Opiate Withdrawal Syndrome

Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of OUD.

Risk factors for OUD include a history of opioid misuse, current opioid misuse, young age, socioeconomic status, race, untreated psychiatric disorders, and environments that promote misuse (social, family, professional, etc.). Complications may include opioid overdose, suicide, HIV/AIDS, hepatitis C, and problems meeting social or professional responsibilities. Diagnosis may be based on criteria by the American Psychiatric Association in the DSM-5. If more than two of 11 criteria are present during a year, the diagnosis is said to be present.

Opioids include substances such as heroin, morphine, fentanyl, codeine, dihydrocodeine, oxycodone, and hydrocodone. A useful standard for the relative strength of different opioids is morphine milligram equivalents (MME). It is recommended for clinicians to refer to daily MMEs when prescribing opioids to decrease the risk of misuse and adverse effects.
File:Opiates v opioids.png, opiates and opioids
File:Morphine Milligram Equivalents.jpg, MME of common opioids

Long-term opioid use occurs in about 4% of people following their use for trauma or surgery-related pain. In the United States, most heroin users begin by using prescription opioids that may also be bought illegally.

People with an opioid use disorder are often treated with opioid replacement therapy using methadone or buprenorphine. Such treatment reduces the risk of death. Additionally, they 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. The medication naltrexone may also be useful to prevent relapse. Naloxone is useful for treating an opioid overdose and giving those at risk naloxone to take home is beneficial. In 2020, the CDC estimated that nearly 3 million people in the U.S. were living with OUD and more than 65,000 people died by opioid overdose, of whom more than 15,000 were heroin overdoses. Recent estimates of the number of people living with OUD and annual opioid overdoses worldwide are 16 million and 120,000, respectively.

Diagnosis

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. To make the diagnosis two or more of 11 criteria must be present in a given year:
#More opioids are taken than intended
#The individual is unable to decrease the number of opioids used
#Large amounts of time are spent trying to obtain opioids, use opioids, or recover from taking them
#The individual has cravings for opioids
#Difficulty fulfilling professional duties at work or school
#Continued use of opioids leading to social and interpersonal consequences
#Decreased social or recreational activities
#Using opioids despite being in physically dangerous settings
#Continued use despite opioids worsening physical or psychological health (i.e. depression, constipation)
#Tolerance
# Withdrawal

The severity can be classified as mild, moderate, or severe based on the number of criteria present. Addiction and dependence are components of a substance use disorder; addiction is the more severe form.

Signs and symptoms

Opioid intoxication

Signs and symptoms of opioid intoxication include:
* Decreased perception of pain
* Euphoria
* Confusion
* Desire to sleep
* Nausea
* Constipation
* Miosis (pupil constriction)
*Bradycardia (slow heart rate)
*Hypotension (low blood pressure)
* Hypokinesis (slowed movement)
*Head nodding
*Slurred speech
*Hypothermia (low body temperature)

Opioid overdose

Signs and symptoms of opioid overdose include, but are not limited to:Kosten TR, Haile CN. Opioid-Related Disorders. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. ''Harrison's Principles of Internal Medicine, 19e'' ''New York, NY: McGraw-Hill; 2014. http://accessmedicine.mhmedical.com/content.aspx?bookid=1130§ionid=79757372 Accessed 9 March 2017.
* Pin-point pupils may occur. Patient presenting with dilated pupils may still be experiencing an opioid overdose.
* Decreased heart rate
* Decreased body temperature
* Decreased breathing
* Altered level of consciousness. People may be unresponsive or unconscious.
* Pulmonary edema (fluid accumulation in the lungs)
* Shock
* Death

Withdrawal

Opioid withdrawal can occur with a sudden decrease in, or cessation of, opioids after prolonged use. Onset of withdrawal depends on the half-life of the opioid that was used last. With heroin this typically occurs five hours after use; with methadone, it may take two days. The length of time that major symptoms occur also depends on the opioid used. For heroin withdrawal, symptoms are typically greatest at two to four days and can last up to two weeks. Less significant symptoms may remain for an even longer period, in which case the withdrawal is known as post-acute-withdrawal syndrome.

*Agitation
*Anxiety
*Muscle pains
*Increased tearing
*Trouble sleeping
*Runny nose
*Sweating
*Yawning
*Goose bumps
*Dilated pupils
*Diarrhea
*Fast heart rate
*High blood pressure
*Abdominal cramps
*Shakiness
*Cravings
*Sneezing

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

Cause

Opioid use disorder can develop as a result of self-medication. Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients. Healthcare practitioners have long been aware that despite the effective use of opioids for managing pain, empirical evidence supporting long-term opioid use is minimal.Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioidtherapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manag 2008;35:214–28. Many studies of patients with chronic pain have failed to show any sustained improvement in their pain or ability to function with long-term opioid use.

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. Some evidence suggests the possibility that opioid use disorders occur due to genetic or other chemical mechanisms that may be difficult to identify or change, such as dysregulation of brain circuitry involving reward and volition. But the exact mechanisms involved are unclear, leading to debate over the influence of biology and free will.

Mechanism

Addiction

Addiction is a brain disorder characterized by compulsive drug use despite adverse consequences. It is a component of substance use disorder and its most severe form.

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. Like other addictive drugs, overuse of opioids leads to increased ΔFosB expression in the nucleus accumbens. 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. 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.

The differences in the genetic regions encoding the dopamine receptors for each individual may help to elucidate part of the risk for opioid addiction and general substance abuse. Studies of the D2 Dopamine Receptor, in particular, have shown some promising results. One specific SNP is at the TaqI RFLP (rs1800497). In a study of 530 Han Chinese heroin-addicted individuals from a Methadone Maintenance Treatment Program, those with the specific genetic variation showed higher mean heroin consumption by around double those without the SNP. This study helps to show the contribution of dopamine receptors to substance addiction and more specifically to opioid abuse.

Neuroimaging has shown functional and structural alterations in the brain. 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. Moreover, neuroimaging and neuropsychological studies demonstrate dysregulation of circuits associated with emotion, stress and high impulsivity.

Dependence

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

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

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.

A study compared the harm and dependence liability of 20 drugs, using a scale from zero to three for physical dependence, psychological dependence, and pleasure to create a mean score for dependence. Selected results can be seen in the chart below. Diacetylmorphine and morphine both scored highest, at 3.0.

Opioid receptors

A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for several specific variations, but 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.

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 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 individuals who require higher dosages to achieve pain control. But 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 that are in linkage disequilibrium with the 118A>G variant and thus contribute to different haplotype patterns more specifically associated 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.

Prevention

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

Opioid-related deaths

Naloxone is used for the emergency treatment of an overdose. 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 the activation of these receptors. Naloxone kits are recommended for laypersons who may witness an opioid overdose, for people with large prescriptions for opioids, those in substance use treatment programs, and those recently released from incarceration. Since this is a life-saving medication, many areas of the U.S. have implemented standing orders for law enforcement to carry and give naloxone as needed. In addition, naloxone can be used to challenge a person's opioid abstinence status before starting a medication such as naltrexone, which is used in the management of opioid addiction.

Good Samaritan laws

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