Pain And Inflammation

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Medications for pain and inflammation

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Pain (analgesics) – Opioids
– Non-opioids – Acetaminophen
• Inflammation – Non-steroidal anti-inflammatory (NSAID) drugs – Steroids (glucocorticoids)

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opoid analgesics

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Source – Beware of eating poppy seeds before drug screening –
now controversial
• Work on same neuroreceptors as endogenous opioids
• Referedtoas‘narcotics’inthepast – Sedative effect is side effect; analgesia is main effect
• Opiate: derived directly from opium • Opioid: refers to all analgesics of this type

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effects of opioid analgesics

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Best used for cases of moderate to severe pain – Surgery, trauma, myocardial infarction (acute pain) – Cancer (chronic pain)
• Alter perception of pain
• Actonthefollowingstructures – Presynaptic nerve terminals
– Postsynaptic neurons
– Spinal cord
– Brain • Medial thalamus, dorsal gray matter, hypothalamus

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opioid receptors

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Exist in the spinal cord
– Mu, delta, and kappa receptors
• May exist in the peripheral nervous system
• Drugs to target peripheral NS would alleviate many CNS side effects
• Stay tuned: more to come in the near future

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opioids - mechanism of action

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Inhibit synaptic transmission in key pain pathways in brain and spinal cord
– Ex: spinal cord – receptors located on primary nociceptive afferents (sensory)
– Effect: bind to receptor; decrease release of transmitters that allow pain transmission
• Decreaseneurotransmitterreleasefrompre- synaptic terminals
• Diminish excitability of post synaptic neurons to transmit pain

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opioids - effect on pain

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Summary: “opioid drugs exert their analgesic effects by interacting with receptors that are linked to several intracellular effector mechanisms that ultimately lead to decreased synaptic transmission in specific pain pathways”

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opioids - various types

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Strong agonists
• Moderate agonists • Mixed agonist/antagonists • Antagonists

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terminology review

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Agonist: – Has affinity and efficacy
• Antagonist – Binds to a receptor, but has no effect on cell function – Serves as a “blocker” – Has affinity, but no efficacy
• Affinity – Attraction to bind to a given receptor
• Efficacy
– Drug will activate receptor and change cell function (ex: increase or decrease excitability)

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opioid strong agonists

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Used to treat severe pain • Effects:
– Analgesia – Sedation – Respiratory depression – Cough suppression – Pupil constriction – Diminished GU and GI motility – Vomiting – Severe skin itching – Can cause euphoria (80%) and dysphoria (20%)
• Examples: – Fentanyl (Duragesic) – Hydromorphone (Hydrostat) – Meperedine (Demerol) – Morphine (MS contin, Roxanol)

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opioid moderate agonists

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More effective in treating moderate intensity pain
• Othereffects: – Cough suppression – Control diarrhea
• Examples: – Codeine
– Hydrocodone (Hycodan) and combinations • + acetaminiphen = Norco and Vicodin
– Oxycodone (Oxycontin) and combinations • + acetaminophen = Percocet • + aspirin = Percodan
– Propoxyphene (Darvon) – Tramadol (Ultram)

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opioid agonist side effects

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Sedativeproperties – Mood changes
– Drowsiness and/or confusion – Euphoria (some patients)
• Respiratorydepression • Orthostatichypotension • Toleranceanddependence
• GIdistress – Nausea, vomiting, constipation

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Tolerance and Dependence

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Tolerance
Side effects
– “the need to progressively increase the dosage of a drug to achieve a therapeutic effect when the drug is used for prolonged periods”
• Dependence – “the onset of withdrawal symptoms when the
drug is abruptly removed”
– Must differentiate physical dependence from addiction and psychological dependence

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opioid mixed agonist/antagonists

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Can produce adequate pain relief, but less that stronger agonists
• May have less side effects than previously mentioned opioids
– Reduced risk of fatal overdose
– Less addictive qualities
– May produce hallucinations and other psychotropic effects
• Agonist/antagonist function may help with treatment for dependency

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examples of opioid mixed agonist/antagonists

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Butorphanol (Stadol) – Buprenorphine (Buprenex) – Pentazocine (Talwin)

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opioid antagonists

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Block opioid receptors, so do not produce analgesia
• Will also displace agonists from opioid receptors • Used primarily to treat opioid overdoses and
opioid dependence
• Rapidlyreversesrespiratorydepression
• Examples: – Naloxone (Narcan)
– Nalmefene (Revex) – Naltrexone

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Opioid Side Effects

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Few problems with opioid use when – Pt. has no Hx of substance abuse – Pt. adheres to prescription regimen – Pain is from physiological causes
• Risk of tolerance and dependence is very low when opioids are used appropriately to treat chronic pain

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patient and treatment concerns

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Schedule patients when drugs have greatest effect on pain relief
• Sedative effects may limit patient ability to accurately describe pain or other response to treatment
• Respiratory depression needs to be accounted for in rehab activity requirements
• GIand constipation issues may affect rehab activities as well
• PT may help manage physical symptoms of withdrawal, which can be dramatic

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acetaminophen

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Tylenol = most common brand name
• Many generic and store brands (OTC)
• Can be combined with codiene in single pill
– Tylenol # 3 (325 mg acetaminophen and 30 mg codiene) = analgesic and opioid agonist

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Acetaminophen (cont..)

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25-50% ingested drug produces therapeutic effect50-80% ingested drug bound to plasma proteins
– Side effects:High doses can be toxic to the liver (hepatic necrosis)
• High doses = 15 grams or morecan have fatal consequences
– Single tablet: ‘regular’ = 325 mg; ‘extra strength’ = 500 mg; ‘arthritis formula’ = 650 mg

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inflammation

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Common clinical scenario
• May be acute or chronic • Many prescription and OTC medications

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inflammation continued..

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Occurs in response to tissue injury or disease
• Pain is only one component
• Injuredcellsproducemanysubstances,including prostaglandins.
• Roleofprostaglandins: – Increase local blood flow and capillary permeability – Increase sensitivity of pain receptors – Help to produce elevated body temperature – May facilitate menstrual cramping
– Increase thrombus formation by increasing thromboxanes, which facilitate platelet aggregation.

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control of inflammation

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Stop prostaglandin formation
• Go back further up cellular breakdown chain, and target cyclooxygenase, which is essential to form prostaglandins
• Inhibit cyclooxygenase = inhibit formation of prostaglandins

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NSAIDS

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Are potent inhibitors of cyclooxygenase enzyme.
• Reduce pain (analgesic) • Reduce inflammation (anti-inflammatory) • Reduce fever (antipyretic) • Reduce thrombus formation (anticoagulant) • Reduce colorectal cancer (anticancer)

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Prostaglandins

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Primarily function as previously described
– Stimulate processes that result in symptoms of inflammatory response
• Some have protective function – Protect gastric mucosa – Help maintain proper renal function

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Cyclooxygenase Enzyme System

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AKA “COX” enzyme system
• Precursor to prostaglandins and some thromboxanes
• Has 2 primary subtypes: – COX -1 enzyme – COX-2 enzyme – Now a COX-3 has been discovered

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COX-1 enzyme

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Normal constituent in certain cells
• Prostaglandins synthesized by COX-1 are responsible for:
– Maintaining normal cell activity
– Protect gastric mucosa
– Maintaining normal renal function, especially when kidney function is compromised
– Regulate normal platelet activity

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COX-2 enzyme

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Produced primarily in injured cells
• Produces prostaglandins that mediate pain and inflammation

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non-selective NSAIDS

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InhibitbothCOX-1andCOX-2enzymes
• Goodeffect – Inhibit COX-2 enzyme – Reduce pain and inflammation
• Badeffect – Inhibit COX-1 – Loss of protective prostaglandins – Result is gastric irritation and decreased renal function
– Associated with Reye’s Syndrome (aspirin) • Occurs in children and teens • High fever, liver dysfunction, can be fatal

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non-selective NSAIDS - examples

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• Ibuprofen (Motrin)
• Aspirin – Advil = OTC version
• Naproxen (Naprosyn) – Aleve = OTC version
• Indomethacin (Indocin) • Diclofenac (Voltaren)
– Diclofenac and Misoprostol (Arthrotec) • Etodolac (Lodine) • Oxaprozin (Daypro) • Ketorolac (Toradol) • Meloxicam (Mobic)

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Aspirin

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Blocks production of prostaglandins and thromboxanes
• Manypositiveeffects – Decrease pain and inflammation – Inhibit platelet formation
• Somenegativeeffects – Binds irreversibly to platelet
• Inhibits binding of other NSAIDs to same receptor – GI upset and bleeding
• Normal (325 mg) dose can cause 3-8 ml blood loss per day in feces
– Overdose • Headache, tinnitus, confusion, respiratory hyperventilation

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Aspirin - NSAID conflict

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Clinical example: pt needs to takes low dose aspirin (75-80 mg) for anticoagulation effect
– Aspirin binds irreversibly onto platelet
• Pt also needs to take NSAID for inflammation – NSAID wants to bind to same platelet receptor – NSAID reversibly binds to platelet
• If NSAID taken before aspirin, will block cardiac effect of low dose aspirin
• Recommendation: take aspirin first, achieve CV effect, wait 2 hours, then take NSAID.

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Selective NSAIDS

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Only inhibit COX-2 enzyme – Spare beneficial prostaglandins – Inhibit inflammatory prostaglandins
• Celecoxib (Celebrex) • Valdecoxib (Bextra) • Rofecoxib (Vioxx) • Lumiracoxib (Prexige) • Etoricoxib (Arcoxia)

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Selective NSAIDs effects positive and negative

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Reduce GI issues present with non-selective NSAIDs
– Certain patients still get diarrhea, GI bleeding, etc. • No more effective in reducing pain and inflammation
than non-selective NSAIDs
• May increase hypertension, and renal toxicity issues also remain
• Do increase risk of URI • May have increased risk of heart attack and stroke in
patients taking high dose, or dosing for > 18 months – Inhibit prostacyclin, which prevents platelet aggregation
• Allows platelet aggregation to occur (inhibit the preventor)
– Allow COX-1 enzymes to produce thromboxane, which also facilitates platelet aggregation

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NSAID effects (bad)

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Similar to aspirin
• Offer no anti-coagulant (cardiac) protection
• GI bleeding
• Decrease effectiveness of ACE inhibitors, diuretics, and beta blockers
– Results in elevated blood pressure
• Can affect proper muscle healing
• Can cause cognitive dysfunction, dizziness, and confusion
• Can cause hypertension – Due to inhibition of vasodalitory prostaglandins

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NSAID Dosage

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10-20% ingested drug produces therapeutic effect
– 80-90% ingested drug bound to plasma proteins • Must be steady and prolonged for anti-inflammatory
effect to occur – Daily dosage variable depending on drug – Minimum of 5-10 days depending on drug
• Campfire example – Water on campfire - stop flow when fire seems to be
extinguished - flames can rekindle
• Single dose will work for pain, but will not control inflammation

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NSAID effect on muscle healing

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Used prolifically to treat muscle injury and muscle soreness
• 1 of 5 athletes had an adverse reaction using prescribed NSAIDs
• Muscle injuries are very common
• Inflammatory response is crucial to healing
• Following injury, satellite cells are activated to proliferate into new muscle fibers

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NSAIDs and muscle healing (2)

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Use of NSAIDs inhibits prostaglandin formation
– Inhibits satellite cell activation • This negates the start of the inflammatory
process
• Cellular recruitment to damaged site in the first 24 hours prevents the initiation of the muscular repair process

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NSAIDs and muscle healing (3)

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NSAIDs delayed muscle healing and recovery
• No difference in pain reduction and return to recovery (NSAIDs or not)
• Severe strains responded better to placebo group than NSAID group
• No effect of NSAIDs on delayed onset muscle soreness
• NSAIDs can stop or inhibit muscular hypertrophy associated with strength training

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what to do with NSAIDs

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ONLY use as prescribed or recommended (OTC also)
• After muscle injury, allow the inflammatory process to occur for 24-48 hours before taking NSAID (except for severe cases)
• EducatepublicthatNSAIDshavenoeffecton physical performance
– Belief of many coaches, trainers, and athletes
• PRICE: best bet for initial 24-48 hours post muscle injury

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what to do with pts on NSAIDs

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During exercise with patients, avoid exercise that increase intra-abdominal pressure.
• Avoid vigorous interventions that may induce bleeding with minimal trauma
– Some examples? – Reduce loads and force applications
• Educate your patients – NSAIDs are not candy

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Glucocorticoids - basics

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Potent and effective anti-inflammatory agents
• Also have other physiological effects – Control glucose metabolism – Involved in the reaction of the body to stress – Can suppress the immune system
• Used for a wide variety of symptoms and disorders beyond inflammation

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Glucocorticoid effects

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Inhibit phospholipase
• Phospholipids can’t be liberated from cell membranes
• Eliminate precursor for production of prostaglandins and leukotrienes
• Synthesis of prostaglandins and leukotrienes prevented
• Inflammation process inhibited • Other mechanisms as well at the cellular level

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Common Glucocorticoids

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Betamethasone (Celestone) • Dexamethasone (Decadron) • Hydrocortisone (Hydorcortone) • Methylprednisone (Medrol) • Prednisone (Deltasone) • Triamcinolone (Azmacort, Nasacort)

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Glucocorticoids - side effects with prolonged use

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Adrenal cortical depression – Exogenous glucocorticoids cause internal production
to be shut down – Withdrawal must be performed gradually
• Drug induced Cushing Syndrome – Facial puffiness and trunk fat deposition – Extremity muscle wasting – Hypertension – Osteoporosis – Increased body hair – Glucose intolerance

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Glucocorticoids - side effects with prolonged use (2)

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Can occur with low dosage • Breakdownofmuscleandconnectivetissue
– Catabolic effect on muscle, bone, tendons, ligaments, and skin
– Inhibit genes responsible for collagen formation • Caution with application of loads to tendons and ligaments
– Increase rate of protein breakdown and decrease the rate of protein synthesis in muscle
• Patients present with proximal extremity muscle weakness – Loss of bone strength
• Suppress bone production stimulators and increase substances that promote bone loss

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Glucocorticoids - normal side effects

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Peptic ulcer • Increased susceptibility to infection • Retard growth in children • Glaucoma • Mood changes, psychoses • Hypertension • Alter glucose metabolism

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Rehab concerns

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Aspirin, OTC NSAIDs, and acetaminophen are significant pharmacological agents
– All have detrimental side effects that are often ignored by the public
• Aspirin is not the same as acetaminophen
• NSAID dosage for inflammation must be higher than dosage for pain, and sustained for longer time period
• Prescription NSAIDs have significant side effects – Neverintendedtobetakenforextendedtimeperiods(years)
• Catabolic action of glucocorticoids on connective tissue is major concern in regard to stretching and load application
• Joint injections of glucocorticoids should be limited to no more than 4 per year
• Be able to answer patient questions, and refer dosage and drug choice back to physician