Combination tramadol plus acetaminophen for postsurgical pain

Scienti?c paper

Combination tramadol plus acetaminophen for postsurgical pain

Adam B.Smith,D.O.a,*,Thanjavur S.Ravikumar,M.D.b,Marc Kamin,M.D.c,

Donna Jordan,B.S.N.c,Jim Xiang,Ph.D.c,

Norman Rosenthal,M.D.c,on behalf of the CAPSS-115Study Group?

a Department of Surgery,University of North Texas Health Science Center,855Montgomery St.,Fort Worth,TX76107,USA

b Department of Surgery,Monte?ore Medical Center,Bronx,NY,USA

c Ortho-McNeil Pharmaceutical,Raritan,NJ,USA

Manuscript received April17,2003;revised manuscript October17,2003

Abstract

Background:This multicenter,randomized,double-blind,active-and placebo-controlled trial evaluated tramadol plus acetaminophen (APAP)for orthopedic(n?153)and abdominal(n?152)postsurgical pain.

Methods:Patients with moderate pain or greater were randomized to an initial two tablets of37.5mg tramadol plus325mg APAP(n?98),codeine30mg plus APAP300mg(n?109),or placebo(n?98);thereafter,they received1to2tablets every4to6hours as needed for pain for6days.Outcome measures were pain relief and pain intensity,total pain relief,sum of pain intensity differences,and sum of pain relief and pain intensity differences during4hours and the daily averages.

Results:Tramadol plus APAP was superior to placebo for total pain relief,sum of pain intensity differences,and sum of pain relief and pain intensity differences(P?0.015);tramadol plus APAP and codeine plus APAP did not separate(P?0.281).For average daily pain relief,average daily pain intensity,and overall medication assessment,tramadol plus APAP was superior to placebo(P?0.038);codeine plus APAP did not separate from placebo(P?0.125).Discontinuation because of adverse events occurred in8.2%of tramadol plus APAP, 10.1%of codeine plus APAP,and3.0%of placebo patients.Except for constipation(4.1%tramadol plus APAP vs10.1%codeine plus APAP)and vomiting(9.2%vs14.7%,respectively),adverse events were similar for active treatments.

Conclusions:Tramadol plus APAP(mean dose4.4tablets)was effective and well tolerated for postsurgical pain and showed better tolerability than did codeine plus APAP.?2004Excerpta Medica,Inc.All rights reserved.

Keywords:Abdominal surgery;Acetaminophen;Codeine;Combination therapy;Orthopedic surgery;Postsurgical pain;Tramadol

The quality of postoperative patient care depends critically on effective pain management,which includes accurately assessing pain and monitoring the patient’s response to treatment[1].Inadequate postoperative pain treatment can contribute to unnecessary discomfort,increased morbidity, delayed discharge,and unanticipated readmission to hospi-tal[2–4].In cases of outpatient hernia surgery,supplemen-tary medication may be needed during outpatient care after postoperative treatment with nonsteroidal anti-in?ammatory drugs(NSAIDs)or opioids[2].Furthermore,orthopedic postoperative patients,who have a high incidence of severe pain in postanesthesia care[4,5],are responsive to acet-aminophen(APAP)combined with opioids as an alternative to NSAIDs for management of their outpatient postopera-tive pain[6].Clearly,additional effective analgesic options are needed,and they need to be optimally utilized.

The combination tablet,tramadol37.5mg plus APAP 325mg,has been found to be an effective,versatile treat-ment for acute nociceptive pain associated with orthopedic surgery[7],osteoarthritis?are[8],and oral surgery[9,10]. Tramadol,an unscheduled medication,exhibits both mild ?-opioid receptor binding and norepinephrine and serotonin reuptake inhibition.This dual mechanism may explain the lower rates of abuse and decreased incidence of respiratory depression compared with scheduled opioids[11,12].APAP may have multiple mechanisms of action,which are be-lieved to include inhibition of prostaglandin-E2release in the spinal cord[13]and inhibition of nitric oxide synthesis

This research was supported by Ortho-McNeil Pharmaceutical,Raritan,

NJ.

*Corresponding author.Tel.:?1-817-735-5450;fax:?817-735-5454.

E-mail address:adsmith@https://www.360docs.net/doc/908047358.html,

?Members of the CAPSS-115Study Group are listed in the Appendix.

The American Journal of Surgery187(2004)521–527

0002-9610/04/$–see front matter?2004Excerpta Medica,Inc.All rights reserved.

doi:10.1016/j.amjsurg.2003.12.038

mediated by N -methyl-D-aspartate or substance P [14].The solitary uses of tramadol,APAP,or propacetamol,which is rapidly hydrolyzed to APAP,in pain management after ortho-pedic surgery have been previously reported [6,15–17].

The purpose of this study was to evaluate the ef ?cacy and safety of the combination analgesic tramadol plus APAP in the treatment of postsurgical pain in patients undergoing an orthopedic or an abdominal procedure.

Methods Study design

Treatment of postsurgical pain with tramadol 37.5mg plus APAP 325mg (Ultracet;Ortho-McNeil,Raritan,NJ)was compared with codeine 30mg plus APAP 300mg and with placebo in a multicenter,randomized,double-blind,active-and placebo-controlled,parallel-group study.The study population consisted of approximately 300patients in generally good health who had undergone a therapeutic arthroscopic procedure of the knee or shoulder or who had undergone abdominal surgery for inguinal or ventral hernia repair.Patients were selected if they met inclusion criteria,which included having at least moderate postsurgical pain,being appropriate for pain management with an oral anal-gesic,and giving informed consent.Pain assessment was based on scores ?40mm on a pain visual analog scale (from 0to 100where 0?no pain and 100?extreme pain)and at least 2on a pain intensity scale (from 0to 3where 0?none,1?mild,2?moderate,and 3?severe).Female participants were required either to be using an appropriate

contraceptive method and to have a negative pregnancy test within 5days of study initiation or to be postmenopausal and/or incapable of becoming pregnant due to hysterectomy or other surgical procedure.

Included among the key exclusion criteria were use of analgesics within 3hours of study medication or concomi-tant use of sedatives (other than during surgery);oral anti-emetics or steroid injections on the day of surgery;admin-istration of long-acting nerve blocks or epidural anesthesia;use of tramadol within 30days of study entry;inability to tolerate tramadol hydrochloride or previously failed treat-ment with tramadol hydrochloride;contraindication to opi-oids or APAP;morbid obesity;history of abnormal hepatic and/or renal function,chronic alcohol abuse or substance abuse,or unstable medical disease;indication of major psychiatric disorder or treatment with antipsychotic medi-cation;or use of an investigational drug or device within 30days of study entry.

After completing a screening phase,the population of abdominal (n ?152)and orthopedic (n ?154)patients was randomized equally to one of the three treatment groups (Fig.1).Blinding was accomplished by packaging study medications to appear identical for all treatment groups and by concealing the composition and strength of the test preparations under a label mask.To ensure randomization to one of three treatment groups,a list of unique medication code numbers was prepared using a random-number gener-ator.The randomization code was broken after therapy was complete and the database had been ?nalized.

The regimen followed during the double-blind phase was as follows.On day 1after surgery,two tablets of medication were taken,and patients were required to remain at

the

Fig.1.Study design.APAP ?acetaminophen;qid ?4times daily.

522 A.B.Smith et al /The American Journal of Surgery 187(2004)521–527

study facility throughout the4-hour evaluation period.Sub-

sequent doses of1to2tablets were taken at least4hours

after the?rst dose and were allowed every4to6hours as

needed for pain through day6.During outpatient treatment,

pain intensity and pain relief were rated on days1to6in the

outpatient diary.The medication was not to exceed300mg

tramadol plus2600mg APAP or240mg codeine plus2400

mg APAP per24-hour period.Patients who received sup-

plemental pain medication or who required the use of anti-

emetics were discontinued from the study.

Patients were predominantly recruited from within inves-

tigators’medical practices.The protocol was reviewed at

each site and approved by an Institutional Review Board.

Patients gave signed written consent at screening before any

of the study-related procedures were performed.Twenty-

seven investigators participated in the study.The trial was

conducted in compliance with the Declaration of Helsinki as

last amended in1989and with the International Committee

on Harmonisation Topic6Guideline for Good Clinical

Practices.Known instances of nonconformance were docu-

mented and were not considered to have had any impact on

the overall conclusions of the study.

Outcome measures

The primary ef?cacy variables were total pain relief

(TOTPAR),sum of pain intensity differences(SPID),and

sum of pain relief and pain intensity differences(SPRID)

during the?rst4hours after the?rst dose of study medica-

tion on day1.These ef?cacy variables were calculated from

pain relief and pain intensity difference measurements made

at30minutes and again at1,2,3,and4hours after the drug

was given.Pain intensity was ranked on a4-point Likert

scale(0?none,1?mild,2?moderate,3?severe),and

pain relief was measured using a6-point Likert scale(4?

complete relief,3?a lot,2?moderate,1?slight,0?no,

and?1?worse pain).

Secondary ef?cacy variables included average daily pain

intensity scores and average daily pain relief scores reported

on days1to6.At the end of each day,patients recorded the

average postsurgical pain intensity(using the4-point Likert

scale previously mentioned)as well as the amount of pain

relief(based on the6-point Likert scale)they experienced

since the last assessment compared with the pain they ex-

perienced before initiation of the study medication.In ad-

dition,at study completion both patients and investigators

rated the study medication overall using a?ve-point scale(2?very good,1?good,0?no change,?1?poor,and?2?very poor).Safety evaluations performed during study visits included physical examinations and recording of vital

signs and adverse events.

Statistical analysis

Statistical analyses were performed on the intention-to-

treat population,which was composed of all randomized patients who took at least one dose of study medication and who recorded at least one postrandomization ef?cacy mea-surement.The primary ef?cacy variables(TOTPAR,SPID, and SPRID)were analyzed by an analysis of covariance model using baseline pain intensity score as a quantitative covariate and treatment,surgery type,and treatment by surgery type interaction as qualitative factors.Treatment by surgery type interaction was to be tested and dropped from the model if not signi?cant.Analysis incorporated the pain measurements made during the?rst4hours after the?rst dose of study medication.The primary comparison was between tramadol plus APAP and placebo;additional com-parisons were also performed between codeine plus APAP and placebo as well as between tramadol plus APAP and codeine plus APAP.Similarly,an analysis was performed of secondary outcomes:average daily pain intensity,aver-age daily pain relief for days1to6,?nal visit pain intensity,?nal visit pain relief,ef?cacy failures,and overall medica-tion assessment.Analysis used the analysis of covariance model with baseline pain intensity score as a quantitative covariate and surgery type and treatment as qualitative fac-tors.For analyses of pain relief scores and overall medica-tion assessments,the baseline pain intensity score was the covariate.

For the inpatient portion(?rst4hours)and outpatient portion(days1to6)of the study,Kaplan-Meier estimates of the cumulative distribution of time to discontinuation be-cause of lack of ef?cacy were determined.The event for the time-to-event analysis was discontinuation because of lack of ef?cacy.Kaplan-Meier estimates were assessed for sta-tistical signi?cance of differences in distributions by a log-rank test.The statistical signi?cance of any difference be-tween tramadol plus APAP and placebo in the proportion of patients who discontinued medication because of lack of ef?cacy was assessed using the logistic regression analysis with treatment and surgery type as qualitative factors.

Statistical tests of main effects were performed at the 2-sided,??0.05signi?cance level.The sample size(50 patients/treatment group/surgery type)was selected using general guidelines for the design of single-dose,oral post-surgery studies and was not powered for intersurgical type analysis.The evaluable-for-safety population consisted of those randomized patients who received at least one dose of study medication and who had at least one postbaseline safety evaluation.

Results

Demographics

After randomization(n?306)was accomplished,the intention-to-treat population(n?305)consisted of152 patients undergoing abdominal surgery(49.8%)and153 patients undergoing orthopedic(50.2%)procedures and in-cluded215(70.5%)men and90(29.5%)women.The pa-

523

A.B.Smith et al/The American Journal of Surgery187(2004)521–527

tients had a mean age of47.3years(range18to79years), a mean baseline pain visual analog scale score of62.9mm, and a baseline pain intensity score of2.2(Table1).The treatment groups were comparable with respect to these variables and other characteristics at baseline.Treatment by surgery type interaction was not signi?cant;therefore,re-sults from the abdominal and orthopedic surgery types were pooled.

Treatment response:drug,active control,and placebo groups

Tramadol plus APAP was signi?cantly better than pla-cebo on all of the primary outcome measures—TOTPAR, SPID,and SPRID—during the?rst4hours(Table2).No statistically signi?cant differences were found for primary ef?cacy measures between tramadol plus APAP and co-deine plus APAP(Table2).

Tramadol plus APAP was also signi?cantly better than placebo in measurement of all secondary ef?cacy variables: average daily pain relief(P?0.013;Fig.2),average daily pain intensity(P?0.038),?nal visit pain intensity(P?0.046),and?nal visit pain relief(P?0.025).Tramadol plus APAP was also numerically better than codeine plus APAP in decreasing average daily pain intensity,but this did not reach statistical signi?cance(P?0.072).Codeine plus APAP did not separate from placebo for these secondary variables(P?0.125).

During the?rst4hours,the tramadol plus APAP group had a lower incidence of discontinuation because of ef?cacy failures(23.5%)compared with the placebo group(39.8%, P?0.021)and the codeine plus APAP group(25.7%,P?not signi?cant).The Kaplan-Meier cumulative distribution of time to discontinuation because of lack of ef?cacy for this group was lower than that for placebo during the?rst4 hours(P?0.019;Fig.3)and during the course of the study (P?0.003;Fig.4).

Tramadol plus APAP was evaluated as signi?cantly bet-ter than placebo(P?0.001)in patients’overall medication assessments(Fig.5)with more patients noting a very good or good analgesic response(P?0.005).Physicians,too, gave signi?cantly higher overall assessments for tramadol plus APAP(P?0.005)and for codeine plus APAP(P?0.035)than for placebo.

Table1

Demographic characteristics for postsurgical pain patients

Characteristic Tramadol/APAP

(n?98)Placebo

(n?98)

Codeine/APAP

(n?109)

Mean age in years(?SD)46.2(?15.0)(range18–77)48.9(?15.2)(range18–79)46.9(?15.5)(range20–77) Sex,n(%)

Male70(71.4)68(69.4)77(70.6)

Female28(28.6)30(30.6)32(29.4)

Race,n(%)

White89(90.8)90(91.8)100(91.7)

Black7(7.1)8(8.2)8(7.3)

Asian1(1.0)0(0.0)0(0.0)

Other1(1.0)0(0.0)1(0.9)

Surgical procedure,n(%)

Abdominal49(50.0)49(50.0)54(49.5)

Orthopedic49(50.0)49(50.0)55(50.5)

Baseline PVA*in mm(mean?SD)61.6(?12.4)63.5(?15.4)63.5(?14.2)

Baseline pain intensity score?(mean?SD) 2.2(?0.4) 2.3(?0.4) 2.2(?0.4)

*PVA?Pain visual analog scale from0to100where0mm?no pain and100mm?extreme pain.

?Scale0to3where0?none,1?mild,2?moderate,3?severe.

APAP?acetaminophen.

Table2

Summary and analysis of primary ef?cacy measures*

Primary ef?cacy measures Tr/APAP

(n?98)

Placebo

(n?98)

Cod/APAP

(n?109)

P values

Tr/APAP vs

placebo

Tr/APAP vs

Cod/APAP

Cod/APAP

vs placebo

TOTPAR,mean(?SD) 6.5(?4.5) 4.5(?4.4) 5.8(?4.2)0.0040.2810.052 SPID,mean(?SD) 2.7(?2.3) 2.0(?2.3) 2.7(?2.4)0.0150.8640.019 SPRID,mean(?SD)9.2(?6.5) 6.6(?6.5)8.5(?6.3)0.0050.4320.033

*Assessments conducted for the?rst4hours after the?rst dose of medication.P value is for the speci?ed treatment contrast using an analysis of covariance model with baseline pain intensity score as covariate.

Cod/APAP?codeine plus acetaminophen;Tr/APAP?tramadol plus acetaminophen.

524 A.B.Smith et al/The American Journal of Surgery187(2004)521–527

The mean daily dose of tramadol plus APAP was 163mg tramadol and 1,415mg APAP (4.4tablets at a cost of $3.61/day),and the mean daily dose of codeine plus APAP was 130mg codeine and 1,296mg APAP (4.3tablets at a cost of $1.76/day).Adverse events

Treatment-emergent adverse events reported by the 2groups receiving active medication were similar.The great-est differences in adverse event incidences in the active treatment groups were noted for constipation (4.1%tram-adol plus APAP vs 10.1%codeine plus APAP)and vomit-ing (9.2%tramadol plus APAP vs 14.7%codeine plus APAP;Table 3).One serious adverse event (constipation)was considered by an investigator to be related to a study medication (codeine plus APAP).Discontinuation because of adverse events occurred in 8.2%of tramadol plus APAP patients,in 10.1%of codeine plus APAP patients,and in 3.0%of placebo patients.

Comments

The results of this study show that postsurgical pain associated with arthroscopic procedures of the knee or shoulder or with abdominal hernia surgery was successfully decreased by treatment with 37.5mg tramadol plus 325mg APAP tablets.The combination of tramadol plus APAP was superior to placebo as an analgesic as measured by all primary (TOTPAR,SPID,and SPRID)and secondary ef ?-cacy outcomes (average daily pain relief,average daily pain intensity,?nal visit pain intensity,?nal visit pain relief,and overall medication assessment scores).Clinical effective-ness was also shown by the estimated rates of discontinua-tion because of lack of ef ?cacy during the 4hours after surgery as well as during the 6-day course of outpatient treatment.This ?nding is consistent with results from a recent meta-analysis of postsurgical patients treated with tramadol plus APAP [18].Moreover,in their overall med-ication assessments,patients evaluated tramadol plus APAP as superior to placebo,and a greater number of patients also gave higher combined ratings of “very good ”or “good ”for the combination tablet compared with codeine plus APAP.These assessments were consistent from orthopedic patients undergoing shoulder or hip procedures and from

abdominal

Fig.2.Average daily pain relief for 3treatment groups during 6days.Pain relief scale:complete ?4,a lot ?3,moderate ?2,slight ?1,none ?0,worse ??1.P value based on analysis of covariance model with surgery type and treatment as qualitative factors and baseline values as covariate.APAP ?

acetaminophen.

Fig.3.Kaplan-Meier cumulative distribution of time to discontinuation because of lack of ef ?cacy during the ?rst 4hours of treatment.APAP ?

acetaminophen.

Fig.4.Kaplan-Meier cumulative distribution of time to discontinuation because of lack of ef ?cacy during a 6-day course of treatment.APAP ?

acetaminophen.

Fig. 5.Patients ’overall medication assessment.APAP ?acetamino-phen.

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A.B.Smith et al /The American Journal of Surgery 187(2004)521–527

surgery patients with inguinal or ventral hernia repair.The favorable outcome of tramadol plus APAP combination tablets in this surgical pain model further extends their utility as a versatile therapy in managing acute pain.

By combining drugs with different mechanisms of action and pharmacokinetic pro?les,one can enhance ef?cacy even though lower doses of the individual drugs are used [12].In3single-dose trials of oral surgery patients experi-encing moderate or severe pain after surgery,treatment with the combination of tramadol plus APAP showed superior performance to tramadol alone for overall pain relief,time to onset,and duration of action and superior performance to APAP for overall pain relief and duration of action[10]. When compared with other commonly used combination opioid analgesics,as done in this study,two tablets of tramadol plus APAP provided pain relief comparable to that provided by60mg codeine plus600mg APAP during the immediate postoperative period,and there was a numerical trend favoring tramadol plus APAP tablets during the out-patient phase.Furthermore,in a single-dose,double-blind study of oral surgery patients,two tablets of tramadol plus APAP showed ef?cacy comparable to that of10mg hydro-codone plus650mg APAP[9].

In addition to the potential for increased ef?cacy with combined medications,decreased rates of adverse events would be expected and consistent with the decreased dose of each medication.This study showed that a greater per-centage of patients treated with codeine plus APAP(51%) experienced treatment-emergent adverse events than did patients treated with tramadol plus APAP or placebo(40% and39%,respectively).In another study,examination of tolerability of hydrocodone plus APAP in adults treated for pain after orthopedic surgery found that89%of patients experienced adverse events[19].

We found that vomiting was more frequent in patients receiving codeine plus APAP(14.7%)than in those receiv-ing tramadol plus APAP(9.2%),a frequency comparable to that found with placebo patients(9.1%).The higher-than-expected rates of nausea for all3groups most likely repre-sented the postanesthetic effect.For the course of the study, constipation rates in patients taking a mean of4.4tablets of tramadol plus APAP daily were comparable with the rates in placebo patients but50%lower than the rates in patients receiving a mean of4.3tablets of codeine plus APAP per day.

The favorable tolerability pro?le seen in this study is consistent with previous studies of tramadol plus APAP tablets and is consistent with the rationale of combination therapy.In a single-dose,double-blind study of oral surgery patients,common treatment-emergent adverse events were signi?cantly decreased by treatment with tramadol plus APAP compared with hydrocodone plus APAP treatment and included a signi?cant decreased in nausea(14.0%vs 36.0%)and vomiting(12.0%vs30.0%)[9].In a compara-tive trial of treatment for chronic pain,the combination medication37.5mg tramadol plus325mg APAP was better tolerated than30mg codeine plus300mg APAP[20].In that study,constipation—a common adverse event with opioids—was signi?cantly lower in the tramadol plus APAP group(11%vs21%).This favorable tolerability pro?le was also observed in patients?65years old being treated for acute painful osteoarthritis?are[21].

Including tramadol in a combination analgesic offers the advantage of an unscheduled opioid with demonstrated ef-?cacy after orthopedic surgery as well as low abuse poten-tial and decreased incidence of respiratory depression [11,15,22,23].Moreover,use of the combination with APAP,rather than a nonselective or selective NSAID,may avoid other issues relevant to surgical patients who are at risk for gastrointestinal,hematologic,and renal complica-tions[12,24,25].Although cyclooxygenase(COX)-2inhib-itors,developed to address the gastrointestinal side effects of typical NSAIDs,have demonstrated ef?cacy for postsur-gical pain in orthopedic patients[19],recent reports of impaired fracture healing have identi?ed another potential limitation.In the rat model,treatment with COX-2inhibi-tors was associated with delayed bone healing,suggesting that COX-2activity is necessary for normal bone repair [26].High doses of other NSAIDs in humans have also been linked to delays in healing fractures and repair of spinal surgery[27].

In summary,these results indicate that tramadol plus APAP tablets,a combination analgesic,were effective and well tolerated for treatment of postsurgical pain in patients undergoing abdominal or orthopedic procedures. Appendix

Members of the CAPSS-115Study Group included:Od-est Frank Cannon Jr.,M.D.,and Sidney Ernest Clevinger, M.D.,Ocala,FL;Thomas M.Corbyons,M.D.,and Mark W.Hollmann,M.D.,DeLand,FL;Richard K.Gaines, M.D.,and J.Richard Rhodes,M.D.,South Daytona,FL; Michael M.Leighton,M.D.,and Barry M.Miskin,M.D., West Palm Beach,FL;Paul Lunseth,M.D.,Tampa,FL; Joseph Portoghese,M.D.,Orlando,FL;Michael Drass, M.D.,Altoona,PA;Richard C.Earnhardt,M.D.,Fred-ericksburg,VA;Kenneth J.Edwards,M.D.,St.Joseph,MI; Eric H.Franks,M.D.,and Stephen Konlian,M.D.,Salis-

Table3

Treatment-emergent adverse events with?4.5%incidence among

postsurgical pain patients*

Adverse event Tramadol/APAP Placebo Codeine/APAP

Nausea21(21.4)16(16.2)26(23.9)

Dizziness10(10.2)3(3.0)9(8.3)

Vomiting9(9.2)9(9.1)16(14.7)

Headache8(8.2)8(8.1)8(7.3)

Somnolence5(5.1)1(1.0)4(3.7)

Constipation4(4.1)5(5.1)11(10.1)

*Values expressed as number of events(%).

APAP?acetaminophen.

526 A.B.Smith et al/The American Journal of Surgery187(2004)521–527

bury,MD;David Garry,M.D.,and Scott T.Jackson,M.D., Provo,UT;David S.Jevsevar,M.D.,St.George,UT;Ran-dall Kay Jones,M.D.,West Jordan,UT;Michael H.Bourne, M.D.,Salt Lake City,UT;Richard Jones,M.D.,Dallas,TX; Adam B.Smith,D.O.,Ft.Worth,TX;Thanjavur S.Ravi-kumar,M.D.,Bronx,NY;Benjamin Rigor,M.D.,Louis-ville,KY;Samuel Berry Thompson Jr.,M.D.,and William Everett Tucker Jr.,M.D.,Little Rock,AR;Roger J.Volk-mann,M.D.,Wenatchee,WA.

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