Analgesics: Types and Classes

Definitions

• Algesia is sensitivity to pain.
• Analgesia is the lessening or absence of pain.
• Analgesics are medications to relieve different types of pain.
• Anesthesia is temporary loss of sensation or awareness.

Classes of Analgesics

• Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of analgesics.
  • Non-Selective Cyclooxygenase inhibitors are included in NSAIDs.
  • Selective Cyclooxygenase 2 inhibitors are also included in NSAIDs.
• Acetaminophen is a class of analgesics.
• Opioids are a class of analgesics.
  • Full agonists are included in Opioids.
  • Partial agonists are included in Opioids.
  • Mixed agonist-antagonists are included in Opioids.
• Adjuvant analgesics are a class of analgesics.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• NSAIDs have a specific mechanism of action.
• Common NSAIDs include ibuprofen, naproxen, diclofenac, and aspirin.
• NSAIDs can be used for musculoskeletal pain, headaches, and inflammatory conditions.
• Potential side effects of NSAIDs include gastrointestinal, renal, and cardiovascular effects.

Mechanism of Action for NSAIDs

• NSAIDs inhibit cyclooxygenase to block prostaglandin, thromboxane, and prostacyclin biosynthesis from arachidonic acid.
• Other possible mechanisms of action include:
  • Inhibition of chemotaxis
  • Down-regulation of IL-1 production
  • Decreased production of radicals and superoxides
  • Interference with calcium-mediated intracellular events

Roles in Pain, Inflammation, and Hemostasis

• Leukotrienes are proinflammatory mediators derived from arachidonic acid.
• Prostaglandins are hormone-like substances affecting bodily functions like inflammation and pain.
• Bradykinin and Histamine act as vasodilators and increase membrane permeability.
• Thromboxane is a vasoconstrictor that facilitates platelet aggregation.
• Thromboxane's homeostatic balance is in the circulatory system with prostacyclin.
• Prostacyclin prevents the formation of the platelet plug involved in primary hemostasis, which inhibits platelet activation.

Cyclooxygenase Isoforms

• Cyclooxygenase 1 (COX 1) exhibits a homeostatic function.
• Cyclooxygenase 2 (COX 2) is induced during inflammation, facilitating the inflammatory response.

Non-Selective COX Inhibitors

• Nonselective Cyclooxygenase inhibitors prevent the formation of prostaglandins by inhibiting cyclooxygenase enzymes.
  • Prostaglandins promote pain and initiate inflammation.
• Nonselective Cyclooxygenase inhibitors prevent the formation of thromboxane by inhibiting cyclooxygenase enzymes.
  • Thromboxane initiates platelet aggregation.
• Nonselective Cyclooxygenase inhibitors prevent the formation of prostacycline by inhibiting cyclooxygenase enzymes.
  • Prostacycline prevents platelet activation.
• Examples of Nonselective Cyclooxygenase inhibitors are Ibuprofen, Naproxen, Diclofenac, Piroxicam, Ketorolac, Mefenamic Acid, Meloxicam, and Aspirin.

Selective COX-2 Inhibitors

• Celecoxib is a Selective COX-2 Inhibitor.
• Celecoxib is 10-20x more potent for COX-2 than COX-1.
• Meloxicam is a Selective COX-2 Inhibitor.
  • Meloxicam is preferential for COX-2 over COX-1.
• Parecoxib and arcoxia are Selective COX-2 Inhibitors.
• Selective COX-2 Inhibitors are Selective COX-2 Inhibitors.
  • Thromboxane activates platelet aggregation.
  • Prostacyclin is an endogenous inhibitor of platelet aggregation.

Thromboxane and Prostacyclin Balance

• Thromboxane A2 activates platelet aggregation.
  • Thromboxane A2 production depends on COX-1 inhibition.
• Selective COX-2 inhibitors do not inhibit thromboxane production.
  • This means they do not inhibit platelet aggregation and do not protect against thrombus formation.
• Prostacyclin (PGI2) vasodilates and inhibits platelet aggregation.
  • Prostacyclin (PGI2) production depends on COX-2 inhibition.
• Selective COX-2 inhibitors inhibit prostacyclin production.
  • This means they do not inhibit platelet aggregation and do not protect against thrombus formation.

NSAIDs: Non-Selective COX Inhibitors

• Aspirin (Acetylsalicylic Acid, ASA) irreversibly inhibits platelet cyclooxygenase.
  • Aspirin's antiplatelet effect lasts 8-10 days, which is the life span of platelets.
  • The antiplatelet dose of Aspirin is 81-325 mg once a day.
  • The effect of Aspirin on other tissues lasts 6-12 hours.
• Other non-selective COX inhibitors reversibly inhibit cyclooxygenase.

Aspirin in Children

• Aspirin can cause Reye’s Syndrome in children.
  • Reye’s Syndrome is a rare but serious condition that can cause swelling in the liver and brain.
  • Reye’s Syndrome can occur in children and teenagers recovering from a viral infection, commonly from the flu or chickenpox.
• Aspirin is not recommended for children with fever due to viral infections.

Aspirin in Gout

• Gout can be treated with doses of Aspirin of less than 2.6 grams/day.
  • Less than 2.6 grams/day of Aspirin inhibits the secretory transporter of uric acid in the renal tubules.
  • Less than 2.6 grams/day of Aspirin causes net retention of uric acid.
• Aspirin is not used as an analgesic in patients with gout.

Patients on Aspirin Conditioned for Heart Condition

• Consider the effect of aspirin on platelets.
  • Aspirin irreversibly inhibits platelet COX, and its effect lasts 8-10 days.
  • Aspirin inhibits platelet aggregation by inhibiting thromboxane synthesis.
• Patients on Aspirin must discontinue Aspirin intake for one week prior to elective surgery.
  • Aspirin intake is only discontinued if the benefits outweigh the risks.
  • Discontinue Aspirin when a patient has major surgery scheduled.
  • Discontinue Aspirin when a patient is at risk of bleeding.

NSAIDs: Therapeutic Effects

• NSAIDs can serve as an analgesic, an anti-inflammatory, and an antipyretic.
• NSAIDs inhibit platelet aggregation, EXCEPT:
  • Selective COX-2 inhibitors, which include celecoxib.
  • Non-acetylated salicylates, which include magnesium choline salicylate and salsalate.
• NSAIDs do not alter the course of any arthritic disorder, unlike methotrexate, biologics, and other DMARDs.

NSAIDs: Adverse Effects

• NSAIDs can cause the following CNS effects: headaches, tinnitus, dizziness, and aseptic meningitis (rare).
• NSAIDs can cause the following CVS effects: fluid retention, hypertension, edema, and MI, CHF (rare).
• NSAIDs can cause the following GIT effects: abdominal pain, dyspepsia, nausea, vomiting, irritation, ulcers, and bleeding (rare).
• NSAIDs can cause the following Hematologic effects: rare thrombocytopenia, neutropenia, and aplastic anemia.
• NSAIDs can cause the following Hepatic effects: abnormal liver function test results, liver failure (rare).
• NSAIDs can cause the following Pulmonary effects: asthma episode.
• NSAIDs can cause the following Skin effects: rashes, pruritus.
• NSAIDs can cause the following Renal effects: renal insufficiency/failure, proteinuria, and hyperkalemia.
  • NSAIDs may cause interference with autoregulation of renal blood flow.

NSAIDs: Pregnancy

• NSAIDs use during pregnancy has potential serious risks, including:
  • Fetal renal dysfunction
  • Oligohydramnios
  • Neonatal renal impairment
• There was an FDAAA Safety Labeling Change on 12/09/2020
  • Patients should avoid the use of NSAIDs at 20 weeks or later.
  • NSAIDs use during pregnancy can cause low amniotic fluid.

FDA Releases Black-Box Template for NSAIDs

• Cardiovascular:
  • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal.
  • The Cardiovascular risk may increase with duration of use.
  • Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
• Gastrointestinal:
  • NSAIDs cause an increased risk of serious gastrointestinal adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.
  • Gastrointestinal events can occur at any time during use and without warning symptoms.
  • Elderly patients are at greater risk for serious gastrointestinal events.

Ketorolac NSAID

• Ketorolac is a parenteral NSAID.
• Ketorolac is a short-term analgesic and is not to be used for more than 1 week.
• Ketorolac treats mild-moderate postop pain, and can replace morphine.
  • When combined with an opioid, Ketorolac can reduce the opioid dose by 25-50o%.
• Ketorolac is not an anti-inflammatory drug.
• Ketorolac has renal toxicity in chronic use.
• Other parenteral NSAIDs are ketoprofen, dexketoprofen, and diclofenac.

Choice of NSAIDs

• When choosing NSAIDs, balance effectiveness, toxicity/safety, and other factors.
• Consider personal factors and cost-effectiveness when choosing NSAIDs.
• There is no best NSAID for all patients.
• One to two NSAIDs are the best NSAIDs for a specific patient.

Acetaminophen/Paracetamol

• Acetaminophen is a Para-amino phenol derivative.
• Phenacetin, a prodrug of Acetaminophen, was removed from the market due to its nephrotoxicity.
• The US FDA approved acetaminophen (Tylenol) in 1951.
• The UK approved paracetamol (Panadol) in 1955.
• The UK approved Intravenous paracetamol (Perfalgan) in 2004.
• The US approved acetaminophen (Ofirmev) in 2010.

Acetaminophen/Paracetamol MOA

• Acetaminophen functions as a weak COX-1 and COX-2 inhibitor in peripheral tissues.
• Acetaminophen exhibits no significant anti-inflammatory effects.
• Acetaminophen has no effect on uric acid levels or platelets.
• Oral acetaminophen peaks in 30-60 minutes.
• Acetaminophen has a half-life of 2-3 hours.
  • Acetaminophen increases in liver disease but is relatively unaffected by kidney disease.
• Acetaminophen is poorly protein-bound and undergoes metabolism.

Acetaminophen/Paracetamol Indications

• Acetaminophen indications include mild to moderate pain and fever.
• Acetaminophen indications include patients with hemophilia and a history of peptic ulcer or bronchospasm precipitated by aspirin.
• Acetaminophen indications include children with fever who are at risk for Reyes syndrome.

Metabolism of Acetaminophen

• Acetaminophen undergoes sulfation and glucuronidation at 95%.
• Acetaminophen has an alternative P450-GSH pathway at 5%.
• Saturation of the main pathway occurs when there is a lack of GSH, leading to an intracellular nucleophile reactive metabolite, specifically (N-acetylbenzoiminoquinone).
• N-acetylbenzoiminoquinone binds with nucleophilic groups of cell proteins.
• N-acetylbenzoiminoquinone undergoes Redox cycling, leading to ROS and oxidative stress.
• NAC and cysteamine serve as antidotes.

Acetaminophen/Paracetamol Adverse Affects

• Acetaminophen has mild and reversible hepatic enzymes and the potential to cause dizziness, excitement, and disorientation.
• 15g of Acetaminophen may be fatal and can cause centrilobular liver necrosis and ATN.
• Early hepatic damage may manifest as nausea, vomiting, diarrhea, and abdominal pain.
• NAC is an antidote that provides sulfhydryl groups to neutralize the.toxic metabolite.
• Rare: hemolytic anemia and methemoglobinuria.
• The therapeutic dose for adults is 1.2 g/day and is not to exceed 3 g/day.

Paracetamol Toxicity

• Paracetamol may be potentially toxic and can be 150-200 mg/kg in children and 7 g total in adults.
• N-acetyl-p-benzoquinone imine (NAPQI) is a toxic metabolite of paracetamol.
• N-acetylcysteine (NAC) provides sulfhydryl groups to neutralize this Acetaminophen toxic metabolite
• NAC should be given within 8-10 hours of ingestion.
• Toxicity of Acetaminophen is mainly centrilobular necrosis of the liver.
• Symptoms of Acetaminophen toxicity include GIT initially, then hepatic encephalopathy, and Renal failure.

Goals in Pain Management

• Relief of symptoms.
• Reduce or relieve the pain.
• Slow down or arrest of tissue-damaging process.
• Reduce or remove the inflammation.
• Maintain bodily function.

Opioids Analgesics

• Opioids are classified as:
  • Full agonists like morphine, oxycodone, and hydromorphone.
  • Partial agonists like buprenorphine.
  • Mixed agonist-antagonists like pentazocine and nalbuphine.
• Opioids have a mechanism of action and opioid receptor.
• Opioids have uses in acute and chronic pain management.
• Common side effects and potential risks of opioids include respiratory depression, sedation, cognitive effects, constipation, gastrointestinal effects, tolerance, dependence, and addiction.

Mu, Delta, and Kappa Opioid Receptors

• Mu Opioid Receptors cause analgesia, euphoria, sedation, respiratory depression, and constipation.
• Delta Opioid Receptors cause hallucinogenic effects and decreased gastrointestinal secretions.
• Kappa Opioid Receptors cause dysphoria via a reduction in dopamine release.

Multimodal Analgesia

• Multimodal analgesia includes adjuvant analgesics, antidepressants.
  • Antidepressants are tricyclic antidepressants (TCAs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs).
• Multimodal analgesia includes anticonvulsants (gabapentin and pregabalin), local anesthetics (lidocaine patches and injections), glucocorticoids, and muscle relaxants.
• Multimodal analgesia definition and rationale combine different classes of analgesics.
• Multimodal analgesia combines them for enhanced pain relief and there are advantages and considerations for multimodal analgesia.
• The special considerations for multimodal analgesia are:
  • Pediatric and geriatric populations.
  • Pregnancy and breastfeeding.
  • Renal and hepatic impairment.
  • Drug interactions and precautions.

Opioids

• Opium is a white substance that exudes from the poppy, Papaver somniferum and P album, that turns into a brown gum.
• Principal Opium alkaloids are morphine and codeine.
• Codeine is synthesized commercially from morphine.

Strong Agonist Opioids

• Morphine is a natural alkaloid.
• Hydromorphone is a semi-synthetic drug that is 2-8 times more potent than morphine
• Oxymorphone is a semi-synthetic drug that is 10 times more potent than morphine -It has a short half-life and a long duration of action
• Heroin, Diacetylmorphine, is semi-synthetic and Prohibited.
• Oxycodone is semi-synthetic, 1.5 times more potent than morphine.

Strong Agonist Synthetic Opioids

• Fentanyl is 50-100 times more potent than morphine and causes respiratory depression.
  • Fentanyl has a faster, shorter duration of action than morphine, and its effects can induce anesthesia and cause bradycardia.
  • Fentanyl patches are also available.
• Methadone
  • Superior analgesia at 10–20% of the morphine-equivalent daily dose.
  • Higher bioavailability than morphine, slower tolerance, physical dependence, and is long acting.

Weak Synthetic Opioids

• Meperidine is synthetic and is used in premedical and stabilizing anesthesia.
• Meperidine has a negative inotropic action on the heart.
• A toxic dose (seizures) of Meperidine is due to its metabolite, Normeperidine.
• Meperidine is 1/10 the potency of Morphine with an onset of action of 10 min (IM,SC) and a duration of Action of 3-5 hours.

Mild to Moderate Opioid Agonists

• Hydrocodone is semi-synthetic, 1:1 potency and is combined with acetaminophen or ibuprofen with short acting and extended release.
  • Hydrocodone's structure is similar to codeine, and it has a potency of 1/10.
  • Has antitussive and analgesic properties.
• Codeine is a natural alkaloid that has a potency of 1/10.
  • Codeine has less analgesic, sedative, and respiratory depression effects and is mainly used as an antitussive.
• Tramadol is synthetic with 1/3 potency and has an onset of 30-60 min and a duration of 4-6hrs.

Opioid Antagonists

• Naloxone antagonizes the action of opioid agonists and mixed agonist-antagonists.
  • Naloxone is administered as a slow IV or continuous infusion and has an onset of action of 1-2 min and a duration of action of 1-2 hrs.
• Nalbuphine is an agonist-antagonist opioid.
  • Nalbuphine acts as a strong Kappa receptor agonist and a potent Mu receptor antagonist.
  • The effects of Nalbuphine includes respiratory depression, headaches, dizziness, and sedation.