Analgesics and Opioids

Analgesics

• Analgesics alleviate pain from various causes

Classification of Analgesics

• Non-opioid analgesics include nonsteroidal anti-inflammatory drugs and paracetamol
• Opioid analgesics include morphine and synthetic opioids
• Non-opioid analgesics treat mild to moderate pain, while opioid analgesics treat moderate to severe pain

Opioid (Narcotic) Analgesics

• Opioids have morphine-like effects
• Plant sources include morphine and codeine, called opiates, which are natural alkaloids from opium poppies
• Synthetic sources are fentanyl, methadone, heroin and pethidine
• Endogenous sources are endorphins, encephalin and dynorphins (opiopeptides) released in the body
• Endogenous sources act on opioid receptors to produce morphine-like effects

Classification of Opioids

• Opioid analgesics are one class of opioids
• Opioid antitussives are less addictive than morphine and include codeine and dextromethorphan
• Dextromethorphan information can be found in the respiration section of the notes
• Opioid anti-diarrheals are less addictive than morphine and include loperamide and diphenoxylate
• Loperamide and diphenoxylate information can be found in the GI Tract section of the notes

Mechanism of Action

• Opioid receptors include Mu, kappa and delta
• Mu receptors mediate most effects of opioids
• Opioid receptors exist in the central nervous system and periphery, such as the GI tract

Actions, Uses, Adverse Effects & Contraindications (CI) of Morphine

• Morphine is an analgesic for acute trauma, chronic visceral pain, postoperative and cancer pain and myocardial infarction
• Morphine is used in pre-anesthesia and CV surgery
• Morphine is used for acute pulmonary edema in LVF following myocardial infarction, reducing preload and afterload and respiratory distress and anxiety
• Codeine or Dextromethorphan are used instead of Morphine as antitussives
• Loperamide or diphenoxylate are used instead of Morphine as antidiarrheals

Main Effects of Morphine

• Morphine causes analgesia by decreasing pain perception and emotional response to pain
• Morphine causes sedation
• Morphine causes euphoria or dysphoria.

Inhibitory Effects of Morphine

• Morphine inhibits VMC, causing venular and arterial vasodilation
• Morphine inhibits the respiratory center causing respiratory depression which leads to increased CO2 and asphyxia neonatorum
• Morphine incrases intracranial pressure due to cerebral vasodilation
• Morphine can cause cough
• Morphine decreases uterine tone, causing a delayed labor

Stimulatory Effects of Morphine

• Morphine stimulates the oculomotor nucleus, causing miosis
• Morphine stimulates the CTZ, causing vomiting
• Morphine stimulates the urinary and GI tracts, which increases tone of wall and sphincters (spasmogenic) but decreases peristalsis, causing stools to stagnate and harden due to fluid absorption
• Morphine causes histamine release

Adverse Effects & Contraindications of Morphine

• Morphine can mask pain
• Morphine is contraindicated in acute undiagnosed abdomen
• Morphine can cause sedation, narcosis, and drug dependence
• Morphine causes hypotension and increased intracranial tension
• Morphine is contraindicated with a head injury
• Morphine can delay labor
• Morphine causes miosis and nausea and vomiting
• Morphine can cause urine retention, so it's contraindicated with enlarged prostates
• Morphine can cause biliary colic and is contraindicated in these scenarios
• Morphine causes constipation, hypotension, itching and bronchospasm
• Morphine is contraindicated with asthma
• Other effects include seizures and rigidity in high doses
• Morphine is contraindicated in extremes of age, hypothyroidism, and liver dysfunction (decreased metabolism)
• Tolerance develops to all effects except constipation and miosis

Acute Morphine Toxicity

• Acute Morphine Toxicity causes coma
• Acute Morphine Toxicity causes respiratory depression
• Acute Morphine Toxicity causes pinpointed pupil
• Treatment for acute morphine toxicity is supporting respiration

Pure Opioid Agonists

• Pure Opioid Agonists include Morphine and Pethidine

Morphine

• Morphine is given IV, IM, SC, epidurally or orally
• Morphine undergoes extensive first pass metabolism

Pethidine [IM - Oral]

• Pethidine is a synthetic drug for acute moderate and severe pain from trauma, postoperative pain, biliary colic or labor pain
• Pethidine is different from morphine because it less constipating, is a less respiratory depressant in neonates and does not delay labor, which makes it preferred during labor

Pethidine Side Effects

• Pethidine causes atropine-like side effects like dry mouth and blurred vision
• Pethidine increases risk of convulsions
• Pethidine accumulates a toxic metabolite called norpethidine, and should not be used for more than 48 hours

Fentanyl

• Fentanyl is 400x more potent than morphine
• Fentanyl is more potent than morphine with rapid onset and shorter action, making it preferred in anesthesia
• High anesthetic doses of fentanyl can cause chest wall rigidity, decreased thoracic compliance and decreased ventilation
• Fentanyl is given IV, epidurally, spinal or in a transdermal patch for patient controlled infusion
• Fentanyl is used for analgesia in severe pain like perioperative and cancer pain
• Fentanyl is used in anesthesia as a pre-anesthetic medication and IV anesthetic in cardiovascular surgery

Conscious Sedation

• Conscious Sedation involves amnesia, sedation and analgesia without complete loss of consciousness
• Conscious Sedation is used for minor procedures or diagnostic purposes like endoscopy
• Conscious Sedation is administered via IV benzodiazepine like midazolam or opioid analgesic like fentanyl
• Fentanyl is easily reversed by flumazenil and naloxone

Tramadol (mixed opioid/non-opioid)

• Tramadol acts by inhibiting the uptake of serotonin and noradrenaline
• Tramadol is a weak Mu agonist, only partially antagonized by naloxone
• Tramadol causes less constipation, respiratory depression and addiction than morphine
• Tramadol has an increased risk of convulsions
• Tramadol is given via oral, IM and IV routes
• Tramadol is used as an analgesic in postoperative and chronic moderate pain and in neuropathic pain

Partial Agonists

• Partial Agonists include Buprenorphine

Buprenorphine (partial Mu receptor agonist)

• Buprenorphine has less addiction (less euphoria) than pure agonists

Buprenorphine Uses

• Buprenorphine is given parenterally or sublingually
• Buprenorphine is used as an analgesic in severe pain at large doses
• Buprenorphine may treat opioid addicts, as it is long-acting and slowly dissociates from receptors, it is also given sublingually

Pure Opioid Antagonists

• Pure Opioid Antagonists include Naloxone and Naltrexone

Naloxone

• Naloxone is given IV and is short acting
• Naloxone manages acute toxicity from morphine

Acute Opioid Toxicity from Naloxone

• Naloxone is repeated if relapse into coma occurs, as the duration of action is shorter than opioids

Asphyxia in Neonatorum from Naloxone

• Naloxone is a respiratory stimulant in opioid-induced respiratory depression in newborns

Naltrexone

• Naltrexone is given orally and is long acting
• Naltrexone is a maintenance therapy for addicts

Opioid Abuse using Naltrexone

• Naltrexone blocks the euphoria of opioids, decreasing the desire to take the drug and prevents relapse

Alcohol Abuse using Naltrexone

• Naltrexone decreases cravings in chronic alcoholics to prevent relapse

Nonsteroidal Anti-Inflammatory Drugs

• Nonsteroidal anti-inflammatory drugs are a heterogeneous group with anti-inflammatory, analgesic and antipyretic effects

Nonsteroidal Anti-Inflammatory Drugs Included

• Prototype NSAID: acetylsalicylic acid (aspirin)
• Nonselective NSAIDs: ibuprofen, naproxen, diclofenac, piroxicam, indomethacin
• Selective COX-2 Inhibitors: Celecoxib
• Paracetamol is an analgesic-antipyretic with weak anti-inflammatory action

Cyclooxygenase Enzymes

• COX-1 is constitutive, is normally present in tissues and regulates its physiologic functions
• COX-1 helps forms protective PGs in GIT and kidney
• COX-2 enzyme is inducible, only present in inflammation, and also found in endothelium and kidney

Mechanism of Action of NSAIDs & Paracetamol

• Acetylsalicylic acid irreversibly inhibits cyclooxygenase enzymes, both COX-1 and COX-2, thereby inhibiting conversion of arachidonic acid to endoperoxides, preventing production of PG and TXA2
• Other NSAIDs competitively and reversibly inhibit COX enzymes
• Celecoxib selectively inhibits the COX-2 enzyme
• Paracetamol inhibits PG synthesis in the central nervous system to produce analgesic and antipyretic effects
• Paracetamol has weak anti-inflammatory effect and poorly inhibits the COX enzyme in the presence of excess peroxides in inflamed tissue
• Inhibition of COX-1 is responsible for the adverse effects of NSAIDs.
• Inhibition of COX-2 is responsible for their anti-inflammatory effects

Acetylsalicylic Acid (Aspirin)

• Acetylsalicylic Acid acts as a Prophylactic at Low-Doses and anti-inflammatory at high doses

Low-Dose Aspirin action

• Antiplatelet by inhibiting TXA2 synthesis
  • Prophylaxis for transient ischemic attacks and angina
  • Neuronal degeneration in Alzheimer
  • Risk of colorectal cancer

High-Dose Aspirin action

• Anti-inflammatory
  • Rheumatic fever
  • Rheumatoid arthritis

Analgesic actions of Aspirin

• Decreases PGs and increases pain threshold, peripherally
• Decreases PGs and inhibits pain transmission at subcortical sites, centrally
  • Mild to moderate pain from inflammation
  • Headache and migraine with dysmenorrhea
  • Postpartum, postoperative and cancer pain

Antipyretic actions of Aspirin

• Decreases pyrogen-induced PGE2 in fever, resetting hypothalamic thermostat to normal
• Increases temperature-regulating mechanisms, vasodilation and sweating, with decreased temperature

Pharmacokinetics of Aspirin

• Aspirin is Acetyl Salicylic Acid
• Aspirin is given orally, rapidly absorbed in stomach non-ionized in acidic medium
• Aspirin is bound to albumin and displaces warfarin to potentiate
• Alkalinization of urine increases excretion in toxicity

Effects Common to all NSAIDs

• Common effects happen in the GIT, causing upset and most-common
  • Direct upset is Dyspepsia, pain and nausea, vomiting and gastritis
  • Decreased protective PGs resulting in ulceration and increased risk of bleeding
• Can be reduced by co-administration with misoprostol PG analogue
• Nephrotoxicity occurs due to kidney issues
  • Analgesic nephropathy: Irreversible nephritis due to NSAID combination doses
  • Leads to Renal insufficiency where dependence of vasodilator PGs with decreased renal blood flow
    • Causes Salt and water retention with higher blood pressure and edema
    • Causes Hyperkalemia and Acute renal insufficiency
  • Hypersensitivity reactions can occur with asthma and skin rash and rhinitis

Effects Specific to Aspirin

• Hypoprothrombinemia and increased bleeding
  • Interferes with > 5 g/d of vitamin K
• Hyperuricemia occurs with low dose aspirin, preventing secretion of uric acid
• Reye’s syndrome in children which can cause encephalopathy, brain malfunction, and liver damage
  • No aspirin antipyretic if < 12 years with viral infection
• Chronic toxicity and salicylism due to administration of large doses
  • Can cause dizziness, vomiting, tinnitus, and nausea ringing in the ears

Advantages of Aspirin over Opioids

• With no dependence and no respiratory depression

No Non-Selective NSAIDs

• Non-Selective NSAIDs cause analgesic, and anti-inflammatory effects, along with antipyretic
  • Increasingly used for inflammatory joint pain, OA, RA, gouty dysmenorrhea, renal pain/colic, and pain after operation
• Ineffective as anti-platelet since they prevent reversible COX and are therefore short anti-plate

Types of Individual NSAIDs

• These meds help stop arthritis
• Ibuprofen is 1st choice and better tolerated with lower side effects
• Naproxen is related with more potent in risks with adverse affects
• Diclofenac works well but less affects than the other two

Side Effects of Individual NSAIDs

• Meloxicam and Piroxicam are used for arthritis
  • Usually taken daily with water Avoid mixing NSAIDs and warfarin, glucocorticoids

Selective COX-2 Inhibitors

• Were supposed to retain anti-inflammatory effects
• Are meant to spare enzymes

Uses of Selective COX-0 Inhibitors

• Treat musculoskeletal disorders with less risk
• Fight slower progression of Alzheimer and risk of colorectal tumor growth

Adverse effects of Selective COX-0 Inhibitors

• Can cause nephrotoxicity, risk strokes and infarction with skin rash

Paracetamol Benefits

• Analgesic antipyretic action with lack of inflammatory
• Aspirin is not recommended in allergy, peptide, gout, bleeding and viral infections

Paracetamol Use

• Administer through an orally dose 2-3 daily with 500 mg each
• Its combined to get in liver and metabolites; 3 % get hepatotoxic metabolite
• A saturation of high enzymes will convert drug to toxic forms and create toxicity

Paracetamol Toxicity

• Leads to minor effects and are well tolerated
• Can lead to toxicity with vomit and nauseous overdose

Paracetamol Treatment

• Use acetylene to allow prevent synthesis and liver function