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Combination Therapy with Ibuprofen and Methadone for Chronic Cancer Pain
Combination Therapy with Ibuprofen and Methadone for Chronic Cancer Pain
THERESA FERRER-BRECHNER, M.D. PATRICIA GANZ, M.D. Los Angeles, California
From the Department of Anesthesiology and Oncology, and the Cancer Pain Control Program, University of California, Los Angeles, California. This work was supported in part by United States Public Health Service, National Institutes of Health CRC Grant No. RR865 and the Upjohn Company, Kalamazoo, Michigan. Requests for reprints should be addressed to Dr. Theresa Ferrer-Brechner, Department of Anesthesiology, U.C.L.A. School of Medicine, Room 56-125, Center for the Health Sciences, Los Angeles, California 90024. The work presented was based on the administration of Motrin tablets, a registered trademark of the Upjohn Manufacturing Company.
78
July 13, 1984
This randomized double-blind crossover study compares the narcotic methadone alone with methadone in combination with the peripherally acting, antiprostaglandin agent ibuprofen (Motrin, Upjohn) in 28 patients with moderate to severe cancer-related pain, who were already using a narcotic for pain relief. Results show that the addition of 600 mg of ibuprofen to either 2.5 or 5 mg of methadone Significantly increased analgesia, without concomitantly increasing side effects or euphoria. Unlike that of chronic benign pain, the management of chronic cancer-related pain must be tailored to include both narcotic and non-narcotic analgesics. Advances in cancer therapy during the past decade have improved life expectancy and therefore have increased the analgesic requirements of the patient with cancer pain. New and innovative approaches are necessary to meet the ultimate goal of analgesic therapy : adequate pain relief with minimal side effects. Various combinations of mild narcotic and non-narcotic analgesic agents have been formulated to provide analgesia and to prevent the development of tolerance or side effects after prolonged use of narcotics. Although combinations such as codeine and acetaminophen may be effective early in the course of the disease, more potent narcotics are often necessary for pain relief in the advanced stages of cancer. Therefore, it seems reasonable that the development of a potent narcotic combined with a peripherally acting agent that does not increase central nervous system side effects would be extremely valuable in patients with chronic cancer pain. We therefore chose to explore the effects of combining a potent narcotic (methadone) with ibuprofen (Motrin, Upjohn), a non-narcotic, nonsteroidal, anti-inflammatory agent in cancer patients with a history of narcotic use for chronic pain. We hypothesized that a nonsteroidal, antiinflammatory drug (NSAID) with proved analgesic efficacy at average doses and anti-inflammatory action only at larger doses [1] would be an ideal candidate, because NSAIDs act peripherally and are less likely to increase side effects involving the central nervous system such as mood changes or drowsiness. Although studies in postoperative, postpartum [2] , and dental pain [3] have clearly shown the analgesic effects of NSAIDs, their use in severe chronic cancer pain has not been fully evaluated [4-7]. We currently have conducted a double-blind, crossover study to compare the analgesic efficacy and side effects of a single dose of oral methadone, 2.5 and 5.0 mg, either alone or in combination with ibuprofen, 600 mg, in patients with moderate to severe chronic cancer pain. Methadone was chosen as the
The American Journal of Medicine
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
narcotic in this study, because 50 percent of the patients were already taking the drug before entry; ibuprofen, a 2-phenyl-propionic acid with anti-inflammatory, antipyretic, and analgesic properties, was selected on the basis of its proved record of safety and low side-effect profile. MATERIAL AND METHODS Subjects were selected from patients referred to the University of California, Los Angeles, Cancer Pain Clinic, or the palliative care Sepulveda Veterans Administration Medical Oncology Unit because of difficult pain problems. To participate in the study, the following criteria had to be met: (1) pain requiring the use of narcotic analgesics ; (2) physical condition not threatened by methadone, 2.5 or 5 mg, or ibuprofen, 600 mg, or both, or by the ordeal of repeated reporting of pain and mood levels; (3) ability to cooperate and communicate with reasonable judgment and reliability. Thirty-five candidates were asked to participate in the study, which was approved by the UCLA Human Subjects Protection Committee and the Sepulveda Veterans Administration Human Studies Committee. Of these patients, five were ultimately unable to enter the study because of sudden progression of their disease, necessitating hospitalization. Thus, 30 patients were admitted to the UCLA Clinical Research Center (18 patients) or the Sepulveda Veterans Administration Medical Oncology Unit (12 patients) for five consecutive days, after informed consent was obtained. In a double-blind fashion, each patient was randomly assigned to a specific drug regimen, receiving one of four drug/dose combinations (oral methadone 2.5 or 5 mg with placebo; methadone 2.5 or 5 mg with ibuprofen 600 mg) on each day of the four-day study. Study medications were administered after at least three hours had elapsed since the last analgesic and only when the patient complained of moderate to severe pain. Of the 30 patients who completed the double-blind, crossover study, 28 were available for complete data analysis. Characteristics of the study population are shown in Table I. Of the patients included in the study, 83 percent were in stage IV of their disease, 63 percent had metastases in more than three sites, and most had received surgery and radiation. Methadone was already being used in 50 percent of the patients. On the first day, patients were trained to respond to the various test parameters and to record their responses before and atter drug administration during each day of the study. Three types of pain intensity ratings were used: (1) Pain Severity Rating (PSR) was determined by having the patient rate pain according to a scale of 0 = none, 1 = slight, 2 = moderate, and 3 = severe. (2) Pain Descriptive Rating (PDR) was calculated by asking patients to rank order 10 randomized words describing pain (neutral, no pain, mild, moderate, unpleasant, strong, distressing, severe, excruciating, and agonizing) , from least to highest intensity. Numbers were then permanently assigned to each word according to individual ranking and were used for subsequent repeated measures. (3) Pain Intensity Rating (PIR) was judged by asking the patient to mark pain intensity on an 8-cm unmarked, horizontal line, of
TABLE 1
Profile of Patients at Entry
Age (years) Sex Stage More than 3 sites of metastases Previous cancer therapy
31-74 18 males; 12 females 83%, stage IV 63% 86% surgery; 60% chemotherapy; 76% radiation Current cancer therapy 33% chemotherapy; 3% radiation 50% methadone; 5% Percodan/ Current use of narcotics Percocet; 5% morphine; 3% Dilaudid; 2% levorphanol Kamofsky's performance status 5 = 74%; 5 = 26%
which one end indicated least possible pain and the other end worst possible pain. This line was then divided into 16 equal segments and a number from 0 to 16 was assigned depending on the location of the mark on subsequent measures. In addition, three types of pain relief scales were employed. Pain Relief Rating (PRR) was determined by having the patient note how much pain relief was obtained from the study drug on a scale of 0 = none, 1 = slight, 2 = moderate, 3 = a lot, and 4 = complete. A 50 percent Pain Relief Rating (50% PRR) was evaluated by a yes and no answer to the question: "Was there more than 50 percent pain relief from the study drug?" The Visual Analog Pain Relief (VAPR) scale was similar to the Visual Analog Pain Scale except that one end of the line indicated complete pain relief, whereas the other end no relief of pain. A Visual Analog Mood Scale (VAMS) was determined by presenting a 16-cm line, one end of which signified worst mood and the other end best mood. The presence of side effects was elicited by questioning, and if present, they were categorized. At the end of the day, the patient and the observer independently gave a global evaluation of the study drug's effect according to the following scale: 0= poor, 1 = fair, 2 = good, and 3 = excellent. Test drugs were assigned to patients in a double-blind manner on the basis of a series of crossover patterns (Figure 1), and each study medication was administered on a separate day. Numerical values were all given pain intensity, pain relief, and mood scales. The percent of change in pain intensity and mood, from a pre-drug rating to observation at one, two, three, four, five, and six hours, was evaluated along with the mean percent change in post-drug ratings. Mean pain relief as well as hourly pain relief ratings and overall global evaluation were recorded . The relative effectiveness of the different drugs and different doses was analyzed using repeated measures analysis of variance with a four-treatment Latin-square design. Least significant t tests were performed in each pairwise comparison. A covariant to estimate the possible signifi-
July 13, 1984
The American Journal of Medicine
79
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
Day I
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Figure 1. Patient assignment according to a double-blind, complete crossover design. M = methadone; I = ibuprofen.
cance of the order in which drugs were administered was included in the analysis. A nonparametric analysis was performed to check for drug and dose differences. All analyses were performed using the SAS 1982 2B statistical package.
RESULTS Comparison of Drug Efficacy. The addition of ibuprofen, 600 mg, to methadone, 2.5 and 5.0 mg, led to significantly increased analgesia, using the three pain in-
10
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Figure 2. Mean Pain Severity Rating (PSR) differences over a four-hour period after study drug, indicating that the addition of 600 mg of ibuprofen (I) to 2.5 and 5 mg of methadone (M) significantly increased analgeSia, beginning two hours after the study drug was administered. (p value indicates Significance of methadone with ibuprofen over corresponding dose of methadone .p < 0.05; ••p < 0.01.)
80
July 13, 1984
The American Journal of Medicine
tensity scales (Figures 2 and 3). Pain severity ratings showed a statistically significant difference at equipotent dosages of methadone (2.5 and 5.0 mg) when ibuprofen 600 mg was added, commencing at two hours and persisting four hours. Pain descriptive ratings showed significantly increased analgesia with methadone 5 mg and ibuprofen 600 mg, starting 30 minutes after drug ingestion, compared with other groups. A significant difference in mean Pain Intensity Rating with 5.0 mg of methadone and 600 mg of ibuprofen compared with 5.0 mg of methadone alone was evident starting two hours after the drug; a significant difference between methadone 2.5 mg and ibuprofen 600 mg versus methadone alone was evident only at three and four hours. Global evaluation also indicated the superiority of the methadone-ibuprofen combination (Figure 4). The patient's willingness to receive the drug again was also greater with this combination. Pain Relief Scales. Superiority of the methadoneibuprofen combination was seen with Pain Relief Ratings, starting two hours after taking the drug. Visual AnalOg Pain Relief also showed a significant difference at 30 minutes (p < 0.05) when 5 mg of methadone alone was compared with 5 mg of methadone plus 600 mg of ibuprofen (Figure 5). However, there was no statistical difference among the four groups using the traditional 50 percent Pain Relief Rating, perhaps signifying a lack of sensitivity in this particular scale. Mood Scales. Visual Analog Mood Scales before and two hours after drug ingestion indicated that increased mood changes correlated with larger doses of methadone and not with increased analgesia produced by the combination of methadone and ibuprofen (Figure 6). Side Effects. Only minimal side effects generally were reported in a total of seven patients including mild epigastric distress in three, nausea in two, and dizziness in two. No statistically significant differences between the four groups were noted in the incidence of side effects; no side effects occurred with the most potent combination of methadone 5.0 mg and ibuprofen 600 mg, indicating that increased analgesia induced by the combination is not accompanied by an increased incidence of side effects . Relation of Pain Syndrome to Pain Relief. Significantly better pain relief occurred in patients with bone metastases compared with those with tissue or visceral involvement when the 5-mg methadone plus 600-mg ibuprofen combination was used. This differentiation was not seen with 2.5 and 5 mg of methadone or with 2.5 mg of methadone combined with ibuprofen.
COMMENTS The results of this study (Table II) indicate that 600 mg of ibuprofen added to 2.5 and 5 mg of methadone significantly increased the analgesic effect of methadone alone. This increased analgesic efficacy was not associated with an increased incidence of side effects or euphoria, a
IBUPROFEN SYMPOSIUM-FERRER·BRECHNER and GANZ
* 4
,,
3 Figure 3. Mean Pain Descriptive Rating (PDR) differences indicate significantly increased analgesia with 5 mg of methadone (M) plus 600 mg of ibuprofen (I) compared with that of other groups at 30 minutes after drug ingestion, suggesting early sensitivity of this pain scale. (p values indicate significance over corresponding dose of methadone without ibuprofen. .p < 0.05; ••p < 0.01.)
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July 13, 1984
The American Journal of Medicine
81
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
VISUAL ANALOG MOOD SCALE
VISUAL ANALOG PAIN INTENSITY
before and 2 hours after study drug II
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Results of Methadone/Ibuprofen for Chronic Cancer Pain Findings
Parameter Pain Intensity Scales Pain Severity Rating (PSR) Pain Descriptive Rating (PDR) Pain Intensity Rating (PIR) Global Evaluation Pain Relief Scales Pain Relief Rating (PRR) Visual Analog Pain Relief (VAPR) 50% Pain Relief Rating (50% PRR)
Statistically significant difference in favor of combinations (2.5 mg M + 600 mg I; 5 mg M + 600 mg I) at 2 hours compared with Malone Increased analgesia with 5 mg M + 600 mg I at 30 minutes, compared with other groups Statistically significant difference in favor of 5 mg M + 600 mg I at 2 hours compared with 5 mg M alone ; and for 2.5 mg M + 600 mg I at 3 and 4 hours compared with 2.5 mg Malone Superiority of combinations over Malone Superiority of combinations at 2 hours, compared with Malone Significant difference in favor of 5 mg M + 600 mg I at 30 minutes compared with 5 mg Malone No statistical difference
major deterrent to the use of high-dose narcotics. Therefore, our finding that ibuprofen increased analgesia without increasing side effects is of great clinical relevance to cancer patients who often need increasing analgesia but cannot tolerate further side effects. The analgeSic effects of NSAIOs in cancer patients have been explored in the past, although not extensively [4]. Indoprofen and naproxen were equally effective in cancer patients for a similar length of time despite differences in half-lives [5]; however, the stage of disease and the concomitant use of narcotics were not specified. In addition , the analgesic efficacy of zomepirac sodium was superior to that of both oxycodone with aspirin, phenacetin and codeine (APC), and placebo, although differences between oxycodone and zomepirac did not reach statistical significance [6]. This lack of significant difference in analgesic efficacy was subsequently confirmed in a larger multicenter study [7] which also recommended the use of
82
25
Methadone + Ibuprofen (600)
Figure 6. Comparison of Visual Analog Mood Scale (right) and Visual Analog Pain Intensity (left) before (and two hours after) the study drug was administered, indicating a significant increase in mood with a larger dose of methadone not related to increased analgesia from the addition of ibuprofen. (*p < 0.05; **p < 0.01 ; * **p < 0.001 .)
July 13, 1984
The American Journal of Medicine
a NSAIO before initiating narcotic therapy in patients with chronic cancer pain. To our knowledge, the current study is the first on the role of an NSAIO in patients with cancer pain who are already taking narcotics for pain associated with advanced disease. Some investigators have implied that the euphoria produced by narcotics may influence the patient's perception or expectation of pain relief [7]. In our study, however, we demonstrated that significant changes in mood scale were related not to reports of decreased pain intensity, but to a larger narcotic dose. This finding may indicate that enhanced analgesia was due to the peripheral effects of ibuprofen and not to the central effects of methadone. The finding that the highest analgesic combination (5 mg of methadone plus 600 mg of ibuprofen) was more effective in bone than tissue/visceral pain is not surprising. The demonstration that antiprostaglandins partially inhibit in vitro animal tumor osteolysis [8,9] in metastatic lesions
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
[10) may be relevant. However, clinical studies have not shown any significant difference in relapse rate, development of bone metastases, survival, or thromboxane levels in cancer patients treated with either an NSAID or placebo [11-13). The incidence of side effects with various NSAIDs, including minute upper gastrointestinal bleeding, must be considered in cancer patients who are frequently anemic and cannot afford further blood loss from the gastrointestinal tract. In a comparative endoscopic study investigating the damaging effects of NSAIDs on gastric and duodenal mucosal, no duodenal mucosal injury was found with ibuprofen, unlike naproxen, indomethacin, and tolmetin [14). Ibuprofen was also associated with significantly less
gastrointestinal blood loss than that with aspirin after two weeks of therapy and, to an even greater degree, after one year [15). Therefore, the safety and low incidence of side effects of ibuprofen are important when choosing an NSAID for patients with advanced cancer, especially those who are already anemic. CONCLUSIONS
This randomized double-blind study of 28 patients with chronic cancer pain indicates that the addition of ibuprofen, 600 mg, to the narcotic methadone, either 2.5 or 5 mg, significantly increased analgesia after a single oral dose, without increaSing side effects or changing mood levels.
REFERENCES 1. Kantor TG: Ibuprofen. Ann Intern Med 1979; 91 : 877-922. 2. Bloomfield SS, Barden TP, Mitchell J: Comparative efficacy of ibuprofen and aspirin in episiotomy pain. Clin Pharmacol Ther 1974; 15: 565-570. 3. Winter L Jr, Bass E, Recant B, et al : Analgesic activity of ibuprofen (Motrin) in postoperative oral surgical pain. Oral Surg 1978; 45: 159-166. 4. Ventafridda V, Fochi C, OeConno 0 , Sganzerla E: Use of nonsteroidal anti-inflammatory drugs in the treatment of pain in cancer. Br J Clin Pharmacol 1980; 10: 343S-346S. 5. Martino G, Emanueli A, Mandelli V, Ventafridda V: A controlled study of the analgesic effect of two non-steroidal anti-inflammatory drugs in cancer pain. Arzneim Forsch 1978; 28: 16571659. 6. Stambaugh JE, Sarajian C: Analgesic efficacy of zomepirac sodium in patients with pain due to cancer. J Clin Pharmacol 1981 ; 21 : 501 - 507. 7. Stambaugh JE Jr: The management of the patient with chronic pain due to advanced malignancy. JMed 1981; 13: 183-190. 8. Galasko CS, Bennett A: Relationship of bone destruction in skeletal metastases to osteoclast activation and prostaglandins. Nature 1976; 263: 508-510. 9. Powles TJ, Clark SA, Easty OM, Easty GC, Neville AM: The
inhibition by aspirin and indomethacin of osteoly1ic tumor depoSits and hypercalcaemia in rats with Walter tumor, and its possible application to human breast cancer. Br J Cancer 1973; 28: 316-321 . 10. Powles TJ, Dowsetl M, Easty GC, Easty OM, Neville AM : Breast-cancer osteolysis, bone metastases, and anti-osteolytic effect of aspirin. Lancet 1976; I: 608-610. 11 . Powles, TJ, Oady PJ, Williams J, Easty GC, Coombes RC: Use of inhibitors of prostaglandin synthesis in patients with breast cancer. Adv Prostaglandin Thromboxane Res 1980; 6: 511516. 12. Coombes RC, Neville AM , Bondy PK, Powles TJ : Failure of indomethacin to reduce hypercalcemia in patients with breast cancer. Prostaglandins 1976; 12: 1027-1035. 13. Powles TJ: Administration of prostaglandins A and E and antiinflammatory drugs to patients with cancer. Adv Prostaglandin Thromboxane Leukotriene Res 1983; 12: 327-331 . 14. Lanza F, Reyer G, Nelson R: An endoscopic evaluation of the effects of non-steroidal anti-inflammatory drugs on the gastriC mucosa. Gastrointest Endosc 1975; 21 : 103-105. 15. Schmid FR, Culic DO: Anti-inflammatory drugs and gastrointestinal bleeding: a comparison of aspirin and ibuprofen (abstr). J Clin Pharmacol 1976; 16: 418.
July 13, 1984
The American Journal of Medicine
83
THERESA FERRER-BRECHNER, M.D. PATRICIA GANZ, M.D. Los Angeles, California
From the Department of Anesthesiology and Oncology, and the Cancer Pain Control Program, University of California, Los Angeles, California. This work was supported in part by United States Public Health Service, National Institutes of Health CRC Grant No. RR865 and the Upjohn Company, Kalamazoo, Michigan. Requests for reprints should be addressed to Dr. Theresa Ferrer-Brechner, Department of Anesthesiology, U.C.L.A. School of Medicine, Room 56-125, Center for the Health Sciences, Los Angeles, California 90024. The work presented was based on the administration of Motrin tablets, a registered trademark of the Upjohn Manufacturing Company.
78
July 13, 1984
This randomized double-blind crossover study compares the narcotic methadone alone with methadone in combination with the peripherally acting, antiprostaglandin agent ibuprofen (Motrin, Upjohn) in 28 patients with moderate to severe cancer-related pain, who were already using a narcotic for pain relief. Results show that the addition of 600 mg of ibuprofen to either 2.5 or 5 mg of methadone Significantly increased analgesia, without concomitantly increasing side effects or euphoria. Unlike that of chronic benign pain, the management of chronic cancer-related pain must be tailored to include both narcotic and non-narcotic analgesics. Advances in cancer therapy during the past decade have improved life expectancy and therefore have increased the analgesic requirements of the patient with cancer pain. New and innovative approaches are necessary to meet the ultimate goal of analgesic therapy : adequate pain relief with minimal side effects. Various combinations of mild narcotic and non-narcotic analgesic agents have been formulated to provide analgesia and to prevent the development of tolerance or side effects after prolonged use of narcotics. Although combinations such as codeine and acetaminophen may be effective early in the course of the disease, more potent narcotics are often necessary for pain relief in the advanced stages of cancer. Therefore, it seems reasonable that the development of a potent narcotic combined with a peripherally acting agent that does not increase central nervous system side effects would be extremely valuable in patients with chronic cancer pain. We therefore chose to explore the effects of combining a potent narcotic (methadone) with ibuprofen (Motrin, Upjohn), a non-narcotic, nonsteroidal, anti-inflammatory agent in cancer patients with a history of narcotic use for chronic pain. We hypothesized that a nonsteroidal, antiinflammatory drug (NSAID) with proved analgesic efficacy at average doses and anti-inflammatory action only at larger doses [1] would be an ideal candidate, because NSAIDs act peripherally and are less likely to increase side effects involving the central nervous system such as mood changes or drowsiness. Although studies in postoperative, postpartum [2] , and dental pain [3] have clearly shown the analgesic effects of NSAIDs, their use in severe chronic cancer pain has not been fully evaluated [4-7]. We currently have conducted a double-blind, crossover study to compare the analgesic efficacy and side effects of a single dose of oral methadone, 2.5 and 5.0 mg, either alone or in combination with ibuprofen, 600 mg, in patients with moderate to severe chronic cancer pain. Methadone was chosen as the
The American Journal of Medicine
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
narcotic in this study, because 50 percent of the patients were already taking the drug before entry; ibuprofen, a 2-phenyl-propionic acid with anti-inflammatory, antipyretic, and analgesic properties, was selected on the basis of its proved record of safety and low side-effect profile. MATERIAL AND METHODS Subjects were selected from patients referred to the University of California, Los Angeles, Cancer Pain Clinic, or the palliative care Sepulveda Veterans Administration Medical Oncology Unit because of difficult pain problems. To participate in the study, the following criteria had to be met: (1) pain requiring the use of narcotic analgesics ; (2) physical condition not threatened by methadone, 2.5 or 5 mg, or ibuprofen, 600 mg, or both, or by the ordeal of repeated reporting of pain and mood levels; (3) ability to cooperate and communicate with reasonable judgment and reliability. Thirty-five candidates were asked to participate in the study, which was approved by the UCLA Human Subjects Protection Committee and the Sepulveda Veterans Administration Human Studies Committee. Of these patients, five were ultimately unable to enter the study because of sudden progression of their disease, necessitating hospitalization. Thus, 30 patients were admitted to the UCLA Clinical Research Center (18 patients) or the Sepulveda Veterans Administration Medical Oncology Unit (12 patients) for five consecutive days, after informed consent was obtained. In a double-blind fashion, each patient was randomly assigned to a specific drug regimen, receiving one of four drug/dose combinations (oral methadone 2.5 or 5 mg with placebo; methadone 2.5 or 5 mg with ibuprofen 600 mg) on each day of the four-day study. Study medications were administered after at least three hours had elapsed since the last analgesic and only when the patient complained of moderate to severe pain. Of the 30 patients who completed the double-blind, crossover study, 28 were available for complete data analysis. Characteristics of the study population are shown in Table I. Of the patients included in the study, 83 percent were in stage IV of their disease, 63 percent had metastases in more than three sites, and most had received surgery and radiation. Methadone was already being used in 50 percent of the patients. On the first day, patients were trained to respond to the various test parameters and to record their responses before and atter drug administration during each day of the study. Three types of pain intensity ratings were used: (1) Pain Severity Rating (PSR) was determined by having the patient rate pain according to a scale of 0 = none, 1 = slight, 2 = moderate, and 3 = severe. (2) Pain Descriptive Rating (PDR) was calculated by asking patients to rank order 10 randomized words describing pain (neutral, no pain, mild, moderate, unpleasant, strong, distressing, severe, excruciating, and agonizing) , from least to highest intensity. Numbers were then permanently assigned to each word according to individual ranking and were used for subsequent repeated measures. (3) Pain Intensity Rating (PIR) was judged by asking the patient to mark pain intensity on an 8-cm unmarked, horizontal line, of
TABLE 1
Profile of Patients at Entry
Age (years) Sex Stage More than 3 sites of metastases Previous cancer therapy
31-74 18 males; 12 females 83%, stage IV 63% 86% surgery; 60% chemotherapy; 76% radiation Current cancer therapy 33% chemotherapy; 3% radiation 50% methadone; 5% Percodan/ Current use of narcotics Percocet; 5% morphine; 3% Dilaudid; 2% levorphanol Kamofsky's performance status 5 = 74%; 5 = 26%
which one end indicated least possible pain and the other end worst possible pain. This line was then divided into 16 equal segments and a number from 0 to 16 was assigned depending on the location of the mark on subsequent measures. In addition, three types of pain relief scales were employed. Pain Relief Rating (PRR) was determined by having the patient note how much pain relief was obtained from the study drug on a scale of 0 = none, 1 = slight, 2 = moderate, 3 = a lot, and 4 = complete. A 50 percent Pain Relief Rating (50% PRR) was evaluated by a yes and no answer to the question: "Was there more than 50 percent pain relief from the study drug?" The Visual Analog Pain Relief (VAPR) scale was similar to the Visual Analog Pain Scale except that one end of the line indicated complete pain relief, whereas the other end no relief of pain. A Visual Analog Mood Scale (VAMS) was determined by presenting a 16-cm line, one end of which signified worst mood and the other end best mood. The presence of side effects was elicited by questioning, and if present, they were categorized. At the end of the day, the patient and the observer independently gave a global evaluation of the study drug's effect according to the following scale: 0= poor, 1 = fair, 2 = good, and 3 = excellent. Test drugs were assigned to patients in a double-blind manner on the basis of a series of crossover patterns (Figure 1), and each study medication was administered on a separate day. Numerical values were all given pain intensity, pain relief, and mood scales. The percent of change in pain intensity and mood, from a pre-drug rating to observation at one, two, three, four, five, and six hours, was evaluated along with the mean percent change in post-drug ratings. Mean pain relief as well as hourly pain relief ratings and overall global evaluation were recorded . The relative effectiveness of the different drugs and different doses was analyzed using repeated measures analysis of variance with a four-treatment Latin-square design. Least significant t tests were performed in each pairwise comparison. A covariant to estimate the possible signifi-
July 13, 1984
The American Journal of Medicine
79
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
Day I
Group I
Groupn
Group][
GroupTIZ:
0(2.5)
0(5.0)
0(2.5)
0(5.0)
1(600)
1(600)
1
Doy2
0(2.5)
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1(600)
0(5.0)
0(2.5)
+
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Figure 1. Patient assignment according to a double-blind, complete crossover design. M = methadone; I = ibuprofen.
cance of the order in which drugs were administered was included in the analysis. A nonparametric analysis was performed to check for drug and dose differences. All analyses were performed using the SAS 1982 2B statistical package.
RESULTS Comparison of Drug Efficacy. The addition of ibuprofen, 600 mg, to methadone, 2.5 and 5.0 mg, led to significantly increased analgesia, using the three pain in-
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Figure 2. Mean Pain Severity Rating (PSR) differences over a four-hour period after study drug, indicating that the addition of 600 mg of ibuprofen (I) to 2.5 and 5 mg of methadone (M) significantly increased analgeSia, beginning two hours after the study drug was administered. (p value indicates Significance of methadone with ibuprofen over corresponding dose of methadone .p < 0.05; ••p < 0.01.)
80
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The American Journal of Medicine
tensity scales (Figures 2 and 3). Pain severity ratings showed a statistically significant difference at equipotent dosages of methadone (2.5 and 5.0 mg) when ibuprofen 600 mg was added, commencing at two hours and persisting four hours. Pain descriptive ratings showed significantly increased analgesia with methadone 5 mg and ibuprofen 600 mg, starting 30 minutes after drug ingestion, compared with other groups. A significant difference in mean Pain Intensity Rating with 5.0 mg of methadone and 600 mg of ibuprofen compared with 5.0 mg of methadone alone was evident starting two hours after the drug; a significant difference between methadone 2.5 mg and ibuprofen 600 mg versus methadone alone was evident only at three and four hours. Global evaluation also indicated the superiority of the methadone-ibuprofen combination (Figure 4). The patient's willingness to receive the drug again was also greater with this combination. Pain Relief Scales. Superiority of the methadoneibuprofen combination was seen with Pain Relief Ratings, starting two hours after taking the drug. Visual AnalOg Pain Relief also showed a significant difference at 30 minutes (p < 0.05) when 5 mg of methadone alone was compared with 5 mg of methadone plus 600 mg of ibuprofen (Figure 5). However, there was no statistical difference among the four groups using the traditional 50 percent Pain Relief Rating, perhaps signifying a lack of sensitivity in this particular scale. Mood Scales. Visual Analog Mood Scales before and two hours after drug ingestion indicated that increased mood changes correlated with larger doses of methadone and not with increased analgesia produced by the combination of methadone and ibuprofen (Figure 6). Side Effects. Only minimal side effects generally were reported in a total of seven patients including mild epigastric distress in three, nausea in two, and dizziness in two. No statistically significant differences between the four groups were noted in the incidence of side effects; no side effects occurred with the most potent combination of methadone 5.0 mg and ibuprofen 600 mg, indicating that increased analgesia induced by the combination is not accompanied by an increased incidence of side effects . Relation of Pain Syndrome to Pain Relief. Significantly better pain relief occurred in patients with bone metastases compared with those with tissue or visceral involvement when the 5-mg methadone plus 600-mg ibuprofen combination was used. This differentiation was not seen with 2.5 and 5 mg of methadone or with 2.5 mg of methadone combined with ibuprofen.
COMMENTS The results of this study (Table II) indicate that 600 mg of ibuprofen added to 2.5 and 5 mg of methadone significantly increased the analgesic effect of methadone alone. This increased analgesic efficacy was not associated with an increased incidence of side effects or euphoria, a
IBUPROFEN SYMPOSIUM-FERRER·BRECHNER and GANZ
* 4
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3 Figure 3. Mean Pain Descriptive Rating (PDR) differences indicate significantly increased analgesia with 5 mg of methadone (M) plus 600 mg of ibuprofen (I) compared with that of other groups at 30 minutes after drug ingestion, suggesting early sensitivity of this pain scale. (p values indicate significance over corresponding dose of methadone without ibuprofen. .p < 0.05; ••p < 0.01.)
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July 13, 1984
The American Journal of Medicine
81
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
VISUAL ANALOG MOOD SCALE
VISUAL ANALOG PAIN INTENSITY
before and 2 hours after study drug II
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Results of Methadone/Ibuprofen for Chronic Cancer Pain Findings
Parameter Pain Intensity Scales Pain Severity Rating (PSR) Pain Descriptive Rating (PDR) Pain Intensity Rating (PIR) Global Evaluation Pain Relief Scales Pain Relief Rating (PRR) Visual Analog Pain Relief (VAPR) 50% Pain Relief Rating (50% PRR)
Statistically significant difference in favor of combinations (2.5 mg M + 600 mg I; 5 mg M + 600 mg I) at 2 hours compared with Malone Increased analgesia with 5 mg M + 600 mg I at 30 minutes, compared with other groups Statistically significant difference in favor of 5 mg M + 600 mg I at 2 hours compared with 5 mg M alone ; and for 2.5 mg M + 600 mg I at 3 and 4 hours compared with 2.5 mg Malone Superiority of combinations over Malone Superiority of combinations at 2 hours, compared with Malone Significant difference in favor of 5 mg M + 600 mg I at 30 minutes compared with 5 mg Malone No statistical difference
major deterrent to the use of high-dose narcotics. Therefore, our finding that ibuprofen increased analgesia without increasing side effects is of great clinical relevance to cancer patients who often need increasing analgesia but cannot tolerate further side effects. The analgeSic effects of NSAIOs in cancer patients have been explored in the past, although not extensively [4]. Indoprofen and naproxen were equally effective in cancer patients for a similar length of time despite differences in half-lives [5]; however, the stage of disease and the concomitant use of narcotics were not specified. In addition , the analgesic efficacy of zomepirac sodium was superior to that of both oxycodone with aspirin, phenacetin and codeine (APC), and placebo, although differences between oxycodone and zomepirac did not reach statistical significance [6]. This lack of significant difference in analgesic efficacy was subsequently confirmed in a larger multicenter study [7] which also recommended the use of
82
25
Methadone + Ibuprofen (600)
Figure 6. Comparison of Visual Analog Mood Scale (right) and Visual Analog Pain Intensity (left) before (and two hours after) the study drug was administered, indicating a significant increase in mood with a larger dose of methadone not related to increased analgesia from the addition of ibuprofen. (*p < 0.05; **p < 0.01 ; * **p < 0.001 .)
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The American Journal of Medicine
a NSAIO before initiating narcotic therapy in patients with chronic cancer pain. To our knowledge, the current study is the first on the role of an NSAIO in patients with cancer pain who are already taking narcotics for pain associated with advanced disease. Some investigators have implied that the euphoria produced by narcotics may influence the patient's perception or expectation of pain relief [7]. In our study, however, we demonstrated that significant changes in mood scale were related not to reports of decreased pain intensity, but to a larger narcotic dose. This finding may indicate that enhanced analgesia was due to the peripheral effects of ibuprofen and not to the central effects of methadone. The finding that the highest analgesic combination (5 mg of methadone plus 600 mg of ibuprofen) was more effective in bone than tissue/visceral pain is not surprising. The demonstration that antiprostaglandins partially inhibit in vitro animal tumor osteolysis [8,9] in metastatic lesions
IBUPROFEN SYMPOSIUM-FERRER-BRECHNER and GANZ
[10) may be relevant. However, clinical studies have not shown any significant difference in relapse rate, development of bone metastases, survival, or thromboxane levels in cancer patients treated with either an NSAID or placebo [11-13). The incidence of side effects with various NSAIDs, including minute upper gastrointestinal bleeding, must be considered in cancer patients who are frequently anemic and cannot afford further blood loss from the gastrointestinal tract. In a comparative endoscopic study investigating the damaging effects of NSAIDs on gastric and duodenal mucosal, no duodenal mucosal injury was found with ibuprofen, unlike naproxen, indomethacin, and tolmetin [14). Ibuprofen was also associated with significantly less
gastrointestinal blood loss than that with aspirin after two weeks of therapy and, to an even greater degree, after one year [15). Therefore, the safety and low incidence of side effects of ibuprofen are important when choosing an NSAID for patients with advanced cancer, especially those who are already anemic. CONCLUSIONS
This randomized double-blind study of 28 patients with chronic cancer pain indicates that the addition of ibuprofen, 600 mg, to the narcotic methadone, either 2.5 or 5 mg, significantly increased analgesia after a single oral dose, without increaSing side effects or changing mood levels.
REFERENCES 1. Kantor TG: Ibuprofen. Ann Intern Med 1979; 91 : 877-922. 2. Bloomfield SS, Barden TP, Mitchell J: Comparative efficacy of ibuprofen and aspirin in episiotomy pain. Clin Pharmacol Ther 1974; 15: 565-570. 3. Winter L Jr, Bass E, Recant B, et al : Analgesic activity of ibuprofen (Motrin) in postoperative oral surgical pain. Oral Surg 1978; 45: 159-166. 4. Ventafridda V, Fochi C, OeConno 0 , Sganzerla E: Use of nonsteroidal anti-inflammatory drugs in the treatment of pain in cancer. Br J Clin Pharmacol 1980; 10: 343S-346S. 5. Martino G, Emanueli A, Mandelli V, Ventafridda V: A controlled study of the analgesic effect of two non-steroidal anti-inflammatory drugs in cancer pain. Arzneim Forsch 1978; 28: 16571659. 6. Stambaugh JE, Sarajian C: Analgesic efficacy of zomepirac sodium in patients with pain due to cancer. J Clin Pharmacol 1981 ; 21 : 501 - 507. 7. Stambaugh JE Jr: The management of the patient with chronic pain due to advanced malignancy. JMed 1981; 13: 183-190. 8. Galasko CS, Bennett A: Relationship of bone destruction in skeletal metastases to osteoclast activation and prostaglandins. Nature 1976; 263: 508-510. 9. Powles TJ, Clark SA, Easty OM, Easty GC, Neville AM: The
inhibition by aspirin and indomethacin of osteoly1ic tumor depoSits and hypercalcaemia in rats with Walter tumor, and its possible application to human breast cancer. Br J Cancer 1973; 28: 316-321 . 10. Powles TJ, Dowsetl M, Easty GC, Easty OM, Neville AM : Breast-cancer osteolysis, bone metastases, and anti-osteolytic effect of aspirin. Lancet 1976; I: 608-610. 11 . Powles, TJ, Oady PJ, Williams J, Easty GC, Coombes RC: Use of inhibitors of prostaglandin synthesis in patients with breast cancer. Adv Prostaglandin Thromboxane Res 1980; 6: 511516. 12. Coombes RC, Neville AM , Bondy PK, Powles TJ : Failure of indomethacin to reduce hypercalcemia in patients with breast cancer. Prostaglandins 1976; 12: 1027-1035. 13. Powles TJ: Administration of prostaglandins A and E and antiinflammatory drugs to patients with cancer. Adv Prostaglandin Thromboxane Leukotriene Res 1983; 12: 327-331 . 14. Lanza F, Reyer G, Nelson R: An endoscopic evaluation of the effects of non-steroidal anti-inflammatory drugs on the gastriC mucosa. Gastrointest Endosc 1975; 21 : 103-105. 15. Schmid FR, Culic DO: Anti-inflammatory drugs and gastrointestinal bleeding: a comparison of aspirin and ibuprofen (abstr). J Clin Pharmacol 1976; 16: 418.
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