Stability and Compatibility of Morphine- Clonidine Admixtures in an Implantable Infusion System

Transcription

1 464 Journal of Pain and Symptom Management Vol. 25 No. 5 May 2003 Original Article Stability and Compatibility of Morphine- Clonidine Admixtures in an Implantable Infusion System Keith R. Hildebrand, DVM, PhD, Dennis D. Elsberry, DVM, PhD, and Samuel J. Hassenbusch, MD, PhD Medtronic, Inc. (K.R.H., D.D.E.), Minneapolis, Minnesota, and Department of Neurosurgery (S.J.H.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Abstract Nonopioid analgesics are often coadministered with intrathecal morphine to increase efficacy. The purpose of this study was to evaluate stability and compatibility of morphine-clonidine admixtures with an implantable infusion system that is commonly used to treat pain patients. Infusion systems were filled with admixture and maintained at 37 C for 90 days. Samples were collected monthly. Drug concentrations were determined using stability-indicating, highperformance liquid chromatography. For compatibility testing, individual materials comprising the fluid pathway of the device were immersed in clonidine solution and stored at 37 C for various periods through 64 weeks and mechanical performance evaluated. After 3 months of containment in the infusion system, morphine and clonidine concentrations remained at 94% of the theoretical starting concentrations. All device materials retained acceptable mechanical performance following clonidine exposure. These results demonstrate that morphine and clonidine are stable when combined in aqueous solution maintained at body temperature in an implantable infusion system for at least 3 months. J Pain Symptom Manage 2003;25: U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words Morphine, clonidine, stability, compatibility, intrathecal, implantable pump, pain Address reprint requests to: Keith R. Hildebrand, DVM, PhD, Medtronic, Inc., 710 Medtronic Parkway, Minneapolis, MN , USA. Accepted for publication: July 25, 2002 Introduction Chronic intrathecal delivery of opioids using implantable infusion systems has become an accepted method for long-term management of severe pain refractory to more traditional methods of analgesic administration. 1 3 The intrathecal route of administration offers the potential of increased analgesia with a concomitant decrease in opioid side effects as compared to oral or other parenteral routes of administration. 4 In addition, implantable infusion technology allows low doses of medication to be infused chronically with improved convenience for the patient and with reduced risk of infection as compared to ambulatory infusion systems. Opioids represent the most commonly used class of intrathecal analgesics for pain. The only agent approved by the United States Food and Drug Administration for long-term intrathecal infusion is morphine sulfate. Unfortunately, intrathecal opioids may have limited efficacy in 2003 U.S. Cancer Pain Relief Committee /03/$ see front matter Published by Elsevier. All rights reserved. doi: /s (03)

2 Vol. 25 No. 5 May 2003 Morphine-Clonidine Stability and Compatibility 465 some patients, especially those with a significant neuropathic pain component. 3 They may produce intolerable side effects in some patients 5 and dose escalation over time is often necessary to maintain effective pain control. 6 To improve the efficacy and durability of intrathecal pain management, other analgesics have been investigated alone and in combination with opioids. A drug used frequently in combination with intrathecal opioids for chronic pain management is clonidine hydrochloride, a selective alpha 2 -adrenergic agonist. 7 9 According to a recently published survey of 413 pain physicians, 55%, 21%, and 34% reported respectively using intrathecal clonidine with morphine, as a monotherapy, or with morphine and bupivacaine. 10 While morphine-clonidine admixtures are frequently used, morphine and clonidine stability in aqueous solution maintained at body temperature and their compatibility with implantable infusion systems have not been confirmed. Pump refill is generally required only 4 to 6 times per year, which reflects the low intrathecal doses needed to manage chronic pain and the 18-mL reservoir volume of the most commonly used implantable infusion pump. Therefore, it is important that the preservative-free drug solution remain stable at body temperature for prolonged intervals. Drugs or drug admixtures that degrade significantly or form precipitates within the infusion reservoir are not suitable for prolonged intrathecal use. Although the infusion system s fluid pathway materials are typically selected because of their mechanical and chemical robustness, material integrity and device performance cannot be assured unless the specific infusion system is tested with the specific drug solution or drug admixture. Stability and compatibility of bupivacaine and hydromorphone with the SynchroMed infusion system following chronic exposure at simulated clinical-use conditions have been demonstrated previously. 11, 12 The stability and material compatibility of morphine sulfate (Infumorph, Cherry Hill, NJ) with a commonly used implantable infusion system (SynchroMed, Minneapolis, MN) has been previously demonstrated (Medtronic data on file). The purpose of this study was to investigate: 1) the stability of admixtures of morphine sulfate and clonidine hydrochloride (HCl) in this delivery system, and 2) the compatibility of clonidine HCl with the device materials that comprise the fluid pathway of the delivery system. Methods Morphine-Clonidine Admixture Stability Two different admixtures of morphine sulfate and clonidine HCl in preservative-free, aqueous solution were evaluated for stability: 20 mg morphine mg clonidine per milliliter (Admixture A) and 2.0 mg morphine mg clonidine per milliliter (Admixture B). These particular admixtures were chosen to: 1) represent extreme combinations (i.e., high concentration of one agent with a low concentration of the second agent) that may be used clinically and 2) promote interaction of these molecules in solution to verify if chemical reactions associated with loss or degradation of either drug occurs. Admixture A was prepared by combining 80.0 ml of morphine sulfate (Infumorph, 25 mg/ml), 2.5 ml of clonidine HCl, USP (2.0 mg/ml) and 17.5 ml of 0.9% sodium chloride for injection. Admixture B was prepared by combining 8.0 ml of morphine sulfate and 92 ml of clonidine HCl. Each admixture was evaluated in three infusion systems comprising a SynchroMed EL pump attached to a silicone elastomer intrathecal catheter (Medtronic, MN). After removing the sterile water and then rinsing the pump reservoirs with admixture solution several times, the reservoirs of the pumps were refilled with freshly prepared admixture solution. The infusion systems were maintained at 37 C to simulate clinical implant conditions. At monthly intervals over three months, each pump was programmed at maximal infusion rate to deliver a 4-mL sample. Samples were collected from the catheter of each infusion system for determinations of morphine and clonidine concentrations. No refills were made to the pump reservoirs during the first 90-day test period. Following this initial test period, the pump reservoirs were emptied, and refilled with freshly prepared admixture and the sample collection procedure continued for an additional three months. The concentration of morphine and clonidine determined at each monthly time point was determined in duplicate and expressed as a percentage of the drug

3 466 Hildebrand et al. Vol. 25 No. 5 May 2003 concentrations contained in the theoretical starting solutions. In addition to evaluating chemical stability of each drug, the physical compatibility of morphine and clonidine in solution was assessed by visually inspecting all samples collected from each infusion system. Specifically, samples collected at monthly intervals were assessed for color and clarity (i.e., particulates). Clonidine Device Compatibility Since previous testing had confirmed the long-term compatibility of morphine sulfate with the SynchroMed infusion system (Medtronic data on file), experiments were conducted to assess the effects of prolonged exposure to clonidine HCl, USP (2 mg/ml) or sterile water for injection (vehicle control) on the mechanical properties of the materials comprising the fluid path of the infusion system. Each material was incubated with clonidine solution contained in sealed, sterile glass vials at ratios approximating drug volume to material surface area ratios of the actual delivery system. Vials were maintained at 37 C with constant mechanical agitation for 64 weeks. Clonidine solution was replaced with fresh solution every 16 weeks. Material samples were collected following 1, 2, 4, 8, 16, 32, and 64 weeks. The ph of the material-exposed clonidine solutions was determined at 1, 2, 4, 8, and 16 weeks using a calibrated ph meter. Tensile strength and percent elongation at break point of elastomeric materials were assessed using a pull-tester machine. 13 Flow rate (sterile water for injection at 5 psi) through the bacterialretentive filter material was evaluated. In the intact device, this 0.22 micron filter is located between the drug reservoir and the intrathecal catheter. Hardness of the septum through which drug solution is added to the pump reservoir was evaluated to ensure proper sealing following hypodermic needle puncture. 13 Statistical comparisons between vehicle- and clonidine-exposed materials were made using Student s two sided, t-test for unpaired observations. To assess the primary function of the infusion system following prolonged exposure to the morphine-clonidine admixtures, accuracy of the fluid volumes dispensed by each infusion system was determined after 90 days of admixture exposure. This was accomplished by collecting the fluid output of the catheter into a tared vessel, accurately weighing the volume, and comparing this experimental value to the theoretical value expected based on the programmed delivery rate and collection time. Analytical Equipment and Conditions Stability analyses for both morphine sulfate and clonidine HCl were performed using high performance liquid chromatography (HPLC). For morphine analysis, the stationary phase was an Alphabond (Deerfield, IL) SI 125A column ( mm, 10- m particle size) maintained at 40 C; the mobile phase was a 72/28/1 (V/V/V) mixture of 5 mm heptane sulfonic acid/methanol/acetic acid. The ultraviolet-visible detector was set at 280 nm. Flow rate of the mobile phase was constant at 1.2 ml/min. Sample injection volume was 25 L. This method displayed good linearity (correlation coefficient in the range of to mg/ml) and precision (coefficient of variation 1%) with accuracy of 97.4 to 101.6% based upon triplicate samples of three dilutions of each admixture. The limit of quantification was approximately g/ml. For clonidine analysis, the stationary phase was a Hypersil BDS (Deerfield, IL) C 8 column ( mm, 3- m particle size) maintained at 40 C; the mobile phase consisted of gradient elution starting with 85% mobile phase A:15% mobile phase B and changing to 0% mobile phase A:100% mobile phase B over 28 min where mobile phase A 1.0 ml phosphoric acid ml water ml methanol g sodium 1-octanesulfonate and mobile phase B 1.0 ml phosphoric acid ml water ml methanol g sodium 1-octanesulfonate. The ultraviolet-visible detector was set at 220 nm. Flow rate of the mobile phase was constant at 1.0 ml/min. Sample injection volume was 15 L. This method displayed good linearity (correlation coefficient in the range of to mg/ml) and precision (coefficient of variation 1%) with accuracy of 99.5 to 105% based upon triplicate injections of three dilutions of each admixture. The limit of quantification was approximately 84.7 ng/ml. For each analytical method, forced degradation experiments were conducted in order to validate that the methods were stability indicating. Specifically, freshly prepared standards of both

4 Vol. 25 No. 5 May 2003 Morphine-Clonidine Stability and Compatibility 467 admixtures were exposed to the following conditions: acid (1 ph 3), base (11 ph 13), oxidation (3% hydrogen peroxide), elevated temperature (90 C), and light (1.2M lux hours). Solutions were maintained in the stressed condition for 72 hours and one week. Aliquots from each forced degradation condition were analyzed using HPLC for specificity with diodearray spectral analysis to determine the purity of the parent compound peak. Alkaline and thermal stresses resulted in the greatest loss of morphine sulfate (89% and 90% of initial concentration remained after one week, respectively) with morphine peak purity remaining Regardless of the stress condition, clonidine HCl remained 97% of initial concentration with parent peak purity remaining for all but extremely acidic conditions where peak purity decreased to Results Morphine-Clonidine Admixture Stability As indicated in Tables 1 and 2, morphine sulfate and clonidine HCl concentrations of admixtures A and B remained at 94% of the theoretical starting concentrations following 90 days of incubation in the infusion system at 37 C. The SynchroMed pump as provided by the manufacturer is filled with sterile water which must be removed prior to use. Despite several rinses with admixture solution after removal of the sterile water and an initial purge of the delivery system by flushing for 30 minutes prior to sample collection, the time zero sample appeared to be slightly diluted. This is evident from the decrease in concentration (as compared to expected theoretical) and the subsequent increase in concentration at the 36-day time point for both morphine and clonidine in both admixtures. After this initial unexpected decrease in concentration, the concentration of each drug in each admixture increased and remained relatively stable for the 90-day duration of the experiment. Moreover, for the second refill phase of the study (Tables 1 and 2, last columns), this initial dilution was not apparent as any residual solution in the pump reservoir was admixture solution from the initial phase of the study, not sterile water. Because of the dilution artifact in the time-zero sample, data was normalized against the theoretical drug concentration of the freshly-prepared admixture solution. A subsequent stability study using the same infusion systems as used for the initial 90-day study was performed after the pump reservoir was emptied, and refilled with fresh drug solution. These results presented in the last columns of Tables 1 and 2 further demonstrate that morphine sulfate and clonidine HCl are stable as admixtures while stored under simulated clinical-use conditions. Morphine concentrations remained at 96% and approximately 100% of initial concentrations for Admixtures A and B, respectively. Clonidine concentrations remained at 97% and 98% of initial concentrations for Admixtures A and B, respectively. When admixtures were examined visually for color and clarity (i.e., physical compatibility), Admixture B remained clear and colorless throughout both successive 90- day test periods. Admixture A (containing the higher morphine concentration) displayed a clear but light-yellow color immediately upon preparation; this admixture displayed the same physical appearance for each successive 90-day test period. This slight discoloration is likely due to formation of small amounts of oxidation products: pseudomorphine and morphine n-oxide. 14 Clonidine solution incubated with individual device materials for compatibility testing also were inspected visually and remained clear and colorless for all intervals of material exposure. Clonidine ph was not significantly affected following 16-week exposure to any device material (Table 3). Clonidine-Device Compatibility Despite small but statistically significant changes in some materials, all device materials exposed to clonidine solution (2 mg/ml) following 64 weeks at 37 C demonstrated acceptable mechanical performance (Table 4). The tensile strength of the elastomer used for pump tubing increased slightly following clonidine exposure with a concomitant decrease in percent elongation but was still well within acceptable limits for use in the delivery system. Likewise, the catheter tubing also demonstrated a slight but statistically significant increase in tensile strength after clonidine exposure but not a significant change in percent elongation. Following 64 weeks, filter material exposed to clonidine had a small but statistically significant decrease in flow rate as compared to vehicle-exposed material. The hardness of the

5 468 Hildebrand et al. Vol. 25 No. 5 May 2003 Table 1 Stability of Admixture A (20.0 mg Morphine Sulfate 0.05 mg Clonidine Hydrochloride/mL) Active Ingredient Test Interval (days) Initial Fill of Reservoir a (%) Refill of Reservoir a,b (%) Morphine sulfate c Clonidine HCl c a Group mean one standard deviation expressed as a percent of theoretical starting concentration. b After the initial 90-day test period, the reservoir of the pump was emptied, rinsed, and fresh admixture solution was added and another 90-day stability study conducted. c The first sample collected from the catheter was slightly diluted from residual water in the pump tubing. septum material following clonidine exposure was not significantly different than material exposed to vehicle. All of the individual materials of the infusion system directly contacting drug solution maintained appropriate mechanical integrity. At the end of the two 90-day test periods, the infusion system flow accuracy was determined for each of the six systems used for admixture stability testing. When expressed as a percent of actual volume delivered to theoretical programmed sample volume, all pumps continued to perform according to the product specification. Discussion Although the management of intractable pain using long-term intrathecal analgesic administration by implantable infusion systems has become accepted clinical practice, this method presents several unique challenges regarding stability of the pharmaceutical agent(s) delivered. Two major challenges include: (1) the requirement to use preservative-free formulations and (2) prolonged storage of the formulation at elevated temperature (i.e., body temperature) within the reservoir of the delivery system. Other analgesics may be added to the treatment infusate because of inadequate efficacy or side effects associated with opioid monotherapy. In these cases the chemical and physical compatibility of the individual drug components of the admixture solution must also be carefully assessed. Clonidine-morphine admixtures may provide several advantages over opioid monotherapy for long-term intrathecal pain management. The addition of clonidine appears to be more effective than opioid monotherapy against neuropathic pain, 7 and many pain syndromes involve both neuropathic and nociceptive components. Because clonidine activates a distinctly different neuronal receptor population from those activated by morphine (alpha 2 -adrenergic versus mu-opioid) within the spinal cord, an additive and potentially synergistic analge- Table 2 Stability of Admixture B (2.0 mg Morphine Sulfate 1.84 mg Clonidine Hydrochloride/mL) Active Ingredient Test Interval (days) Initial Fill of Reservoir a (%) Refill of Reservoir a,b (%) Morphine sulfate c Clonidine HCl c a Group mean one standard deviation expressed as a percent of theoretical starting concentration. b After the initial 90-day test period, the reservoir of the pump was emptied, and fresh admixture solution was added and another 90-day stability study conducted. c The first sample collected from the catheter was slightly diluted from residual water in the pump tubing.

6 Vol. 25 No. 5 May 2003 Morphine-Clonidine Stability and Compatibility 469 Table 3 Clonidine ph Following 16-Week Exposure to Individual Device Materials Material ph Control a 6.42 Pump tubing 6.52 Catheter 6.37 Pump filter 6.22 Refill septum 6.32 Titanium b 6.49 a Control clonidine hydrochloride injection, USP, 2 mg/ml, ph , unexposed to device materials. b The pump reservoir is composed of titanium. sia may be produced. 8,15,16 Using lower doses of these agents in combination as opposed to higher doses associated with monotherapy allows several desirable outcomes to be achieved: 1) reduced side effects (e.g., morphine-induced respiratory depression, clonidine-induced hypotension) and 2) reduced receptor desensitization and analgesic tolerance. Long-term stability and compatibility of morphine sulfate in the SynchroMed system has been previously established (Medtronic data on file). In addition, long-term stability of preservative-free clonidine solution has been previously reported. 17, 18 When clonidine HCl (0.1 mg/ml) was stored at 55 C in glass vials for 6 weeks, no loss in potency (as determined using a stability-indicating HPLC method) or changes in the color or clarity of the clonidine solution were apparent. 17 When formulated in saline at concentrations of 0.15 and 0.5 mg/ml, minimal detectable loss of clonidine HCl (as determined using a stability-indicating HPLC method) occurred after three months at 37 C and for up to 24 months at 4 and 23 C. 18 The stability of admixtures containing morphine (6.66 mg/ml), bupivacaine (3 mg/ml), and clonidine (30 g/ml) has been previously reported. 19 These solutions were preservative free, stored for 90 days, protected from light, and analyzed using HPLC. This study used the morphine HCl (commonly available in Europe) rather than morphine sulfate (the only morphine salt available in the US) with the drug solution stored in plastic ambulatory pump cassettes at room temperature. Under these conditions, none of the three drugs declined in concentration after 90 days. The solution remained clear and colorless. Christie and colleagues 20 reported the stability of a similar three-component admixture. Specifically, preservative-free injectable solutions of each component were added to produce a final admixture containing morphine sulfate (0.2 mg/ml), bupivacaine HCl (1.5 mg/ml) and clonidine HCl (30 g/ml) that was stored in polypropylene syringes for 1 hour at room temperature. This admixture showed no physical incompatibility following macroscopic and microscopic examination and no loss of potency of any component as assessed by GC/MS. Another study reported the stability of morphine sulfate (2 mg/ ml) with clonidine HCl (75 g/ml) in preservative-free sterile saline stored in polyvinyl-chloride pump cassettes for 14 days at 35 C. 14 The concentrations of both agents remained greater than 98% under these conditions. In a recent study, the stability of clonidine HCl (200 g/ml) in combination with baclofen (1 mg/ml) was reported. 21 Intrathecal infusion of baclofen-clonidine admixtures has been used clinically to treat intractable chronic pain and spasticity. When stored in glass vials at 37 C for 10 weeks, no loss of clonidine or baclofen was detected using a stability-indicating HPLC method. In addition, no changes in color Table 4 Mechanical Performance of Device Materials After 64-Week Exposure to Clonidine or Control a Tensile Strength b (psi) % Elongation c Flow rate (ml/min) Hardness (Shore A) Material Clonidine Vehicle Clonidine Vehicle Clonidine Vehicle Clonidine Vehicle Pump tubing d,e e Catheter e Pump filter e Refill septum a Clonidine 2 mg/ml, control sterile water for injection, T 37 C. b Mean force measured at breaking point. c Mean percent elongation at breaking point versus unstretched condition. d Mean one standard deviation based on 10 samples of pump tubing and catheter material, 12 samples of pump filter, and 3 samples of refill septum per control and treatment condition. e Significantly different (P 0.05), Student s unpaired, two-sided t-test.

7 470 Hildebrand et al. Vol. 25 No. 5 May 2003 or turbidity were detected over the 10-week storage period. This report is the first that specifically addresses the long-term stability and compatibility of morphine-clonidine admixtures stored in a commonly used implantable delivery system at 37 C. Results from this study indicate that admixtures of morphine sulfate and clonidine HCl are chemically and physically stable within the SynchroMed infusion system for at least 3 months. This time period is an acceptable standard interval for pump reservoir refills applied to implantable infusion pumps used for treatment of chronic pain. The compatibility of these admixtures with the delivery system is supported by the fact that all infusion systems continued to accurately dispense medication over two 90-day test periods. In addition, all device materials exposed to clonidine HCl (2 mg/ml) for as long as 64 weeks maintained appropriate integrity and mechanical function. Although compatibility testing of clonidinemorphine admixtures was not performed with individual device materials, the compatibility of morphine and clonidine alone with these materials in conjunction with the chemical stability of clonidine-morphine admixtures supports the use of these admixtures with SynchroMed. In conclusion, preservative-free admixtures of morphine and clonidine at clinically relevant concentrations in aqueous solution are stable and compatible with an implantable infusion system at body temperature following 90 days. Long-term (64 weeks) exposure to clonidine solution did not adversely affect the materials of this delivery system. Acknowledgments This research was supported by Medtronic, Inc., Minneapolis, MN, USA. References 1. Wallace M, Yaksh TL. Long-term spinal analgesic delivery: a review of the preclinical and clinical literature. Regional Anesth Pain Med 2000;25: Rainov NG, Heidecke V, Burket W. Long-term intrathecal infusion of drug combinations for chronic back and leg pain. J Pain Symptom Manage 2001;22: Paice JA, Penn RD, Shott S. Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Symptom Manage 1996;11: Mercadante S. Controversies over spinal treatment in advanced cancer patients. Support Care Cancer 1998;6: Coombs DW, Saunders RL, Fratkin JD, et al. Continuous intrathecal hydromorphone and clonidine for intractable cancer pain. J Neurosurg 1986; 64: Bennett G, Serafini M, Burchiel K, et al. Evidence-based review of the literature on intrathecal delivery of pain medication. J Pain Symptom Manage 2000;20:S12 S Siddall PJ, Molloy AR, Walker S, et al. The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury. Anesth Analg 2000;91: Mercadante S, Serratta R, Sapio M, et al. When all else fails: stepwise multiple solutions for a complex cancer pain syndrome. Support Care Cancer 1999;7: Tumber PS, Fitzgibbon DR. The control of severe cancer pain by continuous intrathecal infusion and patient-controlled intrathecal analgesia with morphine, bupivacaine, and clonidine. Pain 1998; 78: 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 Hildebrand KR, Elsberry DE, Deer TR. Stability, compatibility, and safety of intrathecal bupivacaine administered via an implantable delivery system. Clin J Pain 2001; 17: Hildebrand KR, Elsberry DE, Anderson VC. Stability and compatibility of hydromorphone in an implantable infusion system. J Pain Symptom Manage 2001; 22: Elastomeric closures; Evaluation of Significant Performance and Identity Characteristics, Technical Methods Bulletin, No. 2, Bethesda, MD: Parenteral Drug Association, Inc., Vermiere A., Remon JP. Stability and compatibility of morphine. Int J Pharm 1999;187: Tallarida RJ, Stone DJ Jr., McCary JD, et al. Response surface analysis of synergism between morphine and clonidine. J Pharmacol Exp Ther 1999; 289: 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: Kostecka D, Duncan MR, Wagenknecht D. Formulation of a stable parenteral product; clonidine hydrochloride injection. PDA J Pharm Sci Technol 1998;52:

8 Vol. 25 No. 5 May 2003 Morphine-Clonidine Stability and Compatibility Trissel LA, Xu QA, Hassenbusch SJ. Development of clonidine hydrochloride injections for epidural and intrathecal administration. Int J Pharm Compounding 1997;1: Wulf H, Gleim M, Mignat C. The stability of mixtures of morphine hydrochloride, bupivacaine hydrochloride, and clonidine hydrochloride in portable pump reservoirs for the management of chronic pain syndromes. J Pain Symptom Manage 1994;9: Christie JM, Jones CW, Markowsky SJ. Chemical compatibility of regional anesthetic drug combinations. Ann Pharmacother 1992;26: Godwin DA, Kim N-H, Zuniga, R. Stability of a baclofen and clonidine hydrochloride admixture for intrathecal administration. Hosp Pharm 2001;36: