Lesson 30 - Analgesic Drugs (Opioids) PDF

Lesson 30 Analgesic drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  General concepts Analgesia: elimination of the sensation of pain by artificially blocking the pathways of transmission of pain and/or pain mediators, or by disconnecting...

Lesson 30 Analgesic drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  General concepts Analgesia: elimination of the sensation of pain by artificially blocking the pathways of transmission of pain and/or pain mediators, or by disconnecting pain centers. Analgesic drug: Drug designed to relieve pain Inflammation: A response of the body to protect against infection and injury or trauma. Anti-inflammatory drug: drugs capable of inhibiting the inflammatory process by affecting one or more factors involved in the mechanism of inflammation and pain.  Types of analgesics There are different types of analgesic drugs: MAJOR ANALGESICS: (opioid/morphine-like drugs) have an action at the CNS level and are used for postoperative, oncological, myocardial infarction, acute or chronic pain. MINOR ANALGESICS:(paracetamol and NSAIDs) have a peripheral action blocking the biosynthesis of mediators of inflammation and pain. Local anesthetics:(lidocaine) local action on the peripheral nervous system TYPES OF PAIN Somatic pain: is often well localized to specific dermal, subcutaneous, or musculoskeletal tissue. Visceral pain: originating in thoracic or abdominal structures is often poorly localized and may be referred to somatic structures. Neuropathic pain: is usually caused by nerve damage, such as that resulting from nerve compression or inflammation, or from diabetes.  1. Modulatory mechanisms in the nociceptive pathway Glutamate Substance P CGRP (Calcitonin Gene- Related Peptide) Activated by: 5-HT NA Endonegous opioids 1. Modulatory mechanisms in the nociceptive pathway 2. Analgesic drugs SEROTONIN AND OPIOID INHIBIT THE TRANSMISSION OF PAIN  Opioids Papaver somniferum The latex contained in the capsule of opium poppy is a milky sap rich in alkaloids. (morphine, codeine, papaverine...) 2. Analgesic drugs OPIOIDS Terminology Opioid: any substance, whether endogenous or synthetic, that produces morphine -like effects (that are blocked by antagonists such as naloxone). Opiate: compounds such as morphine and codeine that are found in the opium poppy Narcotic analgesic: old term for opioids; narcotic refers to their ability to induce sleep.  2. Analgesic drugs OPIOIDS CHEMICAL ASPECTS Morphine is a phenanthrene derivative The most important parts of the molecule for opioid activity are the free hydroxyl on the benzene ring that is linked by two carbon atoms to a nitrogen atom Tyrosine 2. Analgesic drugs OPIOIDS RECEPTORS There are four opioid receptors, µ, δ, κ and NOP All opioid receptors are linked through Gi/Go proteins μ receptors are responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, constipation, euphoria, sedation and dependence) δ receptor activation results in analgesia but also can be proconvulsant. κ receptors contribute to analgesia at the spinal level and may elicit sedation, dysphoria and hallucinations. Some analgesics are mixed κ agonists/μ antagonists. NOP receptors are also members of the opioid-receptor family. Activation results in an antiopioid effect (supraspinal), analgesia (spinal), immobility and impairment of learning. 2. Analgesic drugs OPIOIDS RECEPTORS Opioid receptors are widely distributed in the brain and spinal cord.  2. Analgesic drugs OPIOIDS Mechanism of action Activation of Gi /Go protein–coupled receptors Opening of K+ channels (hyperpolarization) and inhibit the opening of voltage-gated Ca2+ channels (no release of NT) Decreased neuronal excitability and reduced transmitter release Overall effect is inhibitory at the cellular level. 2. Analgesic drugs OPIOIDS Pharmacological Effects CENTRAL NERVOUS SYSTEM EFFECTS Analgesia Dysphoria or euphoria Inhibition of cough reflex Miosis Physical dependence Respiratory depression Sedation 2. Analgesic drugs OPIOIDS Effects ANALGESIA Acute pain as well as in ‘end of life’ pain resulting from cancer. Much less effective in treating neuropathic and other chronic HYPERALGESIA Prolonged exposure to opioids may paradoxically induce a state of hyperalgesia in which pain sensitisation or allodynia occurs May be reduced by switching from one to another opioid drug EUPHORIA OR DYSPHORIA Produced by morphine depends considerably on the circumstances. In patients who have become accustomed to pain, morphine causes analgesia with little or no euphoria. Euphoria is mediated through μ receptors κ receptor activation produces dysphoria and hallucinations  2. Analgesic drugs OPIOIDS Effects RESPIRATORY DEPRESSION Occurs with a normal analgesic dose Represents a constant danger due to overdose Respiratory depression results from μ receptor activation Associated with a decrease in the sensitivity of the respiratory centres to arterial Pco2 Rapidly reversed by IV administration of naloxone DEPRESSION OF COUGH REFLEX Codeine suppress cough in subanalgesic doses but they cause constipation as an unwanted effect. Dextromethorphan suppresses cough but has very low affinity for opioid receptors and is not antagonised by naloxone  2. Analgesic drugs OPIOIDS Effects NAUSEA AND VOMITING Occur in up to 40% of patients The site of action is chemoreceptor trigger zone (CTZ) Nausea and vomiting following morphine injection are usually transient and disappear with repeated administration GASTROINTESTINAL AND BILIARY EFFECTS Opioids increase tone and reduce motility Constipation (increased intestinal smooth muscle tone) Increased biliary and bladder sphincter tone and pressure PUPILLARY CONSTRICTION (MIOSIS) Opioids cause miosis through activation of μ-receptors and interaction with parasympathetic and sympathetic regulatory mechanisms of pupil control. Miosis is an important diagnostic feature in opioid poisoning 2. Analgesic drugs OPIOIDS Effects OTHER ACTIONS Morphine releases histamine from mast cells: itching, urticaria or systemic effects, bronchoconstriction and hypotension. Hypotension and bradycardia occur with large doses of most opioids, due to an action on the medulla. IMMUNE SYSTEM EFFECTS Suppression of function of natural killer cells  2. Analgesic drugs OPIOIDS Effects Tolerance and Physical Dependence Tolerance is defined as a decrease in initial pharmacologic effect observed after chronic or long-term administration. Drug rotation (changing from one opioid to another) to overcome loss of effectiveness. Repeated administration of an opioid agonist will lead to pharmacodynamic tolerance for both the administered opioid and other opioid analgesics. Tolerance primarily results from down-regulation of opioid receptors 2. Analgesic drugs OPIOIDS Effects Tolerance and Physical Dependence Physical dependence is defined as a physiologic state in which a person’s continued use of a drug is required for his or her well-being Characterised by a clear-cut abstinence syndrome. SYMPTOMS: Restlessness, runny nose, diarrhoea, shivering and piloerection. CODEINE, PENTAZOCINE, TRAMADOL, are less likely to cause physical or psychological dependence. The signs of physical dependence are much less intense if the opioid is withdrawn gradually. Withdrawal syndrome is reduced by µ-receptor antagonists. Also METHADONE AND BUPRENORPHINE (long-acting µ-receptor agonists) may be used to relieve withdrawal symptoms. 2. Analgesic drugs OPIOIDS Effects Tolerance and Physical Dependence 2. Analgesic drugs OPIOIDS 1. Strong opioid agonists MORPHINE, FENTANYL , MEPERIDINE , OXYCODONE, HYDROMORPHONE, METHADONE 2. Moderate opioid agonists CODEINE, HYDROCODONE 3. Other opioid agonists DEXTROMETHORPHAN, LOPERAMIDE, TRAMADOL, TAPENTADOL 4. Mixed opioid agonist/antagonists BUPRENORPHINE , BUTORPHANOL 5. Opioid Antagonists NALOXONE, NALTREXONE 2. Analgesic drugs OPIOIDS MORPHINE Effect on μ receptors Primarily used to treat severe pain associated with trauma, myocardial infarction, and cancer IV: ACUTE SEVERE PAIN ORAL: CHRONIC PAIN TRANSDERMAL:TOUCH-SENSITIVE TRANSDERMAL PATCHES (CANCER) INTRATHECALLY: ANAESTHESIC Slow release preparations: increase its duration of action CHRONIC OR POSTOPERATIVE PAIN: patient-controlled analgesia by INFUSION PUMP (rate limited to avoid acute toxicity) 2. Analgesic drugs OPIOIDS MORPHINE ADRs Side effects related to its pharmacological actions Acute overdosage with morphine results in coma and respiratory depression, with characteristically constricted pupils: treated by giving naloxone.  2. Analgesic drugs OPIOIDS FENTANYL, ALFENTANIL, SUFENTANIL, REMIFENTANIL Most potent opioid agonists available (100 times more powerful than morphine) Effects similar to those of morphine: a more rapid onset and shorter duration of action. Used in anaesthesia (IT) Used in chronic pain (transdermal patches or patient-controlled infusion) Fentanyl has minimal cardiovascular effects and does not release histamine. 2. Analgesic drugs OPIOIDS MEPERIDINE No antitussive effect Effect on gastrointestinal, biliary, and uterine smooth muscle is less pronounced Indications. Analgesia during labour Prefered over morphine: it does not reduce the force of uterine contraction Short-term treatment of acute pain syndromes Slowly eliminated in the neonate NALOXONE may be needed to reverse respiratory depression in the baby ADRs: Antimuscarinic profile:causes restlessness,dry mouth and blurring of vision No to combine with MAO inhibitors. 2. Analgesic drugs OPIOIDS METHADONE Indications Chronic pain FOR TREATING OPIOID USE ADDICTION: heroin substitution treatment It acts on opioid receptors in the brain, reducing withdrawal symptoms without causing the same euphoria as heroin Regular oral doses of methadone Orally active and pharmacologically similar to morphine Duration of action is considerably longer (plasma half-life >24 h) the physical abstinence syndrome is less acute. It replaces heroin with a long-acting opioid, reducing compulsive drug- seeking behavior and the risk of overdose. It prevents withdrawal symptoms and helps stabilize patients.  2. Analgesic drugs OPIOIDS CODEINE Use: antitussive More reliably absorbed by mouth than morphine Undergoes a lesser degree of first-pass metabolism. 20% less analgesic potency of morphine Unlike morphine, it causes little or no euphoria and is rarely addictive. Often combined with paracetamol in proprietary analgesic preparations Contraindicated in asthmatics and COPD OXYCODONE, HYDROCODONE Moderate or severe pain It is available as a slow release oral preparation  2. Analgesic drugs OPIOIDS TRAMADOL Mechanism of action Unique dual-action analgesic Weak agonist at µ opioid receptors: better safety profile than most opioids Inhibits the neuronal reuptake of serotonin and noradrenaline. Administered oral, IM or IV injection Indications For moderate to severe chronic pain Analgesic for postoperative pain Acute and chronic pain, including musculoskeletal pain and the pain associated with neuropathy (diabetes, post-herpetic neuralgia, vulvodinia) Produces minimal cardiovascular and respiratory depression, minimum tolerance and dependence 2. Analgesic drugs BUPRENORPHINE Mixed Opioid Agonist/Antagonists and Partial Agonists Mechanism of action It is a weak partial -opioid receptor agonist and a weak -opioid receptor antagonist Available in daily transmucosal formulations, as an extended-release subcutaneous injection Oral and sublingual formulation combined with naloxone Safer to use with regard to respiratory depression and overdose Indications Approved for outpatient treatment of opioid dependence (in alternative to metadone) Indicated in moderate to severe pain. May precipitate withdrawal in a person physically dependent on a full opioid agonist. 2. Analgesic drugs NALOXONE Pure opioid antagonist, with affinity for all three classic opioid receptors (μ > κ ≥ δ) It blocks the actions of endogenous opioid peptides as well as those of morphine-like drugs It is usually given IV, IM or nasally and its effects are rapid in onset Rapidly metabolised by the liver, and its effect lasts only 2–4 h Indications To treat respiratory depression caused by opioid overdosage or newborn respiratory depression To detect opioid addiction For opioid maintenance therapy, naloxone is available in various combinations with the partial opioid agonist buprenorphine To treat opioid-induced constipation. 2. Analgesic drugs NALTREXONE Longer duration of action (half-life about 10 h) than naloxone. Available in a slow-release subcutaneous implant formulation. Indications Long-term basis use by opioid addicts who have been ‘detoxified’ Used reducing alcohol consumption in heavy drinkers Naltrexone should be used only after the completion of a medically supervised opioid withdrawal, as it may trigger immediate withdrawal symptoms.  USE OF OPIOIDS AND PAIN KILLERS IN COMBINATION If the effects are additive, a lower dose of each drug can be administered while still achieving the same level of analgesia, thus reducing the intensity of the unwanted side effects associated with each drug. Opioids in combination with paracetamol or aspirin, appears to produce synergy rather than simple additivity. 3. Chronic pain Chronic secondary pain: underlying or initiating cause is known (e.g: neuropathic pains due to diabetes, shingles or herpes zoster infection, as well as sciatica and trigeminal neuralgia), post- traumatic and postsurgical pain (e.g. following a stroke, spinal cord injury or phantom limb pain) and musculoskeletal pain. Chronic primary pain in which there is no obvious cause. Common conditions of this type are nonspecific low back pain and fibromyalgia. Cancer pain is a type of pain often due to the tumor pressing on surrounding tissues, nerves, or bones, or from treatments like surgery, chemotherapy, or radiation therapy. (morphine, fentanyl)  3. Chronic pain Neuropathic pain is severe, debilitating, chronic pain affecting millions of people worldwide. Neuropathic pain is a type of pain caused by damage or dysfunction in the nervous system, often presenting as a burning, tingling, or electric shock-like sensation along the nerves. Treatment OPIOIDS: may be effective at higher doses if side effects can be tolerated. VARIOUS ANTIDEPRESSANTS (TCA): provide therapeutic benefit. GABAPENTIN AND PREGABALIN: are now used more to relieve neuropathic pain than as antiepileptic agents. CARBAMAZEPINE: as well as some other antiepileptic agents that block sodium channels, can be effective in treating trigeminal neuralgia. LIDOCAINE: may provide relief when applied topically. 3. Chronic pain Fibromyalgia is a chronic disorder characterised by widespread musculoskeletal pain, fatigue and insomnia. Its cause is unknown, with no obvious characteristic pathology being apparent. It is associated with allodynia. VARIOUS ANTIDEPRESSANT DRUGS AMITRIPTYLINE, CITALOPRAM, DULOXETINE, VENLAFAXINE ANTIEPILEPTIC AGENTS GABAPENTIN, PREGABALIN BENZODIAZEPINES CLONAZEPAM, ZOPICLONE 4. Other pain-relieving drugs CANNABINOIDS Nabilone and Dronabinol Central neuropathic pain of MULTIPLE SCLEROSIS BOTULINUM TOXIN injections Relieving back pain and the pain associated with spasticity. NEFOPAM Inhibitor of amine uptake Treatment of persistent pain unresponsive to non-opioid drugs Relief of muscle spasm Not depress respiration DOPAMINE RECEPTOR AGONISTS: Ropinirole, Pramipexole , Rotigotine Restless leg syndrome which can be painful in some individuals.