Y. Eugene Mironer, MD*, & John C. Haasis, MD y, & Iva Chapple, MD z, Christopher Brown, RN-FNPC*, & John R. Satterthwaite, MD y

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1 Efficacy and Safety of Intrathecal Opioid/ Bupivacaine Mixture in Chronic Nonmalignant Pain: A Double Blind, Randomized, Crossover, Multicenter Study by the National Forum of Independent Pain Clinicians (NFIPC) Y. Eugene Mironer, MD*, & John C. Haasis, MD y, & Iva Chapple, MD z, & Christopher Brown, RN-FNPC*, & John R. Satterthwaite, MD y *NFIPC, Carolinas Center for Advanced Management of Pain, Spartanburg; y NFIPC, Carolinas Center for Advanced Management of Pain, Greenville; and z NFIPC, Carolina Pain Specialist, Columbia, South Carolina & ABSTRACT Objective. Intrathecal opioid/local anesthetic mixtures are a popular alternative in contemporary treatment of chronicnonmalignantpain. Unfortunately, itsuseisbased solely on retrospective studies or anecdotal reports. Materials and Methods. A double blind, randomized, crossover, multicenter study was performed in 24 patients with intrathecal pumps. For four consecutive months, their pumps were refilled with either the original opioid or its mixture with different concentrations of bupivacaine(4, 6, or 8 mg/day). Results. Only one patient experienced mild side effects from intrathecal bupivacaine. A strong placebo response was observed in all patients when they entered the study. Addition of bupivacaine to the intrathecal opioid failed to produce significant improvement in pain control. Conclusion. At currently used doses, intrathecal opioid bupivacaine mixtures are not more efficacious in the treatment of chronic nonmalignant pain than opioid alone. & KEY WORDS: intrathecal, local anesthetic, opioids. Address correspondence and reprint requests to: Y. Eugene Mironer, MD, 279 East Kennedy Street, Spartanburg, SC Y1917@aol.com. # 2002 International Neuromodulation Society, /02/$15.00/0 Neuromodulation, Volume 5, Number 4, INTRODUCTION Use of intrathecal drug delivery systems for chronic nonmalignant pain is a popular option in contemporary pain management. Unfortunately, it is not always effective when an opioid is the only drug used, especially for neuropathic pain. The addition of a local anesthetic, specifically

2 Intrathecal Opioid/Bupivacaine Mixture & 209 bupivacaine, is a popular widely used intervention to improve pain control. Local anesthetics have been used for neuroaxial delivery for many years to provide intraoperative anesthesia and postoperative analgesia (1,2). They are also commonly used adjunct drugs in intrathecal pumps. In a 1996 survey, 19.8% of all pump patients were receiving bupivacaine (3), while, in a recent study, more than 20% of patients had a local anesthetic in their pumps (4). The theoretical application of local anesthetics with opioids for neuroaxial treatment is clear. Meanwhile, the practical situation with opioid/ local anesthetic mixtures is far from being as straightforward as suggested (5,6). Surprisingly, very few studies describe the results of such interventions (1,2,7) and their results differ considerably. No serious effort has been made to establish the efficacy of opioid/local anesthetic mixtures in the neuroaxial therapy of chronic pain. The safety of this treatment has been established only in anecdotal reports. No dosing guidelines have been offered. As a result, an unacceptable variety of dose regimens are being used by pain practitioners (8). In an attempt to resolve some of these questions, the National Forum of Independent Pain Clinicians (NFIPC) performed a double blind, randomized, crossover, multicenter study of the efficacy safety of intrathecal bupivacaine/ opioid mixtures in chronic nonmalignant pain. METHODS General Methodology Twenty-four patients receiving intrathecal opioid treatment for chronic intractable nonmalignant pain using programmable pumps (Synchromed, Medtronic, Inc., Minneapolis, MN) participated in the study, performed in three pain centers. Fourteen of 24 (58%) were female. The average age in the group was 57 years (range, 39 to 85). A detailed description of participants in the study is provided in Table 1. All patients were receiving an infusion of morphine or hydromorphone only rated their pain on a Verbal Analog Scale (VAS) above 5 (0 10). None of the enrolled patients had ever received an intrathecal infusion of local anesthetics via their pump. The information Table 1. Patients with Chronic Nonmalignant Intractable Pain, Participating in the Study Patient number Age Gender Syndrome causing chronic pain/ pain type 1 39 F Brachial plexopathy/neuropathic 2 45 M Abdominal pain/visceral 3 48 F Peripheral neuropathy/neuropathic 4 53 F Degenerative disc disease/ nociceptive 5 67 F Degenerative disc disease/ nociceptive 6 70 F Peripheral neuropathy/neuropathic 7 57 M Failed back surgery syndrome/mixed 8 72 F Ostheoartrosis/nociceptive 9 49 F Failed back surgery syndrome/mixed M Degenerative disc disease/ nociceptive F Peripheral neuropathy/neuropathic F Failed back surgery syndrome/mixed M Failed back surgery syndrome/mixed F Failed back surgery syndrome/mixed F Failed back surgery syndrome/mixed F Failed back surgery syndrome/mixed F Abdominal pain/visceral M Failed back surgery syndrome/mixed M Intercostal neuralgia/neuropathic M Ostheoartrosis/nociceptive M Peripheral neuropathy/neuropathic M Peripheral neuropathy/neuropathic M Failed back surgery syndrome/mixed F Failed back surgery syndrome/mixed about the duration of intrathecal treatment doses of opioids is provided in Table 2. Each of the patients in the study received intrathecal infusion of four different combinations of drugs for four consecutive months: opioid alone or consecutively with three different concentrations of bupivacaine. Every month the patient s pump was refilled in a randomized, double blind fashion with either the same opioid they had received prior to the study, or its mixture with bupivacaine. The rate of infusion was kept constant while the concentrations of local anesthetic were adjusted to provide a daily dose of 4 mg, 6 mg, or 8 mg of bupivacaine. Patients were allowed to increase their consumption of oral short-acting opioids for breakthrough pain if their pain level increased during the study. All intrathecal mixtures were prepared by Custom Care Pharmacy (Tampa, FL). At the time of enrollment in the study and during each change of the intrathecal solution in the pump, all patients rated their pain using the

3 210 & MIRONER ET AL Table 2. Intrathecal Opioids: Duration of Treatment Prior to the Study and Daily Doses Patient number VAS and assessed their satisfaction with treatment using a Quality of Life questionnaire (9). Data Analysis Intrathecal opioid Daily dose (mg/day) Duration of treatment (months) 1 Morphine Morphine Morphine Morphine Morphine Morphine Morphine Morphine Morphine Morphine Morphine Morphine Morphine Hydromorphone Hydromorphone Morphine Morphine Morphine Hydromorphone Morphine Morphine Hydromorphone Morphine Hydromorphone We hyposthesized that the VAS score using bupivacaine + opioid will be reduced statistically significant when compared to the VAS score using opioid alone. H 0 : ðbupivacaine þ opioid opioid aloneþ ¼0 H A : ðbupivacaine þ opioid opioid aloneþ 6¼0 PASS 2000 One-Sample t-test was used with a critical difference of 1.5 in the VAS score (bupivacaine + opioid 7.5 vs. opioid alone 6); = 0.05 (two-sided), a standard deviation of 2.3, at least 80% power which resulted in a minimum sample size requirement of 21 patients. A reduction of 1.5 in the VAS score (from 7.5 to 6) is an average of 20% reduction. A standard deviation for the VAS score of can be expected. Analysis Methods For each bupivacaine dose, the change from baseline to 1 month was assessed using a paired t-test. In a crossover trial, it is possible that the order in which the treatments were given or the sequence in which they were given could affect the results. There were not enough patients to assess whether an order or sequence effect was present in these data. p-values < 0.05 were considered statistically significant. RESULTS Of the 24 patients enrolled in this study only one had side effects. This patient reported mild numbness in his lower extremities, without weakness, after receiving his first refill with the study drug, which turned out to be mixture using 8 mg/day bupivacaine. Two more patients were taken off the study, at their request, unrelated to the results of the treatment. Another two patients mistakenly received the same study drug mixtures twice. Their incomplete results were still included in the statistical analysis. Additionally, one patient did not fill out the Quality of Life questionnaire on an 8-mg/day dose. No increases in consumption of oral, breakthrough, short-acting opioids were observed during the study. The mean baseline VAS score was 6.8. The mean VAS score from the first period was 6.3, the mean from the fourth period was 6.5. The VAS had a clear tendency towards improvement as patients were entering the study. The change in mean VAS from baseline to one month was not statistically significantly different for any dose level (Fig. 1; Table 3). A clinically significant change was defined as 20% (about 1.5 points). The VAS also showed a tendency towards deterioration as the study progressed even though these changes were not statistically significant ( p = 0. 74). The same improvement tendency at the beginning of the study was observed for Quality of Life scores. The change in Quality of Life scores from baseline to one month was statistically significantly lower for the 6 mg/day dose ( p = ) but not for 4 mg/day or 8 mg/day doses. (Fig. 2; Table 4).

4 Intrathecal Opioid/Bupivacaine Mixture & 211 Figure 2. Mean quality of life scores vs. bupivacaine dose. Figure 1. DISCUSSION Mean VAS pain scores vs. bupivacaine dose. The goal of this double blind, randomized, crossover study was to assess the efficacy safety of bupivacaine mixtures with intrathecal opioids in the treatment of nonmalignant pain. Local anesthetics have been used intrathecaly for intra- and postoperative analgesia for many years (10). In recent years there has been a dramatic increase in the use of bupivacaine in intrathecal pumps with opioids for treatment of malignant nonmalignant pain (3,4). Safety of this mixture seems to be established, based on the results in fairly large groups of patients (3,4). On the other hand, efficacy of this treatment mostly rests on anecdotal reports or retrospective analyses. No blinded, randomized studies have been performed so far. The mechanisms of possible synergistic action of spinal opioids and local anesthetics are not completely clear (11). Intrathecal local anesthetics predominantly act on the nerve roots, while the anatomic target for opioids is the spinal cord (10,12). Nevertheless, three classical studies in rats clearly showed synergism between morphine and local anesthetics (13,14). One of the possible mechanisms is the local anesthetic potentiation of antinociceptive activity of spinal opioids at the dorsal root entry zone level (14). Despite the lack of hard scientific data, the bupivacaine/opioid mixture is widely used and even more widely recommended by multiple individuals (2,15,16). In a recent poll, 68% of all responding physicians used a morphine/bupivacaine combination (4). This modality of treatment is so popular that an article has been published dedicated to calculating the right proportions of the opioid/bupivacaine mixture (17). More than that, this option was proposed to be the second -line approach (6). Meanwhile, a review of other research data on the epidural use of opioids with local anesthetics showed some controversy. When epidural Table 3. Pain VAS Scores Change from Baseline to 1 month Table 4. Quality of Life Scores Change from Baseline to 1 month Comparison of baseline vs. bupivacaine dose/day n Mean change Standard deviation P-value Comparison of baseline vs. dose/day N Mean change Standard deviation P-value 0 mg/day mg/day mg/day mg/day mg/day mg/day mg/day mg/day

5 212 & MIRONER ET AL opioids were combined with bupivacaine, not only were good results observed in some studies (18), but a lack of any improvement was also noted in others (1,19). In studies dedicated to intrathecal use of this mixture, other than anecdotal reports and retrospective reviews, only one study showed improved analgesia or decreased opioid use in 10 of 13 patients with chronic nonmalignant pain receiving intraspinal opioid/bupivacaine infusion (18). A study of cancer patients showed a somewhat slower escalation of morphine dose when bupivacaine was added (20), but this research project used a very small population of patients and had significant design problems. On the other hand, a small retrospective review showed a lack of positive effect of bupivacaine addition in all 12 patients (21). There is also a fair amount of confusion regarding the effective doses of bupivacaine in combination with opioids in intrathecal delivery. Our choice of tested doses (4 8 mg/day) was based on the recent survey of 413 physicians who are involved in intrathecal treatment of chronic pain (4). Their average starting dose of bupivacaine, mixed with morphine, was around 4 mg/ day, while the average final dose was around 8 mg/day. In the previously quoted study (18), out of 13 patients who had good results after addition of bupivacaine to intrathecal opioid, 12 had a final bupivacaine dose of 6 mg/day or less. A few studies of cancer patients (20,22) and one of nonmalignant chronic pain patients (23) showed the use of significantly higher doses of intrathecal bupivacaine with opioids on average from 20 to 40 and even 60 mg/day. Needless to say, the rate of side effects (urinary retention, paresthesias, extremity weakness) was very high. Analysis of the results of our study showed some interesting, if not unusual findings. First of all, there seems to be a strong placebo effect present in these data. That means that the 0 mg/day dose in the study showed a trend towards producing improvement in VAS pain scores compared to the baseline dose. Presence of placebo effect is also being indirectly supported by VAS score increase as the study progressed. The next observation is that, in this group of patients, the dose of bupivacaine given in the range of 0 8 mg/day, did not impact pain scores over a one-month period. The sample sizes for the pain scores were large enough (adequately powered) to detect a clinically significant difference of 20% (1.5 point) in the change of pain scores from baseline to one month. Even though adequately powered, clinical significance was not achieved. Another observation is that the ordering of the pain scores was not intuitive in these data, that is, the 4 mg/day dose showed the most reduction and the 8 mg/day dose showed the least reduction. Multiple sources in the literature (2,6,16,18) suggest that use of the opioid/bupivacaine mixture is especially effective in neuropathic pain. In our study nearly 30% of all patients had pure neuropathic pain, while more than 70% had at least a neuropathic component to their pain. Nevertheless, results of the local anesthetic addition were less then striking. It is hard to predict if the addition of bupivacaine, even with good results, could affect the answers to the Quality of Life questionnaire. Again, some tendency towards placebo response was observed. The statistical significance of the 6 mg/day dose improvement in the Quality of Life scores is hard to interpret. This dose is between the other doses used and did not produce the lowest pain score. CONCLUSION We conclude that short-term use of opioid/ bupivacaine in intrathecal pumps seems to be a fairly safe technique, at least at doses of bupivacaine not exceeding 8 mg/day. The addition of bupivacaine to opioids for intrathecal treatment of chronic nonmalignant pain does not produce a significant analgesic effect, at least not at commonly used bupivacaine doses of 8 mg/day or less. A large scale study is needed to establish possible analgesic efficacy of higher doses of local anesthetics with opioids and the ability of local anesthetics to reduce tolerance to intrathecal opioids. ACKNOWLEDGMENTS This study was supported by an unrestricted educational grant from Medtronic, Inc. The authors gratefully acknowledge Kelli Kubitschek,

6 Intrathecal Opioid/Bupivacaine Mixture & 213 CST and Basil Mironer for assistance in data collection, and Lisa M. Tonder, MS for invaluable help with statistical analysis. REFERENCES 1. Rawal N. Current status of epidural and spinal opioids. In: Waldman, SD, Winnie, AP, eds. Interventional Pain Management. Saunders: Philadelphia, 1996: Walia K, Mitchell V, Staats PS. Intrathecal analgesics as we approach the new millennium. Pain Digest 2000;10: Paice JA, Penn RD, Shott S. Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Symptom Manage 1996;11: Hassenbusch SJ, Portenoy RK. Current practices in intraspinal therapy a survey of clinical trends and decision making. J Pain Symptom Manage 2000;20:S4 S Krames E, Buchser E, Hassenbusch SJ, et al. Future trends in the development of local drug delivery systems: intraspinal, intracerebral, and intraparenchymal therapies. Neuromodulation 1999;2: Bennett G, Burchiel K, Buchser E. Clinical guidelines for intraspinal infusion. report of an expert panel. J Pain Symptom Manage 2000;20:S37 S Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995;42: Krames ES, Olson K. Clinical realities and economic considerations: patient selection in intrathecal therapy. J Pain Symptom Manage 1997;14:S3 S Mironer YE, Tollison CD. Methadone in the treatment of chronic nonmalignant pain resistant to other neuroaxial agents: the first experience. Neuromodulation 2000;4: Lambert DH. Spinal anesthesia. In: Rogers, MC, Tinker, JH, Covino, BG et al, eds. Principles and Practice of Anesthesiology. Mosby Year Book: St. Louis, MO, 1993: Solomon RE, Gebhart GF. Synergistic antinociceptive interactions among drugs administered to the spinal cord. Anesth Analg 1994;78: Sinatra RS. Spinal and epidural opioids. In: Rogers, MC, Tinker, JH, Covino, BG et al, eds. Principles and Practice of Anesthesiology. Mosby Year Book, St. Louis. MO, 1993: Maves TJ, Gebhart GF. Antinociceptive synergy between intrathecal morphine and lidocaine during visceral and somatic nociception in the rat. Anesthesiology 1992;76: Penning JP, Yaksh TL. Interaction of intrathecal morphine with bupivacaine and lidocaine in the rat. Anesthesiology 1992;77: Krames ES. Intraspinal opioid therapy for chronic nonmalignant pain. current practice and clinical guidelines. J Pain Symptom Manage 1996;11: Hassenbusch SJ, Garber J, Buchser E, et al. Alternative intrathecal agents for the treatment of pain. Neuromodulation 1999;2: Atlas G. Calculating mixtures of local anesthetic and morphine for implantable intrathecal pumps. Pain Digest 1996;6: Krames ES, Lanning RM. Intrathecal infusional analgesia for nonmalignant pain. analgesic efficacy of intrathecal opioid with or without bupivacaine. J Pain Symptom Manage 1993;8: Parker RK, Sawaki Y, White P. Epidural patientcontrolled analgesia. influence of bupivacaine and hydromorphone basal infusion on pain control after cesarean delivery. Anesth Analg 1992;75: van Dongen RTM, Crul BJP, van Egmond J. Intrathecal coadministration of bupivacaine diminishes morphine dose progression during long-term intrathecal infusion in cancer patients. Clin J Pain 1999;15: Mironer YE, Grumman S. Experience with alternative solutions in intrathecal treatment of chronic nonmalignant pain. Pain Digest 1999;9: Sjoberg M, Nitescu P, Appelgren L. Long-term intrathecal morphine and bupivacaine in patients with refractory cancer pain. Anesthesiology 1994;80: Nitescu P, Dahm P, Appelgren L. Continuous infusion of opioid and bupivacaine by externalized intrathecal catheters in long-term treatment of refractory nonmalignant pain. Clin J Pain 1998;14:

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