Intravenous-Subcutaneous Patient-Controlled Analgesia for Cancer Pain Management

P a t r i c i a H a r r i s o n , M D

Patient-controlled analgesia (PCA) has provided another method of delivering analgesics to cancer patients and the subcutaneous or intravenous route is now used for either inpatients or outpatients. Newer models of pumps contain more durable features such as portability, easier programming capability, and the ability to provide a continuous infusion as well as a self-dosing option. They also have many safety features including alarms but, most importantly, are easy to use. Although several opioids have been described, the most commonly used are morphine and hydromorphone, and b~th are available in concentrated forms. Patients who will benefit from this technique are those who are unable to take oral med!cation, those who require rapid control of an acute exacerbation or very large doses, and for postoperative pain control. This technique may not be appropriate, however, if a patient is not competent to use the device, or where there has not been an adequate trial of oral medication. Similarly, if the medical condition changes or if healthcare personnel are untrained in this technique, alternative methods of analgesia should be used. Side effects from the medication, including sedation, nausea and vomiting, or respiratory depression should be closely monitored as well as complications associated with the pump orthe line. With careful patient selection and monitoring of side effects, intravenous and subcutaneous PCA provides an effective method of pain control in the cancer population. Copyright �9 1997 by W.B. Saunders Company

T he recognition that the previously used methods of postop- erative analgesia were inadequat e has initiated the search

for improvement. The development of different analgesic drugs has broadened the scope of the physician by reducing side effects, while patient-controlled analgesia (PCA) has provided a way of varying the method of delivery. Although this technique was initially studied in the postoperative setting, its application has since been made to cancer patients.

Administration of analgesics via the oral route remains the most common mode of treatment. However, many patients who can be managed in this way initially wil[ require a change of analgesia and/or route as their disease progresses. 1 PCA via the intravenous or subcutaneous routes provides an ideal alternative in patients with mucositis, nausea and vomiting, bowel obstruction or malabsorption 2 or who require larger doses of medication for pain control.

The first case reports using PCA in the treatment of pain in the terminally ill were published in 1976 by Keeri-Szanto. 3

From the Department of Anesthesiology, Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, NY.

Address reprint requests to Patricia Harrison, MD, Roswell Park Cancer Institute, Department of Anesthesiology, Elm and Carlton Streets, Buffalo, NY 14263.

Copyright �9 1997 by W.B. Saunders Company 1084-208X/97/0108-$5.00/0

Subsequent reports contained small numbers of patients and focused on varying the dose and/or interval settings. 4,s Interpa- tient variability was suggested by the wide range of dosing requirements and it was also noted that higher doses were used over the first 4 hours compared with subsequent hours. In a comparative study of 22 patients, pain control was achieved by a continuous subcutaneous infusion of hydromorphone before being randomized to receive either a subcutaneous infusion of hydromorphone via PCA or continuous infusion. 6 After 3 days, the therapy was crossed to the alternate treatment. Patient preference was evaluated at the end of the study with 10 choosing infusion, 7 preferred PCA, and 4 had no preference, ahhough the authors concluded that both routes had similar efficacy and side effects. While subcutaneous infusions have been used extensively in the treatment of cancer pain, there are few-well-controlled comparative studies of PCA in this set- ting. 7,8 PCA use has been adapted from the acute pain therapy experience and has gained widespread popularity. More studies are needed to properly evaluate its use in this population.

IntravenousVersus Subcutaneous P C A

These are parenteral techniques of delivering analgesics and occasionally other medications. Intracenous analgesics can be delivered via peripheral cannulas, central venous catheters, PICC (Bard; Salt Lake City, UT) lines, or implanted central venous catheters such as Hickman or Mediport. Peripheral cannulas need to be changed more frequently because of local irritation but central venous catheters are susceptible to infection that can result in widespread sepsis. Frequently patients will have an implanted central line as a result of their chemotherapy which can be accessed with sterile technique. A PICC line can also be placed percutaneously via an antecubutal vein, thereby avoiding the need for frequent changes of a peripheral cannula. Subcutaneous infusions are most often delivered via a small-gauge butterfly needle placed on the chest, abdomen, upper arms, or thighs after the area is shaved. 7 Reports of the frequency of site change vary from 2 to 6 days II to 2 to 31 days. 6

In a study comparing subcutaneous and intravenous infu- sions of morphine, blood levels were found to be equal even in hypotensive patients. 7 This route has therefore been advocated as safe'~"comfortable, and cost effective, especially in the management of patients at home. a,6,~2 The availability of highly concentrated opioid solutions such as hydromorphone 10 mg/mL and morphine 25 mg/mL allows the administration of small volumes to achieve analgesia.

The main problems with subcutaneous infusions are the need to resite the needle at varying intervals, erythema and swelling of the site, or the accidental removal of the needle, which may go unnoticed. 13

Techniques in RegionalAnesthesia and Pain Management, Vol 1, No 1 (January), 1997: pp 47-52 47

S e t t i n g U p a P C A I n f u s i o n

When initiating and maintaining a PCA, there are a number of variables that can be altered in order for the therapy to be individualized to the requirements of each patient. Tile range and ability to change these settings may also determine which pump is the most suitable to the situation. Barkas and Duafala 2 outlined several desirable features of a PCA pump that are further described, as well as their application (Table 1).

Portability

The early generation of large and cumbersome pumps were pole-mounted machines used primarily for research. With the application of the techniques to ambulatory patients has come the development of more lightweight and durable devices. These are manufactured by several companies, an example of which is illustrated in Fig 1. These are easily used in the hospital setting with the pole-mounted attachment and many are powered by either AC, rechargeable or disposable batteries, which is an advantage for ambulatory patients. A security lock box can be added to hold the medication, or tile pump may be carried in a soft zippered case for its protection or for patient convenience.

Programming Capability

Many devices now contain multiple programming modes. While this allows the physician to deliver a variety of infusions and doses, it is essential that the process is simple and user-friendl}: Frequentl}; a key is needed to unlock tile pump or it may require a digital code for programming. The Cadd II pump (Pharmacia; Piscatawa); NJ) has three programmable lock levels that enable tile patient to alter the operation of the pump to varying degrees. One level allows the patient to choose a basal rate and dose from a range that is preset by the physician, while tile more restrictive level allows no patient selection at all.

Programming has been further simplified by the inclusion of software that directs each step in the process on a screen.

Continuous Infusion Pltls Intermittent Self-Dosing Option

A continuous infusion is frequently used for those patients who have significant pain at rest and who can tolerate the side effects of opioids. When a patient is changed to a PCA and has been on moderate to high doses of opioids, a continuous infusion provides a sustained blood concentration of opioid, thus avoiding the peaks and troughs that occur with intermit-

TABLE 1. Desirable Features of a PCA Pump

Portability Programming capability Continuous infusion plus intermittent self-dosing option Range of intermittent dose Range of continuous flow rate Range of lockout interval Ability to set further limits on patient intermittent self-bolusing Drug reservoir capacity Back pressure limit Memory capability Alarms Cost Ease of patient use

Fig 1. TheAbbott Pain Manager Pump (Reprinted with permis- sion from Abbott Laboratories; North Chicago, IL) is used for PCA therapy. With the application of techniques to ambula- tory patients has come the development of more lightweight and durable devices.

tent dosing. This is also beneficial for patients with pain at rest or at night when the need to awaken to administer more medication is avoided. The potential disadvantage is that the continuous infusion provides the patient with medication they may not require and are therefore more likely to exhibit side effects.

Tile intermittent dose or bolus is also set by the physician and can be administered by the patient when needed. The control is located on a button on the pump itself or by way of a remote cord that has a button on tile end and can be kept within reach of the patient..The bolus dose is particularly helpful for patients who have severe pain on movement or at specific times associated with dressing changes, coughing, or other painful occurrences. The advantage is that the medica- tion is delivered when the patient reqtures it and allows them to maintain control of their therap):

In many patients, the combination of continuous and intermittent dosing will provide the optimal therapy

Range of Intermittent Dose and Continuous Flow Rate

It has been well established that factors including age, type of pain, and tolerance contribute to the variability in analgesic response. 9 This variability of opioid pharmacokinetics compli- cates efforts to tailor analgesic therapy to the specific needs of the patient) While empirical doses are often used for initial settings, these are usually based on prior analgesic intake, severity of the pain, and the experience of the physician who is caring for these patients.

Both the continuous infusion and bolus dose should be varied depending on the pattern of pain as outlined in the previous section and subsequently adjusted based on patient response. Guidelines have been published regarding the use of continuous infusion of opioids in cancer patients, l~ but not with reference to PCAs. The bolus dose is often based on the breakthrough dose that would be added to the continuous infusion. Tile pump being used should be capable of providing a wide range of both continuous and bolus doses.

4 8 PATRICIA HARRISON

Lockout htterval

The lockout interval refers to the time period after which a patient is unable to receive medication following a bolus dose. When the patient presses the button, the lockout interval ensures that he or she cannot activate the pump again until a certain time has elapsed. This interval is set by the physician and applies to the bolus dose onl); as the continuous infusion will not be affected. It is the mechanism that prevents a patient inadvertently pushing the button or overadministering medica- tion.

Ftother Limits on httennitteHt Self Dosing

There is an additional limit that may be set to restrict the amount of medication a patient can receive. This maximum allowable dose is often an hourly or 4 hourly total and provides another measure of safety to the patient. If several doses are administered in a short period of time and the maximum set dose is reached, the ptunp cannot be activated again until the time interval has elap, sed. This will allow a patient to receive several doses if the rieed arises, but not to continue after a specified dose and time limit is reached.

Drug Resetwoir Capacity

The analgesic can be supplied in a cassette, an infusion bag, or a syringe depending On the pump and the clinical setting. A cassette is often preferred when using a concentrated drug with a low volume of infusion and is supplied by the pharmacy where it fits compactly onto several pumps. This is especially beneficial for subcutaneous infusions where it is desirable to use lower volumes compared with the intravenous route. Infusion bags allow a variety of concentrations as well as large volumes to be used whereas a larger bag, although more cumbersome, will avoid frequent medication changes. Pre- mixed syringes are also available for some pumps, but are more frequently used in the hospital setting.

Back Pressure Limit

1-his is an additional safety measure that prevents solutions from flowing in the reverse direction. If the pressure limit is needled, an alarln will alert the user to a possible obstruction to flow.

Memmy Capability

It is an advantage for the physician or nurse io be able to review the histo D' of medication use over a period of time. This is helpful in establishing the pattern of use and in determining if a change of dose or lock-out interval is required. When few doses have been received and the patient is demonstrating signs of opioid side effects, the continuous infusion rate may need to be reduced. Conversel), when muhiple attempts occur at different periods, the bolus dose may be increased as this suggests that several doses are needed for analgesic effect.

Alarms

Alarms serve to notify the user of a malfunction in the system. They include a warning of low batte D' or cessation of power, air bubbles in the tubing, occlusion of the line or an empty cassette or bag. When an alarm sounds, the appropriate action

can rectify the problem and avoid the patient being without medication.

Cost

As pumps have become more sophisticated, so the cost has also increased and this is a consideration when purchasing a pump. Although man)" of the available features are desirable, they may not all be necessary and a less expensive model with the required features onl); may suffice.

Ease of Patient Use

Above all, the pump and its attachments should be easy for the patient to use. Access to a trained heahh care professional should always be available so that a setting can be changed or any associated problems be rectified quickly and easil):

O p i o i d s U s e d f o r P C A

By far the most common opioid used for both the intravenous and subcutaneous route is morphine. Its pbarmacokinetic and pharmacodynamic properties have been extensively stud- ied, 14,15 ahhough not in the PCA setting. Many physicians and nurses are familiar with its effects, it is reasonably priced, titratable, and easily converted from one route to anotber. It is available as a 25 mg/mL solution that can be used undiluted subcutaneously thus allowing the infusion of small volumes and may also be diluted for easy titration intravenousl):

Hydromorphone is also widely used via PCA. It is six times more soluble than morphine and is available as a 10 mg/mL solution. As 1 mg parenterally is equivalent to 7 mg morphine, it is particularly advantageous by the subcutaneous route if large doses are required. Doses of 40 to 4,024 mg/d have been reported 6 confirming a wide therapeutic range and the need for high volmnes in some patients even when using the concen- trated solution.

Drugs that have been administered via PCA and their equivalent doses are shown in Table 2. Methadone and levorphanol are difficult to titrate because of their long duration of action and butophanol has a high incidence of psychotrominetic side effects. These features make these agents an unattractive choice for use in cancer patients. Meperidine is metabolized to nonmeperidine, a toxic metabo- lite that can accumulate due to its long half-life and is also not recommended for use in the management of cancer pain) 6

In a report by Paix et al, 17 11 patients who had intolerable side effects with morphine were changed to subcutaneous fcntanyl infusions. All patients demonstrated an improvement in the side effects and adequate pain relief was achieved in all but one patient. They determined that the relative potency of fentanyl to morphine was 68:1, but recommended cautious dose conversion in opioid-naive cancer patients. When the

TABLE 2. Opioids Described for PCA

Opioid Morphine Equivalent

Morphine 10 mg Hydromorphone 1.5 rng Buprenorphine 0.4 mg Methadone 10 mg Levorphanol 2 mg Meperidine 75 mg

IV AND SUBCUTANEOUS PCA FOR CANCER PAIN 4 9

fentanyl dose became large, two patients were changed to the more potent opioid sufentanil and these patients also experi- enced good analgesia with few side effects. The relative potency of fentanyl to sufentanil was determined to be 16:1 and 24:1. Although this report describes the use of subcutane- ous infusion onl); there may be a place for these drugs via PCA when patients experience intolerable side effects with mor- phine or hydromorphone. More studies are required to clarify the role of these more expensive drugs in this setting.

It has also been suggested that a change of opioid may improve the therapeutic response, a phenomenon that is due to individual variability and possibly genetic factors. Is This may be worth considering when dose escalation is needed or when the analgesic effect of the drug in use decreases.

Patient Selection

As discussed earlier, there are few studies that evaluate patient selection for PCA in the management of cancer pain. Ferrel et a119 considered there to be four areas of potential benefit for these patients: (1) when the oral route is unavailable, (2) when the total dose required is excessive, (3) when the use of PCA may provide the benefit of increased control, and (4) when PCA can provide immediate relief for "breakthrough" pai n. These have been modified as follows and are shown in Table 3.

Absence of Gastrointestinal Function

Those patients with cancer of the mouth, pharynx, or esopha- gus who experience difficulty swallowing may require PCA as an interim measure until the placement of a gastrostomy feeding tube or restoration of swallowing. Similarl); patients with bowel obstruction or uncontrolled nausea and vomiting who may take oral medication intermittently will benefit from PCA. Following chemotherapy or radiation, some patients will develop severe painful mucositis associated with neutropenia and a PCA will provide pain therapy until they are able to resume an oral intake.

Acute Exacerbations

provides one means of postoperative pain control. Intake of large doses of opioids prior to surgery is common, and will necessitate much larger doses of analgesics for pain control than other opioid-naive patients. Regional techniques such as an epidural infusion also provide excellent postoperative pain relief but if it is contraindicated or consent is not given; a PCA can be titrated to optimal effect while limiting side effects. In a study of 30 cancer patients undergoing abdominal surgeD,, z0 half received PCA bolus plus continuous infusion of morphine and half received PCA bolus only for postoperative pain control. Both methods were found to be safe, although patients in the continuous infusion plus bolus group used more total morphine. The outcome measures of the two groups were similar, including good analgesia, no instances of respirator), depression with both groups exhibiting similar levels of sedation. PCA also avoids the delays in receiving medication from nursing staffwhile allowing the control of self-medication to be maintained. Thus, it provides a good method of postop- erative analgesia in this group of patients.

Large Dose Requirements

DOs e requirements may escalate, especially during the terminal phase �9 of the disease, resuhing in the need for large numbers of pills to be taken for pain control. When this becomes difficuh, a PCA allows this iucreased dose to be given in a more comfortable manner.

These situations represent times during which it may be appropriate for consideration of PCA therap}: There is also evidence that children should not be excluded from PCA use. 21 Dunbar et a122 studied 39 children between 4 and 12 years of age undergoing bone marrow transplantation in whom PCA was employed for pain control. Ninety-five percent of patients were able to achieve control with this technique without incident or difficulty in weaning them from the PCA. This technique therefore, should be considered in this population who are able to take an active role in their treatment.

Potentially inappropriate uses have also been described 19 and are modified in Table 3.

During the course of the illness an acute exacerbation of pain may occur. This may be a sign of disease progression, obstruc- tion of a viscus, impending cord compression or a pathologic fracture. A PCA will allow the acute pain to be controlled more rapidly and allow any relevant investigations to be performed or therapy to commence. Once the pain is stable and the dose titrated, oral medications can be recommenced and the PCA discontinued.

Mental Incompetence

PCA should not be given to a patient who is unable to use it effectivel): This applies to patients with encephalopathy due to cerebral metastases or hypercalcemia, both of which are common in this population. Similarl); patients who are over- sedated will not use a PCA appropriately and may even push the button without realizing the implication of their actions.

Postoperative Analgesia

Many of these patients will require one or more operative procedures during the course of their illness and a PCA

TABLE 3. Indications and Inappropriate Conditions for PCA

Indications Inappropdate Conditions

Absence of Gastrointestinal Function Mental Incompetence Acute exacerbations Inadequate trial of oral medication Postoperative analgesia Changed medical condition Large dose requirements Inadequately trained personnel

Overriding factors

Inadequate Trial of Oral Medication

This is an invasive technique and more costly than oral medication. When the oral route is available, parenteral therapy should not be considered until an adequate trial has been given and found to be ineffective. Fentanyl patches have also gained widespread acceptance in this situation as an alternative means of pain control.

Changed Medical Conditions

If the patient's condition changes once a PCA is started, even after it has been in place for a period of time, it is not essential to continue this therap): Patients should be monitored for their ability to use PCA appropriately if their condition deteriorates

5 0 PATRICIA HARRISON

or, ahernativel); the oral route may become available where it was previously nonfunctional.

Inadequately Trained Personnel

No patient should be given a PCA if the personnel monitoring their pain control are unfamiliar with the therapy or untrained in the use of the pump and the various changes in settings that may be required. In this situation, it would be preferable to use therapy that provides relief for the patient and with which the physician or nurse has experience.

Ovet7iding Factors

A PCA should not be started for the convenience of the physician or caregivers if the patient has no desire to use it. Although this therapy gives the patient control of their therap); elderly patients, or those who are very sick, may wish to relinquish this to their caregiver. It should also be stressed that the bolus button is for the use of the patient and not for the family or nurse to administer medication as this will increase the risk of overdose.i It has also been suggested that a PCA is not suitable for patients with a history of drug abuse. 2 This contraindication is t~robably not absolute as long as signs of abuse or overdose are careftdly monitored.

Side Effects and Disadvantages

While there are many benefits to be gained from PCA therap); there are also several problems that may arise. These can be due to the medications being infused or as a result of problems with the pump and equipment, and are summarized in Table 4.

and an antiemetic given when needed, nausea is not a major complication.

Sedation is more likely in the presence of a continuous infusion. The safety factor of the PCA relies on the principle that no drug is delivered to a patient who is sedated and unable to administer the bolus. This is b)qgassed to some degree by the presence of a continuous infusion and signs of oversedation should be sought in this circumstance.

When a patient is not receiving adequate medication, pain control will be poor. This will be reflected by multiple attempts to administer medication, which outnumber the actual doses received. Signs of an allergic reaction to the medication should also be evident by the presence of itching or a rash.

Line Problems

Local skin irritation is a recognized complication of subcutane- ous infusions, 24 usually seen as erythema, irritation, and inflammation. Reports of painful chronic toxicity with indura- tion and subdermal necrosis H although rare, are of greater concern, but when needles are resited every 1 to 3 weeks, few problems arise. 7 Central line infection is a potential problem whe n these are accessed, but can be minimized by an aseptic technique. At the sign of a fever, cultures should be done and antibiotics commenced to avoid the need to remove the line. Peripheral intravenous canl~ulas should be resited if the patient complains of pain or swelling at the site, but venous access may become difficuh over a period of time as thrombosis occurs. Accidental removal of the subcutaneous or intravenous line may occur with associated bleeding and, if unrecognized, the medication will not be delivered.

Medication Problems

The most frequently observed signs of medication overdose are respiratory depression, nausea and vomiting, and sedation. Of these, the most potentially serious is respiratory depression which has been reported as infrequent in chronic cancer pain 4 in contrast to postoperative patients in whom continuous infusions were used. 23 The reduced incidence of this phenom- enon in the cancer population may arise as a result of the gradual titration of closes and tile development of tolerance to the medication. In postoperative patients, the residual effects of anesthesia have been suggested as a contributing factor. 2~

Nausea and vomiting has many etiologies and may even be the indication to initiate the PCA. When doses are well titrated

TABLE 4. Side Effects and Disadvantages of PCA

Medication Problems Overdose

Underdose Allergy

Line Problems Skin irritation Infection Accidental Removal

Pump Problems Failure Misprogramming Disconnection

Patient Problems Deliberate overdose Intolerance of equipment

Respiratory depression Nausea and vomiting Sedation Increased pain

Pump Problems

Although the current pumps have alarms that alert the user to problems in the system, they may still occur. If a pump fails, it may take some time for a replacement to be found, and if the pump is misprogranmted or a line is disconnected, hours may elapse before the error is detected, resulting in too little or too much drug being delivered to the patient.

Patient Problems

Ahhough not reported at this time, deliberate overdose by tile patient or family is possible. It should be stressed to the family or nurse that the bolus dose is for patient use only and thought should be given when ordering a PCA for patient with a history of drug abuse. 2 Occasionally a patient will not accept the presence of a pump and the associated equipment and alterna- tive therapy should be sought.

Conclusion

PCA is now a recognized mode of therapy for the treatment of cancer pain despite the pau.city of well-controlled studies to evaluate its use. It provides an alternative for patients who have no gastrointestinal function, for postoperative analgesia, and for rapid relief of acute exacerbation of pain. Medication can be delivered by either the subcutaneous or intravenous routes for both inpatients and outpatients. The pumps currently available are easy to use, compact, and have alarms for early detection of problems.

With the selection of appropriate patients, tile use of trained

IV AND SUBCUTANEOUS PCA FOR CANCER PAIN 51

personnel and monitoring for side effects, a PCA should provide good pain control for many patients.

References

1. Coyle N, Adelhardt J, Foley KM: Changing patterns in pain, drug use, and routes of administration in the advanced cancer patient. Pain 28:339, 1984 (suppl)

2. Barkas G, Duafala ME: Advances in cancer pain management: a review of patient-controlled analgesia. J Pain Symptom Manage 3:150-160, 1988

3. Keeri-Szanto M: Demand analgesia for the relief of pain problems in terminal "illness." Anesth Rev 3:19-21, 1976

4. Citron ML, Johnston-Early A, Fossieck B: Safety and efficacy of continuous intravenous morphine for severe cancer pain. Am J Med 77:199-204, 1984

5. Baumann T J, Batenhorst RL, Graves DA: Patient-controlled analge- sia in the terminally ill cancer patient. Drug Intell Clin Pharm 20:297- 301, 1986

6. Bruera E, Brennis C, Michaud M: Patient-controlled subcutaneous hydromorphorle versus continuous subcutaneous infusion for the treatment of cancer pain. JNC180:1152-1154, 1988

7. Storey P, Hill HH, St Louis RH: Subcutaneous infusions for control of cancer symptoms. J Pain Symptom Manage 5:33-41, 1990

8. Bruera E: Subcutaneous administration of opioids, in Foley KM, Ventafridda V (eds): Advances in pain research and therapy, vol 16. New York, Raven, 1990, pp 203-218

9. Kaiko R, Wallenstein S, Roger A: Sources of variation in analgesic responses in cancer patients with chronic pain receiving morphine. Pain 15:191-200, 1983

10. Portenoy RK: Continuous infusion of opioid drugs in the treatment of. cancer pain: guidelines for use. J Pain Symptom Manage 1:223-228, 1986

11. Adams F, Cruz L, Deachman M J: Focal subdermal toxicity with subcutaneous opioid infusion in patients with cancer pain. J Pain Symptom Manage 4:31-33, 1989

12. Kerr IG, Sone M, DeAngelis C: Continuous narcotic infusion with patient-controlled analgesia for chronic cancer pain in outpatients. Ann Intern Med 108:554-557, 1988

13. Bruera E, MacEachern T, MacmiIlan K: Local tolerance to subcutane- ous infusions of high concentrations of hydromorphone: a prospective study. J Pain Symptom Manage 8:201-204, 1993

14. Saw J, Dahlstrom B, Paazlow L: Morphine kinetics in cancer patients. Clin Pharm Ther 30:629-635, 1981

15. Graves DA, Arigo JM, Foster RS: Relationship between plasma morphine concentrations and pharmacologic effects in postoperative patients using patient-controlled analgesia. Clin Pharmacol Ther 4:41-47, 1985

16. Kaiko RF, Foley KM, Gravinsky PLJ: Central nervous system excita- tory effects of meperidine in cancer patients. Ann Neuro113:180-185, 1983

17. Paix A, Coleman A, Lees J: Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain manage- ment. Pain 63:263-269, 1995

18. Gaer BS, Coyle N, Pasternak GW: Individual variability in the response to different opioids: Report of 5 cases. Pain 49:87-91, 1992

19. Ferrell BR, Nash CC, Warfield C: The role of patient-controlled analgesia in the management of cancer pain. J Pain Symptom Manage 7:149-154, 1992

20. Hansen LA, Noyes MA, Lehman ME: Evaluation of patient-controlled analgesia (PCA) versus PCA plus continuous infusion in postopera- t!ve cancer patients. J Pain Symptom Manage 6:4-14, 1991

�9 21.. Mowbray M J, Gaukroger PB: Long-term patient-controlled analgesia in children. Anaesthesia 45:941-943, 1990

22. Dunbar P J, Buckley P, Gavrin JR: Use of patient-controlled analgesia for pain control for children receiving bone marrow transplant. J Pain Symptom Manage 10:604-611, 1995

23. Catley DM, Thornton C, Jordan C: Pronounced episodic oxygen desaturation in the postoperative period: its association with ventila- tory patterns and analgesic regimen. Anesthesiology 63:20-28, 1985

24. Brennis C, Michaud M, Bruera E: Local toxicity during the subcutane- ous infusion of narcotics (SCLN). Cancer Nurs 10:172-176, 1987

5 2 PATRICIA HARRISON