I. Looking at pain
 A. Analgesic: from the Greek,  "an"--without
     "algein"--to feel pain

 B. Two types of pain
        1. Organic  "physical"
            a. pressure or injury to neural pain fibers
            b. heat over 45°C (111° F)
            c. injection of chemicals (potassium, hypertonic solutions)

        2. psychogenic
          --fear and anticipation (more on this with Psychotropics section)

 C. The Physiology of Pain
  1. Algesics: substances that cause pain
  2. Examples
           a. histamine
              --part of the allergic response, involved in acid secretion, released from the mast cells
           b. serotonin--from damaged platelets
           c. bradykinins--from plasma proteins
           d. prostaglandins--from cell membranes
           e. electrolytes and chemical neurotransmitters
              --potassium, acetylcholine, et al

 D. Endogenous analgesics--the ENDORPHINS

  1. endogenous--
  2. release of endorphins stimulated by
           a. biofeedback
           b. acupuncture
           c. placebo effect
           d. electrical stimulation of the skin
           e. stress (intentional or environmental)
           f. pain
           g. aerobic exercise

  3. some endorphins have been synthesized and are under investigation of analgesia during childbirth

  4. they are very potent, but they must be injected directly into the central nervous system (i.e., into the spinal cord) in order to work; orally administered endorphin-type compounds are ineffective

II. THREE BROAD CLASSIFICATIONS OF ANALGESICS: Table I
(these classifications are from your text and are occasionally arbitrary; they are presented in this fashion for convenience in discussion)

 General Examples for each category

MILD                                 MODERATE                              STRONG
acetylsalicylic acid                  codeine **                                  morphine **
 (aspirin or “ASA”)                pentazocine ** (Talwin)               hydromorphone ** (Dilaudid)
acetaminophen                       oxycodone **                             methadone**
 (Tylenol, Datril, etc)              NSAIDs                                      meperidine **
propoxyphene **                   hydrocodone **
 (Darvon)

    * = prescription
   ** = prescription and a controlled substance (potential for abuse exists)

III. MILD ANALGESICS
 A. the Salicylates (the "prototype")
       1. for mild to moderate pain, not for visceral pain
       2. THE THREE MAJOR EFFECTS OF THE SALICYLATES
         a. analgesic
         b. antipyretic
              "pyrexis" Greek for "heat", therefore, antipyretic =
         c. anti-inflammatory

       3. Discussion of effects
           a. analgesia
               i. relief without sedation
              ii. decreases synthesis of prostaglandins and bradykinins

          b. antipyretic
              i. affects the hypothalamus (temperature regulation)
              ii. decreases temperature, but not below normal
             iii. inhibition of prostaglandins plays a role here
               (pyrogens stimulate prostaglandin production which in turn causes fever)

         c. anti-inflammatory
             i. blocks kinins, histamine precursors
            ii. used in arthritis, but in high doses (3.6-6 gm/day)(10-20 tablet/day)

4. Other actions of aspirin/salicyclates
         EFFECT ON PLATELETS Anticoagulant–the 4th “A”
         a. inhibits platelet "adhesiveness" and coagulation
         b. 300mg (1 tablet) will decrease clot formation
         c. one tablet daily is indicated to prevent recurrent heart attack, alone or in combination with dipyridamole (Persantine), or a beta blocker, and it is undergoing investigation for treating transient ischemic attacks (TIAs or "mini-strokes")
         d. highly protein bound--INTERFERES WITH ANTICOAGULANTS --warfarin (Coumadin)

Aspirin acts as an
 a. obtundent
 b. antipyretic
 c. antiinflammatory
 d. analgesic
 e. anticoagulant

              iii. loss of tablespoonful of blood occurs with each dose of aspirin

          b. stimulation of CTZ (chemoreceptor trigger zone)
              --nausea results

          c. tinnitus    definition:– “ringing in the ears”  --seen at doses to treat arthritis

       6. OVERDOSAGE SYMPTOMS
           a. nausea/vomiting
           b. diarrhea
           c. tinnitus and hearing loss
           d. sweating, paradoxical fever, thirst, hyperventilation
           e. hypoglycemia, severe GI bleeding

  8. Specific agents
          aspirin, salicylamide, choline and magnesium salicylates
          salsalate (Disalcid *), diflunisal (Dolobid *)
          salicyclic acid and methylsalicylate ("Oil of Wintergreen") are for topical use only!!!!!!!

          3. COMPLETELY SAFE, RIGHT? WRONG!
           a. overdosage causes IRREVERSIBLE kidney and liver damage
           b. death from overdosage not immediate
           c. some damage possible even at chronic therapeutic doses
           d. OVERDOSES TREATED WITH ACETYLCYSTEINE (Mucomyst)
               acetylcysteine smells like rotten eggs; the administration of it is often given to enhance the repelling nature of the therapy in an added attempt to discourage overdosages in the future by the patient (technically, this is called “negative reinforcement”)

 C. Propoxyphene: (Darvon, Darvon N)
  1. structurally related to methadone
        2. used alone or in combination with aspirin (Darvon Compound, Darvon with ASA) or acetaminophen (Darvocet N 100)
        3. low addiction potential, but abuse led to "controlled" status; the original capsules came with the active ingredient in pellet form with filler to add bulk; patients ground up the pellet and injected it
           --effect can be reversed with naloxone (Narcan)
        4. drowsiness is primary side effect

    B. About each type:
        1. codeine
            a. natural substance: from the opium poppy
            b. 1/12 the strength of morphine (see "strong analgesics")
            c. rarely used alone
               --appears in combination with other agents, such as aspirin (Empirin #3), acetaminophen (Tylenol #3), promethazine (Synalgos DC)

              --the "number nomenclature"
                #3 as in Tylenol #3 indicates amount of codeine present
                #2=15mg
                #3=30mg
                #4=60mg
The amount of acetaminophen (Tylenol) used in each of the above preparations is 5 grains, or 325mg

            d. analgesic and antitussive properties
                --the "AC" of Robitussin AC cough syrup
            e. opioid side effects
                --CTZ stimulation
                --addiction potential
                --constipation
                --respiratory depression

        2. oxycodone
           a. semi-synthetic
           b. less potent than morphine when given alone
           c. therefore, not given alone
                i. with aspirin: PERCODAN
                ii. with acetaminophen: TYLOX, PERCOCET-5

        2a. Hydrocodone
  This product has the dubious distinction of being THE most popular, commerically manufactured, drug of abuse (as of 1998).  An extremely effective analgesic, it has addictive potential and a history of inducing euphoria.  Considered to be as effective as the CII narcotics Percodan and Tylox, it has the advantage of CIII status, meaning less strict controls exist on its prescribing (special prescription forms are not needed, for example).

  Hydrocodone is usually in combination with acetaminophen and goes under the trade names of ANEXIA, VICODIN, VICODIN ES (extra strength), LORCET, LORTAB, and many others.

  Recently, it has been combined with 200mg of ibuprofen to create VICOPROFEN.

  It also has antitussive properties, and appears in the strong cough syrups HYCODAN, ENTUSS, and DETUSSIN.
  This is a very popular selection of “patients” presenting fake prescriptions to pharmacies.

A further note on hydrocodone abuse:
Heroin addicts have discovered the combination of hydrocodone and carisoprodol (Soma) can give a heroin-type euphoria.  Carisoprodol (Soma) is used as a muscle relaxant.  Creative abusers go from physician to physician with varying vague “symptoms” until they get the combination they want.  Occasionally they find a physician willing to “accommodate” them with the combination on the same prescription blank!  So much for subtlety!

  3. pentazocine (Talwin)
          a. narcotic agonist/weak antagonist
          b. developed with the intention of producing an agent with analgesia with low/no abuse potential; however, it was soon found to be a favorite for its ability to produce some euphoria, especially in the injection form
             BUT abuse with tripylennamine (PBZ) (a blue capsule, hence the name "Ts and Blues") caused the manufacturer to add naloxone (Narcan), a narcotic antagonist, to prevent this abuse
          c. less respiratory depression than with natural opioids
          d. may precipitate mild withdrawal in patients stabilized (or addicted) to other opioid derivatives
           --consider moderate morphine usage in early post-MI patients who may have a mild tolerance to the morphine who are then released from the hospital with prescriptions for Talwin; discomfort is often noted; this is also NOT a good analgesic for cancer patients who have been getting healthy doses of morphine to control pain.

       4. NSAIDs
        a. very popular, ibuprofen, naproxen, and ketoprofen are currently available without a prescription
           b. a list:
     *Ibuprofen (Motrin, IBU, Motrin IB, Rufen, Nuprin, Advil)
   -200mg strengths are available without a prescription
     *Naproxen (Anaprox, Naprosyn)
   -220mg strength is over the counter (Alleve)
     *Ketoprofen (Orudis)
   -12.5mg strength is over the counter (Orudis KT)
     Fenoprofen (Nalfon)
     Sulindac (Clinoril)
     Indomethacin (Indocin)
     Tolmetin (Tolectin)
     Mefanamic acid (Ponstel)
     Meclofenamate (Meclomen)
     Piroxicam (Feldene)
     Suprofen (Suprol)
     Oxyphenbutazone (Tanderil)
     Phenylbutazone (Butazoladin)
     Ketorolac (Toradol)--injection and oral
     Flurbiprofen (Ansaid)
     Meloxicam (Mobic) – relatively new – 7.5 and 15mg strengths/selective COX-2
     Zompirac (Zomax)--withdrawn in 1982 (of historical interest only)

        c. none are controlled substances, indicating little or no abuse potential
            d. in general, they work by decreasing the synthesis of prostaglandins
            e. originally used to treat arthritis only; current indications for many include general moderate pain,headache, and premenstrual cramping
            f. phenylbutazone (Butazoladin) and oxyphenbutazone (Tanderil) reserved for more severe cases due to toxicity reactions (especially leucopenia; first sign is a sore throat)
            g. allergies possible
                i. ASA crossover
               ii. asthmatics more susceptible
            h. possible interaction with anticoagulants (can be directly, due to interference with blood plasma protein affinity or indirectly, due to aggravation of side effects)

            i. side effects
               (1) nausea and vomiting (n/v); gastrointestinal (GI) distress
               (2) take with food

       5. Relatively recent additions
          a. tramadol (Ultram) 50mg – usually every 4-6 hours, up to 4 tablets in 24 hours
               –becoming a popular drug for abuse; users discover euphoria if taking more than 12 tablets a day; potential for liver damage exists, so the company has decided to combine tramadol with acetaminophen to form Ultracet. Cha-ching!
          b. Duract 25mg
              --1998 warnings on this NSAID indicated that its three times daily dosing should be restricted to a total of 10 days due to the potential for severe liver damage; the FDA later decided to pull it from the market completely since this liver damage was causing many deaths... a brief flurry on the market, but a bad bad track record

 7. COX-2 Inhibitors New as of January 1999!
  The entire concept of COX, or cyclooxygenase, has only been understood recently.  Schematically it breaks down as part of the production of prostaglandins:

 In 1991, there was a second COX enzyme discovered, and their functions were found to be different on the body.

 COX-1 “Good COX” – involved in most cells for purposes of “housekeeping.”  In the stomach, COX-1 catalyzes the synthesis of prostaglandins E2 and I2 which have cytoprotective functions.  Elsewhere, COX-1 it is involved with platelet and renal function.

 COX-2 “Bad COX” – involved in the inflammatory response and in immune cells (neutrophils, macrophages, mast cells, etc).  COX-2 is responsible for creation of hyperalgesic and proinflammatory prostaglandins.  This inflammatory response has also been implicated in some colon cancers and in development of Alzheimer’s disease.  COX-2 is also in the nervous system where it is involved in the transmission of pain.

 NSAIDs inhibit BOTH COX-1 and COX-2 enzymes.  As a result, they reduce inflammation (COX-2) and the GI protective process (COX-1).

 January 1999, the first COX-2 selective agent, celecoxib (Celebrex from Searle labs), was made available.  Until now, the closest COX-2 selective agent was from the relative specificity of  sulindac (Clinoril).  Other more potent agents are under investigation.

 While both these agents are supposed to be protective of the stomach lining, administration with food or milk is still strongly suggested!

 As a sidebar here, two spices also demonstrate COX-2 inhibition: ginger and tumeric.  These agents have been part of naturopathic treatments for arthritis for many years.

 Celebrex is being studied as a treatment for FAP (familial adenomatous polyposis) and as supportive therapy in Alzheimer’s.

 B. MORPHINE SULFATE
  1. opioid receptor--recall discussion
            --this receptor is the site of action for morphine, its congeners, and the narcotic antagonists--

         2. elevates pain threshold and alters pain perception --you just don't care

         3. other general effects
             a. respiratory depression, even in small doses
             b. drowsiness, mental clouding, inability to concentrate
             c. constipation
               --opioids used to treat diarrhea
               --camphorated tincture of opium PAREGORIC
               --diphenoxylate (mixed with atropine, it is called LOMOTIL)

             d. physical dependence
             e. constriction of pupils

             f. effect on urinary tract
                a. increase in urethral tone
                   --constriction, causing urinary retention
                   --consider KIDNEY STONE patients!
                b. increase in bladder tone
                   --increased urge to urinate
                 (but! the urethra is constricted, making urination difficult...what a dilemma)

             g. tolerance possible

  4. uses
             a. analgesic/pre-op
             b. has antitussive properties, but not used for this

  5. absorption
             a. IM, SQ, IV best
             b. oral absorption less reliable, but sustained release preparations help this somewhat

         6. side effects/toxicity
             a. N/V (CTZ stimulation)
             b. dependence/withdrawal
             c. allergic reactions
   d. drowsiness and sedation

  7. contraindications
             a. asthma, emphysema--respiratory depression
             b. neurotic patients--mental clouding, euphoria
             c. head injuries--increase in intracranial pressure
   d. and, of course, allergy to morphine

         8. dosing
             a. varies: usually 8-15mg, IM,SQ, or IV
             b. orally, 15-30mg
             c. cancer patient tolerance–some patients with terminal cancer can find their doses expressed not in milligrams, but in grams

  C. OTHER STRONG ANALGESICS
      1. Semisynthetics
         --minor alterations in the structure of the morphine molecule, usually altering comparative potency
          a. hydromorphone (Dilaudid) --5x potency of morphine (1-3mg SQ)
          b. oxymorphone--10x potency (1mg SQ)

      2. Synthetics
          a. meperidine (Demerol)
              i. 1/10 potency of morphine, 50-100mg IM, PO
              ii. fewer side effects, less constipation

          b. methadone
              i. 5-10mg po, IM
              ii. less euphoria
              iii. some withdrawal symptoms
              iv. use for heroin addiction

          c. fentanyl citrate (Sublimaze) --short acting; surgical use only in injection form

         d. alfentanyl (Alfenta) --also short acting, and also reserved for surgical use
 

III. NARCOTIC ANTAGONISTS
 Narcotic antagonists have a strong affinity for the opioid receptor but lack any opioid activity–affinity without intrinsic activity.  Contraindications would therefore include patients receiving opioid analgesics (ie cancer patients with high doses of narcotic pain relievers), opioid dependent patients; patients in acute opioid withdrawal; positive urine screen for opioids; also, acute hepatitis or liver failure are also situations that preclude the use of these antagonists.

       A. Naloxone (Narcan)
        1. 0.4mg naloxone (Narcan) injection reverses narcotic effect of morphine
        2. use in misadventure overdose episodes where respiratory depression may prove fatal, excessive MS administration during surgery (recovery room administration with excessive respiratory depression)
        3. larger doses during respiratory/cardiac arrest to prevent cerebral anoxia (experimental)
        4. COMPLETELY ANTAGONISTIC WITH NO ANALGESIC EFFECT (definition of an antagonist)

 B. Naltrexone (ReVia)
  1. Unused for years, it became popular recently for use as a treatment of alcoholism
  2. reduces the side effects of alcohol withdrawal
  3. unlike naloxone, therapy is oral, 50mg daily
  4. ironically, the patient has to be carefully monitored for liver damage while taking naltrexone (one way or the other, the liver is going to be hurt, it seems)
 

IV. ADDING TO ANALGESIA
      --non-analgesics added to enhance effect
 --these drugs primarily cause added drowsiness or muscle relaxation to potentiate the effect of the analgesic

       A. meprobamate (Equanil) added to aspirin, acetaminophen (EQUAGESIC)
       B. phenobarbital and the barbiturate derivatives (Fiorinal)
       C. antihistamines (hydroxyzine [Vistaril]; promethazine [Phenergan])
   antihistamines are usually added in injection form as pre-op

KCC Dental Hygiene Students: to send your homework, highlight the questions below, go to "edit," click on "copy," then click onto my email address below...when the email appears, go to "edit" in the email menu, click on "paste," and the questions will appear as the body of the email.  Answer the questions and then press "send." Your homework will be reviewed and returned via email within 72 hours.  Or just do it all on paper and bring your work to the next class session.

1. List four pharmacological properties of aspirin.  Which one(s) is/are not shared by acetaminophen?
2. What is the drug treatment for acetaminophen overdosage?  Describe its smell.
3. List three conditions that would prohibit the use of morphine.
4. List three side effects of morphine.
5. Define tinnitis
6. Give two examples of pure narcotic antagonists and describe their primary use(s).
7. When is the best time to administer an analgesic to a dental patient?
8. Give two reasons why a patient with bleeding problems should not be given aspirin.
9. List three trade or “brand” names for acetaminophen.
10. How can you identify the amount of codeine in a combination product such as “Tylenol #2?”  How much codeine is represented by the “#2?” “3?” “#4?”
11. What are the breakdown products of aspirin?  What is the indicator of an aspirin tablet having broken down?
12. Define antipyretic
13. Define endorphin
14. Discuss the abuse potential of hydrocodone and which muscle relaxant is often added to enhance the “abuse experience.”
15.  List five methods by which endorphin release can be stimulated.
16. Discuss the unique effect of COX-2 inhibitors that sets them apart from other NSAIDs.
17. Define NSAID.
18. What is the name of a narcotic that is worn as a patch?  What is its duration of activity?
19. What is the problem with using morphine to treat the pain of a not-quite-passed kidney stone?
20. What is a good administration suggestion for a patient taking an NSAID?
 

Module Four
KCC Pharmacology for Dental Hygiene DEHY34
Jim Middleton, Pharmacist, Instructor