121
Pain, 40 (1990) 121-129 Elsevier
PAIN 01527
Clinical Section
Self-administration of morphine in bone marrow transplant patients reduces drug requirement Harlan F. Hill *, C. Richard Chapman *,* *, Judy A. Kornell *, Keith M. Sullivan *, Louis C. Saeger * * and Costantino Benedetti * * * Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98104 (U.S.A.), and * * Department of Anesthesiology, University of Washington School (Received
8 November
of Medicine,Seattle,
1988, revision received 25 July 1989, accepted
17 August
WA 98195 (U.S.A.) 1989)
Bone marrow transplant recipients were randomly assigned to receive morphine by either continuous infusion (32 Summary patients) or self-administration of small boluses (patient-controlled analgesia (PCA), 26 patients) for control of chemoradiotherapyinduced oral mucositis pain. All patients received morphine for a minimum of 9 days and most required morphine for at least 14 days. Patients rated their pain and side-effect intensity daily using visual analogue scales. Patient pain ratings did not differ between the groups although PCA patients used only 53% as much morphine as the continuous infusion group. Tolerance did not develop in the PCA group; in patients receiving continuous infusion morphine dosage continued to increase throughout the study while pain scores remained constant, indicating that tolerance had developed. Nausea, alertness and respiratory rate measurements did not differ between groups. PCA appeared more effective than the hospital staff determined treatment at delivering the least amount of morphine required to produce maximal pain relief. Patients self-administering morphine did not appear to restrict morphine intake in order to minimize opioid side-effects. Key words:
Patient-controlled
analgesia;
Self-administration;
Bone marrow
Introduction Two major limitations in pharmacological pain control are the frequent delays between patient request and staff administration of analgesic drugs and the marked variability between patients in the amount of analgesic needed for equivalent pain relief. These problems are minimized when pa-
Correspondence to: Harlan F. Hill, Ph.D., Pain and Toxicity Research Program AB-122, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, U.S.A. 0304-3959/90/$03.50
0 1990 Elsevier Science Publishers
transplant:
Chemoradiotherapy;
Oral mucositis
tients are allowed to self-administer small bolus doses of analgesic as frequently as needed to control pain. This procedure, called patient-controlled analgesia (PCA), has gained considerable acceptance in treatment of postsurgical pain in the past few years as microprocessor-controlled infusion pumps have become widely available. However, concern about the development of tolerance and physical dependence with prolonged opioid use has limited application of PCA in areas of chronic and persisting pain. Most previous PCA studies have been l-4 day investigations performed with surgical patients
B.V. (Biomedical
Division)
122
during the postoperative period [13,27]. Analgesic efficacy, patient acceptability, amount of opioid required, and side-effects experienced have been similar across studies. These short-term postsurgical investigations have shown that PCA patients: (1) require about one-half as much drug to achieve equivalent or better pain control than patients who receive the same drug by conventional means [3,15,19,25]; (2) experience fewer or less severe side-effects [4,24]; and (3) demonstrate a better course of recovery from the surgical procedures [2]. In other reports [14,28], patients stated that they preferred PCA to previously experienced pain control practices in which the analgesic drug was administered conventionally by the staff. There is a consensus that PCA works well in the majority of postsurgical patients; however, its applicability in non-surgical settings is still largely undetermined. The few uncontrolled studies using PCA for pain management in cancer patients suggest that the methodology may have important applications in painful conditions which persist for much longer than the typical 2 or 3 days of postsurgical pain [1,8,16,20]. However, controlled clinical studies are necessary to establish whether patients with persistent and severe pain will benefit from PCA, whether patients will continue to use opioids appropriately by PCA when analgesia is required for longer periods, and whether tolerance and physical dependence will develop. Cancer patients undergoing intensive cytoreductive therapy before bone marrow transplantation receive supralethal doses of chemoradiotherapy and often suffer from severe and persisting oral pain. Pre-transplant preparative regimens cause mucosal damage and desquamation severe enough to produce oropharyngeal inflammation, ulceration and extremely painful mucositis in about 90% of cancer patients [6,7]. In most cases oral mucositis is evident a day or two after transplant and persistent until marrow engraftment is noted about 2-3 weeks later. Throughout this period, patients are usually unable to speak normally or eat without pain. Daily oral rinses with local anesthetic solutions reduce the pain somewhat but become ineffective within a few days. Typically, marrow transplant recipients require parenteral morphine for pain relief soon after
mucositis appears. In many respects the duration of severe pain and the prolonged need for opioid analgesics seen in this patient population are similar to experience with pain control in burn, trauma and terminal cancer patients, and afford an opportunity to evaluate PCA over many days of use. Although oral mucositis pain is not strictly cancer pain. it does represent a prolonged, painful condition and is a very common treatment-related pain in many cancer patients. In the current randomized study, we compared pain relief, drug requirement, and side-effects in marrow transplant patients who received intravenous morphine administered by staff-controlled continuous infusion with those who received morphine by PCA. We predicted that PCA patients would: (1) balance opioid side-effects against pain relief and thus have more pain, less nausea, more alertness and use less morphine than similar patients receiving morphine by continuous infusion; and (2) be less likely to develop opioid tolerance and physical dependence because of more conservative morphine usage.
Methods Patients Between November 1985 and January 1987, a total of 84 patients with hematologic malignancies were randomly assigned to receive morphine by continuous infusion or by PCA for control of oropharyngeal pain and developed oral mucositis pain severe enough to begin the study. Patients aged 18-50 years, with acute lymphocytic leukemia (ALL), acute non-lymphocytic leukemia (ANL), chronic myelogenous leukemia (CML), Hodgkin’s and non-Hodgkin’s lymphoma or preleukemic syndrome were eligible for the study. All patients received high-dose chemotherapy and total body irradiation before transplant [26]. Exclusion criteria included history of drug abuse, inability to understand verbal or written English, or life threatening cardiac, hepatic or renal disease. Twenty-six patients remained on study for between 1 and 6 days only; reasons for early termination are shown in Table I. Only the patients who remained on study for 7 days or longer
123 TABLE I REASONS FOR DISCONTINUATION STUDY LESS THAN SEVEN DAYS
FOR PATIENTS ON
Reason
PCA
Continuous infusion
Veno-occlusive disease Received other opioids Encephalopathy Renal failure Abused PCA * Psychological Oral herpes Experienced side-effects Mucositis resolved
4 1 1 2 1 2 0 1 2
2 2 1 2 2 1 0 2
* Although this patient’s morphine usage pattern was appropriate for his oral mucositis severity, we disqualified him from the study because of physical signs that he had tampered with the infusion device.
were considered for the study reported here. There were 32 patients in the continuous infusion group and 26 in the PCA group who met this criterion. Characteristics of these 58 patients are displayed in Table II and the distribution of patients across preparative chemoradiotherapy treatment regimens is presented in Table III. Study design Within the first 2 days of admission to the marrow transplant unit, eligible patients were contacted by one of the investigators for explanation of the study, informed donsent and enrollment. Enrolled patients were then assigned randomly to receive morphine by either continuous infusion or PCA upon development of oral mucositis pain. When oral pain became severe enough to require intravenous morphine boluses every 4 h, treatment with morphine by continuous infusion or PCA was initiated and that day was designated as study day 1. All patients were fully instructed in proper use of the drug delivery instrument. Patients remained on study until they no longer required pain control, elected not to continue, or developed medical consequences (renal failure, hepatic dysfunction, encephalopathy) which adversely affected study progress.
Instrumentation PCA patients used the Abbott Lifecare PCA Infuser, an electronically controlled infusion pump with a push-button hand grip at the end of an extension cable. Both the size of morphine boluses and the minimum time period between doses (lock-out interval) were preset by the medical staff, and controls for these settings were not accessible to the patient. During this study, PCA patients received a 2-5 mg loading dose of morphine to initiate ‘therapy and the PCA infuser was set to deliver a 1.0 mg bolus per patient request with a lock-out interval of 10 min. As treatment progressed, the size of bolus doses could be adjusted up to 5 mg and the lockout interval could be lowered to 5 min depending on the adequacy of pain control. The maximum allowable morphine intake was 60 mg/h. At night, all PCA patients received a continuous infusion of morphine to facilitate sleep. Although the option of nighttime PCA use was available, it was rarely selected. The nighttime continuous infusions were from 23.00 to 07.00 h and the hourly infusion rate during that period was set equal to the preceding day’s average hourly morphine self-ad~~stration for each patient. Patients in the continuous infusion group received morphine via a constant rate infusion pump at rates selected by primary care nurses within a prescribed dosage range in accordance with our usual medical practice. Nurses were instructed to follow their normal practice of adjusting the morphine infusion rate as often as required to maximize pain control and patient comfort. Continuous infusion of morphine has been the standard method of management of oral mucositis pain for several years at this institution and the nursing staff is very familiar with its implementation. Measures The variables measured were: (1) patient pain intensity report; (2) daily mean morphine intake per hour; (3) self-report of nausea; (4) self-report of alertness; (5) respiration rate as measured by nursing staff; and (6) number of days of morphine use. Patients reported pain intensity, nausea and alertness each day (14.00-17.00 h) by completion
124
of visual analogue scales administered by a research nurse. Patients were asked to report the levels of pain, nausea and alertness typical for that day by marking the appropriate point along a 100 mm solid line. The pain and nausea scale were anchored on the left by ‘none at all’ and on the right by ‘as bad as it could be.’ Anchors for the patient alertness scale were ‘not alert at all’ and ‘as alert as I could be.’ Primary care nurses recorded total morphine consumption and respiratory rate at the end of each shift. Severity of oral mucositis was rated intermittently using a scoring system which estimates total area of erythema and ulceration. The oral mucositis severity scale ranged from 0 to 66 (maximal severity) [21]. Patients were examined by a dental hygienist who completed the mucositis severity ratings every 3-4 days during the study. Statistical analysis The statistical analysis was performed on data collected through the first 9 study days since the patient population remained constant during that period. Thereafter the sample size varied from day to day as patients recovered from mucositis or were discontinued from study for medical reasons unrelated to morphine administration. Since PCA patients received continuous morphine infusions at night, daily morphine intake rates for both groups were calculated by summing morphine used during day and evening shifts and dividing the total by 16 to obtain mg/h averages. Morphine intake scores were subjected to a square root transform prior to analysis to improve approximation to a normal distribution. Morphine intake rate and daily patient ratings of pain intensity were averaged for study days 1-3, 4-6 and 779 and analyzed for group, time, and group X time interaction effects over the 9 study days using a repeated measures multivariate analysis of variance (MANOVA). A similar analysis was performed for nausea and alertness side-effect measures over the same days. A comparable analysis of variance was performed on respiratory rates. Differences between group means for number of days on study and total morphine intake during the study were tested for significance by 2-tailed t tests.
Results
Characteristics of patients in the 2 treatment groups of this study are displayed in Tables II and III. Group means for age and body weight did not differ. The distributions of diagnoses and preparative regimens were nearly identical for PCA and continuous infusion patients. Also, the time after transplant when patients in the 2 groups started on study was not significantly different. Pain scores und morphine intuke The MANOVA performed on pain and morphine intake scores yielded a significant overall group effect (F (2, 55) = 6.685, P = 0.003) and time effect (F (4, 53) = 18.332, P < O.OOO),but no time X group interaction (F (4, 53) = 1.695, P = 0.165). The specific outcomes for each variable are described below. Mean pain scores for the first 9 study days are shown in Figs. 1 and 2. For both groups. pain ratings approximated 50 on this loo-point visual
TABLE
II
CHARACTERISTICS
OF EVALUABLE
PATIENTS
PCA
Continuous infusion
N Male Female Age at (mean) Transplant (range)
26 22 4 29.1 1 x-47
32 18 14 30.0 19-49
Diagnosis all ANL CML Lymphoma Other
4 7 12 3
4 7 16 4
Study initiation Mean Range
__-
1 *
Body weight (kg) Mean Range
3.96 2-8
3.69 1-8
74.7 55-94
15.2 55-102
* Days after marrow transplantation when patients began receiving morphine by PCA or continuous infusion for oral mucositis pain control.
0
TABLE III
*
PREPA~TIVE CHEMO~DIOTHE~PY FOR STUDY PATIENTS
Cy + I 575 Gy TBI Cy+1200GyTBI ~y+Bu+~2~GyTBI Other
Morphine Pain
Use
REGIMENS
PCA
Continuous infusion
16 6 1 3
19 7 3 3
Cy = cyclophosphamide, 60 mg/kg/day x 2; Bu = busulfan, 2 mg/kg/day X 4; Gy = grey; TBI = total body irradiation. Days
analogue scale and the ratings were consistent from day to day. The groups did not differ significantly on this measure (t; (1, 56) = 0.925, P = 0.340); however, there was a significant time effect characterized by a quadratic trend (F (1, 56) = 12.013, P = 0.001). This reflects the progressive onset and then gradual recovery from oral mucositis after marrow transplantation as the mucosal epithelium undergoes repair. There was no group x time interaction (F (4, 53) = 1.695, P = 0.165). This outcome indicates that PCA patients did not elect a lesser degree of pain relief than that ob-
On
Study
Fig. 2. Patient pain report and morphine intake for patientcontrolled analgesia (PCA) group. Group means for PCA patients (N = 26) are presented over the first 9 days on study (morphine intake = 0, and pain report = *). The standard errors of the mean ranged from 2.61 to 4.66 for pain and from 0.14 to 0.40 mg/h for morphine intake. VAS = visual analogue scale.
tamed by their counterparts receiving standard drug administration. Patients using PCA for morphine administration required less drug than the continuous infusion patients throughout the first 9 study days (Figs. 1 and 2). A significant group effect (F (1, 56) = 8.075, P = 0.006) and a quadratic trend over time (F (1, 56) = 27.716, P < 0.001) were observed for morphine intake. Nausea and alertness
00
30 1
2
3
Days
4
5
On
6
7
8
9
10
Study
Fig. 1. Patient pain report and morphine intake for continuous infusion (CI) group. The group means for CI patients (N = 32) are shown for the initial 9 study days. Numerical values for morphine intake are on the left ordinate and patient pain rating values are on the right. Morphine intake data are represented as open circles connected by dashed lines and pain report data are shown as asterisks connected by solid lines. The standard errors of the mean ranged from 3.53 to 4.53 for pain and from 0.22 to 0.45 mg/h for drug intake. VAS = visual analogue scafe.
MANOVA performed on the 9 day data revealed a lack of significant group effect (F (2, 55) = 0.846, P = 0.473), and neither the time effect (F (4, 53) = 1.940, P = 0.117) nor the group X time interaction (F (4, 53) = 1.452, P = 0.230) were significant (data not shown). Thus, the data did not support our prediction that patients who self-administer morphine will minimize side-effects. However, alertness was not significantly reduced by morphine in either group of patients so reduction of drug dosage to avoid decreased alertness was not a likely outcome in this study. Respiration No significant between group differences were observed in respiration rate (F (3, 54) = 2.136,
126 ORAL MUCXXlTlS SCORE 2Qr
Fig. 3. Oral mucositis severity ratings. Severity of oral mucositis was estimated at 4 time points during the study. Group means for PCA (open bars) and continuous infusion (hatched bars) patients are shown with vertical bars indicating standard error of the means.
P = 0.106). Both groups of patients maintained respiration rates in the normal range throughout the study. No patient had a rate less than 14 breaths/mm at any observation point.
Fig. 5. Morphine intake for continuous infusion and PC.4 patients. Mean daily morphine utilization is shown for 14 study days (PCA = 0, and continuous infusion = A). The number of patients remaining on study after day 9 is shown above each data point. Standard errors of the means ranged from 0.14 to 0.64 mg/h for PCA and 0.22 to 0.77 mg/h for continuous infusion patients.
plete. Nonetheless, the data support our assumption that the severity of mucositis was similar in both groups.
Oral mucositis severity Fig. 3 displays the oral mucositis severity scores as 3 day averages for patients in each group. The data set for this measure were only partially com-
Days
On
Study
Fig. 4. Patient pain report for continuous infusion and PCA patients. The plots show daily mean values for reported pain for 14 study days. After 9 days, the number of PCA (KI} and continuous infusion (A) patients varied as patients left the study due to resolution of oral mucositis or transplant treatment complications. Number of patients in study after day 9 is as shown above each data point in Fig. 5. Standard errors ranged from 3.67 to 8.30 for PCA and 2.70 to 5.97 for continuous infusion patients.
Fourteen day data
To examine the possibility of tolerance development, those patients who remained on study were studied out to 14 days of continuous infusion or patient-controlled analgesia. Beyond 9 days the number of patients in each group gradually diminished. As seen in Fig. 4, patients in both groups exhibited stable pain scores through study day 14. Morphine intake increased rapidly during the first 3-5 days in both groups (Fig. 5). Thereafter, PCA patients maintained a stable level of morphine intake while patients on continuous infusion gradually increased drug usage. Differences in morphine intake between groups became more pronounced with time as PCA patients decreased drug usage after study day 10. Over the entire course of the study, PCA patients used 53% as much morphine as the continuous infusion group (PCA = 454 mg f 102; continuous infusion = 875 mg ~fi123; P = 0.015). Days on study
The mean number of days that the group of 26 patients using PCA remained on study was signifi-
127
cantly less than for continuous infusion patients (12.9 vs. 17.4 days, respectively; P = 0.018).
Discussion
We initially reasoned that PCA patients would limit the use of morphine and accept less than optimal pain control in order to avoid unpleasant opioid side-effects. We found that PCA patients did use less morphine than continuous infusion patients but nausea and decreased alertness, which were not different between groups, did not account for the lower morphine intake. The difference in morphine intake in patients receiving continuous infusion may be due to overestimation by the hospital staff of the amount of morphine needed by patients receiving drug by continuous infusion. Two considerations underscore the importance of minimizing morphine intake when managing persistent pain. First, by requiring less morphine for equivalent pain reduction, PCA may lessen the likelihood of serious side-effects. Second, more conservative use of morphine may retard physical dependence and tolerance development. Our second hypothesis was that patients selfadministering morphine would be less likely than continuous infusion patients to exhibit tolerance to opioid analgesia. Studies in laboratory animals clearly document that tolerance to antinociceptive effects and physical dependence are produced by repeated bolus morphine doses [10,22]. Since PCA patients reached peak morphine intake within 3 days of treatment initiation, did not show progressive elevation of morphine intake thereafter, and had stable pain scores throughout the study, we conclude that tolerance to morphine analgesia did not occur in this group. The increase in morphine intake by PCA patients in the first 3 days was associated with an increase in oral mucositis severity and, presumably, increased nociception during this period. Further support for the lack of tolerance development in PCA patients is evidenced by the fact that they were able to decrease morphine intake promptly as oral mucositis resolved. Other investigators have also recently shown that tolerance and physical dependence are not necessarily
inevitable outcomes of long-term pain control with opioids [11,12,18,30]. In contrast to patients self-administering morphine, those in the continuous infusion group received morphine at an increasing rate throughout the study even while pain scores remained constant. At the end of the study, they required a slow tapering of morphine intake in most cases in order to minimize or avoid withdrawal symptoms. As a consequence, PCA patients used morphine for fewer days than continuous infusion patients. Whether morphine was administered by continuous infusion or PCA, pain relief was never complete and usually amounted to reductions to about 50 on the loo-point scale. This limitation in pain relief with morphine has also been observed in other studies [9,16] and may be attributable to a lack of selectivity of morphine for central opioid receptors mediating analgesia and other receptors involved in the therapy-limiting side-effects of non-selective opioids. In situations like this, the goal of drug administration must be to titrate to the point of maximum relief possible instead of achieving total pain relief. Our data indicate that patients were more successful than treatment staff in achieving this goal. The limited efficacy of morphine in both groups in this study may indicate that oral mucositis pain is not entirely due to nociceptive processes. Does the exercise of personal control by PCA patients present a unique advantage in pain control? Patterns of morphine self-administration in this study are consistent with those predicted by control theory [5,17,23], a behavioral implementation of cybernetic principles first introduced by Wiener [29]. Put simply, patients self-regulate drug intake to maintain the lowest level of pain possible. They determine whether or not increased dosing leads to further pain reduction and refrain from doing so when it does not. The treatment staff administering drug by continuous infusion cannot detect the point of diminishing analgesic return as morphine intake increases. Consequently, they typically give more than enough drug to reach this point. Our results demonstrate the efficacy and safety of PCA compared to continuous infusion in pain control extending beyond the usual length of post-
12X
surgical pain. We have shown that patients can use PCA for 2 weeks or more to achieve acceptable pain control without escalation of morphine consumption. Our outcomes are consistent with postsurgical studies showing that PCA patients use only about half as much morphine as controls to achieve equal pain control. However. PCA patients did not experience fewer or less severe sideeffects than their continuous infusion counterparts in the present study. Finally, patients using PCA did not develop tolerance and required morphine for fewer days than patients receiving the drug by continuous infusion. The apparent shortening of the length of morphine requirement by PCA may lead to improvements in patient well-being and to shortened hospital stays in some cases. We conclude that PCA may be advantageous for management of cancer pain and other persistent pain states.
This work was supported by Program Project Grant CA 38552 from the National Cancer Institute and assistance from Abbott Laboratories. We wish to thank Dr. E.D. Thomas and colleagues at the Fred Hutchinson Cancer Research Center for permission to conduct this study with patients under their care and research protocols (Grant No. CA 18029). Also, we thank Dr. Terry Jackson for assistance with conduct of the project. We are indebted to the marrow transplant nursing staff at the Fred Hutchinson Cancer Research Center and Swedish Hospital Medical Center for their valuable day-by-day assistance in completing this study.
References Bennett, R.L., Patient controlled analgesia for the treatment of the pain of terminal cancer: description of an initial clinical experience. In: M. Harmer, M. Rosen and M.D. Vickers (Ed%), Patient Controlled Analgesia, Blackwell Scientific Publications, Oxford, 1985, pp. 160-169. Bennett, R.L., Batenhorst, R.L., Foster, T.S., Griffen, W.O. and Wright, B.D., Postoperative pulmonary function with
patient-controlled
analgesia.
Aneath.
Analg.. hl
(19X2)171A
~abstl-.). 3 Bennett. R.L.. Batenhorst. R.L., Bivins. B.A..
Pain, 40 (1990) 121-129 Elsevier
PAIN 01527
Clinical Section
Self-administration of morphine in bone marrow transplant patients reduces drug requirement Harlan F. Hill *, C. Richard Chapman *,* *, Judy A. Kornell *, Keith M. Sullivan *, Louis C. Saeger * * and Costantino Benedetti * * * Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98104 (U.S.A.), and * * Department of Anesthesiology, University of Washington School (Received
8 November
of Medicine,Seattle,
1988, revision received 25 July 1989, accepted
17 August
WA 98195 (U.S.A.) 1989)
Bone marrow transplant recipients were randomly assigned to receive morphine by either continuous infusion (32 Summary patients) or self-administration of small boluses (patient-controlled analgesia (PCA), 26 patients) for control of chemoradiotherapyinduced oral mucositis pain. All patients received morphine for a minimum of 9 days and most required morphine for at least 14 days. Patients rated their pain and side-effect intensity daily using visual analogue scales. Patient pain ratings did not differ between the groups although PCA patients used only 53% as much morphine as the continuous infusion group. Tolerance did not develop in the PCA group; in patients receiving continuous infusion morphine dosage continued to increase throughout the study while pain scores remained constant, indicating that tolerance had developed. Nausea, alertness and respiratory rate measurements did not differ between groups. PCA appeared more effective than the hospital staff determined treatment at delivering the least amount of morphine required to produce maximal pain relief. Patients self-administering morphine did not appear to restrict morphine intake in order to minimize opioid side-effects. Key words:
Patient-controlled
analgesia;
Self-administration;
Bone marrow
Introduction Two major limitations in pharmacological pain control are the frequent delays between patient request and staff administration of analgesic drugs and the marked variability between patients in the amount of analgesic needed for equivalent pain relief. These problems are minimized when pa-
Correspondence to: Harlan F. Hill, Ph.D., Pain and Toxicity Research Program AB-122, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, U.S.A. 0304-3959/90/$03.50
0 1990 Elsevier Science Publishers
transplant:
Chemoradiotherapy;
Oral mucositis
tients are allowed to self-administer small bolus doses of analgesic as frequently as needed to control pain. This procedure, called patient-controlled analgesia (PCA), has gained considerable acceptance in treatment of postsurgical pain in the past few years as microprocessor-controlled infusion pumps have become widely available. However, concern about the development of tolerance and physical dependence with prolonged opioid use has limited application of PCA in areas of chronic and persisting pain. Most previous PCA studies have been l-4 day investigations performed with surgical patients
B.V. (Biomedical
Division)
122
during the postoperative period [13,27]. Analgesic efficacy, patient acceptability, amount of opioid required, and side-effects experienced have been similar across studies. These short-term postsurgical investigations have shown that PCA patients: (1) require about one-half as much drug to achieve equivalent or better pain control than patients who receive the same drug by conventional means [3,15,19,25]; (2) experience fewer or less severe side-effects [4,24]; and (3) demonstrate a better course of recovery from the surgical procedures [2]. In other reports [14,28], patients stated that they preferred PCA to previously experienced pain control practices in which the analgesic drug was administered conventionally by the staff. There is a consensus that PCA works well in the majority of postsurgical patients; however, its applicability in non-surgical settings is still largely undetermined. The few uncontrolled studies using PCA for pain management in cancer patients suggest that the methodology may have important applications in painful conditions which persist for much longer than the typical 2 or 3 days of postsurgical pain [1,8,16,20]. However, controlled clinical studies are necessary to establish whether patients with persistent and severe pain will benefit from PCA, whether patients will continue to use opioids appropriately by PCA when analgesia is required for longer periods, and whether tolerance and physical dependence will develop. Cancer patients undergoing intensive cytoreductive therapy before bone marrow transplantation receive supralethal doses of chemoradiotherapy and often suffer from severe and persisting oral pain. Pre-transplant preparative regimens cause mucosal damage and desquamation severe enough to produce oropharyngeal inflammation, ulceration and extremely painful mucositis in about 90% of cancer patients [6,7]. In most cases oral mucositis is evident a day or two after transplant and persistent until marrow engraftment is noted about 2-3 weeks later. Throughout this period, patients are usually unable to speak normally or eat without pain. Daily oral rinses with local anesthetic solutions reduce the pain somewhat but become ineffective within a few days. Typically, marrow transplant recipients require parenteral morphine for pain relief soon after
mucositis appears. In many respects the duration of severe pain and the prolonged need for opioid analgesics seen in this patient population are similar to experience with pain control in burn, trauma and terminal cancer patients, and afford an opportunity to evaluate PCA over many days of use. Although oral mucositis pain is not strictly cancer pain. it does represent a prolonged, painful condition and is a very common treatment-related pain in many cancer patients. In the current randomized study, we compared pain relief, drug requirement, and side-effects in marrow transplant patients who received intravenous morphine administered by staff-controlled continuous infusion with those who received morphine by PCA. We predicted that PCA patients would: (1) balance opioid side-effects against pain relief and thus have more pain, less nausea, more alertness and use less morphine than similar patients receiving morphine by continuous infusion; and (2) be less likely to develop opioid tolerance and physical dependence because of more conservative morphine usage.
Methods Patients Between November 1985 and January 1987, a total of 84 patients with hematologic malignancies were randomly assigned to receive morphine by continuous infusion or by PCA for control of oropharyngeal pain and developed oral mucositis pain severe enough to begin the study. Patients aged 18-50 years, with acute lymphocytic leukemia (ALL), acute non-lymphocytic leukemia (ANL), chronic myelogenous leukemia (CML), Hodgkin’s and non-Hodgkin’s lymphoma or preleukemic syndrome were eligible for the study. All patients received high-dose chemotherapy and total body irradiation before transplant [26]. Exclusion criteria included history of drug abuse, inability to understand verbal or written English, or life threatening cardiac, hepatic or renal disease. Twenty-six patients remained on study for between 1 and 6 days only; reasons for early termination are shown in Table I. Only the patients who remained on study for 7 days or longer
123 TABLE I REASONS FOR DISCONTINUATION STUDY LESS THAN SEVEN DAYS
FOR PATIENTS ON
Reason
PCA
Continuous infusion
Veno-occlusive disease Received other opioids Encephalopathy Renal failure Abused PCA * Psychological Oral herpes Experienced side-effects Mucositis resolved
4 1 1 2 1 2 0 1 2
2 2 1 2 2 1 0 2
* Although this patient’s morphine usage pattern was appropriate for his oral mucositis severity, we disqualified him from the study because of physical signs that he had tampered with the infusion device.
were considered for the study reported here. There were 32 patients in the continuous infusion group and 26 in the PCA group who met this criterion. Characteristics of these 58 patients are displayed in Table II and the distribution of patients across preparative chemoradiotherapy treatment regimens is presented in Table III. Study design Within the first 2 days of admission to the marrow transplant unit, eligible patients were contacted by one of the investigators for explanation of the study, informed donsent and enrollment. Enrolled patients were then assigned randomly to receive morphine by either continuous infusion or PCA upon development of oral mucositis pain. When oral pain became severe enough to require intravenous morphine boluses every 4 h, treatment with morphine by continuous infusion or PCA was initiated and that day was designated as study day 1. All patients were fully instructed in proper use of the drug delivery instrument. Patients remained on study until they no longer required pain control, elected not to continue, or developed medical consequences (renal failure, hepatic dysfunction, encephalopathy) which adversely affected study progress.
Instrumentation PCA patients used the Abbott Lifecare PCA Infuser, an electronically controlled infusion pump with a push-button hand grip at the end of an extension cable. Both the size of morphine boluses and the minimum time period between doses (lock-out interval) were preset by the medical staff, and controls for these settings were not accessible to the patient. During this study, PCA patients received a 2-5 mg loading dose of morphine to initiate ‘therapy and the PCA infuser was set to deliver a 1.0 mg bolus per patient request with a lock-out interval of 10 min. As treatment progressed, the size of bolus doses could be adjusted up to 5 mg and the lockout interval could be lowered to 5 min depending on the adequacy of pain control. The maximum allowable morphine intake was 60 mg/h. At night, all PCA patients received a continuous infusion of morphine to facilitate sleep. Although the option of nighttime PCA use was available, it was rarely selected. The nighttime continuous infusions were from 23.00 to 07.00 h and the hourly infusion rate during that period was set equal to the preceding day’s average hourly morphine self-ad~~stration for each patient. Patients in the continuous infusion group received morphine via a constant rate infusion pump at rates selected by primary care nurses within a prescribed dosage range in accordance with our usual medical practice. Nurses were instructed to follow their normal practice of adjusting the morphine infusion rate as often as required to maximize pain control and patient comfort. Continuous infusion of morphine has been the standard method of management of oral mucositis pain for several years at this institution and the nursing staff is very familiar with its implementation. Measures The variables measured were: (1) patient pain intensity report; (2) daily mean morphine intake per hour; (3) self-report of nausea; (4) self-report of alertness; (5) respiration rate as measured by nursing staff; and (6) number of days of morphine use. Patients reported pain intensity, nausea and alertness each day (14.00-17.00 h) by completion
124
of visual analogue scales administered by a research nurse. Patients were asked to report the levels of pain, nausea and alertness typical for that day by marking the appropriate point along a 100 mm solid line. The pain and nausea scale were anchored on the left by ‘none at all’ and on the right by ‘as bad as it could be.’ Anchors for the patient alertness scale were ‘not alert at all’ and ‘as alert as I could be.’ Primary care nurses recorded total morphine consumption and respiratory rate at the end of each shift. Severity of oral mucositis was rated intermittently using a scoring system which estimates total area of erythema and ulceration. The oral mucositis severity scale ranged from 0 to 66 (maximal severity) [21]. Patients were examined by a dental hygienist who completed the mucositis severity ratings every 3-4 days during the study. Statistical analysis The statistical analysis was performed on data collected through the first 9 study days since the patient population remained constant during that period. Thereafter the sample size varied from day to day as patients recovered from mucositis or were discontinued from study for medical reasons unrelated to morphine administration. Since PCA patients received continuous morphine infusions at night, daily morphine intake rates for both groups were calculated by summing morphine used during day and evening shifts and dividing the total by 16 to obtain mg/h averages. Morphine intake scores were subjected to a square root transform prior to analysis to improve approximation to a normal distribution. Morphine intake rate and daily patient ratings of pain intensity were averaged for study days 1-3, 4-6 and 779 and analyzed for group, time, and group X time interaction effects over the 9 study days using a repeated measures multivariate analysis of variance (MANOVA). A similar analysis was performed for nausea and alertness side-effect measures over the same days. A comparable analysis of variance was performed on respiratory rates. Differences between group means for number of days on study and total morphine intake during the study were tested for significance by 2-tailed t tests.
Results
Characteristics of patients in the 2 treatment groups of this study are displayed in Tables II and III. Group means for age and body weight did not differ. The distributions of diagnoses and preparative regimens were nearly identical for PCA and continuous infusion patients. Also, the time after transplant when patients in the 2 groups started on study was not significantly different. Pain scores und morphine intuke The MANOVA performed on pain and morphine intake scores yielded a significant overall group effect (F (2, 55) = 6.685, P = 0.003) and time effect (F (4, 53) = 18.332, P < O.OOO),but no time X group interaction (F (4, 53) = 1.695, P = 0.165). The specific outcomes for each variable are described below. Mean pain scores for the first 9 study days are shown in Figs. 1 and 2. For both groups. pain ratings approximated 50 on this loo-point visual
TABLE
II
CHARACTERISTICS
OF EVALUABLE
PATIENTS
PCA
Continuous infusion
N Male Female Age at (mean) Transplant (range)
26 22 4 29.1 1 x-47
32 18 14 30.0 19-49
Diagnosis all ANL CML Lymphoma Other
4 7 12 3
4 7 16 4
Study initiation Mean Range
__-
1 *
Body weight (kg) Mean Range
3.96 2-8
3.69 1-8
74.7 55-94
15.2 55-102
* Days after marrow transplantation when patients began receiving morphine by PCA or continuous infusion for oral mucositis pain control.
0
TABLE III
*
PREPA~TIVE CHEMO~DIOTHE~PY FOR STUDY PATIENTS
Cy + I 575 Gy TBI Cy+1200GyTBI ~y+Bu+~2~GyTBI Other
Morphine Pain
Use
REGIMENS
PCA
Continuous infusion
16 6 1 3
19 7 3 3
Cy = cyclophosphamide, 60 mg/kg/day x 2; Bu = busulfan, 2 mg/kg/day X 4; Gy = grey; TBI = total body irradiation. Days
analogue scale and the ratings were consistent from day to day. The groups did not differ significantly on this measure (t; (1, 56) = 0.925, P = 0.340); however, there was a significant time effect characterized by a quadratic trend (F (1, 56) = 12.013, P = 0.001). This reflects the progressive onset and then gradual recovery from oral mucositis after marrow transplantation as the mucosal epithelium undergoes repair. There was no group x time interaction (F (4, 53) = 1.695, P = 0.165). This outcome indicates that PCA patients did not elect a lesser degree of pain relief than that ob-
On
Study
Fig. 2. Patient pain report and morphine intake for patientcontrolled analgesia (PCA) group. Group means for PCA patients (N = 26) are presented over the first 9 days on study (morphine intake = 0, and pain report = *). The standard errors of the mean ranged from 2.61 to 4.66 for pain and from 0.14 to 0.40 mg/h for morphine intake. VAS = visual analogue scale.
tamed by their counterparts receiving standard drug administration. Patients using PCA for morphine administration required less drug than the continuous infusion patients throughout the first 9 study days (Figs. 1 and 2). A significant group effect (F (1, 56) = 8.075, P = 0.006) and a quadratic trend over time (F (1, 56) = 27.716, P < 0.001) were observed for morphine intake. Nausea and alertness
00
30 1
2
3
Days
4
5
On
6
7
8
9
10
Study
Fig. 1. Patient pain report and morphine intake for continuous infusion (CI) group. The group means for CI patients (N = 32) are shown for the initial 9 study days. Numerical values for morphine intake are on the left ordinate and patient pain rating values are on the right. Morphine intake data are represented as open circles connected by dashed lines and pain report data are shown as asterisks connected by solid lines. The standard errors of the mean ranged from 3.53 to 4.53 for pain and from 0.22 to 0.45 mg/h for drug intake. VAS = visual analogue scafe.
MANOVA performed on the 9 day data revealed a lack of significant group effect (F (2, 55) = 0.846, P = 0.473), and neither the time effect (F (4, 53) = 1.940, P = 0.117) nor the group X time interaction (F (4, 53) = 1.452, P = 0.230) were significant (data not shown). Thus, the data did not support our prediction that patients who self-administer morphine will minimize side-effects. However, alertness was not significantly reduced by morphine in either group of patients so reduction of drug dosage to avoid decreased alertness was not a likely outcome in this study. Respiration No significant between group differences were observed in respiration rate (F (3, 54) = 2.136,
126 ORAL MUCXXlTlS SCORE 2Qr
Fig. 3. Oral mucositis severity ratings. Severity of oral mucositis was estimated at 4 time points during the study. Group means for PCA (open bars) and continuous infusion (hatched bars) patients are shown with vertical bars indicating standard error of the means.
P = 0.106). Both groups of patients maintained respiration rates in the normal range throughout the study. No patient had a rate less than 14 breaths/mm at any observation point.
Fig. 5. Morphine intake for continuous infusion and PC.4 patients. Mean daily morphine utilization is shown for 14 study days (PCA = 0, and continuous infusion = A). The number of patients remaining on study after day 9 is shown above each data point. Standard errors of the means ranged from 0.14 to 0.64 mg/h for PCA and 0.22 to 0.77 mg/h for continuous infusion patients.
plete. Nonetheless, the data support our assumption that the severity of mucositis was similar in both groups.
Oral mucositis severity Fig. 3 displays the oral mucositis severity scores as 3 day averages for patients in each group. The data set for this measure were only partially com-
Days
On
Study
Fig. 4. Patient pain report for continuous infusion and PCA patients. The plots show daily mean values for reported pain for 14 study days. After 9 days, the number of PCA (KI} and continuous infusion (A) patients varied as patients left the study due to resolution of oral mucositis or transplant treatment complications. Number of patients in study after day 9 is as shown above each data point in Fig. 5. Standard errors ranged from 3.67 to 8.30 for PCA and 2.70 to 5.97 for continuous infusion patients.
Fourteen day data
To examine the possibility of tolerance development, those patients who remained on study were studied out to 14 days of continuous infusion or patient-controlled analgesia. Beyond 9 days the number of patients in each group gradually diminished. As seen in Fig. 4, patients in both groups exhibited stable pain scores through study day 14. Morphine intake increased rapidly during the first 3-5 days in both groups (Fig. 5). Thereafter, PCA patients maintained a stable level of morphine intake while patients on continuous infusion gradually increased drug usage. Differences in morphine intake between groups became more pronounced with time as PCA patients decreased drug usage after study day 10. Over the entire course of the study, PCA patients used 53% as much morphine as the continuous infusion group (PCA = 454 mg f 102; continuous infusion = 875 mg ~fi123; P = 0.015). Days on study
The mean number of days that the group of 26 patients using PCA remained on study was signifi-
127
cantly less than for continuous infusion patients (12.9 vs. 17.4 days, respectively; P = 0.018).
Discussion
We initially reasoned that PCA patients would limit the use of morphine and accept less than optimal pain control in order to avoid unpleasant opioid side-effects. We found that PCA patients did use less morphine than continuous infusion patients but nausea and decreased alertness, which were not different between groups, did not account for the lower morphine intake. The difference in morphine intake in patients receiving continuous infusion may be due to overestimation by the hospital staff of the amount of morphine needed by patients receiving drug by continuous infusion. Two considerations underscore the importance of minimizing morphine intake when managing persistent pain. First, by requiring less morphine for equivalent pain reduction, PCA may lessen the likelihood of serious side-effects. Second, more conservative use of morphine may retard physical dependence and tolerance development. Our second hypothesis was that patients selfadministering morphine would be less likely than continuous infusion patients to exhibit tolerance to opioid analgesia. Studies in laboratory animals clearly document that tolerance to antinociceptive effects and physical dependence are produced by repeated bolus morphine doses [10,22]. Since PCA patients reached peak morphine intake within 3 days of treatment initiation, did not show progressive elevation of morphine intake thereafter, and had stable pain scores throughout the study, we conclude that tolerance to morphine analgesia did not occur in this group. The increase in morphine intake by PCA patients in the first 3 days was associated with an increase in oral mucositis severity and, presumably, increased nociception during this period. Further support for the lack of tolerance development in PCA patients is evidenced by the fact that they were able to decrease morphine intake promptly as oral mucositis resolved. Other investigators have also recently shown that tolerance and physical dependence are not necessarily
inevitable outcomes of long-term pain control with opioids [11,12,18,30]. In contrast to patients self-administering morphine, those in the continuous infusion group received morphine at an increasing rate throughout the study even while pain scores remained constant. At the end of the study, they required a slow tapering of morphine intake in most cases in order to minimize or avoid withdrawal symptoms. As a consequence, PCA patients used morphine for fewer days than continuous infusion patients. Whether morphine was administered by continuous infusion or PCA, pain relief was never complete and usually amounted to reductions to about 50 on the loo-point scale. This limitation in pain relief with morphine has also been observed in other studies [9,16] and may be attributable to a lack of selectivity of morphine for central opioid receptors mediating analgesia and other receptors involved in the therapy-limiting side-effects of non-selective opioids. In situations like this, the goal of drug administration must be to titrate to the point of maximum relief possible instead of achieving total pain relief. Our data indicate that patients were more successful than treatment staff in achieving this goal. The limited efficacy of morphine in both groups in this study may indicate that oral mucositis pain is not entirely due to nociceptive processes. Does the exercise of personal control by PCA patients present a unique advantage in pain control? Patterns of morphine self-administration in this study are consistent with those predicted by control theory [5,17,23], a behavioral implementation of cybernetic principles first introduced by Wiener [29]. Put simply, patients self-regulate drug intake to maintain the lowest level of pain possible. They determine whether or not increased dosing leads to further pain reduction and refrain from doing so when it does not. The treatment staff administering drug by continuous infusion cannot detect the point of diminishing analgesic return as morphine intake increases. Consequently, they typically give more than enough drug to reach this point. Our results demonstrate the efficacy and safety of PCA compared to continuous infusion in pain control extending beyond the usual length of post-
12X
surgical pain. We have shown that patients can use PCA for 2 weeks or more to achieve acceptable pain control without escalation of morphine consumption. Our outcomes are consistent with postsurgical studies showing that PCA patients use only about half as much morphine as controls to achieve equal pain control. However. PCA patients did not experience fewer or less severe sideeffects than their continuous infusion counterparts in the present study. Finally, patients using PCA did not develop tolerance and required morphine for fewer days than patients receiving the drug by continuous infusion. The apparent shortening of the length of morphine requirement by PCA may lead to improvements in patient well-being and to shortened hospital stays in some cases. We conclude that PCA may be advantageous for management of cancer pain and other persistent pain states.
This work was supported by Program Project Grant CA 38552 from the National Cancer Institute and assistance from Abbott Laboratories. We wish to thank Dr. E.D. Thomas and colleagues at the Fred Hutchinson Cancer Research Center for permission to conduct this study with patients under their care and research protocols (Grant No. CA 18029). Also, we thank Dr. Terry Jackson for assistance with conduct of the project. We are indebted to the marrow transplant nursing staff at the Fred Hutchinson Cancer Research Center and Swedish Hospital Medical Center for their valuable day-by-day assistance in completing this study.
References Bennett, R.L., Patient controlled analgesia for the treatment of the pain of terminal cancer: description of an initial clinical experience. In: M. Harmer, M. Rosen and M.D. Vickers (Ed%), Patient Controlled Analgesia, Blackwell Scientific Publications, Oxford, 1985, pp. 160-169. Bennett, R.L., Batenhorst, R.L., Foster, T.S., Griffen, W.O. and Wright, B.D., Postoperative pulmonary function with
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Aneath.
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(19X2)171A
~abstl-.). 3 Bennett. R.L.. Batenhorst. R.L., Bivins. B.A..
