16 Anti-Inflammatory, Analgesic and Anti-Pyretic Therapies

PRICE Therapy for Inflammation and Pain

PRICE is an acronym which helps to remember effective non-medical remedies for inflammation.  Bumps, bruises, burns and cuts are often quikly treated in this manner to reduce both inflammation and pain.  In brief, PRICE and its mode of action is as follows:

• Protection: The P in the acronym stands for Protection and refers to the practice of protecting the damaged area from further injury.  This may be with a splint, cast, or crutches, etc.
• Rest: Rest reduces blood flow to the area which can reduce inflammation.  Rest can also help with reducing movement that may delay any blood vessel repair that is required.  In order to preserve joint function, range of motion, and muscle strength, the recommended rest period may be temporary.
• Ice:  Applying ice wrapped in towel (or a cold compress) reduces inflammation and swelling by inducing vasoconstriction (and therefore less exudate leakage).  Ice also depressed nerve activity which can reduce pain.
• Compression:  Compression can help stop bleeding if there is an external wound and can also reduce the accumulation of leaked exudate and inflammation.
• Elevation: Elevation of a wounded area can reduce inflammation by helping to drain or move fluid away from the damaged area.

*With muscle or joint injuries often alternating warm and cold compresses is advised with the rationale that heat and moderate activity improves circulation which will help in removing excess fluid, pain-causing chemicals and cellular waste.  The movement also helps with maintaining joint mobility.

*Other recommendations for ensuring optimal healing include nutrition and adequate hydration.

Treatment of Inflammation, Pain, and/or Fever

There are several effective non-narcotic medications used to treat inflammation, pain and fever, many of which are sold over-the-counter.  In this section their mode of action will be discussed as well as the pros and cons of using each one.

• Acetylsalicylic acid (ASA): eg. Aspirin
  ASA is considered a NSAID (Non-Steroidal Anti-Inflammatory Drug).  ASA is a non-narcotic, analgesic (reduces pain) and antipyretic (reduces fever).  ASA’s mode of action is through decreasing the WBC production of prostaglandins that are responsible for inducing inflammation and fever.  Specifically ASA blocks  cyclooxygenase enzymes (COX-1 and COX-2) which are required for the production of several types of  prostaglandins.   While ASA is an effective anti-inflammatory and an antipyretic medication, there are several potential negative side-effect.  Firstly, ASA should never be given to children or teenagers that have viral infections, and ASA can cause Reye’s syndrome, which results in potentially fatal liver and brain damage.  Secondly, long-term use of ASA has been found to block the production of non-inflammatory prostaglandins that play an important and necessary role in the daily production of protective gastric mucus and ability of platelets to adhere during hemostasis.  Long-term use of ASA is therefore associated with the loss of gastric mucus and formation of gastric and peptic ulcers as well as excessive bleeding due to slowed ability to perform hemostasis.   Finally, as with any medication, ASA should be taken properly as directed by the instructions to avoid damaging liver or kidneys and ASA can be an allergen for some people.
• Summary:    In response to cell or tissue injury, Mast cells and Basophils convert phosopholipids → arachidonic acid → pro-inflammatory prostaglandins with the use of enzymes that include cyclooxygenases (e.g. COX-1/2)
• Side note:  Mast cell and Basophils also convert phospholipids into other lipid based pro-inflammatory cytokines (e.g. leukotrienes).
• ASA has been found to work by blocking COX-1/2 → ↓ production of PGs reducing inflammation, pain, & fever
  Not to be used during viral infection → Reye’s syndrome (liver & brain damage)
  Can ↓ gastric mucus → can cause stomach irritation & ulcers
  Can interfere with blood clotting (reduces platelet adhesion); Can be an allergen
• Due to its anti-coagulant properties, at times a small dose of aspirin has been prescribed by physicians to reduce the chance of clotting in those that are risk for clot formation.  Clot emboli are dangerous in that they can obstruct blood vessels preventing the delivery of oxygen and nutrients to downstream tissues.

• Acetaminophen (e.g. Tylenol, Paracetamol)
  Acetaminophen is not an anti-inflammatory, but does decrease both pain and fever.  Specifically, it’s mode of action is to block the production of specific prostaglandins (e.g. prostaglandin E₂) which are responsible for inducing pain and fever (but not inflammation).  Again, as with ASA, Acetaminophen should be taken properly as directed by the instructions to avoid damaging liver or kidneys and it can be an allergen for some people.
• Summary:  Blocks part of COX-2 downstream pathway →↓production of PG E₂ → ↓fever & pain , but not inflammation

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) e.g. Ibuprofen, Advil, Motrin

These NSAIDs are similar to ASA, in that they are also non-narcotic analgesics, and also are effective anti-inflammatories and antipyretics.  However, they are thought to block the production of various prostaglandins to a different degrees and are not linked to Reye’s syndrome, gastric ulcers, or excessive bleeding.  As with ASA, NSAIDs work by blocking the enzymes COX-1 and COX-2 and production of various prostaglandins (though to a different degree).  Overall these NSAIDS are associated with less negative side-effects in comparison with ASA.  The reason for this is that ASA is thought to block COX-1 more than COX-2, and that COX-1 is associated with the production of non-inflammatory prostaglandins (e.g. PG1₂) required for daily gastric mucus production, thromboxane (required for platelet function – specifically platelet adhesion during clotting).

Summary:  Also works by blocking COX-1/2  → ↓ production of PGs (though blocks COX-1 less than ASA does)
Decrease fever, pain & inflammation; with less negative side-effects of aspirin

• COX-2 Selective Drugs (C2s) e.g. Celecoxib

COX-2 selective drugs have been designed to preferentially block the COX-1 enzyme which is required for the production of pro-inflammatory and fever-inducing prostaglandins.  Overall these C2s are associated with less negative side-effects in comparison with ASA.

Summary:  Also works by blocking COX-2 → ↓ production of PGs associated with inflammation, fever, and pain; with less negative side-effects of aspirin

• Glucocorticoids (steroidal anti-inflammatory drugs) e.g. Corticosteroids
  Over-the-counter Glucocorticoids (e.g. Corticosteroids) mimic the endogenous glucocorticoids produced by the body and have the same effects.  Glucocorticoids reduce WBC migration, proliferation, and activity and are therefore immunosuppressive and reduce the production of pro-inflammatory cytokines by WBCs.  Interestingly, glucocorticoids are not considered analgesics or antipyretics, though due to reduction in pro-inflammatory cytokine production, there is a reduction of vasodilation, capillary permeability and swelling.  Reduced swelling can alleviate some pressure and pain.  Glucocorticoids are used cautiously as they are catabolic in nature and stimulate the breakdown of proteins and glycogen.  The breakdown of proteins to form glucose is called gluconeogenesis and the breakdown of glycogen is termed glycogenolysis.  This can lead to higher blood glucose levels as well as tissue wasting (and impaired growth and healing).
• Summary: Decreases: capillary permeability (limits emigration/chemotaxis), # of WBCs, # mast cells, release of histamine, prostaglandins & leukotrienes
  Negative side-effects: lymphoid tissue atrophy (decreased # WBCs leading to risk of infection & reduced immune response); catabolism; thinning skin (peptic ulcers), delayed healing, delayed growth, Long-term higher doses can cause high blood pressure & edema (Na⁺ and H₂O retention) due to glucocorticoids’ weak mineralcorticoid (ADH-like) activity.

Note:  By its definition, the above classses of drugs (ASA, acetaminophen, NSAIDs, glucocorticoids) discussed are not narcotics (e.g. opiods – morphine, heroin, fentanyl) and do not induce narcosis (sleep) and are not linked with addiction (physical dependence and increasing tolerance), sedation, depressed heart and breathing rates, apathy, reduced ability to concentrate, and potentally fatal substance abuse.  Narcotics are addictive and are responsible for the current opioid crisis in N. America.