Opioid withdrawal

Short description: Withdrawal symptoms of opioids

Opioid withdrawal

Specialty| Toxicology, Addiction medicine, Psychiatry
Symptoms| Flu-like symptoms, depression, anxiety, nausea and vomiting, muscle aches, sweating, diarrhea, fever, restless legs, rapid heartbeat
Causes| Stopping or reducing intake of opioids in a state of dependence
Prevention| Gradual dose reduction
Medication| Symptomatic: Clonidine, lofexidine Preventative: Buprenorphine, methadone
Suboxone tablet (Buprenorphine/naloxone) delivers the opioid drug through a sublingual route, giving fast onset of effects.

Opioid withdrawal is a set of symptoms arising from the sudden cessation or reduction of opioids where previous usage has been heavy and prolonged.[1][2] Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs syndrome, nausea, vomiting, diarrhea, sweating, and an elevated heart rate. Opioid use triggers a rapid adaptation in cellular signaling pathways that, when reduced or stopped, can cause adverse physiological effects. All opioids, both recreational drugs and medications, when reduced or stopped, can lead to opioid withdrawal symptoms. When withdrawal symptoms are due to recreational opioid use, the term opioid use disorder is used, whereas when due to prescribed medications, the term prescription opioid use disorder is used.[3] Opioid withdrawal can be managed by the use of opioid replacement therapy, while symptoms may be relieved by the use of medications such as lofexidine and clonidine.[4]

## Contents

* 1 Signs and symptoms
* 1.1 Short-term withdrawal symptoms
* 1.2 Long-term withdrawal symptoms
* 2 Pathophysiology
* 3 Diagnosis
* 4 Treatment
* 4.1 Monitoring and management
* 4.2 Acute withdrawal
* 4.2.1 Alpha-2 adrenergic receptor agonists
* 4.2.2 GABA analogues
* 4.3 Withdrawal in opioid use disorder
* 4.3.1 Buprenorphine and Methadone
* 4.4 Psychosocial therapy
* 4.4.1 For patients with lower severity of opioid dependency
* 4.4.2 For patients with greater severity of dependence (in addition to the four interventions above)
* 4.5 Dangerous or ineffective treatments
* 5 Neonatal opioid withdrawal
* 6 Pathophysiology
* 6.1 Dopaminergic pathway
* 6.2 Neuron adaptation
* 7 See also
* 8 Further reading
* 9 References

## Signs and symptoms

Withdrawal from any opioid produces similar signs and symptoms. However, the severity and duration of withdrawal depend on the type and dose of opioid taken and the duration and frequency of use.[5]

The symptoms of opioid withdrawal may develop within minutes or up to several days following reduction or stopping.[1] Symptoms can include: extreme anxiety, nausea or vomiting, muscle aches, runny nose, sneezing, diarrhea, sweating, and fever.[1]

The withdrawal from various opioid medications, including morphine, causes similar effects, most of which is caused by stimulation and overstimulation of the central nervous system.[6][7] The effects of morphine withdrawal can range from gastrointestinal disturbances to symptoms like tremors (most commonly in hands), opioid cravings, anxiety, and insomnia.[8][9] While morphine withdrawal is not fatal, patients in withdrawal may experience mental symptoms that become difficult to manage.[10]

### Short-term withdrawal symptoms

The onset of withdrawal symptoms varies with the duration of action of the medication. For instant-release morphine (shorter duration of action), withdrawal symptoms begin 8 to 24 hours after the last dose and persist for 4 to 10 days. For extended-release morphine (longer duration of action), withdrawal symptoms begin 12 to 48 hours after the last dose and persist for 10 to 20 days.[10]

* Initial symptoms include: an agitated state, feeling anxious, muscle aches, increased tears, insomnia, runny nose, excessive sweating, and yawning.[11]
* Late symptoms include: abdominal cramps, diarrhea, pupil dilation, goosebumps, nausea, vomiting.[11]

### Long-term withdrawal symptoms

Withdrawal from opioids such as morphine also leads to an extended withdrawal phase.[10] It persists for up to half a year, and is categorised by a strong craving for opioids and a decline in well-being.[10]

## Pathophysiology

Repeated dosages of opioids can quickly lead to tolerance and physical dependence. This is due to the marked decrease in opioid receptor sensitivity caused by long-term receptor stimulation triggering receptor desensitisation (in this case receptor internalisation).[2] Tolerance causes a decrease in opioid sensitivity, impairing the efficacy of endogenous (our own body's) opioid molecules that function in multiple brain regions. Opioids partially signal through the decrease in cellular cAMP. Cells with decreased cAMP adapt to regulate cAMP and increase production. In the tolerant brain the sudden withdrawal of opioids coupled with the reduced sensitivity to inhibitory signals from the endogenous opioid systems can cause abnormally high levels of cAMP that may be responsible for withdrawal behaviours.[5] Similar changes may also be responsible for the peripheral gastrointestinal effects such as diarrhea, as there is a reversal of the effect on gastrointestinal motility.[12]

While morphine is primarily indicated as an analgesic (painkiller), morphine and other opioids are also abused due to the euphoric feeling and mental relaxation experienced when taken.[7] Prolonged use of morphine leads to morphine dependence, in which people experience withdrawal symptoms when the amount of morphine is reduced or stopped completely.[7]

Due to the difference in lipophilicity and mode of release between different opioids, the severity and duration of withdrawal symptoms may differ.

The followings are the general descriptions of duration of opioid withdrawal symptoms:[13]

* High intake for a long duration (> 6 months) is associated with a more severe level of withdrawal symptoms.
* Short-acting or instant-release opioids result in more rapid onset and shorter duration of withdrawal symptoms.
* Longer-acting opioids result in slower onset but longer duration of withdrawal symptoms.

## Diagnosis

The diagnosis of opioid withdrawal requires recent use or exposure to opioids and symptoms consistent with the disorder.[14] The severity of symptoms can be assessed by validated withdrawal scales, such as the Clinical Opiate Withdrawal Scale (COWS).[15]

There is no test to diagnose for morphine withdrawal.[7] However, a toxicology test using urine is conducted to determine if withdrawal symptoms are caused by other non-opioid drugs or a combination of both.[7] In addition, heart tests such as an electrocardiography (ECG), or blood tests such as complete blood count (CBCs) are also conducted.[7]

## Treatment

Treatment for opioid withdrawal is based on underlying diagnostic features. A person with an acute opioid withdrawal but no underlying opioid use disorder can be managed by slowly reducing opioids and treatments aimed at the symptoms.[2]

### Monitoring and management

Monitoring of patients' symptoms and complications from morphine withdrawal should be done 3 to 4 times a day.[10] Monitoring and subsequent management can be determined via the Short Opiate Withdrawal Scale or the Clinical Opioid Withdrawal Scale.[10][7]

The scores obtained from the scales vary based on the current symptoms a person with morphine withdrawal is suffering from, where different severities of withdrawal are identified based on these scores along with the respective treatment strategies. For the Short Opiate Withdrawal Scale, a score of 0–10 indicates mild withdrawal, while 10–20 indicates moderate withdrawal, and 20–30 indicates severe withdrawal.[10] Patients with mild withdrawal are given medications based on symptoms experienced.[10] Patients with moderate withdrawal are given medications for symptomatic relief or medications against opioid dependence like opioid agonists (buprenorphine, methadone) and clonidine.[10] Patients with severe withdrawal are given medication against opioid dependence.[10][6] Apart from the methods above, patients may also choose to simply stop the opioid "cold turkey".[6]

### Acute withdrawal

#### Alpha-2 adrenergic receptor agonists

A picture of clonidine patches and pills

A major feature of opioid withdrawal is exacerbated norepinephrine (noradrenaline) release in the locus coeruleus. Alpha-2 adrenergic receptor agonists can be used to manage the symptoms of acute withdrawal. Lofexidine and clonidine are used for this purpose; both are considered to be equally effective, though clonidine has more side effects than lofexidine.[16]

Clonidine is an alpha-2 adrenergic agonist primarily used in the treatment of hypertension.[17] Additionally, it has several off-label uses (use of a drug for purpose different than what it is approved for), one being the management of symptoms due to opioid withdrawal.[17][10] While it can alleviate symptoms mentioned above, it can also lead to drowsiness and low blood pressure.[10] Clonidine is only prescribed if the patient has a measured heart rate greater than 50bpm or a blood pressure greater than 90/50mmHg, and does not show a drop in blood pressure after initial administration of clonidine.[10]

#### GABA analogues

While some studies indicate that gabapentin does not significantly reduce the symptoms of opioid withdrawal, there is increasing evidence that gabapentinoids are effective in controlling some of the symptoms during opioid detoxification. Pregabalin, another GABA analogue, was more effective than clonidine in reducing opioid withdrawal symptoms.[18]

### Withdrawal in opioid use disorder

The treatment of withdrawal in people with opioid use disorder also relies on symptomatic management and tapering with medications that replace typical opioids, including buprenorphine and methadone. The principle of managing the syndrome is to allow the concentration of drugs in blood to fall to near zero and reverse physiological adaptation. This allows the body to adapt to the absence of drugs to reduce the withdrawal symptoms. The most commonly used strategy is to offer opioid drug users long-acting opioid drugs and slowly taper the dose of the drug. Methadone, buprenorphine/naloxone, and naltrexone are all commonly used medications for opioid use disorder.[19]

A review of UK hospital policies found that local guidelines delayed access to substitute opioids. For instance, requiring lab tests to demonstrate recent use or input from specialist drug teams before prescribing. A lack of access to these substitutes may increase the risk of people discharging themselves early against medical advice.[20][21]

Buprenorphine patches can deliver the opioid drug via a transdermal route, with long-lasting effects.

#### Buprenorphine and Methadone

File:Buprenorphine naloxone Tablets Bottle.jpgA bottle of tablets containing Buprenorphine and Naloxone, used to treat symptoms arising from morphine withdrawal

Buprenorphine is an FDA-approved medication that can be prescribed in clinics to treat opioid dependence.[22][10] It is a partial agonist to opioid receptors.[23] It is used as a low-potency substitute (comparatively weak) to treat dependency to more-potent opioids such as morphine and heroin, and functions by alleviating withdrawal symptoms and cravings to opioids.[23][22] Naloxone, a drug that blocks the opioid receptors, may be added to the medication regimen to avoid misuse of buprenorphine.[22] Under the Mainstreaming Addiction Treatment (MAT) Act, buprenorphine is prescribed in events of opioid misuse.[7]

Methadone is an opioid agonist also used to treat opioid dependence. Similar to buprenorphine, methadone reduces cravings to opioids and symptoms of withdrawals.[24] It also has detoxifying effects against morphine.[24] However, as it is a full agonist and not a partial agonist like buprenorphine, it has more addictive properties. It is considered an effective treatment to opioid dependency when used under medical supervision.[24] Methadone is also included in the WHO's list of essential medicines.[24]

Buprenorphine should be used with caution if the patient has diabetes, respiratory problems, or urethral obstruction, while methadone should be used in caution if the patient has problems such as respiratory problems and severe hepatic impairment.[25][22] Furthermore, the dose and frequency of dosage of both buprenorphine and methadone should be altered based on symptomatic control and degree of opioid use.[10][22][25]

### Psychosocial therapy

In addition to drug therapy, psychosocial intervention is also used to reduce the relapse of morphine addiction.[10] Some interventions are given below based on the severity of morphine dependence.

#### For patients with lower severity of opioid dependency

* Education on Drugs: Allow the patient to understand how the drug affects the brain to learn to manage the craving.[26]
* Refusing Drugs: Educate the patient to refuse drugs, as they may come across the opportunity again.[26]
* Acceptance and relaxation training: Train the patient to understand how to cope with negative feelings to prevent them from resorting to drugs.[26][27][28]
* Planning: Teach the patient to have a plan when leaving a closed setting to reduce the risk of relapse.[26]
* Contingency Management: using positive reinforcement to encourage drug-free behaviors.[29]

#### For patients with greater severity of dependence (in addition to the four interventions above)

* Finding motivations to reduce drug use: Guide the patient to find a reason for them to reduce or stop drug use.[26][30]
* Cognitive behavioral therapy: Allow the patient to understand negative, unreasonable thoughts and guide them to replace them with realistic thoughts.[26][28][31][30]
* Problem solving skills: Allow the patient to understand that drugs are not a solution to problems that arise.[26]
* Craving management: Teach the patient how to manage cravings when they experience it.[26][27]

### Dangerous or ineffective treatments

The expense of opioid replacement treatments in some countries has led some people to try treatments with limited evidence. At high doses, loperamide has been reported by some drug users to alleviate opioid withdrawal syndrome.[32] The doses reported in the literature are associated with a high risk of damage to the heart.[33]

## Neonatal opioid withdrawal

Many thousands of newborns each year are affected by being exposed to opioids during their prenatal development.[34] Maternal use of opioids has become prolific. The use of opioids during pregnancy creates a dependency in the newborn who experiences withdrawal symptoms shown in clinical signs of opioid withdrawal. These signs are grouped as the neonatal opioid withdrawal syndrome, also known more broadly as neonatal abstinence syndrome.[34] The central nervous system (CNS), and the autonomic nervous system (ANS) are affected. Common signs associated with the CNS are high-pitched crying, reduced sleep, tremors, seizures, gastrointestinal dysfunction, and vomiting. Common ANS-associated signs include sweating, hyperthermia, yawning, sneezing, faster breathing rate, and nasal congestion.[34]

## Pathophysiology

An illustration showing the mesocortical and mesolimbic pathway (in blue)

The dopaminergic pathway and neuron adaptations are two possible mechanisms that lead to the development of morphine dependence and withdrawal symptoms.

### Dopaminergic pathway

Addiction to opioids such as morphine occur due to the changes in the dopaminergic signalling of the mesocorticolimbic system as a result of chronic opioid use.[35] Changes to the dopaminergic signalling gives rise to drug craving behavior.[35] Changes to the dopaminergic signalling leads to signs and symptoms of morphine withdrawal when amount of morphine is reduced or discontinued.[35] The impairment of the dopaminergic signalling also leads to a decrease in dopamine (a neurotransmitter used to transmit signals across nerve cells in the central nervous system) in the mesocorticolimbic system, otherwise known as the reward system, which is suggested to have a critical role in morphine withdrawal.[36][37][38] It can lead to morphine sensitization, or tolerance, such that more morphine is needed to achieve the same pharmacological effect.[36]

### Neuron adaptation

Addiction to morphine may also arise due to various adaptations of the neurons, including the desensitization of the μ-opioid receptor (MOR), the impairment of the cell communication of MOR, the changes in brain systems that interact with neurons sensitive to μ-opioid receptors, and the activation of supporting cells in the brain known as glial cells.[39][40]

In the sudden discontinuation or reduced dose of opioids, physiological responses occur in response to the decreased occupancy of the μ-opioid receptor, thus producing signs and symptoms of morphine withdrawal.[39]

## See also

* Opioid-induced hyperalgesia

## Further reading

* Kosten, T. R., & Baxter, L. E. (2019). Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment. American Journal on Addictions, 28(2), 55–62. doi:10.1111/ajad.12862

## References

1. ↑ 1.0 1.1 1.2 Diagnostic and statistical manual of mental disorders: DSM-5. (5th ed.). American Psychiatric Association. 2013. pp. 547–549. ISBN 978-0-89042-554-1.
2. ↑ 2.0 2.1 2.2 Volkow, Nora D.; Blanco, Carlos (2020-01-02). "Medications for opioid use disorders: clinical and pharmacological considerations" (in en). The Journal of Clinical Investigation 130 (1): 10–13. doi:10.1172/JCI134708. ISSN 0021-9738. PMID 31763992.
3. ↑ Blandthorn, J; Leung, L; Loke, Y (October 2018). "Prescription opioid use in pregnancy.". The Australian & New Zealand Journal of Obstetrics & Gynaecology 58 (5): 494–498. doi:10.1111/ajo.12823. PMID 29744859.
4. ↑ Rehman, Saif Ur; Maqsood, Muhammad Haisum; Bajwa, Hamza; Tameez Ud Din, Asim; Malik, Mustafa N (2019). "Clinical Efficacy and Safety Profile of Lofexidine Hydrochloride in Treating Opioid Withdrawal Symptoms: A Review of Literature". Cureus 11 (6). doi:10.7759/cureus.4827. ISSN 2168-8184. PMID 31403015.
5. ↑ 5.0 5.1 Christie, M J (May 2008). "Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction". British Journal of Pharmacology 154 (2): 384–396. doi:10.1038/bjp.2008.100. ISSN 0007-1188. PMID 18414400.
6. ↑ 6.0 6.1 6.2 "Opioid Toxicity and Withdrawal - Special Subjects" (in en-US). https://www.merckmanuals.com/professional/special-subjects/illicit-drugs-and-intoxicants/opioid-toxicity-and-withdrawal.
7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "Opioid Withdrawal". StatPearls. Treasure Island (FL): StatPearls Publishing. 2024. https://www.ncbi.nlm.nih.gov/books/NBK526012/. Retrieved 2024-03-11.
8. ↑ "Opioid withdrawal symptoms" (in en-AU). Healthdirect Australia. Australian Government. 2023-10-12. https://www.healthdirect.gov.au/opioid-withdrawal-symptoms?t=.
9. ↑ "Tremor | National Institute of Neurological Disorders and Stroke" (in en). https://www.ninds.nih.gov/health-information/disorders/tremor.
10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 "Withdrawal Management" (in en). Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization. 2009. https://www.ncbi.nlm.nih.gov/books/NBK310652/. Retrieved 2024-03-10.
11. ↑ 11.0 11.1 "Opiate and opioid withdrawal: MedlinePlus Medical Encyclopedia" (in en). https://medlineplus.gov/ency/article/000949.htm.
12. ↑ Thomas, Jay (2008-01-01). "Opioid-Induced Bowel Dysfunction" (in en). Journal of Pain and Symptom Management 35 (1): 103–113. doi:10.1016/j.jpainsymman.2007.01.017. ISSN 0885-3924. PMID 17981003.
13. ↑ "Opioid withdrawal management: SA Health". https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/clinical+resources/clinical+topics/substance+misuse+and+dependence/substance+withdrawal+management/opioid+withdrawal+management.
14. ↑ Kosten, Thomas R.; Baxter, Louis E. (2019). "Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment" (in en). The American Journal on Addictions 28 (2): 55–62. doi:10.1111/ajad.12862. ISSN 1521-0391. PMID 30701615.
15. ↑ "Clinical Opiate Withdrawal Scale". https://www.drugabuse.gov/sites/default/files/files/ClinicalOpiateWithdrawalScale.pdf.
16. ↑ Gowing, Linda; Farrell, Michael; Ali, Robert; White, Jason M (2016-05-03). "Alpha 2 -adrenergic agonists for the management of opioid withdrawal". Cochrane Database of Systematic Reviews 2016 (5). doi:10.1002/14651858.cd002024.pub5. ISSN 1465-1858. PMID 27140827.
17. ↑ 17.0 17.1 "Clonidine". StatPearls. Treasure Island (FL): StatPearls Publishing. 2024. https://www.ncbi.nlm.nih.gov/books/NBK459124/. Retrieved 2024-03-10.
18. ↑ Pregabalin for Opiate Withdrawal Syndrome ClinicalTrials.gov ID NCT03017430. 2020-04-07
19. ↑ Koehl, Jennifer L; Zimmerman, David E; Bridgeman, Patrick J (2019-07-18). "Medications for management of opioid use disorder" (in en). American Journal of Health-System Pharmacy 76 (15): 1097–1103. doi:10.1093/ajhp/zxz105. ISSN 1079-2082. PMID 31361869. https://academic.oup.com/ajhp/article/76/15/1097/5532635.
20. ↑ "Many hospital policies create barriers to good management of opioid withdrawal". NIHR Evidence (National Institute for Health and Care Research). 16 November 2022. doi:10.3310/nihrevidence_54639. https://evidence.nihr.ac.uk/alert/many-hospital-policies-create-barriers-to-good-management-of-opioid-withdrawal/.
21. ↑ Harris, Magdalena; Holland, Adam; Lewer, Dan; Brown, Michael; Eastwood, Niamh; Sutton, Gary; Sansom, Ben; Cruickshank, Gabby et al. (2022-04-14). "Barriers to management of opioid withdrawal in hospitals in England: a document analysis of hospital policies on the management of substance dependence". BMC Medicine 20 (1): 151. doi:10.1186/s12916-022-02351-y. ISSN 1741-7015. PMID 35418095.
22. ↑ 22.0 22.1 22.2 22.3 22.4 "Buprenorphine". https://www.samhsa.gov/medications-substance-use-disorders/medications-counseling-related-conditions/buprenorphine.
23. ↑ 23.0 23.1 "Buprenorphine". StatPearls. Treasure Island (FL): StatPearls Publishing. 2024. https://www.ncbi.nlm.nih.gov/books/NBK459126/. Retrieved 2024-03-10.
24. ↑ 24.0 24.1 24.2 24.3 "Methadone maintenance treatment" (in en). Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization. 2009. https://www.ncbi.nlm.nih.gov/books/NBK310658/. Retrieved 2024-03-10.
25. ↑ 25.0 25.1 "Methadone". https://www.samhsa.gov/medications-substance-use-disorders/medications-counseling-related-conditions/methadone.
26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 26.6 26.7 "Psychosocial interventions" (in en). Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization. 2009. https://www.ncbi.nlm.nih.gov/books/NBK310657/. Retrieved 2024-03-11.
27. ↑ 27.0 27.1 "A stage I pilot study of acceptance and commitment therapy for methadone detoxification". Drug and Alcohol Dependence 125 (3): 215–222. October 2012. doi:10.1016/j.drugalcdep.2012.02.015. PMID 22425411.
28. ↑ 28.0 28.1 "A Systematic Review on the Use of Psychosocial Interventions in Conjunction With Medications for the Treatment of Opioid Addiction". Journal of Addiction Medicine 10 (2): 93–103. March 2016. doi:10.1097/ADM.0000000000000193. PMID 26808307.
29. ↑ Petry, Nancy M.; Carroll, Kathleen M. (December 2013). "Contingency management is efficacious in opioid-dependent outpatients not maintained on agonist pharmacotherapy." (in en). Psychology of Addictive Behaviors 27 (4): 1036–1043. doi:10.1037/a0032175. ISSN 1939-1501. PMID 23528194.
30. ↑ 30.0 30.1 "Effectiveness of intervention on improvement of drug use among methadone maintained adults". Journal of Addictive Diseases 30 (1): 6–16. January 2011. doi:10.1080/10550887.2010.531669. PMID 21218306.
31. ↑ "How does cognitive behaviour therapy work with opioid-dependent clients? Results of the UKCBTMM study" (in en). Drugs: Education, Prevention and Policy 19 (3): 253–258. June 23, 2011. doi:10.3109/09687637.2011.579194. ISSN 0968-7637.
32. ↑ Daniulaityte, Raminta; Carlson, Robert; Falck, Russel; Cameron, Delroy; Perera, Sujan; Chen, Lu; Sheth, Amit (2013-06-01). ""I Just Wanted to Tell You That Loperamide WILL WORK": A Web-Based Study of Extra-Medical Use of Loperamide". Drug and Alcohol Dependence 130 (1–3): 241–244. doi:10.1016/j.drugalcdep.2012.11.003. ISSN 0376-8716. PMID 23201175.
33. ↑ Borron, Stephen W.; Watts, Susan H.; Tull, Jonathan; Baeza, Salvador; Diebold, Stephanie; Barrow, Alison (July 2017). "Intentional Misuse and Abuse of Loperamide: A New Look at a Drug with "Low Abuse Potential"". The Journal of Emergency Medicine 53 (1): 73–84. doi:10.1016/j.jemermed.2017.03.018. ISSN 0736-4679. PMID 28501383.
34. ↑ 34.0 34.1 34.2 Piccotti, L; Voigtman, B; Vongsa, R; Nellhaus, EM; Rodriguez, KJ; Davies, TH; Quirk, S (1 May 2019). "Neonatal Opioid Withdrawal Syndrome: A Developmental Care Approach.". Neonatal Network 38 (3): 160–169. doi:10.1891/0730-0832.38.3.160. PMID 31470383.
35. ↑ 35.0 35.1 35.2 "Preclinical evidence for the use of the atypical antipsychotic, brexpiprazole, for opioid use disorder". Neuropharmacology 233. August 2023. doi:10.1016/j.neuropharm.2023.109546. PMID 37068603.
36. ↑ 36.0 36.1 "Neurobiological mechanisms in the transition from drug use to drug dependence". Neuroscience and Biobehavioral Reviews 27 (8): 739–749. January 2004. doi:10.1016/j.neubiorev.2003.11.007. PMID 15019424.
37. ↑ "Chapter 17 - The generation of midbrain dopaminergic neurons". Patterning and Cell Type Specification in the Developing CNS and PNS (Second ed.). Academic Press. January 2020. pp. 369–398. doi:10.1016/b978-0-12-814405-3.00017-5. ISBN 978-0-12-814405-3.
38. ↑ "Mechanism of action of methylphenidate: insights from PET imaging studies". Journal of Attention Disorders 6 (1_suppl): S31–S43. April 2002. doi:10.1177/070674370200601S05. PMID 12685517.
39. ↑ 39.0 39.1 "Medications for opioid use disorders: clinical and pharmacological considerations". The Journal of Clinical Investigation 130 (1): 10–13. January 2020. doi:10.1172/JCI134708. PMID 31763992.
40. ↑ "Neuroglial Cells" (in en). Neuroscience (2nd ed.). Sinauer Associates. 2001. https://www.ncbi.nlm.nih.gov/books/NBK10869/. Retrieved 2024-04-07.

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Original source: https://en.wikipedia.org/wiki/Opioid withdrawal. Read more

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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase