Vol. 5 No. i December 1990

Journal of Pain and Symptom Management

Clive H. Wilder-Smith, MD, Luzia Schuler, RN, Bruno Parvis Naji, MD, and Hans-Joerg Senn, MD




Division of Hematology-Uncology (C. W.S., L.S., B.0, H.J.S.), Kantonsspital, St. Gallen, Switzerland; and Department 01 Anesthesiology (P.N.), Klinik am Rosenberg, Heiden,


Abstract Nausea and emesis during cancer chemotherapy are very common, but can often be controlled with repetitive boli of antiemetic drugs. However, some patients, especially those with anticipatory symptoms, experience nausea and ernesti despite antiemetic pophylaxis. An increased participation $f these patients in the prophylaxis and treatment of these highly subjective symptoms may bad to better palliation. A patientcontrolled infusion pump was assessed in nine patients receiving &p&in, in whom high-dose metoclopramide (5 mglkg) had failed (>3 emetic epkodes) during previous treatment cycles. Impoved palliation was achieved in every case with on-demand boli in combination with a continuous infusion of metoclopramide or droperidol. Eight of the nine patients prefewed the patient-controlled system to the conventional fied-dose 601~sregimens. The infusion pump functioned safely and reliably. Antiemetic treatment with the patient-controlled device was superior to previous conventional methoa!s in this group of dij<-to-treat patients. J Pain Symptom Manage 1990;5:375-378. Key Words Antiemetics, patient-controlled, infusion pumps, metoclopramide, nausea, vomiting. cancer chemotherapy

Introduction Cancer patients are often required to submit to very protracted, distressing and toxic diagnostic and therapeutic procedures, in which they play a predominantly passive role. Even under the most ideal conditions, patients have

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requests to: CH Wilder-Smith, MD, Gast;rointestinal Unit, Department of Medicine, [email protected], University of Berne, CH-3010 Berne, Switzer1Ind. 1kcepted for publication: January 22, 1990.

0 U.S. Cancer Pain Relief Committee, 1990 Published by Elsevier, New York, New York

limited participation in their own therapy. Active participation of the patient in procedures may have palliative effects by giving the patient greater control, thereby increasing motivation and sense of personal integrity, and possibly affecting the tolerance of demanding therape&c regimens. The rationale for iudividualized tk erapy also lies in the interindividual variability of patient physiology, which is demonstrated by differences in emetic response and tolerability of side effects. An individualized approach to paiq therapy, another very variable and subjective



Wilder-Smith et al.

symptom, has recently been developed in tbe form of ~tient~ont~ll~ analgesia (PCA) for postoperative pain, With this method, patients can give themselves boli of an analgesic drug, up to a p~p~~rnrn~ m~mum dosage, when they feel analgesia to be inadequate. The majority of studies have demonstrated excellent patient acceptance, efficacy, and safety.‘& This method of patient participation in pain therapy is now also being evaluated for chronic pain in cancer patients.’ Oral and intravenous treatment of cisplatin chemotherapy=induced nausea and vomiting with highboy metoclopram~e has been shown to be effective in app~ximately two-thirds of paticntl. [email protected] of andemetic treatment is often due to anti~i~to~ nausea or vomiting, which occun in 15~~?~, of ~tients given chemotherapy, despite previous antiemetic prophylaxis for postchemotherapy toxicity.“‘“‘” The o~~ti~ of the present study was to assess a patient-controlled infusion system for antiemetic prophylaxis of chemotherapy-induced nausea and vomiting (~tient~ont~lled antiemesis, PCAE) in patients experiencing nausea and vomiting despite fixed-bolus high-dnsc inet ~lopmmid~ treatment regimens.

Patient-controlled antiemesis was used in nine successivecancerpatients who repeatedlyvomited mcxe than three times during p~vious chemotherapy courses, despite antiemetic prophylaxis with highdose metoclopramide (5 mg/kg int~~~u~y~ 2 mg/kg 30 min before and 90 min titer and 1 mglklp 180 min after beginning chemotherapy). The chemotherapy regimens, which remained u~han~d in the 19 chemotherapycyclesthat f&owed the switch to PCAE, included cisplatin at a mean dose (range) of 71 mg/mp (60-80). Fourteen of these cycles occurred in six patients who had devebped anticipatory nausea and vomiting. The average age of the patients was 36 z!z2f yr. All q>vere male. Five patients had testicular cancer, two had lung cancer, ~a had an osteosarcoma ati another had a rhabdomyosarcoma. All patients had me&static disease, but none had evidence of hepatic infdtration or other gastrointestinal &orders, The PcAlr procedure was as follows: A pump was attached to an intravenous catheter 2 hr

Journal of Pain and Symptom Management

before the start of chemotherapy. Five patients (12 cycles) were given metoclopmmide 1 mg!kg as loading bolus 30 min before chemotherapy, followed by 0.5 mg/kg/hr for a minimum of 6 hr by continuous infusion. Additional ondemand boli of 0.5 mglkg were available every hour. Four patients in this group had previously had ~tici~to~ nausea and vomi~~g. For comparison, four patients (seven cycles) received 5 mg droperidol 1 hr before chemotherapy, followed by 1 mglhr continuous infusion for 2 minimum of 6 hr and 0.5 mg on-demand boli maximally every hour. In this group, two patients had experienced anticipator syrnp~~. No additional antiemetic drugs, steroids included, were allowed, unless over three emetic episodes occurred. The usual requirements for cisplatincontaining cl~emotberapy regimens were followed (for example, hydration). Patients regulated their degree of activity and eating. The attending nurse recorded the number of emetic episodes or retches, the degree of nausea (none, slight, severe) and any side effects, especially ex~py~mi~l signs, every 2 hr for the first 8 hr and then I-hourly up to 24 hr after chemucimrayy.

The PharmacialDeltec CADD-PCA 5200 pump {Pha~acia, Duebendorf, Switze~and) was in every case loaded, programmed, and checked by the same doctor. The pump was freely programmable for continuous infusion rates of up to 90 mL/hr. The minimum interval and size of on-demand boli were adjustable between 5 and 199 min and 0.1-40 mg, respectively. Alarm functions existed for low battery, low residual drug volume, electronic malfunction, occlusion of tubing, and pump failure. Interchangeable drug reservoirs were locked onto the base of the pump. Initially, the sterile lOO-mL pump reservoirs were discarded after a single use. This was very costly and prior bacteriological tests performed after repeated refilling and emptying showed that, if filling of the reservoirs was performed under sterile conditions, they could be reused.

In the five patients receiving metoclopramide, PCAE yielded less than three emetic episodes in i! of the 12 cisplatin-asp chemotherapy cycles (Table 1). The median number of emetic



Patient-ControlledAntiemesis with Meto&qmtmide and Droperidol in Patients with Cisplatinkduced Emesis Previously Inadequately C:s8,trolIedby ~ig~-~~ ~et~lop~ide:a h’umberof Cycles (Fenzentage)with Em&s v-

Number of emetic episodes





Metoclopramide” 92= 12 6 (50%) 11 (92%) 1 (8%) 0.5 D~~ridolb n=7 2 (29%) 5 (71%) 2 (29%) 2.0 “Morethan three emeticepisodes with high-dose metoclopramide.

“For dosages used, see Table 2. episodes in the observed 24-hr period was O,!!. Six chemotherapy cycles were completely free of vomiting and nausea. None of the four patients who had previously experienced anticipatory nausea and em&s vomited more than twice per cycle. PCAE with droperijol completely inhibited nausea and vomiting Gt two cycles and less than three emetic episodes occurred in an additional three of the total seven cisplatin-based cycles in four patients. Mo;e than three vomiting episodes were noted in two cycles and additional antiemetics were prescribed. The median number of emetic episodes in the droperidol treatment group was two. Both patients with anticipatory symptoms in earlier cycles now vomited between 0 and once per cycle. Eight of the nine patients retrosp~tively stated that the chemotherapy cycles with PCAE were tolerated better than previous cycles. On average, the on-demand bolus was used twice per cycle (range, O-5) (Table 2). The total time on PCAE was 173 hr. The mean dosages used per cycle were 5.5 2 1.3 m&kg of metoclopramide and 11.3 + 2.1 mg of drope~dol. Overall, 17 cycles were without antiemetic or PCAE-related side effects. Akathisia aud an acute dystonic reaction each occurred once with metoclopramide.

These results suggest that patient-controlled devices can be beneticial in the prophylaxis and treatment of chemotherapy-induced nausea and vomiting in cancer patients not adequately controlled by a high-dose metoclopramide reg-

imen. Patient-controlled antiemetic therapy has not been reported previously and there are various application modes possible with this system. Isolated boli can be given on-demand or combined with 3 Iow-dose continuous infusion. Conventional high-dose metoclopramide therapy (3-10 m&kg), given as repetitive boli, can suppress nausea and vomiting in approximately two-thirds of patients receiving cisplatincontaining chemotherapies,89 Continuous infusions of met~lop~mide have been shown to be as effective in reducing nausea and vomiting as high-dose metoclopramide given as repetitive boli, despite lower total dosages.‘s Nowever, -30% of patients are not controlled adequately with any conventional dosing technique.*‘“~‘s-‘” This group presents a serious problem, as emesis and nausea become worse from cycle to cycle and a high pe~entage of these patients develop anticipatory symptoms and may refuse further chemotherapy.” Our patients, who had been resistant to fixed bolus high-dose metoclopramide for the ttcatment of nausea and vomiting following low to medium doses of cisplatin, demonstrated markedly improved antiemetic results, both objectively and subjectively, using a combination of on-demand bolus and background continuous infusion. Less than three emetic episodes and mild or no nausea occurred in 16 (84%) of 19 chemotherapy cycles in these nine patients. Half of those receiving metoclopramide reported no nausea or vomiting while using PCAE. No compari~n of toxicity with other reports is possible, but side effects were not severe and combination with biperidine or diphenhydramine may reduce these further Treatment with droperidol also seemed to improve the antiemetic control and may be useful as an alteruativc ro met.oclopramide in patients unsuitable for treatment with the latter. Droperidol has been showr, to be less effective than metoclopramide as an antiemetic agent, but it was included in this study because its neurolep tic, tranquilizing effect may he of benefit, specifically in the anxious patient with anticipatory symptoms.‘6 It is likely that the improved response seen with PCAE is partly attributable to psy~hologi~l mechanisms, such as the feeling of self-control over symptoms. This was expressed positively by most of the patients. The high incidence of anticipatory nausea and vomiting in patients receiving repeated courses of emetogenic chemo-

~ost+ge,sof Met~op~de

M~~lop~ide ~~~~1

T&e 2 and Drop&do1 Given and Number of Action Patient-CornroBed Antiemesis

Bali Appfied by

Total dosage”

No. of additional boli” (range)

Duration of infusion’ (hr)

5.5 2 1 mglkg 11.3+2mg

2.2 f 1 (O-5) 1.9% 1 (O-3)

9.5 f 1 8.3 + 3

‘Mean values f s.d. therapy d~m~nst~tes the irn~rtan~~ of these ~y~holo~ca~ ~haRisrns. Between S 1% and 57% of cancer patients with various cytotoxic regimens reportedanticipatoryreactionsin a recent study, hut these patients are often excluded from nodal tri& of a~t~emeti~drug.” A simple device that allows more personai control may be important in this difficult subgroup of patients. The superior ~~li~t~~ may also be due to ~~~n~s in pharm~~~ineti~ of drugs given by patient-controlled syraems, as has been shown with opioids. 1-9p6 This needs to be assessed with studies that measure plasma drug ~ncent~tion, as well as p~~acod~amics. Patients generally grasped the concept of PCAE and the control of the on-demand dose button well after the initial or second explanation. The high priceof the pump, ~a~ttes~ and tubing extensions were a disadvantage,but the pump functioned reliably and without fault. It was decided to reuse the drug cassettes to reduce the number of expensive cassettes re-

Re~llin~ must be ~~o~~ under strictly sterile conditions. The pro~mming functions were very flexible and simple, with different lockabIeaccessiblity levels for safety, The di~e~nt PCA devices availableand a summary 4’ their clinical use have been recently reviewed.r In conclusion, the patient-controlled pump principle was demonstrated to be effective where individuals antiemeticcontrol was implant.

The PCAE-pump used was reliable

and simple to operate.

1. ~~~~a~y K, Tucker W, Rosen M, et al. Cornparison of buprenorphine and pethidiie given intravenously on demand to t&eve postoperative pain. Br Med J 19?9;2:895-897. 2. Stattery PJJaffmerM, R-n M, et al. Comparison iJEmeptaainol and pethiine given iv on demand in tbe management c&~pfxtopera&e pain. Br J Anaesth 1981;53:927-930

3. Bennet RL, Batenhorst RL, Bivens BA, et al. Pati~nt~~nt~~led analgesia: a new concept of post-operative pain relief. Ann Surg 198%195:7OO-704. 4. Lehmann KA, Gordes B. Postoperative on demand Analgesie mit Buprenorphin, Anaesthesist 1988;37:6~70. 5. Bennett RL, Batenhorst RL, Graves D, et al. Drug use pattern in patient-controlledanalgesia. Anesthesiology 1982:57:A216 6. Tamsen A, Hartvig P, Fagerlund C, et al. Patient~nt~ll~ ana~~s~c therapy. IL i~iv~ual analgesic demand and anafgesic plasma concentrations of pethidine in post-operative pain. Clin Pharmacokinet 1982;7:164-175. 7. Barkas G, Duafala ME. Advances in cancer pain ~~~ernent: a review of ~tient-controll~ analgesia. J Pain Symptom Manage 1988;3:150-160, 8. Senn HJ, Claus A, Bachmann-Mettler I. Effective control of chemotherapy-induced nausea and votuiting with ora! prednisone and metoclopramide. J Chin Gncol 1984:2:32~325. 9. Gralla RJ. Metoclopramide: a review ofantiemetic trials. Drugs 1983;25(Suppl 1):63-73. 10. Stefanek ME, Sheidler VR, Fetting JH. Anticipatory nausea and vomiting: does it remain a sign~~~nt clinical problem? Cancer 1988:62:26~2657, 11. Cohen RE, Blanchard EB, Ruckdeschel JC, Smolen RC. Prevalence and correlates of posttreatment and anticipatory nausea and vomiting in cancer chemothe~py. J Psych~m Res ~98~3~64~54. 12. Andrykowski MA, Jacobsen PB, Marks E, et al. Prevalence, predictors and course of anticipatory nausea in women receiving adjuvant chemotherapy for breast cancer. Cancer 1988;62:2607-2613. 13. Dana EW, Mc~~ott M, Ever& E, et al. A randomised trial of highdose bolus metoclopramide in the prevention of cisplatin-induced emesis. Am J Clin Oncol (CCT) 1987: 10:253-257. 14, Meyer BR, Lewtn M, Drayer DE, et al. Optimizing met~lop~mide control of cisp~atin-induct emesis. Ann Intern Med ~984:10~39~395. 15.. Dearsley JH, Tattersall MH. Recent advances in the prevention or Fzduction of cytotoxic-induced emesis. Med J Aust 1985;143:341-345. 16. Sailer R, Hellenbr~ht D. High doses of metoclopramide or droperidol in the prevention of cisplatininduced emesis. Eur J Cancer Clin Oncol 1986;22:1199-1203.

Patient-controlled antiemesis for cancer chemotherapy-induced nausea and vomiting.

Nausea and emesis during cancer chemotherapy are very common, but can often be controlled with repetitive boli of antiemetic drugs. However, some pati...
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