Opioid use disorder

Signs and symptoms

Signs and symptoms include:

Withdrawal

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

Early symptoms

Late symptoms

Opioid intoxication

Signs and symptoms include:

Opioid overdose

Signs and symptoms include:

Cause

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

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. Additionally, detoxification alone does not constitute adequate treatment.

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.

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

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. It has been shown that when an opiate-naive person begins using opiates at levels inducing euphoria, this same increase in BDNF occurs.

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

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.

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.

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.

Diagnosis

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

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

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

The use of naloxone, an opioid reversal agent, can be useful in preventing deaths related to opioid overdose. Naloxone kits are recommended for laypersons who may witness an opioid overdose and individuals with large prescriptions for opioids. In addition, they are also recommended for individuals in substance use treatment programs and for those recently released from incarceration and individuals with large prescriptions for opioids.

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. Most strategies aim ultimately to reduce drug use and lead to abstinence.

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

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

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

Medications

Opioid replacement therapy (ORT) (also called opioid substitution therapy or opioid maintenance therapy) involves replacing an opioid, such as heroin, with a longer acting but less euphoric opioid. Commonly used drugs for ORT are methadone or buprenorphine which are taken under medical supervision.

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

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

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. 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. 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. It is also indicated for pregnant women addicted to opiates. 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.

Buprenorphine

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. 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.

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.

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.

Heroin-assisted treatment

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

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

Morphine (extended-release)

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

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.

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 can be an effective way to obtain and maintain sobriety. 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.

Epidemiology

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

United States

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 prior month. In 2015, it was estimated the 20.5 million American's had a substance use disorder. 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.

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

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

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.

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, and men also account for more opioid overdoses than women, although this gap is closing. 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.

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

Levacetylmethadol

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

Research

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