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Differential effects on pain and mood in chronic pain patients with time- versus pain-contingent medication delivery
BEHAVIORTHERAPY16, 28-38 (1985)
Differential Effects on Pain and Mood in Chronic Pain Patients With Time- Versus Pain-Contingent Medication Delivery BARBARA WHITE STEVE H. SANDERS University of Utah Medical Center Pain Center The current study was conducted to determine whether there were any differential effects on self-reported pain and mood levels in chronic pain patients subjected to time-contingent versus pain-contingent (PRN) medication delivery schedule during detoxification. Eight naive chronic pain patients admitted for treatment in a behaviorally oriented pain center were used as subjects. Following a 3-day drug intake baseline, all subjects were shifted to a mg equivalent dose of oral methadone delivered in a "cocktail" mixture and alternately assigned to one of two detoxification groups. One group received time-contingent delivery of methadone doses (every 6 hr), with the amount per dosage gradually decreased over the course of five days. The second group received daily methadone doses on a pain-contingentas-needed schedule (four equal doses available upon request), with the level of methadone also gradually reduced over 5 days. All other treatment and medications were held constant across groups. While no between-group differences existed during baseline in pain or mood levels, the time-contingentgroup exhibited significantly lower pain and, to a lesser extent, higher mood than the pain-contingentgroup at postdetoxification. Trend analyses supported these differences. It was concluded that time-contingentdelivery of pain medications produces significantly more improvement in collateral pain and mood measures compared to pain-contingent delivery schedules. T h e a b u s e o f p a i n m e d i c a t i o n b y c h r o n i c p a i n p a t i e n t s is a m a j o r c o n c e r n o f h e a l t h care p r o f e s s i o n a l s (e.g., M a r u t a , S w a n s o n , & F i n l a y s o n , 1979; R e a d y , Sarkis, & T u r n e r , 1982; T u r n e r , C a l s y n , F o r d y c e , & R e a d y , 1982; Ziesat, Angle, G e n t r y , & E l l i n w o o d , 1979). Likewise, a n i m p o r t a n t goal o f m o s t c h r o n i c p a i n t r e a t m e n t p r o g r a m s is the r e d u c t i o n o r e l i m i n a t i o n o f p a i n m e d i c a t i o n . I n a n a t t e m p t to e n h a n c e a c h i e v e m e n t o f this goal, F o r d y c e (1976) has a d v o c a t e d the use o f t i m e - c o n t i n g e n t (fixed i n t e r v a l ) m e d i c a t i o n d e l i v e r y s c h e d u l e s v e r s u s the m o r e t r a d i t i o n a l p a i n Request for reprints should be sent to Steve H. Sanders, Department of Rehabilitation Medicine, Emory University School of Medicine, 1441 Clifton Rd., N.E., Atlanta, GA 30322. 28 0005-7894/85/0028--003851.00/0 Copyright1985by Associationfor Advancementof BehaviorTherapy Allrightsof reproductionin anyformreserved.
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contingent ( " P R N " - - a s needed) schedule. He proposed that the timecontingent method disrupted the positive reinforcement contingency between learned pain behavior and the consequent delivery of analgesics. This approach has gained widespread acceptance among clinicians, with most chronic pain treatment programs using the time-contingent delivery schedule. While the time-contingent method contains strong intuitive support, little empirical data are available comparing it to the pain-contingent, PRN, medication delivery system. Studies that are available have examined certain aspects of medication delivery schedules on patients other than those with chronic pain (see Fulwiler, Hargreaves, & Bortman, 1979, with heroin addicts; Kinsman, Dirks, & Dahlem, 1980, with asthmatics). Likewise, findings have been mixed, with P R N methods having both positive and negative effects. Added to the confusion are recent studies demonstrating that chronic pain patients could successfully reduce and eliminate medication usage, exhibit reduction in pain intensity, and increase activity levels while on P R N delivery schedules (Keefe, Block, Williams, & Surwit, 1981; Sanders, 1983). Thus, there is obvious need for empirical scrutiny of claims by behavioral therapists that time-contingent pain medication delivery is preferred and superior to pain-contingent methods. The current study was conducted to expand our empirical knowledge base in this area. Specifically, it sought to determine whether there were any differential effects on self-reported pain and mood levels in chronic pain patients subjected to time-contingent versus pain-contingent medication delivery during therapist-controlled detoxification.
METHOD
Subjects Subjects consisted of eight chronic pain patients sequentially admitted to the University of Utah Pain Center for inpatient treatment. They were alternately assigned to a time-contingent (Subjects 1-4) or pain-contingent (Subjects 5-8) medication delivery detoxification group. Table 1 presents basic demographic and clinical characteristics for subjects by group assignment. Review of the table shows that there were no apparent differences in these characteristics across groups. In addition, all subjects had a family support system and were showing abusive patterns of prescription analgesic medication (i.e., oxycodone, codeine, meperidine, or pentazocine) usage. Other medications used by subjects included low doses of diazepam (Subjects 6, 7, 8), flurazepam (Subjects 2, 3, 5, 8), and hydroxyzine (Subject 3). Subject selection criteria consisted of (a) admission for inpatient treatment, (b) an abuse pattern of prescription analgesic usage for at least 3 months just prior to admission, and (c) willingness to voluntarily participate. (Note: No patients asked to participate in the study were unwilling to do so.) All subjects were naive to the study's intent.
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WHITE AND SANDERS
TABLE l DEMOGRAPHIC AND CLINICAL CHARACTERISTICS BY TREATMENT GROUP
Treatment group Characteristics Sex
Mean age Mean education Number receiving painrelated compensation Pain location
Mean pain duration
Time-Contingent detoxify
Pain-Contingent detoxify
2 males/2 females 41.3 yr(13 yr) 11.8 yr(3 yr) 2
1 male/3 females 43.1 yr(16 yr) 12.2 yr (3.5 yr) 1
2 abdominal 1 head 1 low back
1 abdominal 2 head 1 low back
6.3 yr (3.7 yr)
6.1 yr (4.1 yr)
Note. Numbers in parentheses equal standard deviations.
Procedure The study was conducted over a 12-month period. Subjects were housed on an open 18-bed psychiatric inpatient unit. Three to six other pain patients were on the unit at any given time. Not more than one subject, however, was on the unit at any given time. Outpatient baseline. Prior to admission, subjects were contacted by mail and asked to record baseline data for 14 days. This consisted of completing a daily diary of hourly activity, medication intake, pain intensity, and mood level (cf. Fordyce, 1976; Taylor, Zlutnick, Corley, & Flora, 1980). Pain and mood rating scales ranged from 0 (no pain, low mood) to 5 (unbearable pain, high mood). Data were mailed in by the subject as a prerequisite for admission. Inpatient baseline. Upon admission, subjects were recruited and again started the activity, medication, pain, and mood self-monitoring diary. Medication was administered and independently recorded by naive nurses, with baseline intake established by making all prescription analgesics taken available on a PRN basis. Antianxiety and sedative-hypnotic medications (e.g., flurazepam) were also administered PRN within recommended safe limits. (Note: Antianxiety and sedative-hypnotic medication administration was held constant throughout the study.) This baseline phase continued for 3 days. Detoxification. Following baseline, subjects were shifted to oral methadone medication at an analgesic dosage level equivalent to that observed during inpatient baseline. Equivalent conversion to methadone was accomplished using tables reported by Halpern (1978). Subjects were also alternately assigned at this time to one of the two detoxification groups. During the first 48 hr, time-contingent subjects received a constant mg dose of methadone every 6 hr in a cherry syrup medium at a constant
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liquid volume of 10 cc per dose. Gradual reduction to zero in the mg of methadone per dose was then carried out over the next 5 days at a rate of 20% reduction per 24 hr. Dosage frequency and liquid volume remained constant. Subjects were informed that their analgesic medication was being tapered, but were not aware of specific levels. They were instructed to take all doses offered. Review of medication charts revealed that all doses were taken. During the first 48 hr, pain-contingent subjects were given access to a total of four equal mg doses of methadone per 24 hr in cherry syrup at a constant liquid volume of 10 cc per dose. These doses were available upon request. As with the time-contingent group, pain-contingent subjects then received a gradual reduction (20% per 24 hr) to zero in the mg of methadone per dose over 5 days. The PRN delivery schedule and liquid volume per dose remained constant. These subjects were also aware that methadone was being reduced, but not of specific levels. They were encouraged to take all doses available each 24 hr at times they felt the most pain. Review of charts showed that subjects took all doses available. To determine if there had been an actual difference between groups in the pattern of methadone usage, mean time intervals between doses per 24 hr were computed. While the time-contingent group showed a mean of 5.8 hr (_.2 hr) between doses, the pain-contingent group exhibited a mean of 3.9 hr (+3 hr). Thus, the pain-contingent group displayed a much shorter interval between doses per 24 hr, with a,much larger degree of variation. Such group differences confirmed that the experimental manipulation had been achieved. Postdetoxification. Within 3 days of detoxification, subjects in both groups were started on additional treatment (e.g., progressive relaxation training and individualized physical therapy). Prior to this time, no other treatment was offered except detoxification. Gradual reduction to zero in antianxiety and sedative-hypnotic medications was also begun. Subjects and nursing staff were debriefed at the end of their participation. None were able to correctly state the purpose of the study.
RESULTS Medication and Activity Analysis Prior to examination of pain and mood data, analgesic, antianxiety, sedative-hypnotic medication usage, and self-reported up-time (i.e., standing or walking time) levels were compared across groups by inpatient treatment phase using two-tailed uncorrelated t tests. Findings showed no significant differences (p > .05) in antianxiety plus sedative-hypnotic mg doses or up-time between groups. Mean antianxiety plus sedativehypnotic medication usage across phases equaled a phenobarbital equivalent dose (Halpern, 1978) per 24 hr of 24.2 mg (+6) for the time-contingent group and 29.3 mg (+ 5) for the pain-contingent group. Likewise, up-time across phases equaled 2.9 hr (_+ 1.5) and 3.0 hr (+ 1), respectively, for the two groups. Analgesic medication comparisons using methadone equivalent doses
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WHITE AND SANDERS
(cf. Halpern, 1978) showed a statistically significant difference between groups during inpatient baseline, t(6) = 3.22, p < .05). The time-contingent group's analgesic usage was equivalent to 32 mg (+7) per 24 hr of methadone, while pain-contingent subjects required the equivalent of 13 nag of methadone. This difference was also noted with the actual administration of methadone during the first 2 days ofdetoxification. In contrast, mean group methadone levels during the last 2 days of detoxification did not differ, t(6) = .5, p > .05, with the time-contingent group given a 24hr average of 3.2 mg (___1) and the pain-contingent group given 1.2 mg
(___.8). Adding to the lack of statistical significance for group differences in methadone levels during the last 2 days of detoxification, are questions regarding the clinical significance of dosage differences at the beginning of detoxification. Pharmacologically, the 32 mg and 13 mg per 24-hr average methadone doses across groups during the first 2 days of detoxification are both considered relatively low (United States Pharmacopeial Convention, 1982). Likewise, S~iwe et al. (1983) have shown that there is no consistent relationship between absolute methadone dose or blood plasma levels and analgesic effect. Clinical analgesic equivalence can exist between two markedly different mg doses of methadone. Thus, group differences in absolute level of methadone do not necessarily have any clinical significance with respect to analgesia or physical withdrawal. Establishment of such significance, or the lack of it, within this context must be determined empirically. (This matter will be addressed in a subsequent section.)
Pain and Mood Analysis For ease of comparison and to allow parametric statistical analysis, pain and mood ratings were converted to percentage of maximum rating possible scores. This was done by dividing subjects' hourly ratings by 5 and multiplying by 100. Hourly percentage scores were then averaged each day for each subject. These mean daily pain and mood percentage scores were used as basic data for analysis. Fig. 1 depicts mean daily pain and mood percentage scores for the two groups by treatment phase. Review of outpatient baselines reveals more variability in the time-contingent group compared to the pain-contingent group, although no major differences were apparent. The time-contingent group did, however, show a gradual increase in pain scores during this phase. The inpatient baseline data indicated further increase in pain and a reduction in mood for the time-contingent group during the 1st day, with a return to outpatient baseline levels by the 3rd day. The paincontingent group's inpatient baseline showed little variation, with no differences noted between groups during the last 2 days of inpatient baseline. With the onset of detoxification, Fig. 1 depicts clear and consistent differences between groups. While the time-contingent group exhibited gradual reduction in pain and increase in mood scores (i.e., 54% reduction
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in pain and 42% increase in mood scores from last inpatient baseline day to first day of postdetoxify), the pain-contingent group showed a gradual increase in pain (i.e., 30%) and no major change in mood. The reduction trend in pain scores during detoxification and postdetoxification was found to be highly significant for the time-contingent group; linear trend, F(1, 27) = 32.26, p < .001, and quadratic trend, F(1, 27) -- 10.55, p < .001 (Winer, 1971). Likewise, this group's increased mood scores were highly significant for linear, F(1, 2 7 ) = 19.36, p < .001, and quadratic, F(1, 27) = 15.17, p < .001, trends. Increases seen in pain scores for the pain-contingent group during these latter two phases were also significant for a linear trend F(1, 27) = 8.67, p < .001. Pain-contingent group mood scores failed to show a significant trend. To further assess the extent of statistical significance for differences seen in Fig. 1, and given the a priori clinical assumptions about differences between groups, selected individual phase comparisons between groups
34
WHITE AND SANDERS TABLE 2 GROUP MEAN PAIN AND MOOD PERCENTAGESCORESBY TREATMENTPHASE Treatment phase Group
Inpatient baseline last 2 days
Postdetoxify first 2 days Pain
Time-Contingent detoxify Pain-Contingent detoxify
53.23 (20.33) 63.30 (15.73)
23.65 (19.93) 75.40 (21.16) Mood
Time-Contingent detoxify Pain-Contingent detoxify
45.60 (14.91) 49.40 (18.53)
77.10 (25.14) 38.70 (23.72)
Note. Numbers in parentheses equal standard deviations.
were conducted. Comparisons were limited to two per measure, with significance levels set at p < .025 to correct for any increases in error rate as a function o f multiple analyses (Hays, 198 I). Comparisons focused on determining whether any statistically significant differences existed between groups immediately prior to, or after, detoxification. Data were c o m p a r e d across groups over the last 2 days o f inpatient baseline and the first 2 days o f postdetoxification. Table 2 delineates group means and standard deviations for pain and m o o d percentage scores by the two relevant treatment phases. Two-tailed uncorrelated t tests on the inpatient baseline data were nonsignificant (p > .05). In contrast, one-tailed uncorrelated t tests on the postdetoxify data revealed significant differences. A highly significant difference, t(6) = -3.56, p < .01, was observed in pain scores and a strong difference trend was noted for m o o d scores, t(6) = 2.22, p < .05 but > .025. These findings statistically supported the differences seen in Fig. 1. T o empirically examine the clinical significance o f group differences in absolute m e t h a d o n e doses, individual subject data were compared. It was reasoned that if an absolute difference in m e t h a d o n e dose was a clinically significant (i.e., confounding) factor, then individual subjects across groups receiving equal doses o f m e t h a d o n e should exhibit markedly different results than those receiving maximally discrepant doses. Fig. 2 depicts m e a n daily pain and m o o d percentage scores for individual subjects from each group who coincidentally received equal doses o f m e t h a d o n e (i.e., Subject 4 and Subject 8 = 20 mg per 24 hr) and those who received the most discrepant doses o f m e t h a d o n e (i.e., Subject 6 = 8 mg and Subject 3 = 38 mg per 24 hr) during the first 2 days o f detox-
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FIG. 2. Subject (S) mean daily pain and mood percentage scores by treatment phase, group assignment, and absolute methadone dosage (i.e., equal dosage for $4 and $8 versus maximally discrepant dosage for $3 and $6). Outpatient baseline is depicted for the last 7 days (Days 8-14) of baseline. Inpatient detoxify data represent the first 2 (Days 4 and 5) and last 3 (Days 8-10) days of this phase. Postdetoxify data represent the first 5 days (Days 11-15) following detoxification.
ification. Review of the figure shows that the absolute level of methadone did not affect subjects' response pattern. Regardless of whether absolute methadone dosage was equal or maximally discrepant, time-contingent subjects (Subjects 3 and 4) exhibited similar reductions in pain and increases in mood, while pain-contingent subjects (Subjects 6 and 8) showed an increase in pain and no change in mood. These data are quite consistent with those depicted in Fig. 1 and clearly demonstrate that the group difference in absolute methadone dosage seen in the current study was not a clinically significant (confounding) factor. Pain and mood ratings for pain-contingent subjects did show improvement with the implementation of additional treatments subsequent to the postdetoxification phase. At the time of discharge these subjects reported mean pain and mood percentage scores of 50 and 68, respectively. Timecontingent subjects' mean discharge percentage scores continued to be superior and equaled 20 for pain and 80 for mood.
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WHITE AND SANDERS
DISCUSSION The present findings support the clinical assumption that time-contingent delivery of medication during detoxification is preferred to paincontingent delivery. Time-contingent subjects showed significant trends toward improved pain and mood levels, while pain-contingent subjects did not. In fact, these latter subjects actually exhibited a significant trend toward pain increase during, and initially after, detoxification. In addition, statistical analysis indicated no group differences in pain or mood prior to detoxification, with time-contingent subjects showing significantly lower pain and, to a lesser extent, higher mood levels after detoxification than pain-contingent subjects. Results can not be adequately explained by differences in basic demographic or clinical characteristics, amounts of antianxiety plus sedative-hypnotic medication used, activity level, pain or mood baseline levels, or concurrent treatments. No major differences were observed in these variables, with no other treatments implemented during the study. While Fig. 1 did show a potential "trend" toward reduced pain and increased mood for time-contingent subjects during inpatient baseline, comparisons with outpatient baselines would suggest these trends were simply a return to outpatient levels. The group difference in absolute methadone dosage levels during the first 2 days of detoxification is also an inadequate explanation of results. Not only were daily doses of methadone considered rather low for both groups, but individual subject comparisons (see Fig. 2) clearly demonstrated that absolute methadone dosage level did not significantly affect results obtained. Subject by group response patterns were consistent whether absolute methadone doses were equivalent or discrepant. The preceding points lead to the conclusion that group differences in pain and mood were primarily due to the schedule of medication delivery during detoxification. The mechanism(s) of action for this effect can not be conclusively delineated from current findings. It could be argued that group differences were due to differences in the stability of methadone blood plasma levels. Given the more stable rate of administration for the time-contingent group, a more steady-state blood plasma level of methadone could have occurred and led to more effective analgesia. While such an explanation can not be ruled out without repeated sampling of plasma levels, the pharmacokinetic properties of methadone make this explanation unlikely. The long half-life (over 24 hr) of methadone with repeated doses markedly reduces the amount of lability in blood plasma levels that might be expected with changes in administration rates (United States Pharmacopeial Convention, 1982). A more consistent explanation of differences in pain reports can be found within the learning principle of extinction (Fordyce, 1976). Assuming that time-contingent delivery of pain medication (i.e., a potential reinforcer) eliminated any contingent relationship between pain reports and the delivery of such medication and social reinforcers (e.g., nurses'
PAIN MEDICATION DELIVERY SCHEDULES
37
attention), then reduction in rate or intensity of pain reports would be predicted within an extinction learning model. Increases in mood ratings are not explained by extinction. However, such an effect could have been the result of pain reduction itself. Obviously, further empirical scrutiny is needed before conclusive explanations of observed effects are possible. Regardless of explanation, present findings do offer empirical support for the use of time-contingent medication delivery schedules during therapistcontrolled detoxification with chronic pain patients. While supportive of the time-contingent medication delivery method advocated by behavioral therapists, current results should be viewed with caution. Replication with a larger sample and more stringent experimental control is needed before definitive conclusions are possible. Likewise, these data do not address the question of whether chronic pain patients might be able to effectively use a pain-contingent P R N schedule of medication delivery during patient-controlled detoxification (cf. Keefe et al., 1981; Sanders, 1983). Instead, current results support the position that in those patients where detoxification is agreed upon and the rate of reduction is controlled by health care professionals, time-contingent medication delivery schedules can significantly facilitate improvement in pain and mood levels when compared to pain-contingent schedules. Questions regarding whether and with which patients pain-contingent P R N medication schedules might be applicable during patient-controlled detoxification await further study.
REFERENCES Fordyce, W. E. (1976). Behavioral methods for chronic pain and illness. St. Louis: Mosby. Fulwiler, R. L., Hargreaves, W. A., & Bortman, R . A . (1979). Detoxification from heroin using self vs physician regulation of methadone dose. International Journal of Addictions, 14, 289-298. Halpern, L. (1978). Relative potencies of stronger analgesics compared to morphine. Patient Care, 12, 121. Hays, W. L. (1981). Statistics. New York: Holt, Rinehart, & Winston. Keefe, F. H., Block, A. R., Williams, R, B., & Surwit, R. S. (1981). Behavioral treatment of chronic low back pain: Clinical outcome and individual differences in pain relief. Pain, 11, 221-231. Kinsman, R. A., Dirks, J. F., & Dahlem, N. W. (1980). Noncompliance to prescribed-asneeded (PRN) medication use in asthma: Usage patterns and patient characteristics. Journal of Psychosomatic Research, 24, 97-107. Maruta, T., Swanson, D. W., & Finlayson, R. E. (1979). Drug abuse and dependency in patients with chronic pain. Mayo Clinic Proceedings, 54, 241-244. Ready, L. B., Sarkis, E., & Turner, J. A. (1982). Self-reported vs actual use of medications in chronic pain patients. Pain, 12, 285-294. Sanders, S.H. (1983). Component analysis of a behavioral treatment program for chronic low-back pain. Behavior Therapy, 14, 697-705. Sawe, J., Hansen, J., Ginman, C., Hartvig, R., Jakobsson, P. A., Nilsson, M. E., Rane, A., & Anggard, E. (1983). Patient-controlled dose regimen of methadone for chronic cancer pain. British Medical Journal 282, 771-773.
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Taylor, C. B., Zlutnik, S. I., Corley, M. J., & Flora, J. (1980). The effects ofdetoxification, relaxation, and brief suggestion therapy on chronic pain patients. Pain, 8, 263-266. Turner, J. A., Calsyn, D. A., Fordyce, W. E., & Ready, L. B. (1982). Drug utilization patterns in chronic pain patients. Pain, 12, 357-363. United States Pharmacopeial Convention. (1982). Drug information for the health care provider. Kingsport, TN: Kingsport Press. Winer, B. J. (1971). Statistical principles in experimental design. New York: McGrawHill. Ziesat, H. A., Angle, H. V., Gentry, D., & Ellinwood, E. H. (1979). Drug use and misuse in operant pain patients. Addictive Behaviors, 4, 263-266. RECEIVED"December 5, 1983 FINAL ACCEPTANCE;June 29, 1984
Differential Effects on Pain and Mood in Chronic Pain Patients With Time- Versus Pain-Contingent Medication Delivery BARBARA WHITE STEVE H. SANDERS University of Utah Medical Center Pain Center The current study was conducted to determine whether there were any differential effects on self-reported pain and mood levels in chronic pain patients subjected to time-contingent versus pain-contingent (PRN) medication delivery schedule during detoxification. Eight naive chronic pain patients admitted for treatment in a behaviorally oriented pain center were used as subjects. Following a 3-day drug intake baseline, all subjects were shifted to a mg equivalent dose of oral methadone delivered in a "cocktail" mixture and alternately assigned to one of two detoxification groups. One group received time-contingent delivery of methadone doses (every 6 hr), with the amount per dosage gradually decreased over the course of five days. The second group received daily methadone doses on a pain-contingentas-needed schedule (four equal doses available upon request), with the level of methadone also gradually reduced over 5 days. All other treatment and medications were held constant across groups. While no between-group differences existed during baseline in pain or mood levels, the time-contingentgroup exhibited significantly lower pain and, to a lesser extent, higher mood than the pain-contingentgroup at postdetoxification. Trend analyses supported these differences. It was concluded that time-contingentdelivery of pain medications produces significantly more improvement in collateral pain and mood measures compared to pain-contingent delivery schedules. T h e a b u s e o f p a i n m e d i c a t i o n b y c h r o n i c p a i n p a t i e n t s is a m a j o r c o n c e r n o f h e a l t h care p r o f e s s i o n a l s (e.g., M a r u t a , S w a n s o n , & F i n l a y s o n , 1979; R e a d y , Sarkis, & T u r n e r , 1982; T u r n e r , C a l s y n , F o r d y c e , & R e a d y , 1982; Ziesat, Angle, G e n t r y , & E l l i n w o o d , 1979). Likewise, a n i m p o r t a n t goal o f m o s t c h r o n i c p a i n t r e a t m e n t p r o g r a m s is the r e d u c t i o n o r e l i m i n a t i o n o f p a i n m e d i c a t i o n . I n a n a t t e m p t to e n h a n c e a c h i e v e m e n t o f this goal, F o r d y c e (1976) has a d v o c a t e d the use o f t i m e - c o n t i n g e n t (fixed i n t e r v a l ) m e d i c a t i o n d e l i v e r y s c h e d u l e s v e r s u s the m o r e t r a d i t i o n a l p a i n Request for reprints should be sent to Steve H. Sanders, Department of Rehabilitation Medicine, Emory University School of Medicine, 1441 Clifton Rd., N.E., Atlanta, GA 30322. 28 0005-7894/85/0028--003851.00/0 Copyright1985by Associationfor Advancementof BehaviorTherapy Allrightsof reproductionin anyformreserved.
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29
contingent ( " P R N " - - a s needed) schedule. He proposed that the timecontingent method disrupted the positive reinforcement contingency between learned pain behavior and the consequent delivery of analgesics. This approach has gained widespread acceptance among clinicians, with most chronic pain treatment programs using the time-contingent delivery schedule. While the time-contingent method contains strong intuitive support, little empirical data are available comparing it to the pain-contingent, PRN, medication delivery system. Studies that are available have examined certain aspects of medication delivery schedules on patients other than those with chronic pain (see Fulwiler, Hargreaves, & Bortman, 1979, with heroin addicts; Kinsman, Dirks, & Dahlem, 1980, with asthmatics). Likewise, findings have been mixed, with P R N methods having both positive and negative effects. Added to the confusion are recent studies demonstrating that chronic pain patients could successfully reduce and eliminate medication usage, exhibit reduction in pain intensity, and increase activity levels while on P R N delivery schedules (Keefe, Block, Williams, & Surwit, 1981; Sanders, 1983). Thus, there is obvious need for empirical scrutiny of claims by behavioral therapists that time-contingent pain medication delivery is preferred and superior to pain-contingent methods. The current study was conducted to expand our empirical knowledge base in this area. Specifically, it sought to determine whether there were any differential effects on self-reported pain and mood levels in chronic pain patients subjected to time-contingent versus pain-contingent medication delivery during therapist-controlled detoxification.
METHOD
Subjects Subjects consisted of eight chronic pain patients sequentially admitted to the University of Utah Pain Center for inpatient treatment. They were alternately assigned to a time-contingent (Subjects 1-4) or pain-contingent (Subjects 5-8) medication delivery detoxification group. Table 1 presents basic demographic and clinical characteristics for subjects by group assignment. Review of the table shows that there were no apparent differences in these characteristics across groups. In addition, all subjects had a family support system and were showing abusive patterns of prescription analgesic medication (i.e., oxycodone, codeine, meperidine, or pentazocine) usage. Other medications used by subjects included low doses of diazepam (Subjects 6, 7, 8), flurazepam (Subjects 2, 3, 5, 8), and hydroxyzine (Subject 3). Subject selection criteria consisted of (a) admission for inpatient treatment, (b) an abuse pattern of prescription analgesic usage for at least 3 months just prior to admission, and (c) willingness to voluntarily participate. (Note: No patients asked to participate in the study were unwilling to do so.) All subjects were naive to the study's intent.
30
WHITE AND SANDERS
TABLE l DEMOGRAPHIC AND CLINICAL CHARACTERISTICS BY TREATMENT GROUP
Treatment group Characteristics Sex
Mean age Mean education Number receiving painrelated compensation Pain location
Mean pain duration
Time-Contingent detoxify
Pain-Contingent detoxify
2 males/2 females 41.3 yr(13 yr) 11.8 yr(3 yr) 2
1 male/3 females 43.1 yr(16 yr) 12.2 yr (3.5 yr) 1
2 abdominal 1 head 1 low back
1 abdominal 2 head 1 low back
6.3 yr (3.7 yr)
6.1 yr (4.1 yr)
Note. Numbers in parentheses equal standard deviations.
Procedure The study was conducted over a 12-month period. Subjects were housed on an open 18-bed psychiatric inpatient unit. Three to six other pain patients were on the unit at any given time. Not more than one subject, however, was on the unit at any given time. Outpatient baseline. Prior to admission, subjects were contacted by mail and asked to record baseline data for 14 days. This consisted of completing a daily diary of hourly activity, medication intake, pain intensity, and mood level (cf. Fordyce, 1976; Taylor, Zlutnick, Corley, & Flora, 1980). Pain and mood rating scales ranged from 0 (no pain, low mood) to 5 (unbearable pain, high mood). Data were mailed in by the subject as a prerequisite for admission. Inpatient baseline. Upon admission, subjects were recruited and again started the activity, medication, pain, and mood self-monitoring diary. Medication was administered and independently recorded by naive nurses, with baseline intake established by making all prescription analgesics taken available on a PRN basis. Antianxiety and sedative-hypnotic medications (e.g., flurazepam) were also administered PRN within recommended safe limits. (Note: Antianxiety and sedative-hypnotic medication administration was held constant throughout the study.) This baseline phase continued for 3 days. Detoxification. Following baseline, subjects were shifted to oral methadone medication at an analgesic dosage level equivalent to that observed during inpatient baseline. Equivalent conversion to methadone was accomplished using tables reported by Halpern (1978). Subjects were also alternately assigned at this time to one of the two detoxification groups. During the first 48 hr, time-contingent subjects received a constant mg dose of methadone every 6 hr in a cherry syrup medium at a constant
PAIN MEDICATION DELIVERY SCHEDULES
31
liquid volume of 10 cc per dose. Gradual reduction to zero in the mg of methadone per dose was then carried out over the next 5 days at a rate of 20% reduction per 24 hr. Dosage frequency and liquid volume remained constant. Subjects were informed that their analgesic medication was being tapered, but were not aware of specific levels. They were instructed to take all doses offered. Review of medication charts revealed that all doses were taken. During the first 48 hr, pain-contingent subjects were given access to a total of four equal mg doses of methadone per 24 hr in cherry syrup at a constant liquid volume of 10 cc per dose. These doses were available upon request. As with the time-contingent group, pain-contingent subjects then received a gradual reduction (20% per 24 hr) to zero in the mg of methadone per dose over 5 days. The PRN delivery schedule and liquid volume per dose remained constant. These subjects were also aware that methadone was being reduced, but not of specific levels. They were encouraged to take all doses available each 24 hr at times they felt the most pain. Review of charts showed that subjects took all doses available. To determine if there had been an actual difference between groups in the pattern of methadone usage, mean time intervals between doses per 24 hr were computed. While the time-contingent group showed a mean of 5.8 hr (_.2 hr) between doses, the pain-contingent group exhibited a mean of 3.9 hr (+3 hr). Thus, the pain-contingent group displayed a much shorter interval between doses per 24 hr, with a,much larger degree of variation. Such group differences confirmed that the experimental manipulation had been achieved. Postdetoxification. Within 3 days of detoxification, subjects in both groups were started on additional treatment (e.g., progressive relaxation training and individualized physical therapy). Prior to this time, no other treatment was offered except detoxification. Gradual reduction to zero in antianxiety and sedative-hypnotic medications was also begun. Subjects and nursing staff were debriefed at the end of their participation. None were able to correctly state the purpose of the study.
RESULTS Medication and Activity Analysis Prior to examination of pain and mood data, analgesic, antianxiety, sedative-hypnotic medication usage, and self-reported up-time (i.e., standing or walking time) levels were compared across groups by inpatient treatment phase using two-tailed uncorrelated t tests. Findings showed no significant differences (p > .05) in antianxiety plus sedative-hypnotic mg doses or up-time between groups. Mean antianxiety plus sedativehypnotic medication usage across phases equaled a phenobarbital equivalent dose (Halpern, 1978) per 24 hr of 24.2 mg (+6) for the time-contingent group and 29.3 mg (+ 5) for the pain-contingent group. Likewise, up-time across phases equaled 2.9 hr (_+ 1.5) and 3.0 hr (+ 1), respectively, for the two groups. Analgesic medication comparisons using methadone equivalent doses
32
WHITE AND SANDERS
(cf. Halpern, 1978) showed a statistically significant difference between groups during inpatient baseline, t(6) = 3.22, p < .05). The time-contingent group's analgesic usage was equivalent to 32 mg (+7) per 24 hr of methadone, while pain-contingent subjects required the equivalent of 13 nag of methadone. This difference was also noted with the actual administration of methadone during the first 2 days ofdetoxification. In contrast, mean group methadone levels during the last 2 days of detoxification did not differ, t(6) = .5, p > .05, with the time-contingent group given a 24hr average of 3.2 mg (___1) and the pain-contingent group given 1.2 mg
(___.8). Adding to the lack of statistical significance for group differences in methadone levels during the last 2 days of detoxification, are questions regarding the clinical significance of dosage differences at the beginning of detoxification. Pharmacologically, the 32 mg and 13 mg per 24-hr average methadone doses across groups during the first 2 days of detoxification are both considered relatively low (United States Pharmacopeial Convention, 1982). Likewise, S~iwe et al. (1983) have shown that there is no consistent relationship between absolute methadone dose or blood plasma levels and analgesic effect. Clinical analgesic equivalence can exist between two markedly different mg doses of methadone. Thus, group differences in absolute level of methadone do not necessarily have any clinical significance with respect to analgesia or physical withdrawal. Establishment of such significance, or the lack of it, within this context must be determined empirically. (This matter will be addressed in a subsequent section.)
Pain and Mood Analysis For ease of comparison and to allow parametric statistical analysis, pain and mood ratings were converted to percentage of maximum rating possible scores. This was done by dividing subjects' hourly ratings by 5 and multiplying by 100. Hourly percentage scores were then averaged each day for each subject. These mean daily pain and mood percentage scores were used as basic data for analysis. Fig. 1 depicts mean daily pain and mood percentage scores for the two groups by treatment phase. Review of outpatient baselines reveals more variability in the time-contingent group compared to the pain-contingent group, although no major differences were apparent. The time-contingent group did, however, show a gradual increase in pain scores during this phase. The inpatient baseline data indicated further increase in pain and a reduction in mood for the time-contingent group during the 1st day, with a return to outpatient baseline levels by the 3rd day. The paincontingent group's inpatient baseline showed little variation, with no differences noted between groups during the last 2 days of inpatient baseline. With the onset of detoxification, Fig. 1 depicts clear and consistent differences between groups. While the time-contingent group exhibited gradual reduction in pain and increase in mood scores (i.e., 54% reduction
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in pain and 42% increase in mood scores from last inpatient baseline day to first day of postdetoxify), the pain-contingent group showed a gradual increase in pain (i.e., 30%) and no major change in mood. The reduction trend in pain scores during detoxification and postdetoxification was found to be highly significant for the time-contingent group; linear trend, F(1, 27) = 32.26, p < .001, and quadratic trend, F(1, 27) -- 10.55, p < .001 (Winer, 1971). Likewise, this group's increased mood scores were highly significant for linear, F(1, 2 7 ) = 19.36, p < .001, and quadratic, F(1, 27) = 15.17, p < .001, trends. Increases seen in pain scores for the pain-contingent group during these latter two phases were also significant for a linear trend F(1, 27) = 8.67, p < .001. Pain-contingent group mood scores failed to show a significant trend. To further assess the extent of statistical significance for differences seen in Fig. 1, and given the a priori clinical assumptions about differences between groups, selected individual phase comparisons between groups
34
WHITE AND SANDERS TABLE 2 GROUP MEAN PAIN AND MOOD PERCENTAGESCORESBY TREATMENTPHASE Treatment phase Group
Inpatient baseline last 2 days
Postdetoxify first 2 days Pain
Time-Contingent detoxify Pain-Contingent detoxify
53.23 (20.33) 63.30 (15.73)
23.65 (19.93) 75.40 (21.16) Mood
Time-Contingent detoxify Pain-Contingent detoxify
45.60 (14.91) 49.40 (18.53)
77.10 (25.14) 38.70 (23.72)
Note. Numbers in parentheses equal standard deviations.
were conducted. Comparisons were limited to two per measure, with significance levels set at p < .025 to correct for any increases in error rate as a function o f multiple analyses (Hays, 198 I). Comparisons focused on determining whether any statistically significant differences existed between groups immediately prior to, or after, detoxification. Data were c o m p a r e d across groups over the last 2 days o f inpatient baseline and the first 2 days o f postdetoxification. Table 2 delineates group means and standard deviations for pain and m o o d percentage scores by the two relevant treatment phases. Two-tailed uncorrelated t tests on the inpatient baseline data were nonsignificant (p > .05). In contrast, one-tailed uncorrelated t tests on the postdetoxify data revealed significant differences. A highly significant difference, t(6) = -3.56, p < .01, was observed in pain scores and a strong difference trend was noted for m o o d scores, t(6) = 2.22, p < .05 but > .025. These findings statistically supported the differences seen in Fig. 1. T o empirically examine the clinical significance o f group differences in absolute m e t h a d o n e doses, individual subject data were compared. It was reasoned that if an absolute difference in m e t h a d o n e dose was a clinically significant (i.e., confounding) factor, then individual subjects across groups receiving equal doses o f m e t h a d o n e should exhibit markedly different results than those receiving maximally discrepant doses. Fig. 2 depicts m e a n daily pain and m o o d percentage scores for individual subjects from each group who coincidentally received equal doses o f m e t h a d o n e (i.e., Subject 4 and Subject 8 = 20 mg per 24 hr) and those who received the most discrepant doses o f m e t h a d o n e (i.e., Subject 6 = 8 mg and Subject 3 = 38 mg per 24 hr) during the first 2 days o f detox-
PAIN MEDICATION DELIVERY SCHEDULES
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FIG. 2. Subject (S) mean daily pain and mood percentage scores by treatment phase, group assignment, and absolute methadone dosage (i.e., equal dosage for $4 and $8 versus maximally discrepant dosage for $3 and $6). Outpatient baseline is depicted for the last 7 days (Days 8-14) of baseline. Inpatient detoxify data represent the first 2 (Days 4 and 5) and last 3 (Days 8-10) days of this phase. Postdetoxify data represent the first 5 days (Days 11-15) following detoxification.
ification. Review of the figure shows that the absolute level of methadone did not affect subjects' response pattern. Regardless of whether absolute methadone dosage was equal or maximally discrepant, time-contingent subjects (Subjects 3 and 4) exhibited similar reductions in pain and increases in mood, while pain-contingent subjects (Subjects 6 and 8) showed an increase in pain and no change in mood. These data are quite consistent with those depicted in Fig. 1 and clearly demonstrate that the group difference in absolute methadone dosage seen in the current study was not a clinically significant (confounding) factor. Pain and mood ratings for pain-contingent subjects did show improvement with the implementation of additional treatments subsequent to the postdetoxification phase. At the time of discharge these subjects reported mean pain and mood percentage scores of 50 and 68, respectively. Timecontingent subjects' mean discharge percentage scores continued to be superior and equaled 20 for pain and 80 for mood.
36
WHITE AND SANDERS
DISCUSSION The present findings support the clinical assumption that time-contingent delivery of medication during detoxification is preferred to paincontingent delivery. Time-contingent subjects showed significant trends toward improved pain and mood levels, while pain-contingent subjects did not. In fact, these latter subjects actually exhibited a significant trend toward pain increase during, and initially after, detoxification. In addition, statistical analysis indicated no group differences in pain or mood prior to detoxification, with time-contingent subjects showing significantly lower pain and, to a lesser extent, higher mood levels after detoxification than pain-contingent subjects. Results can not be adequately explained by differences in basic demographic or clinical characteristics, amounts of antianxiety plus sedative-hypnotic medication used, activity level, pain or mood baseline levels, or concurrent treatments. No major differences were observed in these variables, with no other treatments implemented during the study. While Fig. 1 did show a potential "trend" toward reduced pain and increased mood for time-contingent subjects during inpatient baseline, comparisons with outpatient baselines would suggest these trends were simply a return to outpatient levels. The group difference in absolute methadone dosage levels during the first 2 days of detoxification is also an inadequate explanation of results. Not only were daily doses of methadone considered rather low for both groups, but individual subject comparisons (see Fig. 2) clearly demonstrated that absolute methadone dosage level did not significantly affect results obtained. Subject by group response patterns were consistent whether absolute methadone doses were equivalent or discrepant. The preceding points lead to the conclusion that group differences in pain and mood were primarily due to the schedule of medication delivery during detoxification. The mechanism(s) of action for this effect can not be conclusively delineated from current findings. It could be argued that group differences were due to differences in the stability of methadone blood plasma levels. Given the more stable rate of administration for the time-contingent group, a more steady-state blood plasma level of methadone could have occurred and led to more effective analgesia. While such an explanation can not be ruled out without repeated sampling of plasma levels, the pharmacokinetic properties of methadone make this explanation unlikely. The long half-life (over 24 hr) of methadone with repeated doses markedly reduces the amount of lability in blood plasma levels that might be expected with changes in administration rates (United States Pharmacopeial Convention, 1982). A more consistent explanation of differences in pain reports can be found within the learning principle of extinction (Fordyce, 1976). Assuming that time-contingent delivery of pain medication (i.e., a potential reinforcer) eliminated any contingent relationship between pain reports and the delivery of such medication and social reinforcers (e.g., nurses'
PAIN MEDICATION DELIVERY SCHEDULES
37
attention), then reduction in rate or intensity of pain reports would be predicted within an extinction learning model. Increases in mood ratings are not explained by extinction. However, such an effect could have been the result of pain reduction itself. Obviously, further empirical scrutiny is needed before conclusive explanations of observed effects are possible. Regardless of explanation, present findings do offer empirical support for the use of time-contingent medication delivery schedules during therapistcontrolled detoxification with chronic pain patients. While supportive of the time-contingent medication delivery method advocated by behavioral therapists, current results should be viewed with caution. Replication with a larger sample and more stringent experimental control is needed before definitive conclusions are possible. Likewise, these data do not address the question of whether chronic pain patients might be able to effectively use a pain-contingent P R N schedule of medication delivery during patient-controlled detoxification (cf. Keefe et al., 1981; Sanders, 1983). Instead, current results support the position that in those patients where detoxification is agreed upon and the rate of reduction is controlled by health care professionals, time-contingent medication delivery schedules can significantly facilitate improvement in pain and mood levels when compared to pain-contingent schedules. Questions regarding whether and with which patients pain-contingent P R N medication schedules might be applicable during patient-controlled detoxification await further study.
REFERENCES Fordyce, W. E. (1976). Behavioral methods for chronic pain and illness. St. Louis: Mosby. Fulwiler, R. L., Hargreaves, W. A., & Bortman, R . A . (1979). Detoxification from heroin using self vs physician regulation of methadone dose. International Journal of Addictions, 14, 289-298. Halpern, L. (1978). Relative potencies of stronger analgesics compared to morphine. Patient Care, 12, 121. Hays, W. L. (1981). Statistics. New York: Holt, Rinehart, & Winston. Keefe, F. H., Block, A. R., Williams, R, B., & Surwit, R. S. (1981). Behavioral treatment of chronic low back pain: Clinical outcome and individual differences in pain relief. Pain, 11, 221-231. Kinsman, R. A., Dirks, J. F., & Dahlem, N. W. (1980). Noncompliance to prescribed-asneeded (PRN) medication use in asthma: Usage patterns and patient characteristics. Journal of Psychosomatic Research, 24, 97-107. Maruta, T., Swanson, D. W., & Finlayson, R. E. (1979). Drug abuse and dependency in patients with chronic pain. Mayo Clinic Proceedings, 54, 241-244. Ready, L. B., Sarkis, E., & Turner, J. A. (1982). Self-reported vs actual use of medications in chronic pain patients. Pain, 12, 285-294. Sanders, S.H. (1983). Component analysis of a behavioral treatment program for chronic low-back pain. Behavior Therapy, 14, 697-705. Sawe, J., Hansen, J., Ginman, C., Hartvig, R., Jakobsson, P. A., Nilsson, M. E., Rane, A., & Anggard, E. (1983). Patient-controlled dose regimen of methadone for chronic cancer pain. British Medical Journal 282, 771-773.
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WHITE AND SANDERS
Taylor, C. B., Zlutnik, S. I., Corley, M. J., & Flora, J. (1980). The effects ofdetoxification, relaxation, and brief suggestion therapy on chronic pain patients. Pain, 8, 263-266. Turner, J. A., Calsyn, D. A., Fordyce, W. E., & Ready, L. B. (1982). Drug utilization patterns in chronic pain patients. Pain, 12, 357-363. United States Pharmacopeial Convention. (1982). Drug information for the health care provider. Kingsport, TN: Kingsport Press. Winer, B. J. (1971). Statistical principles in experimental design. New York: McGrawHill. Ziesat, H. A., Angle, H. V., Gentry, D., & Ellinwood, E. H. (1979). Drug use and misuse in operant pain patients. Addictive Behaviors, 4, 263-266. RECEIVED"December 5, 1983 FINAL ACCEPTANCE;June 29, 1984