substance Use & Misuse | volume = 50 | issue = 13 | pages = 1660–1667 | date = 10 November 2015 | pmid = 26584180 | doi = 10.3109/10826084.2015.1027929 | s2cid = 5520930 }} This does not reflect opioid use as a whole, which includes younger people. Overdoses from opioids are highest among people between the ages of 40 and 50, in contrast to heroin overdoses, which are highest among people between the ages of 20 and 30. 21- to 35-year-olds represent 77% of people who enter treatment for opioid use disorder,{{Cite web |url=https://thisismap.com/insights/data-infographics |title=Facts & Faces of Opioid Addiction: New Insights |date=2015 |website=MAP Health Management |access-date=12 September 2016 |archive-date=29 February 2020 |archive-url=https://web.archive.org/web/20200229134735/https://thisismap.com/insights/data-infographics |url-status=dead }} but the average age of first-time use of prescription painkillers was 21.2 years in 2013.{{Cite web |url=http://www.samhsa.gov/atod/opioids |title=Opioids |date=23 February 2016 |website=Substance Abuse and Mental Health Services Administration |access-date=12 September 2016 |archive-date=12 September 2016 |archive-url=https://web.archive.org/web/20160912011349/http://www.samhsa.gov/atod/opioids |url-status=dead }} Among the middle class, means of acquiring funds include elder financial abuse and international dealers noticing a lack of enforcement in their transaction scams throughout the Caribbean.{{cite web |url=https://eu.usatoday.com/story/news/nation-now/2017/07/24/grandson-sold-refrigerator-drugs/504167001/ |title=Grandson sold refrigerator for drugs, grandma says |vauthors=DeVencentis P |date=24 July 2017 |website=USA Today}}

Since 2018, with the federal government's passing of the SUPPORT (Substance Use-Disorder Prevention That Promotes Opioid Recovery and Treatment for Patients and Communities Act) Act, federal restrictions on methadone use for patients receiving Medicare have been lifted.{{cite journal | vauthors = Peterman NJ, Palsgaard P, Vashi A, Vashi T, Kaptur BD, Yeo E, Mccauley W | title = Demographic and Geospatial Analysis of Buprenorphine and Methadone Prescription Rates | journal = Cureus | volume = 14 | issue = 5 | pages = e25477 | date = May 2022 | pmid = 35800815 | pmc = 9246456 | doi = 10.7759/cureus.25477 | doi-access = free }} Since March 2020, as a result of the COVID-19 pandemic, buprenorphine may be dispensed via telemedicine in the U.S.{{cite web |date=15 May 2018 |title=Use of Telemedicine While Providing Medication Assisted Treatment (MAT) |url=https://www.samhsa.gov/sites/default/files/programs_campaigns/medication_assisted/telemedicine-dea-guidance.pdf |access-date=15 May 2018 |website=SAMHSA }}{{cite journal | vauthors = Nunes EV, Levin FR, Reilly MP, El-Bassel N | title = Medication treatment for opioid use disorder in the age of COVID-19: Can new regulations modify the opioid cascade? | journal = Journal of Substance Abuse Treatment | volume = 122 | pages = 108196 | date = March 2021 | pmid = 33221125 | pmc = 7666540 | doi = 10.1016/j.jsat.2020.108196 }}

In October 2021, New York Governor Kathy Hochul signed legislation to combat the opioid crisis. This included establishing a program for the use of medication-assisted substance use disorder treatment for incarcerated individuals in state and local correctional facilities, decriminalizing the possession and sale of hypodermic needles and syringes, establishing an online directory for distributors of opioid antagonists, and expanding the number of eligible crimes committed by individuals with a substance use disorder that may be considered for diversion to a substance use treatment program.{{Cite web|url=https://www.wnypapers.com/news/article/current/2021/10/08/148186/hochul-signs-legislation-package-to-combat-opioid-crisis|title = Hochul signs legislation package to combat opioid crisis| work=Niagara Frontier Publications }}

Until these laws were signed, incarcerated New Yorkers did not reliably have access to medication-assisted treatment. Syringe possession was still a class A misdemeanor despite New York authorizing and funding syringe exchange and access programs.{{Cite web|url=https://citylimits.org/2021/10/07/ny-decriminalizes-syringe-possession-as-part-of-overdose-prevention-efforts/|title = NY Decriminalizes Syringe Possession as Part of Overdose Prevention Efforts|date = 7 October 2021}} This legislation acknowledges the ways New York State laws have contributed to opioid deaths: in 2020 more than 5,112 people died from overdoses in New York State, with 2,192 deaths in New York City.{{Cite web |url=https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm|title=Products – Vital Statistics Rapid Release – Provisional Drug Overdose Data |date=4 November 2021}}

In 2023, the [https://mattersnetwork.org/mat-act/ Waiver Elimination (MAT Act)], as part of Section 1262 of the Consolidated Appropriations Act, 2023 (or "Omnibus Bill"), removed the federal requirement for medical providers to obtain a waiver to prescribe buprenorphine, in an attempt to increase access to OUD treatment. Before this bill, practitioners were required to receive a Drug Addiction Treatment Act of 2000 (DATA) waiver, also known as "x-waiver", before prescribing buprenorphine. There is also now no longer any limit to the number of patients to whom a provider may prescribe buprenorphine for OUD.

File:NIDA overdose deaths.png|U.S. yearly deaths from all opioid drugs. Included in this number are opioid analgesics, along with heroin and illicit synthetic opioids.{{Cite web |date=2022-01-20 |title=Overdose Death Rates |url=https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates |access-date=2022-11-10 |website=National Institute on Drug Abuse }}

File:NIDA overdose all.png|U.S. yearly deaths by drug category

File:NIDA overdose prescription.png|U.S. yearly opioid overdose deaths involving prescription opioids. Non-methadone synthetics is a category dominated by illegally acquired fentanyl, and has been excluded.[http://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates Overdose Death Rates]. By National Institute on Drug Abuse (NIDA).

File:NIDA overdose heroin.png|U.S. yearly opioid overdose deaths involving heroin

File:NIDA overdose stimulants.png|U.S. yearly opioid overdose deaths involving psychostimulants (primarily methamphetamine)

Canada recorded 32,632 opioid-related deaths between January 2016 and June 2022. The marked increase in opioid toxicity deaths is largely attributed to the COVID-19 pandemic.{{Cite journal |last=Statistics Canada |date=2023 |title=Exploring the intersectionality of characteristics among those who experienced opioid overdoses: A cluster analysis |url=https://www150.statcan.gc.ca/n1/pub/82-003-x/2023003/article/00001-eng.htm |journal=Health Reports |volume=34 |issue=3 |pages=3–14 |doi=10.25318/82-003-X202300300001-ENG|pmid=36921072 }}

Epidemiological research has shown that the COVID-19 pandemic accelerated the opioid crisis.{{cite journal | vauthors = Skolnick P | title = Treatment of overdose in the synthetic opioid era | journal = Pharmacology & Therapeutics | volume = 233 | pages = 108019 | date = May 2022 | pmid = 34637841 | doi = 10.1016/j.pharmthera.2021.108019 | doi-access = free }}{{cite journal | vauthors = Gomes T, Ledlie S, Tadrous M, Mamdani M, Paterson JM, Juurlink DN | title = Trends in Opioid Toxicity-Related Deaths in the US Before and After the Start of the COVID-19 Pandemic, 2011-2021 | journal = JAMA Network Open | volume = 6 | issue = 7 | pages = e2322303 | date = July 2023 | pmid = 37418260 | pmc = 10329206 | doi = 10.1001/jamanetworkopen.2023.22303 }} The overarching trend of opioid overdose data has shown a plateau in deaths around 2017–18, with a sudden and acute rise in 2019 primarily attributed to synthetic opioids like fentanyl. In 2020, there were 93,400 drug overdoses in the U.S. with >73% (approximately 69,000) due to opioid overdose.{{Cite web |date=August 2022 |title=A qualitative assessment of circumstances surrounding drug overdose deaths during early stages of the COVID-19 pandemic |url=https://www.cdc.gov/drugoverdose/databriefs/sudors-2.html |website=cdc.gov}} One JAMA review by Gomes et al. showed that estimated years of life loss (YLL) due to opioid toxicity in the U.S. increased by 276%. This increase was particularly felt by those ages 15 to 19, whose YLL increased nearly threefold. Younger male adults had the largest effect size. Other reviews of U.S. and Canadian opioid data coinciding with the onset of COVID-19 suggested significant increases in opioid-related emergency medicine utilization, increased positivity for opioids, and surprisingly no to decreased change in naloxone dispensation.{{cite journal | vauthors = Simha S, Ahmed Y, Brummett CM, Waljee JF, Englesbe MJ, Bicket MC | title = Impact of the COVID-19 pandemic on opioid overdose and other adverse events in the USA and Canada: a systematic review | journal = Regional Anesthesia and Pain Medicine | volume = 48 | issue = 1 | pages = 37–43 | date = January 2023 | pmid = 36202619 | doi = 10.1136/rapm-2022-103591 | s2cid = 252753865 }}

Telehealth played a large role in OUD treatment access, and legislation on telehealth continues to evolve. A study of Medicare beneficiaries with new-onset OUD showed that those who received telehealth services had a 33% lower risk of death by overdose.{{cite journal | vauthors = Jones CM, Shoff C, Blanco C, Losby JL, Ling SM, Compton WM | title = Association of Receipt of Opioid Use Disorder-Related Telehealth Services and Medications for Opioid Use Disorder With Fatal Drug Overdoses Among Medicare Beneficiaries Before and During the COVID-19 Pandemic | journal = JAMA Psychiatry | volume = 80 | issue = 5 | pages = 508–514 | date = May 2023 | pmid = 36988913 | pmc = 10061313 | doi = 10.1001/jamapsychiatry.2023.0310 }} Minority groups such as Black and Hispanic Americans have also been shown to benefit from the increased access due to telehealth programs introduced during the pandemic, despite increasing disparity gaps in other OUD-related outcomes.{{cite journal | vauthors = Moran KM, Mullachery PH, Lankenau S, Bilal U | title = Changes in Racial/Ethnic Disparities in Opioid-Related Outcomes in Urban Areas during the COVID-19 Pandemic: A Rapid Review of the Literature | journal = International Journal of Environmental Research and Public Health | volume = 19 | issue = 15 | page = 9283 | date = July 2022 | pmid = 35954640 | pmc = 9368442 | doi = 10.3390/ijerph19159283 | doi-access = free }} The DEA and HHS have extended telemedicine flexibility in regard to prescribing controlled substances such as buprenorphine for OUD through 31 December 2024.{{Cite web |date=16 October 2023 |title=Prescribing controlled substances via telehealth |url=https://telehealth.hhs.gov/providers/telehealth-policy/prescribing-controlled-substances-via-telehealth}}\\

China's relationship with opioids, particularly opium, dates back centuries, with significant use for medicinal purposes by the 7th century and increased demand in the 17th century due to smoking practices from Southeast Asia. The Opium Wars in the 19th century exacerbated the problem, leading to social and health crises. After 1949, under the Communist regime, strict legislation and punishment significantly reduced opioid use, creating a drug-free atmosphere by the 1950s. But with the economic reforms and open-door policies of the 1980s, drug abuse, including opiate dependence, reemerged as a major public health issue.{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/16669899/ | pmid=16669899 | date=2006 | title=Opiate addiction in China: Current situation and treatments | journal=Addiction (Abingdon, England) | volume=101 | issue=5 | pages=657–665 | doi=10.1111/j.1360-0443.2006.01367.x | vauthors = Tang YL, Zhao D, Zhao C, Cubells JF }}

From 2000 to 2020, the prevalence of OUD in China showed significant trends, though exact figures are hard to obtain due to underreporting. In 2004, Tang et al. reported approximately 1.14 million registered drug addicts, with over 75% being heroin addicts, suggesting a substantial burden, though the actual number is likely higher due to the hidden nature of drug use.{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/16669899/ | pmid=16669899 | date=2006 | title=Opiate addiction in China: Current situation and treatments | journal=Addiction (Abingdon, England) | volume=101 | issue=5 | pages=657–665 | doi=10.1111/j.1360-0443.2006.01367.x | vauthors = Tang YL, Zhao D, Zhao C, Cubells JF }} This figure aligns with the understanding that official statistics often undercount, as noted in later reports like a 2019 Associated Press article that discussed pain pill addiction and suggested undercounting problems.{{cite web | url=https://apnews.com/article/health-ap-top-news-opioids-international-news-weekend-reads-9766f96258fae13a2bc13e1486011120 | title=China has pain pill addicts too, but no one's counting them | website=Associated Press News | date=31 December 2019 }}

Opioid abuse has been linked to significant health implications, particularly the spread of HIV/AIDS. In 2004, intravenous drug use was the most prevalent route of HIV transmission, accounting for 51.2% of cases, underscoring the public health threat.{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/16669899/ | pmid=16669899 | date=2006 | title=Opiate addiction in China: Current situation and treatments | journal=Addiction (Abingdon, England) | volume=101 | issue=5 | pages=657–665 | doi=10.1111/j.1360-0443.2006.01367.x | vauthors = Tang YL, Zhao D, Zhao C, Cubells JF }} This suggests OUD and associated infectious illness therapies are needed.

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Brown TK, Alper K | title = Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes | journal = The American Journal of Drug and Alcohol Abuse | volume = 44 | issue = 1 | pages = 24–36 | date = 2018 | pmid = 28541119 | doi = 10.1080/00952990.2017.1320802 | s2cid = 4401865 | doi-access = free }}
• {{cite journal | vauthors = Neighbors CJ, Choi S, Healy S, Yerneni R, Sun T, Shapoval L | title = Age related medication for addiction treatment (MAT) use for opioid use disorder among Medicaid-insured patients in New York | journal = Substance Abuse Treatment, Prevention, and Policy | volume = 14 | issue = 1 | pages = 28 | date = June 2019 | pmid = 31238952 | pmc = 6593566 | doi = 10.1186/s13011-019-0215-4 | doi-access = free }}
• {{cite journal | vauthors = Seabra P, Sequeira A, Filipe F, Amaral P, Simões A, Sequeira R | title = Substance addiction consequences: Outpatients severity indicators in a medication-based program. | journal = International Journal of Mental Health and Addiction | date = June 2022 | volume = 20 | issue = 3 | pages = 1837–1853 | doi = 10.1007/s11469-021-00485-3 }}

{{refend}}

• [https://nida.nih.gov/publications/drugfacts/heroin Heroin information from the National Institute on Drug Abuse]
• [https://www.asam.org/quality-care/clinical-guidelines/national-practice-guideline Opioid Dependence Treatment and Guidelines]
• [https://www.healthprosinrecovery.com/ Bill Kinkle Recovery From Opioid Use Disorder]

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