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long-term(maintenance) medication is still the first-line treatment for patients with OUD, and many patients prefer it. the evidence for the three medications that have been approved for the treatment of OUD- [[Methadone]], [[Buprenorphine]], [[Naltrexone]]- will be discussed in the following section. long-term maintenance therapy with [[agonists]] is the mainstay treatment for OUD.<ref name="Mattick Breen Kimber Davoli p. ">{{cite journal | last=Mattick | first=Richard P | last2=Breen | first2=Courtney | last3=Kimber | first3=Jo | last4=Davoli | first4=Marina | title=Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence | journal=Cochrane Database of Systematic Reviews | publisher=Wiley | date=2014-02-06 | issn=1465-1858 | doi=10.1002/14651858.cd002207.pub4 | page=}}</ref> a systematic review of 19 [[cohort]] studies in 2017 showed that [[pharmacotherapy]] with methadone and buprenorphine significantly reduces [[mortality]] for all reasons in the patients using [[opioid]] [[agonist]] comparing to the people without medical treatment.<ref name="Sordo Barrio Bravo Indave p=j1550">{{cite journal | last=Sordo | first=Luis | last2=Barrio | first2=Gregorio | last3=Bravo | first3=Maria J | last4=Indave | first4=B Iciar | last5=Degenhardt | first5=Louisa | last6=Wiessing | first6=Lucas | last7=Ferri | first7=Marica | last8=Pastor-Barriuso | first8=Roberto | title=Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies | journal=BMJ | publisher=BMJ | date=2017-04-26 | issn=0959-8138 | doi=10.1136/bmj.j1550 | page=j1550}}</ref>
long-term(maintenance) medication is still the first-line treatment for patients with OUD, and many patients prefer it. the evidence for the three medications that have been approved for the treatment of OUD- [[Methadone]], [[Buprenorphine]], [[Naltrexone]]- will be discussed in the following section. long-term maintenance therapy with [[agonists]] is the mainstay treatment for OUD.<ref name="Mattick Breen Kimber Davoli p. ">{{cite journal | last=Mattick | first=Richard P | last2=Breen | first2=Courtney | last3=Kimber | first3=Jo | last4=Davoli | first4=Marina | title=Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence | journal=Cochrane Database of Systematic Reviews | publisher=Wiley | date=2014-02-06 | issn=1465-1858 | doi=10.1002/14651858.cd002207.pub4 | page=}}</ref> a systematic review of 19 [[cohort]] studies in 2017 showed that [[pharmacotherapy]] with methadone and buprenorphine significantly reduces [[mortality]] for all reasons in the patients using [[opioid]] [[agonist]] comparing to the people without medical treatment.<ref name="Sordo Barrio Bravo Indave p=j1550">{{cite journal | last=Sordo | first=Luis | last2=Barrio | first2=Gregorio | last3=Bravo | first3=Maria J | last4=Indave | first4=B Iciar | last5=Degenhardt | first5=Louisa | last6=Wiessing | first6=Lucas | last7=Ferri | first7=Marica | last8=Pastor-Barriuso | first8=Roberto | title=Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies | journal=BMJ | publisher=BMJ | date=2017-04-26 | issn=0959-8138 | doi=10.1136/bmj.j1550 | page=j1550}}</ref>
*[[Buprenorphine]]
*[[Buprenorphine]]
[[Buprenorphine]] is a highly effective long-acting partial [[opioid]] agonist for the treatment of OUD. [[Buprenorphine]] is available in different formulations in the USA. Most of them are combined with naloxone to avoid injection or intranasal use. sublingual tablets are available in 2, and 8 mg doses with or without [[naloxone]]. many patients may need doses above 16mg/day up to 32 mg. for those who do not respond to 32mg/day of buprenorphine, methadone therapy should be considered. long term maintenance treatment with buprenorphine is more effective than short-term or medically supervised withdrawal treatment.<ref name="Weinstein Kim Cheng Quinn 2017 pp. 65–70">{{cite journal | last=Weinstein | first=Zoe M. | last2=Kim | first2=Hyunjoong W. | last3=Cheng | first3=Debbie M. | last4=Quinn | first4=Emily | last5=Hui | first5=David | last6=Labelle | first6=Colleen T. | last7=Drainoni | first7=Mari-Lynn | last8=Bachman | first8=Sara S. | last9=Samet | first9=Jeffrey H. | title=Long-term retention in Office Based Opioid Treatment with buprenorphine | journal=Journal of Substance Abuse Treatment | publisher=Elsevier BV | volume=74 | year=2017 | issn=0740-5472 | doi=10.1016/j.jsat.2016.12.010 | pages=65–70}}</ref> [[Buprenorphine]] has a high tendency to bind to the [[receptor]], which adds to its safety. however it can dislodge other [[narcotics]] and lead to unwanted [[withdrawal]] if given too soon after using an agonist.<ref name="Coe Lofwall Walsh 2019 pp. 93–103">{{cite journal | last=Coe | first=Marion A. | last2=Lofwall | first2=Michelle R. | last3=Walsh | first3=Sharon L. | title=Buprenorphine Pharmacology Review: Update on Transmucosal and Long-acting Formulations | journal=Journal of Addiction Medicine | publisher=Ovid Technologies (Wolters Kluwer Health) | volume=13 | issue=2 | year=2019 | issn=1932-0620 | doi=10.1097/adm.0000000000000457 | pages=93–103}}</ref> to prevent this buprenorphine should be started when [[withdrawal]] symptoms begin in the patient. usually, after 8 to 12 hours of using short-acting [[opioids]] such as [[heroin]], [[buprenorphine]] can be started with a low dose.<ref name="Vogel Hämmig Kemter Strasser 2016 pp. 99–105">{{cite journal | last=Vogel | first=Marc | last2=Hämmig | first2=Robert | last3=Kemter | first3=Antje | last4=Strasser | first4=Johannes | last5=von Bardeleben | first5=Ulrich | last6=Gugger | first6=Barbara | last7=Walter | first7=Marc | last8=Dürsteler | first8=Kenneth | title=Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the “Bernese method” | journal=Substance Abuse and Rehabilitation | publisher=Informa UK Limited | volume=Volume 7 | year=2016 | issn=1179-8467 | doi=10.2147/sar.s109919 | pages=99–105}}</ref>
[[Buprenorphine]] is a highly effective long-acting partial [[opioid]] agonist for the treatment of OUD. [[Buprenorphine]] is available in different formulations in the USA. Most of them are combined with naloxone to avoid injection or intranasal use. sublingual tablets are available in 2, and 8 mg doses with or without [[naloxone]]. many patients may need doses above 16mg/day up to 32 mg. for those who do not respond to 32mg/day of buprenorphine, methadone therapy should be considered. long term maintenance treatment with buprenorphine is more effective than short-term or medically supervised withdrawal treatment.<ref name="Weinstein Kim Cheng Quinn 2017 pp. 65–70">{{cite journal | last=Weinstein | first=Zoe M. | last2=Kim | first2=Hyunjoong W. | last3=Cheng | first3=Debbie M. | last4=Quinn | first4=Emily | last5=Hui | first5=David | last6=Labelle | first6=Colleen T. | last7=Drainoni | first7=Mari-Lynn | last8=Bachman | first8=Sara S. | last9=Samet | first9=Jeffrey H. | title=Long-term retention in Office Based Opioid Treatment with buprenorphine | journal=Journal of Substance Abuse Treatment | publisher=Elsevier BV | volume=74 | year=2017 | issn=0740-5472 | doi=10.1016/j.jsat.2016.12.010 | pages=65–70}}</ref> [[Buprenorphine]] has a high tendency to bind to the [[receptor]], which adds to its safety. however it can dislodge other [[narcotics]] and lead to unwanted [[withdrawal]] if given too soon after using an agonist.<ref name="Coe Lofwall Walsh 2019 pp. 93–103">{{cite journal | last=Coe | first=Marion A. | last2=Lofwall | first2=Michelle R. | last3=Walsh | first3=Sharon L. | title=Buprenorphine Pharmacology Review: Update on Transmucosal and Long-acting Formulations | journal=Journal of Addiction Medicine | publisher=Ovid Technologies (Wolters Kluwer Health) | volume=13 | issue=2 | year=2019 | issn=1932-0620 | doi=10.1097/adm.0000000000000457 | pages=93–103}}</ref> to prevent this buprenorphine should be started when [[withdrawal]] symptoms begin in the patient. usually, after 8 to 12 hours of using short-acting [[opioids]] such as [[heroin]], [[buprenorphine]] can be started with a low dose.<ref name="Vogel Hämmig Kemter Strasser 2016 pp. 99–105">{{cite journal | last=Vogel | first=Marc | last2=Hämmig | first2=Robert | last3=Kemter | first3=Antje | last4=Strasser | first4=Johannes | last5=von Bardeleben | first5=Ulrich | last6=Gugger | first6=Barbara | last7=Walter | first7=Marc | last8=Dürsteler | first8=Kenneth | title=Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the “Bernese method” | journal=Substance Abuse and Rehabilitation | publisher=Informa UK Limited | volume=Volume 7 | year=2016 | issn=1179-8467 | doi=10.2147/sar.s09919 | pages=99–105}}</ref>
*[[Methadone]]
*[[Methadone]]
Methadone is a highly effective long-acting agonist, which noticeably reduces the use of illicit opioid use.<ref name="Mattick Breen Kimber Davoli p. ">{{cite | last=Mattick | first=Richard P. | last2=Breen | first2=Courtney | last3=Kimber | first3=Jo | last4=Davoli | first4=Marina | last5=Breen | first5=Rosie | editor-last=Mattick | editor-first=Richard P. | title=Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence | publisher=John Wiley & Sons, Ltd | publication-place=Chichester, UK | date=2003-04-22 | doi=10.1002/14651858.cd002209 | page=}}</ref>. considering that methadone has a long half-life, the starting dose is at 30-40 mg/day and increases slowly until an effective therapeutic dose is reached. The goal and effective dose are to suppress opioid craving and at the same time to avoid over-sedation. The studies show that higher doses of methadone( doses of at least 60-100 mg) are linked with maintaining treatment and reduction of overdose mortality.<ref name="Faggiano Vigna-Taglianti Versino Lemma p. ">{{cite journal | last=Faggiano | first=Fabrizio | last2=Vigna-Taglianti | first2=Federica | last3=Versino | first3=Elisabetta | last4=Lemma | first4=Patrizia | title=Methadone maintenance at different dosages for opioid dependence | journal=Cochrane Database of Systematic Reviews | publisher=Wiley | date=2003-07-21 | issn=1465-1858 | doi=10.1002/14651858.cd002208 | page=}}</ref>
Methadone is a highly effective long-acting agonist, which noticeably reduces the use of illicit opioid use.<ref name="Mattick Breen Kimber Davoli p. ">{{cite | last=Mattick | first=Richard P. | last2=Breen | first2=Courtney | last3=Kimber | first3=Jo | last4=Davoli | first4=Marina | last5=Breen | first5=Rosie | editor-last=Mattick | editor-first=Richard P. | title=Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence | publisher=John Wiley & Sons, Ltd | publication-place=Chichester, UK | date=2003-04-22 | doi=10.1002/14651858.cd002209 | page=}}</ref>. considering that methadone has a long half-life, the starting dose is at 30-40 mg/day and increases slowly until an effective therapeutic dose is reached. The goal and effective dose are to suppress opioid craving and at the same time to avoid over-sedation. The studies show that higher doses of methadone( doses of at least 60-100 mg) are linked with maintaining treatment and reduction of overdose mortality.<ref name="Faggiano Vigna-Taglianti Versino Lemma p. ">{{cite journal | last=Faggiano | first=Fabrizio | last2=Vigna-Taglianti | first2=Federica | last3=Versino | first3=Elisabetta | last4=Lemma | first4=Patrizia | title=Methadone maintenance at different dosages for opioid dependence | journal=Cochrane Database of Systematic Reviews | publisher=Wiley | date=2003-07-21 | issn=1465-1858 | doi=10.1002/14651858.cd002208 | page=}}</ref>
*[[Naltrexone]]
Naltrexone is an [[opium]] [[antagonist]], the newest medication for the treatment of OUD in primary care settings. The oral form has low efficacy. However, [[RCT]] studies have shown that injection of the intramuscular [extended-release]] formulation is superior to the [[placebo]] and the oral form of it and reduces craving and relapse in patients with [[OUD]].


==References==
==References==

Revision as of 16:07, 22 August 2021


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Synonyms and keywords: Opioid use disorder

Overview

With chronic use for treatment of pain, dependence may lead to substance abuse and "aberrant medication-taking behaviors" may occur.[1] From 2000-2005, the abuse of prescribed opiods, especially oxycodone extended release (OxyContin) and hydrocodone, has increased.[2]

Terminology

Opioid Use Disorder

Opioid use disorder(OUD) is defined as a loss of control over opioid use leading to physical, psychological, and social consequences. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) includes diagnostic criteria for OUD that are universal across all drugs and are based on the presence of at least two of 11 criteria organized into four clusters: 1-Impaired control 2-Social impairment 3- Risky use 4- Pharmacologic dependence[3] Opioid abuse happens for different of reasons, including self-medication, use for reward, compulsive use due to addiction, and diversion for profit. treatment methods that balance chronic pain while reducing the risks for drug abuse, misuse, and distraction are strongly needed.[4][5]

Tolerance

Tolerance is the process whereby neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others - tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects. Impaired control leads to the use in bigger amounts or for longer periods of time than anticipated; persistent desire to reduce or stop use; many unsuccessful attempts to reduce or stop use; a significant amount of time spent using or recovering from the effects of the substance; a strong urge to use or crave the substance.[3]

Tolerance to opioids is attenuated by a number of substances, including calcium channel blockers[6][7], intrathecal magnesium[8] and zinc[9], and NMDA antagonists such as ketamine.[10]

Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common[11] due to low magnesium/zinc content in food and use of substances which deplete them including diuretics (such as alcohol, caffeine/theophylline) and smoking. Reducing intake of these substances and taking zinc/magnesium supplements may slow the development of tolerance to opiates.

Dependence

Dependence is characterized by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed. The withdrawal symptoms include severe dysphoria, sweating, nausea, rhinorrhea, depression, severe fatigue, vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms.[12] The speed and severity of withdrawal depend on the half-life of the opioid — heroin and morphine withdrawal occur more quickly and are more severe than methadone withdrawal, but methadone withdrawal takes longer. The acute withdrawal phase is often followed by a protracted phase of depression and insomnia that can last for months. The symptoms of opioid withdrawal can also be treated with other medications, but with low efficacy.[13]

Addiction

Addiction is the process whereby physical and/or psychological addiction develops to a drug - including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Psychological addiction is more common in people taking opioids recreationally, it is rare in patients taking opioids for pain relief.[14]

Abuse

Drug abuse is the misuse of drugs producing negative consequences.

Differential Diagnosis

Epidemiology and Demographics

Prevalence

The 12 month prevalence of opioid use disorder is 370 per 100,000 (0.37%) in ages 18 years and older in the community population.[15] In 2016, an estimated 26.8 million persons worldwide with OUD, up 47.3 percent from 1990. The highest prevalence was found in high-income North America, North Africa, and the Middle East.[16]

Risk factors

Variability in opioid prescribing in emergency departments is a risk factor.[17][18] The Centers for Disease Control and Prevention has studied risk factors[19]. Substance use disorders are linked to psychiatric problems; those who have one are more likely to have the other. Substance use causing mental diseases, people with psychiatric disorders using substances to manage symptoms, and common risk factors for both conditions are all possible explanations. The lifetime prevalence of comorbid psychiatric disorders in patients with OUD has been found to range between 24 and 86 percent, with mood and anxiety disorders being the most common axis I disorders and antisocial personality disorder being the most commonly diagnosed axis II condition. Determining whether a person has a substance-induced disorder or a basic psychiatric disorder can be difficult in people with co-occurring disorders.[20][21]

Diagnostic Criteria

DSM-V Diagnostic Criteria for Opioid Use Disorder(OUD)[15]

“
  • A. A problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
  • 1. Opioids are often taken in larger amounts or over a longer period than was intended.
  • 2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use.
  • 3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects.
  • 4. Craving, or a strong desire or urge to use opioids.
  • 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home.
  • 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
  • 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use.
  • 8. Recurrent opioid use in situations in which it is physically hazardous.
  • 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
  • 10. Tolerance, as defined by either of the following:
  • a. A need for markedly increased amounts of opioids to achieve intoxication or desired effect.
  • b. A markedly diminished effect with continued use of the same amount of an opioid.

Note: This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision.

  • 11. Withdrawal, as manifested by either of the following:
  • a. The characteristic opioid withdrawal syndrome.
  • b. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms.

Note: This criterion is not considered to be met for those individuals taking opioids solely under appropriate medical supervision .

Specify if:

  • In early remission: After full criteria for opioid use disorder were previously met, none of the criteria for opioid use disorder have been met for at least 3 months but for less than 12 months (with the exception that Criterion A4, “Craving, or a strong desire or urge to use opioids,” maybe met).
  • In sustained remission: After full criteria for opioid use disorder were previously met, none of the criteria for opioid use disorder have been met at any time during a period of 12 months or longer (with the exception that Criterion A4, “Craving, or a strong desire or urge to use opioids,” maybe met).

Specify if:

  • On maintenance therapy: This additional specifier is used if the individual is taking a prescribed agonist medication such as methadone or buprenorphine and none of the criteria for opioid use disorder have been met for that class of medication (except tolerance to, or withdrawal from, the agonist). This category also applies to those Individuals being maintained on a partial agonist, an agonist/antagonist, or a full antagonist such as oral naltrexone or depot naltrexone.
  • In a controlled environment: This additional specifier is used if the individual is in an environment where access to opioids is restricted.
 ”

Screening for OUD

There are several ways to test for unhealthy drug abuse. one of the simplest is to ask two questions:

  • 1. In the last 12 months, how many days have you used drugs other than alcohol? ( a score of seven or more considered as positive)
  • 2. In the last 12 months, how many days have you used medicines more than you intended? (it is positive if two or more are positive)

These two questions were proved to be more than 90% sensitive and specific for drug use disorder in a study of over 1200 primary care patients.[22]

Treatment

several methods of psychosocial interventions such as individual counseling or group therapy can benefit people with OUD. Clinicians in primary care can assist patients who are interested in these treatments in getting connected to them. there is limited evidence to recommend these kinds of interventions either alone or in combination with pharmacotherapy. Most of the surveys on these therapeutic interventions are used in conjunction with medication.[23][24]

long-term(maintenance) medication is still the first-line treatment for patients with OUD, and many patients prefer it. the evidence for the three medications that have been approved for the treatment of OUD- Methadone, Buprenorphine, Naltrexone- will be discussed in the following section. long-term maintenance therapy with agonists is the mainstay treatment for OUD.[25] a systematic review of 19 cohort studies in 2017 showed that pharmacotherapy with methadone and buprenorphine significantly reduces mortality for all reasons in the patients using opioid agonist comparing to the people without medical treatment.[26]

Buprenorphine is a highly effective long-acting partial opioid agonist for the treatment of OUD. Buprenorphine is available in different formulations in the USA. Most of them are combined with naloxone to avoid injection or intranasal use. sublingual tablets are available in 2, and 8 mg doses with or without naloxone. many patients may need doses above 16mg/day up to 32 mg. for those who do not respond to 32mg/day of buprenorphine, methadone therapy should be considered. long term maintenance treatment with buprenorphine is more effective than short-term or medically supervised withdrawal treatment.[27] Buprenorphine has a high tendency to bind to the receptor, which adds to its safety. however it can dislodge other narcotics and lead to unwanted withdrawal if given too soon after using an agonist.[28] to prevent this buprenorphine should be started when withdrawal symptoms begin in the patient. usually, after 8 to 12 hours of using short-acting opioids such as heroin, buprenorphine can be started with a low dose.[29]

Methadone is a highly effective long-acting agonist, which noticeably reduces the use of illicit opioid use.[25]. considering that methadone has a long half-life, the starting dose is at 30-40 mg/day and increases slowly until an effective therapeutic dose is reached. The goal and effective dose are to suppress opioid craving and at the same time to avoid over-sedation. The studies show that higher doses of methadone( doses of at least 60-100 mg) are linked with maintaining treatment and reduction of overdose mortality.[30]

Naltrexone is an opium antagonist, the newest medication for the treatment of OUD in primary care settings. The oral form has low efficacy. However, RCT studies have shown that injection of the intramuscular [extended-release]] formulation is superior to the placebo and the oral form of it and reduces craving and relapse in patients with OUD.

References

  1. ↑ Martell BA, O'Connor PG, Kerns RD; et al. (2007). "Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction". Ann. Intern. Med. 146 (2): 116–27. PMID 17227935.
  2. ↑ Cicero TJ, Inciardi JA, Muñoz A (2005). "Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2004". J Pain. 6 (10): 662–72. doi:10.1016/j.jpain.2005.05.004. PMID 16202959.
  3. ↑ 3.0 3.1 Vahia VN (July 2013). "Diagnostic and statistical manual of mental disorders 5: A quick glance". Indian J Psychiatry. 55 (3): 220–3. doi:10.4103/0019-5545.117131. PMC 3777342. PMID 24082241.
  4. ↑ Kaye AD, Jones MR, Kaye AM, Ripoll JG, Galan V, Beakley BD, Calixto F, Bolden JL, Urman RD, Manchikanti L (February 2017). "Prescription Opioid Abuse in Chronic Pain: An Updated Review of Opioid Abuse Predictors and Strategies to Curb Opioid Abuse: Part 1". Pain Physician. 20 (2S): S93–S109. PMID 28226333.
  5. ↑ Buresh, Megan; Stern, Robert; Rastegar, Darius (2021-05-19). "Treatment of opioid use disorder in primary care". BMJ. BMJ: n784. doi:10.1136/bmj.n784. ISSN 1756-1833.
  6. ↑ Santillán R, Maestre JM, Hurlé MA, Flórez J. "Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report." Pain. 1994 Jul;58(1):129-32. PMID 7970835
  7. ↑ Smith FL, Dombrowski DS, Dewey WL. "Involvement of intracellular calcium in morphine tolerance in mice." Pharmacology, Biochemistry, and Behavior. 1999 Feb;62(2):381-8. PMID 9972707
  8. ↑ McCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. "Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats." Anesthesia and Analgesia. 1998 Apr;86(4):830-6. PMID 9539610
  9. ↑ Larson AA, Kovács KJ, Spartz AK. "Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance." European Journal of Pharmacology. 2000 Nov 3;407(3):267-72. PMID 11068022
  10. ↑ Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS. "Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors." Eur J Pharmacol. 1996 Feb 15;297(1-2):27-33. PMID 8851162
  11. ↑ http://www.worldwidehealthcenter.net/articles-360.html
  12. ↑ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  13. ↑ Hermann D, Klages E, Welzel H, Mann K, Croissant B. Low efficacy of non-opioid drugs in opioid withdrawal symptoms. Addict Biol. 2005 Jun;10(2):165-9. PMID: 16191669
  14. ↑ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  15. ↑ 15.0 15.1 15.2 Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C: American Psychiatric Association. 2013. ISBN 0890425558.
  16. ↑ "The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016". Lancet Psychiatry. 5 (12): 987–1012. December 2018. doi:10.1016/S2215-0366(18)30337-7. PMC 6251968. PMID 30392731.
  17. ↑ Young N, Silverman D, Bradford H, Finkelstein J (2017). "Multicenter prevalence of opioid medication use as abortive therapy in the emergency department treatment of migraine headaches". Am J Emerg Med. doi:10.1016/j.ajem.2017.06.015. PMID 28645559.
  18. ↑ Barnett ML, Olenski AR, Jena AB (2017). "Opioid-Prescribing Patterns of Emergency Physicians and Risk of Long-Term Use". N Engl J Med. 376 (7): 663–673. doi:10.1056/NEJMsa1610524. PMC 5428548. PMID 28199807.
  19. ↑ Shah A, Hayes CJ, Martin BC (2017). "Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use - United States, 2006-2015". MMWR Morb Mortal Wkly Rep. 66 (10): 265–269. doi:10.15585/mmwr.mm6610a1. PMID 28301454.
  20. ↑ Astals M, Domingo-Salvany A, Buenaventura CC, Tato J, Vazquez JM, Martín-Santos R, Torrens M (2008). "Impact of substance dependence and dual diagnosis on the quality of life of heroin users seeking treatment". Subst Use Misuse. 43 (5): 612–32. doi:10.1080/10826080701204813. PMID 18393080.
  21. ↑ Roncero C, Barral C, Rodríguez-Cintas L, Pérez-Pazos J, Martinez-Luna N, Casas M, Torrens M, Grau-López L (September 2016). "Psychiatric comorbidities in opioid-dependent patients undergoing a replacement therapy programme in Spain: The PROTEUS study". Psychiatry Res. 243: 174–81. doi:10.1016/j.psychres.2016.06.024. PMID 27416536.
  22. ↑ Tiet QQ, Leyva YE, Moos RH, Frayne SM, Osterberg L, Smith B (August 2015). "Screen of Drug Use: Diagnostic Accuracy of a New Brief Tool for Primary Care". JAMA Intern Med. 175 (8): 1371–7. doi:10.1001/jamainternmed.2015.2438. PMID 26075352.
  23. ↑ Timko, C; Debenedetti, A; Billow, R (2006). "Intensive referral to 12-Step self-help groups and 6-month substance use disorder outcomes". Addiction (Abingdon, England). 101 (5): 678–88. doi:10.1111/j.1360-0443.2006.01391.x. ISSN 0965-2140. PMID 16669901.
  24. ↑ McAuliffe, William E. (1990). "A Randomized Controlled Trial of Recovery Training and Self-help for Opioid Addicts in New England and Hong Kong". Journal of Psychoactive Drugs. Informa UK Limited. 22 (2): 197–209. doi:10.1080/02791072.1990.10472544. ISSN 0279-1072.
  25. ↑ 25.0 25.1 Mattick, Richard P; Breen, Courtney; Kimber, Jo; Davoli, Marina (2014-02-06). "Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence". Cochrane Database of Systematic Reviews. Wiley. doi:10.1002/14651858.cd002207.pub4. ISSN 1465-1858.
  26. ↑ Sordo, Luis; Barrio, Gregorio; Bravo, Maria J; Indave, B Iciar; Degenhardt, Louisa; Wiessing, Lucas; Ferri, Marica; Pastor-Barriuso, Roberto (2017-04-26). "Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies". BMJ. BMJ: j1550. doi:10.1136/bmj.j1550. ISSN 0959-8138.
  27. ↑ Weinstein, Zoe M.; Kim, Hyunjoong W.; Cheng, Debbie M.; Quinn, Emily; Hui, David; Labelle, Colleen T.; Drainoni, Mari-Lynn; Bachman, Sara S.; Samet, Jeffrey H. (2017). "Long-term retention in Office Based Opioid Treatment with buprenorphine". Journal of Substance Abuse Treatment. Elsevier BV. 74: 65–70. doi:10.1016/j.jsat.2016.12.010. ISSN 0740-5472.
  28. ↑ Coe, Marion A.; Lofwall, Michelle R.; Walsh, Sharon L. (2019). "Buprenorphine Pharmacology Review: Update on Transmucosal and Long-acting Formulations". Journal of Addiction Medicine. Ovid Technologies (Wolters Kluwer Health). 13 (2): 93–103. doi:10.1097/adm.0000000000000457. ISSN 1932-0620.
  29. ↑ Vogel, Marc; Hämmig, Robert; Kemter, Antje; Strasser, Johannes; von Bardeleben, Ulrich; Gugger, Barbara; Walter, Marc; Dürsteler, Kenneth (2016). "Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the "Bernese method"". Substance Abuse and Rehabilitation. Informa UK Limited. Volume 7: 99–105. doi:10.2147/sar.s09919. ISSN 1179-8467.
  30. ↑ Faggiano, Fabrizio; Vigna-Taglianti, Federica; Versino, Elisabetta; Lemma, Patrizia (2003-07-21). "Methadone maintenance at different dosages for opioid dependence". Cochrane Database of Systematic Reviews. Wiley. doi:10.1002/14651858.cd002208. ISSN 1465-1858.

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