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Stability of clonidine in clonidine-hydromorphone mixture from implanted intrathecal infusion pumps in chronic pain patients
Vol. 28 No. 6 December 2004
Journal of Pain and Symptom Management
599
Original Article
Stability of Clonidine in Clonidine-Hydromorphone Mixture from Implanted Intrathecal Infusion Pumps in Chronic Pain Patients Zvia Rudich, MD, Philip Peng, MBBS, FRCPC, Edward Dunn, PhD, and Colin McCartney, MBChB, FRCA Department of Anesthesiology (Z.R.) and Wasser Pain Management Center (Z.R., P.P., C.M.), Mount Sinai Hospital, University of Toronto, Toronto; Department of Anesthesiology (P.P., C.M.), Toronto Western Hospital, University of Toronto, Toronto; and Department of Psychiatry (E.D.), Psychopharmacology Research Laboratory, Center for Addiction and Mental Health, Toronto, Ontario, Canada
Abstract Clonidine is frequently added to opioids in implantable intrathecal pumps for the management of chronic pain. In such devices, a small non-retrievable volume is always present in the reservoir, and its effect on drug stability is unknown. Furthermore, stability of clonidine, when mixed with hydromorphone, has not been previously determined. This study examined the stability of clonidine when co-administered with hydromorphone in implanted intrathecal pumps. Samples of hydromorphone-clonidine before pump refill and from residual solution at subsequent refill were obtained from chronic pain patients. Clonidine concentration was measured using HPLC. Twenty paired samples from 3 patients were analyzed. All 3 patients had a SynchroMed pump implanted for 3–5 years. We found no loss in clonidine concentration during the time between refills (35 ⫾ 13 days), and no correlation between clonidine concentration and time interval between refills. In conclusion, clonidine, mixed with hydromorphone, is stable when delivered by implantable intrathecal pump for long-term use. J Pain Symptom Manage 2004;28:599–602. 쑖 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Clonidine, stability, intrathecal implantable pump, hydromorphone, intrathecal opioids, chronic non-cancer pain
Introduction Address reprint requests to: Philip Peng, MBBS, FRCPC, Department of Anesthesiology, Toronto Western Hospital, 399 Bathurst St., EC 2-046, Toronto, ON, Canada M5T 2S8. Accepted for publication: February 27, 2004.
쑖 2004 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Clonidine is frequently added to opioids for long-term intrathecal delivery in the management of chronic pain patients.1 The analgesic effect of clonidine via its α2 adrenoreceptoragonist activity has been well documented in animal and human studies.2–5 The spinal route 0885-3924/04/$–see front matter doi:10.1016/j.jpainsymman.2004.02.018
600
Rudich et al.
for drug administration offers a more targeted analgesic effect as compared to the oral or parenteral administration, allowing lower doses with equal or even superior analgesic outcome and fewer systemic adverse effects. One major indication for adding clonidine to intrathecal opioids is in patients with chronic neuropathic pain.6 In such patients, implantable intrathecal infusion pumps allow steady delivery of drug mixtures. Depending on the reservoir volume of the pump and the delivery infusion rate, the reservoir needs to be refilled every 1 to 3 months. Although this technology has clear technical and pharmacological advantages, the long-term stability of the drugs is of concern. A previous in vitro study that evaluated a solution inside the infusion pump at 37⬚C concluded that clonidine was stable when added to morphine.7 However, when applying these data to clinical settings, two concerns arise. First, in pumps such as the SynchroMed EL (Medtronic, Inc., Minneapolis, MN), a 2.4-mL non-retrievable volume of the reservoir is present at all times (Technical Manual for SynchroMed EL, Medtronic Inc., 2000). Despite being small, the effect of this volume in patients with implantable pumps after repeated refills over years is unknown. Second, the stability of clonidine when mixed with opioids other than morphine is largely unknown. To date, no data on stability of clonidine is available when added to hydromorphone in an implantable pump at body temperature over years. Thus, the aim of the present study was to examine the stability of clonidine when administered with hydromorphone in implanted intrathecal pumps to noncancer, chronic pain patients.
Vol. 28 No. 6 December 2004
Toronto Western Hospital for the Chronic Pain Clinic. Clonidine was obtained with special approval of the Health Protection Branch of Health Canada and was available in concentration of 150 µg/mL (Catapres; Boehringer Ingelheim, Barcelona, Spain). All samples were collected in sterile conditions during scheduled patient visits for pump refill, and were immediately frozen at ⫺20⬚C before being transferred to the laboratory on ice. The interval between the pump refill and the prescribed concentration of both hydromorphone and clonidine were recorded.
Measurements of Clonidine Concentration An aliquot of each sample was diluted with methanol directly into auto-sampler vials for the clonidine assay. To each vial, an aliquot of cotinine solution was added as internal standard to correct for any variations in the analysis. Standard solutions ranging from 0–200 mg/mL were prepared and analyzed with the samples. Final volumes in the auto-sampler vials were made up to 300µL and 3µL of each of the samples and standards were analyzed by High Performance Liquid Chromatography-Ion Trap Mass Spectrometry (HPLC-MS) using electrospray ionization (Finnigan LCQ Advantage). The analysis was performed using a 75 ⫻ 4.6 mm C18 column (Waters Symmetry) with a mobile phase of acetonitrile and water (20:80) at a flow rate of 0.3 mL/min. Clonidine was measured using the areas of the chromatographic peaks monitored at a mass of 230 for clonidine and at 177 for cotinine. The standard curve was found to be linear over the entire concentration range. Concentrations in the samples were calculated using this clonidine standard curve.
Statistical Analysis
Methods Patients and Sample Collection Following ethical approval and informed consent, paired samples were taken from hydromorphone–clonidine mixtures collected before pump refill and from the residual solution in the subsequent refill. Patients recruited in this study were those who were treated by SynchroMed EL implantation and received intrathecal infusion of hydromorphone–clonidine mixture. All the intrathecal drug mixtures were prepared by the Pharmacy Department at
All data are presented as mean ⫾ standard deviation (SD). Comparison between clonidine concentration values in the paired samples was performed by paired Student’s t-test. Based on a previous study,7 5 paired samples would be required to detect a 10% difference in paired samples with type I and type II errors of 5% and 20% respectively. Correlations of data were assessed using Pearson’s test.
Results A total of 20 paired samples were obtained from 3 patients during a 7-month period. Three
Vol. 28 No. 6 December 2004
Clonidine Stability in Implantable Pumps
patients were prescribed clonidine at a concentration of 150 µg/mL and hydromorphone at varying concentrations (25–75 mg/L). Synchromed pumps were implanted 2–4 years prior to the study. The refilling interval was 35 ⫾ 13 days. The result of the clonidine concentration before and after the pump refill was as shown in Fig. 1. We found no significant decrease in clonidine concentrations in the paired samples (145.6 ⫾ 5.6 vs. 145.6 ⫾ 7.1 µg/mL respectively). There was no correlation between the refill interval and the difference in clonidine concentrations before and after pump refill.
Discussion This is the first study investigating the stability of clonidine in hydromorphone–clonidine mixture in implanted intrathecal pumps after longterm repeated refills in chronic pain patients. We reported that under these conditions clonidine concentrations were stable between consecutive refills. The use of implantable pump and catheter systems for the delivery of intrathecal opioids was first reported in 1981 for the treatment of chronic cancer pain.8 The efficacy and safety of this delivery method of intrathecal opioids was later established in various clinical trials.9–13 Since then, the use of implantable delivery systems was also extended to patients with chronic nonmalignant pain.14 Despite the popular use of the intrathecal pump delivery system, the stability of the various medications used has not been thoroughly investigated.15 Morphine is the most commonly used medication for intrathecal pump delivery system.1 At present, the only opioid approved by the U.S. Food and Drug Administration for continuous long-term intrathecal administration to treat chronic intractable pain is preservative-free
601
morphine sulfate. Both hydromorphone and clonidine are commonly used either alone or in combination with other intrathecal medications.1 When higher doses of morphine are required (⬎22 mg/mL) or when morphine yields toxicities, hydromorphone is the recommended alternative.6 Clonidine is usually considered in patients with neuropathic pain not responsive to high doses of opioids1 and can provide synergistic effect to opioids.3,16 An additional benefit of adding clonidine to opioids is its potential to minimize the occurrence of opioidinduced catheter-tip inflammatory mass.17 A recent study in dogs demonstrated that high concentration of intrathecal morphine administration led to aseptic inflammatory masses, resulting in significant local tissue compression. Although clonidine alone did not lead to such inflammatory reaction, a combination of morphine and clonidine led to smaller inflammatory reaction when compared to morphine alone. The long-term stability of clonidine and morphine has been previously investigated. When clonidine was formulated in normal saline at concentration of 0.15 and 0.5 mg/mL in glass vials, there was minimal loss of clonidine hydrochloride at body temperature for up to three months.18 When mixed with morphine sulfate in different admixture concentrations (20 mg morphine ⫹ 0.05 mg clonidine per mL or 2 mg morphine ⫹ 1.84 mg clonidine per mL) at body temperature, morphine and clonidine concentrations remained at ⱖ94% of the theoretical starting concentrations after being stored inside the SynchroMed pump for 90 days.7 The stability of hydromorphone has been investigated when stored in SynchroMed pump at body temperature.19 This showed that hydromorphone concentration remained greater than 95% of starting material after 16 weeks of storage. The stability of medications may be
Fig. 1. Comparison of the clonidine concentrations before and after refill. Bars indicate the concentration of clonidine before (white) and after (dark) refill.
602
Rudich et al.
altered when used in combination with other agents, however, and there are no stability data for clonidine mixed with hydromorphone. So far, the stability data for clonidine or hydromorphone has been obtained when the medications were stored in either glass vials or implantable pumps incubating at various temperatures. No data were obtained when the drug samples were actually retrieved from the pump after implantation into the patients. This type of data would be valuable in view of unknown effects of the non-retrievable volume in the SynchroMed pump. The major limitation of this study was that the refilling period was not fixed. Unlike those studies performed in laboratory settings, it is impractical to fix the refill interval. The duration of refill in our study was 35.4 ⫾ 13 days. However, we found no correlation between the refill interval and the difference in concentration of the clonidine before and after refill. Our results demonstrate that clonidine concentration remains stable in clonidine–hydromorphone mixtures with an average refill interval of 35 days when delivered by the implantable intrathecal pump.
Acknowledgments
Vol. 28 No. 6 December 2004
anesthetic improves postoperative analgesia for total knee arthroplasty. Anesth Analg 2003;96:1083– 1088. 6. Bennett G, Burchiel K, Buchser E, et al. Clinical guidelines for intraspinal infusion: report of an expert panel. PolyAnalgesic Consensus Conference 2000. J Pain Symptom Manage 2000;20:S37–S43. 7. Hildebrand KR, Elsberry DD, Hassenbusch SJ. Stability and compatibility of morphine-clonidine admixtures in an implantable infusion system. J Pain Symptom Manage 2003;25:464–471. 8. Onofrio BM, Yaksh TL, Arnold PG. Continuous low-dose intrathecal morphine administration in the treatment of chronic pain of malignant origin. Mayo Clin Proc 1981;56:516–520. 9. Penn RD, Paice JA, Gottschalk W, Ivankovich AD. Cancer pain relief using chronic morphine infusion. Early experience with a programmable implanted drug pump. J Neurosurg 1984;61:302–306. 10. Shetter AG, Hadley MN, Wilkinson E. Administration of intraspinal morphine sulfate for the treatment of intractable cancer pain. Neurosurgery 1986; 18:740–747. 11. Spaziante R, Cappabianca P, Ferone A, et al. Treatment of chronic cancer pain by means of continuous intrathecal low dose morphine administration with a totally implantable subcutaneous pump. Case report. J Neurosurg Sci 1985;29:143–151. 12. Krames ES, Gershow J, Glassberg A, et al. Continuous infusion of spinally administered narcotics for the relief of pain due to malignant disorders. Cancer 1985;56:696–702.
The authors would like to acknowledge Ms. Maggie Lee for her technical assistance in performing the clonidine assay.
13. Hassenbusch SJ, Pillay PK, Magdinec M, et al. Constant infusion of morphine for intractable cancer pain using an implanted pump. J Neurosurg 1990; 73:405–409.
References
14. Krames ES. Intraspinal opioid therapy for chronic nonmalignant pain: current practice and clinical guidelines. J Pain Symptom Manage 1996;11: 333–352.
1. Hassenbusch SJ, Portenoy RK. Current practices in intraspinal therapy—a survey of clinical trends and decision making. J Pain Symptom Manage 2000;20: S4–S11. 2. D’Angelo R, Evans E, Dean LA, Gaver R, Eisenach JC. Spinal clonidine prolongs labor analgesia from spinal sufentanil and bupivacaine. Anesth Analg 1999;88:573–576. 3. Hao S, Takahata O, Iwasaki H. Antinociceptive interaction between spinal clonidine and lidocaine in the rat formalin test: an isobolographic analysis. Anesth Analg 2001;92:733–738. 4. Fairbanks CA, Stone LS, Kitto KF, et al. Alpha(2C)-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther 2002;300:282–290. 5. Sites BD, Beach M, Biggs R, et al. Intrathecal clonidine added to a bupivacaine-morphine spinal
15. Bennet G, Deer T, Du Pen S, et al. Future directions in the management of pain by intraspinal drug delivery. J Pain Symptom Manage 2000;20:S44–S50. 16. Fairbanks CA, Wilcox GL. Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine. J Pharmacol Exp Ther 1999;288:1107–1116. 17. Yaksh TL, Horais KA, Tozier NA, et al. Chronically infused intrathecal morphine in dogs. Anesthesiology 2003;99:174–187. 18. Trissel LAXQ, Hassenbusch SJ. Development of clonidine hydrochloride injections for epidural and intrathecal administration. Int J Pharm Compounding 1997;1:274–277. 19. Hildebrand KR, Elsberry DE, Anderson VC. Stability and compatibility of hydromorphone hydrochloride in an implantable infusion system. J Pain Symptom Manage 2001;22:1042–1047.
Journal of Pain and Symptom Management
599
Original Article
Stability of Clonidine in Clonidine-Hydromorphone Mixture from Implanted Intrathecal Infusion Pumps in Chronic Pain Patients Zvia Rudich, MD, Philip Peng, MBBS, FRCPC, Edward Dunn, PhD, and Colin McCartney, MBChB, FRCA Department of Anesthesiology (Z.R.) and Wasser Pain Management Center (Z.R., P.P., C.M.), Mount Sinai Hospital, University of Toronto, Toronto; Department of Anesthesiology (P.P., C.M.), Toronto Western Hospital, University of Toronto, Toronto; and Department of Psychiatry (E.D.), Psychopharmacology Research Laboratory, Center for Addiction and Mental Health, Toronto, Ontario, Canada
Abstract Clonidine is frequently added to opioids in implantable intrathecal pumps for the management of chronic pain. In such devices, a small non-retrievable volume is always present in the reservoir, and its effect on drug stability is unknown. Furthermore, stability of clonidine, when mixed with hydromorphone, has not been previously determined. This study examined the stability of clonidine when co-administered with hydromorphone in implanted intrathecal pumps. Samples of hydromorphone-clonidine before pump refill and from residual solution at subsequent refill were obtained from chronic pain patients. Clonidine concentration was measured using HPLC. Twenty paired samples from 3 patients were analyzed. All 3 patients had a SynchroMed pump implanted for 3–5 years. We found no loss in clonidine concentration during the time between refills (35 ⫾ 13 days), and no correlation between clonidine concentration and time interval between refills. In conclusion, clonidine, mixed with hydromorphone, is stable when delivered by implantable intrathecal pump for long-term use. J Pain Symptom Manage 2004;28:599–602. 쑖 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Clonidine, stability, intrathecal implantable pump, hydromorphone, intrathecal opioids, chronic non-cancer pain
Introduction Address reprint requests to: Philip Peng, MBBS, FRCPC, Department of Anesthesiology, Toronto Western Hospital, 399 Bathurst St., EC 2-046, Toronto, ON, Canada M5T 2S8. Accepted for publication: February 27, 2004.
쑖 2004 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Clonidine is frequently added to opioids for long-term intrathecal delivery in the management of chronic pain patients.1 The analgesic effect of clonidine via its α2 adrenoreceptoragonist activity has been well documented in animal and human studies.2–5 The spinal route 0885-3924/04/$–see front matter doi:10.1016/j.jpainsymman.2004.02.018
600
Rudich et al.
for drug administration offers a more targeted analgesic effect as compared to the oral or parenteral administration, allowing lower doses with equal or even superior analgesic outcome and fewer systemic adverse effects. One major indication for adding clonidine to intrathecal opioids is in patients with chronic neuropathic pain.6 In such patients, implantable intrathecal infusion pumps allow steady delivery of drug mixtures. Depending on the reservoir volume of the pump and the delivery infusion rate, the reservoir needs to be refilled every 1 to 3 months. Although this technology has clear technical and pharmacological advantages, the long-term stability of the drugs is of concern. A previous in vitro study that evaluated a solution inside the infusion pump at 37⬚C concluded that clonidine was stable when added to morphine.7 However, when applying these data to clinical settings, two concerns arise. First, in pumps such as the SynchroMed EL (Medtronic, Inc., Minneapolis, MN), a 2.4-mL non-retrievable volume of the reservoir is present at all times (Technical Manual for SynchroMed EL, Medtronic Inc., 2000). Despite being small, the effect of this volume in patients with implantable pumps after repeated refills over years is unknown. Second, the stability of clonidine when mixed with opioids other than morphine is largely unknown. To date, no data on stability of clonidine is available when added to hydromorphone in an implantable pump at body temperature over years. Thus, the aim of the present study was to examine the stability of clonidine when administered with hydromorphone in implanted intrathecal pumps to noncancer, chronic pain patients.
Vol. 28 No. 6 December 2004
Toronto Western Hospital for the Chronic Pain Clinic. Clonidine was obtained with special approval of the Health Protection Branch of Health Canada and was available in concentration of 150 µg/mL (Catapres; Boehringer Ingelheim, Barcelona, Spain). All samples were collected in sterile conditions during scheduled patient visits for pump refill, and were immediately frozen at ⫺20⬚C before being transferred to the laboratory on ice. The interval between the pump refill and the prescribed concentration of both hydromorphone and clonidine were recorded.
Measurements of Clonidine Concentration An aliquot of each sample was diluted with methanol directly into auto-sampler vials for the clonidine assay. To each vial, an aliquot of cotinine solution was added as internal standard to correct for any variations in the analysis. Standard solutions ranging from 0–200 mg/mL were prepared and analyzed with the samples. Final volumes in the auto-sampler vials were made up to 300µL and 3µL of each of the samples and standards were analyzed by High Performance Liquid Chromatography-Ion Trap Mass Spectrometry (HPLC-MS) using electrospray ionization (Finnigan LCQ Advantage). The analysis was performed using a 75 ⫻ 4.6 mm C18 column (Waters Symmetry) with a mobile phase of acetonitrile and water (20:80) at a flow rate of 0.3 mL/min. Clonidine was measured using the areas of the chromatographic peaks monitored at a mass of 230 for clonidine and at 177 for cotinine. The standard curve was found to be linear over the entire concentration range. Concentrations in the samples were calculated using this clonidine standard curve.
Statistical Analysis
Methods Patients and Sample Collection Following ethical approval and informed consent, paired samples were taken from hydromorphone–clonidine mixtures collected before pump refill and from the residual solution in the subsequent refill. Patients recruited in this study were those who were treated by SynchroMed EL implantation and received intrathecal infusion of hydromorphone–clonidine mixture. All the intrathecal drug mixtures were prepared by the Pharmacy Department at
All data are presented as mean ⫾ standard deviation (SD). Comparison between clonidine concentration values in the paired samples was performed by paired Student’s t-test. Based on a previous study,7 5 paired samples would be required to detect a 10% difference in paired samples with type I and type II errors of 5% and 20% respectively. Correlations of data were assessed using Pearson’s test.
Results A total of 20 paired samples were obtained from 3 patients during a 7-month period. Three
Vol. 28 No. 6 December 2004
Clonidine Stability in Implantable Pumps
patients were prescribed clonidine at a concentration of 150 µg/mL and hydromorphone at varying concentrations (25–75 mg/L). Synchromed pumps were implanted 2–4 years prior to the study. The refilling interval was 35 ⫾ 13 days. The result of the clonidine concentration before and after the pump refill was as shown in Fig. 1. We found no significant decrease in clonidine concentrations in the paired samples (145.6 ⫾ 5.6 vs. 145.6 ⫾ 7.1 µg/mL respectively). There was no correlation between the refill interval and the difference in clonidine concentrations before and after pump refill.
Discussion This is the first study investigating the stability of clonidine in hydromorphone–clonidine mixture in implanted intrathecal pumps after longterm repeated refills in chronic pain patients. We reported that under these conditions clonidine concentrations were stable between consecutive refills. The use of implantable pump and catheter systems for the delivery of intrathecal opioids was first reported in 1981 for the treatment of chronic cancer pain.8 The efficacy and safety of this delivery method of intrathecal opioids was later established in various clinical trials.9–13 Since then, the use of implantable delivery systems was also extended to patients with chronic nonmalignant pain.14 Despite the popular use of the intrathecal pump delivery system, the stability of the various medications used has not been thoroughly investigated.15 Morphine is the most commonly used medication for intrathecal pump delivery system.1 At present, the only opioid approved by the U.S. Food and Drug Administration for continuous long-term intrathecal administration to treat chronic intractable pain is preservative-free
601
morphine sulfate. Both hydromorphone and clonidine are commonly used either alone or in combination with other intrathecal medications.1 When higher doses of morphine are required (⬎22 mg/mL) or when morphine yields toxicities, hydromorphone is the recommended alternative.6 Clonidine is usually considered in patients with neuropathic pain not responsive to high doses of opioids1 and can provide synergistic effect to opioids.3,16 An additional benefit of adding clonidine to opioids is its potential to minimize the occurrence of opioidinduced catheter-tip inflammatory mass.17 A recent study in dogs demonstrated that high concentration of intrathecal morphine administration led to aseptic inflammatory masses, resulting in significant local tissue compression. Although clonidine alone did not lead to such inflammatory reaction, a combination of morphine and clonidine led to smaller inflammatory reaction when compared to morphine alone. The long-term stability of clonidine and morphine has been previously investigated. When clonidine was formulated in normal saline at concentration of 0.15 and 0.5 mg/mL in glass vials, there was minimal loss of clonidine hydrochloride at body temperature for up to three months.18 When mixed with morphine sulfate in different admixture concentrations (20 mg morphine ⫹ 0.05 mg clonidine per mL or 2 mg morphine ⫹ 1.84 mg clonidine per mL) at body temperature, morphine and clonidine concentrations remained at ⱖ94% of the theoretical starting concentrations after being stored inside the SynchroMed pump for 90 days.7 The stability of hydromorphone has been investigated when stored in SynchroMed pump at body temperature.19 This showed that hydromorphone concentration remained greater than 95% of starting material after 16 weeks of storage. The stability of medications may be
Fig. 1. Comparison of the clonidine concentrations before and after refill. Bars indicate the concentration of clonidine before (white) and after (dark) refill.
602
Rudich et al.
altered when used in combination with other agents, however, and there are no stability data for clonidine mixed with hydromorphone. So far, the stability data for clonidine or hydromorphone has been obtained when the medications were stored in either glass vials or implantable pumps incubating at various temperatures. No data were obtained when the drug samples were actually retrieved from the pump after implantation into the patients. This type of data would be valuable in view of unknown effects of the non-retrievable volume in the SynchroMed pump. The major limitation of this study was that the refilling period was not fixed. Unlike those studies performed in laboratory settings, it is impractical to fix the refill interval. The duration of refill in our study was 35.4 ⫾ 13 days. However, we found no correlation between the refill interval and the difference in concentration of the clonidine before and after refill. Our results demonstrate that clonidine concentration remains stable in clonidine–hydromorphone mixtures with an average refill interval of 35 days when delivered by the implantable intrathecal pump.
Acknowledgments
Vol. 28 No. 6 December 2004
anesthetic improves postoperative analgesia for total knee arthroplasty. Anesth Analg 2003;96:1083– 1088. 6. Bennett G, Burchiel K, Buchser E, et al. Clinical guidelines for intraspinal infusion: report of an expert panel. PolyAnalgesic Consensus Conference 2000. J Pain Symptom Manage 2000;20:S37–S43. 7. Hildebrand KR, Elsberry DD, Hassenbusch SJ. Stability and compatibility of morphine-clonidine admixtures in an implantable infusion system. J Pain Symptom Manage 2003;25:464–471. 8. Onofrio BM, Yaksh TL, Arnold PG. Continuous low-dose intrathecal morphine administration in the treatment of chronic pain of malignant origin. Mayo Clin Proc 1981;56:516–520. 9. Penn RD, Paice JA, Gottschalk W, Ivankovich AD. Cancer pain relief using chronic morphine infusion. Early experience with a programmable implanted drug pump. J Neurosurg 1984;61:302–306. 10. Shetter AG, Hadley MN, Wilkinson E. Administration of intraspinal morphine sulfate for the treatment of intractable cancer pain. Neurosurgery 1986; 18:740–747. 11. Spaziante R, Cappabianca P, Ferone A, et al. Treatment of chronic cancer pain by means of continuous intrathecal low dose morphine administration with a totally implantable subcutaneous pump. Case report. J Neurosurg Sci 1985;29:143–151. 12. Krames ES, Gershow J, Glassberg A, et al. Continuous infusion of spinally administered narcotics for the relief of pain due to malignant disorders. Cancer 1985;56:696–702.
The authors would like to acknowledge Ms. Maggie Lee for her technical assistance in performing the clonidine assay.
13. Hassenbusch SJ, Pillay PK, Magdinec M, et al. Constant infusion of morphine for intractable cancer pain using an implanted pump. J Neurosurg 1990; 73:405–409.
References
14. Krames ES. Intraspinal opioid therapy for chronic nonmalignant pain: current practice and clinical guidelines. J Pain Symptom Manage 1996;11: 333–352.
1. Hassenbusch SJ, Portenoy RK. Current practices in intraspinal therapy—a survey of clinical trends and decision making. J Pain Symptom Manage 2000;20: S4–S11. 2. D’Angelo R, Evans E, Dean LA, Gaver R, Eisenach JC. Spinal clonidine prolongs labor analgesia from spinal sufentanil and bupivacaine. Anesth Analg 1999;88:573–576. 3. Hao S, Takahata O, Iwasaki H. Antinociceptive interaction between spinal clonidine and lidocaine in the rat formalin test: an isobolographic analysis. Anesth Analg 2001;92:733–738. 4. Fairbanks CA, Stone LS, Kitto KF, et al. Alpha(2C)-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther 2002;300:282–290. 5. Sites BD, Beach M, Biggs R, et al. Intrathecal clonidine added to a bupivacaine-morphine spinal
15. Bennet G, Deer T, Du Pen S, et al. Future directions in the management of pain by intraspinal drug delivery. J Pain Symptom Manage 2000;20:S44–S50. 16. Fairbanks CA, Wilcox GL. Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine. J Pharmacol Exp Ther 1999;288:1107–1116. 17. Yaksh TL, Horais KA, Tozier NA, et al. Chronically infused intrathecal morphine in dogs. Anesthesiology 2003;99:174–187. 18. Trissel LAXQ, Hassenbusch SJ. Development of clonidine hydrochloride injections for epidural and intrathecal administration. Int J Pharm Compounding 1997;1:274–277. 19. Hildebrand KR, Elsberry DE, Anderson VC. Stability and compatibility of hydromorphone hydrochloride in an implantable infusion system. J Pain Symptom Manage 2001;22:1042–1047.