Opioid use disorder
|Opioid use disorder|
|Synonyms||Opioid addiction, problematic opioid use opioid abuse|
|Molecular structure of morphine|
|Symptoms||Opioid use that causes impairment or distress, addiction, dependence|
|Treatment||Opioid replacement therapy, behavioral therapy, twelve-step programs|
|Medication||Buprenorphine, methadone, naltrexone|
Opioid use disorder is a medical condition characterized by a problematic pattern of opioid use that causes clinically significant impairment or distress. It often includes a strong desire to use opioids, increased tolerance to opioids, and withdrawal syndrome when opioids are abruptly discontinued. Addiction and dependence are components of a substance use disorder and addiction represents the most severe form of the disorder. Opioid dependence can manifest as physical dependence, psychological dependence, or both.
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. 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.
Opioid use disorder can be treated with opioid replacement therapy using methadone or buprenorphine. Being on such treatment reduces the risk of death. 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. The medication naltrexone may also be useful to prevent relapse. Naloxone is useful for the treatment of an opioid overdose.
In 2013 opioid use disorders affects about 0.4% of people. About 16 million people have been affected at one point in time. It resulted in 122,000 deaths worldwide in 2015, up from 18,000 deaths in 1990. In the United States in 2015 there were 33,000 deaths due to drug overdose involving opioids. Of those 33,000 deaths, about 15,000 were from prescribed opioids and 13,000 from heroin.
- 1 Signs and symptoms
- 2 Cause
- 3 Mechanism
- 4 Diagnosis
- 5 Prevention
- 6 Management
- 7 Epidemiology
- 8 History
- 9 See also
- 10 References
- 11 External links
Signs and symptoms
- Drug seeking behavior
- Multiple prescriptions from different providers
- Increased use over time
- Opioid cravings
- Multiple medical complications from drug use (HIV/AIDS, hospitalizations, abscesses)
- Legal or social ramifications secondary to drug use
- Withdrawal symptoms
- Altered perception of temperature (hot/cold flashes)
- Change in libido (abnormally high or low)
- Muscle aches
- Mental fog or confusion
- Lack of motivation
- Increased tearing
- Restless legs
- Runny nose
- Pin-point pupils may occur. Patient presenting with dilated pupils may still be suffering 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)
Most people who have an opioid use disorder have at least one other psychiatric comorbidity. Opioid use disorder can develop as a result of self-medication, though this is controversial. 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 use disorder as the result of a weak character or will. Additionally, detoxification alone does not constitute adequate treatment.
Addiction is a brain disorder characterized by compulsive drug use despite adverse consequences. Addiction is a component of a substance use disorder and represents the most severe form of the disorder.
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 opiates leads to increased ΔFosB expression in the nucleus accumbens. Opiates 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, opiates 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.
Neuroimaging has shown functional and structural alterations in the brain. A 2017 study showed that chronic intake of opiate, 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.[non-primary source needed] Moreover, neuroimaging and neuropsychological studies demonstrated dysregulation of circuits associated with emotion, stress and high impulsivity.
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 opiate-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 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.
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.
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:
- More opioids are taken than intended
- The individual is unable to decrease the amount 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 it being physically dangerous settings
- Continued use despite opioids worsening physical or psychological health (i.e. depression, constipation)
There are efforts to decrease the number of opioids prescribed in an effort to decrease opioid use disorder and deaths related to opioid use.
The use of naloxone, an opioid receptor antagonist, can reduce the risk of death due to an opioid overdose. 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.
Opioid use disorders require long-term treatment and care with the goal 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.
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.
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 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 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.
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.
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.
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 was approved by the FDA in 1984 for the treatment of opioid addiction by preventing relapse after detoxification (withdrawal). It is available both by mouth and as a monthly injectable. Some authors question whether oral naltrexone is as effective in the treatment of opioid addiction as methadone and buprenorphine mainly due to non-compliance.
Cognitive behavioral therapy
|This section needs expansion. You can help by adding to it. (March 2017)|
|This section needs expansion. You can help by adding to it. (September 2017)|
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.[needs update]
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."
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. In 2015, it was estimated the 20.5 million Americans 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.
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 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.
- Benzodiazepine withdrawal syndrome
- Doctor shopping
- Opioid receptor
- Physical dependence
- Post-acute-withdrawal syndrome
- Prescription drug abuse
- Walid–Robinson Opioid-Dependence Questionnaire
- "Press Announcements - FDA approves first buprenorphine implant for treatment of opioid dependence". www.fda.gov. 26 May 2016. Retrieved 16 March 2017.
- "3 Patient Assessment". Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville (MD): Substance Abuse and Mental Health Services Administration (US). 2004.
- "Injury Prevention & Control: Opioid Overdose – Opioid Basics". www.cdc.gov. United States Centers for Disease Control and Prevention. Retrieved 2017-03-09.
- American Psychiatric Association (2013), Diagnostic and Statistical Manual of Mental Disorders (5th ed.), Arlington: American Psychiatric Publishing, pp. 540–546, ISBN 0890425558
- Sordo, Luis; Barrio, Gregorio; Bravo, Maria J; Indave, B Iciar; Degenhardt, Louisa; Wiessing, Lucas; Ferri, Marica; Pastor-Barriuso, Roberto (26 April 2017). "Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies". BMJ: j1550. doi:10.1136/bmj.j1550.
- Substance Abuse and Mental Health Services Administration. "Treatment for Substance Use Disorders".
- Sharma, B; Bruner, A; Barnett, G; Fishman, M (July 2016). "Opioid Use Disorders.". Child and adolescent psychiatric clinics of North America. 25 (3): 473–87. PMID 27338968. doi:10.1016/j.chc.2016.03.002.
- Substance Use and Mental Health Services Administration. "Substance Use Disorders".
- Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". N. Engl. J. Med. 374 (4): 363–371. PMID 26816013. doi:10.1056/NEJMra1511480.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
- Nestler EJ (2015). "Reflections on: "A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function"". Brain Res. PMID 26740398. doi:10.1016/j.brainres.2015.12.039.
Specifically, opiates in several CNS regions including NAc, and cocaine more selectively in NAc induce expression of certain adenylyl cyclase isoforms and PKA subunits via the transcription factor, CREB, and these transcriptional adaptations serve a homeostatic function to oppose drug action. In certain brain regions, such as locus coeruleus, these adaptations mediate aspects of physical opiate dependence and withdrawal, whereas in NAc they mediate reward tolerance and dependence that drives increased drug self-administration.
- "Opioid Overdose Prevention Programs Providing Naloxone to Laypersons — United States, 2014". www.cdc.gov. Retrieved 2017-03-09.
- Longo, Dan L.; Schuckit, Marc A. (28 July 2016). "Treatment of Opioid-Use Disorders". New England Journal of Medicine. 375 (4): 357–368. doi:10.1056/NEJMra1604339.
- GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.". Lancet. 388 (10053): 1459–1544. PMID 27733281. doi:10.1016/S0140-6736(16)31012-1.
- GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.". Lancet. 385: 117–171. PMC . PMID 25530442. doi:10.1016/S0140-6736(14)61682-2.
- "Drug Overdose Death Data| Drug Overdose | CDC Injury Center". www.cdc.gov. Retrieved 2017-03-09.
- "Heroin Overdose Data| Drug Overdose | CDC Injury Center". www.cdc.gov. Retrieved 2017-03-09.
- "Prescription Opioid Overdose Data | Drug Overdose | CDC Injury Center". www.cdc.gov. Retrieved 2017-03-09.
- "Opiate withdrawal". Medline Plus. Retrieved 1 November 2014.
- 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 March 09, 2017.
- Chen, Kevin W.; Banducci, Annie N.; Guller, Leila; MacAtee, Richard J.; Lavelle, Anna; Daughters, Stacey B.; Lejuez, C.W. (2011). "An examination of psychiatric comorbidities as a function of gender and substance type within an inpatient substance use treatment program". Drug and Alcohol Dependence. 118 (2–3): 92–9. PMC . PMID 21514751. doi:10.1016/j.drugalcdep.2011.03.003.
- Webster, L. R.; Webster, R. M. (2005). "Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the Opioid Risk Tool". Pain Medicine. 6 (6): 432–42. PMID 16336480. doi:10.1111/j.1526-4637.2005.00072.x.
- Substitution maintenance therapy in the management of opioid dependence and HIV/AIDS prevention (PDF). World Health Organization. 2004. ISBN 92-4-159115-3.
- "Treatment of opioid dependence". WHO. Retrieved August 28, 2016.
- Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci. 15 (4): 431–443. PMC . PMID 24459410.
DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
- "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
- Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. PMC . PMID 21989194. doi:10.1038/nrn3111.
- Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. PMC . PMID 21459101. doi:10.1016/j.neuropharm.2011.03.010.
- Ruffle JK (Nov 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–37. PMID 25083822. doi:10.3109/00952990.2014.933840.
- Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs. 44 (1): 38–55. PMC . PMID 22641964. doi:10.1080/02791072.2012.662112.
- Bourdy R, Barrot M (November 2012). "A new control center for dopaminergic systems: pulling the VTA by the tail". Trends Neurosci. 35 (11): 681–690. PMID 22824232. doi:10.1016/j.tins.2012.06.007.
- "Morphine addiction – Homo sapiens (human)". KEGG. Kanehisa Laboratories. 18 June 2013. Retrieved 11 September 2014.
- Goldstein, Rita Z.; Volkow, Nora D. (2011-11-01). "Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications". Nature Reviews Neuroscience. 12 (11): 652–669. ISSN 1471-003X. PMC . PMID 22011681. doi:10.1038/nrn3119.
- Ieong, Hada Fong-ha; Yuan, Zhen (2017-04-19). "Abnormal resting-state functional connectivity in the orbitofrontal cortex of heroin users and its relationship with anxiety: a pilot fNIRS study". Scientific Reports. 7. ISSN 2045-2322. doi:10.1038/srep46522.
- Ieong, Hada Fong-ha; Yuan, Zhen (2017-01-01). "Resting-State Neuroimaging and Neuropsychological Findings in Opioid Use Disorder during Abstinence: A Review". Frontiers in Human Neuroscience. 11. ISSN 1662-5161. doi:10.3389/fnhum.2017.00169.
- "Opioid Use Disorder: Diagnostic Criteria" (PDF). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association. pp. 1–9. Retrieved 27 March 2017.
- Vargas-Perez, H.; Ting-A-Kee, R.; Walton, C. H.; Hansen, D. M.; Razavi, R.; Clarke, L.; Bufalino, M. R.; Allison, D. W.; Steffensen, S. C. (2009). "Ventral Tegmental Area BDNF Induces an Opiate-Dependent-Like Reward State in Naive Rats". Science. 324 (5935): 1732–34. PMC . PMID 19478142. doi:10.1126/science.1168501.
- Laviolette, Steven R.; Van Der Kooy, Derek (2001). "GABAA receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non-dopaminergic neural motivational systems". European Journal of Neuroscience. 13 (5): 1009–15. PMID 11264674. doi:10.1046/j.1460-9568.2001.01458.x.
- Hall, F. Scott; Drgonova, Jana; Jain, Siddharth; Uhl, George R. (December 2013). "Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?". Pharmacology & Therapeutics. 140 (3): 267–279. PMC . PMID 23872493. doi:10.1016/j.pharmthera.2013.07.006.
- Bruehl, Stephen; Apkarian, A. Vania; Ballantyne, Jane C.; Berger, Ann; Borsook, David; Chen, Wen G.; Farrar, John T.; Haythornthwaite, Jennifer A.; Horn, Susan D.; Iadarola, Michael J.; Inturrisi, Charles E.; Lao, Lixing; Mackey, Sean; Mao, Jianren; Sawczuk, Andrea; Uhl, George R.; Witter, James; Woolf, Clifford J.; Zubieta, Jon-Kar; Lin, Yu (February 2013). "Personalized Medicine and Opioid Analgesic Prescribing for Chronic Pain: Opportunities and Challenges". The Journal of Pain. 14 (2): 103–113. PMC . PMID 23374939. doi:10.1016/j.jpain.2012.10.016.
- Khokhar, Jibran Y.; Ferguson, Charmaine S.; Zhu, Andy Z.X.; Tyndale, Rachel F. (February 2010). "Pharmacogenetics of Drug Dependence: Role of Gene Variations in Susceptibility and Treatment". Annual Review of Pharmacology and Toxicology. 50 (1): 39–61. doi:10.1146/annurev.pharmtox.010909.105826.
- Nicholls L, Bragaw L, Ruetsch C (February 2010). "Opioid Dependence Treatment and guidelines". J Manag Care Pharm. 16 (1 Suppl B): S14–21. PMID 20146550.
- Matthew Daubresse; Patrick P. Gleason; Yi Peng; Nilay D. Shah; Stephen T. Ritter; G. Caleb Alexander (2013). "Impact of a drug utilization review program on high-risk use of prescription controlled substances". Pharmacoepidemiology and Drug Safety. 23: 419–427. doi:10.1002/pds.3487.
- Amy Maxmen (June 2012), "Tackling the US pain epidemic". Nature News doi:10.1038/nature.2012.10766
- Richard P. Mattick et al.: National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendation
- Gowing, L; Farrell, M; Ali, R; White, JM (3 May 2016). "Alpha₂-adrenergic agonists for the management of opioid withdrawal.". The Cochrane database of systematic reviews (5): CD002024. PMID 27140827. doi:10.1002/14651858.CD002024.pub5.
- Michel et al.: Substitution treatment for opioid addicts in Germany, Harm Reduct J. 2007; 4: 5.
- WHO; UNODC; UNAIDS (January 2013). WHO, UNODC, UNAIDS technical guide for countries to set targets for universal access to HIV prevention, treatment and care for injecting drug users – 2012 revision. p. 13. ISBN 978 92 4 150437 9.
- Michael Schwartz (22 July 2008). "Russia Scorns Methadone for Heroin Addiction". The New York Times. Retrieved 5 April 2014.
- Joseph, H; Stancliff, S; Langrod, J (2000). "Methadone maintenance treatment (MMT): A review of historical and clinical issues". The Mount Sinai journal of medicine, New York. 67 (5–6): 347–64. PMID 11064485.
- Connock, M; Juarez-Garcia, A; Jowett, S; Frew, E; Liu, Z; Taylor, RJ; Fry-Smith, A; Day, E; Lintzeris, N (2007). "Methadone and buprenorphine for the management of opioid dependence: A systematic review and economic evaluation". Health technology assessment. 11 (9): 1–171, iii–iv. PMID 17313907. doi:10.3310/hta11090.
- Bunten, H; Liang, W J; Pounder, D J; Seneviratne, C; Osselton, D (28 July 2010). "OPRM1 and CYP2B6 Gene Variants as Risk Factors in Methadone-Related Deaths". Clinical Pharmacology & Therapeutics. 88 (3): 383–389. PMID 20668445. doi:10.1038/clpt.2010.127.
- Darke, Shane; Sims, Jamie; McDonald, Skye; Wickes, Wendy (2000-05-01). "Cognitive impairment among methadone maintenance patients". Addiction. 95 (5): 687–695. ISSN 1360-0443. doi:10.1046/j.1360-0443.2000.9556874.x.
- "Subutex and Suboxone Approved to Treat Opiate Dependence". FDA. 8 October 2002. Retrieved 1 November 2014.
- Haasen, C.; Verthein, U.; Degkwitz, P.; Berger, J.; Krausz, M.; Naber, D. (2007). "Heroin-assisted treatment for opioid dependence: Randomised controlled trial". The British Journal of Psychiatry. 191: 55–62. PMID 17602126. doi:10.1192/bjp.bp.106.026112.
- Robertson, J. Roy; Raab, Gillian M.; Bruce, Malcolm; McKenzie, James S.; Storkey, Helen R.; Salter, Amy (2006). "Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial". Addiction. 101 (12): 1752–9. PMID 17156174. doi:10.1111/j.1360-0443.2006.01603.x.
- Rehm J, Gschwend P, Steffen T, Gutzwiller F, Dobler-Mikola A, Uchtenhagen A (2001). "Feasibility, safety, and efficacy of injectable heroin prescription for refractory opioid addicts: a follow-up study". Lancet. 358 (9291): 1417–23. PMID 11705488. doi:10.1016/S0140-6736(01)06529-1. Retrieved 2016-03-04.
- "Drogenpolitik: Heroinabgabe gemäss Experten ein Erfolg - NZZ Schweiz". Retrieved 2016-03-04.
- "Bundesamt für Gesundheit - Substitutionsgestützte Behandlung mit Diacetylmorphin (Heroin)".
- "Dank der ärztlichen Heroinabgabe können rund 1400 Süchtige legal konsumieren – Einige schaffen den Anschluss an die Gesellschaft: Heroinsüchtige mitten im Leben - NZZ".
- "Heroin Assisted Treatment | Drug Policy Alliance". Retrieved 2016-03-04.
- Ferri, Marica; Minozzi, Silvia; Bo, Alessandra; Amato, Laura; Ferri, Marica (2013). "Slow-release oral morphine as maintenance therapy for opioid dependence". Reviews. doi:10.1002/14651858.CD009879.pub2.
- Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A (2011). "Oral naltrexone maintenance treatment for opioid dependence". Cochrane Database of Systematic Reviews (4): CD001333. PMID 21491383. doi:10.1002/14651858.CD001333.pub4.
- Brigham, Gregory (2003). "12-Step Participation as a Pathway to Recovery: The Maryhaven Experience and Implications for Treatment and Research". Science & Practice Perspectives. 2 (1): 43–51. PMC . PMID 18552722. doi:10.1151/spp032143.
- Data Overview. Drug Overdose. CDC Injury Center. Centers for Disease Control and Prevention.
- Health, United States, 2016: With Chartbook on Long-term Trends in Health (PDF). Hyattsville, MD.: CDC, National Center for Health Statistics. 2017. p. 4.
- Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.
- American Society of Addiction Medicine. "Opioid Addiction 2016 Facts and Figures" (PDF).
- Wilkerson, Richard Gentry; Kim, Hong K.; Windsor, Thomas Andrew; Mareiniss, Darren P. (May 2016). "The Opioid Epidemic in the United States". Emergency Medicine Clinics of North America. 34 (2): e1–e23. doi:10.1016/j.emc.2015.11.002.
- Owens PL, Barrett ML, Weiss AJ, Washington RE, Kronick R (August 2014). "Hospital Inpatient Utilization Related to Opioid Overuse Among Adults, 1993–2012". HCUP Statistical Brief #177. Rockville, MD: Agency for Healthcare Research and Quality.
- "Prescription Opioid Overdose Data". Center for Disease Control and Prevention. Retrieved 12 September 2016.
- Paulozzi, Len (12 April 2012). "Populations at risk for opioid overdose" (PDF). FDA. Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control Centers for Disease Control and Prevention. Retrieved 12 September 2016.
- "Opioid Addiction: 2016 Facts and Figures" (PDF). American Society of Addiction Medicine. Retrieved 12 September 2016.
- "How Bad is the Opioid Epidemic?". Retrieved 2016-09-12.
- Han, Benjamin; Polydorou, Soteri; Ferris, Rosie; Blaum, Caroline S.; Ross, Stephen; McNeely, Jennifer (2015-11-10). "Demographic Trends of Adults in New York City Opioid Treatment Programs—An Aging Population". Substance Use & Misuse. 50 (13): 1660–1667. ISSN 1082-6084. PMID 26584180. doi:10.3109/10826084.2015.1027929.
- "Facts & Faces of Opioid Addiction: New Insights". MAP Health Management. 2015. Retrieved 12 September 2016.
- "Opioids". Substance Abuse and Mental Health Services Administration. 23 February 2016. Retrieved 12 September 2016.
- James W. Kalat, Biological Psychology. Cengage Learning. Page 81.
- EMEA April 19, 2001 EMEA Public Statement on the Recommendation to Suspend the Marketing Authorisation for Orlaam (Levacetylmethadol) in the European Union
- US FDA Safety Alerts: Orlaam (levomethadyl acetate hydrochloride) Page Last Updated: Aug 20, 2013