Opioid dependence

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Opioid dependence
Classification and external resources
Morphin - Morphine.svg
ICD-10 F11.2
ICD-9 304.0
MeSH D009293

Opioid dependence is a medical diagnosis of an opioid addiction, and is characterized by an individual's compulsive use of opioids (e.g., morphine, heroin, codeine, oxycodone, hydrocodone, etc.) in spite of consequences of continued drug use. The necessary descriptive characteristics of the medical diagnosis are preoccupation with a desire to obtain and take the drug and persistent drug-seeking behaviour. In a non-diagnostic context, opioid dependence properly refers to a dependence-withdrawal syndrome that is characterized by both psychological dependence and marked physical dependence upon opioid compounds; this dependence-withdrawal syndrome is a significant component of opioid addiction. 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.[1][2][3] ΔFosB overexpression and altered regulation of cAMP response element binding protein (CREB) in the group of dopaminergic projections from the ventral tegmental area are also responsible for the induction of the negative emotional withdrawal state that characterizes opioid-related psychological dependence;[1][3] the associated mechanism(s) underlying the development of physical dependence are not currently understood.

Symptoms of withdrawal[edit]

Addiction glossary[4][1]
addiction – a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake
physical dependence – dependence that involves physical–somatic withdrawal symptoms (e.g., fatigue)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
(edit | history)

Symptoms of withdrawal from opiates include, but are not limited to:[5]

Early symptoms[edit]

  • Agitation
  • Anxiety
  • Muscle aches
  • Increased tearing
  • Insomnia
  • Runny nose
  • Sweating
  • Yawning

Late symptoms[edit]

  • Abdominal cramping
  • Diarrhea
  • Dilated pupils
  • Goose bumps
  • Nausea
  • Vomiting

Causes[edit]

Part of this section is transcluded from FOSB. (edit | history)
Material used for intravenous injection of opiates

Like many other forms of behavioral addiction and drug addiction, overuse of opiates leads to increased ΔFosB expression in the nucleus accumbens.[2][3][6] Opiates affect dopamine neurotransmission in the nucleus accumbens through their disinhibition of the GABA-based negative dopaminergic feedback system in the tail of the ventral tegmental area (tVTA).[7][8][9]

It has been demonstrated that most people who are opioid-dependent have at least one other psychiatric comorbidity.[10] Since opioids used in pain therapy rarely cause any of these conditions, they are assumed to have existed prior to the development of dependence.[citation needed] Opioids are known to have strong antidepressive, anxiolytic and antipsychotic effects and thus opioid dependence often develops as a result of self medication.[citation needed] Opioids are excellent acute pain medication, but it is their ability to produce euphoria that makes them attractive to addicts.[11] Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.[12]

Furthermore 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 BDNF, brain-derived neurotrophic factor, 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.[13] It has been shown that when an opiate-naive person begins using opiates at levels inducing euphoria, this same increase in BDNF occurs.[14]

Another recent study concluded to have shown "a direct link between morphine abstinence and depressive-like symptoms" and postulates "that serotonin dysfunction represents a main mechanism contributing to mood disorders in opiate abstinence".[15]

Summary of addiction-related plasticity
Form of neural or behavioral plasticity Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual reward Exercise Environmental enrichment
ΔFosB expression
in the nucleus accumbens
[3]
Behavioral Plasticity
Escalation of intake Yes Yes Yes [3]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [3]
Psychostimulant
self-administration
[3]
Psychostimulant
conditioned place preference
[3]
Reinstatement of drug-seeking behavior [3]
Neurochemical Plasticity
CREB phosphorylation
in the nucleus accumbens
[3]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [3]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [3]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [3]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [3]
Mesocorticolimbic Synaptic Plasticity
Number of dendrites in the nucleus accumbens [3]
Dendritic spine density in
the nucleus accumbens
No change [3]

Opioid receptor pharmacogenomics[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 has 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.[16]

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[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 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.[17]

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.[18]

Diagnosis[edit]

The core concept of the WHO's definition of a "drug dependence" is exactly the same as a drug addiction: compulsive drug use. The WHO and DSM-IV-TR clinical guidelines for a definite diagnosis of "dependence" 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 mistake opioid dependence for a weakness of character or will.[19][20] Accordingly, detoxification alone does not constitute adequate treatment.

Treatment[edit]

Opioid dependence is a complex health condition that often requires long-term treatment and care. The treatment of opioid dependence is important to reduce its health and social consequences and to improve the well-being and social functioning of people affected. The main objectives of treating and rehabilitating persons with opioid dependence are to reduce dependence on illicit drugs; to reduce the morbidity and mortality caused by the use of illicit opioids, or associated with their use, such as infectious diseases; to improve physical and psychological health; to reduce criminal behaviour; to facilitate reintegration into the workforce and education system and to improve social functioning.

As no single treatment is effective for all individuals with opioid dependence, diverse treatment options are needed, including psychosocial approaches and pharmacological treatment.[21]

Relapse following detoxification alone is extremely common, and therefore detoxification rarely constitutes an adequate treatment of substance dependence on its own. However, it is a first step for many forms of longer-term abstinence-based treatment. Both detoxification with subsequent abstinence-oriented treatment and substitution maintenance treatment are essential components of an effective treatment system for people with opioid dependence.[22]

Current trends in the US reveal a significant increase of prescription opioid abuse compared to illicit opiates such as heroin.[23] This development has also implications for the prevention, treatment and therapy of opioid dependence.[24]

Methadone[edit]

40 mg of Methadone
Main article: Methadone maintenance

MMT (Methadone Maintenance Treatment), a form of opioid replacement therapy, reduces and/or eliminates the use of illicit opiates, the criminality associated with opiate use, and allows patients to improve their health and social productivity.[25][26] 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.[25] 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.[25] It is also indicated for pregnant women addicted to opiates.[25] 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.[27] Methadone toxicity has been shown to be associated with specific phenotypes of CYP2B6.[28]

Buprenorphine[edit]

Suboxone 8 mg tablet
Main article: Buprenorphine

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.[29] Buprenorphine sublingual preparations are often used in the management of opioiddependence (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.[30]

Naltrexone[edit]

Main article: 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.[31] The monthly injectable naltrexone preparations have been designed to overcome the problems of compliance encountered with the oral formulation, and are often included as part of Medication-Assisted Treatment in conjunction with counseling and behavioral therapy.[32] Medication-Assisted Treatment is one of the few opioid dependence treatments covered by insurance providers.[33]

Diamorphine[edit]

In Switzerland, Germany, the Netherlands, and the United Kingdom, longterm injecting drug users who do not benefit from methadone and other medication options are being 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.[34] Studies show that even after years of homelessness and delinquency and despite severe comorbidities, about half of the patients find employment within the first year of treatment.[35]

LAAM[edit]

LAAM 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.[36]

Experimental treatments[edit]

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

12-step support groups[edit]

Main article: Twelve-step program

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.[46] 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.[47][48]

Epidemiology[edit]

As of 2010 opioid use disorder resulted in about 43,000 deaths globally up from 8,900 in 1990.[49]

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.[50]

See also[edit]

References[edit]

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