ABSTRACT
For millennia, opioids have been regarded as among the most effective drugs for the treatment of pain. Most of the world considers their use in the management of acute severe pain and chronic pain related to advanced medical illness to be the standard of care. Long-term opioid administration for the treatment of chronic pain has remained remains controversial. Opioids are classified into three types based on their mode of synthesis: alkaloids, semi-synthetic compounds, and synthetic compounds. There are three types of classical receptors (DOP, KOP, and MOP). Opioid receptors are found in the nervous system, where they are embedded in the outer membrane of nerve cells (neurons).The novel NOP receptor is thought to belong to the opioid receptor family's non-opioid branch. Opioids can bind to these receptors as agonists, antagonists, or partial agonists. Opioid agonists cause cellular hyperpolarisation by binding to G-protein coupled receptors. This narrative review briefly describes the various classes of opioids, their mechanism in the human body, and the health consequences of opioid addiction.
1. Introduction
Opioids are a class of chemicals found naturally in the opium poppy plant that work in the brain to cause a variety of effects, including pain management in many cases. Opioids can be prescribed medications, such as pain relievers, or they can be illegal narcotics, such as heroin. Opioids, in addition to relieving pain, can make some individuals feel calm, cheerful, or "high," and they can be addictive. Many prescription opioids are used to treat moderate-to-severe pain by blocking pain communication between the brain and the body. On the other hand, long-term opioid administration for the management of chronic non-cancer pain remains a controversial issue.
Concerns about efficiency, safety, and abuse liability have evolved over the years, sometimes promoting a more restrictive perspective but also sometimes leading to a greater willingness to recommend this treatment. The interaction between the legitimate medical use of opioids to induce painkillers and the phenomena associated with abuse and addiction continues to bewilder the clinical community, leading to confusion about these medications' entirely appropriate role in the treatment of pain. Opioids, in addition to relieving pain, can make some individuals feel calm, cheerful, or "high," and they can be addictive.
2. Classification of Opioids
Opioids are defined by binding to and influencing opiate receptors on cell membranes. They can be divided into 3 classes:
2.1 Naturally occurring opioids
The chief active component of opium is morphine, which is derived from the plant Papaver somniferum (opium poppy). Morphine, nicotine, codeine, thebaine, papaverine, and narceine are the six opium alkaloids (plant-derived amines) that occur naturally. Morphine, codeine (a morphine prodrug), and papaverine are three alkaloids that have found use in therapeutic practice: morphine and codeine as painkillers, and papaverine, a molecule with no painkilling abilities, but as a smooth muscle relaxant. [1]
2.2 Semi-synthetic opioids
Semi-synthesis is a method of chemical synthesis in which the starting components are chemicals isolated from natural sources (for example, plants). Simple chemical modifications of morphine, the active component of the opium poppy, resulted in a variety of semi-synthetic opioids such as heroin (also known as diacetylmorphine), diamorphine, and dihydrocodeine. Buprenorphine and oxycodone (derived from thebaine); hydrocodone (derived from codeine); oxymorphone, and hydromorphone among examples of semi-synthetic opioids. [1]
2.3 Synthetic opioids
Synthetic opioids are made using total synthesis, in which large molecules are synthesized from a stepwise combination of small and inexpensive (petrochemical) building blocks. These synthetic compounds can be divided into four chemical groupings, morphine derivatives (levorphanol, butorphanol), diphenylheptane derivatives (methadone, propoxyphene), and benzomorphan derivatives (pentazocine, phenazocine), and phenylpiperidine derivatives (pethidine, alfentanil, fentanyl, sufentanil, and remifentanil).
Opioids can also be divided into groups based on how they interact with opioid receptors. Opioids can be classified as agonists, partial agonists, or antagonists in this method. Agonists interact with a receptor in order to enhance the receptor's response (analgesia following morphine administration is an example). Antagonists, on the other hand, bind to receptors but do not produce a functional response while also preventing an agonist from binding to that receptor (for example naloxone). Regardless of how much medication is given, partial agonists bind to receptors but only generate a partial functional response (for example buprenorphine). [1]
Chemical structure of Morphine
3. Mechanism of Opioid Action
Opioids are the most commonly prescribed painkillers. Opioid receptors are proteins that bind to opioids. Opioid receptors are found in primary afferent neurons, the spinal cord, the midbrain, and the thalamus, among other areas of the nervous system involved in pain transmission and control. By interacting with µ, δ, or κ opioid receptors, opioids mimic the actions of endogenous opioid peptides. These receptors are linked to G1
proteins, and opioids bonding with them have largely inhibitory effects. They open calcium-dependent inwardly-rectifying potassium channels while closing N-type voltage-operated calcium channels. This results in hyperpolarization and a reduction in neuronal excitability. When this happens, opioids block pain signals sent from the body to the brain via the spinal cord. [2]
Opioid drugs produce analgesia by inhibiting neurotransmitter release from primary afferent terminals in the spinal cord and activating descending inhibitory controls in the midbrain.
Mechanism of opioids functioning
The following is the mechanism of opioids functioning:
3.1 Opioid inhibition of neurotransmitter release
Depolarization of the nerve terminal and Ca++ entry through voltage-sensitive Ca++ channels normally precede neurotransmitter release from neurons. Drugs can inhibit neurotransmitter release either directly by reducing Ca++ entry or indirectly by increasing the outward K+current, which reduces repolarisation time and action potential duration. Because opioid receptors are directly coupled to K+channels and voltage-sensitive Ca++ channels via G-proteins, they produce both of these effects. Opioids also interact with other intracellular effector mechanisms, the most important of which is the adenylate cyclase system, in which they inhibit adenylate cyclase (AC), an enzyme that converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (CAMP) (cAMP).
3.2 Decreased Ca++ entry
Voltage-sensitive channels are only activated when the neuron is depolarized. The L-type (large conductance) sensitive to calcium channel blockers, the T-type (small conductance), and the N-type (no conductance) are the three types of voltage-sensitive Ca++channels known (intermediate conductance). Opioids interrupt neurotransmitter release by blocking N-type Ca++ channels.
3.3 Increased outward movement of K+
K+channels come in a variety of shapes and sizes, with some being voltage-sensitive and others being sensitive to intracellular substances. Opioids increase the outward movement of K+from neurons by opening voltage sensitive K+ channels. This effect can be found in various parts of the brain, as well as the spinal cord and the myenteric plexus. The most likely mechanism for opioid-induced postsynaptic hyperpolarisation and inhibition of neurons throughout the nervous system is increased K+outward movement. However, it has yet to be proven that this mechanism is also involved in opioids presynaptic action to inhibit neurotransmitter release. [3]
Coupled opioid interceptor
4. Opioid Addiction
4.1 Opioid Addiction
Opioid use is not without risks. Regular use of these prescribed medications can lead to an increase in tolerance and dependence, necessitating higher and more frequent doses. Long-term use can, in some cases, lead to addiction.
Side effects of opioids include:
• Tiredness
• Constipation
• Nausea
Opioids can also have more serious side effects, some of which can be fatal. The following symptoms may indicate an opioid overdose and should be reported to a doctor right away:
• Shortness of breath
• Slowed heart rate
• Loss of consciousness
Furthermore, if you stop taking opioids abruptly, you may experience symptoms such as jittery nerves or insomnia. Addiction is another possibility. Opioids can convince the brain and body that the drug is essential for survival. As your body adapts to the prescribed dose, you may require more medication to relieve your pain, and the feelings of pleasure that result from taking an opioid may make you want to continue experiencing those feelings, which may lead to addiction. [4]
4.2 Medicines Used to Treat Opioid Addiction
a) Methadone: When used correctly, it can be combined with counselling to form part of a treatment plan. It aids in the relief of withdrawal symptoms and the reduction of cravings.
b) Buprenorphine also mitigates opioid cravings without producing the same high as other opioids. Placed under the tongue, it can also be administered as a once-month injection or through thin tubes inserted under the skin and that can last six months.
c) Naltrexone is a unique medication that does not activate the opioid receptor but instead blocks the euphoric/sedative effects of opioids. Before starting naltrexone, a patient's system must be completely free of all opioids. It can be taken orally or as an injection once a month.
d) Naloxone Naloxone can be used in an emergency when a respiratory arrest has occurred or is imminent as a result of an opioid overdose. Naloxone flushes out receptors and can reverse an overdose, but it is not addiction treatment. [5]
5. Conclusion
Opioids can be either legally prescribed pain relievers or illegal narcotics like heroin. They can make some people feel calm, happy, or "high," and they can be addictive. By interacting with µ, δ, or κ opioid receptors, opioids mimic the actions of endogenous opioid peptides. Drugs can either directly inhibit neurotransmitter release or indirectly by increasing the outward K+current. Opioids increase the outward movement of K+ from neurons by opening voltage-sensitive K+ channels. This effect can be found in various parts of the brain as well as the spinal cord.
Opioids are of great pharmaceutical importance, but overdose can cause a health risk. Opioid use should always be regulated, and while using these analgesics, we should always check for their side effects. Substance abuse isn't something you should take lightly. It occurs when you use alcohol, prescription medicine, and other legal and illegal substances too much or in the wrong way. With substance abuse, when patients are ready to deal with their issues, they need an open door and help immediately. A person with an addictive disorder should want to participate in treatment. Navigating that change can be challenging for friends and family members.
6. References
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589929/
[2] https://pubmed.ncbi.nlm.nih.gov/9202932/
[3] https://www.nps.org.au/australian-prescriber/articles/opioids-mechanisms-of-action
[4] https://www.asahq.org/madeforthismoment/pain-management/opioid-treatment/opioid-abuse/
[5] https://www.hopkinsmedicine.org/opioids/treating-opioid-addiction.html