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Amorphinism
alt=Chemical Structure of Morphine IUPAC ID: (4R,4aR,7S,7aR,12bS)-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol
Morphine
Pronunciation
  • /ɐmˈɔːfɪnˌɪzəm/
SymptomsTremors, insomnia, anxiety, gastrointestinal disturbances
TreatmentWithdrawal Management
MedicationBuprenorphine, Methadone, Clonidine

Amorphinism refers to the mental and physical symptoms arising when a morphine-addict is deprived of morphine. Morphine is a potent opioid agonist derived from poppy plants and was originally used as a painkiller before being abused for euphoric and relieving purposes. It gave rise to morphine dependence, which caused the development of morphine withdrawal symptoms when morphine is reduced or stopped.

Two of many possible mechanisms that give rise to morphine addiction and withdrawal symptoms include changes to the dopaminergic pathway, which gives drug craving behaviours and withdrawal symptoms, and neuronal adaptations, which gives withdrawal symptoms as well.

Symptoms of morphine withdrawal may include tremors, insomnia, anxiety, gastrointestinal disorders and more. While no diagnostic tests are done specifically for morphine withdrawal, urine toxicology tests, electrocardiogram, complete blood count, basic metabolic panel, and blood alcohol level tests are conducted for differential diagnosis.

To treat morphine withdrawal, the severity of morphine dependence is measured, via scales, to determine the appropriate withdrawal management. Examples of scales used include the Short Opiate Withdrawal Scale (SOWS) and the Clinical Opiate Withdrawal Scale (COWS). Patients with mild severity of dependence are given medications for symptomatic relief, while more patients of more severe dependence are give opioid agonists like methadone, opioid partial agonists like buprenorphine, or alpha-2 adrenergic agonists like clonidine. Psychosocial therapy may also be conducted in addition to drug therapy, where interventions differ based on lower or greater severity of morphine dependence.

History of morphine

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Friedrich Wilhelm Adam Sertürner

Morphine, a morphian-framed alkaloid, is a potent opioid agonist (stimulates the opioid receptors) found naturally in poppy plants.[1][2] It was discovered in 1806 by German pharmacist Friedrich Wilhelm Sertürner when he isolated a pure alkaloid base from opium.[3] He then named it "morphinum", which we now call morphine, in 1817 in honour of the god of dreams.[3]

Cause of morphine dependence and withdrawal

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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.[4] Prolonged use of morphine leads to morphine dependence, and people with morphine dependence experience amorphinism when the amount of morphine is reduced or stopped completely.[4]

Pathophysiology

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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

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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.[5] Changes to the dopaminergic signalling gives rise to drug craving behavior.[5] Changes to the dopaminergic signalling leads to signs and symptoms of morphine withdrawal when amount of morphine is reduced or discontinued.[5] 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.[6][7][8] It can lead to morphine sensitization, or tolerance, such that more morphine is needed to achieve the same pharmacological effect.[6]

Neuron adaptation

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Addiction to morphine may also arise due to various adaptations of the neurons, including the desensitization of the μ-opioid receptor (MOR) (MOR has less response to stimuli), the impairment of the cell communication of MOR, the changes in brain systems that interact with neurons sensitive to μ-opioid, and the activation of supporting cells in the brain known as glial cells.[9][10]

In the sudden discontinuation or reduced dose of opioids like morphine, physiological responses occur in response to the decreased occupancy of the μ-opioid receptor (MOR), thus producing signs and symptoms of morphine withdrawal.[9]

Symptoms

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The withdrawal from various opioid medications, including morphine, causes similar effects, most of which is caused by stimulation and over-stimulation of the central nervous system.[11][4] The effects of morphine withdrawal can range from gastrointestinal disturbances to symptoms like tremors (involuntary shaking, most commonly in hands), opioid cravings, anxiety and insomnia.[12][13] While morphine withdrawal is not fatal, patients in withdrawal may experience anxiousness, fear and become difficult to manage.[14]

Short-term withdrawal symptoms

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The onset of withdrawal symptoms varies with the duration of action of the medication. For short-acting morphine (morphine with short duration of action), withdrawal symptoms begin 8 to 24 hours after the last dose and persist for 4 to 10 days. For long-acting morphine (morphine with long duration of action), withdrawal symptoms begin 12 to 48 hours after the last dose and persist for 10 to 20 days.[14]

Long-term withdrawal symptoms

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Withdrawal from opioids such as morphine also leads to a extended withdrawal phase.[14] It persists for up to half a year, and is categorised by a strong craving for opioids and a decline in well-being.[14]

Diagnosis

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There is no test to diagnose for morphine withdrawal.[4] 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.[4] In addition, heart tests such as an electrocardiography (ECG), or blood tests such as complete blood count (CBCs) are also conducted.[4]

Treatment

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The severity of a patient in withdrawal can be estimated based on scales such as the Short Opioid Withdrawal Scale and the Clinical Opiate Withdrawal Scale (COWS) . Patients with mild withdrawal are given medicine for symptomatic relief, while patients suffering from more severe withdrawal are given medications against opioids dependence.

Monitoring and management

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Monitoring of patients’ symptoms and complications from morphine withdrawal should be done 3 to 4 times a day.[14] Monitoring and subsequent management can be determined via the Short Opiate Withdrawal Scale or the Clinical Opioid Withdrawal Scale.[14][4]

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.[14] Patients with mild withdrawal are given medications based on symptoms experienced.[14] Patients with moderate withdrawal are given medications for symptomatic relief or medications against opioid dependence like opioid agonists (buprenorphine, methadone) and clonidine.[14] Patients with severe withdrawal are given medication against opioid dependence.[14][11] Apart from the methods above, patients may also choose to simply stop the opioid (“cold-turkey”).[11]

Opioid Agonists

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Buprenorphine and Methadone

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A 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.[16][14] It is a partial agonist to opioids, which means it can partially activate the opioid receptors, as it mimics the structure of thebaine, another drug in the opium family found in the opium poppy.[17] 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.[17][16] Naloxone, a drug that blocks the opioid receptors, may be added to the medication regimen to avoid misuse of Buprenorphine.[16] Under the Mainstreaming Addiction Treatment (MAT) Act, Buprenorphine is prescribed in events of Opioid misuse.[4]

Methadone is an opioid agonist also used to treat opioid dependence. Similar to Buprenorphine, methadone reduces cravings to opioids and symptoms of withdrawals.[18] It also has detoxifying effects against morphine.[18] However, as it is a full agonist and not a partial agonist like Buprenorphine, it has addictive properties. While it is addictive, it is an effective treatment to opioid dependency under medical supervision.[18] Methadone is also included in the WHO’s list of essential medicines.[18]

While Opioid agonists and partial agonists are safe and efficacious, they should be used carefully to minimize unwanted side effects.[16][19] For example, buprenorphine should be used in 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.[19][16]  Furthermore, the dose and frequency of dosage of both buprenorphine and methadone should be altered based on symptomatic control and degree of morphine use.[14][16][19]

Alpha-2 Adrenergic Agonists

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A picture of clonidine patches and pills

Clonidine

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Clonidine is an alpha-2 adrenergic agonist primarily used in the treatment of hypertension.[20] 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.[20][14] While it can alleviate symptoms mentioned above, it can also lead to drowsiness and low blood pressure.[14] 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.[14]

Psychosocial therapy

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In addition to drug therapy, psychosocial intervention is also used to reduce the relapse of morphine addiction.[14] Some interventions are given below based on the severity of morphine dependence.

For patients with lower severity of morphine dependence

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  • Education on Drugs: Allow the patient to understand how the drug affects the brain to learn to manage the craving.[21]
  • Refusing Drugs: Educate the patient to refuse drugs, as they may come across the opportunity again.[21]
  • Acceptance and relaxation training: Train the patient to understand how to cope with negative feelings to prevent them from resorting to drugs.[21][22][23]
  • Planning: Teach the patient to have a plan when leaving a closed setting to reduce the risk of relapse.[21]

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

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  • Finding motivations to reduce drug use: Guide the patient to find a reason for them to reduce or stop drug use.[21][24]
  • Cognitive Behavioural Therapy: Allow the patient to understand negative, unreasonable thoughts and guide them to replace them with realistic thoughts.[21][23][25][24]
  • Problem solving skills: Allow the patient to understand that drugs is not a solution to problems that arise.[21]
  • Craving management: Teach the patient how to manage cravings when they experience it.[21][22]

References

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  1. ^ Christrup LL (January 1997). "Morphine metabolites". Acta Anaesthesiologica Scandinavica. 41 (1 Pt 2): 116–122. doi:10.1111/j.1399-6576.1997.tb04625.x. PMID 9061094.
  2. ^ Davies MK, Hollman A (July 2002). "The opium poppy, morphine, and verapamil". Heart. 88 (1): 3. doi:10.1136/heart.88.1.3-a. PMC 1767178.
  3. ^ a b Blakemore PR, White JD (June 2002). "Morphine, the Proteus of organic molecules". Chemical Communications (11): 1159–1168. doi:10.1039/B111551K. PMID 12109065.
  4. ^ a b c d e f g h Shah M, Huecker MR (2024). "Opioid Withdrawal". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30252268. Retrieved 2024-03-11.
  5. ^ a b c Nickols JE, Dursun SM, Taylor AM (August 2023). "Preclinical evidence for the use of the atypical antipsychotic, brexpiprazole, for opioid use disorder". Neuropharmacology. 233: 109546. doi:10.1016/j.neuropharm.2023.109546. PMID 37068603.
  6. ^ a b Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, et al. (January 2004). "Neurobiological mechanisms in the transition from drug use to drug dependence". Neuroscience and Biobehavioral Reviews. 27 (8): 739–749. doi:10.1016/j.neubiorev.2003.11.007. PMID 15019424.
  7. ^ Blaess S, Stott SR, Ang SL (January 2020). "Chapter 17 - The generation of midbrain dopaminergic neurons". In Rubenstein J, Rakic P, Chen B, Kwan KY (eds.). Patterning and Cell Type Specification in the Developing CNS and PNS (Second ed.). Academic Press. pp. 369–398. doi:10.1016/b978-0-12-814405-3.00017-5. ISBN 978-0-12-814405-3.
  8. ^ Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ (April 2002). "Mechanism of action of methylphenidate: insights from PET imaging studies". Journal of Attention Disorders. 6 (1_suppl): S31–S43. doi:10.1177/070674370200601S05. PMID 12685517.
  9. ^ a b Volkow ND, Blanco C (January 2020). "Medications for opioid use disorders: clinical and pharmacological considerations". The Journal of Clinical Investigation. 130 (1): 10–13. doi:10.1172/JCI134708. PMC 6934219. PMID 31763992.
  10. ^ Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia AS, McNamara JO, et al. (2001). "Neuroglial Cells". Neuroscience (2nd ed.). Sinauer Associates. Retrieved 2024-04-07.
  11. ^ a b c "Opioid Toxicity and Withdrawal - Special Subjects". Merck Manuals Professional Edition. Retrieved 2024-03-10.
  12. ^ "Opioid withdrawal symptoms". Healthdirect Australia. Australian Government. 2023-10-12. Retrieved 2024-03-10.
  13. ^ "Tremor | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 2024-04-06.
  14. ^ a b c d e f g h i j k l m n o p "Withdrawal Management". Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization. 2009. Retrieved 2024-03-10.
  15. ^ a b "Opiate and opioid withdrawal: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2024-03-10.
  16. ^ a b c d e f "Buprenorphine". Substance Abuse and Mental Health Services Administration. Retrieved March 10, 2024.
  17. ^ a b Kumar R, Viswanath O, Saadabadi A (2024). "Buprenorphine". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 29083570. Retrieved 2024-03-10.
  18. ^ a b c d "Methadone maintenance treatment". Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization. 2009. Retrieved 2024-03-10.
  19. ^ a b c "Methadone". Substance Abuse and Mental Health Services Administration. Retrieved March 10, 2024.
  20. ^ a b Yasaei R, Saadabadi A (2024). "Clonidine". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 29083638. Retrieved 2024-03-10.
  21. ^ a b c d e f g h "Psychosocial interventions". Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. World Health Organization. 2009. Retrieved 2024-03-11.
  22. ^ a b Stotts AL, Green C, Masuda A, Grabowski J, Wilson K, Northrup TF, et al. (October 2012). "A stage I pilot study of acceptance and commitment therapy for methadone detoxification". Drug and Alcohol Dependence. 125 (3): 215–222. doi:10.1016/j.drugalcdep.2012.02.015. PMC 3386351. PMID 22425411.
  23. ^ a b Dugosh K, Abraham A, Seymour B, McLoyd K, Chalk M, Festinger D (March 2016). "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. doi:10.1097/ADM.0000000000000193. PMC 4795974. PMID 26808307.
  24. ^ a b Nyamathi AM, Nandy K, Greengold B, Marfisee M, Khalilifard F, Cohen A, et al. (January 2011). "Effectiveness of intervention on improvement of drug use among methadone maintained adults". Journal of Addictive Diseases. 30 (1): 6–16. doi:10.1080/10550887.2010.531669. PMC 3077081. PMID 21218306.
  25. ^ Kouimtsidis C, Reynolds M, Coulton S, Drummond C (June 23, 2011). "How does cognitive behaviour therapy work with opioid-dependent clients? Results of the UKCBTMM study". Drugs: Education, Prevention and Policy. 19 (3): 253–258. doi:10.3109/09687637.2011.579194. ISSN 0968-7637.
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