In patients with an advanced disease or a terminal illness, it may become necessary to institute parenteral opioid therapy either on a temporary basis (for acute breakthrough pain) or permanently. Continuous intravenous or subcutaneous opioid infusions have been the mainstay of parenteral opioid therapy for oncologic pain. Patient-controlled analgesia (PCA) now offers an alternative modality, and Drs. Bruera and Ripamonti review the current status of this relatively new technique. Is there any evidence to suggest the superiority of one modality over the other for the treatment of oncologic pain?
In patients with an advanced disease or a terminal illness, it may becomenecessary to institute parenteral opioid therapy either on a temporarybasis (for acute breakthrough pain) or permanently. Continuous intravenousor subcutaneous opioid infusions have been the mainstay of parenteral opioidtherapy for oncologic pain. Patient-controlled analgesia (PCA) now offersan alternative modality, and Drs. Bruera and Ripamonti review the currentstatus of this relatively new technique. Is there any evidence to suggestthe superiority of one modality over the other for the treatment of oncologicpain?
Comparison of Efficacy of PCA and Continuous-Infusion Modalities
Bruera and co-workers reported on a crossover study that compared 3days of continuous subcutaneous hydromorphone infusion vs patient-controlledsubcutaneous hydromorphone for the treatment of cancer pain. The demanddose selected for PCA was equivalent to the cumulative hydromorphone doseadministered over 4 hours of infusion. Supplemental doses were allowedfor breakthrough pain during both phases of the crossover study.
A total of 22 patients were evaluated for daily dose of hydromorphone,number of supplemental doses for breakthrough pain, pain intensity, sleepiness,anxiety, depression, and nausea during the two study phases. In addition,patient preference for either mode of therapy was elicited at the study'send. There were no statistical differences between the two groups withregard to any of the aforementioned end points.
The major question that a crossover design can address is patient preferencefor one mode of therapy. It is interesting to note that 7 patients preferredPCA, while 10 patients preferred continuous-infusion therapy. Because ofthe small sample size, no real determination of preference can be madefrom the data.
To determine whether a particular technique is superior to another requiresa prospective study with large numbers of patients so that true differencesbetween treatments can be seen. Such a multicenter endeavor has recentlybeen completed by the Cancer and Leukemia Group B (CALGB). This studyrandomized 79 inpatients with severe cancer pain to either PCA or continuousintravenous morphine for 5 days. The PCA group took significantly lessmorphine than the continuous-infusion group over the 5 days. While meanpain intensity for days 2 through 5 was significantly higher in the PCA-treatedpatients, mean pain relief was similar in the two groups. Patients on PCAhad less psychological distress than patients on the morphine infusion;moreover, patients on PCA who experienced the least sedation had the lowestdistress of all.
The results of this study will not be fully available until the manuscriptis published. Nonetheless, it appears that patients on PCA minimized sedationand reduced psychological distress by administering less morphine. Perhapspatients' perception that they can, at any time, control pain relief allowsthem to tolerate greater pain intensity in order to lessen psychologicaldistress.
These results support the superiority of intravenous PCA over continuousintravenous morphine for hospitalized patients with severe cancer pain.
PCA as a Clinical Regimen for the Treatment of Cancer Pain
The studies to date indicate that pure PCA can be safely and effectivelyadministered subcutaneously or intravenously, either in the inpatient oroutpatient setting. For the purposes of optimizing therapy, treatment shouldbe started in the hospital, as was done in the CALGB study, so thataccurate assessments of response and toxicity can be made.
If the analgesic requirements of the patient are unknown, single injectionsof intravenous morphine (2 to 5 mg) can be given every 15 to 20 minutesuntil pain relief is achieved. This "loading" should be performedover 4 hours to allow sufficient time to evaluate the patient's analgesicneeds. At the end of 4 hours, the cumulative amount of morphine is dividedby the time spent in the loading period in order to calculate the hourlymorphine dose. For example, if 20 mg of morphine were given over 4 hours,the hourly morphine requirement would be 5 mg/h.
Over the next 4 hours, the patient is permitted to self-administer 60%of the hourly dose (3 mg) as the demand dose, with a lock-out intervalof 10 minutes. This accomplishes final "titration" of the patient'sanalgesic requirement. A demand dose is then selected that equals the amountof opioid used over a preceding 90- to 120-minute period. This is givenwith a 15-minute lock-out interval. For example, if the patient self-administeredeight (3-mg) doses over 240 minutes, a demand dose of 9 to 12 mg is given,with a lock-out interval of 15 minutes.
For patients with known narcotic exposure, the amount of morphine perhour can be calculated using a 3:1 ratio in converting oral to intravenousor subcutaneous drug. A demand dose is then selected that equals the amountof opioid used over a 60- to 120-minute period, with a lock-out intervalof 15 minutes. The patient should be monitored for toxicity and reevaluatedapproximately 4 and 8 hours later to evaluate adequacy of pain relief.
Patients with cancer will tolerate large demand doses, as the intensityof their pain is great. They are not "opioid-naive" and havedeveloped some degree of tolerance to opioids. The dosing regimen justoutlined is designed for patients with oncologic pain and cannot necessarilybe extrapolated for use with other types of patients or pain models, suchas postoperative pain. Likewise, a 1-mg dose with a 6-minute lock-out interval,as has been used for postoperative pain, is not practical for a cancerpatient with chronic pain who may require long-term use of PCA. Higherdoses of morphine prevent cancer patients from self-administering medicationso frequently that it would interfere with their activity.
A continuous opioid infusion plus patient-controlled demand mode isanother therapeutic option. However, the proper ratio of the continuousinfusion to the demand mode needs to be better defined and individualizedto the patients' unique pain pattern. One approach for the patient withchronic cancer pain is to give 50% of the total daily narcotic dose asa continuous infusion supplemented initially by a demand dose that is 50%to 100% of the hourly rate, with a lock-out interval of 30 to 60 minutes.
Over time, some individuals develop analgesic tolerance to this typeof regimen, requiring frequent dose escalation. As noted above, if lessnarcotic reduces psychological distress, one might rely on pure PCA duringthe daytime and a combination of PCA and continuous infusion during thenight hours. Thus, these two modes of delivering PCA are not mutually exclusive.
Patient-controlled analgesia can be adequately monitored by followingpatients' respiratory rate and mental status. In individuals with a normalbaseline respiratory rate, a decrease of 40% or more, attended by clinicalmanifestation of hypoxemia or somnolence, indicates the need for closerobservation and adjustment of dosing parameters.
In summary, recent trials have demonstrated that PCA is a safe and effectivemeans for relieving cancer- associated pain. Conducting prospective trialson PCA is labor-intensive because of the data management necessary to evaluateits many end points. However, these trials will better define its uniquemerits and optimal use in oncology patients.
1. Bruera E, Brenneis C, Michaud M, et al: Patient-controlled subcutaneoushydromorphone versus continuous subcutaneous infusion for the treatmentof cancer pain. J Natl Cancer Inst 80:1152-1154, 1988.
2. Citron M, Conaway M, Zhukovsky D, et al: Efficacy of patient-controlledanalgesia (PCA) vs. continuous intravenous morphine (CIVM) for the treatmentof severe cancer pain: CALGB 8872. Proc Am Soc Clin Oncol 12:433, 1993.