Current Status of Patient-Controlled Analgesia in Cancer Patients
Current Status of Patient-Controlled Analgesia in Cancer Patients
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?
Comparison of Efficacy of PCA and Continuous-Infusion Modalities
Bruera and co-workers reported on a crossover study that compared 3 days of continuous subcutaneous hydromorphone infusion vs patient-controlled subcutaneous hydromorphone for the treatment of cancer pain. The demand dose selected for PCA was equivalent to the cumulative hydromorphone dose administered over 4 hours of infusion. Supplemental doses were allowed for 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's end. There were no statistical differences between the two groups with regard to any of the aforementioned end points.
The major question that a crossover design can address is patient preference for one mode of therapy. It is interesting to note that 7 patients preferred PCA, while 10 patients preferred continuous-infusion therapy. Because of the small sample size, no real determination of preference can be made from the data.
To determine whether a particular technique is superior to another requires a prospective study with large numbers of patients so that true differences between treatments can be seen. Such a multicenter endeavor has recently been completed by the Cancer and Leukemia Group B (CALGB). This study randomized 79 inpatients with severe cancer pain to either PCA or continuous intravenous morphine for 5 days. The PCA group took significantly less morphine than the continuous-infusion group over the 5 days. While mean pain intensity for days 2 through 5 was significantly higher in the PCA-treated patients, mean pain relief was similar in the two groups. Patients on PCA had less psychological distress than patients on the morphine infusion; moreover, patients on PCA who experienced the least sedation had the lowest distress of all.
The results of this study will not be fully available until the manuscript is published. Nonetheless, it appears that patients on PCA minimized sedation and reduced psychological distress by administering less morphine. Perhaps patients' perception that they can, at any time, control pain relief allows them to tolerate greater pain intensity in order to lessen psychological distress.
These results support the superiority of intravenous PCA over continuous intravenous 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 effectively administered subcutaneously or intravenously, either in the inpatient or outpatient setting. For the purposes of optimizing therapy, treatment should be started in the hospital, as was done in the CALGB study, so that accurate assessments of response and toxicity can be made.
If the analgesic requirements of the patient are unknown, single injections of intravenous morphine (2 to 5 mg) can be given every 15 to 20 minutes until pain relief is achieved. This "loading" should be performed over 4 hours to allow sufficient time to evaluate the patient's analgesic needs. At the end of 4 hours, the cumulative amount of morphine is divided by the time spent in the loading period in order to calculate the hourly morphine 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 interval of 10 minutes. This accomplishes final "titration" of the patient's analgesic requirement. A demand dose is then selected that equals the amount of opioid used over a preceding 90- to 120-minute period. This is given with a 15-minute lock-out interval. For example, if the patient self-administered eight (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 per hour can be calculated using a 3:1 ratio in converting oral to intravenous or subcutaneous drug. A demand dose is then selected that equals the amount of opioid used over a 60- to 120-minute period, with a lock-out interval of 15 minutes. The patient should be monitored for toxicity and reevaluated approximately 4 and 8 hours later to evaluate adequacy of pain relief.
Patients with cancer will tolerate large demand doses, as the intensity of their pain is great. They are not "opioid-naive" and have developed some degree of tolerance to opioids. The dosing regimen just outlined is designed for patients with oncologic pain and cannot necessarily be extrapolated for use with other types of patients or pain models, such as 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 cancer patient with chronic pain who may require long-term use of PCA. Higher doses of morphine prevent cancer patients from self-administering medication so frequently that it would interfere with their activity.
A continuous opioid infusion plus patient-controlled demand mode is another therapeutic option. However, the proper ratio of the continuous infusion to the demand mode needs to be better defined and individualized to the patients' unique pain pattern. One approach for the patient with chronic cancer pain is to give 50% of the total daily narcotic dose as a 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 type of regimen, requiring frequent dose escalation. As noted above, if less narcotic reduces psychological distress, one might rely on pure PCA during the daytime and a combination of PCA and continuous infusion during the night hours. Thus, these two modes of delivering PCA are not mutually exclusive.
Patient-controlled analgesia can be adequately monitored by following patients' respiratory rate and mental status. In individuals with a normal baseline respiratory rate, a decrease of 40% or more, attended by clinical manifestation of hypoxemia or somnolence, indicates the need for closer observation and adjustment of dosing parameters.
In summary, recent trials have demonstrated that PCA is a safe and effective means for relieving cancer- associated pain. Conducting prospective trials on PCA is labor-intensive because of the data management necessary to evaluate its many end points. However, these trials will better define its unique merits and optimal use in oncology patients.
2. Citron M, Conaway M, Zhukovsky D, et al: Efficacy of patient-controlled analgesia (PCA) vs. continuous intravenous morphine (CIVM) for the treatment of severe cancer pain: CALGB 8872. Proc Am Soc Clin Oncol 12:433, 1993.