Opioid use disorder

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Opioid use disorder
Other names: Opioid addiction,[1] problematic opioid use,[1] opioid abuse,[2] opioid dependence[3]
Morphin - Morphine.svg
Molecular structure of morphine
SymptomsStrong desire to use opioids, increased tolerance to opioids, failure to meet obligations, trouble with reducing use, withdrawal syndrome with discontinuation[4][5]
ComplicationsOpioid overdose, hepatitis C, marriage problems, unemployment[4][5]
DurationLong term[6]
Diagnostic methodBased on criteria in the DSM-5[4]
Differential diagnosisAlcoholism
TreatmentOpioid replacement therapy, behavioral therapy, twelve-step programs, take home naloxone[7][8][9]
MedicationBuprenorphine, methadone, naltrexone[7][10]
Frequency27 million (c. 0.4%)[11][4]
Deaths122,000 (2015)[12]

Opioid use disorder (OUD) is a 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, difficulty fulfilling obligations, trouble reducing use, and withdrawal syndrome with discontinuation.[4][5] Opioid withdrawal symptoms may include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood.[5] Addiction and dependence are components of a substance use disorder.[13] 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, which may also be bought illegally.[14][15] Risk factors for misuse include a history of substance use, substance use among family and friends, mental illness, low socioeconomic status, and race.[16][17] 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 disorder 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 2016, about 27 million people are affected.[11] Long term opioid use occurs in about 4% of people following their use for trauma or surgery related pain.[18] Onset is often in young adulthood.[4] Males are affected more often than females.[4] It resulted in 122,000 deaths worldwide in 2015,[12] up from 18,000 deaths in 1990.[19] 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.[20]

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.[13] Opioid dependence can occur as physical dependence, psychological dependence, or both.[21]


Opioid withdrawal can occur with a sudden decrease in, or the cessation of opioids after prolonged use.[22][23] Onset of withdrawal depends on which opioid was used last.[24] With heroin this typically occurs five hours after use, while with methadone it might not occur until two days later.[24] The length of time that major symptoms occur also depends on the opioid used.[24] For heroin withdrawal, symptoms are typically greatest at two to four days, and can last for up to two weeks.[25][24] Less significant symptoms may remain for an even longer period, in which case the withdrawal is known as post-acute-withdrawal syndrome.[24]

Treatment of withdrawal may include methadone and buprenorphine. Medications for nausea or diarrhea may also be used.[23]

Opioid intoxication

Signs and symptoms of opioid intoxication include:[5][26]

Opioid overdose

Fentanyl 2 mg. A lethal dose in most people.[27]

Signs and symptoms of opioid overdose include, but are not limited to:[28]


Opioid use disorder can develop as a result of self-medication, though this is controversial.[29] Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.[30] Prescription opioids are the source of nearly half of misused opioids and the majority of these are initiated for trauma or surgery pain management.[18]

According to position papers on the treatment of opioid dependence published by the United Nations Office on Drugs and Crime and the World Health Organization, care providers should not treat opioid use disorder as the result of a weak moral character or will but as a medical condition.[16][31][32] Some evidence suggests the possibility that opioid use disorders occur due to genetic or other chemical mechanisms which may be difficult to identify or change, such as dysregulation of brain circuitry involving reward and volition. However, the exact mechanisms involved are unclear, leading to debate regarding where the influence of biology and free will.[33][34]



Addiction is a brain disorder characterized by compulsive drug use despite adverse consequences.[13][35][36][37] Addiction is a component of a substance use disorder and represents the most severe form of the disorder.[13]

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.[35][38][39][40] Like other addictive drugs, overuse of opioids leads to increased ΔFosB expression in the nucleus accumbens.[38][39][40][41] 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.[42][43] 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.[42][43]

Neuroimaging has shown functional and structural alterations in the brain.[44] A 2017 study showed that chronic intake of opioids, such as heroin, may cause long-term effects in the orbitofrontal area (OFC), which is essential for regulating reward-related behaviors, emotional responses, and anxiety.[45] Moreover, neuroimaging and neuropsychological studies demonstrated dysregulation of circuits associated with emotion, stress and high impulsivity.[46]


Drug dependence is an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake).[35][36][37] Dependence is a component of a substance use disorder.[13][47] Opioid dependence can manifest as physical dependence, psychological dependence, or both.[21][36][47]

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).[35][48] 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).[35] It has been shown that when an opiate-naive person begins using opiates in concentrations that induce euphoria, BDNF signaling increases in the VTA.[49]

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.[21][35] Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid-induced physical dependence.[21][35]

Opioid receptors

A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for several 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.[50]

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 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 associated with opioid dependence.[51]

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.[52]


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

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

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


The CDC gives specific recommendations for prescribers regarding initiation of opioids, clinically appropriate use of opioids, and assessing possible risks associated with opioid therapy.[53] Large retail pharmacy chains in the US are implementing protocols, guidelines, and initiatives to take back unused opioids, providing naloxone kits, and being vigilant for suspicious prescriptions.[54][55] Insurance programs can help limit opioid use by setting quantity limits on prescriptions or requiring prior authorizations for certain medications.[56]

Opioid related deaths

Naloxone is used for the emergency treatment of an overdose.[57] 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.[58] 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.[59] 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.[60][61] 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.[62]

Good Samaritan laws typically protect bystanders that administer naloxone. In the United States, at least 40 states have Good Samaritan laws to encourage bystanders to take action without fear of prosecution.[63] As of 2019, 48 states allow for a pharmacist to have the authority to distribute naloxone without an individual prescription.[64]


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.[32] Some strategies aim to reduce drug use and lead to abstinence from opioids, while others attempt to stabilize on prescribed methadone or buprenorphine with continued replacement therapy indefinitely.[32] No single treatment works for everyone, so several strategies have been developed including therapy and drugs.[32][65]'

As of 2013 in the US, there was a significant increase of prescription opioid abuse compared to illegal opiates like heroin.[66] This development has also implications for the prevention, treatment and therapy of opioid dependence.[67] 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]


Opioid replacement therapy (ORT) involves replacing an opioid, such as heroin, with a longer acting but less euphoric opioid.[68][69] Commonly used drugs for ORT are methadone or buprenorphine which are taken under medical supervision.[69] As of 2018, buprenorphine/naloxone is preferentially recommended, as the addition of the opioid antagonist naloxone is believed to reduce the risk of abuse via injection or insufflation.[70]

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.[69] In some countries (not the US, or Australia),[69] regulations enforce a limited time for people on ORT programs that conclude when a stable economic and psychosocial situation is achieved. (People with HIV/AIDS or hepatitis C are usually excluded from this requirement.) In practice, 40–65% of patients maintain abstinence from additional opioids while receiving opioid replacement therapy and 70–95% can reduce their use significantly.[69] 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.[69] Clonidine or lofexidine can help treat the symptoms of withdrawal.[71]

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 illegal opiate use or dependence, including mortality reduction[69][72][7] and overall societal costs, such as the economic loss from drug-related crime and healthcare expenditure.[69] ORT 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]

Buprenorphine and methadone work by reducing opioid cravings, easing withdrawal symptoms, and blocking the euphoric effects of opioids via cross-tolerance,[73] and in the case of buprenorphine, a high-affinity partial agonist, also due to opioid receptor saturation.[74] It is this property of buprenorphine that can induce acute withdrawal when administered before other opioids have left the body. Naltrexone, a μ-opioid receptor antagonist, also blocks the euphoric effects of opioids by occupying the opioid receptor, but it does not activate it, so it does not produce sedation, analgesia, or euphoria, and thus it has no potential for abuse or diversion.[75][76]

In the United States, since March 2020 as a result of the COVID-19 pandemic, buprenorphine may be dispensed via telemedicine.[77]


40 mg of 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.[78][79] Methadone is a μ-opioid receptor agonist. 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.[78] 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 is medically safe and non-sedating.[78] It is also indicated for pregnant women addicted to opiates.[78] 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.[80]

Some impairment in cognition has been demonstrated in those using methadone.[46][81] Currently, 55 countries worldwide use methadone replacement therapy, while some countries such as Russia do not.[82]


Buprenorphine/naloxone tablet

Buprenorphine is a partial opioid receptor agonist. Unlike methadone and other full opioid receptor agonists, buprenorphine is less likely to cause respiratory depression due to its ceiling effect.[75] 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.[83] 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.[69]

Other opioids

Evidence of effects of heroin maintenance compared to methadone are unclear as of 2010.[84] A Cochrane review found some evidence in opioid users who had not improved with other treatments.[85] In Switzerland, Germany, the Netherlands, and the United Kingdom, long-term injecting drug users who do not benefit from methadone and other medication options may be treated with injectable heroin that is administered under the supervision of medical staff.[86] Other countries where it is available include Spain, Denmark, Belgium, Canada, and Luxembourg.[87]

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.[88] Dihydrocodeine is an opioid agonist.[89] It may be used as a second line treatment.[90] As of 2020 there is low quality evidence that dihydrocodeine may be no more effective than other routinely used medication interventions in reducing illicit opiate use.[91]

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.[92] It is used in Switzerland and more recently in Canada.[93]


Naltrexone is an opioid receptor antagonist used for the treatment of opioid addiction.[94][95] Naltrexone is not as widely used as buprenorphine or methadone for OUD due to low rates of patient acceptance, non-adherence due to daily dosing, and difficulty achieving abstinence from opioids before beginning treatment. Additionally, dosing naltrexone after recent opioid use could lead to precipitated withdrawal. Conversely, naltrexone antagonism at the opioid receptor can be overcome with higher doses of opioids.[96] Naltrexone monthly IM injections received FDA approval in 2010, for the treatment of opioid dependence in abstinent opioid users.[94][97]

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.[98] 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).[99] 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 both were found to be more efficacious than CBT alone. A form of CBT therapy known as motivational interviewing (MI) is often used opioid use disorder. MI leverages a person intrinsic motivation to recover through education, formulation of relapse prevention strategies, reward for adherence to treatment guidelines, and positive thinking to keep motivation high--which are based on a person's socioeconomic status, gender, race, ethnicity, sexual orientation, and their readiness to recover.[100][101][102]

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.[103] Narcotics Anonymous is a global service that provides multilingual recovery information and public meetings free of charge.[104] Some evidence supports the use of these programs in adolescents as well.[105]

The 12-step program is an adapted form of the Alcoholics Anonymous program. The program strives to help create behavioural 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 be able to recognize the problem. It also helps maintain self-control and restraint to help promote one's capabilities.[106]

Digital care programs

Digital care programs (see telehealth or digital health) have increased in number since the Coronavirus pandemic mandated the increased usage of remote healthcare options. These programs offer treatment and continuing care remotely, via smartphone and desktop applications. This often includes remote substance testing, access to peer support meetings, recovery coaching or therapy, and self-guided learning modules.



Globally, the number of people with opioid dependence increased from 10.4 million in 1990 to 15.5 million in 2010.[7] In 2016, the numbers rose to 27 million people who experienced this disorder.[11] Opioid use disorders resulted in 122,000 deaths worldwide in 2015,[12] up from 18,000 deaths in 1990.[19] Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013.[19][12]

United States

Overdose deaths involving opioids, United States. Deaths per 100,000 population by year.[107]

The current epidemic of opioid abuse is the most lethal drug epidemic in American history.[15] In 2008, there were four times as many deaths due to overdose than there were in 1999.[108] 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."[109]

In 2017, the U.S. Department of Health and Human Services (HHS) announced a public health emergency due to an increase in the misuse of opioids.[110] The administration introduced a strategic framework called the Five-Point Opioid Strategy, which includes providing access recovery services, increasing the availability of reversing agents for overdose, funding opioid misuse and pain research, changing treatments of people managing pain, and updating public health reports related to combating opioid drug misuse.[110][111]

The US epidemic in the 2000s is related to a number of factors.[16] Rates of opioid use and dependency vary by age, sex, race, and socioeconomic status.[16] With respect to race the discrepancy in deaths is thought to be due to an interplay between physician prescribing and lack of access to healthcare and certain prescription drugs.[16] Men are at higher risk for opioid use and dependency than women,[112][113] and men also account for more opioid overdoses than women, although this gap is closing.[112] 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.[114]

Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs.[113][115][116] 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,[116] in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30.[115] 21 to 35-year olds represent 77% of individuals who enter treatment for opioid use disorder,[117] however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013.[118] 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.[119]

In 2018, the Massachusetts Supreme Judicial Court found that a probationer with opioid use disorder could be detained for a parole violation after she tested positive for fentanyl.[120][121]


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.[28]

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.[123] In 2001, levacetylmethadol was removed from the European market due to reports of life-threatening ventricular rhythm disorders.[124] In 2003, Roxane Laboratories, Inc. discontinued Orlaam in the US.[125]

See also


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