Pharmacology

CHAPTER 5

Pharmacology

WHAT ARE AUTACOIDS?

• PRODUCED IN ONE ORGAN AND ARE TRANSPORTED VIA THE LYMPH SYSTEM

• ALL OCCUR (MADE) NATURALLY IN THE BODY.

OCCUR NATURALLY IN THE BODY

Terms & DefinitionsAutacoids - Examples:

Prostaglandins – lipids that are synthesized locally by inflammatory stimuli –↑↑ PAIN receptors

Thromboxanes (a vasoconstrictor and a potent hypertensive agent, and facilitates platelet aggregation [clotting]).

Leukotrienes (Inflammatory molecules; precursor of prostaglandins)

“-kinins” - messengers

IS PAIN DIFFERENT FOR EVERYONE?

YES

WHAT ARE PLACEBOS?

FOR SOME PEOPLE, PAIN CAN ALSO BE EFFECTIVELY TREATED WITH INACTIVE

PILLS (PLACEBOS)

‘’FAKE’ DRUGS

WHAT ARE ANTIPYRETICS ALSO CALLED?

NON OPIOID ANALGESICS ARE ALSO CALLED:NONNARCOTIC, PERIPHERAL, MILD, AND ANTIPYRETIC (AGENTS THAT REDUCE FEVER)

OPIOID ANALGESICS ARE ALSO CALLED: NARCOTIC, CENTRAL, OR STRONG ANALGESICS.

NON-OPIODS

1. Nonopioids (nonnarcotics) Act primarily at the:

peripheral nerve endings

Inhibit prostaglandin synthesis (regulating the contraction and relaxation of smooth muscle tissue)

Not effective for severe pain

3 subgroups:• Salicylates (aspirin-like group)

• NSAIDs • Acetaminophen

2. Opioids (narcotics)Act primarily within the:

central nervous system

Depress the central nervous system

Effective for severe pain

Examples: Morphine, Codeine, Agents in cough suppressants

We will discuss this area more in the next chapter

Difference is in their site of action

Classification of Analgesic Agents

Difference in their mode of action

WHAT CATEGORY IS ASPIRIN UNDER?

ASPIRIN IS THE MOST USEFUL AND COMMON SALICYLATE TO REDUCE PAIN

(ANALGESIC ACTION)

ACETYL SALICYLIC ACID (ASA) – THE CHEMICAL NAME FOR ASPIRIN

SALICYLATES

WHAT DOES NSAIDS STAND FOR AND WHAT DOES IT MEEAN?

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Salicylates• Aspirin belongs to a class of medications called

nonsteroidal antiinflammatory drugs (NSAIDs). – Aspirin and other NSAIDs, for example, ibuprofen

(eg. Motrin, Advil) and naproxen (eg. Aleve), are widely used to treat fever (antipyretic action), pain (analgesic action), and inflammatory (anti-inflammatory action) conditions such as arthritis

– Aspirin is also known for its anti-platelet action

ASA

• Aspirin have: –anti-inflammatory, –antipyretic, –analgesic, and –antiplatelet actions.

• These actions are related to the ability to inhibit prostaglandin synthesis

Salicylates:

MECHANISM OF ACTION

Whereas, Acetaminophen drugs have only antipyretic &

analgesic actions.

ASA

• Aspirin inhibits cyclo-oxy-genase (COX) to block production of prostaglandins

• Prostaglandins can sensitize pain receptors to substances such as BRADYKININ (SEE NOTE)

–A reduction in prostaglandins results in a reduction in pain

Salicylates:

MECHANISM OF ACTION

HOW LONG BEFORE ASPIRINS PEAK EFFECT?

REMEMBER NOT TO APPLY TOPICALLY TO ORAL MUCOSA!! ! !

30 MINUTES

ASA

3. Reye’s Syndrome• Associated with use of aspirin in children &

adolescents who took it when they had the chickenpox or influenza

• Fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver.

• ACETAMINOPHEN and NSAIDs are now used for fever (antipyretic action) or pain (analgesic action) in pediatric and adolescents to reduce the chances of Reye’s Syndrome

Salicylates:

ADVERSE REACTIONS

WHAT DRUG SHOULD YOU NOT TAKE WITH

ASPIRIN?

A DRUG INTERACTION BETWEEN ASPIRIN AND WARFARIN CAN RESULT IN

SIGNIFICANT BLEEDING

WARFARIN

NSAIDs• A rapidly growing group with important

application in dentistry– Mechanism of action and many of their

pharmacologic effects and adverse reactions resemble aspirin

• Many authors agree that the NSAIDs are the most useful drug group for the treatment of dental pain.– Most are available without a prescription.

WHEN IS THE PEAK PERIOD FOR MOST

NSAIDS?

1-2 hours

NSAIDs

• Most NSAIDs peak in about 1-2 hours–Well absorbed orally and food reduces

the rate but not the extent of absorption

• Metabolized in liver, excreted in kidneys

PHARMACOKINETICS

NSAIDs

• have a significant anti-inflammatory effect

• Similar as aspirin:–analgesic–antipyretic –anti-inflammatory

• They inhibit prostaglandin synthesis

PHARMACOLOGIC EFFECTS

ARE NSAIDS ADDICTING?

NSAIDS ARE NOT ADDICTING, TOLERANCE DOES NOT DEVELOP, AND NO

WITHDRAWAL SYNDROME CAN BE INDUCED.

NO!

NSAIDs

7. Pregnancy and Nursing

• Contraindicated in pregnancy; • Like aspirin, NSAIDs given late in pregnancy

can prolong gestation• IBUPROFEN is drug of choice for nursing

ADVERSE REACTIONS

DENTAL PAIN IS BEST MANAGED BY HOW MUCH MG OF

IBUPROFEN?

IN USUAL PRESCRIPTION DOSES, NSAIDS CAN BE SHOWN TO BE STATISTICALLY

SIGNIFICANTLY BETTER THAN CODEINE ALONE, ASPIRIN, ACETAMINOPHEN, OR

PLACEBO.

400MG

NSAIDs

• NSAIDs should be used with caution in patients with:

1. asthma2. cardiovascular disease3. Renal diseases with fluid retention 4. coagulation problems5. peptic ulcer disease6. ulcerative colitis

CONTRAINDICATIONS & CAUTIONS

Contraindicated in pregnancy

WHAT IS THE MOST COMMONLY USED

NSAID?

IBUPROFEN

WHAT HAS NO ANTI-INFLAMMATORY EFFECT?

ACETAMINOPHEN

Acetaminophen

• Used as an analgesic and antipyretic in children and adults when aspirin is contraindicated

• Has no anti-inflammatory action

Acetaminophen

• Rapidly and completely absorbed from the GI tract

• Peak plasma level in 1 – 3 hours• Half life of 1 to 4 hours• Metabolized by the liver• Excreted by the kidneys in 24 hours• When large doses are ingested, an intermediate

metabolite is produced that is thought to be hepatotoxic and possibly nephrotoxic.

.

PHARMACOKINETICS

AN ACUTE OVERDOSE OF ACETAMINOPHEN CAN CAUSE

WHAT?

LIVER DAMAGE

Acetaminophen

• Acetaminophen is used as an:

–Analgesic agent (↓ pain)–Antipyretic agent (↓ fever)

USES

Acetaminophen

• Used when hypersensitivity to aspirin or for patients experiencing aspirin-gastric induced irritation.

• Used as an antipyretic instead of aspirin for young children; due to aspirin’s association with Reye’s syndrome.

• Can be used in all stages of pregnancy (always ask doctor)

USES

WHAT DRUGS ARE USED TO TREAT GOUT?

Allopurinol AND Probenecid

Drugs Used to Treat Gout

Allopurinol (Zyloprim)• used in PREVENTION of a gout attack.

– Inhibits the synthesis of uric acid–Also used in patients receiving either

chemotherapy or irradiation – If a pruritic rash should occur, the drug

should be promptly discontinuedProbenecid (Benemid)

• used in PREVENTION of a gout attack.– Is an uricosuric drug that increases uric acid

excretion in the urine

CHAPTER 6

WHAT ARE OPIODS USED TO TREAT?

AT FIRST REFERRED TO DRUGS THAT ARE DERIVATIVES OF OPIUM POPPY

OPIOID OR NARCOTIC ANALGESICS ARE USED TO MANAGE DENTAL PAIN IN

PATIENTS IN WHOM NSAIDS ARE CONTRAINDICATED

MODERATE TO SEVERE PAIN

1. Mechanism of action at the receptor site:

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CLASSIFICATION-THREE GROUPS-

GROUP SUBGROUP EXAMPLE

OPIOID AGONISTS

morphine, codeine

MIXED OPIOIDS

AGONIST-ANTAGONISTS

PARTIAL AGONIST

pentazocine

buprenorphine

ANTAGONISTS Naloxone

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CLASSIFICATION: CHEMICAL STRUCTURE

BOX 6-1 OPIOD ANALGESIC AGENTS BY STRUCTURE GROUP

MORPHINE AND CODEINE(Largest Group)

• hydromorphone (Dilaudid) agonist• hydrocodone (in Vicodin) agonist• dihydrocodeine (in Synalgos-DC)• oxycodone (in Percodan, Percocet, Tylox) agonist

METHADONE • methadone (Dolophine) agonist• propoxyphene (Darvon) agonist

MORPHINAN • butorphanol (Stadol) agonist-antagonist• pentazocine (in Talwin-NX) agonist-antagonist

MEPERIDINE • meperidine (Demerol) agonist• fentanyl (Sublimaze) agonist• diphenoxylate (in Lomotil)

OTHER • buprenorphine (Buprenex, Subutex) partial agonist

Do not give any of these drugs if the patient has an

allergy to morphine or codeine

WHAT ARE WEAKER FORMS OF OPIODS?

Codeine (in Tylenol#3) and Hydrocodone (in Vicodin) are some of

the weakest

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DRUG NAME (SOME EXAMPLES)

COMMENTS SCHEDULE FOR

CONTROLLED

SUBSTANCE

STRONGEST

MORPHINE Standard agent; prototype

II

MERPERIDENE (Demerol)

Abused by professionals

II

INTERMEDIATE

OXYCODONE (in Percocet)

Popular with addicts ‘shopping’ for opioids

II

WEAKEST

HYDROCODONE (in Vicodin)

III

CODEINE (in Tylenol#3)

#2=15mg; #3-30mg; #4=60mg

III

WHERE DO NONOPIODS ACT?

OPIOIDS BIND TO RECEPTORS IN BOTH THE CENTRAL NERVOUS SYSTEM (CNS) AND THE SPINAL CORD, PRODUCING AN ALTERED PERCEPTION OF REACTION TO

PAIN

PERIPHERAL NERVE ENDINGS

WHAT ARE NATURAL OPIODS?

NATURAL OPIOIDS (ALSO CALLED ENDOGENOUS OPIOIDS) , INCLUDE:

ENKEPHALINSENDORPHINSDYNORPHINS

THESE ARE THE CHEMICALS THAT MAKE SURE WE CAN FUNCTION DURING ACCIDENTS,

LIKE AFTER BREAKING OUR LEG…

RELIEVE PAIN AND RELAXATION

1. Enkephalins

2. Endorphins

3. Dynorphins

All 3 have opioid-like action and are found in the body.They are naturally occurring peptides that possess

analgesic action and addiction potential62

The Discovery of 3 Groups of Endogenous Substances

Probably function as

neurotransmitters, although their

exact function has not been

elucidated.

reduces pain & positively affects mood.

stimulates delta() receptor

stimulates the kappa ()-receptor

MECHANISM OF ACTION

WHEN DO OPIODS START WORKING?

THE DOSING INTERVALS OF MOST OPIOIDS ARE BETWEEN 4-6 HOURS; THE

USUAL DOSE DEPENDS ON THE DRUG.

DURATION – NECESSITATES DOSING EVERY 4-6 HOURS

WITHIN 1 HOUR

WHAT IS THE FIRST PASS EFFECT?

UNDERGOES FIRST PASS METABOLISM IN THE LIVER AND INTESTINE, REDUCING

ITS BIOAVAILABILITY.

REDUCES THE BIOAVAILABILITY

Distribution:Oral bioavailability of opioids is primarily limited by first pass metabolism.

Undergoes first pass metabolism in the liver and intestine, reducing its bioavailability.

Degree of first pass differs among individuals.May cause respiratory depression in fetus when mother is given opioids near term.

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PHARMACOKINETICS

Excretion:Most opioids are excreted through the kidneys, but this action does not selectively affect their availability after oral administration.

Metabolized opioids and the unchanged drug are excreted in the urine.

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A.D.M.EPHARMACOKINETICS

TRUE OR FALSE?

severity of side effects is proportional to the efficacy (strength)?

A PHARMACOLOGIC EFFECT MAY ALSO BE AN ADVERSE REACTION, DEPENDING ON

THE CLINICAL USE OF THE AGENT.

TRUE

IS MORPHINE THE STRONGEST OR WEAKEST OPIOD?

• MORPHINE IS THE OPIOID AGONIST BY WHICH ALL OTHERS ARE MEASURED.

• STRONGEST CAN RELIEVE SEVERE PAIN WHILE WEAKER AGENTS MIXED WITH

NON-OPIOIDS ARE EQUIVALENT TO NSAIDS.

THE STRONGEST

Aspirin (ASA) and ibuprofen (NSAID) are analgesic, antipyretic, and antiinflammatory, and they inhibit platelet aggregation.

Acetaminophen is analgesic and antipyretic.

Codeine is analgesic.73

AnalgesiaPHARMACOLOGI

C EFFECTS

What do aspirin, acetaminophen, ibuprofen, and codeine have in common?

WHAT IS AN ANTITUSSIVE?

DEXTROMETHORPHAN

SUPRESSES A COUGH

Opioid analgesics ↑ smooth muscle tone and ↓ propulsive contractions and motility (some opioids have constipation as a side effect).

Useful for treating diarrhea.

Example: diphenoxylate (in Lomotil)

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Gastrointestinal Effects

Opioids are not used for depression, infections, or hypertension

PHARMACOLOGIC EFFECTS

Combining an opioid with a nonopioid analgesic produces an additive analgesic

effect with fewer adverse reactions.

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ADVERSE REACTIONSTRUE or FALSE

TRUE

These agents work at two different levels on pain and produce an additive analgesic effect. In

combination products, lower doses of each analgesic may be used, and a potential exists for a reduction in

adverse reactions.

DO OPIODS INCREASE OR DEPRESS THE RESPIRATORY

CENTRE?

THE RATE AND DEPTH OF BREATHING ARE REDUCED.

THE DEPRESSION IS RELATED TO A DECREASE IN THE SENSITIVITY OF THE

BRAINSTEM TO CARBON DIOXIDE.

DEPRESS THE RESPIRATORY CENTER IN A DOSE RELATED

MANNER

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Respiratory Depression (RP)

Not a problem with usual doses

in normal patients

RP is usually the cause of

death with an overdose

ADVERSE REACTIONS

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Nausea and EmesisAnalgesic doses of opioids often produce nausea and vomiting.

Result of their direct stimulation of the chemoreceptor trigger zone (CTZ) located in the medulla.

Repeated administration of regular doses can prevent vomiting at the vomiting center (VC).

ADVERSE REACTIONS

WHAT IS A VERY COMMON SIDE EFFECT

OF OPIOD USE?

THEIR DURATION OUTLASTS THEIR ANALGESIC EFFECT

CONSTIPATION

WHAT IS A SIGN IN RECOGNIZING AN OPIOD ADDICT?

MIOSIS – ‘PINPOINT PUPILS’. RESPIRATORY

DEPRESSION

HOW DO YOU TREAT AN OVERDOSE TO OPIODS?

AN ANTAGONIST SUCH AS NALOXONE ( IN NARCAN)

AN ANTAGONIST

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Biliary Tract Constriction

Opioids may constrict the biliary duct, causing biliary colic (bile duct obstruction leading to gall stones).

ADVERSE REACTIONS

Importance in patients passing gallstones who are being treated with opioids.

A MOTHER ON OPIODS – WHAT CAN HAPPEN TO THE BABY?

NOT TERATOGENIC, BUT MAY PROLONG LABOR OR DEPRESS FETAL RESPIRATION

IF GIVEN NEAR TERM..

NOT USUALLY A PROBLEM WITH MOTHER’S MILK WITH THERAPEUTIC

DOSES.

THE INFANT MAY HAVE DEPRESSED RESPIRATION AND

WITHDRAWL SYMPTOMS

Use of opioids is

NOT contraindica

ted in hypertensiv

e patients.

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ADVERSE REACTIONSAddiction

The degree of addiction potential is proportional to analgesic strength.

An addict will develop tolerance to the effects of opioids, EXCEPT for miosis and constipation.

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AddictionSince the duration of use in dentistry is usually short – addiction for dentistry does not pose a problem

NSAIDs should be used to control dental pain in the addict.

AN ADVANTAGE OF NSAIDs OVER OPIOIDS:

NSAIDs are not addictive, tolerance does not develop, and no withdrawal syndrome can be

induced.

ADVERSE REACTIONS

IF A CLIENT CLAIMS ALLERGIES TO NSAIDS, WHAT COULD THIS

MEAN?

TERMED ‘SHOPPERS’ THE CLIENT IS LOOKING FOR A SPECIFIC OPIOD.

KEEP IN MIND – THIS ISNT ALWAYS THE CASE…LOOK FOR OTHER SIGNS NOT JUST

ONE

OPIOD ADDICT

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Addiction: Identification of an Addict

The “shoppers” - What to look for:Asks for the opioid analgesic by name and says that this is the only drug that

works for them.Claims allergies to NSAIDs .Cancels dental appointment but still requests the opioid analgesic even

though they will be “out of town on business”.Experiences pain for days after scaling and root planingMoves from office to office because “others don’t understand”.Claims a “low pain threshold”.Needs refills several days after a procedure without complications.Calls with a request for an opioid analgesic just as the office is closing or after

hours.

ADVERSE REACTIONS

WHAT IS METHADONE?

MAINTAINING PATIENTS ON HIGH DOSES OF METHADONE (METHADONE

MAINTENANCE) .

USED TO TREAT OPIOD ADDICTION AND WITHDRAWL

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Addiction: 4 Treatment

OptionsAddiction, overdose, and withdrawal can be treated with opioid antagonists

1. Substituting addict with oral opioid (methadone).2. Going cold turkey and using medication such as

phenothiazines, clonidine or benzodiazepines (to alleviate symptoms of withdrawal).

3. Maintaining patients on high doses of methadone (methadone maintenance).

4. Administering an orally effective, long-acting antagonist Naltrexone (Trexan).

ADVERSE REACTIONS

100

Addiction: Treatment Options Example: The Heroin Addict

The following drugs can be used to treat heroin addiction

ADVERSE REACTIONS

METHADONE, is used by substituting methadone for heroin and then tapering

off or maintaining the addict on oral methadone.

NALTREXONE, a long-acting opioid antagonist, is used to block the action of

usual doses of opioid administered illegally

IS TRUE OPIOD ALLERGY COMMON?

MOST COMMON TYPES OF TRUE ALLERGIC REACTIONS TO OPIOIDS IS

DERMATOLOGIC IN NATURE.

DUE TO THE HISTAMINE -RELEASING PROPERTIES OF OPIOID ANALGESICS.

INCLUDES SKIN RASHES AND URTICARIA.GI SIDE EFFECTS ARE OFTEN REPORTED.

NO

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A patient with a true allergy to codeine

should NOT be given an analgesic in that group

This includes:

oxycodone hydromorphone, hydrocodone, and dihydrocodone

Because they are all members of the same

morphine and codeine group.

WHAT IS THE PROTOTYPE OPIOD AGONIST WHICH OTHER OPIODS

ARE MEASURED?

MORPHINE

The prototype opioid agonist which other opioids are measured

107

Agonists: MorphineSPECIFIC OPIODS

Parenterally: used to control postoperative pain

Orally: used primarily in the treatment of cancer

Used alone or combined with aspirin (in Percodan) or acetaminophen (in Percocet, Tylox) with fewer adverse reactions.

For moderate to severe pain.

It is located in the middle of the chart for strength value.

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Agonists: OxycodoneSPECIFIC OPIODS

Weak opioid analgesic with fewer adverse reactions.

Less potential for abuse. Combination of Hydrocodone (5mg) with acetaminophen (500mg) is recommended for the majority of dental patients with pain

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Agonists: HydrocodoneSPECIFIC OPIODS

In Vicodin, it has been reported as being safe to use when breastfeeding

WHAT IS THE MOST COMMON OPIOD IN DENTISTRY?

MOST COMMONLY USED OPIOID IN DENTISTRY AND IS OFTEN COMBINED

WITH ACETAMINOPHEN (TYLENOL #3) FOR ORAL ADMINISTRATION

CODEINE

Favorite drug of abuse for medical personnel; 100mg meperidine=10mg morphine.

For acute management of moderate to severe pain.

Poor choice for oral use because it has a high first pass effect; short duration of action.

Less constipating, and without miosis or cough suppression.

EXAMPLE: meperidine HCl (Demerol)

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Agonists: MeperidineSPECIFIC OPIODS

WHAT IS HYDROMORPHINE USED

FOR?

MANAGEMENT OF SEVERE PAIN, MORE POTENT THEN MORPHINE

An orally effective opioid, reserved for management of severe pain.

More potent than morphineSimilar adverse reactions to morphine.Favourite of the addicts because of its high strength; requires careful monitoring.

EXAMPLE: Dilaudid

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Agonists: HydromorphoneSPECIFIC OPIODS

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Agonists: Methadone

SPECIFIC OPIODS

Methadone is used either to withdraw the patient gradually or for

methadone maintenance. Because it has a longer duration of action, withdrawal from methadone is

easier than from heroin. Because it is an

opioid analgesic, however, the risk for

dependence still exists.

Used primarily to treat any opioid

addicts (eg. Heroin addicts)

Similar to morphine.

Slower onset and longer duration of action.

EXAMPLE: Dolophine

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Antagonists SPECIFIC OPIODS

Naloxone will block the therapeutic and toxic actions of opioids

Methadone is an opioid used in treatment of addiction, but will exacerbate symptoms of an opioid overdose.

An pure opioid antagonist that is active parenterally.

Drug of choice for treating agonist or mixed opioid overdoses.

naloxone (Narcan)

WHAT IS TRAMADOL?

AN ORALLY ADMINISTERED NON-OPIOID WITH WEAK ANALGESIC ACTIVITY

(ULTRAM)

Few studies have confirmed its efficacy:Binds with mu (μ) opioid receptors; inhibits reuptake of serotonin and norepinephrine,

and modifies ascending pain pathways.

Its analgesic efficacy is equivalent to that of codeine.Side effects can include: miosis and CNS effects, such as

dizziness, headache and stimulation and GI tract effects include nausea, diarrhea, constipation and vomiting.

Is moving up the top 200 most prescribed drugs.

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SPECIFIC OPIODSTramadol (Ultram)

Most dental pain can be managed with NSAIDs.

If NSAIDs are contraindicated - the DDS has a wide variety of opioids to choose from.

Eg. Beginning with codeine or hydrocodone combinations, and progressing to oxycodone combinations.

Only in rare cases and for short periods of time (approx. 1-2 days) should stronger opioids be prescribed for outpatient dental pain.

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DENTAL USE OF OPIODS

ARE OPIODS USED FOR CHRONIC OR ACUTE

PAIN?

ACUTE IS PREFERRED* BUT CAN BE USED FOR CHRONIC PAIN

Opioids are considered first-line therapy for:Pain associated with procedures (bone marrow biopsy)Pain due to trauma or cancer (burns)Visceral pain (appendicitis)

Majority used to relieve acute or chronic pain.Few, such as fentanyl (Sublimaze, Duragesic), alfentanil (Alfenta), and sufentanil (Sufenta), are primarily indicated for preoperative sedation to reduce patient apprehension.

Also used to suppress cough and treat diarrhea

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REVIEW: USE OF OPIODS

#1. Hydrocodone#32. Tramadol#105. Oxycodone#133. OxyContin#156. Fentanyl transdermal#175. Methadone HCl noninjectable

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Some of the Opioids found in the TOP 200