Opioid use disorder

Opioid use disorder
Synonyms Opioid addiction and dependence
Classification and external resources
Specialty psychiatry
ICD-10 F11.2
ICD-9-CM 304.0
MeSH D009293

An opioid use disorder is a medical condition that is characterized by the compulsive use of opioids despite adverse consequences from continued use and the development of a withdrawal syndrome when opioid use stops. It involves both an addiction to and dependence upon opioids.

Opioids include substances such as morphine, heroin, codeine, oxycodone, hydrocodone, etc. The necessary descriptive characteristics of the medical diagnosis are preoccupation with a desire to obtain and take the drug and persistent drug-seeking behaviour. The opioid dependence-withdrawal syndrome involves both psychological dependence and marked physical dependence upon opioid compounds.

Opioid use disorders resulted in 51,000 deaths worldwide in 2013, up from 18,000 deaths in 1990.[1]

Symptoms of withdrawal

Total number of U.S. overdose deaths involving opioid pain relievers from 2001 to 2014.[2]

Symptoms of withdrawal from opiates include, but are not limited to:[3]

Early symptoms

Late symptoms

Cause

Most people who are opioid-dependent have at least one other psychiatric comorbidity.[4] Opioid dependence often develops as a result of self medication.[4] Opioids are excellent acute pain medication, but it is their ability to produce euphoria that makes them attractive to addicts.[5] Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.[6]

Mechanism

Addiction

Material used for intravenous injection of opiates

Overexpression of the gene transcription factor "ΔFosB" in the nucleus accumbens plays a crucial role in the development of opioid addiction by directly modulating compulsive drug-seeking behaviors.[7][8][9]

Like many other forms of behavioral addiction and drug addiction, overuse of opiates leads to increased ΔFosB expression in the nucleus accumbens.[8][9][10] Opiates affect dopamine neurotransmission in the nucleus accumbens through their disinhibition of the GABA-based negative dopaminergic feedback system in the rostromedial tegmental nucleus.[11][12][13]

Dependence

Some studies suggest a permanent dysregulation of the endogenous opioid receptor system after chronic exposure to opioids. A recent study has shown that an increase in brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) in rats can cause opiate-naive rats to begin displaying opiate-dependent behavior, including withdrawal and drug-seeking behavior.[14] It has been shown that when an opiate-naive person begins using opiates at levels inducing euphoria, this same increase in BDNF occurs.[15]

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.[7][16] Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid-induced physical dependence.[16]

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.[17]

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.

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.[18]

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.[19]

Diagnosis

The WHO and DSM-IV-TR clinical guidelines for a definite diagnosis require that three or more of the following six characteristic features be experienced or exhibited:

  1. A strong desire or sense of compulsion to take the drug;
  2. Difficulties in controlling drug-taking behaviour in terms of its onset, termination, or levels of use;
  3. A physiological withdrawal state when drug use is stopped or reduced, as evidenced by: the characteristic withdrawal syndrome for the substance; or use of the same (or a closely related) substance with the intention of relieving or avoiding withdrawal symptoms;
  4. Evidence of tolerance, such that increased doses of the drug are required in order to achieve effects originally produced by lower doses;
  5. Progressive neglect of alternative pleasures or interests because of drug use, increased amount of time necessary to obtain or take the drug or to recover from its effects;
  6. Persisting with drug use despite clear evidence of overtly harmful consequences, such as harm to the liver, depressive mood states or impairment of cognitive functioning.

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 dependence as the result of a weak character or will.[20][21] Accordingly, detoxification alone does not constitute adequate treatment.

Management

Opioid dependence requires long-term treatment and care with the goals of reducing health risks for the consumer, reducing criminal behaviour, and improving the long-term physical and psychological condition of the addicted person.[21] Most strategies aim ultimately to reduce drug use and lead to abstinence.[21]

No single treatment works for everyone, so several strategies have been developed including therapy and drugs.[21][22]

Detox programs are rarely a good solution, and people often relapse after going through them, but it is an important first step.[21]

As of 2013 in the US, there was a significant increase of prescription opioid abuse compared to illegal opiates like heroin.[23] This development has also implications for the prevention, treatment and therapy of opioid dependence.[24]

Medications

Opioid replacement therapy (ORT) (also called opioid substitution therapy or opioid maintenance therapy) involves replacing an illegal opioid, such as heroin, with a longer acting but less euphoric opioid; methadone or buprenorphine are typically used and the drug is taken under medical supervision.[25]

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.[25] In some countries (not the US, or Australia),[25] regulations enforce a limited time period for people on ORT programs that conclude when a stable economic and psychosocial situation is achieved. (Patients suffering from HIV/AIDS or Hepatitis C are usually excluded from this requirement.) In practice, 40-65% of patients maintain complete abstinence from opioids while receiving opioid replacement therapy, and 70-95% are able to reduce their use significantly, while experiencing 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.[25] Clonidine or lofexidine can help treat the symptoms of withdrawal.[26]

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[25][27] and overall societal costs, such as the economic loss from drug-related crime and healthcare expenditure.[25] 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.[28] Currently, 55 countries worldwide use methadone replacement therapy, while some countries such as Russia do not offer it.[29]

Methadone

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.[30][31] 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.[30] 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.[30] It is also indicated for pregnant women addicted to opiates.[30] Methadone maintenance treatment is given to addicted individuals who feel unable to go the whole way and get clean. For those individuals who wish to completely move away from drugs, a methadone reduction program is indicated, where the individual is prescribed an amount of methadone which is titrated up until withdrawal symptoms subside, followed by 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.[32] Methadone toxicity has been shown to be associated with specific phenotypes of CYP2B6.[33]

Buprenorphine

Suboxone tablet

Studies have shown buprenorphine to be a safer alternative over methadone in opiate replacement therapy, primarily due to its lower instance of overdose related deaths during the course of treatment.[34] Buprenorphine sublingual preparations are often used to manage opioid dependence (that is, dependence on heroin, oxycodone, hydrocodone, morphine, oxymorphone, fentanyl or other opioids). The Suboxone and Subutex preparations were approved for this indication by the United States Food and Drug Administration in October 2002.[35] 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.[25]

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.[36]

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.[37]

Heroin-assisted treatment

Heroin-assisted treatment (HAT, the medical prescription of heroin) has been available in Switzerland since 1994.[38] 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.[38] The study found that the most common reason for discharge was the start of abstinence treatment or methadone treatment.[38] 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.[38]

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.[39] Usually, only a small percentage of patients receive heroin and have to fulfil a number of criteria.[40][41] Since then, HAT programs have been adopted in the Netherlands, United Kingdom, Germany, Spain, Denmark, Belgium, Canada, and Luxembourg.[42]

LAAM

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.[43] In 2001, levacetylmethadol was removed from the European market due to reports of life-threatening ventricular rhythm disorders.[44] In 2003, Roxane Laboratories, Inc. discontinued Orlaam in the US.[45]

Morphine (extended-release)

According to a Cochrane review in 2013, 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.[46] It used in Switzerland.[40]

Naltrexone

Naltrexone was approved by the FDA in 1984 for the treatment of opioid dependence. It is available both as an oral medication and as a monthly injectable (approved in 2010). Some authors question whether oral Naltrexone is as effective in the treatment of opioid dependence as methadone and buprenorphine mainly due to non-compliance.[47]

Therapy

12-step support groups

While medical treatment may help with the initial symptoms of opioid withdrawal, once an opiate addict overcomes the first stages of withdrawal, a method for long-term preventative care is attendance at 12-step groups such as Alcoholics Anonymous or Narcotics Anonymous. Attendance and participation in a 12 step program is an effective way to obtain and maintain sobriety.[48] Among primarily inner city minorities who had a "long severe history of (primarily) crack and/or heroin use", 51.7% of the individuals with continuous 12-step attendance had over 3 years of sustained abstinence, in contrast to 13.5% among those who had less than continuous 12-step attendance.[49][50]

Epidemiology

Opioid use disorders resulted in 51,000 deaths in 2013 up from 18,000 deaths in 1990.[1] Deaths from all causes rose from 47.5 million in 1990 to 54.9 million in 2013.[1]

United States

Non-medical consumption of opioids peaked around 2010 and then started to decrease between 2011 and 2013.[51]

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 that were admitted from the emergency department increased from 43% in 1993 to 64% in 2005, but have remained relatively constant since.[52]

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,[53][54] and men also account for more opioid overdoses than women, although this gap is closing.[53] 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.[55]

Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs.[54][56][57] 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,[57] in contrast to heroin overdoses, which are highest among individuals who are between the ages of 20 and 30.[56] 21 to 35-year olds represent 77% of individuals who enter treatment for opioid use disorder,[58] however, the average age of first-time use of prescription painkillers was 21.2 years of age in 2013.[59]

Research

Each of these treatments is experimental, and some remain quite far from having been proven to be effective.

See also

References

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    The tVTA is rich in inhibitory GABA neurons expressing μ-opioid receptors and sends extensive projections toward midbrain dopamine cells. It is proposed as a major brake for dopamine systems.
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