Amorphinism

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Amorphinism
Morphine structure.svg
Morphine
Pronunciation
  • /ɐmˈɔːfɪnˌɪzəm/
Symptoms Tremors, insomnia, anxiety, gastrointestinal disturbances
TreatmentWithdrawal Management
Medication Buprenorphine, 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.

Contents

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 including 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 buprenorphine, opioid partial agonists like methadone, 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

Friedrich Wilhelm Adam Serturner Friedrich Wilhelm Adam Sertuerner.jpg
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

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

An illustration showing the mesocortical and mesolimbic pathway (in blue) Mesolimbic pathway.svg
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. [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

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

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

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

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

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

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

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

Buprenorphine and Methadone

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

A picture of clonidine patches and pills Clonidine pills and patch.jpg
A picture of clonidine patches and pills

Clonidine

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

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

  • 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)

  • 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]

Related Research Articles

<span class="mw-page-title-main">Methadone</span> Opioid medication

Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid use disorder. It is used to treat chronic pain, and it is also used to treat addiction to heroin or other opioids. Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.

<span class="mw-page-title-main">Hydromorphone</span> Opioid medication used for pain relief

Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is a morphinan opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours. A 2016 Cochrane review found little difference in benefit between hydromorphone and other opioids for cancer pain.

<span class="mw-page-title-main">Opioid</span> Psychoactive chemical

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.

<span class="mw-page-title-main">Opioid use disorder</span> Medical condition

Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of opioid use disorder.

<span class="mw-page-title-main">Buprenorphine</span> Opioid used to treat pain & opioid use disorder

Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, the patient must have moderate opioid withdrawal symptoms before buprenorphine can be administered under direct observation of a health-care provider.

<span class="mw-page-title-main">Naltrexone</span> Medication

Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found effective in the treatment of other addictions and may be used for them off-label. An opioid-dependent person should not receive naltrexone before detoxification. It is taken by mouth or by injection into a muscle. Effects begin within 30 minutes, though a decreased desire for opioids may take a few weeks to occur. Side effects may include trouble sleeping, anxiety, nausea, and headaches. In those still on opioids, opioid withdrawal may occur. Use is not recommended in people with liver failure. It is unclear if use is safe during pregnancy. Naltrexone is an opioid antagonist and works by blocking the effects of opioids, including both opioid drugs as well as opioids naturally produced in the brain.

Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has developed within the individual from psychoactive substance consumption that results in the experience of withdrawal and that necessitates the re-consumption of the drug. A drug addiction, a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences. An addictive drug is a drug which is both rewarding and reinforcing. ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions, but not dependence.

A methadone clinic is a medical facility where medications for opioid use disorder (MOUD) are dispensed-—historically and most commonly methadone, although buprenorphine is also increasingly prescribed. Medically assisted drug therapy treatment is indicated in patients who are opioid-dependent or have a history of opioid dependence. Methadone is a schedule II (USA) opioid analgesic, that is also prescribed for pain management. It is a long-acting opioid that can delay the opioid withdrawal symptoms that patients experience from taking short-acting opioids, like heroin, and allow time for withdrawal management. In the United States, by law, patients must receive methadone under the supervision of a physician, and dispensed through the Opioid Treatment Program (OTP) certified by the Substance Abuse and Mental Health Services Administration and registered with the Drug Enforcement Administration.

<span class="mw-page-title-main">Opioid antagonist</span> Receptor agonist that acts on one or more of the opioid receptors

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.

<span class="mw-page-title-main">Lefetamine</span> Chemical compound

Lefetamine (Santenol) is a drug which is a stimulant and also an analgesic with effects comparable to codeine.

<span class="mw-page-title-main">Lofexidine</span> Medication used for opioid withdrawal

Lofexidine, sold under the brand name Lucemyra among others, is a medication historically used to treat high blood pressure; today, it is more commonly used to help with the physical symptoms of opioid withdrawal. It is taken by mouth. It is an α2A adrenergic receptor agonist. It was approved for use by the Food and Drug Administration in the United States in 2018.

Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms – such as anxiety or anhedonia – upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent exposure to certain psychoactive substances or behaviors, which leads to an individual requiring further exposure to avoid withdrawal symptoms, as a result of negative reinforcement. Neuronal counter-adaptation is believed to play a role in generating withdrawal symptoms, which could be mediated through changes in neurotransmitter activity or altered receptor expression. Environmental enrichment and physical activity can attenuate withdrawal symptoms.

Drug detoxification is variously construed or interpreted as a type of "medical" intervention or technique in regards to a physical dependence mediated by a drug; as well as the process and experience of a withdrawal syndrome or any of the treatments for acute drug overdose (toxidrome). The first definition however, in relation to substance dependence and its treatment is arguably a misnomer and even directly contradictory since withdrawal is neither contingent upon nor alleviated through biological excretion or clearance of the drug. In fact, excretion of a given drug from the body is one of the very processes that leads to withdrawal since the syndrome arises largely due to the cessation itself and the drug being absent from the body; especially the blood plasma, not from ‘leftover toxins’ or traces of the drug still being in the system.

<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

Neonatal withdrawal or neonatal abstinence syndrome (NAS) or neonatal opioid withdrawal syndrome (NOWS) is a withdrawal syndrome of infants after birth caused by in utero exposure to drugs of dependence, most commonly opioids. Common signs and symptoms include tremors, irritability, vomiting, diarrhea, and fever. NAS is primarily diagnosed with a detailed medication history and scoring systems. First-line treatment should begin with non-medication interventions to support neonate growth, though medication interventions may be used in certain situations.

<span class="mw-page-title-main">Buprenorphine/naloxone</span> Opioid treatment

Buprenorphine/naloxone, sold under the brand name Suboxone among others, is a fixed-dose combination medication that includes buprenorphine and naloxone. It is used to treat opioid use disorder, and reduces the mortality of opioid use disorder by 50%. It relieves cravings to use and withdrawal symptoms. Buprenorphine/­naloxone is available for use in two different forms, under the tongue or in the cheek.

Clinical Opiate Withdrawal Scale (COWS) is a method used by registered practitioners to measure the severity of a patient's opioid withdrawal symptoms. This method consists of a series of 11 topics each comprising 4 - 5 common symptoms experienced by a patient undergoing opioid withdrawal. In each topic a rank is given depending on what the patient responds to. Generally, 0 is considered to be no symptom shown and 4 or 5 is considered to be the most common and severe symptom shown. These results are then added up and a final diagnosis is made based on the value obtained. This test is crucial as it allows the practitioner to assess the physiological and psychological behaviours of the patient as well as the severity of each symptom during the duration of the examination. The results are grouped into 3 categories of mild, moderately severe and severe. Mild consists of 5 to 12 points, moderately severe consists of 13 to 24 points and anything above 36 points is severe and requires direct medical attention.

<span class="mw-page-title-main">Opioid withdrawal</span> Withdrawal symptoms of opiates

Opioid withdrawal is a set of symptoms arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, nausea, vomiting, diarrhea, sweating, and an increased heart rate. Opioid use triggers a rapid adaptation in cellular signalling pathways that means, when rapidly withdrawn, there can be 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. Opioid withdrawal can be helped by the use of opioid replacement therapy, and symptoms may be relieved by the use of medications including lofexidine and clonidine.

Opioid agonist therapy (OAT) is a treatment in which prescribed opioid agonists are given to patients who live with Opioid use disorder (OUD). In the case of methadone maintenance treatment (MMT), methadone is used to treat dependence on heroin or other opioids, and is administered on an ongoing basis.

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