Opioid use disorder

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Opioid use disorder
Synonyms Opioid addiction,[1] problematic opioid use,[1] opioid abuse[2]
Morphin - Morphine.svg
Molecular structure of morphine
Specialty Psychiatry
Symptoms Opioid use that causes impairment or distress, addiction, dependence[3][4]
Treatment Opioid replacement therapy, behavioral therapy, twelve-step programs[5][6]
Medication Buprenorphine, methadone, naltrexone[5][7]

Opioid use disorder is a medical condition characterized by a problematic pattern of opioid use that causes clinically significant impairment or distress.[3] It often includes a strong desire to use opioids, increased tolerance to opioids, and withdrawal syndrome when opioids are abruptly discontinued.[4][8] Addiction and dependence are components of a substance use disorder and addiction represents the most severe form of the disorder.[4][9] Opioid dependence can manifest as physical dependence, psychological dependence, or both.[4][10]

Opioids include substances such as morphine, heroin, codeine, and oxycodone. These can be bought illegally or prescribed. The diagnosis of opioid use disorder is often based on criteria by the American Psychiatric Association in the DSM-5.[4] These include a preoccupation with a desire to obtain and take opioids, as well as using more than intended despite social and professional consequences due to these behaviors.[8]

Opioid use disorder can be treated with opioid replacement therapy using methadone or buprenorphine.[5] Being on such treatment reduces the risk of death.[5] Additionally, individuals with opioid use disorder may benefit from twelve-step programs, other peer support, and support from mental health professionals such as individual or group therapy.[6] The medication naltrexone may also be useful to prevent relapse.[7] Naloxone is useful for the treatment of an opioid overdose.[11]

In 2013 opioid use disorders affected about 0.4% of people.[4] About 16 million people have been affected at one point in time.[12] It resulted in 122,000 deaths worldwide in 2015,[13] up from 18,000 deaths in 1990.[14] In the United States in 2015 there were 33,000 deaths due to drug overdose involving opioids.[15] Of those 33,000 deaths, about 15,000 were from prescribed opioids and 13,000 from heroin.[16][17]

Video explanation

Signs and symptoms[edit]

Material used for intravenous injection of opioids

Signs and symptoms include:[4][8]

  • 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

Withdrawal[edit]

Symptoms of withdrawal from opioids include:[18]

Early symptoms[edit]

Late symptoms[edit]

Opioid intoxication[edit]

Signs and symptoms of opioid intoxication include:[8]

Opioid overdose[edit]

Main article: Opioid overdose

Signs and symptoms of opioid overdose include, but are not limited to:[19]

Cause[edit]

Opioid use disorder can develop as a result of self-medication, though this is controversial.[20] Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.[21]

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.[22][23] Additionally, detoxification alone does not constitute adequate treatment.

Mechanism[edit]

Addiction[edit]

Addiction is a brain disorder characterized by compulsive drug use despite adverse consequences.[9][24][25][26] Addiction is a component of a substance use disorder and represents the most severe form of the disorder.[9]

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.[24][27][28][29] Like other addictive drugs, overuse of opioids leads to increased ΔFosB expression in the nucleus accumbens.[27][28][29][30] 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.[31][32] 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.[31][32]

Neuroimaging has shown functional and structural alterations in the brain.[33] 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.[34][non-primary source needed] Moreover, neuroimaging and neuropsychological studies demonstrated dysregulation of circuits associated with emotion, stress and high impulsivity.[35]

Dependence[edit]

Drug dependence is an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake).[24][25][26] Dependence is a component of a substance use disorder.[9][36] Opioid dependence can manifest as physical dependence, psychological dependence, or both.[10][25][36]

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).[24][37] 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).[24] It has been shown that when an opiate-naive person begins using opiates in concentrations that induce euphoria, BDNF signaling increases in the VTA.[38]

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.[10][24] Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid-induced physical dependence.[10][24]

Opioid receptors[edit]

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.[39]

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[edit]

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.[40]

Non-opioid receptor genes[edit]

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.[41]

Diagnosis[edit]

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 diagnosed 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 amount 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 it being physically dangerous settings
  9. Continued use despite opioids worsening physical or psychological health (i.e. depression, constipation)
  10. Tolerance
  11. Withdrawal

Prevention[edit]

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[edit]

Naloxone is used for the emergency treatment of an overdose.[42] 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.[43] 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.[11] 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.[44][45] 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.[46]

Management[edit]

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.[23] Most strategies aim ultimately to reduce drug use and lead to abstinence.[23] No single treatment works for everyone, so several strategies have been developed including therapy and drugs.[23][47]

As of 2013 in the US, there was a significant increase of prescription opioid abuse compared to illegal opiates like heroin.[48] This development has also implications for the prevention, treatment and therapy of opioid dependence.[49] 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.[5]

Medications[edit]

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.[50] Commonly used drugs for ORT are methadone or buprenorphine which are taken under medical supervision.[50] As of 2018 buprenorphine/naloxone is preferencially recommended.[51]

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.[50] In some countries (not the US, or Australia),[50] 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.[50] 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.[50] Clonidine or lofexidine can help treat the symptoms of withdrawal.[52]

Participation in methadone and buprenorphine treatment reduces the risk of mortality due to overdose.[5] 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.[53] 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[50][54][53] and overall societal costs, such as the economic loss from drug-related crime and healthcare expenditure.[50] 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.[5] Currently, 55 countries worldwide use methadone replacement therapy, while some countries such as Russia do not.[55]

Methadone[edit]

40 mg of methadone
Main article: 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.[56][57] 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.[53] 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.[56] 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.[56] It is also indicated for pregnant women addicted to opiates.[56] 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.[58]

Some impairment in cognition has been demonstrated in those using methadone.[35][59]

Buprenorphine[edit]

Buprenorphine/naloxone tablet

Treatment with buprenorphine may be associated with reduced mortality.[5] Buprenorphine under the tongue is often used to manage opioid dependence. Preparations were approved for this use in the United Statesin 2002.[60] 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.[50]

Diamorphine[edit]

See also: Heroin maintenance

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.[61]

Dihydrocodeine[edit]

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.[62]

Heroin-assisted treatment[edit]

Heroin-assisted treatment (HAT, the medical prescription of heroin) has been available in Switzerland since 1994.[63] 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.[63] The study found that the most common reason for discharge was the start of abstinence treatment or methadone treatment.[63] 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.[63]

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.[64] Usually, only a small percentage of patients receives heroin and have to fulfil a number of criteria.[65][66] Since then, HAT programs have been adopted in the Netherlands, United Kingdom, Germany, Spain, Denmark, Belgium, Canada, and Luxembourg.[67]

Morphine (extended-release)[edit]

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.[68] It is used in Switzerland.[65]

Naltrexone[edit]

Naltrexone is used for the treatment of opioid addiction.[69][70] It works by blocking the physiological, euphoric, and reinforcing effects of opioids.[70][71] Non-compliance with naltrexone therapy is a concern with oral formulations because of its daily dosing,[71] 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.[69][71]

Behavioral therapy[edit]

Further information: Addiction § Behavioral therapy

Cognitive behavioral therapy[edit]

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.[72] 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).[73] 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.[74]

Twelve-step programs[edit]

Main article: 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.[75] Some evidence supports the use of these programs in adolescents as well.[76]

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.[77]

Epidemiology[edit]

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.[5] Opioid use disorders resulted in 122,000 deaths worldwide in 2015,[13] up from 18,000 deaths in 1990.[14] Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013.[14][13]

United States[edit]

Overdose Deaths Involving Opioids, United States, 2000-2015. Deaths per 100,000 population.[78]

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."[79]

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.[80] In 2015, it was estimated the 20.5 million Americans had a substance use disorder.[81] 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.[81]

In 2015, in the US there were 33,000 deaths due to drug overdose that involved opioid use.[15] Of these, about 15,000 were from prescribed opioids and 13,000 were from heroin use.[16][17]

Non-medical consumption of opioids peaked around 2010 and then started to decrease between 2011 and 2013.[82]

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.[83]

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,[84][85] and men also account for more opioid overdoses than women, although this gap is closing.[84] 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.[86]

Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs.[85][87][88] 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,[88] in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30.[87] 21 to 35-year olds represent 77% of individuals who enter treatment for opioid use disorder,[89] however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013.[90] 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.[91]

History[edit]

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 200 years ago.[19]

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.[92] In 2001, levacetylmethadol was removed from the European market due to reports of life-threatening ventricular rhythm disorders.[93] In 2003, Roxane Laboratories, Inc. discontinued Orlaam in the US.[94]

See also[edit]

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