review article the impact of complementary and …orthodoc.aaos.org/williamfbennettmd/impact...

David T. Rispler, MD

•? - Jul/e Sara, MD

Review Article

The Impact of Complementaryand Alternative TreatmentModalities on the Care ofOrthopaedic Patients

! Abstract

i The use of complementary and alternative medicine is widespread! and popular with the lay public. Although prevalence of use variesamong specific patient populations, complementary and alternativemedicine, in particular herbal remedies, are widely marketed andused by orthopaedic patients. Herbal supplements can have a

i negative impact on the perioperative period and may interact with; conventional medicines used to manage chronic conditions.| Physician-patient communication often'does not include the subjectI of alternative medicines, leading to underreporting of use.I Orthopaedic surgeons should adopt methods to routinely elicit fromj their patients the use of complementary and alternative medicine: and should monitor and counsel patients on potential side effectsand drug-herb interactions. Preoperative instructions should includecessation of the use of herbal supplements.

From the Department ofOrthopaedic Surgery, Michigan StateUniversity College of HumanMedicine, Grand Rapids, Ml.

Neither of the authors nor anyimmediate family member hasreceived anything of value from orhas stock in a commercial companyor institution related directly orindirectly to the subject of thisarticle.

JAmAcad Orthop Su/g2011;19:634-643

Copyright 2011 by the American! Academy of Orthopaedic Surgeons.

The use of complementary and al-ternative medicine (CAM) in the

United States is widespread. Theprevalence of use increased exponen-tially from 1990 to 1997 but sincethen appears to have stabilized, atapproximately one third of the USpopulation.1'2 Specific subpopula-tions of patients exhibit greater use.Older patients (>65 years) and thosewith chronic pain or chronic condi-tions associated with pain have thegreatest prevalence, ranging from52% to 64%.3'4 Among ambulatorysurgical patients, prevalence of CAMuse ranged from 27% to 43% within2 weeks of surgery.5'6 Among ortho-paedic patients, trends are similar,with a prevalence ranging from 35%to as high as 70%.7'8 The associatedcost is large: an estimated $33.9 bil-lion__was spent on CAM productsand services in 2007.9

Many forms of CAM exist, includ-ing herbal, nutritional, and megavi-tamin supplements; physical manipu-lation (eg, massage, chiropractic);and other modalities, (eg, aromather-apy, self-help organizations, folk andayurvedic remedies, hypnosis, energyhealing). Herbal supplementation isperhaps the most common: an esti-mated 38 million US adults useherbs.2

Unlike conventional medicines,herbal remedies are not regulated bygovernmental agencies such as theFDA. The Dietary and SupplementHealth and Education Act of 1994classified herbal remedies as dietarysupplements, which rendered themexempt from the safety and efficacyregulations required of prescriptionand over-the-counter medications.As a result, the safety and efficacy ofindividual herbal remedies have not

634 Journal of the American Academy of Orthopaedic Surgeons

34. Roberts JW, Grindel SI, Rebholz B,Wang M: Biomechanical evaluation oflocking plate radial shaft fixatitjn: ;|i'Unicortical locking fixation versusTmbobicortical and unicortical fixation in asawbone model. JHand Surg Am 2007;32(7):971-975.

35. Eglseder WA, Jasper LE, Davis CW,Belkoff SM: A biomechanical evaluationof lateral plating of distal radial shaftfractures. / Hand Surg Am 2003;28(6):959-963.

36. Katolik LI, Trumble T: Distal radioulnarjoint dysfunction, journal of theAmerican Society for Surgery of theHand200S;5(l):S-29.

<r,adio.ulnar joint and distal ulna fractures.'andClm 2010;26(4):503-51S.

37. Carlsen BT, Dennison DG, Moran SL:Acute dislocations of the distal

?Keltam JF: Diaphysealfractures of the forearm, in Browner BD,Jupiter JB, Levine AM, Trafton PG,Krettek C, eds: Skeletal Trauma.Philadelphia, PA, Saunders Elsevier,2009, pp 1478-1481.

39. Kikuchi Y, Nakamura T: IrreducibleGaleazzi fracture-dislocation due to anavulsion fracture of the fovea of theulna. J Hand Surg Br 1999;24(3):379-381.

40. Gunes T, Erdem M, Sen C: IrreducibleGaleazzi fracture-dislocation due tointra-articular fracture of the distal ulna.JHand Surg Ear Vol 2007;32(2):1S5-187.

41. Fujiwara M: Galeazzi fracture nonuniontreated with a free vascularizedcorticoperiosteal graft. JReconstfi..Microsurg 2006;22(5):357-362. "'"'\

42. Mulford JS, Axelrod TS: Traumatic !

injuries of the distal radioulnar joint.Hand Cttn 2010^2S(1):155-163.

43. Szabo RM: Distal radioulnar jointinstability. J Bone Joint Surg Am 2006;88(4):884-894.

44. ChuPJ, Lee HM, Hung ST,ShihJT:Stabilization of the proximal uhiarstump after the Darrach or Sauve-Kapandji procedure by using theextensor carpi ulnaris tendon. Hand(NYJ2008;3(4):34S-351.

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David T. Rispler, MD, and Julie Sara, MD

been thoroughly evaluated in largeclinical trials. Furthermore, limitedinformation is available in the medi-cal literature on drug-herb interac-tions. Compounding these issues,herbal remedies in particular aremarketed to consumers with labelssuch as "natural" and "homeo-pathic," which consumers may inter-pret as being synonymous with"safe." This attitude may contributeto the widespread practice of takingprescription medications simultane^ously with herbal medicines, which ispracticed by approximately one infive prescription users (approxi-mately 15 million adults).2 In con-trast to the assumption that theseremedies are safe, a recent study re-ported the deaths of four childrenthat resulted from the use of alterna-tive medicine used in place of con-ventional medicines.10

Given the widespread use of CAM,orthopaedic physicians must educatethemselves regarding the potentialside effects, drug interactions, andperioperative complications of herl>^airemedv_use. It is also necessary todevelop standard techniques for elic-iting from patients their history of al-ternative therapy use.

Eliciting CAM Use byPatients

Underreporting of CAM use is awell-documented phenomenon. Inone study, 64% of patients with os-teoarthritis (OA) in an orthopaedicclinic underreported CAM use, and asurgical population with OA under-reported its use by 40.6%.8 Nondis-closure of CAM use creates the po-tential for drug-herb interaction andrisk.

One of the main reasons that pa-tients do not disclose the use ofCAM is that they may not believe itis important information to conveyto the physician.7 This attitude may

be a reflection of marketing strate-gies, which tout supplements as nat-ural remedies, in turn creating the

, perception that no side effects are as-sociated with herbal supplementuse.7 However, at least one study hasdocumented that physicians maychoose not to record the use of CAMwhen patients report it.3 Other rea-sons for nondisclosure include pa-tient perception of prejudice againsttheir use by physicians and physicianignorance of herbal medications.11

Because of the prevalence of theuse of CAM, it is important that theuse of these supplements be docu-mented in all patiejits. However, rou-tine patient histories often do notelicit CAM use.3'8 Physicians mustdevelop and implement techniques tomonitor CAM use in their patients.Unbiased, specific questions regard-ing CAM use, with checklists, in-creases patient reporting of herbalsupplement use.7'8 Such lists mayprompt patients to name nonpre-scription medications that they useeven if the medications are not pres-ent on the list. Patients shouldbe counseled to fully disclose allmedications—prescription, over-the-counter, and herbal remedies. Finally,continual monitoring, in the form ofan annual update of this informa-tion, helps in the assessment of newherbal medications that patients maybegin taking.

Counseling PatientsPerioperatively

The perioperative period presents aunique challenge in monitoringCAM use because of the physiologicalterations associated with surgery aswell as with the drugs administeredduring and after surgery. CAM usemay contribute to increased bloodloss and the potential need for bloodtrarisfnsmris. _ As mentioned, theproblem for surgeons is a pervasive

one; the prevalence of herbal supple-ment use perioperatively was re-ported in one study to be 27%.5 Be-cause of the absence of regulatoryoversight, no comprehensive re-search is available on the physiologiceffects of many herbal remedies. Nei-ther the half-lives of the active ingre-dient or ingredients of herbal reme-dies nor the pharmacokinetic andpharmacodynamic properties arewell established. Adding to this un-certainty, formulations often arenot standardized from product toproduct.

As a result of this lack of data, nostandardized timetables exist for ces-sation of herbal medications beforesurgery. This is in contrast with con-ventional medicines, use of which isstopped before surgery on a timeta-ble that reflects the half-life of thesedrugs and their potential for periop-erative complications. For example,the half-life of ibuprofen is 1.6 to 1.91o5urs7and it is recommended" thatthlFdrug be discontinued 1 to 2 daysbefofe~surgery to reduce the risk ofbleeding.12 Likewise, naproxen, witha half-life of 15 hours, is discontin-ued j__days before snrgpry. By con-trast, jjpirin, which irreversibly^ in-hibits platelet activity, must bediscontinued 7 to 10 days before sur-gery, thereby allowing sufficient timefor platelet regeneration.

In general, given the lack of infor-mation on the metabolism of herbalremedies, it is prudent to counsel pa-tients to cease taking herbal remediesat least 1 week before surgery ~Be-cause of the possibility of producingnegative outcomes.13 In regard toherbal remedies with long or un-known half-lives, cessation 2 weeksbefore surgery is warranted.Tlerbalsupplementation should be avoidedin the postsurgical period until thewound_heals and the risk of hema-toma and subsequent infection hassubsided, usually 1 to 2 weeks, de-

October 2011, Vol 19, No 10 635

The Impact of Complementary and Alternative Treatment Modalities on the Care of Orthopaedic Patients

pending on the magnitude of thesurgery.

Conservatively, any herbal remedywith the potential to interact withanticoagulant therapy should not betaken within 2 weeks of surgery. Ad-ditionally, such herbs should not beused until anticoagulants are discon-tinued. Depending on the anticoagu-lant, this delay may be for 2 to 4weeks. Finally, in patients whoseCAM use stems from cultural beliefsor lifestyle, communication betweenthe primary care physician, anesthe-siologist and naturopath may bewarranted.

The 20 Top-selling Herbal Supplements'1

I Common Supplements\d Potential Side Effects

The popularity of herbal supple-ments changes over time, but use ofthe herbs discussed here has beendemonstrated as recently as 200914

(Table 1). Table 2 provides a sum-mary of the marketed uses, the po-tential side effects and drug interac-tions, and the perioperative andpostoperative recommendations forthe 12 popular herbal supplementsdiscussed below.

The assessment of risks associatedwith herbal use is complicated byseveral factors, but the most impor-tant is the lack of data from large,well-designed placebo-controlled clin-ical trials. The incidence and severityof adverse events associated withherbal supplement use is not studied,and postmarketing surveillance in-formation is not cohesively moni-tored by the FDA or any other gov-ernmental agency.16'17 Adverse effectsand drug-herb interaction have beenreported in the literature, mainly ascase reports.18 Such case reports arehelpful, but often they do not estab-lish a cause-and-effect relationshipbetween herbal remedy and side ef-fect. In general, herbal remedies canpotentiate the side effects or change

Rank

EI

Supplement

CranberrySoySaw palmettoGarlicEchinaceaGinkgo bilobaMilk thistleSt. John's wortGinsengBlack cohoshGreen teaEvening primroseValerianHorny goatweedBilberryElderberryGrape seedGingerAloe veraHorse chestnut

2009

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

2008

1

2

4

3

6

5

7

8

9

10

11

12

13

14

17

16

15

18—

19

Popular herbal supplements sold via food, drug, and mass market"retailers in 2009.14 Datado not include all retail markets (eg, Internet sales direct marketing, warehouse club sales).Rankings in 2008 are given as a comparison.15

— = not reported

the efficacy of conventional medi-cines by interfering with the metabo-lism or bioavailability of these medi-rTnes_via rytnrhrnmp P4TO (C.VP)enzymes.3'7'19'20 FnrfVier, herbs caj actsynergistically or additively tochange the efficacy "f a drng. Therecommendations below are basedon such resources and represent ourcurrent understanding of these herbs.

Cranberry (Vacdnium macrocar-pon) is mainly used to treat or pre-vent urinary tract infections (UTIs)by preventing adherence of harmfulbacteria to the urinary tract epithe-lium. Several clinical trials supportthe assertion that cranberry productsreduce the number of UTIs inwomen with recurrent infections;however, the dropout rates in these

trials were high, and no reliable evi-dence exists that cranberry can treatUTIs.21 Anecdotal evidence thatcranberry juice interacts with warfa-rin to potentiate anticoagulation wastested in a clinical trial of warfarinusers; no pharmacokinetic effect onwarfarin was observed.22 Side effectsinclude mild diarrhea. Cranberry canpotentiate kidney stones in at-riskpatients.

Echinacea (Echinacea purpurea, Eangustifolia, E pallida) is used asprophylactic treatment for upper re-spiratory tract infections. Researchshows that echinacea stimulates theimmune system.13'17'23 However, long-tfvrrn nge-oiLpf-liinarpa may Higjrmnn-

nosuppressive and increase the riskof perioperative opportunistic infec-



| Table 2

;' Common Supplements, _ _ _

\t!j Cranberry

j Echinacea

1ij Feverfew

I Garlic

Ginger

Ginkgo

Ginseng

Milk thistle

Saw palmetto

Soy

St. John's wort

Valerian

Marketed Uses

Prevent/treat UTI

Upper respiratory infec-tions (prophylaxis)

Prevention of migraineheadaches

Hypercholesterolemia/blood pressure reducer

Motion sickness, postop-erative nausea, arthri-tis, bronchitis

Memory loss, vasculardisease, tinnitus, mac-ular degeneration

Bleeding disorders,stress, atherosclerosis,memory, headaches,cancer

Liver cirrhosis, hepatitis

Urinary dysfunction dueto prostatic hyperplasia

Menopause, osteoporo-sis, hypercholesterol-emia, cancer

Depression, anxiety

Sedative

Potential SideEffects

—

Long-term use maylead to immuno-suppression

Rebound headaches

Bad breath, bodyodor

Mild heartburn

Rare; Gl upset,headaches, dizzi-ness

Lower blood glucose;insomnia, headache

Mild Gl upset

Cardiac symptoms,hypoglycemia

Mild Gl upset

Mild nausea, bloat-ing, constipation

Headache, drowsi-ness, rare hepato-toxicity

AC = anticoagulant, COX-2 = cyclooxygenase-2, Gl = gastrointestinal,— = not reported

Drug-herb Perioperative PostoperativeInteractions Cessation Resumption

Potentially warfarin

Immunosuppressives

Warfarin, aspirin

Disrupts anticoagulantsand cyclosporine,inhibits platelet aggre-gation

Warfarin and aspirin

Aspirin, ibuprofen, rofe-coxib, COX-2 inhibi-tors, cilostazol

May antagonize warfa-rin, may act synergisti-cally with MAOIs

Halothane, clopidogrel,warfarin

May have additive effectwith anticoagulant ther-apy

May antagonize tamox-ifen

Antifungals, statins, Ca2+

channel blockers,immunosuppressives,warfarin

Anesthetic synergism

MAOI = monamine oxidase inhibitor,

2 wk 2 wk

2 wk 2 wk

1 wk After AC therapy



36 h After AC therapy



2wk After AC therapy

None None


1 wk 2 wk

UTI = urinary tract infection,

tion; thus, concomitant use with im-munosuppressive medicines is dis-couraged.17 For this reason, it isprudent for patients to stop takingechinacea 2 weeks before surgerya:ridj^sjamejts_use_no_earlier than 2weeks after surgery.

Feverfew (Tanacetum partbenium}.,a popular herbal remedy used for theprevention of migraine headaches,functions by inhibiting serotonin re-lease. Feverfew has shown some ben-efit in several clinical trials, although

the largest trial to date did not showany benefit.24 Feverfew inhibitscollagen-induced platelet aggrega-tion. Thus, persons taking bioodthinners (eg, warfarin, enoxaparin,ticlopidine, clopidogrel, aspirin)should avoid taking feverfew. Acutewithdrawal symptoms after cessationmay occur, including rebound head-aches. Postoperatively, feverfewshould not be resumed until after an-ticoagulant therapy.

Garlic (Allium sativum) is used to

reverse hypercholesterolemia and todecrease blood pressure. The mech-anism of action is unknown. Datafrom clinical studies are inconclu-sive; garlic shows only very modestor no improvements in total choles-terol.23 Research has shown that gar-lic inhibits thromboxane productionand platelet aggregation in a dose-dependent manner=J±_alsD_nia$_43O-tentiate_r]ost:operative bleeding byinteraction with other platelet inhibi-_tors (eg, prostacyclin, forskolin, in-

October2011, Vol 19, No 10 637


domethacin, dipyridamole).13 Garlichas a short half-life; it should bestopped 1 week before surgery andshould not be resumed postopera-tively until anticoagulant therapy isstopped. Garlic reduces serum levelsof cyclosporine and therefore shouldbe avoided in persons taking thisdrug.25

Ginger (Zingiber offidnale) is used totreat motion sickness, postoperativenausea, and inflammation resultingfrom arthritis and bronchitis. Themechanism of action is unknown butis thought to be increased gastrointes-tinal (GI) cell motility, mediated in partthrough 5-hydroxytryptamine receptorinhibition. Ginger may inhibit plateletaggregation and cause GI upset.13'26

It has the potential to interact withantiplatelet therapies and increasethe risk of bleeding.

Ginkgo (Ginkgo biloba) is marketedfor several uses, including cognitive de-cline associated with Alzheimer disease,peripheral vascular disease, vertigo,macular degeneration, tinnitus, anderectile dysfunction. Among its effects,ginkgo appears to inhibit platelet-activating factor, and bleeding timemay be prolonged when used with cil-ostazol: several case reports attributespontaneous intracranial hemorrhageor postoperative bleeding to use ofginkgo.13'25 Ginkgo increases the riskof 'stomach bleeding and shouldnot be used concurrently with non-steroidal anti-inflammatory drugs(NSAJDs), including cyclooxygenase-2 inhibitors.18

Ginseng (Panax quinquefolius) isused to prevent the effects of aging,decrease stress, improve energy lev-els, and treat bleeding disorders, ath-erosclerosis, appetite loss, memoryloss, headaches, and cancer. Ginsengdecreases postprandial blood glucoselevels and inhibits platelet aggrega-tion, leading to increased coagula-tion times in animal models.27 How-ever, ginseng use leading to adecrease in warfarin anticoagulation

has been reported.28 Concerns re-garding its use include hypoglycemiain the perioperative period andbleeding.

Milk thistle (Silybum marianum) ismarketed for the treatment of livercirrhosis and hepatitis and for gen-eral liver health. It is thought to alterhepatic cell membrane structure andprevent its penetration by toxins.25

More recently, it has been marketedas an agent to reduce insulin resis-tance in patients with type II diabetesmellitus and as an anticancer agent,based on reported antioxidant prop-erties. Clinical research supporting abenefit to patients with cirrhosis re-sulting from alcohol use or hepatitiscomes from trials that were not welldesigned, leaving open the questionof any benefit to be derived frommilk thistle.29 Side effects are mildand can include stomach upset.

Saw palmetto (Serenoa repens) iscommonly used to alleviate urinarydysfunction associated with benignprostatic hyperplasia. Saw palmettoappears to decrease the uptake oftestosterone and dihydroxytestoster-one. Results from blinded clinical tri-als suggest that saw palmetto doesnot significantly decrease symptoms,prostate size, or peak urinary flowcompared with placebo, although itcauses few side effects.17'30'31 Patientsshould stop taking saw palmetto atleast 2 weeks before surgery becauseit may increase bleeding time.

Soy is used as a remedy for hyper-cholesterolemia, hot flashes associ-ated with menopause, memory diffi-culty, elevated blood pressuremeasures, several forms of cancer,and osteoporosis. Little evidence ex-ists to support the beneficial role ofsoy in these conditions, with the ex-ception of a slight decrease in low-density lipoprotein associated withits use.32 The isoflavones in soy areconsidered to be the active compo-nents, but the mechanism of actionof soy is unknown.32 Soy consump-

tion has not been associated withnegative side effects other than mildnausea, constipation, and bloating.

St. John's wort (Hypericum perfo-ratum] is commonly used to treatmood disorders such as depression.Hypericin and hyperforin arethought to be the active ingredients;hypericin inhibits monoamine oxi-dase, and hyperforin inhibits thereuptake of serotonin, norepineph-rine, dopamine, and y-aminobutyricacid (GABA). A systematic review ofclinical trial data suggests that St.John's wort is effective in the treat-ment of major depression, withfewer side effects than conventionalmedicines.33 Side effects include nau-sea, headaches, confusion, fatigue,constipation, and photosensitivity.St. John's wort interacts with manyother conventional medicines. It in-cfeases the metabolism of concomi-tantly administered drugs by induc-

the metabolic liver—enzymes

ducing the efficacy of antifungaldrugs, statins, and calcium channelblockers. St. John's wort may inter-act with immunosuppressive drugsand can potentially lead to trans-plant rejection. Finally, it reduces theeffectiveness of warfarin. St. John'sw^rT^hrnildr^Ee^stopped at least 1week before surgery or chemother-apy.

Valerian _ (Valerian officinalis) iscommonly used as a sedative for in-somnia. Clinical data on valerian areheterogeneous and suggest that it isof little benefit to insomnia. Valerianis reported to act on GABAergicpathways. Side effects include head-ache, drowsiness, and cardiac symp-toms.34 One case of cardiac symp-toms and delirium following surgeryhas been reported and attributed tovalerian withdrawal, suggesting thatvalerian may interact with periorjera-tive anesthesia.26 Valerian should be'stopped at least 1 week before sur-gery to avoid such interaction.



Table 3

Supplements Marketed for Osteoarthritis

Supplement

Glucosamine

Chondroitin

>• SAM-e

ASUs

Black cohosh

Boswellia

Bromelain

Cat's claw

Flavocoxid

Thunder godvine

Turmeric

Marketed Uses

OA, inflammation

OA, inflammation

OA, depression

OA, inflammation

Menopause, OA

OA, cough, asthma

Burn wounds, OA

Immunostimulant, OA

OA

Immunostimulant, RA

OA, RA, digestive aid

Potential SideEffects

Gl upset, headache,leg pain, itching,allergic reaction

Gl upset, heartburn

Nausea, diarrhea oninitiation of therapy

Headache, Gl upset

Gl upset, rash, dizzi-ness, hepatotoxicity

Unknown

Gl upset

Hypotension, diar-rhea

Nausea, diarrhea,gas

Gl upset, rash, head-ache, hair loss

Indigestion, allergicdermatitis

Drug-herb Perioperative PostoperativeInteractions Cessation Resumption -

Warfarin, hypoglycemia

Blood thinners

Serotonin syndrome

None characterized

Tamoxifen, anticanceragents

Mild nausea, diarrhea

Warfarin, phenytoin, tetra-cycline

Antihypertensives, antico-agulants, cyclosporine

Additive with antiplateletdrugs, statin interference

Unknown

Inhibits many cytochromeP450 enzymes, warfarin

2 wk

2 wk

1 wk

1 wk

1 wk

1 wk

2 wk

2 wk

2 wk

1 wk

2 wk

After AC therapy .

After AC therapy

2 wk

2 wk

2 wk

2 wk

After AC therapy

After AC therapy

After AC therapy

2 wk

After AC therapy

AC = anticoagulant, ASUs = avocado/soybean unsaponifiables, Gl = gastrointestinal, OA = osteoarthritis, RA = rheumatoid arthritis,SAM-e = S-adenosylmethionine

Osteoarthritis

The treatment of painful musculo-skeletal disease, in particular, OA, isa large proportion of any orthopae-dic surgeon's practice. In this patientpopulation, it is important to con-sider that conventional medicinesprescribed for OA are prone to pro-duce their own set of undesirableside effects. For instance, patientswith OA are readily prescribedNSAIDs, which reduce inflamma-tion, pain, and stiffness in arthriticjoints. However, side effects can in-clude Gl ulcers and bleeding, renalfailure, and worsening of the symp-toms of preexisting congestive heartfailure. An estimated 16,000 deathsannually are related to bleeding ofpeptic ulcers in patients takingNSAIDs.35

Another example is the injection of

natural hyaluronic acid (ie, viscosup-plementation) from rooster comb.Side effects range from mild allergicreaction to anaphylaxis in personswith chicken or egg allergies. Cur-rently, five FDA viscosupplementsare approved for use in the UnitedStates. Synvisc (Genzyme, Cam-bridge, MA), Hyalgan (Sanofi-aventis, Bridgewater, NJ), and Su-partz (Smith & Nephew, Memphis,TN) have the potential for allergicreaction and carry black box warn-ings against their use in allergic per-sons. The bioengineered viscosupjple-ments_Orthovisc (DePuy. Warsaw.IN)_and Euflexxa (Ferring Pharma-

NJ) can beused to avoid such reactions.

A large number of CAM supple-ments are marketed to patients withOA. Because of the high probabilityof unwanted side effects from con-ventional medicines, monitoring the

use of herbal medicines is critical tothe successful management of symp-toms and side effects in these pa-tients (Table 3). Careful history tak-ing and thoughtful prescribing arecritical.

Several herbal remedies show somepromise in reducing inflammationwithout the side effects produced byconventional medicines. However,there may be more to the function ofthese herbs than we are aware of.Figure 1 illustrates the arachidonicacid pathway in. inflammation, withthe reported activities of herbal med-icines highlighted.

Glucosamine sulfate and chondroi-tin are the most common supple-ments marketed to those with OA.Glucosamine is an aminosaccharidethat is a substrate for the biosynthe-sis of chondroitin sulfate, hyaluronicacid, and other cartilage molecules.Chondroitin is a constituent of the

October 2011, Vol 19, No 10 639


Figure 1

Injury/cell membrane disturbance

IPhospholipids

1 ^ Corticosteroids

Arachidonic acid NSAIDs

Leukotrienes

\' IMOMLL-'&

\ \• (COXiT/CUX-2)

Endo peroxides

/ I \e Prostacyclin

Prostaglandins

The arachidonic acid pathway, an important mechanism for producingpain and inflammation. Shown are the reported mechanisms of action ofseveral herbal remedies (orange) and conventional medicines (blue).ASU = avocado/soybean unsaponifiables, COX = cyclooxygenase

extracellular matrix, increasing theload-bearing properties of cartilageby increasing its water content. Thesesupplements have been heavily mar-keted to arthritis pain sufferers. How-ever, the benefit of using these supple-ments for the treatment of OA isdebatable. Several early studies haveshown a benefit of using either glu-cosamine or chondroitin, althoughthese studies were small.36 A large,6-month randomized controlled trialsponsored by the National Institutesof Health, the Glucosamine/chondroitin Arthritis InterventionTrial (GAIT), compared the use ofglucosamine, chondroitin, or a com-bination of the two to celecoxib andplacebo in the treatment of knee OA.The tri'al_failedto show significantbenefit with respect to pain or joint

prlrtw-Qj in rnrnT-iinatinn, However, a

subgroup of patients with moderateto severe pain taking the combina-

tion of both glucosamine and chon-droitin showed a trend towards ameasurable improvement.35'37

Glucosamine and chondroitin ap-pear to be safe, with mild side effectsthat include headache, edema, legpain, and GI upset. However, glu-cosamine, which is isolated from theexoskeleton of shellfish, hasme po-tential to produce an allergic reac-tion_ in sensitive inrlhaAials^ al-though this potential is not greatbecause_the protein__that causes theallergyp-t-repeflfty^sifi^K> found onlyin the muscle of shellfish. Neverthe-less, patients with shellfish allergiesshould consult their physicians be-fore taking glucosamine. Whetherglucosamine affects blood glucoselevels in patients with type II diabe-tes is unclear, but caution should beexercised regarding these patients.Glucosamine sulfate does not presentconcerns for patients with sulfa drugallergies because such allergies in-

volve drugs with sulfonamide groupsand not sulfate chemicals (eg, glu-cosamine, chondroitin). Several casereports have shown that glucosamineincreased the international normal-ized ratio or bruising/bleeding in pa-tients taking warfarin.38 Chondroitinmay cause bleeding in persons withbleeding disorders or in those usingblood thinners. Glucosamine andchondroitin should be stopped 2weeks before surgery and not re-sumed until anticoagulant therapy iscompleted.

S-adenosylmethionine (SAM-e) isoften used by patients with OA to al-leviate pain and to increase functionin arthritic joints. It is also marketedas an antidepressant, particularly forpatients who do not respond to sero-tonin reuptake inhibitors. Authors ofa recent meta-analysis found thatthere may be some benefit with itsuse, although clinical trials to datehave been small.39 Side effects ofSAM-e are mild and include head-aches, flatulence, nausea, and vomit-ing; the SAM-e dose should betitrated over 1 to 2 weeks to avoidthese side effects. Serotonin syn-drome (ie, altered mental and neuro-muscular status resulting from highlevels of serotonin) can occur whenSAM-e is administered concomi-tantly with prescription antidepres-sants, including serotonin reuptakeinhibitors, tricyclics, and monoamineoxidase inhibitors.

Avocado/soybean unsaponifiables(ASUs), a nutritional supplementheavily marketed to patients withOA, are composed of the oily frac-tions isolated from the parent com-pounds after hydrolysis, predomi-nantly phytosterols. In vitro, ASUsdemonstrate anti-inflammatory ac-tivity, and clinical trials suggestshort-term symptomatic but notlong-term benefit from its use.40 Ef-fects of ASU include increased colla-gen synthesis and inhibition of colla-genase as well as reduction of


David T, Rispler, MD, and Julie Sara, MD

prostaglandin E2.40 Side effects aremild and include headache and stom-ach upset.

Black cohosh (Actaea racemosa,Gimicifuga racemosa} root has tradi-tionally been used as a remedy formenstrual discomfort and the symp-toms of menopause. It is also used torelieve inflammation associated withOA and to reduce bone loss in osteo-porosis. Black cohosh is thought tohave estrogenic effects, but data areconflicting. Preliminary studies sug-gest that it reduces inflammation andinfluences markers of bone turnover,but more research is needed.41 Sideeffects include GI upset, rash, dizzi-ness, headache, nausea, and vomit-ing, especially when higher-than-recommended doses are taken.Critical analysis of several case re-ports of hepatotoxicity associatedwith black cohosh uncovered con-founding variables, thus preventingthe establishment of a causal rela-tionship.42 Further study is required.

Boswellia serrata (ie, frankincense,salai guggal) is an ayurvedic remedyused to treat arthritis and musculo-skeletal pain. It has been shown tohave anti-inflammatory properties,and clinical trials have demonstratedthat it is effective in the treatment ofOA pain, although these trials hadsmall sample sizes.43 Boswellia is welltolerated; side effects include nauseaand diarrhea.

Bromelain is a sulfhydryl pro-teolytic enzyme extract of pineappleused to debride burn wounds and asan anti-inflammation remedy forOA. Its anti-inflammatory propertiesresult from the reduction of prosta-glandin E2 and thromboxane A2,and inhibition of bradykinin by de-pletion of in kallikrein system.44 Todate, however, research results areunconvincing. A small double-blindplacebo-controlled study did not findbromelain to be effective in relievingsymptoms or enhancing quality oflife in patients with diagnosed knee

OA.40'45 Bromelain is an antithrom-botic, and it may cause bleeding ifused in conjunction with warfarinand enoxaparin by increasing the ac-tivity of these drugs. Patients shouldstop taking bromelain 2 weeks be-fore surgery. If postoperative antico-agulant therapy is necessary, brome-lain should not be taken untilanticoagulant therapy has beenstopped. Bromelain is metabolizedby and inhibits the enzyme C YP2 C9;thus, it may decrease the. metabolismof its substrates (eg, tetracycline).

Cat's claw (Uncaria tomentosa, Uguianensis] is used to enhance immu-nity and as an anti-inflammatory totreat OA. Several studies suggest itsuse is beneficial, alone or in combi-nation, in the treatment of OA; how-ever, these studies were small, andfurther research is required.40'46 Cat'sclaw is generally regarded as safe, al-though its use should be avoided bypregnant women. Side effects includehypotension and GI symptoms. Cat'sclaw also could have an additive ef-fect when taken with hypotensive oranticoagulant medications. It inhibitsCYP3A4 and should not be takenwith its substrates (eg, cyclosporine,some benzodiazepines).

Flavocoxid is a prescription medi-cal food isolated from Chinese scull-cap (Scutellaria baicalensis) and Aca-cia catechu bark. Flavocoxid is usedto treat OA and is thought to inhibitcyclooxygenase and 5-lipoxygenaseeznymes.47 One study has shown thatflavocoxid significantly reduces kneeOA (P < 0.001) and is safe.48 Becauseof its purported mechanism of ac-tion, its use should be avoided inthose with ulcers or GI bleeding. Sideeffects are mild and include nausea.

Thunder god vine (Tripterygiumwilfordii] is a Chinese herb used totreat inflammation and conditionsinvolving overactivity of the immunesystem. It is marketed as an oraland/or topical remedy for rheuma-toid arthritis. Several small clinical

trials have demonstrated a benefit ofits use in the symptomatic treatmentof rheumatoid arthritis.49 This herbis extracted from the root of theplant, but the skin of the root andthe plant leaves and flowers are poi-sonous and can cause death. Otherside effects include diarrhea, head-ache, rash, nausea, hair loss, andchanges in menstrual cycle. Drug-herb interactions are uncharacter-ized._Turm£n£-_SCurcuma longa) hasbeen used to treat inflammatory dis-ease, in addition to other applica-tions. Its anti-inflammatory proper-ties are thought to derive fromleukotriene inhibition; however, nolarge clinical trials have been under-taken to support its use in relievingsymptoms of OA.50 Although tur-meric is safe, it may cause indiges-tion or exacerbate symptoms of gall-bladder disease. Turmeric inhibitsmany of the GYP enzymes and bythis mechanism can potentially inter-act with many drugs.51

i Summary

Orthopaedic use of CAM is evolving.Lack of safety and efficacy data forherbal remedies is compounded bythe lack of communication regardingtheir use by patients and physicians.Although the use of herbal medicinesshould be monitored by the patient'sprimary care physician to prevent ortreat possible drug-herb interactionsor side effects, orthopaedic surgeonsmust have an understanding of themost common remedies used by theirpatients. This knowledge may help incounseling patients about the possi-ble interactions between conven-tional medicines and herbal supple-ments. In addition, providinginstructions to help patients stop tak-ing herbal supplements periopera-tively may lead to reduced postoper-ative blood loss, thereby decreasing

October 2011, Vol 19, No 10 641


the incidence of hematoma forma-tion, infection, and need for transfu-sion. Specific questionnaires to elicitsuch information from patients, par-ticularly in the presurgical interview,should be developed.

, References j

Evidence-based Medicine: References22-24, 27, 31, 36, and 37 are level Istudies. References 3, 5, 6, 18, 25,29, 33, 34, 40, 43-45, 47-49, and 51are level II studies. References 1, 2,4, 7, 8, 26, 39, 41, and 46 are levelIII studies. References 10, 11, and 42are level IV studies. References 12-17, 19, 21, 28, 30, 32, 35, 38, and50 are level V expert opinion.

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2. Tindle HA, Davis KB, Phillips RS,Eisenberg DM: Trends in use ofcomplementary and alternative medicineby US adults: 1997-2002. Altem TherHealth Med2005;ll(l):42-49.

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8. Rispler D, Sara J, Davenport L, Mills B,Iskra C: Underreporting ofcomplementary and alternative medicineuse among arthritis patients in anorthopedic clinic. Am] Orthop (BelleMead NJ) 2011;40(5):E92-E95.

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12. Howe CR, Gardner GC, Kadel NT:Perioperative medication managementfor the patient with rheumatoid arthritis.JAm Acad Orthop Sttrg 2006;14(9):544-551.

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14. Cavaliere C, Rea P, Lynch M,Blumenthal M: Herbal supplement salesexperience slight increase in 2008.Herbal Gram 2009;82:58-S1.

15. Cavaliere C, Rea P, Lynch M,Blumenthal M: Herbal supplement salesrise in all channels in 2009. HerbalGram 2010;S6:62-S5.

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17. O'Hara M, Kiefer D, Farrell K, KemperK: A review of 12 commonly usedmedicinal herbs. Arch Fam Med 1998;7(6):523-536.

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19. Abebe W: Herbal medication: Potentialfor adverse interactions with analgesicdrugs./ Clin Harm Ther 2002;27(6):391-401.

20. Brazier NC, Levine MA: Drug-herbinteraction among commonly usedconventional medicines: A compendiumfor health care professionals. Am ] Ther2003;10(3):163-169.

21. Guay DR: Cranberry and urinary tractinfections. Drugs 2009;69(7):775-807.

22. Ansell J, McDonough M, Zhao Y,Harmatz JS, Greenblatt DJ: The absence

of an interaction between warfarin andcranberry juice: A randomized, double-blind trial./ Clin Pharmacol 2009;49(7):S24-S30.

23. See DM, Broumand N, Sahl L, Tilles JG:In vitro effects of echinacea and ginsengon natural killer and antibody-dependentcell cytotoxicity in healthy subjects andchronic fatigue syndrome or acquiredimmunodeficiency syndrome patients.Immunopharmacologyl997;35(3):229-235.

24. Pittler MH, Ernst E: Kava extract fortreating anxiety. Cochrane Database SystRey2002;2:CD003383.

25. Reinhart KM, Talari R, White CM,Coleman CI: The impact of garlic onlipid parameters: A systematic reviewand meta-analysis. Nutr Res Rev 2009;22(l):39-48.

26. Ang-Lee MK, Moss J, Yuan CS: Herbalmedicines and perioperative care.JAMA 2001;286(2):208-216.

27. ParkHJ, Lee JH, Song YB, Park KH:Effects of dietary supplementation oflipophilic fraction from Panax ginsengon cGMP and cAMP in rat platelets andon blood coagulation. Biol Pharm Bull1996;19(11):1434-1439.

28. Janetzky K, Morreale AP: Probableinteraction between warfarin andginseng. Am J Health Syst Pharm 1997;54(6):692-693.

29. Rambaldi A, Jacobs BP, Gluud C: Milkthistle for alcoholic and/or hepatitis B orC virus liver diseases. CochraneDatabase Syst Rev 2007;4:CD003620.

30. Suzuki M, Ito Y, Fujino T, et al:Pharmacological effects of saw palmettoextract in the lower urinary tract. ActaPharmacol Sin 2009;30(3):227-281.

31. Tacklind J, MacDonald R, Rutks I, WiltTJ: Serenoa repens for benign prostatichyperplasia. Cochrane Database SystRew2009;2:CD001423.

32. Blachier F, Lancha AH Jr, Boutry C,Tome D: Alimentary proteins, aminoacids and cholesterolemia. Amino Acids2010;38(l):15-22.

33. Linde K, Berner MM, Kriston L: StJohn's wort for major depression.Cochrane Database Syst Rev 200S;4:CD000448.

34. Taibi DM, Landis CA, Petry H, VitielloMV: A systematic review of valerian as asleep aid: Safe but not effective. SleepMed Rev 2007;11(3):209-230.

35. Berger RG: Nonsteroidal anti-inflammatory drugs: Making the rightchoices. / Am Acad Orthop Surg 1994;2(5):255-260.

36. Clegg DO, Reda DJ, Harris CL, et al:Glucosamine, chondroitin sulfate, and



the two in combination for painful kneeosteoarthritis. NEnglJ Meet 2006;354(S):795-S08.

37. Sawitzke AD, Shi H, Finco MF, et al:The effect of glucosamine and/orchondroitin sulfate on the progression ofknee osteoarthritis: A report from theglucosamine/chondroitin arthritisintervention trial. Arthritis Rheum 2008;58(10):3183-3191.

38. Knudsen JF, Sokol GH: PotentialgJucosamine-warfarin interactionresulting in increased internationalnormalized ratio: Case report and reviewof the literature and MedWatchdatabase. Pharmacotherapy 2008;28(4):540-548.

39. Rutjes AW, Niiesch E, Reichenbach S,Juni P: S-adenosylmethionine forosteoarthritis of the knee or hip.Cochmne Database SystRev 2009;4:CD007321.

40. Ameye LG, Chee WS: Osteoarthritis andnutrition: From nutraceuticals tofunctional foods. A systematic review ofthe scientific evidence. Arthritis Res Ther2006;8(4):R127.

41. Yang CL, Chik SC, Li JC, Cheung BK,Lau AS: Identification of the bioactive

constituent and its mechanisms of actionin mediating the anti-inflammatoryeffects of black cohosh and relatedCimicifuga species on human primaryblood macrophages./Med Chem 2009;52(21):6707-6715.

42. Teschke R, Schwarzenboeck A,Hennermann KH: Kava hepatotoxicity:A clinical survey and critical analysis of26 suspected cases. EurJ GastroenterolHepatol 2008;20(12):11S2-1193.

43. Ernst E: Frankincense: Systematic review.BM/200S;337:a2S13.

44. Kumakura S, Yamashita M, Tsurufuji S:Effect of bromelain on kaolin-inducedinflammation in rats. EurJ Pharmacol19S8;150(3):295-301.

45. Brien S, Lewith G, Walker AF,Middleton R, Prescott P, Bundy R:Bromelain as an adjuuctive treatment formoderate-to-severe osteoarthritis of theknee: A randomized placebo-controlledpilot study. QJM 2006;99(12):841-850.

46. Rosenbaum CC, O'Mathuna DP, ChavezM, Shields K: Antioxidants andantiinflammatory dietary supplementsfor osteoarthritis and rheumatoidarthritis. Altem Ther Health Med 2010;16(2):32-40.

47. Altavilla D, Squadrito F, Bitto A, et al:Flavocoxid, a dual inhibitor ofcyclooxygenase and 5-lipoxygenase,blunts pro-inflammatory phenotypeactivation in endotoxin-stimulatedmacrophages. BrJ Pharmacol 2009;157(8):1410-1418.

48. Levy RM, Saikovsky R, Shmidt E,Khokhlov A, Burnett BP: Flavocoxid isas effective as naproxen for managingthe signs and symptoms of osteoarthritisof the knee in humans: A short-termrandomized, double-blind pilot study.NutrRes 2009;29(5}:29S-304.

49. Canter PH, Lee HS, Ernst E: Asystematic review of randomised clinicaltrials of Tripterygium wilfordii forrheumatoid arthritis. Phytomedicine2006;13(5):371-377.

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51. Sun DX, Fang ZZ, Zhang YY, Cao YF,Yang L, Yin J: Inhibitory effects ofcurcumenol on human liver cytochromeP450 enzymes. PhytotherRes 2010;24(8):1213-1216.

October 2011, Voi 19, No 10 643

October 2011

Vol 19, Ncfio

Additional AAOSRESOURCES

Further Information Related to Topics in This Issue

The following are available to Academy members on Orthopaedic Knowledge Online (http://orthoportal.aaos.org/oko/default.aspx) or from the AAOS store (http://www3.aaos.org/product/products.cfm).

Biologic and Pharmacologic Augmentation of Rotator Cuff Repairs• OKO Clinical Topics: Massive Rotator Cuff Tears: Current Concepts, by Eric D. Bava, MD; Sumant G.Krishnan, MD; Leah T. Cyran, MD; Wayne Z. Burkhead, MD

• OKO Clinical Topics: Arthroscopic Transosseous Equivalent Double-Row Rotator Cuff Repair, byAnand M. Murthi, MD

The Role of High Tibial Osteotomy in theVarus Knee• OKO Clinical Topics: Opening Wedge Proximal Tibial Osteotomy for the Varus Knee, by Robert E.Hunter, MD

Pediatric Cervical Spine Trauma• OKO Clinical Topics: Clearing the Cervical Spine in the Child Under 8 Years, by Eric T. Jones, MD

• OKO Clinical Topics: Subaxial Cervical and Cervicothoracic Spine Fractures and Dislocations, byChristopher A. Hulen, MD;TerranceT. Crowder, MD; Harry Herkowitz, MD

Pilon Fractures: Advances in Surgical Management• OKO Clinical Topics: Distal Tibia Fractures, by John L Marsh, MD; Thomas A. DeCoster, MD

• AAOS Store: Orthopaedic Knowledge Update: Trauma 4, by Andrew H. Schmidt, MD; David C.Teague, MD, Editors (Book)

Galeazzi Fracture• OKO Clinical Topics: Pediatric Forearm Fractures: Distal and Diaphyseal Radius and Ulna Fractures,by Kelly D. Carmichael, MD

• AAOS Store: Surgical Management of Pediatric Long-Bone Fractures, by Susan A. Scherl, MD,Editor (Book)

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