Opioid analgesics are a class of drugs commonly used to relieve moderate to severe pain. They exert their effects by binding to opioid receptors in the central nervous system (CNS) and the gastrointestinal (GI) tract. Opioid antagonists, on the other hand, block the effects of opioid agonists by binding to the same receptors without activating them. These drugs play a crucial role in pain management but come with a risk of dependence and a range of side effects.
 Classification of Opioid Analgesics
Opioid analgesics can be classified based on their origin, receptor activity, and chemical structure:
1. Origin:
– Natural Opioids: Derived from opium poppy (e.g., morphine, codeine).
– Semi-synthetic Opioids: Chemically modified natural opioids (e.g., oxycodone, hydrocodone).
– Synthetic Opioids: Fully synthetic compounds (e.g., fentanyl, methadone).
2. Receptor Activity:
– Full Agonists: Fully activate opioid receptors (e.g., morphine, fentanyl).
– Partial Agonists: Partially activate opioid receptors (e.g., buprenorphine).
– Antagonists: Block opioid receptors without activating them (e.g., naloxone, naltrexone).
3. Chemical Structure:
– Phenanthrenes: (e.g., morphine, codeine).
– Phenylpiperidines: (e.g., fentanyl, meperidine).
– Diphenylheptanes: (e.g., methadone).
– Benzomorphans: (e.g., pentazocine).
 Mechanism of Action of Opioid Analgesics
Opioid analgesics exert their effects primarily through interaction with opioid receptors, which are G-protein-coupled receptors (GPCRs). The main opioid receptors are:
1. Mu (μ) Receptors:
– Primary Effects: Analgesia, euphoria, respiratory depression, miosis, reduced GI motility.
– Mechanism: Activation of μ receptors leads to inhibition of adenylate cyclase, decreased cyclic AMP (cAMP) levels, and subsequent reduction in neurotransmitter release.
2. Delta (δ) Receptors:
– Primary Effects: Modulation of analgesia, antidepressant effects.
– Mechanism: Similar to μ receptors, δ receptors inhibit adenylate cyclase and reduce cAMP levels.
3. Kappa (κ) Receptors:
– Primary Effects: Analgesia, dysphoria, sedation, diuresis.
– Mechanism: Activation of κ receptors also inhibits adenylate cyclase but may have different effects on neurotransmitter release compared to μ and δ receptors.
Opium
Opium is a complex mixture derived from the latex of the opium poppy (Papaver somniferum). It has been used for centuries for its analgesic and euphoric properties. The primary active alkaloids in opium include morphine, codeine, and thebaine, which are responsible for its pharmacological effects. These compounds interact with the opioid receptors in the body, producing a range of effects on various physiological systems.
 Pharmacological Actions on Different Systems
1. Central Nervous System (CNS):
– Analgesia: Opium’s primary pharmacological action is pain relief. Morphine, the main active component, binds to mu-opioid receptors in the brain and spinal cord, altering the perception of pain.
– Euphoria: Activation of opioid receptors in the brain’s reward pathway leads to a feeling of well-being and pleasure, which can contribute to its potential for abuse.
– Sedation: Opium induces drowsiness and a sense of relaxation, which is beneficial for pain management but can impair cognitive and motor functions.
– Respiratory Depression: One of the most serious effects, where the activation of opioid receptors in the brainstem reduces the respiratory rate and depth, potentially leading to life-threatening situations.
– Antitussive Effect: Opium and its derivatives suppress the cough reflex by acting on the cough center in the medulla.
2. Cardiovascular System:
– Hypotension: Opium can cause a drop in blood pressure, primarily due to the dilation of blood vessels and the release of histamine.
– Bradycardia: Slowing of the heart rate can occur as a result of opioid action on the vagus nerve.
3. Gastrointestinal System:
– Constipation: Opium slows down GI motility by increasing smooth muscle tone and decreasing peristalsis, leading to constipation, a common side effect.
– Reduced Secretions: It decreases the secretion of digestive enzymes and fluids, further contributing to constipation and dry mouth.
– Nausea and Vomiting: Activation of the chemoreceptor trigger zone (CTZ) can induce nausea and vomiting, particularly with initial doses.
4. Immune System:
– Immunosuppression: Chronic use of opium and opioids can suppress immune function, increasing susceptibility to infections.
5. Endocrine System:
– Hormonal Effects: Opium use can disrupt the hypothalamic-pituitary-adrenal (HPA) axis, leading to alterations in cortisol levels and other hormonal imbalances.
6. Renal System:
– Urinary Retention: Opium increases the tone of the urinary sphincter and reduces bladder muscle contractility, leading to difficulty in urination.
Other opioids
Codeine
Codeine is a naturally occurring alkaloid found in the opium poppy (Papaver somniferum). It is commonly used for its analgesic, antitussive (cough suppressant), and antidiarrheal properties. Codeine is often considered a prodrug because it is metabolized in the liver to morphine, which is primarily responsible for its analgesic effects. It is available in various formulations, including tablets, syrups, and combination products with other analgesics like acetaminophen.
 Pharmacological Actions of Codeine
1. Central Nervous System (CNS):
– Analgesia: Codeine provides mild to moderate pain relief. It is less potent than morphine but is effective for treating conditions like headaches, dental pain, and minor injuries. Codeine binds to mu-opioid receptors in the brain and spinal cord, altering the perception of pain.
– Sedation: Codeine can cause drowsiness and sedation, which can be beneficial in managing pain and cough but may impair cognitive and motor functions.
– Antitussive Effect: Codeine is widely used to suppress coughs. It acts directly on the cough center in the medulla to reduce the frequency and intensity of coughing.
– Euphoria and Dependence: Codeine can produce feelings of euphoria, particularly in higher doses or in individuals with a predisposition to substance abuse. Chronic use can lead to physical dependence and addiction.
2. Respiratory System:
– Respiratory Depression: Similar to other opioids, high doses of codeine can suppress the respiratory centers in the brainstem, leading to reduced respiratory rate and depth. This effect is less pronounced than with stronger opioids but can still be dangerous, especially in overdose situations.
3. Gastrointestinal System:
– Constipation: Codeine slows down GI motility by increasing smooth muscle tone and reducing peristalsis, leading to constipation. This is a common side effect and can be severe with chronic use.
– Nausea and Vomiting: Codeine can stimulate the chemoreceptor trigger zone (CTZ) in the brain, causing nausea and vomiting, particularly when initiating therapy or increasing the dose.
4. Renal System:
– Urinary Retention: Codeine increases the tone of the urinary sphincter and reduces bladder muscle contractility, which can lead to difficulty in urination.
5. Immune System:
– Immunosuppression: Prolonged use of codeine and other opioids can suppress immune function, increasing susceptibility to infections.
6. Endocrine System:
– Hormonal Effects: Codeine can disrupt the hypothalamic-pituitary-adrenal (HPA) axis, potentially leading to hormonal imbalances with chronic use.
Metabolism and Pharmacokinetics
– Metabolism: Codeine is metabolized in the liver primarily by the enzyme CYP2D6 into morphine, which is responsible for most of its analgesic effects. Other metabolites include norcodeine and codeine-6-glucuronide.
– Pharmacokinetics: Codeine has a variable oral bioavailability due to first-pass metabolism. It typically reaches peak plasma concentrations within one to two hours after oral administration. The half-life of codeine is approximately three to four hours, but this can vary based on individual metabolic differences.
Side Effects
– Common Side Effects: Drowsiness, dizziness, constipation, nausea, vomiting, and dry mouth.
– Serious Side Effects: Respiratory depression, severe allergic reactions, confusion, and dependence.
 Pethidine (meperidine)
Pethidine, also known as meperidine, is a synthetic opioid analgesic used primarily for the relief of moderate to severe pain. It is classified as a Schedule II controlled substance due to its potential for abuse and dependence.
 Mechanism of Action of Pethidine
Pethidine works by binding to the mu-opioid receptors in the brain and spinal cord, which are involved in the perception of pain. This binding inhibits the release of neurotransmitters involved in pain transmission, leading to pain relief.
Indications
Pethidine is used for:
– Acute pain management
– Postoperative pain
– Labor pain
– Severe pain where other treatments are ineffective
Administration
Pethidine can be administered via various routes, including:
– Oral
– Intramuscular
– Subcutaneous
– Intravenous
The dosage and administration depend on the severity of pain and the patient’s response to the medication.
Side Effects
Common side effects include:
– Dizziness, Nausea, Vomiting, Sweating, Lightheadedness
Serious side effects can include:
– Respiratory depression, Hypotension, Seizures, Dependency and addiction
Contraindications
Pethidine should not be used in patients with:
– Severe respiratory impairment
– Acute asthma
– Head injury or raised intracranial pressure
– Concurrent use of monoamine oxidase inhibitors (MAOIs)
Precautions
– Pethidine should be used with caution in elderly patients and those with renal or hepatic impairment.
– It should be used with caution in patients with a history of substance abuse.
– Abrupt discontinuation should be avoided to prevent withdrawal symptoms.
Drug Interactions
Pethidine can interact with other central nervous system depressants, such as alcohol, benzodiazepines, and other opioids, enhancing their effects. It also interacts with MAOIs, potentially leading to severe reactions, including serotonin syndrome.
Tramadol
Tramadol is a synthetic opioid analgesic used to treat moderate to moderately severe pain. It is available in immediate-release and extended-release formulations and is less potent than other opioids, making it a commonly prescribed pain medication.
 Mechanism of Action of Tramadol
Tramadol works by binding to mu-opioid receptors in the brain, which helps to block pain signals. It also inhibits the reuptake of serotonin and norepinephrine, neurotransmitters involved in the modulation of pain. This dual mechanism contributes to its analgesic effects.
Indications
Tramadol is used for:
– Chronic pain management
– Acute pain relief, such as after surgery or injury
– Neuropathic pain
Administration
Tramadol can be administered orally in tablet or capsule form. The dosage depends on the patient’s pain level, response to treatment, and medical condition.
Side Effects
Common side effects include:
– Dizziness, Nausea, Constipation, Headache, Drowsiness
Serious side effects can include:
– Seizures, Serotonin syndrome, Respiratory depression, Dependency and addiction
Contraindications
Tramadol should not be used in patients with:
– Severe respiratory impairment
– Acute asthma
– Severe hepatic or renal impairment
– Concurrent use of monoamine oxidase inhibitors (MAOIs)
Precautions
– Tramadol should be used with caution in patients with a history of seizures, as it can lower the seizure threshold.
– It should be used with caution in patients with a history of substance abuse or those taking other medications that affect serotonin levels.
– Abrupt discontinuation should be avoided to prevent withdrawal symptoms.
Drug Interactions
Tramadol can interact with other central nervous system depressants, such as alcohol, benzodiazepines, and other opioids, enhancing their effects. It also interacts with drugs that affect serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), increasing the risk of serotonin syndrome.
Dose: 50 to 100 mg 4 to 6 hourly oral/IM for moderate to severe pain.
Pentazocine
Pentazocine is a prescription medication used to treat moderate to severe pain. It belongs to a class of drugs called opioid analgesics. Here are some key points about pentazocine:
1. Mechanism of Action: Pentazocine works by binding to opioid receptors in the brain and spinal cord, altering the perception and response to pain. It is a mixed agonist-antagonist, meaning it activates some opioid receptors while blocking others.
2. Forms and Administration: Pentazocine is available in several forms, including tablets, injectable solutions, and combination products with other medications such as acetaminophen or naloxone.
3. Uses: It is typically prescribed for the relief of moderate to severe pain, including pain following surgery, injury, or chronic conditions like cancer.
4. Side Effects: Common side effects of pentazocine include dizziness, drowsiness, nausea, vomiting, constipation, and sweating. Serious side effects can include respiratory depression, severe allergic reactions, and dependence or addiction.
5. Warnings and Precautions: Pentazocine should be used with caution in patients with a history of substance abuse or addiction. It can interact with other medications, especially other central nervous system depressants like alcohol, benzodiazepines, and other opioids.
6. Contraindications: It is contraindicated in patients with a known hypersensitivity to pentazocine or any of its components. It should not be used in patients with significant respiratory depression or acute or severe bronchial asthma.
7. Dose: 30 to 60 mg IM 3 to 4 hourly; 15 to 30 mg orally tds.
Buprenorphine
Buprenorphine is a medication used to treat opioid addiction, and acute and chronic pain. Here are the key points about buprenorphine:
1. Mechanism of Action: Buprenorphine is a partial opioid agonist, meaning it activates opioid receptors in the brain but to a lesser extent than full agonists like heroin or methadone. This helps reduce cravings and withdrawal symptoms without producing a strong euphoric effect.
2. Forms and Administration: It is available in various forms, including sublingual tablets, sublingual films, buccal films, and injectable formulations. It is also available in combination with naloxone (e.g., Suboxone) to deter intravenous misuse.
3. Uses: Primarily used in medication-assisted treatment (MAT) for opioid use disorder, buprenorphine helps individuals reduce or quit their use of heroin or other opiates. It is also prescribed for pain management in certain cases.
4. Side Effects: Common side effects include headache, nausea, vomiting, constipation, sweating, and insomnia. Serious side effects can include respiratory depression, liver problems, and allergic reactions.
5. Warnings and Precautions: Buprenorphine can interact with other medications, particularly other central nervous system depressants. It carries a risk of dependence and should be used under the supervision of a healthcare provider, especially in individuals with a history of substance abuse.
6. Contraindications: It is contraindicated in patients with a known hypersensitivity to buprenorphine or any component of the product. It should be used with caution in patients with respiratory insufficiency, severe liver impairment, or acute abdominal conditions.
7. Dose: 0.3 mg 6 hourly IM/IV; 0.4 to 0.8 mg sublingually.
Methadone
Methadone is a long-acting opioid medication used primarily in the treatment of opioid addiction and chronic pain. Here are the key points about methadone:
1. Mechanism of Action: Methadone works by binding to opioid receptors in the brain, reducing cravings and withdrawal symptoms in individuals with opioid dependence. It also blocks the euphoric effects of other opioids, helping to prevent relapse.
2. Forms and Administration: Methadone is available in oral tablets, oral solutions, and injectable forms. It is often administered in a supervised setting for opioid dependence treatment, but can also be prescribed for chronic pain management.
3. Uses: Methadone is used for opioid replacement therapy (ORT) or medication-assisted treatment (MAT) for opioid use disorder. It helps patients reduce or stop their use of heroin or other opiates. It is also prescribed for managing moderate to severe chronic pain.
4. Side Effects: Common side effects include drowsiness, dry mouth, nausea, vomiting, constipation, and sweating. Serious side effects can include respiratory depression, cardiac arrhythmias, and dependency.
5. Warnings and Precautions: Methadone has a high risk of overdose, especially when starting treatment or adjusting the dose. It can interact with many other medications, increasing the risk of serious side effects. Regular monitoring by a healthcare provider is essential.
6. Contraindications: Methadone should not be used in individuals with known hypersensitivity to the drug or its components. It should be used cautiously in patients with respiratory insufficiency, acute asthma, or a history of cardiac arrhythmias.
7. Dose: 2.5 to 10 mg 3 to 8 hourly oral/IM/SC.
Naloxone
Naloxone is a medication used to rapidly reverse opioid overdose. Here are the key points about naloxone:
1. Mechanism of Action: Naloxone is an opioid antagonist. It works by binding to opioid receptors in the brain, displacing opioid molecules, and reversing their effects, particularly respiratory depression caused by opioid overdose.
2. Forms and Administration: Naloxone is available as an injectable solution, an intranasal spray (e.g., Narcan), and an auto-injector (e.g., Evzio). These formulations allow for rapid administration during an overdose emergency.
3. Uses: The primary use of naloxone is to treat known or suspected opioid overdose, characterized by symptoms such as extreme drowsiness, slowed or stopped breathing, and loss of consciousness. It can be administered by healthcare professionals, first responders, or bystanders.
4. Side Effects: Common side effects include nausea, vomiting, sweating, increased heart rate, and increased blood pressure. Because naloxone reverses opioid effects, it can precipitate acute withdrawal symptoms in opioid-dependent individuals.
5. Warnings and Precautions: While naloxone is effective in reversing opioid overdose, its effects are temporary, and medical attention is still necessary after administration. Multiple doses may be required if the opioid-involved has a longer duration of action than naloxone.
6. Availability: Naloxone is often distributed to individuals at risk of opioid overdose and their families, as well as to community organizations and first responders. In many regions, naloxone can be obtained without a prescription.
7. Dose: 0.1 to 0.4 mg IV, repeat if necessary
Side Effects
The use of opioid analgesics is associated with a range of side effects, which can be acute or chronic:
1. Common Side Effects:
– Sedation: Drowsiness and impaired cognitive function.
– Constipation: Reduced GI motility leading to difficulty in bowel movements.
– Nausea and Vomiting: Activation of the chemoreceptor trigger zone (CTZ).
– Miosis: Constriction of the pupils.
2. Serious Side Effects:
– Respiratory Depression: Suppression of the brainstem respiratory centers, leading to reduced respiratory rate and depth.
– Dependence and Addiction: Development of physical dependence and psychological addiction with prolonged use.
– Tolerance: Gradual reduction in drug efficacy, necessitating higher doses for the same effect.
– Hyperalgesia: Increased sensitivity to pain with long-term use.
3. Adverse Effects with Specific Drugs:
– Methadone: Prolongation of the QT interval, leading to potential cardiac arrhythmias.
– Meperidine: Accumulation of toxic metabolites (normeperidine) causing seizures.
