Opioid addiction and dependence

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

Opioid addiction and opioid dependence, sometimes classified together as an opioid use disorder, are medical conditions that characterize the compulsive use of opioids (e.g., morphine, heroin, codeine, oxycodone, hydrocodone, etc.) in spite of consequences of continued use and the withdrawal syndrome that occurs when opioid use stops. The necessary descriptive characteristics of the medical diagnosis are preoccupation with a desire to obtain and take the drug and persistent drug-seeking behaviour. The opioid dependence-withdrawal syndrome involves both psychological dependence and marked physical dependence upon opioid compounds.

Opioid use disorders resulted in 51,000 deaths in 2013 up from 18,000 deaths in 1990.[1]

Symptoms of withdrawal[edit]

Total number of U.S. overdose deaths involving opioid pain relievers from 2001 to 2014.[2]

Symptoms of withdrawal from opiates include, but are not limited to:[3]

Early symptoms[edit]

  • Altered perception of temperature (hot/cold flashes)
  • Agitation
  • Anxiety
  • Change in libido (abnormally high or low)
  • Dehydration
  • Fatigue
  • Muscle aches
  • Mental fog/confusion/lack of motivation
  • Increased tearing
  • Insomnia
  • Restless legs
  • Runny nose
  • Sweating
  • Yawning
  • Skin-Crawling

Late symptoms[edit]

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


It has been demonstrated that most people who are opioid-dependent have at least one other psychiatric comorbidity.[4] Opioid dependence often develops as a result of self medication.[citation needed] Opioids are excellent acute pain medication, but it is their ability to produce euphoria that makes them attractive to addicts.[5] Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.[6]



Material used for intravenous injection of opiates

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.[7][8][9] ΔFosB overexpression and altered regulation of cAMP response element binding protein (CREB) in the group of dopaminergic projections from the ventral tegmental area are also responsible for the induction of the negative emotional withdrawal state that characterizes opioid-related psychological dependence;[7][9] the associated mechanism(s) underlying the development of physical dependence are not currently understood.

Like many other forms of behavioral addiction and drug addiction, overuse of opiates leads to increased ΔFosB expression in the nucleus accumbens.[8][9][10] Opiates affect dopamine neurotransmission in the nucleus accumbens through their disinhibition of the GABA-based negative dopaminergic feedback system in the rostromedial tegmental nucleus.[11][12][13]


Furthermore, some studies suggest a permanent dysregulation of the endogenous opioid receptor system after chronic exposure to opioids. A recent study has shown that an increase in BDNF, brain-derived neurotrophic factor, in the ventral tegmental area (VTA) in rats can cause opiate-naive rats to begin displaying opiate-dependent behavior, including withdrawal and drug-seeking behavior.[14] It has been shown that when an opiate-naive person begins using opiates at levels inducing euphoria, this same increase in BDNF occurs.[15]

Opioid receptor pharmacogenomics[edit]

A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for a number of specific variations; however, the evidence for clinical differences in opioid effects is ambiguous. The pharmacogenomics of the opioid receptors and their endogenous ligands has been the subject of intensive activity in association studies. These studies test broadly for a number of phenotypes, including opioid dependence, cocaine dependence, alcohol dependence, methamphetamine dependence/psychosis, response to naltrexone treatment, personality traits, and others. Major and minor variants have been reported for every receptor and ligand coding gene in both coding sequences, as well as regulatory regions. Newer approaches shift away from analysis of specific genes and regions, and are based on an unbiased screen of genes across the entire genome, which have no apparent relationship to the phenotype in question. These GWAS studies yield a number of implicated genes, although many of them code for seemingly unrelated proteins in processes such as cell adhesion, transcriptional regulation, cell structure determination, and RNA, DNA, and protein handling/modifying.[16]

Currently there are no specific pharmacogenomic dosing recommendations for opioids due to a lack of clear evidence connecting genotype to drug effect, toxicity, or likelihood of dependence.

118A>G variant[edit]

While over 100 variants have been identified for the opioid mu-receptor, the most studied mu-receptor variant is the non-synonymous 118A>G variant, which results in functional changes to the receptor, including lower binding site availability, reduced mRNA levels, altered signal transduction, and increased affinity for beta-endorphin. In theory, all of these functional changes would reduce the impact of exogenous opioids, requiring a higher dose to achieve the same therapeutic effect. This points to a potential for a greater addictive capacity in these individuals who require dosages to achieve pain control. However, evidence linking the 118A>G variant to opioid dependence is mixed, with associations shown in a number of study groups, but negative results in other groups. One explanation for the mixed results is the possibility of other variants which are in linkage disequilibrium with the 118A>G variant and thus contribute to different haplotype patterns that more specifically associate with opioid dependence.[17]

Non-opioid receptor genes[edit]

The preproenkephalin gene, PENK, encodes for the endogenous opiates that modulate pain perception, and are implicated in reward and addiction. (CA) repeats in the 3' flanking sequence of the PENK gene was associated with greater likelihood of opiate dependence in repeated studies. Variability in the MCR2 gene, encoding melanocortin receptor type 2 has been associated with both protective effects and increased susceptibility to heroin addiction. The CYP2B6 gene of the cytochrome P450 family also mediates breakdown of opioids and thus may play a role in dependence and overdose.[18]


The WHO and DSM-IV-TR clinical guidelines for a definite diagnosis require that three or more of the following six characteristic features be experienced or exhibited:

  1. A strong desire or sense of compulsion to take the drug;
  2. Difficulties in controlling drug-taking behaviour in terms of its onset, termination, or levels of use;
  3. A physiological withdrawal state when drug use is stopped or reduced, as evidenced by: the characteristic withdrawal syndrome for the substance; or use of the same (or a closely related) substance with the intention of relieving or avoiding withdrawal symptoms;
  4. Evidence of tolerance, such that increased doses of the drug are required in order to achieve effects originally produced by lower doses;
  5. Progressive neglect of alternative pleasures or interests because of drug use, increased amount of time necessary to obtain or take the drug or to recover from its effects;
  6. Persisting with drug use despite clear evidence of overtly harmful consequences, such as harm to the liver, depressive mood states or impairment of cognitive functioning.

According to position papers on the treatment of opioid dependence published by the United Nations Office on Drugs and Crime and the World Health Organization, care providers should not mistake opioid dependence for a weakness of character or will.[19][20] Accordingly, detoxification alone does not constitute adequate treatment.




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

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

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

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


40 mg of Methadone
Main article: Methadone maintenance

Methadone maintenance treatment (MMT), a form of opioid replacement therapy, reduces and/or eliminates the use of illicit opiates, the criminality associated with opiate use, and allows patients to improve their health and social productivity.[25][26] In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV.[25] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. Methadone maintenance has been found to be medically safe and non-sedating.[25] It is also indicated for pregnant women addicted to opiates.[25] Methadone maintenance treatment is given to addicted individuals who feel unable to go the whole way and get clean. For those individuals who wish to completely move away from drugs, a methadone reduction program is indicated, where the individual is prescribed an amount of methadone which is titrated up until withdrawal symptoms subside, followed by a period of stability, the dose will then be gradually reduced until the individual is either free of the need for methadone or is at a level which allows a switch to a different opiate with an easier withdrawal profile, such as Suboxone.[27] Methadone toxicity has been shown to be associated with specific phenotypes of CYP2B6.[28]


Suboxone tablet

Studies have shown buprenorphine to be a safer alternative over methadone in opiate replacement therapy, primarily due to its lower instance of overdose related deaths during the course of treatment.[29] Buprenorphine sublingual preparations are often used in the management of 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.[30]


Naltrexone was approved by the FDA in 1984 for the treatment of opioid dependence. It is available both as an oral medication and as a monthly injectable (approved in 2010). Some authors question whether oral Naltrexone is as effective in the treatment of opioid dependence as methadone and buprenorphine mainly due to non-compliance.[31]


In Switzerland, Germany, the Netherlands, and the United Kingdom, longterm injecting drug users who do not benefit from methadone and other medication options are being treated with pure injectable diamorphine that is administered under the supervision of medical staff. For this group of patients, diamorphine treatment has proven superior in improving their social and health situation.[32] Studies show that even after years of homelessness and delinquency and despite severe comorbidities, about half of the patients find employment within the first year of treatment.[33]


LAAM was previously used to treat opioid dependence. In 2003 the drug's manufacturer discontinued production. There are no available generic versions. LAAM produced long-lasting effects, which allowed the person receiving treatment to visit a clinic only three times per week, as opposed to daily as with methadone.[34]

12-step support groups[edit]

Main article: Twelve-step program

While medical treatment may help with the initial symptoms of opioid withdrawal, once an opiate addict overcomes the first stages of withdrawal, a method for long-term preventative care is attendance at 12-step groups such as Alcoholics Anonymous or Narcotics Anonymous. Attendance and participation in a 12 step program is an effective way to obtain and maintain sobriety.[35] 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.[36][37]


Opioid use disorders resulted in 51,000 deaths in 2013 up from 18,000 deaths in 1990.[1] Deaths from all causes rose from 47.5 million in 1990 to 54·9 million in 2013.[1]

Among adults, the rate of inpatient hospital stays in the United States related to opioid overuse increased by an average of 5% annually from 1993–2012. The percentage of inpatient stays due to opioid overuse that were admitted from the emergency department increased from 43% in 1993 to 64% in 2005, but have remained relatively constant since.[38]


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

See also[edit]


  1. ^ a b c 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. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. 
  2. ^ Overdose Death Rates. By National Institute on Drug Abuse (NIDA).
  3. ^ "Opiate withdrawal". Medline Plus. Retrieved 1 November 2014. 
  4. ^ 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. doi:10.1016/j.drugalcdep.2011.03.003. PMC 3188332. PMID 21514751. 
  5. ^ Praveen, KT; Law, F; O'Shea, J; Melichar, J (2012). "Opioid dependence". American family physician 86 (6): 565–6. PMID 23062049. 
  6. ^ 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. doi:10.1111/j.1526-4637.2005.00072.x. PMID 16336480. 
  7. ^ a b Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci 15 (4): 431–443. PMC 3898681. PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement 
  8. ^ a b Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. 
  9. ^ a b c Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. 
  10. ^ 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. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. 
  11. ^ 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. doi:10.1016/j.tins.2012.06.007. PMID 22824232. In light of the crucial role of the tVTA in the opiate control of dopamine activity ...
    In the context of addiction, the tVTA is a target for psychostimulant-induced plasticity [1,6,23] and is also essential for morphine action on dopamine neurons [19]. This latter finding suggests that the classical disinhibition model may need to be revisited in light of the GABAergic control that the tVTA exerts on dopamine systems. ...
    The tVTA is rich in inhibitory GABA neurons expressing μ-opioid receptors and sends extensive projections toward midbrain dopamine cells. It is proposed as a major brake for dopamine systems.
  12. ^ Barrot M, Sesack SR, Georges F, Pistis M, Hong S, Jhou TC (October 2012). "Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions". J. Neurosci. 32 (41): 14094–14101. doi:10.1523/JNEUROSCI.3370-12.2012. PMC 3513755. PMID 23055478. The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons. ...
    Indeed, tVTA/RMTg cells express high levels of mu-opioid receptors (Jhou et al., 2009a, 2012; Jalabert et al., 2011), and in vivo, ex vivo and optogenetic electrophysiological approaches demonstrated that morphine excites dopamine neurons by targeting receptors localized to tVTA/RMTg cell bodies as well as its terminals within the VTA (Jalabert et al., 2011; Lecca et al., 2011; Matsui and Williams, 2011; Lecca et al., 2012).
  13. ^ "Morphine addiction – Homo sapiens (human)". KEGG. Kanehisa Laboratories. 18 June 2013. Retrieved 11 September 2014. 
  14. ^ 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. doi:10.1126/science.1168501. PMC 2913611. PMID 19478142. 
  15. ^ 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. doi:10.1046/j.1460-9568.2001.01458.x. PMID 11264674. 
  16. ^ 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. doi:10.1016/j.pharmthera.2013.07.006. 
  17. ^ 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. doi:10.1016/j.jpain.2012.10.016. PMC 3564046. PMID 23374939. 
  18. ^ 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. 
  19. ^ Substitution maintenance therapy in the management of opioid dependence and HIV/AIDS prevention. World Health Organization. 2004. ISBN 92-4-159115-3. 
  20. ^ http://whqlibdoc.who.int/unaids/2004/9241591153_eng.pdf
  21. ^ 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. 
  22. ^ – Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence – World Health Organization
  23. ^ 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. 
  24. ^ Amy Maxmen (June 2012), "Tackling the US pain epidemic". Nature News doi:10.1038/nature.2012.10766
  25. ^ a b c d 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. 
  26. ^ 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. doi:10.3310/hta11090. PMID 17313907. 
  27. ^ http-www.rcgp.org.uk-PDF-drug_meth%20guidance.pdf
  28. ^ 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. doi:10.1038/clpt.2010.127. PMID 20668445. 
  29. ^ Bell, J.R; Butler, B., Lawrence, A., Batey, R. & Salmelainen (2009). "Comparing overdose mortality associated with methadone and buprenorphine treatment". Drug and Alcohol Dependence 104 (1–2): 73–7. doi:10.1016/j.drugalcdep.2009.03.020. PMID 19443138. 
  30. ^ "Subutex and Suboxone Approved to Treat Opiate Dependence". FDA. 8 October 2002. Retrieved 1 November 2014. 
  31. ^ 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. doi:10.1002/14651858.CD001333.pub4. PMID 21491383. 
  32. ^ 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. doi:10.1192/bjp.bp.106.026112. PMID 17602126. 
  33. ^ http://relaunch.bundestag.de/bundestag/ausschuesse/a14/anhoerungen/113/stllg/ZIS.pdf[dead link]
  34. ^ James W. Kalat, Biological Psychology. Cengage Learning. Page 81.
  35. ^ 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. doi:10.1151/spp032143. PMC 2851040. PMID 18552722. 
  36. ^ Alexandre B. Laudet, Ph.D – PowerPoint PPT Presentation – 12-step attendance and involvement over 3 years on odds of sustained abstinence
  37. ^ Manning, V; Best D., Faulkner N., Titherington E., Morinan A., Keaney F., Gossop M., Strang J. (November 2012). "Does active referral by a doctor or 12-Step peer improve 12-Step meeting attendance? Results from a pilot randomised control trial". Drug Alcohol Depend; Research study (NCBI Pubmed.gov) 126 (1–2): 131–7. doi:10.1016/j.drugalcdep.2012.05.004. PMID 22677458. 
  38. ^ 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. 
  39. ^ Brewer, C; H Rezae, C Bailey (1988). "Opioid withdrawal and naltrexone induction in 48–72 hours with minimal drop-out, using a modification of the naltrexone-clonidine technique". The British Journal of Psychiatry 153 (3): 340–343. doi:10.1192/bjp.153.3.340. PMID 3250670. 
  40. ^ Ling, W; L Amass, S Shoptaw, JJ Annon, M Hillhouse, D Babcock, G Brigham, J Harrer, M Reid, J Muir, B Buchan, D Orr, G Woody, J Krejci, D Ziedonis (2005). "A multi-center randomized trial of buprenorphine–naloxone versus clonidine for opioid, detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network". Addiction 100 (8): 1090–1100. doi:10.1111/j.1360-0443.2005.01154.x. PMC 1480367. PMID 16042639. 
  41. ^ a b Herman, BH; F Vocci, P Bridge (1995). "The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal: Medication development issues for opiate addiction" (PDF). Neuropsychopharmacology 13 (4): 269–293. doi:10.1016/0893-133X(95)00140-9. PMID 8747752. 
  42. ^ Alper, Kenneth R.; Lotsof, Howard S.; Kaplan, Charles D. (January 2008). "The ibogaine medical subculture". Journal of Ethnopharmacology 115 (1): 9–24. doi:10.1016/j.jep.2007.08.034. PMID 18029124. 
  43. ^ Boyer, Edward W.; Kavita M. Babu, Jessica E. Adkins, Christopher R. McCurdy, John H. Halpern (28 June 2008). "Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth)". Addiction 103 (6): 1048–1050. doi:10.1111/j.1360-0443.2008.02209.x. PMC 3670991. PMID 18482427. 

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