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  Section III: Types of Treatments  A. P HARMACOLOGIC T REATMENT Treatments for pain can be broadly categorizedas pharmacologic and nonpharmacologic. Thissection of the monograph provides an overviewof: 1) a commonly used analgesic classificationsystem, 2) some commonly used analgesic classesand individual drugs, and 3) general principlesof pharmacologic treatment. 1. Drug Classifications andTerminology Pharmacologic treatment is the mainstay of pain therapy. Almost half of individuals who suf-fer from pain choose a nonprescription analgesicas their initial choice for pain relief. 1 Up to onein five Americans take an over-the-counter orprescription analgesic on a daily basis. 2 As withtypes of pain, multiple systems for classifyinganalgesics exist. In the below system, analgesicsare broadly categorized as:   Nonopioid analgesics (nonopioids) :acetamino-phen and nonsteroidal anti-inflammatorydrugs (NSAIDs), including aspirin andother salicylic acid derivatives  Opioid analgesics (opioids) :mu opioid ago-nists (i.e., morphine-like agonists) and ago-nist-antagonist opioids   Adjuvant analgesics or co-analgesics: adiversegroup of drugs, with primary indications forconditions other than pain, with analgesicproperties relevant to some conditions.Commonly used adjuvant analgesics includeantiepileptic drugs (AEDs), tricyclic antide-pressants (TCAs), and local anesthetics(LAs).Variations of this classification system exist, a and terminology in the field is also evolving.The term “opioids” has replaced “narcotics,” and“co-analgesics” is an alternate termfor “adjuvantanalgesics.” 2. Common Analgesic Agents a. Nonopioids i. Mechanism of action and effects The primary mechanism of action of NSAIDsis inhibition of the enzyme cyclooxygenase(COX), resulting in blockade of prostaglandinsynthesis. 4,5 Acetaminophen, another nonopioid,appears to act mostly via a central mechanism. 3,6-7 All nonopioids have anti-inflammatory,antipyretic, and analgesic effects, but the anti-inflammatory effect of acetaminophen is essen-tially negligible. 8 The analgesic effect of NSAIDsis prompt (minutes to hours), whereas the anti-inflammatory effect may take longer (1-2 weeksor longer). 9 This latter effect can indirectlyrelieve some pain by reducing tissue swelling.The relatively recent discovery that COX hasat least two isoforms, COX-1 and COX-2, hasadvanced NSAID pharmacology. COX-1 is con-stitutively expressed in most normal tissues, 10 butplays an especially important role in the gastroin-testinal (GI) tract, kidneys, and platelets; COX-1primarily produces prostaglandins with beneficialeffects (e.g., regulation of blood flow to the gastricmucosa and kidneys). 8,11 In contrast, COX-2 isnormally not present but may be induced inresponse to inflammatorystimuli; COX-2 primari-ly produces prostaglandins that activate and sensi-tize nociceptors (see I.B). b  Nonselective NSAIDsinhibit COX-1 and COX-2, which contributes toboth their therapeutic actions and side effects.Agents that selectively inhibit COX-2 wereintro-duced to minimize the risk of GI side effects with-out compromising analgesic efficacy. 17-18 The“coxibs” affect COX-2 both centrally and periph-erally. However, an increased risk of myocardialinfarction, stroke, and death has been linked toselective COX-2 inhibitors, and this increasedrisk of cardiovascular side effects appears to be aclass effect of NSAIDs, including nonselectiveagents. 18a Rofecoxib and valdecoxib werevolun-tarily withdrawn from the market in 2004 and2005, respectively,because of these cardiovascularsafety concerns. Celecoxib is still availablebecause its benefits appear to outweigh its poten-tial risks in certain patients.Athird COX isoform, COX-3, recently wasidentified. Thereis evidence that inhibition of COX-3 represents the primary central mecha-nism by which acetaminophen relieves pain. 18b National Pharmaceutical Council 33 Section III: Types of Treatments a Because acetaminophen has some, albeit extremely limited,anti-inflammatory properties, 3 some experts consider acetamino-phen an NSAID and use the term “NSAIDs” rather than “nonopi-oids.” Other experts disagree with this classification due to the dif-ferent mechanisms of action and side effects of these drugs. b The division of function between COX-1 and COX-2 is notperfect. COX-1 produces some prostaglandins that contribute toinflammation. 12 COX-2 is constitutively expressed in some organs(e.g., the kidney) where it produces prostaglandins with protectiveeffects. 13-14  Table 19. Examples of Nonopioid Analgesics UsualOral DosageDosing Forms and Chemical Generic Interval or Routes of Major Side ClassNameIndicationsFrequencyAdministrationEffectsCommentsParaaminophenolsAcetamin-Mild to moderate q 4-6 h a Multiple oral Acute overdose: Lacks anti-inflammatory ophenpain due to (e.g., tablets, hepatic necrosiseffects of NSAIDs, butmultiple causes caplets, (liver damage) b noadverse effects on including head-powder, elixir, gastric mucosa or ache, toothache, suspensions,Chronic plateletsmuscular aches,liquid); rectaloverdose: liver Analgesic and backache,suppositoriestoxicity,antipyretic effectsmenstrual cramps, nephrotoxicity,comparable to aspirinarthritis, common thrombocytopenia Useful in patients cold, and flu; intolerant of NSAIDsfever reductionand for fever control inchildren with fluSalicylatesAspirinMild to moderate ASA: Multiple oralNSAID class effects c Combination pain due to q 4-6 h a (caplet, tablet,formulations availableDiflunisalmultiple causes gelcap,Diflunisal(aspirin and including headache, Diflunisal:effervescent hypersensitivity: acetaminophen, and/or CMTtoothache, sinus q 8-12 htablet, gum, life-threateningcaffeine)pain, muscular liquid); rectal reaction that Diflunisal causes less GI aches, bursitis, CMT:QD,suppositoriesmay involve irritation and antiplatelet backache,BID, multiple organseffects than aspirinsprains, arthritis, orTIDpain due to fever, cold, fluTrolamine Mild muscle or BID,TID,Topical cream, Skin peelingNot for use on acutely salicylatejoint pain, such or QIDlotioninflamed skin or raw, as in inflammatory weeping surfacesdisease (e.g., RA)Propionic acid IbuprofenMild to q4-6 hOral (tablets, NSAID class effectsCommonly used NSAIDderivativesmoderate pain, caplets, Toxic amblyopiaOTC formulations including pain geltabs, availableassociated with the suspension);Combinations with common cold, rectalcodeine and headache, toothache, suppositorieshydrocodone muscular aches, availablebackache, menstrual Fewer GI effects cramps, and arthritis; than other non-fever reductionselective NSAIDsNaproxenRA, OA, AS, JA, q 6-12 hTablets, oralNSAID class effects OTC formulations tendonitis, bursitis, suspension, Other: availablegout, primary delayed-pseudoporphyriaDelayed-release tablets dysmenorrhea release tabletsare NR for initial treatment of acute painKetoprofenSigns and symptoms q6-8 h;Capsules, NSAID class effectsOTC formulations of OA and RA, pain, ER capsulesavailableand primary q 24 h ER capsules NR for dysmenorrhea for ER formtreatment of acute painFlurbiprofenOA, RABID,TID,TabletsNSAID class effectsor QID OxaprozinAcute and long-term q 24 hCapletsNSAID class effectsLong half-life management of Other: (55 hours), thus OAand RA photosensitivity,can be given rashonce dailyIndoleacetic acidsIndomethacinModerate to severe BID, TID, Oral (capsules,NSAID class effectsLimited use due toOA, RA, AS; acute or QIDsuspension, Ocular effects side effectsgouty arthritis; acute slow-release (corneal deposits, painful shoulder capsules)retinal (bursitis and/or rectaldisturbances)tendonitis)suppositoriesExacerbation of Parkinson’s disease, epilepsy, or psychiatric disorders 34 Pain: Current Understanding of Assessment, Management, and Treatments Section III: Types of Treatments  ii. Indications and uses  Nonopioids relieve a variety of types of acuteand chronic pain (e.g., trauma, postoperative,cancer, arthritis pain) and are especially effectivefor certain types of somatic pain (e.g., muscleand joint pain, bone/dental pain, inflammatorypain, postoperative pain) (Table 19). 19-21 Acetaminophen and NSAIDs, alone, oftenrelieve mild pain, and some NSAIDs relieve cer-tain types of moderate pain (Table 19). 51 Evenfor moderate or severepain that does requireanopioid, nonopioids are often added to the regi-men for their opioid-sparing effect (i.e., theylower the dose of opioid required). 19 Sincenonopioids and opioids relieve pain via differentmechanisms, combination therapy offers thepotential for improved relief with fewer sideeffects. Nonopioids do not produce tolerance, National Pharmaceutical Council 35 Section III: Types of Treatments Table 19. Examples of Nonopioid Analgesics (continued) UsualOral DosageDosing Forms and Chemical Generic Interval or Routes of Major Side ClassNameIndicationsFrequencyAdministrationEffectsCommentsBenzothiazine PiroxicamAcute and long-term q 24 hCapsulesNSAID class effects Single daily dosederivatives management of Insomnia(oxicams)OA and RAMeloxicamOAq 24 hTabletsNSAID class effectsSingle daily dosePyrroleacetic acid DiclofenacOA, RA, AS, BID, TID, Tablets, NSAID class effectsLower risk of GI effects derivativesprimary or QIDER tablets Other: acute dysmenorrheahemolytic anemia, ERform aseptic meningitis,q24 hrashAvoid use in patients with porphyria Combination with misoprostol contraindicated in pregnant womenKetorolacShort term Varies for Oral(tablets), NSAID class effects Parenteral form useful(<5 days) treatment parenteral IV (injector, Warning indicating when PO NSAIDs areofmoderately severe therapysterile potential for undesirable and for acute pain that cartridges)serious NSAID opioid-sparing effectrequires analgesia at q4-6 h side effects if usedCombined oral and the opioid level oral forminappropriatelyparenteral therapy (e.g., postoperativeNR for minor or should not exceed pain) chronic pain5 daysIV administrationprovides pain relief comparable to 10 mg of IM morphineSelective CelecoxibOA, RA, FAPq 12 CapsulesMost common: Does not inhibit COX-2 or 24 hHA, URI, dyspepsiaplatelet aggregationinhibitorsNSAID class effects Rare anaphylactoid reactionsSources: References 8, 19-22, and 27-50. a Some sources (e.g., 2001 Physicians’ Desk Reference for Nonprescription Drugs and Dietary Supplements, 22 the American Pain Society’sPrinciples of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 19 McCaffery and Pasero 23 )list the dosing interval for aspirin andacetaminophen as 4 to 6 hours. Other sources (e.g., Agency for Health Care Policy and Research Acute Pain Management: Operative orMedical Procedures and Trauma Clinical Practice Guideline No. 1) 24 list the dosing interval for these drugs as 4 hours. b Use with caution in certain populations (i.e., patients with chronic alcoholism, liver disease, malnourishment). 19,25-26c Adverse effects of nonselectiveNSAIDs as a class include gastrointestinal problems (e.g., dyspepsia, ulcers, perforation, bleeding), liverdysfunction, bleeding due to inhibited platelet aggregation (i.e., “antiplatelet effect”), kidney problems (e.g., renal insufficiency, acute renalfailure), hypersensitivity reactions (i.e., aspirin sensitivity), and CNS effects (e.g., attention and memory deficits, headache, dizziness,drowsiness). 19 Recommended monitoring includes standard laboratory tests (e.g., complete blood count, liver and kidney function) and stoolguaiac test (for occult blood). NSAIDs are generally contraindicated in patients with a history of asthma, urticaria, or allergic-type reactionsafter taking NSAIDs, including aspirin.AS: ankylosing spondylitis; ASA: aspirin; BID; twice daily; CMT: choline magnesium trisalicylate; CNS: central nervous system; COX-cyclooxygenase; ER: extended release; ESRD: end-stage renal disease; FAP: familial adenomatous polyposis; GI: gastrointestinal; HA:headache; HTN: hypertension; IM: intramuscular; IV: intravenous; JA: juvenile arthritis, NR: not recommended; NSAID: nonsteroidal anti-inflammatory drug; OA: osteoarthritis; OTC: over-the-counter; PI: package insert; PO: per os (by mouth); QD: once per day; QID: four timesdaily; RA: rheumatoid arthritis; TID: three times daily; URI: upper respiratory infection.
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