Opioid use disorder: Difference between revisions

Opioid use disorder
Opioid use disorder
Other names	Opioid addiction, problematic opioid use, opioid abuse, opioid dependence
	Molecular structure of morphine
Specialty	Psychiatry
Symptoms	Strong desire to use opioids, increased tolerance to opioids, failure to meet obligations, trouble with reducing use, withdrawal syndrome with discontinuation
Complications	Opioid overdose, hepatitis C, marriage problems, unemployment
Duration	Long term
Causes	Opioids
Diagnostic method	Based on criteria in the DSM-5
Differential diagnosis	Alcoholism
Treatment	Opioid replacement therapy, behavioral therapy, twelve-step programs, take home naloxone
Medication	Buprenorphine, methadone, naltrexone
Frequency	c. 0.4%
Deaths	122,000 (2015)

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Opioid use disorder is a problematic pattern of opioid use that causes significant impairment or distress.^[3] Symptoms of the disorder include a strong desire to use opioids, increased tolerance to opioids, failure to fulfill obligations, trouble reducing use, and withdrawal syndrome with discontinuation.^[4]^[5] Opioid withdrawal symptoms may include nausea, muscle aches, diarrhea, trouble sleeping, or a low mood.^[5] Addiction and dependence are components of a substance use disorder.^[12] Complications may include opioid overdose, suicide, HIV/AIDS, hepatitis C, marriage problems, or unemployment.^[4]^[5]

Opioids include substances such as heroin, morphine, fentanyl, codeine, oxycodone, and hydrocodone.^[5]^[6] In the United States, a majority of heroin users begin by using prescription opioids.^[13]^[14] These can be bought illegally or prescribed.^[13] Diagnosis may be based on criteria by the American Psychiatric Association in the DSM-5.^[4] If more than two of eleven criteria are present during a year the diagnosis is said to be present.^[4] If a person is appropriately taking opioids for a medical condition issues of tolerance and withdrawal do not apply.^[4]

Individuals with an opioid use disorders are often treated with opioid replacement therapy using methadone or buprenorphine.^[7] Being on such treatment reduces the risk of death.^[7] Additionally, individuals may benefit from cognitive behavioral therapy, other forms of support from mental health professionals such as individual or group therapy, twelve-step programs, and other peer support programs.^[8] The medication naltrexone may also be useful to prevent relapse.^[10] Naloxone is useful for treating an opioid overdose and giving those at risk naloxone to take home is beneficial.^[9]

In 2013, opioid use disorders affected about 0.4% of people.^[4] As of 2015, it was estimated that about 16 million people worldwide have been affected at one point in their lives.^[15] Long term opioid use occurs in about 4% of people following their use for trauma or surgery related pain.^[16] Onset is often in young adulthood.^[4] Males are affected more often than females.^[4] It resulted in 122,000 deaths worldwide in 2015,^[11] up from 18,000 deaths in 1990.^[17] In the United States during 2016, there were more than 42,000 deaths due to opioid overdose, of which more than 15,000 were the result of heroin use.^[18]

Signs and symptoms

Material used for intravenous injection of opioids

Signs and symptoms include:^[4]^[5]

Drug seeking behavior
Increased use over time
Legal or social ramifications secondary to drug use
Multiple prescriptions from different providers
Multiple medical complications from drug use (HIV/AIDS, hospitalizations, abscesses)
Opioid cravings
Withdrawal symptoms

Addiction and dependence are components of a substance use disorder and addiction represents the more severe form.^[12] Opioid dependence can occur as physical dependence, psychological dependence, or both.^[19]

Withdrawal

Onset of withdrawal from opioids depends on which opioid was used last.^[20] With heroin this typically occurs 5 hours after use, while with methadone it might not occur until 2 days later.^[20] The length of time that major symptoms occur also depends on the opioid used.^[20] For heroin symptoms are typically greatest at two to four days and can last for up to two weeks.^[20]^[21] Less significant symptoms may remain for an even longer period, in which case it is known as a protracted abstinence syndrome.^[20]

Agitation^[4]
Anxiety^[4]
Muscle pains^[4]
Increased tearing^[4]
Trouble sleeping^[4]
Runny nose^[4]
Sweating^[4]
Yawning^[4]
Goose bumps^[4]
Dilated pupils^[4]
Diarrhea^[4]
Fast heart rate^[20]
High blood pressure^[20]
Abdominal cramps^[20]
Shakiness^[20]
Cravings^[20]
Sneezing^[20]

Opioid intoxication

Signs and symptoms of opioid intoxication include:^[5]

Decreased perception of pain
Euphoria
Confusion
Desire to sleep
Nausea
Constipation
Miosis

Opioid overdose

Signs and symptoms of opioid overdose include, but are not limited to:^[23]

Pin-point pupils may occur. Patient presenting with dilated pupils may still be suffering 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

Cause

Opioid use disorder can develop as a result of self-medication, though this is controversial.^[24] Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.^[25] Prescription opioids are the source of nearly half of misused opioids and the majority of these are initiated for trauma or surgery pain management.^[16]

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 character or will.^[26]^[27] Additionally, detoxification alone does not constitute adequate treatment.

Mechanism

Addiction

Addiction is a brain disorder characterized by compulsive drug use despite adverse consequences.^[12]^[28]^[29]^[30] Addiction is a component of a substance use disorder and represents the most severe form of the disorder.^[12]

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.^[28]^[31]^[32]^[33] Like other addictive drugs, overuse of opioids leads to increased ΔFosB expression in the nucleus accumbens.^[31]^[32]^[33]^[34] 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 modulate dopamine neurotransmission.^[35]^[36] 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.^[35]^[36]

Neuroimaging has shown functional and structural alterations in the brain.^[37] A 2017 study showed that chronic intake of opioid, such as heroin, may cause long-term effect in the orbitofrontal area (OFC), which is essential for regulating reward-related behaviors, emotional responses, and anxiety.^[38]^{[non-primary source needed]} Moreover, neuroimaging and neuropsychological studies demonstrated dysregulation of circuits associated with emotion, stress and high impulsivity.^[39]

Dependence

Drug dependence is an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake).^[28]^[29]^[30] Dependence is a component of a substance use disorder.^[12]^[40] Opioid dependence can manifest as physical dependence, psychological dependence, or both.^[19]^[29]^[40]

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).^[28]^[41] 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).^[28] It has been shown that when an opiate-naive person begins using opiates in concentrations that induce euphoria, BDNF signaling increases in the VTA.^[42]

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.^[19]^[28] Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid-induced physical dependence.^[19]^[28]

Opioid receptors

A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for a number of specific variations; however, the evidence for clinical differences in opioid effects is ambiguous. 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. Newer approaches shift away from analysis of specific genes and regions, and are based on an unbiased screen of genes across the entire genome, which have no apparent relationship to the phenotype in question. These GWAS studies yield 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.^[43]

Currently, there are no specific pharmacogenomic dosing recommendations for opioids due to a lack of clear evidence connecting genotype to drug effect, toxicity, or likelihood of dependence.^{[citation needed]}

118A>G variant

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 of 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 a greater addictive capacity in these individuals who require higher dosages to achieve pain control. However, evidence linking the 118A>G variant to opioid dependence is mixed, with associations shown in a number of study groups, but negative results in other groups. One explanation for the mixed results is the possibility of other variants which are in linkage disequilibrium with the 118A>G variant and thus contribute to different haplotype patterns that more specifically associate with opioid dependence.^[44]

Non-opioid receptor genes

The preproenkephalin gene, PENK, encodes for the endogenous opiates that modulate pain perception, and are implicated in reward and addiction. (CA) repeats in the 3' flanking sequence of the PENK gene was associated with greater likelihood of opiate dependence in repeated studies. Variability in the MCR2 gene, encoding melanocortin receptor type 2 has been associated with both protective effects and increased susceptibility to heroin addiction. The CYP2B6 gene of the cytochrome P450 family also mediates breakdown of opioids and thus may play a role in dependence and overdose.^[45]

Diagnosis

The DSM-5 guidelines for diagnosis of opioid use disorder require that the individual has significant impairment or distress related to opioid uses.^[4] In order to make the diagnosis two or more of eleven criteria must be present in a given year:^[4]

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

The severity can be classified as mild, moderate, or severe based on the number of criteria present.^[6]

Prevention

There are efforts to decrease the number of opioids prescribed in an effort to decrease opioid use disorder and deaths related to opioid use.

Opioid related deaths

Naloxone is used for the emergency treatment of an overdose.^[46] It can be given by many routes (e.g., intramuscular, intravenous, subcutaneous, intranasal, and inhalation) and acts quickly by displacing opioids from opioid receptors and preventing activation of these receptors by opioids.^[47] Naloxone kits are recommended for laypersons who may witness an opioid overdose, for individuals with large prescriptions for opioids, those in substance use treatment programs, or who have been recently released from incarceration.^[48] Since this is a life-saving medication, many areas of the United States have implemented standing orders for law enforcement to carry and give naloxone as needed.^[49]^[50] In addition, naloxone could be used to challenge a person's opioid abstinence status prior to starting a medication such as naltrexone, which is used in the management of opioid addiction.^[51]

Management

Opioid use disorders typically require long-term treatment and care with the goal of reducing risks for the individual, reducing criminal behaviour, and improving the long-term physical and psychological condition of the person.^[27] Most strategies aim ultimately to reduce drug use and lead to abstinence.^[27] No single treatment works for everyone, so several strategies have been developed including therapy and drugs.^[27]^[52]

As of 2013 in the US, there was a significant increase of prescription opioid abuse compared to illegal opiates like heroin.^[53] This development has also implications for the prevention, treatment and therapy of opioid dependence.^[54] Though treatment reduces mortality rates, the period during the first four weeks after treatment begins and the four weeks after treatment ceases are the times that carry the highest risk for drug related deaths. These periods of increased vulnerability are significant because many of those in treatment leave programs during these critical periods.^[7]

Medications

Opioid replacement therapy (ORT), also called opioid substitution therapy or opioid maintenance therapy, involves replacing an opioid, such as heroin, with a longer acting but less euphoric opioid.^[55] Commonly used drugs for ORT are methadone or buprenorphine which are taken under medical supervision.^[55] As of 2018 buprenorphine/naloxone is preferentially recommended.^[56]

The driving principle behind ORT is the program's capacity to facilitate a resumption of stability in the user's life, while the patient experiences reduced symptoms of drug withdrawal and less intense drug cravings; a strong euphoric effect is not experienced as a result of the treatment drug.^[55] In some countries (not the US, or Australia),^[55] regulations enforce a limited time period 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% are able to reduce their use significantly.^[55] Along with this is a concurrent elimination or reduction in 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.^[55] Clonidine or lofexidine can help treat the symptoms of withdrawal.^[57]

Participation in methadone and buprenorphine treatment reduces the risk of mortality due to overdose.^[7] The starting of methadone and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies.^[7] ORT has proven to be the most effective treatment for improving the health and living condition of people experiencing problematic illegal opiate use or dependence, including mortality reduction^[55]^[58]^[7] and overall societal costs, such as the economic loss from drug-related crime and healthcare expenditure.^[55] Opioid Replacement Therapy is endorsed by the World Health Organization, United Nations Office on Drugs and Crime and UNAIDS as being effective at reducing injection, lowering risk for HIV/AIDS, and promoting adherence to antiretroviral therapy.^[7] Currently, 55 countries worldwide use methadone replacement therapy, while some countries such as Russia do not.^[59]

Methadone

Methadone maintenance treatment (MMT), a form of opioid replacement therapy, reduces and/or eliminates the use of illegal opiates, the criminality associated with opiate use, and allows patients to improve their health and social productivity.^[60]^[61] Methadone is an agonist of opioids. If initial doses during the beginning of treatment are too high or are concurrent with illicit opioid use, this may present an increased risk of death from overdose.^[7] In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV.^[60] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. Methadone maintenance has been found to be medically safe and non-sedating.^[60] It is also indicated for pregnant women addicted to opiates.^[60] Methadone maintenance treatment is given to addicted individuals who feel unable to go the whole way and get clean. For individuals who wish to completely move away from drugs, they can start a methadone reduction program. A methadone reduction program is where an individual is prescribed an amount of methadone which is increased until withdrawal symptoms subside, after a period of stability, the dose will then be gradually reduced until the individual is either free of the need for methadone or is at a level which allows a switch to a different opiate with an easier withdrawal profile, such as suboxone. Methadone toxicity has been shown to be associated with specific phenotypes of CYP2B6.^[62]

Some impairment in cognition has been demonstrated in those using methadone.^[39]^[63]

Buprenorphine

Treatment with buprenorphine may be associated with reduced mortality.^[7] Buprenorphine under the tongue is often used to manage opioid dependence. Preparations were approved for this use in the United States in 2002.^[64] Some formulations of buprenorphine incorporate the opiate antagonist naloxone during the production of the pill form to prevent people from crushing the tablets and injecting them, instead of using the sublingual (under the tongue) route of administration.^[55]

Diamorphine

In Switzerland, Germany, the Netherlands, and the United Kingdom, long-term injecting drug users who do not benefit from methadone and other medication options are treated with pure injectable diamorphine that is administered under the supervision of medical staff. For this group of patients, diamorphine treatment has proven superior in improving their social and health situation.^[65]

Dihydrocodeine

Dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.^[66] Dihydrocodeine is an opioid agonist.^[67] It may be used as a second line treatment.^[68] There is a lack of effective data suggesting its safety of use with concerns of more deaths.^[69]

Heroin-assisted treatment

Heroin-assisted treatment (HAT, the medical prescription of heroin) has been available in Switzerland since 1994.^[70] A 2001 study found a high rate of treatment retention and significant improvement in health, social situation and likelihood to leave the illegal drug scene in enrolled participants.^[70] The study found that the most common reason for discharge was the start of abstinence treatment or methadone treatment.^[70] The study also found that heroin-assisted treatment is cost-beneficial on a society level due to reduced criminality and improved overall health of participants.^[70]

The heroin-assisted treatment program was introduced in Switzerland to combat the increase in heroin use in the 1980s and 1990s and written into law 2010 as one pillar of a four-pillar strategy using repression, prevention, treatment and risk reduction.^[71] Usually, only a small percentage of patients receives heroin and have to fulfil a number of criteria.^[72]^[73] Since then, HAT programs have been adopted in the Netherlands, United Kingdom, Germany, Spain, Denmark, Belgium, Canada, and Luxembourg.^[74]

Morphine (extended-release)

An extended-release morphine confers a possible reduction of opioid use and with fewer depressive symptoms but overall more adverse effects when compared to other forms of long-acting opioids. Retention in treatment was not found to be significantly different.^[75] It is used in Switzerland and more recently in Canada.^[72]

Naltrexone

Naltrexone is used for the treatment of opioid addiction.^[76]^[77] It works by blocking the physiological, euphoric, and reinforcing effects of opioids.^[77]^[78] Non-compliance with naltrexone therapy is a concern with oral formulations because of its daily dosing,^[78] and although the alternative intramuscular (IM) injection has better compliance due to its monthly dosing, attempts to override the blocking effect with higher doses and stronger drugs have proven dangerous. Naltrexone monthly IM injections received FDA approval in 2010 for the treatment of opioid dependence in abstinent opioid users.^[76]^[78]

Behavioral therapy

Cognitive behavioral therapy

Cognitive behavioral therapy (CBT), a form of psychosocial intervention that is used to improve mental health, may not be as effective as other forms of treatment.^[79] CBT primarily focuses on an individual's coping strategies to help change their cognition, behaviors and emotions about the problem. This intervention has demonstrated success in many psychiatric conditions (e.g., depression) and substance use disorders (e.g., tobacco).^[80] However, the use of CBT alone in opioid dependence has declined due to the lack of efficacy and many are relying on medication therapy or medication therapy with CBT since it was found to be more efficacious than CBT alone.^[81]

Twelve-step programs

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.^[82] Some evidence supports the use of these programs in adolescents as well.^[83]

The 12-step program is an adapted form of the Alcoholics Anonymous program. The program strives to help create behavioral change by fostering peer-support and self-help programs. The model helps assert the gravity of addiction by enforcing the idea that addicts must surrender to the fact that they are addicted and to be able to recognize the problem. It also helps maintain self-control and restraint to help promote one's capabilities.^[84]

Epidemiology

Globally, the number of people with opioid dependence increased from 10.4 million in 1990 to 15.5 million in 2010.^[7] Opioid use disorders resulted in 122,000 deaths worldwide in 2015,^[11] up from 18,000 deaths in 1990.^[17] Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013.^[17]^[11]

United States

The current epidemic of opioid abuse is the most lethal drug epidemic in American history.^[14] In 2008, there were four times as many deaths due to overdose than there were in 1999. ^[86] According to the CDC in 2017, in the US, "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, decreased to 5.1 in 2012 and 2013, then increased to 5.9 in 2014, and to 7.0 in 2015. The age-adjusted drug poisoning death rate involving heroin doubled from 0.7 to 1.4 deaths per 100,000 resident population between 1999 and 2011 and then continued to increase to 4.1 in 2015."^[87]

In 2012 it was estimated that 9.2 percent of the population over the age of 12 years old had used an illicit drug in the previous month.^[88] In 2015, it was estimated the 20.5 million Americans had a substance use disorder.^[86] Of these 20.5 million, two million used prescribed pain medications (most of those being opioids) and one-half of a million were using heroin.^[86] About a quarter of people who use heroin end up having opioid addiction. ^[86]

In 2015, in the US there were 33,000 deaths due to drug overdose that involved opioid use.^[89] Of these, about 15,000 were from prescribed opioids and 13,000 were from heroin use.^[90]^[91] Approximately 4% of patients who received opioids for pain management following trauma or surgery continued using opioids for at least 2 months.^[16]

Non-medical consumption of opioids peaked around 2010 and then started to decrease between 2011 and 2013.^[92]

Among adults, the rate of inpatient hospital stays in the United States related to opioid overuse increased by an average of 5% annually from 1993–2012. The percentage of inpatient stays due to opioid overuse admitted from the emergency department increased from 43% in 1993 to 64% in 2005, but have remained relatively constant since 2005.^[93]

The prevalence of opioid use and opioid or opiate dependency varies by age and gender, among a myriad of other factors. Men are at higher risk for opioid use and dependency than women,^[94]^[95] and men also account for more opioid overdoses than women, although this gap is closing.^[94] Women are more likely to be prescribed pain relievers, be given higher doses, use them for longer durations, and may become dependent upon them faster.^[96]

Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs.^[95]^[97]^[98] This does not reflect opioid use as a whole, which includes individuals in younger age demographics. Overdoses from opioids are highest among individuals who are between the ages of 40 and 50,^[98] in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30.^[97] 21 to 35-year olds represent 77% of individuals who enter treatment for opioid use disorder,^[99] however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013.^[100] Among the middle class means of acquiring funds have included Elder financial abuse through a vulnerability of financial transactions of selling items and international dealers noticing a lack of enforcement in their transaction scams throughout the Caribbean.^[101]

Charts of deaths involving specific opioids and classes of opioids
US yearly deaths from all opioid drugs. Included in this number are opioid analgesics, along with heroin and illicit synthetic opioids.^[102]
US yearly deaths involving other synthetic opioids, predominately Fentanyl.^[102]
US yearly deaths involving prescription opioids. Non-methadone synthetics is a category dominated by illegally acquired fentanyl, and has been excluded.^[102]
US yearly overdose deaths involving heroin.^[102]

History

Opiate misuse has been recorded at least since 300 BC. Greek mythology describes Nepenthe (Greek “free from sorrow”) and how it was used by the hero of the Odyssey. Opioids have been used in the Near East for centuries. The purification of and isolation of opiates occurred in the early 19th century.^[23]

Levacetylmethadol was previously used to treat opioid dependence. In 2003 the drug's 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.^[103] In 2001, levacetylmethadol was removed from the European market due to reports of life-threatening ventricular rhythm disorders.^[104] In 2003, Roxane Laboratories, Inc. discontinued Orlaam in the US.^[105]

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[:6-23] 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&sectionid=79757372 Accessed 9 March 2017.

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[WHOmain-27] "Treatment of opioid dependence". WHO. 2004. Retrieved 28 August 2016.^{[needs update]}

[Cellular_basis-28] ^ ^a ^b ^c ^d ^e ^f ^g Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–43. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS

[Addiction_glossary-29] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.

[Nestler_Labs_Glossary-30] "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.

[Nestler-31] Robison AJ, Nestler EJ (October 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews. Neuroscience. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.

[Natural_and_drug_addictions-32] Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101.

[What_the_ΔFosB?-33] Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–37. doi:10.3109/00952990.2014.933840. PMID 25083822.

[ΔFosB_reward-34] Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964.

[VTA_tail-35] Bourdy R, Barrot M (November 2012). "A new control center for dopaminergic systems: pulling the VTA by the tail". Trends in Neurosciences. 35 (11): 681–90. doi:10.1016/j.tins.2012.06.007. PMID 22824232.

[KEGG_Morphine_addiction-36] "Morphine addiction – Homo sapiens (human)". KEGG. Kanehisa Laboratories. 18 June 2013. Retrieved 11 September 2014.

[37] Goldstein RZ, Volkow ND (October 2011). "Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications". Nature Reviews. Neuroscience. 12 (11): 652–69. doi:10.1038/nrn3119. PMC 3462342. PMID 22011681.

[pmid28422138-38] Ieong HF, Yuan Z (April 2017). "Abnormal resting-state functional connectivity in the orbitofrontal cortex of heroin users and its relationship with anxiety: a pilot fNIRS study". Scientific Reports. 7: 46522. doi:10.1038/srep46522. PMC 5395928. PMID 28422138.

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@@ Line 2: / Line 2: @@
 {{Infobox medical condition (new)
 | name            = Opioid use disorder
-| synonyms        = Opioid addiction,<ref name=FDA2016/> problematic opioid use,<ref name=FDA2016>{{cite web|title=Press Announcements – FDA approves first buprenorphine implant for treatment of opioid dependence|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503719.htm|website=www.fda.gov|accessdate=16 March 2017|language=en|date=26 May 2016}}</ref> opioid abuse,<ref>{{cite book|title=Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.|date=2004|publisher=Substance Abuse and Mental Health Services Administration (US)|location=Rockville (MD)|url=https://www.ncbi.nlm.nih.gov/books/NBK64237/|language=en|chapter=3 Patient Assessment}}</ref> opioid dependence<ref name=CDC2018Def/>
+| synonyms        = Opioid addiction,<ref name=FDA2016/> problematic opioid use,<ref name=FDA2016>{{cite web|title=Press Announcements – FDA approves first buprenorphine implant for treatment of opioid dependence|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503719.htm|website=www.fda.gov|access-date=16 March 2017|language=en|date=26 May 2016}}</ref> opioid abuse,<ref>{{cite book|title=Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.|date=2004|publisher=Substance Abuse and Mental Health Services Administration (US)|location=Rockville (MD)|url=https://www.ncbi.nlm.nih.gov/books/NBK64237/|language=en|chapter=3 Patient Assessment}}</ref> opioid dependence<ref name=CDC2018Def/>
 | image           = Morphin - Morphine.svg
 | width           = 300
@@ Line 18: / Line 18: @@
 | prevention      =
 | treatment       = [[Opioid replacement therapy]], [[Addiction#Behavioral therapy|behavioral therapy]], [[twelve-step program]]s, take home [[naloxone]]<ref name=BMJ2017Re/><ref name=Sam2017Tx/><ref name=Mc2016/>
-| medication      = [[Buprenorphine]], [[methadone]], [[naltrexone]]<ref name=BMJ2017Re/><ref name=Shar2016>{{cite journal|last1=Sharma|first1=B|last2=Bruner|first2=A|last3=Barnett|first3=G|last4=Fishman|first4=M|title=Opioid Use Disorders.|journal=Child and Adolescent Psychiatric Clinics of North America|date=July 2016|volume=25|issue=3|pages=473–87|doi=10.1016/j.chc.2016.03.002|pmid=27338968|pmc=4920977}}</ref>
+| medication      = [[Buprenorphine]], [[methadone]], [[naltrexone]]<ref name=BMJ2017Re/><ref name=Shar2016>{{cite journal | vauthors = Sharma B, Bruner A, Barnett G, Fishman M | title = Opioid Use Disorders | journal = Child and Adolescent Psychiatric Clinics of North America | volume = 25 | issue = 3 | pages = 473–87 | date = July 2016 | pmid = 27338968 | pmc = 4920977 | doi = 10.1016/j.chc.2016.03.002 }}</ref>
 | prognosis       =
 | frequency       = c. 0.4%<ref name=DSM5/>
@@ Line 24: / Line 24: @@
 }}
 <!-- Definition and symptoms -->
-'''Opioid use disorder''' is a problematic pattern of [[opioid]] use that causes significant impairment or distress.<ref name=CDC2018Def>{{cite web |title=Commonly Used Terms |url=https://www.cdc.gov/drugoverdose/opioids/terms.html |website=www.cdc.gov |accessdate=16 July 2018 |language=en-us |date=29 August 2017}}</ref> Symptoms of the disorder include a strong desire to use opioids, increased [[drug tolerance|tolerance]] to opioids, failure to fulfill obligations, trouble reducing use, and [[withdrawal syndrome]] with discontinuation.<ref name=DSM5/><ref name=Sam2015>{{Cite web|url=https://www.samhsa.gov/disorders/substance-use|title=Substance Use Disorders|last=Substance Use and Mental Health Services Administration|first=|date=|website=|access-date=}}</ref> Opioid withdrawal symptoms may include nausea, muscle aches, diarrhea, trouble sleeping, or a low mood.<ref name=Sam2015/> [[Addiction]] and [[drug dependence|dependence]] are components of a [[substance use disorder]].<ref name="Brain disease"/> Complications may include [[opioid overdose]], [[suicide]], [[HIV/AIDS]], [[hepatitis C]], marriage problems, or unemployment.<ref name=DSM5/><ref name=Sam2015/>
+'''Opioid use disorder''' is a problematic pattern of [[opioid]] use that causes significant impairment or distress.<ref name=CDC2018Def>{{cite web |title=Commonly Used Terms |url=https://www.cdc.gov/drugoverdose/opioids/terms.html |website=www.cdc.gov |access-date=16 July 2018 |language=en-us |date=29 August 2017}}</ref> Symptoms of the disorder include a strong desire to use opioids, increased [[drug tolerance|tolerance]] to opioids, failure to fulfill obligations, trouble reducing use, and [[withdrawal syndrome]] with discontinuation.<ref name=DSM5/><ref name=Sam2015>{{Cite web|url=https://www.samhsa.gov/disorders/substance-use|title=Substance Use Disorders| author = Substance Use and Mental Health Services Administration }}</ref> Opioid withdrawal symptoms may include nausea, muscle aches, diarrhea, trouble sleeping, or a low mood.<ref name=Sam2015/> [[Addiction]] and [[drug dependence|dependence]] are components of a [[substance use disorder]].<ref name="Brain disease"/> Complications may include [[opioid overdose]], [[suicide]], [[HIV/AIDS]], [[hepatitis C]], marriage problems, or unemployment.<ref name=DSM5/><ref name=Sam2015/>
 <!-- Cause and diagnosis -->
-Opioids include substances such as [[heroin]], [[morphine]], [[fentanyl]], [[codeine]], [[oxycodone]], and [[hydrocodone]].<ref name=Sam2015/><ref name=ACOG2017>{{cite web |title=Opioid Use and Opioid Use Disorder in Pregnancy |url=https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Obstetric-Practice/Opioid-Use-and-Opioid-Use-Disorder-in-Pregnancy |website=ACOG |accessdate=16 July 2018 |date=August 2017}}</ref> In the United States, a majority of heroin users begin by using prescription opioids.<ref name=NIH2018Risk>{{cite web |title=Prescription opioid use is a risk factor for heroin use |url=https://www.drugabuse.gov/publications/research-reports/relationship-between-prescription-drug-heroin-abuse/prescription-opioid-use-risk-factor-heroin-use |website=National Institute on Drug Abuse |accessdate=16 July 2018 |language=en}}</ref><ref name=NYT2018>{{cite news|last1=Hughes|first1=Evan|title=The Pain Hustlers|url=https://www.nytimes.com/interactive/2018/05/02/magazine/money-issue-insys-opioids-kickbacks.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=photo-spot-region&region=top-news&WT.nav=top-news|accessdate=3 May 2018|publisher=New York Times|date=2 May 2018}}</ref> These can be bought illegally or prescribed.<ref name=NIH2018Risk/> Diagnosis may be based on criteria by the [[American Psychiatric Association]] in the [[Diagnostic and Statistical Manual of Mental Disorders|DSM-5]].<ref name=DSM5>{{citation|author=American Psychiatric Association|year=2013|title=Diagnostic and Statistical Manual of Mental Disorders (5th ed.)|location=Arlington|publisher=American Psychiatric Publishing|pages=540–546|isbn=978-0890425558}}</ref> If more than two of eleven criteria are present during a year the diagnosis is said to be present.<ref name=DSM5/> If a person is appropriately taking opioids for a medical condition issues of tolerance and withdrawal do not apply.<ref name=DSM5/>
+Opioids include substances such as [[heroin]], [[morphine]], [[fentanyl]], [[codeine]], [[oxycodone]], and [[hydrocodone]].<ref name=Sam2015/><ref name=ACOG2017>{{cite web |title=Opioid Use and Opioid Use Disorder in Pregnancy |url=https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Obstetric-Practice/Opioid-Use-and-Opioid-Use-Disorder-in-Pregnancy |website=ACOG |access-date=16 July 2018 |date=August 2017}}</ref> In the United States, a majority of heroin users begin by using prescription opioids.<ref name=NIH2018Risk>{{cite web |title=Prescription opioid use is a risk factor for heroin use |url=https://www.drugabuse.gov/publications/research-reports/relationship-between-prescription-drug-heroin-abuse/prescription-opioid-use-risk-factor-heroin-use |website=National Institute on Drug Abuse |access-date=16 July 2018 |language=en}}</ref><ref name=NYT2018>{{cite news|last1=Hughes|first1=Evan|title=The Pain Hustlers|url=https://www.nytimes.com/interactive/2018/05/02/magazine/money-issue-insys-opioids-kickbacks.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=photo-spot-region&region=top-news&WT.nav=top-news|access-date=3 May 2018|publisher=New York Times|date=2 May 2018}}</ref> These can be bought illegally or prescribed.<ref name=NIH2018Risk/> Diagnosis may be based on criteria by the [[American Psychiatric Association]] in the [[Diagnostic and Statistical Manual of Mental Disorders|DSM-5]].<ref name=DSM5>{{citation|author=American Psychiatric Association|year=2013|title=Diagnostic and Statistical Manual of Mental Disorders (5th ed.)|location=Arlington|publisher=American Psychiatric Publishing|pages=540–546|isbn=978-0890425558}}</ref> If more than two of eleven criteria are present during a year the diagnosis is said to be present.<ref name=DSM5/> If a person is appropriately taking opioids for a medical condition issues of tolerance and withdrawal do not apply.<ref name=DSM5/>
 <!-- Treatment -->
-Individuals with an opioid use disorders are often treated with [[opioid replacement therapy]] using [[methadone]] or [[buprenorphine]].<ref name=BMJ2017Re/> Being on such treatment reduces the risk of death.<ref name=BMJ2017Re>{{cite journal|last1=Sordo|first1=Luis|last2=Barrio|first2=Gregorio|last3=Bravo|first3=Maria J|last4=Indave|first4=B Iciar|last5=Degenhardt|first5=Louisa|last6=Wiessing|first6=Lucas|last7=Ferri|first7=Marica|last8=Pastor-Barriuso|first8=Roberto|title=Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies|journal=BMJ|date=26 April 2017|pages=j1550|doi=10.1136/bmj.j1550|pmid=28446428|volume=357|pmc=5421454}}</ref> Additionally, individuals may benefit from [[cognitive behavioral therapy]], other forms of support from mental health professionals such as individual or group therapy, [[twelve-step program]]s, and other peer support programs.<ref name=Sam2017Tx>{{Cite web|url=https://www.samhsa.gov/treatment/substance-use-disorders|title=Treatment for Substance Use Disorders|last=Substance Abuse and Mental Health Services Administration|first=|date=|website=|access-date=}}</ref> The medication [[naltrexone]] may also be useful to prevent relapse.<ref name=Shar2016/> [[Naloxone]] is useful for treating an [[opioid overdose]] and giving those at risk naloxone to take home is beneficial.<ref name=Mc2016>{{cite journal |last1=McDonald |first1=R |last2=Strang |first2=J |title=Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. |journal=Addiction |date=July 2016 |volume=111 |issue=7 |pages=1177–87 |doi=10.1111/add.13326 |pmid=27028542|pmc=5071734 }}</ref>
+Individuals with an opioid use disorders are often treated with [[opioid replacement therapy]] using [[methadone]] or [[buprenorphine]].<ref name=BMJ2017Re/> Being on such treatment reduces the risk of death.<ref name=BMJ2017Re>{{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 }}</ref> Additionally, individuals may benefit from [[cognitive behavioral therapy]], other forms of support from mental health professionals such as individual or group therapy, [[twelve-step program]]s, and other peer support programs.<ref name=Sam2017Tx>{{Cite web|url=https://www.samhsa.gov/treatment/substance-use-disorders|title=Treatment for Substance Use Disorders| authors =Substance Abuse and Mental Health Services Administration }}</ref> The medication [[naltrexone]] may also be useful to prevent relapse.<ref name=Shar2016/> [[Naloxone]] is useful for treating an [[opioid overdose]] and giving those at risk naloxone to take home is beneficial.<ref name=Mc2016>{{cite journal | vauthors = McDonald R, Strang J | title = Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria | journal = Addiction | volume = 111 | issue = 7 | pages = 1177–87 | date = July 2016 | pmid = 27028542 | pmc = 5071734 | doi = 10.1111/add.13326 }}</ref>
 <!-- Epidemiology and culture -->
-In 2013, opioid use disorders affected about 0.4% of people.<ref name=DSM5/> As of 2015, it was estimated that about 16&nbsp;million people worldwide have been affected at one point in their lives.<ref>{{cite journal|last1=Longo|first1=Dan L.|last2=Schuckit|first2=Marc A.|title=Treatment of Opioid-Use Disorders|journal=New England Journal of Medicine|date=28 July 2016|volume=375|issue=4|pages=357–368|doi=10.1056/NEJMra1604339|pmid=27464203}}</ref> Long term opioid use occurs in about 4% of people following their use for trauma or surgery related pain.<ref name=Moh2018>{{Cite journal|last=Mohamadi|first=Amin|last2=Chan|first2=Jimmy J.|last3=Lian|first3=Jayson|last4=Wright|first4=Casey L.|last5=Marin|first5=Arden M.|last6=Rodriguez|first6=Edward K.|last7=von Keudell|first7=Arvind|last8=Nazarian|first8=Ara|date=2018-08-01|title=Risk Factors and Pooled Rate of Prolonged Opioid Use Following Trauma or Surgery: A Systematic Review and Meta-(Regression) Analysis|journal=The Journal of Bone and Joint Surgery. American Volume|volume=100|issue=15|pages=1332–1340|doi=10.2106/JBJS.17.01239|issn=1535-1386|pmid=30063596}}</ref> Onset is often in young adulthood.<ref name=DSM5/> Males are affected more often than females.<ref name=DSM5/> It resulted in 122,000 deaths worldwide in 2015,<ref name=GBD2015>{{cite journal|last1=GBD 2015 Mortality and Causes of Death|first1=Collaborators.|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|date=8 October 2016|volume=388|issue=10053|pages=1459–1544|pmid=27733281|doi=10.1016/S0140-6736(16)31012-1|pmc=5388903}}</ref> up from 18,000 deaths in 1990.<ref name=GDB2013/> In the United States during 2016, there were more than 42,000 deaths due to opioid overdose, of which more than 15,000 were the result of heroin use.<ref>{{cite web|title=Data Brief 294. Drug Overdose Deaths in the United States, 1999–2016|url=https://www.cdc.gov/nchs/data/databriefs/db294_table.pdf|website=CDC|accessdate=18 May 2018}}</ref>
+In 2013, opioid use disorders affected about 0.4% of people.<ref name=DSM5/> As of 2015, it was estimated that about 16&nbsp;million people worldwide have been affected at one point in their lives.<ref>{{cite journal | vauthors = Schuckit MA | title = Treatment of Opioid-Use Disorders | journal = The New England Journal of Medicine | volume = 375 | issue = 4 | pages = 357–68 | date = July 2016 | pmid = 27464203 | doi = 10.1056/NEJMra1604339 }}</ref> Long term opioid use occurs in about 4% of people following their use for trauma or surgery related pain.<ref name=Moh2018>{{cite journal | vauthors = Mohamadi A, Chan JJ, Lian J, Wright CL, Marin AM, Rodriguez EK, von Keudell A, Nazarian A | title = Risk Factors and Pooled Rate of Prolonged Opioid Use Following Trauma or Surgery: A Systematic Review and Meta-(Regression) Analysis | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 100 | issue = 15 | pages = 1332–1340 | date = August 2018 | pmid = 30063596 | doi = 10.2106/JBJS.17.01239 }}</ref> Onset is often in young adulthood.<ref name=DSM5/> Males are affected more often than females.<ref name=DSM5/> It resulted in 122,000 deaths worldwide in 2015,<ref name=GBD2015>{{cite journal | vauthors =  | 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 }}</ref> up from 18,000 deaths in 1990.<ref name=GDB2013/> In the United States during 2016, there were more than 42,000 deaths due to opioid overdose, of which more than 15,000 were the result of heroin use.<ref>{{cite web|title=Data Brief 294. Drug Overdose Deaths in the United States, 1999–2016|url=https://www.cdc.gov/nchs/data/databriefs/db294_table.pdf|website=CDC|access-date=18 May 2018}}</ref>
 {{TOC limit}}
@@ Line 50: / Line 50: @@
 ===Withdrawal===
-Onset of [[Drug withdrawal|withdrawal]] from opioids depends on which opioid was used last.<ref name=Rie2009/> With heroin this typically occurs 5 hours after use, while with methadone it might not occur until 2 days later.<ref name=Rie2009>{{cite book |last1=Ries |first1=Richard K. |last2=Miller |first2=Shannon C. |last3=Fiellin |first3=David A. |title=Principles of Addiction Medicine |date=2009 |publisher=Lippincott Williams & Wilkins |isbn=9780781774772 |pages=593–594 |url=https://books.google.ca/books?id=j6GGBud8DXcC&pg=PA593 |language=en}}</ref> The length of time that major symptoms occur also depends on the opioid used.<ref name=Rie2009/> For heroin symptoms are typically greatest at two to four days and can last for up to two weeks.<ref name=Rie2009/><ref>{{cite journal |last1=Rahimi-Movaghar |first1=A |last2=Gholami |first2=J |last3=Amato |first3=L |last4=Hoseinie |first4=L |last5=Yousefi-Nooraie |first5=R |last6=Amin-Esmaeili |first6=M |title=Pharmacological therapies for management of opium withdrawal. |journal=The Cochrane Database of Systematic Reviews |date=21 June 2018 |volume=6 |pages=CD007522 |doi=10.1002/14651858.CD007522.pub2 |pmid=29929212}}</ref> Less significant symptoms may remain for an even longer period, in which case it is known as a [[protracted abstinence syndrome]].<ref name=Rie2009/>
+Onset of [[Drug withdrawal|withdrawal]] from opioids depends on which opioid was used last.<ref name=Rie2009/> With heroin this typically occurs 5 hours after use, while with methadone it might not occur until 2 days later.<ref name=Rie2009>{{cite book |last1=Ries |first1=Richard K. |last2=Miller |first2=Shannon C. |last3=Fiellin |first3=David A. | name-list-format = vanc |title=Principles of Addiction Medicine |date=2009 |publisher=Lippincott Williams & Wilkins |isbn=9780781774772 |pages=593–594 |url=https://books.google.ca/books?id=j6GGBud8DXcC&pg=PA593 |language=en}}</ref> The length of time that major symptoms occur also depends on the opioid used.<ref name=Rie2009/> For heroin symptoms are typically greatest at two to four days and can last for up to two weeks.<ref name=Rie2009/><ref>{{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 = 6 | pages = CD007522 | date = June 2018 | pmid = 29929212 | doi = 10.1002/14651858.CD007522.pub2 }}</ref> Less significant symptoms may remain for an even longer period, in which case it is known as a [[protracted abstinence syndrome]].<ref name=Rie2009/>
 *Agitation<ref name=DSM5/>
@@ Line 95: / Line 95: @@
 ==Cause==
-Opioid use disorder can develop as a result of [[self medication|self-medication]], though this is controversial.<ref name="pmid21514751">{{cite journal |title=An examination of psychiatric comorbidities as a function of gender and substance type within an inpatient substance use treatment program |year=2011 |last1=Chen |first1=Kevin W. |last2=Banducci |first2=Annie N. |last3=Guller |first3=Leila |last4=MacAtee |first4=Richard J. |last5=Lavelle |first5=Anna |last6=Daughters |first6=Stacey B. |last7=Lejuez |first7=C.W. |journal=Drug and Alcohol Dependence |volume=118 |issue=2–3 |pages=92–9 |doi=10.1016/j.drugalcdep.2011.03.003 |pmid=21514751 |pmc=3188332}}</ref> Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.<ref name="pmid16336480">{{Cite journal | pmid = 16336480| year = 2005| author1 = Webster| first1 = L. R.| title = Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the Opioid Risk Tool| journal = Pain Medicine| volume = 6| issue = 6| pages = 432–42| last2 = Webster| first2 = R. M.| doi = 10.1111/j.1526-4637.2005.00072.x}}</ref> Prescription opioids are the source of nearly half of misused opioids and the majority of these are initiated for trauma or surgery pain management.<ref name=Moh2018 />
+Opioid use disorder can develop as a result of [[self medication|self-medication]], though this is controversial.<ref name="pmid21514751">{{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 = 92–9 | date = November 2011 | pmid = 21514751 | pmc = 3188332 | doi = 10.1016/j.drugalcdep.2011.03.003 }}</ref> Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.<ref name="pmid16336480">{{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 = 432–42 | year = 2005 | pmid = 16336480 | doi = 10.1111/j.1526-4637.2005.00072.x }}</ref> Prescription opioids are the source of nearly half of misused opioids and the majority of these are initiated for trauma or surgery pain management.<ref name=Moh2018 />
-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|character]] or [[will (philosophy)|will]].<ref name=WHOsub2004>{{cite book |title=Substitution maintenance therapy in the management of opioid dependence and HIV/AIDS prevention |publisher=World Health Organization |year=2004 |isbn=92-4-159115-3 |url=http://whqlibdoc.who.int/unaids/2004/9241591153_eng.pdf}}</ref><ref name=WHOmain>{{cite web|title=Treatment of opioid dependence|url=http://www.who.int/hiv/pub/idu/position_paper_substitution_opioid/en/index.html|publisher=WHO|date=2004|accessdate=28 August 2016}}{{update after|2018|3|7}}</ref> Additionally, [[detoxification]] alone does not constitute adequate treatment.
+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|character]] or [[will (philosophy)|will]].<ref name=WHOsub2004>{{cite book |title=Substitution maintenance therapy in the management of opioid dependence and HIV/AIDS prevention |publisher=World Health Organization |year=2004 |isbn=92-4-159115-3 |url=http://whqlibdoc.who.int/unaids/2004/9241591153_eng.pdf}}</ref><ref name=WHOmain>{{cite web|title=Treatment of opioid dependence|url=http://www.who.int/hiv/pub/idu/position_paper_substitution_opioid/en/index.html|publisher=WHO|date=2004|access-date=28 August 2016}}{{update after|2018|3|7}}</ref> Additionally, [[detoxification]] alone does not constitute adequate treatment.
 ==Mechanism==
@@ Line 103: / Line 103: @@
 ===Addiction===
-[[Addiction]] is a [[brain disorder]] characterized by compulsive drug use despite adverse consequences.<ref name="Brain disease">{{cite journal | vauthors = Volkow ND, Koob GF, McLellan AT | title = Neurobiologic Advances from the Brain Disease Model of Addiction | journal = N. Engl. J. Med. | volume = 374 | issue = 4 | pages = 363–371 | date = January 2016 | pmid = 26816013 | 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.}}</ref><ref name="Cellular basis" /><ref name="Addiction glossary">{{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 = 9780071481274 | pages = 364–375| edition = 2nd | chapter = Chapter 15: Reinforcement and Addictive Disorders}}</ref><ref name="Nestler Labs Glossary">{{cite web|title=Glossary of Terms | url=http://neuroscience.mssm.edu/nestler/glossary.html | website=Mount Sinai School of Medicine | publisher=Department of Neuroscience | accessdate=9 February 2015}}</ref> Addiction is a component of a [[substance use disorder]] and represents the most severe form of the disorder.<ref name="Brain disease" />
+[[Addiction]] is a [[brain disorder]] characterized by compulsive drug use despite adverse consequences.<ref name="Brain disease">{{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 = 363–71 | date = January 2016 | pmid = 26816013 | 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. }}</ref><ref name="Cellular basis" /><ref name="Addiction glossary">{{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 = 9780071481274 | pages = 364–375| edition = 2nd | chapter = Chapter 15: Reinforcement and Addictive Disorders}}</ref><ref name="Nestler Labs Glossary">{{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}}</ref> Addiction is a component of a [[substance use disorder]] and represents the most severe form of the disorder.<ref name="Brain disease" />
-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 [[reward sensitization|sensitizing drug reward]] and amplifying compulsive drug-seeking behavior.<ref name="Cellular basis">{{cite journal | author = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues Clin Neurosci | volume = 15 | issue = 4 | pages = 431–443 |date=December 2013  | pmid = 24459410 | pmc = 3898681 | doi = | quote = DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS}}</ref><ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="What the ΔFosB?">{{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 = 428–37 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840}}</ref> Like other [[addictive drug]]s, overuse of opioids leads to increased ΔFosB expression in the [[nucleus accumbens]].<ref name="Nestler">{{cite journal |vauthors=Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 |date=November 2011  | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111}}</ref><ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–22 |date=December 2011  | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | url = }}</ref><ref name="What the ΔFosB?" /><ref name="ΔFosB reward">{{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 = J. Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | year = 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112 }}</ref> 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 modulate dopamine neurotransmission.<ref name="VTA tail">{{cite journal |vauthors=Bourdy R, Barrot M | title = A new control center for dopaminergic systems: pulling the VTA by the tail | journal = Trends Neurosci. | volume = 35 | issue = 11 | pages = 681–690 |date=November 2012  | pmid = 22824232 | doi = 10.1016/j.tins.2012.06.007}}</ref><ref name="KEGG Morphine addiction">{{cite web | title = Morphine addiction – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05032 | website=KEGG | publisher=Kanehisa Laboratories | accessdate=11 September 2014 | date=18 June 2013}}</ref> 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.<ref name="VTA tail" /><ref name="KEGG Morphine 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 [[reward sensitization|sensitizing drug reward]] and amplifying compulsive drug-seeking behavior.<ref name="Cellular basis">{{cite journal | vauthors = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues in Clinical Neuroscience | volume = 15 | issue = 4 | pages = 431–43 | date = December 2013 | pmid = 24459410 | pmc = 3898681 | doi =  | quote = DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS }}</ref><ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="What the ΔFosB?">{{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 = 428–37 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 }}</ref> Like other [[addictive drug]]s, overuse of opioids leads to increased ΔFosB expression in the [[nucleus accumbens]].<ref name="Nestler">{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–37 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}</ref><ref name="Natural and drug addictions">{{cite journal | vauthors = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–22 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 }}</ref><ref name="What the ΔFosB?" /><ref name="ΔFosB reward">{{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 }}</ref> 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 modulate dopamine neurotransmission.<ref name="VTA tail">{{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 = 681–90 | date = November 2012 | pmid = 22824232 | doi = 10.1016/j.tins.2012.06.007 }}</ref><ref name="KEGG Morphine addiction">{{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}}</ref> 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.<ref name="VTA tail" /><ref name="KEGG Morphine addiction" />
-Neuroimaging has shown functional and structural alterations in the brain.<ref>{{Cite journal|last=Goldstein|first=Rita Z.|last2=Volkow|first2=Nora D.|date=1 November 2011|title=Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications|url=http://www.nature.com/nrn/journal/v12/n11/full/nrn3119.html|journal=Nature Reviews Neuroscience|language=en|volume=12|issue=11|pages=652–669|doi=10.1038/nrn3119|issn=1471-003X|pmc=3462342|pmid=22011681}}</ref> A 2017 study showed that chronic intake of opioid, such as heroin, may cause long-term effect in the orbitofrontal area (OFC), which is essential for regulating reward-related behaviors, emotional responses, and anxiety.<ref name="pmid28422138">{{cite journal | vauthors = Ieong HF, Yuan Z | title = Abnormal resting-state functional connectivity in the orbitofrontal cortex of heroin users and its relationship with anxiety: a pilot fNIRS study | journal = Sci Rep | volume = 7 | issue = | pages = 46522 | date = April 2017 | pmid = 28422138 | pmc = 5395928 |issn = 2045-2322| doi = 10.1038/srep46522 }}</ref>{{secondary source needed|date=April 2017}} Moreover, neuroimaging and neuropsychological studies demonstrated dysregulation of circuits associated with emotion, stress and high impulsivity.<ref name="Ieong"/>
+Neuroimaging has shown functional and structural alterations in the brain.<ref>{{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 = 652–69 | date = October 2011 | pmid = 22011681 | pmc = 3462342 | doi = 10.1038/nrn3119 | url = http://www.nature.com/nrn/journal/v12/n11/full/nrn3119.html }}</ref> A 2017 study showed that chronic intake of opioid, such as heroin, may cause long-term effect in the orbitofrontal area (OFC), which is essential for regulating reward-related behaviors, emotional responses, and anxiety.<ref name="pmid28422138">{{cite journal | vauthors = Ieong HF, Yuan Z | title = Abnormal resting-state functional connectivity in the orbitofrontal cortex of heroin users and its relationship with anxiety: a pilot fNIRS study | journal = Scientific Reports | volume = 7 | issue =  | pages = 46522 | date = April 2017 | pmid = 28422138 | pmc = 5395928 | doi = 10.1038/srep46522 }}</ref>{{secondary source needed|date=April 2017}} Moreover, neuroimaging and neuropsychological studies demonstrated dysregulation of circuits associated with emotion, stress and high impulsivity.<ref name="Ieong"/>
 ===Dependence===
-[[Drug dependence]] is an adaptive state associated with a [[drug withdrawal|withdrawal syndrome]] upon cessation of repeated exposure to a stimulus (e.g., drug intake).<ref name="Cellular basis" /><ref name="Addiction glossary" /><ref name="Nestler Labs Glossary" /> Dependence is a component of a [[substance use disorder]].<ref name="Brain disease" /><ref name="Opioid use disorder - DSM-5 criteria">{{cite encyclopedia|section=Opioid Use Disorder: Diagnostic Criteria|title=Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition|chapter-url=http://pcssmat.org/wp-content/uploads/2014/02/5B-DSM-5-Opioid-Use-Disorder-Diagnostic-Criteria.pdf|publisher=American Psychiatric Association|accessdate=27 March 2017|pages=1–9}}</ref> Opioid dependence can manifest as [[physical dependence]], [[psychological dependence]], or both.<ref name="pmid26740398" /><ref name="Addiction glossary" /><ref name="Opioid use disorder - DSM-5 criteria" />
+[[Drug dependence]] is an adaptive state associated with a [[drug withdrawal|withdrawal syndrome]] upon cessation of repeated exposure to a stimulus (e.g., drug intake).<ref name="Cellular basis" /><ref name="Addiction glossary" /><ref name="Nestler Labs Glossary" /> Dependence is a component of a [[substance use disorder]].<ref name="Brain disease" /><ref name="Opioid use disorder - DSM-5 criteria">{{cite encyclopedia|section=Opioid Use Disorder: Diagnostic Criteria|title=Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition|chapter-url=http://pcssmat.org/wp-content/uploads/2014/02/5B-DSM-5-Opioid-Use-Disorder-Diagnostic-Criteria.pdf|publisher=American Psychiatric Association|access-date=27 March 2017|pages=1–9}}</ref> Opioid dependence can manifest as [[physical dependence]], [[psychological dependence]], or both.<ref name="pmid26740398" /><ref name="Addiction glossary" /><ref name="Opioid use disorder - DSM-5 criteria" />
-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).<ref name="Cellular basis" /><ref>{{cite journal |pages=1732–34 |doi=10.1126/science.1168501 |title=Ventral Tegmental Area BDNF Induces an Opiate-Dependent-Like Reward State in Naive Rats |year=2009 |last1=Vargas-Perez |first1=H. |last2=Ting-A-Kee |first2=R. |last3=Walton |first3=C. H. |last4=Hansen |first4=D. M. |last5=Razavi |first5=R. |last6=Clarke |first6=L. |last7=Bufalino |first7=M. R. |last8=Allison |first8=D. W. |last9=Steffensen |first9=S. C. |journal=Science |volume=324 |issue=5935 |pmid=19478142 |pmc=2913611 }}</ref> As a result of downregulated signaling through these proteins, opiates cause VTA neuronal hyperexcitability and shrinkage (specifically, the size of the [[Soma (biology)|neuronal soma]] is reduced).<ref name="Cellular basis" /> It has been shown that when an opiate-naive person begins using opiates in concentrations that induce [[euphoria]], BDNF signaling increases in the VTA.<ref>{{cite journal |pages=1009–15 |doi=10.1046/j.1460-9568.2001.01458.x |title=GABAA receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non-dopaminergic neural motivational systems |year=2001 |last1=Laviolette |first1=Steven R. |last2=Van Der Kooy |first2=Derek |journal=European Journal of Neuroscience |volume=13 |issue=5 |pmid=11264674}}</ref>
+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).<ref name="Cellular basis" /><ref>{{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 = 1732–4 | date = June 2009 | pmid = 19478142 | pmc = 2913611 | doi = 10.1126/science.1168501 }}</ref> As a result of downregulated signaling through these proteins, opiates cause VTA neuronal hyperexcitability and shrinkage (specifically, the size of the [[Soma (biology)|neuronal soma]] is reduced).<ref name="Cellular basis" /> It has been shown that when an opiate-naive person begins using opiates in concentrations that induce [[euphoria]], BDNF signaling increases in the VTA.<ref>{{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 = 1009–15 | date = March 2001 | pmid = 11264674 | doi = 10.1046/j.1460-9568.2001.01458.x }}</ref>
-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.<ref name="pmid26740398">{{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 Res. | volume = | issue = | pages = | year = 2015 | pmid = 26740398 | 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. }}</ref><ref name="Cellular basis" /> Upregulation of the same pathway in the [[locus coeruleus]] is also a mechanism responsible for certain aspects of opioid-induced [[physical dependence]].<ref name="pmid26740398" /><ref name="Cellular basis" />
+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.<ref name="pmid26740398">{{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 | issue =  | pages = 71–4 | date = August 2016 | pmid = 26740398 | 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. }}</ref><ref name="Cellular basis" /> Upregulation of the same pathway in the [[locus coeruleus]] is also a mechanism responsible for certain aspects of opioid-induced [[physical dependence]].<ref name="pmid26740398" /><ref name="Cellular basis" />
 ===Opioid receptors===
 A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for a number of specific variations; however, the evidence for clinical differences in opioid effects is ambiguous. 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|methamphetamine dependence]]/[[Stimulant psychosis|psychosis]], response to naltrexone treatment, personality traits, and others. [[Substance dependence#Genetic Factors|Major and minor variants]] have been reported for every receptor and ligand coding gene in both coding sequences, as well as regulatory regions.
-Newer approaches shift away from analysis of specific genes and regions, and are based on an unbiased screen of genes across the entire genome, which have no apparent relationship to the phenotype in question. These [[Genome-wide association study|GWAS]] studies yield 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.<ref name="pmid23872493">{{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 = Pharmacol. Ther. | volume = 140 | issue = 3 | pages = 267–79 | date = December 2013 | pmid = 23872493 | pmc = 3797854 | doi = 10.1016/j.pharmthera.2013.07.006 }}</ref>
+Newer approaches shift away from analysis of specific genes and regions, and are based on an unbiased screen of genes across the entire genome, which have no apparent relationship to the phenotype in question. These [[Genome-wide association study|GWAS]] studies yield 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.<ref name="pmid23872493">{{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 = 267–79 | date = December 2013 | pmid = 23872493 | pmc = 3797854 | doi = 10.1016/j.pharmthera.2013.07.006 }}</ref>
 Currently, there are no specific pharmacogenomic dosing recommendations for opioids due to a lack of clear evidence connecting genotype to drug effect, toxicity, or likelihood of dependence.{{citation needed|date=March 2017}}
 ====118A>G variant====
-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 of 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 a greater addictive capacity in these individuals who require higher dosages to achieve pain control. However, evidence linking the 118A>G variant to opioid dependence is mixed, with associations shown in a number of study groups, but negative results in other groups. One explanation for the mixed results is the possibility of other variants which are in [[linkage disequilibrium]] with the 118A>G variant and thus contribute to different [[haplotype]] patterns that more specifically associate with opioid dependence.<ref name="pmid23374939">{{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 = J Pain | volume = 14 | issue = 2 | pages = 103–13 | date = February 2013 | pmid = 23374939 | pmc = 3564046 | doi = 10.1016/j.jpain.2012.10.016 }}</ref>
+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 of 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 a greater addictive capacity in these individuals who require higher dosages to achieve pain control. However, evidence linking the 118A>G variant to opioid dependence is mixed, with associations shown in a number of study groups, but negative results in other groups. One explanation for the mixed results is the possibility of other variants which are in [[linkage disequilibrium]] with the 118A>G variant and thus contribute to different [[haplotype]] patterns that more specifically associate with opioid dependence.<ref name="pmid23374939">{{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 = 103–13 | date = February 2013 | pmid = 23374939 | pmc = 3564046 | doi = 10.1016/j.jpain.2012.10.016 }}</ref>
 ====Non-opioid receptor genes====
-The [[preproenkephalin]] gene, PENK, encodes for the endogenous opiates that modulate pain perception, and are implicated in reward and addiction. [[Microsatellite|(CA) repeats]] in the 3' flanking sequence of the PENK gene was associated with greater likelihood of opiate dependence in repeated studies. Variability in the MCR2 gene, encoding [[melanocortin receptor]] type 2 has been associated with both protective effects and increased susceptibility to heroin addiction. The CYP2B6 gene of the [[cytochrome P450]] family also mediates breakdown of opioids and thus may play a role in dependence and overdose.<ref name="pmid20055697">{{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 = Annu. Rev. Pharmacol. Toxicol. | volume = 50 | issue = | pages = 39–61 | date = 2010 | pmid = 20055697 | doi = 10.1146/annurev.pharmtox.010909.105826 }}</ref>
+The [[preproenkephalin]] gene, PENK, encodes for the endogenous opiates that modulate pain perception, and are implicated in reward and addiction. [[Microsatellite|(CA) repeats]] in the 3' flanking sequence of the PENK gene was associated with greater likelihood of opiate dependence in repeated studies. Variability in the MCR2 gene, encoding [[melanocortin receptor]] type 2 has been associated with both protective effects and increased susceptibility to heroin addiction. The CYP2B6 gene of the [[cytochrome P450]] family also mediates breakdown of opioids and thus may play a role in dependence and overdose.<ref name="pmid20055697">{{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 | issue =  | pages = 39–61 | date = 2010 | pmid = 20055697 | doi = 10.1146/annurev.pharmtox.010909.105826 }}</ref>
 ==Diagnosis==
@@ Line 148: / Line 148: @@
 === Opioid related deaths ===
-[[Naloxone]] is used for the [[Opioid overdose#Treatment|emergency treatment of an overdose]].<ref name="HMDB Naloxone">{{cite encyclopedia | title = Naloxone | url = http://www.hmdb.ca/metabolites/HMDB0015314 | work = Human Metabolome Database&nbsp;– Version 4.0 | accessdate = 2 November 2017 | date = 23 October 2017 }}</ref> It can be given by many routes (e.g., intramuscular, intravenous, subcutaneous, intranasal, and inhalation) and acts quickly by displacing opioids from opioid receptors and preventing activation of these receptors by opioids.<ref>{{cite web|title=Naloxone for Treatement of Opioide Overdose|url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM522690.pdf|website=FDA|accessdate=7 November 2017}}</ref> Naloxone kits are recommended for laypersons who may witness an opioid overdose, for individuals with large prescriptions for opioids, those in substance use treatment programs, or who have been recently released from incarceration.<ref name=":11">{{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|language=en|access-date=9 March 2017}}</ref> Since this is a life-saving medication, many areas of the United States have implemented standing orders for law enforcement to carry and give naloxone as needed.<ref name="FDA – law enforcement and naloxone">{{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 = United States Food and Drug Administration | publisher = North Carolina Harm Reduction Coalition | accessdate = 2 November 2017 | pages = 1–24}}</ref><ref name="Naloxone standing orders">{{cite web | title = Case studies: Standing orders | url = http://naloxoneinfo.org/case-studies/standing-orders | website = NaloxoneInfo.org | publisher = Open Society Foundations | accessdate = 2 November 2017}}</ref> In addition, naloxone could be used to challenge a person's opioid abstinence status prior to starting a medication such as [[naltrexone]], which is used in the management of opioid addiction.<ref name="pmid27464203">{{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 | url = http://www.nejm.org/doi/full/10.1056/NEJMra1604339#t=article}}</ref>
+[[Naloxone]] is used for the [[Opioid overdose#Treatment|emergency treatment of an overdose]].<ref name="HMDB Naloxone">{{cite encyclopedia | title = Naloxone | url = http://www.hmdb.ca/metabolites/HMDB0015314 | work = Human Metabolome Database&nbsp;– Version 4.0 | access-date = 2 November 2017 | date = 23 October 2017 }}</ref> It can be given by many routes (e.g., intramuscular, intravenous, subcutaneous, intranasal, and inhalation) and acts quickly by displacing opioids from opioid receptors and preventing activation of these receptors by opioids.<ref>{{cite web|title=Naloxone for Treatement of Opioide Overdose|url=https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM522690.pdf|website=FDA|access-date=7 November 2017}}</ref> Naloxone kits are recommended for laypersons who may witness an opioid overdose, for individuals with large prescriptions for opioids, those in substance use treatment programs, or who have been recently released from incarceration.<ref name=":11">{{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|language=en|access-date=9 March 2017}}</ref> Since this is a life-saving medication, many areas of the United States have implemented standing orders for law enforcement to carry and give naloxone as needed.<ref name="FDA – law enforcement and naloxone">{{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 = United States Food and Drug Administration | publisher = North Carolina Harm Reduction Coalition | access-date = 2 November 2017 | pages = 1–24}}</ref><ref name="Naloxone standing orders">{{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}}</ref> In addition, naloxone could be used to challenge a person's opioid abstinence status prior to starting a medication such as [[naltrexone]], which is used in the management of opioid addiction.<ref name="pmid27464203">{{cite journal | vauthors = Schuckit MA | title = Treatment of Opioid-Use Disorders | journal = The New England Journal of Medicine | volume = 375 | issue = 4 | pages = 357–68 | date = July 2016 | pmid = 27464203 | doi = 10.1056/NEJMra1604339 | url = http://www.nejm.org/doi/full/10.1056/NEJMra1604339#t=article }}</ref>
 ==Management==
-Opioid use disorders typically require [[Long-term care|long-term treatment and care]] with the goal of reducing risks for the individual, reducing criminal behaviour, and improving the long-term physical and psychological condition of the person.<ref name=WHOmain/> Most strategies aim ultimately to reduce drug use and lead to abstinence.<ref name=WHOmain/> No single treatment works for everyone, so several strategies have been developed including therapy and drugs.<ref name=WHOmain/><ref>{{cite journal |vauthors=Nicholls L, Bragaw L, Ruetsch C |title=Opioid Dependence Treatment and guidelines |journal=J Manag Care Pharm. |date=February 2010 |volume=16 |issue=1 Suppl B |pages=S14–21 |pmid=20146550 |url=http://www.healthanalytic.com/LinkClick.aspx?fileticket=osz9-YYUsUU%3D&tabid=78 }}</ref>
+Opioid use disorders typically require [[Long-term care|long-term treatment and care]] with the goal of reducing risks for the individual, reducing criminal behaviour, and improving the long-term physical and psychological condition of the person.<ref name=WHOmain/> Most strategies aim ultimately to reduce drug use and lead to abstinence.<ref name=WHOmain/> No single treatment works for everyone, so several strategies have been developed including therapy and drugs.<ref name=WHOmain/><ref>{{cite journal | vauthors = Nicholls L, Bragaw L, Ruetsch C | title = Opioid dependence treatment and guidelines | journal = Journal of Managed Care Pharmacy | volume = 16 | issue = 1 Suppl B | pages = S14-21 | date = February 2010 | pmid = 20146550 | url = http://www.healthanalytic.com/LinkClick.aspx?fileticket=osz9-YYUsUU%3D&tabid=78 }}</ref>
-As of 2013 in the US, there was a significant increase of prescription opioid abuse compared to [[illicit drugs|illegal opiates]] like [[heroin]].<ref name="pmid23881609">{{cite journal | vauthors = Daubresse M, Gleason PP, Peng Y, Shah ND, Ritter ST, Alexander GC | title = Impact of a drug utilization review program on high-risk use of prescription controlled substances | journal = Pharmacoepidemiol Drug Saf | volume = 23 | issue = 4 | pages = 419–27 | date = April 2014 | pmid = 23881609 | doi = 10.1002/pds.3487 }}</ref> This development has also implications for the prevention, treatment and therapy of opioid dependence.<ref>Amy Maxmen (June 2012), "Tackling the US pain epidemic". ''Nature News'' {{DOI|10.1038/nature.2012.10766}}</ref> Though treatment reduces mortality rates, the period during the first four weeks after treatment begins and the four weeks after treatment ceases are the times that carry the highest risk for drug related deaths. These periods of increased vulnerability are significant because many of those in treatment leave programs during these critical periods.<ref name="BMJ2017Re" />
+As of 2013 in the US, there was a significant increase of prescription opioid abuse compared to [[illicit drugs|illegal opiates]] like [[heroin]].<ref name="pmid23881609">{{cite journal | vauthors = Daubresse M, Gleason PP, Peng Y, Shah ND, Ritter ST, Alexander GC | title = Impact of a drug utilization review program on high-risk use of prescription controlled substances | journal = Pharmacoepidemiology and Drug Safety | volume = 23 | issue = 4 | pages = 419–27 | date = April 2014 | pmid = 23881609 | doi = 10.1002/pds.3487 }}</ref> This development has also implications for the prevention, treatment and therapy of opioid dependence.<ref>Amy Maxmen (June 2012), "Tackling the US pain epidemic". ''Nature News'' {{DOI|10.1038/nature.2012.10766}}</ref> Though treatment reduces mortality rates, the period during the first four weeks after treatment begins and the four weeks after treatment ceases are the times that carry the highest risk for drug related deaths. These periods of increased vulnerability are significant because many of those in treatment leave programs during these critical periods.<ref name="BMJ2017Re" />
 ===Medications===
-Opioid replacement therapy (ORT), also called opioid substitution therapy or opioid maintenance therapy, involves replacing an [[opioid]], such as [[heroin]], with a longer acting but less euphoric opioid.<ref name="NEPOD Report" /> Commonly used drugs for ORT are [[methadone]] or [[buprenorphine]] which are taken under medical supervision.<ref name="NEPOD Report">Richard P. Mattick et al.: [http://content.webarchive.nla.gov.au/gov/wayback/20140211195842/http://www.nationaldrugstrategy.gov.au/internet/drugstrategy/Publishing.nsf/content/8BA50209EE22B9C6CA2575B40013539D/$File/mono52.pdf National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendation]</ref> As of 2018 [[buprenorphine/naloxone]] is preferentially recommended.<ref name=CMAJ2018>{{cite journal | vauthors = Bruneau J, Ahamad K, Goyer MÈ, Poulin G, Selby P, Fischer B, Wild TC, Wood E | title = Management of opioid use disorders: a national clinical practice guideline | journal = CMAJ | volume = 190 | issue = 9 | pages = E247–E257 | date = March 2018 | pmid = 29507156 | pmc = 5837873 | doi = 10.1503/cmaj.170958 }}</ref>
+Opioid replacement therapy (ORT), also called opioid substitution therapy or opioid maintenance therapy, involves replacing an [[opioid]], such as [[heroin]], with a longer acting but less euphoric opioid.<ref name="NEPOD Report" /> Commonly used drugs for ORT are [[methadone]] or [[buprenorphine]] which are taken under medical supervision.<ref name="NEPOD Report">Richard P. Mattick et al.: [http://content.webarchive.nla.gov.au/gov/wayback/20140211195842/http://www.nationaldrugstrategy.gov.au/internet/drugstrategy/Publishing.nsf/content/8BA50209EE22B9C6CA2575B40013539D/$File/mono52.pdf National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendation]</ref> As of 2018 [[buprenorphine/naloxone]] is preferentially recommended.<ref name=CMAJ2018>{{cite journal | vauthors = Bruneau J, Ahamad K, Goyer MÈ, Poulin G, Selby P, Fischer B, Wild TC, Wood E | title = Management of opioid use disorders: a national clinical practice guideline | journal = Cmaj | volume = 190 | issue = 9 | pages = E247-E257 | date = March 2018 | pmid = 29507156 | pmc = 5837873 | doi = 10.1503/cmaj.170958 }}</ref>
-The driving principle behind ORT is the program's capacity to facilitate a resumption of stability in the user's life, while the patient experiences reduced symptoms of [[drug withdrawal]] and less intense [[Craving (withdrawal)|drug cravings]]; a strong euphoric effect is not experienced as a result of the treatment drug.<ref name="NEPOD Report"/> In some countries (not the US, or Australia),<ref name="NEPOD Report"/> regulations enforce a limited time period for people on ORT programs that conclude when a stable economic and psychosocial situation is achieved. (People with [[HIV|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% are able to reduce their use significantly.<ref name="NEPOD Report" /> Along with this is a concurrent elimination or reduction in medical (improper [[diluent]]s, non-[[Sterilization (microbiology)|sterile]] injecting equipment), psychosocial ([[mental health]], relationships), and legal ([[arrest]] and [[imprisonment]]) issues that can arise from the use of illegal opioids.<ref name="NEPOD Report"/> [[Clonidine]] or [[lofexidine]] can help treat the symptoms of withdrawal.<ref>{{cite journal|last1=Gowing|first1=L|last2=Farrell|first2=M|last3=Ali|first3=R|last4=White|first4=JM|title=Alpha₂-adrenergic agonists for the management of opioid withdrawal.|journal=The Cochrane Database of Systematic Reviews|date=3 May 2016|issue=5|pages=CD002024|pmid=27140827|doi=10.1002/14651858.CD002024.pub5}}</ref>
+The driving principle behind ORT is the program's capacity to facilitate a resumption of stability in the user's life, while the patient experiences reduced symptoms of [[drug withdrawal]] and less intense [[Craving (withdrawal)|drug cravings]]; a strong euphoric effect is not experienced as a result of the treatment drug.<ref name="NEPOD Report"/> In some countries (not the US, or Australia),<ref name="NEPOD Report"/> regulations enforce a limited time period for people on ORT programs that conclude when a stable economic and psychosocial situation is achieved. (People with [[HIV|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% are able to reduce their use significantly.<ref name="NEPOD Report" /> Along with this is a concurrent elimination or reduction in medical (improper [[diluent]]s, non-[[Sterilization (microbiology)|sterile]] injecting equipment), psychosocial ([[mental health]], relationships), and legal ([[arrest]] and [[imprisonment]]) issues that can arise from the use of illegal opioids.<ref name="NEPOD Report"/> [[Clonidine]] or [[lofexidine]] can help treat the symptoms of withdrawal.<ref>{{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 | issue = 5 | pages = CD002024 | date = May 2016 | pmid = 27140827 | doi = 10.1002/14651858.CD002024.pub5 }}</ref>
-Participation in methadone and buprenorphine treatment reduces the risk of mortality due to overdose.<ref name="BMJ2017Re" /> The starting of methadone and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies.<ref name=BMJ2017Re/> ORT has proven to be the most effective treatment for improving the health and living condition of people experiencing problematic illegal opiate use or dependence, including mortality reduction<ref name="NEPOD Report"/><ref>Michel et al.: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1797169 Substitution treatment for opioid addicts in Germany], Harm Reduct J. 2007; 4: 5.</ref><ref name=BMJ2017Re/> and overall societal costs, such as the economic loss from [[drug-related crime]] and healthcare expenditure.<ref name="NEPOD Report"/> Opioid Replacement Therapy is endorsed by the [[World Health Organization]], [[United Nations Office on Drugs and Crime]] and [[UNAIDS]] as being effective at reducing injection, lowering risk for HIV/AIDS, and promoting adherence to antiretroviral therapy.<ref name="BMJ2017Re" /> Currently, 55 countries worldwide use methadone replacement therapy, while some countries such as Russia do not.<ref>{{cite news|title=Russia Scorns Methadone for Heroin Addiction|url=https://www.nytimes.com/2008/07/22/health/22meth.html?pagewanted=all|accessdate=5 April 2014|newspaper=The New York Times|date=22 July 2008|author=Michael Schwartz}}</ref>
+Participation in methadone and buprenorphine treatment reduces the risk of mortality due to overdose.<ref name="BMJ2017Re" /> The starting of methadone and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies.<ref name=BMJ2017Re/> ORT has proven to be the most effective treatment for improving the health and living condition of people experiencing problematic illegal opiate use or dependence, including mortality reduction<ref name="NEPOD Report"/><ref>Michel et al.: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1797169 Substitution treatment for opioid addicts in Germany], Harm Reduct J. 2007; 4: 5.</ref><ref name=BMJ2017Re/> and overall societal costs, such as the economic loss from [[drug-related crime]] and healthcare expenditure.<ref name="NEPOD Report"/> Opioid Replacement Therapy is endorsed by the [[World Health Organization]], [[United Nations Office on Drugs and Crime]] and [[UNAIDS]] as being effective at reducing injection, lowering risk for HIV/AIDS, and promoting adherence to antiretroviral therapy.<ref name="BMJ2017Re" /> Currently, 55 countries worldwide use methadone replacement therapy, while some countries such as Russia do not.<ref>{{cite news|title=Russia Scorns Methadone for Heroin Addiction|url=https://www.nytimes.com/2008/07/22/health/22meth.html?pagewanted=all|access-date=5 April 2014|newspaper=The New York Times|date=22 July 2008| first = Michael | last = Schwartz | name-list-format = vanc }}</ref>
 ====Methadone====
 [[File:Methadone 40mg.jpg|thumb|40&nbsp;mg of methadone]]
 {{Main|Methadone maintenance}}
-[[Methadone]] maintenance treatment (MMT), a form of opioid replacement therapy, reduces and/or eliminates the use of illegal opiates, the criminality associated with opiate use, and allows patients to improve their health and social productivity.<ref name="JosephStancliffLangrod"/><ref name="Connock">{{cite journal |pmid=17313907 |year=2007 |last1=Connock |first1=M |last2=Juarez-Garcia |first2=A |last3=Jowett |first3=S |last4=Frew |first4=E |last5=Liu |first5=Z |last6=Taylor |first6=RJ |last7=Fry-Smith |first7=A |last8=Day |first8=E |last9=Lintzeris |first9=N |title=Methadone and buprenorphine for the management of opioid dependence: A systematic review and economic evaluation |volume=11 |issue=9 |pages=1–171, iii–iv |journal=Health technology assessment |url=http://www.hta.ac.uk/execsumm/summ1109.htm |doi=10.3310/hta11090}}</ref> Methadone is an [[agonist]] of opioids. If initial doses during the beginning of treatment are too high or are concurrent with illicit opioid use, this may present an increased risk of death from overdose.<ref name=BMJ2017Re/>  In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV.<ref name="JosephStancliffLangrod"/> The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. Methadone maintenance has been found to be medically safe and non-sedating.<ref name="JosephStancliffLangrod"/> It is also indicated for pregnant women addicted to opiates.<ref name="JosephStancliffLangrod">{{cite journal |pmid=11064485 |year=2000 |last1=Joseph |first1=H |last2=Stancliff |first2=S |last3=Langrod |first3=J |title=Methadone maintenance treatment (MMT): A review of historical and clinical issues |volume=67 |issue=5–6 |pages=347–64 |journal=The Mount Sinai journal of medicine, New York}}</ref>
+[[Methadone]] maintenance treatment (MMT), a form of opioid replacement therapy, reduces and/or eliminates the use of illegal opiates, the criminality associated with opiate use, and allows patients to improve their health and social productivity.<ref name="JosephStancliffLangrod"/><ref name="Connock">{{cite journal | vauthors = Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, Fry-Smith A, Day E, Lintzeris N, Roberts T, Burls A, Taylor RS | title = Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation | journal = Health Technology Assessment | volume = 11 | issue = 9 | pages = 1–171, iii-iv | date = March 2007 | pmid = 17313907 | doi = 10.3310/hta11090 | url = http://www.hta.ac.uk/execsumm/summ1109.htm }}</ref> Methadone is an [[agonist]] of opioids. If initial doses during the beginning of treatment are too high or are concurrent with illicit opioid use, this may present an increased risk of death from overdose.<ref name=BMJ2017Re/>  In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV.<ref name="JosephStancliffLangrod"/> The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. Methadone maintenance has been found to be medically safe and non-sedating.<ref name="JosephStancliffLangrod"/> It is also indicated for pregnant women addicted to opiates.<ref name="JosephStancliffLangrod">{{cite journal | vauthors = Joseph H, Stancliff S, Langrod J | title = Methadone maintenance treatment (MMT): a review of historical and clinical issues | journal = The Mount Sinai Journal of Medicine, New York | volume = 67 | issue = 5-6 | pages = 347–64 | year = 2000 | pmid = 11064485 }}</ref>
-[[Methadone maintenance]] treatment is given to addicted individuals who feel unable to go the whole way and get clean. For individuals who wish to completely move away from drugs, they can start a methadone reduction program. A methadone reduction program is where an individual is prescribed an amount of methadone which is increased until withdrawal symptoms subside, after a period of stability, the dose will then be gradually reduced until the individual is either free of the need for methadone or is at a level which allows a switch to a different opiate with an easier withdrawal profile, such as [[suboxone]]. Methadone toxicity has been shown to be associated with specific phenotypes of [[CYP2B6]].<ref name="pmid20668445">{{cite journal | vauthors = Bunten H, Liang WJ, Pounder DJ, Seneviratne C, Osselton D | title = OPRM1 and CYP2B6 gene variants as risk factors in methadone-related deaths | journal = Clin. Pharmacol. Ther. | volume = 88 | issue = 3 | pages = 383–9 | date = September 2010 | pmid = 20668445 | doi = 10.1038/clpt.2010.127 }}</ref>
+[[Methadone maintenance]] treatment is given to addicted individuals who feel unable to go the whole way and get clean. For individuals who wish to completely move away from drugs, they can start a methadone reduction program. A methadone reduction program is where an individual is prescribed an amount of methadone which is increased until withdrawal symptoms subside, after a period of stability, the dose will then be gradually reduced until the individual is either free of the need for methadone or is at a level which allows a switch to a different opiate with an easier withdrawal profile, such as [[suboxone]]. Methadone toxicity has been shown to be associated with specific phenotypes of [[CYP2B6]].<ref name="pmid20668445">{{cite journal | vauthors = Bunten H, Liang WJ, Pounder DJ, Seneviratne C, Osselton D | title = OPRM1 and CYP2B6 gene variants as risk factors in methadone-related deaths | journal = Clinical Pharmacology and Therapeutics | volume = 88 | issue = 3 | pages = 383–9 | date = September 2010 | pmid = 20668445 | doi = 10.1038/clpt.2010.127 }}</ref>
-Some impairment in cognition has been demonstrated in those using methadone.<ref name="Ieong">{{Cite journal|last=Ieong|first=Hada Fong-ha|last2=Yuan|first2=Zhen|date=1 January 2017|title=Resting-State Neuroimaging and Neuropsychological Findings in Opioid Use Disorder during Abstinence: A Review|url=http://journal.frontiersin.org/article/10.3389/fnhum.2017.00169/full|journal=Frontiers in Human Neuroscience|language=English|volume=11|doi=10.3389/fnhum.2017.00169|issn=1662-5161}}</ref><ref>{{Cite journal|last=Darke|first=Shane|last2=Sims|first2=Jamie|last3=McDonald|first3=Skye|last4=Wickes|first4=Wendy|date=1 May 2000|title=Cognitive impairment among methadone maintenance patients|url=http://onlinelibrary.wiley.com/doi/10.1046/j.1360-0443.2000.9556874.x/abstract|journal=Addiction|language=en|volume=95|issue=5|pages=687–695|doi=10.1046/j.1360-0443.2000.9556874.x|issn=1360-0443}}</ref>
+Some impairment in cognition has been demonstrated in those using methadone.<ref name="Ieong">{{cite journal | vauthors = Ieong HF, Yuan Z | title = Resting-State Neuroimaging and Neuropsychological Findings in Opioid Use Disorder during Abstinence: A Review | language = English | journal = Frontiers in Human Neuroscience | volume = 11 | pages = 169 | date = 1 January 2017 | pmid = 28428748 | doi = 10.3389/fnhum.2017.00169 }}</ref><ref>{{cite journal | vauthors = Darke S, Sims J, McDonald S, Wickes W | title = Cognitive impairment among methadone maintenance patients | journal = Addiction | volume = 95 | issue = 5 | pages = 687–95 | date = May 2000 | pmid = 10885043 | doi = 10.1046/j.1360-0443.2000.9556874.x }}</ref>
 ====Buprenorphine====
 [[File:Suboxone.jpg|thumb|Buprenorphine/naloxone tablet]]
-Treatment with buprenorphine may be associated with reduced mortality.<ref name="BMJ2017Re" /> Buprenorphine [[Sublingual administration|under the tongue]] is often used to manage opioid [[Chemical dependency|dependence]]. Preparations were approved for this use in the United States in 2002.<ref>{{cite web | url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm191521.htm | title=Subutex and Suboxone Approved to Treat Opiate Dependence | publisher=FDA | date=8 October 2002 | accessdate=1 November 2014}}</ref> Some formulations of buprenorphine incorporate the opiate antagonist [[naloxone]] during the production of the [[Tablet (pharmacy)|pill]] form to prevent people from crushing the tablets and injecting them, instead of using the [[sublingual]] (under the tongue) route of administration.<ref name="NEPOD Report"/>
+Treatment with buprenorphine may be associated with reduced mortality.<ref name="BMJ2017Re" /> Buprenorphine [[Sublingual administration|under the tongue]] is often used to manage opioid [[Chemical dependency|dependence]]. Preparations were approved for this use in the United States in 2002.<ref>{{cite web | url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm191521.htm | title=Subutex and Suboxone Approved to Treat Opiate Dependence | publisher=FDA | date=8 October 2002 | access-date=1 November 2014}}</ref> Some formulations of buprenorphine incorporate the opiate antagonist [[naloxone]] during the production of the [[Tablet (pharmacy)|pill]] form to prevent people from crushing the tablets and injecting them, instead of using the [[sublingual]] (under the tongue) route of administration.<ref name="NEPOD Report"/>
 ====Diamorphine====
 {{See also|Heroin maintenance}}
-In Switzerland, Germany, the Netherlands, and the United Kingdom, long-term [[Injecting Drug User|injecting drug user]]s who do not benefit from [[methadone]] and other medication options are treated with pure injectable [[diamorphine]] that is administered under the supervision of medical staff. For this group of patients, diamorphine treatment has proven superior in improving their social and health situation.<ref>{{cite journal |pages=55–62 |doi=10.1192/bjp.bp.106.026112 |title=Heroin-assisted treatment for opioid dependence: Randomised controlled  trial |year=2007 |last1=Haasen |first1=C. |last2=Verthein |first2=U. |last3=Degkwitz |first3=P. |last4=Berger |first4=J. |last5=Krausz |first5=M. |last6=Naber |first6=D. |journal=The British Journal of Psychiatry |volume=191 |pmid=17602126}}</ref>
+In Switzerland, Germany, the Netherlands, and the United Kingdom, long-term [[Injecting Drug User|injecting drug user]]s who do not benefit from [[methadone]] and other medication options are treated with pure injectable [[diamorphine]] that is administered under the supervision of medical staff. For this group of patients, diamorphine treatment has proven superior in improving their social and health situation.<ref>{{cite journal | vauthors = Haasen C, Verthein U, Degkwitz P, Berger J, Krausz M, Naber D | title = Heroin-assisted treatment for opioid dependence: randomised controlled trial | journal = The British Journal of Psychiatry | volume = 191 | pages = 55–62 | date = July 2007 | pmid = 17602126 | doi = 10.1192/bjp.bp.106.026112 }}</ref>
 ====Dihydrocodeine====
-[[Dihydrocodeine]] in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.<ref>{{cite journal |doi=10.1111/j.1360-0443.2006.01603.x |title=Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial |year=2006 |last1=Robertson |first1=J. Roy |last2=Raab |first2=Gillian M. |last3=Bruce |first3=Malcolm |last4=McKenzie |first4=James S. |last5=Storkey |first5=Helen R. |last6=Salter |first6=Amy |journal=Addiction |volume=101 |issue=12 |pages=1752–9 |pmid=17156174}}</ref> Dihydrocodeine is an opioid agonist.<ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/dihydrocodeine#section=Top|title=Dihydrocodeine|last=Pubchem|first=|date=|website=pubchem.ncbi.nlm.nih.gov|language=en|archive-url=|archive-date=|dead-url=|access-date=2018-11-02}}</ref> It may be used as a second line treatment.<ref>{{Cite web|url=https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6747#f_uses|title=Login|website=online.lexi.com|language=en-US|access-date=2018-11-02}}</ref> There is a lack of effective data suggesting its safety of use with concerns of more deaths.<ref>{{Cite journal|last=Zamparutti|first=Giuliano|last2=Schifano|first2=Fabrizio|last3=Corkery|first3=John M|last4=Oyefeso|first4=Adenekan|last5=Ghodse|first5=A Hamid|date=2011-8|title=Deaths of opiate/opioid misusers involving dihydrocodeine, UK, 1997–2007|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162662/|journal=British Journal of Clinical Pharmacology|volume=72|issue=2|pages=330–337|doi=10.1111/j.1365-2125.2011.03908.x|issn=0306-5251|pmc=PMC3162662|pmid=21235617}}</ref>
+[[Dihydrocodeine]] in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.<ref>{{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 = 1752–9 | date = December 2006 | pmid = 17156174 | doi = 10.1111/j.1360-0443.2006.01603.x }}</ref> Dihydrocodeine is an opioid agonist.<ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/dihydrocodeine#section=Top|title=Dihydrocodeine|work = Pubchem }}</ref> It may be used as a second line treatment.<ref>{{Cite web |url=https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6747#f_uses|title=Login|website=online.lexi.com|language=en-US|access-date=2018-11-02}}</ref> There is a lack of effective data suggesting its safety of use with concerns of more deaths.<ref>{{cite journal | vauthors = Zamparutti G, Schifano F, Corkery JM, Oyefeso A, Ghodse AH | title = Deaths of opiate/opioid misusers involving dihydrocodeine, UK, 1997-2007 | journal = British Journal of Clinical Pharmacology | volume = 72 | issue = 2 | pages = 330–7 | date = August 2011 | pmid = 21235617 | pmc = 3162662 | doi = 10.1111/j.1365-2125.2011.03908.x }}</ref>
 ==== Heroin-assisted treatment ====
-[[Heroin-assisted treatment]] (HAT, the medical prescription of heroin) has been available in Switzerland since 1994.<ref name="pmid11705488">{{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=1417–23 |year=2001 |pmid=11705488 |doi=10.1016/S0140-6736(01)06529-1 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(01)06529-1 |accessdate=4 March 2016}}</ref> A 2001 study found a high rate of treatment retention and significant improvement in health, social situation and likelihood to leave the illegal drug scene in enrolled participants.<ref name="pmid11705488"/> The study found that the most common reason for discharge was the start of abstinence treatment or methadone treatment.<ref name="pmid11705488"/> The study also found that heroin-assisted treatment is cost-beneficial on a society level due to reduced criminality and improved overall health of participants.<ref name="pmid11705488"/>
+[[Heroin-assisted treatment]] (HAT, the medical prescription of heroin) has been available in Switzerland since 1994.<ref name="pmid11705488">{{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 = 1417–23 | date = October 2001 | pmid = 11705488 | doi = 10.1016/S0140-6736(01)06529-1 | url = http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(01)06529-1 }}</ref> A 2001 study found a high rate of treatment retention and significant improvement in health, social situation and likelihood to leave the illegal drug scene in enrolled participants.<ref name="pmid11705488"/> The study found that the most common reason for discharge was the start of abstinence treatment or methadone treatment.<ref name="pmid11705488"/> The study also found that heroin-assisted treatment is cost-beneficial on a society level due to reduced criminality and improved overall health of participants.<ref name="pmid11705488"/>
-The heroin-assisted treatment program was introduced in Switzerland to combat the increase in heroin use in the 1980s and 1990s and written into law 2010 as one pillar of a four-pillar strategy using repression, prevention, treatment and risk reduction.<ref name="urlDrogenpolitik2013">{{cite web |url=http://www.nzz.ch/schweiz/heroinabgabe-gemaess-experten-ein-erfolg-1.18194137 |title=Drogenpolitik: Heroinabgabe gemäss Experten ein Erfolg – NZZ Schweiz |format= |work= |accessdate=4 March 2016}}</ref> Usually, only a small percentage of patients receives heroin and have to fulfil a number of criteria.<ref name="bag_heroin">{{cite web|url=http://www.bag.admin.ch/themen/drogen/00042/00629/00799/index.html?lang=de|title=Bundesamt für Gesundheit – Substitutionsgestützte Behandlung mit Diacetylmorphin (Heroin)|format=|work=|accessdate=|deadurl=yes|archiveurl=https://web.archive.org/web/20160313061735/http://www.bag.admin.ch/themen/drogen/00042/00629/00799/index.html?lang=de|archivedate=13 March 2016}}</ref><ref name="nzz_heroin2012">{{cite web |url=http://www.nzz.ch/heroinsuechtige-mitten-im-leben-1.14171541 |title=Dank der ärztlichen Heroinabgabe können rund 1400 Süchtige legal konsumieren – Einige schaffen den Anschluss an die Gesellschaft: Heroinsüchtige mitten im Leben – NZZ |format= |work= |accessdate=}}</ref> Since then, HAT programs have been adopted in the Netherlands, United Kingdom, Germany, Spain, Denmark, Belgium, Canada, and Luxembourg.<ref name="urlHeroin Assisted Treatment | Drug Policy Alliance">{{cite web |url=http://www.drugpolicy.org/resource/heroin-assisted-treatment-hat |title=Heroin Assisted Treatment &#124; Drug Policy Alliance |format= |work= |accessdate=4 March 2016}}</ref>
+The heroin-assisted treatment program was introduced in Switzerland to combat the increase in heroin use in the 1980s and 1990s and written into law 2010 as one pillar of a four-pillar strategy using repression, prevention, treatment and risk reduction.<ref name="urlDrogenpolitik2013">{{cite web |url=http://www.nzz.ch/schweiz/heroinabgabe-gemaess-experten-ein-erfolg-1.18194137 |title=Drogenpolitik: Heroinabgabe gemäss Experten ein Erfolg – NZZ Schweiz |format= |work= |access-date=4 March 2016}}</ref> Usually, only a small percentage of patients receives heroin and have to fulfil a number of criteria.<ref name="bag_heroin">{{cite web|url=http://www.bag.admin.ch/themen/drogen/00042/00629/00799/index.html?lang=de|title=Bundesamt für Gesundheit – Substitutionsgestützte Behandlung mit Diacetylmorphin (Heroin)|format=|work=|access-date=|deadurl=yes|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}}</ref><ref name="nzz_heroin2012">{{cite web |url=http://www.nzz.ch/heroinsuechtige-mitten-im-leben-1.14171541 |title=Dank der ärztlichen Heroinabgabe können rund 1400 Süchtige legal konsumieren – Einige schaffen den Anschluss an die Gesellschaft: Heroinsüchtige mitten im Leben – NZZ |format= |work= |access-date=}}</ref> Since then, HAT programs have been adopted in the Netherlands, United Kingdom, Germany, Spain, Denmark, Belgium, Canada, and Luxembourg.<ref name="urlHeroin Assisted Treatment | Drug Policy Alliance">{{cite web |url=http://www.drugpolicy.org/resource/heroin-assisted-treatment-hat |title=Heroin Assisted Treatment &#124; Drug Policy Alliance |format= |work= |access-date=4 March 2016}}</ref>
 ====Morphine (extended-release)====
-An [[extended-release morphine]] confers a possible reduction of opioid use and with fewer depressive symptoms but overall more adverse effects when compared to other forms of long-acting opioids. Retention in treatment was not found to be significantly different.<ref name="FerriMinozzi2013">{{cite journal|last1=Ferri|first1=Marica|last2=Minozzi|first2=Silvia|last3=Bo|first3=Alessandra|last4=Amato|first4=Laura|last5=Ferri|first5=Marica|title=Slow-release oral morphine as maintenance therapy for opioid dependence|year=2013|doi=10.1002/14651858.CD009879.pub2|journal=Reviews}}</ref> It is used in Switzerland and more recently in Canada.<ref name="bag_heroin"/>
+An [[extended-release morphine]] confers a possible reduction of opioid use and with fewer depressive symptoms but overall more adverse effects when compared to other forms of long-acting opioids. Retention in treatment was not found to be significantly different.<ref name="FerriMinozzi2013">{{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 }}</ref> It is used in Switzerland and more recently in Canada.<ref name="bag_heroin"/>
 ====Naltrexone====
-[[Naltrexone]] is used for the treatment of opioid addiction.<ref name=":12">{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf|title=Vivitrol Prescribing Information|last=Alkermes|first=Inc.|date=July 2013|website=|access-date=2 November 2017}}</ref><ref name=":13">{{Cite journal|last=Skolnick|first=Phil|title=The Opioid Epidemic: Crisis and Solutions|url=http://www.annualreviews.org/doi/pdf/10.1146/annurev-pharmtox-010617-052534|journal=Annual Review of Pharmacology and Toxicology|volume=58|issue=1|doi=10.1146/annurev-pharmtox-010617-052534|year=2018|pages=143–159}}</ref> It works by blocking the physiological, [[Euphoria|euphoric]], and [[Reinforcement|reinforcing]] effects of opioids.<ref name=":13" /><ref name=":14">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK64042/|title=Chapter 4—Oral Naltrexone|last=Treatment|first=Center for Substance Abuse|date=2009|publisher=Substance Abuse and Mental Health Services Administration (US)|language=en}}</ref> Non-[[Adherence (medicine)|compliance]] with naltrexone therapy is a concern with oral [[Dosage form|formulations]] because of its daily dosing,<ref name=":14" /> and although the alternative [[Intramuscular injection|intramuscular (IM) injection]] has better compliance due to its monthly dosing, attempts to override the blocking effect with higher doses and stronger drugs have proven dangerous. Naltrexone monthly IM injections received FDA approval in 2010 for the treatment of opioid dependence in [[Abstinence#Medicine|abstinent]] opioid users.<ref name=":12" /><ref name=":14" />
+[[Naltrexone]] is used for the treatment of opioid addiction.<ref name=":12">{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf|title=Vivitrol Prescribing Information|publisher = Alkermes Inc. |date=July 2013|access-date=2 November 2017}}</ref><ref name=":13">{{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 | url = http://www.annualreviews.org/doi/pdf/10.1146/annurev-pharmtox-010617-052534 }}</ref> It works by blocking the physiological, [[Euphoria|euphoric]], and [[Reinforcement|reinforcing]] effects of opioids.<ref name=":13" /><ref name=":14">{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK64042/|title=Chapter 4—Oral Naltrexone | author = Center for Substance Abuse Treatment |date=2009|publisher=Substance Abuse and Mental Health Services Administration (US)|language=en}}</ref> Non-[[Adherence (medicine)|compliance]] with naltrexone therapy is a concern with oral [[Dosage form|formulations]] because of its daily dosing,<ref name=":14" /> and although the alternative [[Intramuscular injection|intramuscular (IM) injection]] has better compliance due to its monthly dosing, attempts to override the blocking effect with higher doses and stronger drugs have proven dangerous. Naltrexone monthly IM injections received FDA approval in 2010 for the treatment of opioid dependence in [[Abstinence#Medicine|abstinent]] opioid users.<ref name=":12" /><ref name=":14" />
 ===Behavioral therapy===
@@ Line 196: / Line 196: @@
 ====Cognitive behavioral therapy====
-[[Cognitive behavioral therapy]] (CBT), a form of psychosocial intervention that is used to improve mental health, may not be as effective as other forms of treatment.<ref>{{Cite book|url=https://www.worldcat.org/oclc/698332858|title=Cognitive behavior therapy : basics and beyond|last=S.,|first=Beck, Judith|publisher=|year=|isbn=9781609185046|edition=Second|location=New York|pages=19–20|oclc=698332858}}</ref> CBT primarily focuses on an individual's coping strategies to help change their cognition, behaviors and emotions about the problem. This intervention has demonstrated success in many psychiatric conditions (e.g., depression) and substance use disorders (e.g., tobacco).<ref>{{Cite journal|last=Huibers|first=M. J. H.|last2=Beurskens|first2=A. J. H. M.|last3=Bleijenberg|first3=G.|last4=van Schayck|first4=C. P.|date=18 July 2007|title=Psychosocial interventions by general practitioners|journal=The Cochrane Database of Systematic Reviews|issue=3|pages=CD003494|doi=10.1002/14651858.CD003494.pub2|issn=1469-493X|pmid=17636726}}</ref> However, the use of CBT alone in opioid dependence has declined due to the lack of efficacy and many are relying on medication therapy or medication therapy with CBT since it was found to be more efficacious than CBT alone.<ref>{{Cite web|url=https://www.uptodate.com/contents/psychosocial-interventions-for-opioid-use-disorder|title=Psychosocial interventions for opioid use disorder|website=www.uptodate.com|access-date=2 November 2017}}</ref>
+[[Cognitive behavioral therapy]] (CBT), a form of psychosocial intervention that is used to improve mental health, may not be as effective as other forms of treatment.<ref>{{Cite book|url=https://www.worldcat.org/oclc/698332858|title=Cognitive behavior therapy : basics and beyond | vauthors = Beck JS |publisher=|year=|isbn=9781609185046|edition=Second|location=New York|pages=19–20|oclc=698332858}}</ref> CBT primarily focuses on an individual's coping strategies to help change their cognition, behaviors and emotions about the problem. This intervention has demonstrated success in many psychiatric conditions (e.g., depression) and substance use disorders (e.g., tobacco).<ref>{{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 | issue = 3 | pages = CD003494 | date = July 2007 | pmid = 17636726 | doi = 10.1002/14651858.CD003494.pub2 }}</ref> However, the use of CBT alone in opioid dependence has declined due to the lack of efficacy and many are relying on medication therapy or medication therapy with CBT since it was found to be more efficacious than CBT alone.<ref>{{Cite web|url=https://www.uptodate.com/contents/psychosocial-interventions-for-opioid-use-disorder|title=Psychosocial interventions for opioid use disorder|website=www.uptodate.com|access-date=2 November 2017}}</ref>
 ====Twelve-step programs====
 {{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]].<ref>{{cite journal|last1=Melemis|first1=SM|title=Relapse Prevention and the Five Rules of Recovery.|journal=The Yale journal of biology and medicine|date=September 2015|volume=88|issue=3|pages=325–32|pmid=26339217|pmc=4553654}}</ref> Some evidence supports the use of these programs in adolescents as well.<ref>{{cite journal|last1=Sussman|first1=S|title=A review of Alcoholics Anonymous/ Narcotics Anonymous programs for teens.|journal=Evaluation & the health professions|date=March 2010|volume=33|issue=1|pages=26–55|doi=10.1177/0163278709356186|pmid=20164105|pmc=4181564}}</ref>
+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]].<ref>{{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 = 325–32 | date = September 2015 | pmid = 26339217 | pmc = 4553654 }}</ref> Some evidence supports the use of these programs in adolescents as well.<ref>{{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 }}</ref>
 The [[12-step program]] is an adapted form of the [[Alcoholics Anonymous]] program. The program strives to help create behavioral change by fostering peer-support and self-help programs. The model helps assert the gravity of addiction by enforcing the idea that addicts must surrender to the fact that they are addicted and to be able to recognize the problem. It also helps maintain self-control and restraint to help promote one's capabilities.<ref>{{Cite news|url=https://americanaddictioncenters.org/rehab-guide/12-step/|title=12 Step Programs for Drug Rehab & Alcohol Treatment|work=American Addiction Centers|access-date=24 October 2017|language=en-US}}</ref>
@@ Line 206: / Line 206: @@
 ==Epidemiology==
 {{see also|Opioid crisis}}
-Globally, the number of people with opioid dependence increased from 10.4 million  in 1990 to 15.5 million in 2010.<ref name="BMJ2017Re" /> Opioid use disorders resulted in 122,000 deaths worldwide in 2015,<ref name=GBD2015>{{cite journal|last1=GBD 2015 Mortality and Causes of Death|first1=Collaborators.|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|date=8 October 2016|volume=388|issue=10053|pages=1459–1544|pmid=27733281|doi=10.1016/S0140-6736(16)31012-1|pmc=5388903}}</ref> up from 18,000 deaths in 1990.<ref name=GDB2013>{{cite journal|last1=GBD 2013 Mortality and Causes of Death|first1=Collaborators|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|date=17 December 2014|pmid=25530442|doi=10.1016/S0140-6736(14)61682-2|pmc=4340604|volume=385|pages=117–171}}</ref> Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013.<ref name=GDB2013/><ref name=GBD2015/>
+Globally, the number of people with opioid dependence increased from 10.4 million  in 1990 to 15.5 million in 2010.<ref name="BMJ2017Re" /> Opioid use disorders resulted in 122,000 deaths worldwide in 2015,<ref name=GBD2015>{{cite journal | vauthors =  | 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 }}</ref> up from 18,000 deaths in 1990.<ref name=GDB2013>{{cite journal | vauthors =  | 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 = 117–71 | date = January 2015 | pmid = 25530442 | pmc = 4340604 | doi = 10.1016/S0140-6736(14)61682-2 }}</ref> Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013.<ref name=GDB2013/><ref name=GBD2015/>
 ===United States===
@@ Line 213: / Line 213: @@
 The current epidemic of opioid abuse is the most lethal drug epidemic in American history.<ref name=NYT2018/>  In 2008, there were four times as many deaths due to overdose than there were in 1999. <ref name=":10" /> According to the CDC in 2017, in the US, "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, decreased to 5.1 in 2012 and 2013, then increased to 5.9 in 2014, and to 7.0 in 2015. The age-adjusted drug poisoning death rate involving heroin doubled from 0.7 to 1.4 deaths per 100,000 resident population between 1999 and 2011 and then continued to increase to 4.1 in 2015."<ref>{{cite book|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|url=https://www.cdc.gov/nchs/data/hus/hus16.pdf}}</ref>
-In 2012 it was estimated that 9.2 percent of the population over the age of 12 years old had used an [[Illegal drug trade|illicit drug]] in the previous month.<ref>Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.</ref> In 2015, it was estimated the 20.5 million Americans had a [[substance use disorder]].<ref name=":10">{{Cite web|url=http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf|title=Opioid Addiction 2016 Facts and Figures|last=American Society of Addiction Medicine|first=|date=|website=|access-date=}}</ref> Of these 20.5 million, two million used prescribed pain medications (most of those being opioids) and one-half of a million were using heroin.<ref name=":10" /> About a quarter of people who use heroin end up having opioid addiction. <ref name=":10" />
+In 2012 it was estimated that 9.2 percent of the population over the age of 12 years old had used an [[Illegal drug trade|illicit drug]] in the previous month.<ref>Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.</ref> In 2015, it was estimated the 20.5 million Americans had a [[substance use disorder]].<ref name=":10">{{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 }}</ref> Of these 20.5 million, two million used prescribed pain medications (most of those being opioids) and one-half of a million were using heroin.<ref name=":10" /> About a quarter of people who use heroin end up having opioid addiction. <ref name=":10" />
 In 2015, in the US there were 33,000 deaths due to drug overdose that involved opioid use.<ref name=":7">{{Cite web|url=https://www.cdc.gov/drugoverdose/data/statedeaths.html|title=Drug Overdose Death Data&#124; Drug Overdose &#124; CDC Injury Center|website=www.cdc.gov|language=en-us|access-date=9 March 2017}}</ref> Of these, about 15,000 were from prescribed opioids and 13,000 were from heroin use.<ref name=":8">{{Cite web|url=https://www.cdc.gov/drugoverdose/data/heroin.html|title=Heroin Overdose Data&#124; Drug Overdose &#124; CDC Injury Center|website=www.cdc.gov|language=en-us|access-date=9 March 2017}}</ref><ref name=":9">{{Cite web|url=https://www.cdc.gov/drugoverdose/data/overdose.html|title=Prescription Opioid Overdose Data &#124; Drug Overdose &#124; CDC Injury Center|website=www.cdc.gov|language=en-us|access-date=9 March 2017}}</ref> Approximately 4% of patients who received opioids for pain management following trauma or surgery continued using opioids for at least 2 months.<ref name=Moh2018 />
-Non-medical consumption of opioids peaked around 2010 and then started to decrease between 2011 and 2013.<ref>{{cite journal|last1=Wilkerson|first1=Richard Gentry|last2=Kim|first2=Hong K.|last3=Windsor|first3=Thomas Andrew|last4=Mareiniss|first4=Darren P.|title=The Opioid Epidemic in the United States|journal=Emergency Medicine Clinics of North America|date=May 2016|volume=34|issue=2|pages=e1–e23|doi=10.1016/j.emc.2015.11.002}}</ref>
+Non-medical consumption of opioids peaked around 2010 and then started to decrease between 2011 and 2013.<ref>{{cite journal | vauthors = Wilkerson RG, Kim HK, Windsor TA, Mareiniss DP | title = The Opioid Epidemic in the United States | journal = Emergency Medicine Clinics of North America | volume = 34 | issue = 2 | pages = e1-e23 | date = May 2016 | pmid = 27133253 | doi = 10.1016/j.emc.2015.11.002 }}</ref>
 Among adults, the rate of inpatient hospital stays in the United States related to opioid overuse increased by an average of 5% annually from 1993–2012. The percentage of inpatient stays due to opioid overuse admitted from the emergency department increased from 43% in 1993 to 64% in 2005, but have remained relatively constant since 2005.<ref>{{cite web |vauthors=Owens PL, Barrett ML, Weiss AJ, Washington RE, Kronick R | title =  Hospital Inpatient Utilization Related to Opioid Overuse Among Adults, 1993–2012 | work = HCUP Statistical Brief #177 | publisher = Agency for Healthcare Research and Quality | location = Rockville, MD | date = August 2014 | url = https://www.hcup-us.ahrq.gov/reports/statbriefs/sb177-Hospitalizations-for-Opioid-Overuse.jsp}}</ref>
-The prevalence of opioid use and opioid or opiate dependency varies by age and gender, among a myriad of other factors. Men are at higher risk for opioid use and dependency than women,<ref name=":0">{{Cite web|url=https://www.cdc.gov/drugoverdose/data/overdose.html|title=Prescription Opioid Overdose Data|last=|first=|date=|website=Center for Disease Control and Prevention|publisher=|access-date=12 September 2016}}</ref><ref name=":1">{{Cite web|url=http://www.fda.gov/downloads/Drugs/NewsEvents/UCM300859.pdf|title=Populations at risk for opioid overdose|last=Paulozzi|first=Len|date=12 April 2012|website=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}}</ref> and men also account for more opioid overdoses than women, although this gap is closing.<ref name=":0" /> Women are more likely to be prescribed pain relievers, be given higher doses, use them for longer durations, and may become dependent upon them faster.<ref>{{Cite web|url=http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf|title=Opioid Addiction: 2016 Facts and Figures|last=|first=|date=|website=American Society of Addiction Medicine|publisher=|access-date=12 September 2016}}</ref>
+The prevalence of opioid use and opioid or opiate dependency varies by age and gender, among a myriad of other factors. Men are at higher risk for opioid use and dependency than women,<ref name=":0">{{Cite web|url=https://www.cdc.gov/drugoverdose/data/overdose.html|title=Prescription Opioid Overdose Data |website=Center for Disease Control and Prevention|publisher=|access-date=12 September 2016}}</ref><ref name=":1">{{Cite web|url=http://www.fda.gov/downloads/Drugs/NewsEvents/UCM300859.pdf|title=Populations at risk for opioid overdose|last=Paulozzi|first=Len | name-list-format = vanc |date=12 April 2012|website=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}}</ref> and men also account for more opioid overdoses than women, although this gap is closing.<ref name=":0" /> Women are more likely to be prescribed pain relievers, be given higher doses, use them for longer durations, and may become dependent upon them faster.<ref>{{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|publisher=|access-date=12 September 2016}}</ref>
-Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs.<ref name=":1" /><ref name=":3">{{Cite web|url=https://www.pbs.org/wgbh/frontline/article/how-bad-is-the-opioid-epidemic/|title=How Bad is the Opioid Epidemic?|access-date=12 September 2016}}</ref><ref name=":4">{{Cite journal|last=Han|first=Benjamin|last2=Polydorou|first2=Soteri|last3=Ferris|first3=Rosie|last4=Blaum|first4=Caroline S.|last5=Ross|first5=Stephen|last6=McNeely|first6=Jennifer|date=10 November 2015|title=Demographic Trends of Adults in New York City Opioid Treatment Programs—An Aging Population|url=https://dx.doi.org/10.3109/10826084.2015.1027929|journal=Substance Use & Misuse|volume=50|issue=13|pages=1660–1667|doi=10.3109/10826084.2015.1027929|issn=1082-6084|pmid=26584180}}</ref> This does not reflect opioid use as a whole, which includes individuals in younger age demographics. Overdoses from opioids are highest among individuals who are between the ages of 40 and 50,<ref name=":4" /> in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30.<ref name=":3" /> 21 to 35-year olds represent 77% of individuals who enter treatment for opioid use disorder,<ref name=":2">{{Cite web|url=https://thisismap.com/insights/data-infographics|title=Facts & Faces of Opioid Addiction: New Insights|last=|first=|date=2015|website=MAP Health Management|publisher=|access-date=12 September 2016}}</ref> however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013.<ref>{{Cite web|url=http://www.samhsa.gov/atod/opioids|title=Opioids|last=|first=|date=23 February 2016|website=Substance Abuse and Mental Health Services Administration|publisher=|access-date=12 September 2016}}</ref> Among the middle class means of acquiring funds have included [[Elder financial abuse]] through a vulnerability of financial transactions of selling items and international dealers noticing a lack of enforcement in their transaction scams throughout the Caribbean.<ref>{{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=July 24, 2017 |website=USA Today |publisher=|access-date= }}</ref>
+Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs.<ref name=":1" /><ref name=":3">{{Cite web|url=https://www.pbs.org/wgbh/frontline/article/how-bad-is-the-opioid-epidemic/|title=How Bad is the Opioid Epidemic?|access-date=12 September 2016}}</ref><ref name=":4">{{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 = 1660–7 | date = 10 November 2015 | pmid = 26584180 | doi = 10.3109/10826084.2015.1027929 }}</ref> This does not reflect opioid use as a whole, which includes individuals in younger age demographics. Overdoses from opioids are highest among individuals who are between the ages of 40 and 50,<ref name=":4" /> in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30.<ref name=":3" /> 21 to 35-year olds represent 77% of individuals who enter treatment for opioid use disorder,<ref name=":2">{{Cite web|url=https://thisismap.com/insights/data-infographics|title=Facts & Faces of Opioid Addiction: New Insights |date=2015|website=MAP Health Management|publisher=|access-date=12 September 2016}}</ref> however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013.<ref>{{Cite web|url=http://www.samhsa.gov/atod/opioids|title=Opioids |date=23 February 2016|website=Substance Abuse and Mental Health Services Administration|publisher=|access-date=12 September 2016}}</ref> Among the middle class means of acquiring funds have included [[Elder financial abuse]] through a vulnerability of financial transactions of selling items and international dealers noticing a lack of enforcement in their transaction scams throughout the Caribbean.<ref>{{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=July 24, 2017 |website=USA Today |publisher=|access-date= }}</ref>
 <gallery mode="packed" style="text-align:left" heights="170px" caption="Charts of deaths involving specific opioids and classes of opioids">
@@ Line 237: / Line 237: @@
 [[Levacetylmethadol]] was previously used to treat opioid dependence. In 2003 the drug's 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.<ref>James W. Kalat, ''Biological Psychology''. Cengage Learning. Page 81.</ref>  In 2001, levacetylmethadol was removed from the European market due to reports of life-threatening [[ventricular arrhythmia|ventricular rhythm disorders]].<ref>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]</ref> In 2003, Roxane Laboratories, Inc. discontinued Orlaam in the US.<ref>[http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm153332.htm US FDA Safety Alerts: Orlaam (levomethadyl acetate hydrochloride)] Page Last Updated: 20 August 2013</ref>
-==See also==
+== See also ==
 {{col div|colwidth=30em}}
 *[[Benzodiazepine withdrawal syndrome]]
@@ Line 247: / Line 247: @@
 {{colend}}
-==References==
+== References ==
 {{Reflist}}

v t e Treatment of drug dependence (N07B)
Nicotine dependence	Bupropion^# Cytisine Lobeline Mecamylamine Varenicline AATooltip Adrenergic agonist (Clonidine)
Alcohol dependence	AD inhibitor Disulfiram Acamprosate Calcium carbimide Hydrogen cyanamide General anesthetics Nitrous oxide Opioid antagonists Naltrexone Nalmefene Topiramate AATooltip Adrenergic agonist (Clonidine) Baclofen Phenibut
Opioid dependence	AATooltip Adrenergic agonist (Clonidine Lofexidine) Ibogaine Opioids Buprenorphine (+naloxone) Levacetylmethadol Methadone Dihydrocodeine Dihydroetorphine Hydromorphone (extended-release) Morphine (extended-release) Opioid antagonists (Naltrexone Nalmefene)
Benzodiazepine dependence	AATooltip Adrenergic agonist (Clonidine) Benzodiazepines (Diazepam Lorazepam Chlordiazepoxide Oxazepam) Barbiturates (Phenobarbital)